WO2025121418A1 - Hepatitis c virus inhibitor - Google Patents
Hepatitis c virus inhibitorDownload PDFInfo
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- WO2025121418A1 WO2025121418A1PCT/JP2024/043265JP2024043265WWO2025121418A1WO 2025121418 A1WO2025121418 A1WO 2025121418A1JP 2024043265 WJP2024043265 WJP 2024043265WWO 2025121418 A1WO2025121418 A1WO 2025121418A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
Definitions
- the present inventionrelates to a compound having inhibitory activity against hepatitis C virus and a medicine containing said compound. More specifically, the present invention relates to a compound having inhibitory activity against hepatitis C virus, which is an indole derivative and/or a tetrahydrocarbazole derivative, and a hepatitis C virus inhibitor containing said compound.
- Hepatitis Cis a general term for liver diseases (chronic hepatitis, cirrhosis, and hepatocellular carcinoma) caused by infection with the hepatitis C virus (HCV).
- HCVhepatitis C virus
- HCVwas discovered in 1989 by Choo et al. in the United States, and it was revealed that more than 90% of cases previously diagnosed as non-A, non-B hepatitis and more than half of cases previously diagnosed as alcoholic liver disease were due to HCV-induced liver damage. According to recent estimates, there are 58 million HCV carriers worldwide, and 900,000 to 1.3 million in Japan.
- Non-Patent Document 1HCV infection is established, only about 30% of healthy adults are cured after an acute course, and in about 70% of infected cases, HCV infection persists and progresses to chronic hepatitis. When chronic, natural clearance of the virus is rare, at 0.2% per year, and persistent inflammation due to HCV infection induces liver fibrosis, which progresses to cirrhosis and hepatocellular carcinoma (Non-Patent Document 1).
- hepatitis C treatmentis to improve the long-term prognosis of chronic liver disease caused by persistent HCV infection, in other words, to prevent the development of liver cancer and deaths related to liver disease.
- antiviral treatmentis administered with the aim of eliminating HCV.
- IFNinterferon
- HCVis a positive single-stranded RNA virus belonging to the Hepacivirus genus of the Flaviviridae family. It is classified into six genotypes, HCV1 to 6. These genotypes are further classified into several subtypes. The full-length genome sequences of several HCV genotypes have been determined.
- the genome of the hepatitis C virusis approximately 9,600 nucleotides long and has a single open reading frame (ORF) that encodes a single large polyprotein of approximately 3,000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by the viral protease to generate structural and nonstructural (NS) proteins.
- ORFopen reading frame
- nonstructural proteins that are not incorporated into viral particlesare divided into NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
- NS3/4A, NS5A, and NS5B regionsare targeted by DAA, and each of these regions has protease activity, viral genome replication complex formation function, and RNA-dependent RNA polymerase activity.
- NS3/4A protease inhibitorsNS5A inhibitors
- NS5B RNA polymerase inhibitorsRNA polymerase inhibitors
- seven types of NS3/4A protease inhibitorstelaprevir, simeprevir, asunaprevir, vaniprevir, paritaprevir, grazoprevir, and glecaprevir
- six types of NS5A replication complex inhibitorsdaclatasvir, ledipasvir, ombitasvir, elbasvir, pibrentasvir, and velpatasvir
- the NS5B polymerase inhibitorssovosbuvir (nucleoside type) and beclabuvir (non-nucleoside type) have been approved.
- HCV NS2has cysteine protease activity that acts to cleave the viral precursor polyprotein, and mutation analysis has shown that it is also important in the particle formation process.
- pharmaceutical companies and othersconducted drug discovery research using inhibition of NS2 protease activity as an indicator, but this was unsuccessful, and no compound that targets NS2 and could serve as an active ingredient in an HCV inhibitor has yet been developed.
- the objective of the present inventionis to provide a compound that targets NS2 and has inhibitory activity against HCV, and a composition containing said compound.
- HCV NS2is a three-transmembrane protein that is difficult to purify, making it difficult to construct an experimental system in a test tube, which has been an obstacle to high-throughput screening of inhibitors.
- the present inventorsmade full use of a cell-free protein synthesis system that also enables the preparation of active membrane proteins to construct an in vitro NS2-SPCS1 binding assay system and succeeded in realizing inhibitor screening. Then, a small molecule compound library was screened using the NS2-SPCS1 binding assay system, and several compounds were selected that have NS2-SPCS1 binding inhibitory properties. From among the candidate compounds, the inventors identified Compound A, a tetrahydrocarbazole derivative, as a proof-of-concept compound that has HCV particle production inhibitory activity. They were also able to confirm that the compound has low cytotoxicity.
- the inventorsfocused on the structure of Compound A, designed and synthesized a number of analogous compounds having a partial structure of Compound A and further screened them, resulting in the acquisition of indole derivatives and/or tetrahydrocarbazole derivative compounds with high anti-HCV activity, and thus completing the present invention.
- the compounds discovered through the present inventionare characterized by having inhibitory activity against HCV virus particle formation, unlike existing DAA.
- the present inventionrelates to a compound having the structure of formula (I) or (IV), a composition containing said compound, etc. Since a compound having the structure of formula (I) or (IV) exhibits anti-HCV activity of inhibiting NS2-SPCS1 binding and inhibiting HCV virus particle formation, one aspect of the present invention relates to an HCV inhibitor or a hepatitis C therapeutic agent containing said compound. More specifically, the present invention relates to the following [1] to [49].
- R 1is a hydrogen atom or a group represented by -COOR 9 or -CONHR 10 ; wherein R 9 and R 10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
- R2is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
- R3is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
- R 4 and R 5are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloal
- R3 and R6 to R8are all hydrogen atoms
- X, R 3 , R 9 and R 11are each as defined in formula (II);
- R3is a hydrogen atom
- R9is ethyl
- R11 (n)does not necessarily have to be 0.
- [5]The compound according to [1], or a salt or solvate thereof, wherein R 1 is -COOR 9 , where R 9 is a hydrogen atom, methyl or ethyl.
- R 9is a hydrogen atom, methyl or ethyl.
- R 6 to R 8are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
- R 11 (n)is an integer of 0 to 8
- R 11are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom
- R 12 to R 16are each independently a hydrogen atom, a
- R 12 to R 16are each independently a group represented by a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, a heterocyclyl which may be substituted by one or more substituents, a (C1-C6) alkoxycarbonyl which may be substituted by one or more substituents, a carboxy, or a nitro.
- Z and R 12 to R 16are each as defined in formula (IV).
- [11]A compound according to [7] or [8], or a salt thereof, or a solvate thereof, represented by the following formula (VII):
- R 12 to R 16are each as defined in formula (IV).
- the compound represented by formula (IV)is any one of the following, or a salt thereof, or a solvate thereof:
- a compositioncomprising the compound according to any one of [1] to [13], or a salt thereof, or a solvate thereof, and a pharma- ceutically acceptable carrier.
- a hepatitis C virus inhibitorcomprising the compound according to any one of [1] to [13], or a salt thereof, or a solvate thereof, and a pharma- ceutically acceptable carrier.
- a prophylactic and/or therapeutic agent for hepatitis Ccomprising the compound according to any one of [1] to [13], or a salt thereof, or a solvate thereof, and a pharma- ceutically acceptable carrier.
- hepatitis Cis a liver disease caused by infection with hepatitis C virus (HCV) selected from the group consisting of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma.
- HCVhepatitis C virus
- the prophylactic and/or therapeutic agent according to [17]which is an orally administered agent.
- a method for inhibiting hepatitis C viruscomprising the step of administering a compound represented by the following formula (I), or a salt thereof, or a solvate thereof:
- R 1is a hydrogen atom or a group represented by -COOR 9 or -CONHR 10 ; wherein R 9 and R 10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
- R2is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
- R3is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
- R 4 and R 5are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloal
- R 6 to R 8are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
- R 11 (n)is an integer of 0 to 8
- R 11are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom
- R 12 to R 16are each independently a hydrogen atom, a
- a method for preventing and/or treating hepatitis Ccomprising the step of administering to a subject a compound represented by the following formula (I), or a salt thereof, or a solvate thereof:
- R 1is a hydrogen atom or a group represented by -COOR 9 or -CONHR 10 ; wherein R 9 and R 10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
- R2is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
- R3is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
- R 4 and R 5are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloal
- R3 and R6 to R8are all hydrogen atoms
- X, R 4 , R 9 and R 11are each as defined in formula (II);
- R 3 Xis S( ⁇ O) 2
- R 3is a hydrogen atom
- R 9is ethyl
- a method for preventing and/or treating hepatitis Ccomprising a step of administering to a subject a compound represented by the following formula (IV), or a salt thereof, or a solvate thereof:
- R 6 to R 8are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
- R 11 (n)is an integer of 0 to 8
- R 11are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom
- R 12 to R 16are each independently a hydrogen atom, a
- R 12 to R 16are each as defined in formula (IV).
- R 1is a hydrogen atom or a group represented by -COOR 9 or -CONHR 10 ; wherein R 9 and R 10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
- R2is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
- R3is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
- R 4 and R 5are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloal
- R 6 to R 8are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
- R 11 (n)is an integer of 0 to 8
- R 11are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom
- R 12 to R 16are each independently a hydrogen atom, a
- R 1is a hydrogen atom or a group represented by -COOR 9 or -CONHR 10 ; wherein R 9 and R 10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
- R2is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
- R3is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
- R 4 and R 5are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloal
- R3 and R6 to R8are all hydrogen atoms
- R9is ethyl
- R 6 to R 8are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
- R 11 (n)is an integer of 0 to 8
- R 11are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom
- R 12 to R 16are each independently a hydrogen atom, a
- R 12 to R 16are each as defined in formula (IV).
- kitscomprising an interferon and the composition according to [14].
- the kit according to [40]further comprising ribavirin.
- kitscomprising a composition containing DAA and the composition described in [14].
- the kit according to [45]further comprising ribavirin.
- the present inventionprovides a compound having the structure of formula (I) or (IV) or a composition containing the compound.
- the compound, composition, hepatitis C virus inhibitor, preventive and/or therapeutic agent, medicine, treatment method, use, or kit of the present inventioncan reduce hepatitis C virus, and provide a new prevention and/or treatment for hepatitis C and diseases caused by hepatitis C.
- the therapeutic agent, medicine, pharmaceutical composition, treatment method, use, or combination of the present inventioncan provide prevention and/or treatment for hepatitis C and diseases caused by hepatitis C in a form with few side effects and high safety.
- Figure 1is a schematic representation of a complex containing Hepatitis C virus signal peptidase complex subunit 1 (SPSC1) and NS2 protein in the endoplasmic reticulum membrane.
- SPSC1Hepatitis C virus signal peptidase complex subunit 1
- Figure 2is a schematic diagram of a screening system for in vitro selection of compounds that inhibit the interaction between NS2 and SPSC1.
- the interaction between NS2 and SPSC1is inhibited in the presence of a test compound, the emission at 520-620 nm in response to irradiation with 680 nm excitation light is attenuated (compared to a control in the absence of the test compound), and compounds that have inhibitory activity against the interaction can be selected using the attenuation of emission as an indicator.
- the present inventionprovides a compound of formula (I)
- R 1is a hydrogen atom or a group represented by -COOR 9 or -CONHR 10 ; wherein R 9 and R 10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
- R2is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
- R3is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
- R 4 and R 5are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloal
- the present inventionrelates to a compound represented by formula (I) having the following formula (II):
- Another aspect of the present inventionis a hepatitis C virus inhibitor containing a compound represented by the above formula (
- the present inventionrelates to a compound represented by formula (II) having the following formula (III):
- Another aspect of the present inventionis a hepatitis C virus inhibitor containing a compound represented by the above formula (III), or a salt thereof, or a solvate of the compound or the salt.
- Another aspect of the present inventionis a hepatitis C virus inhibitor comprising a compound represented by any one of the above formulas (I) to (III), or a salt thereof, or a solvate of the compound or the salt.
- the present inventionrelates to a compound represented by formula (I), or a salt thereof, or a solvate thereof, in which R 1 is -COOR 9 , where R 9 is a hydrogen atom, methyl or ethyl, or a salt thereof, or a solvate thereof.
- R 1is -COOR 9
- R 9is a hydrogen atom, methyl or ethyl, or a salt thereof, or a solvate thereof.
- a hepatitis C virus inhibitorcomprising a compound represented by formula (I), a salt thereof, or a solvate thereof, wherein R 1 is -COOR 9 , where R 9 is a hydrogen atom, methyl, or ethyl, or a salt thereof, or a solvate thereof.
- the present inventionrelates to a compound represented by formula (II) or (III), or a salt thereof, or a solvate thereof, wherein R 9 is a hydrogen atom, methyl or ethyl, or a salt thereof, or a solvate thereof.
- the present inventionrelates to a hepatitis C virus inhibitor comprising a compound represented by formula (II) or (III), a salt thereof, or a solvate thereof, wherein R9 is a hydrogen atom, methyl, or ethyl, or a salt thereof, or a solvate thereof.
- the present inventionrelates to a compound represented by formula (I), or a salt thereof, or a solvate thereof, wherein the compound represented by formula (I) is any one of the following:
- the present inventionprovides a compound of formula (IV)
- R 6 to R 8are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
- R 11 (n)is an integer of 0 to 8
- R 11are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom
- R 12 to R 16are each independently a hydrogen atom, a
- the present inventionrelates to a compound represented by formula (IV) having the following formula (V):
- X, Z, and R 12 to R 16are each as defined in formula (IV)] or a salt or solvate thereof.
- Another aspect of the present inventionis a hepatitis C virus inhibitor containing a compound represented by the above formula (V), or a salt thereof, or a solvate of the compound or the salt.
- the present inventionrelates to a compound represented by formula (IV) having the following formula (VI):
- Z and R 12 to R 16are each as defined in formula (IV)] or a salt or solvate thereof.
- Another aspect of the present inventionis a hepatitis C virus inhibitor containing a compound represented by the above formula (VI), or a salt thereof, or a solvate of the compound or the salt.
- the present inventionrelates to a compound represented by formula (IV) having the following formula (VII):
- Z and R 12 to R 16are each as defined in formula (IV)] or a salt or solvate thereof.
- Another aspect of the present inventionis a hepatitis C virus inhibitor containing a compound represented by the above formula (VII), or a salt thereof, or a solvate of the compound or the salt.
- Another aspect of the present inventionis a hepatitis C virus inhibitor comprising a compound represented by any one of the above formulas (IV) to (VII), or a salt thereof, or a solvate of the compound or the salt.
- the present inventionrelates to a compound represented by formula (IV), or a salt or solvate thereof, in which R 12 to R 16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, a heterocyclyl group which may be substituted by one or more substituents, a (5-12) heteroaryl which may be substituted by one or more substituents, a (C1-C6) alkoxycarbonyl which may be substituted by one or more substituents, carboxy, or nitro, or a salt or solvate thereof.
- R 12 to R 16are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substitu
- the present inventionrelates to a hepatitis C virus inhibitor comprising a compound represented by formula (IV), a salt thereof, or a solvate thereof, in which R 12 to R 16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted with one or more substituents, a (C1-C6) alkoxy which may be substituted with one or more substituents, a (C6-C12) aryl which may be substituted with one or more substituents, a heterocyclyl group which may be substituted with one or more substituents, a (5-12) heteroaryl which may be substituted with one or more substituents, a (C1-C6) alkoxycarbonyl which may be substituted with one or more substituents, carboxy, or a group represented by nitro, or a salt thereof, or a solvate thereof.
- R 12 to R 16are each independently a hydrogen atom, a halogen
- the present inventionrelates to a compound represented by formula (V) or (VI), or a salt or solvate thereof, wherein Z is C-R 12 , and R 12 to R 16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl optionally substituted with one or more substituents, a (C1-C6) alkoxy optionally substituted with one or more substituents, a (C6-C12) aryl optionally substituted with one or more substituents, a heterocyclyl group optionally substituted with one or more substituents, a (5-12) heteroaryl optionally substituted with one or more substituents, a (C1-C6) alkoxycarbonyl optionally substituted with one or more substituents, carboxy, or nitro, or a salt or solvate thereof.
- the present inventionrelates to a hepatitis C virus inhibitor comprising a compound represented by formula (V) or (VI), or a salt or solvate thereof, wherein Z is C-R 12 , and R 12 to R 16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted with one or more substituents, a (C1-C6) alkoxy which may be substituted with one or more substituents, a (C6-C12) aryl which may be substituted with one or more substituents, a heterocyclyl group which may be substituted with one or more substituents, a (5-12) heteroaryl which may be substituted with one or more substituents, a (C1-C6) alkoxycarbonyl which may be substituted with one or more substituents, carboxy, or a group represented by nitro, or a salt or solvate thereof.
- Zis C-R 12
- R 12 to R 16are
- the present inventionrelates to a compound represented by formula (IV), or a salt thereof, or a solvate thereof, wherein the compound represented by formula (IV) is any one of the following, or a salt thereof, or a solvate thereof:
- Examples of compounds of the present inventioninclude, but are not limited to, the following compounds: 4-((9-(2-ethylhexyl)-2,3,4,9-tetrahydro-1H-carbazole)-6-sulfonamido)benzoic acid; ethyl 4-(1,2,3,4-tetrahydrocyclopenta[b]indole-7-sulfonamido)benzoate; ethyl 4-(5,6,7,8,9,10-hexahydrocyclohepta[b]indole-2-sulfonamido)benzoate; ethyl 4-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indole-2-sulfonamido)benzoate; 4-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indole-2-sulfonamido)benz
- (Ca-Cb)means that the number of carbon atoms is a to b.
- the "(C1-C12)" in “(C1-C12) alkyl”means that the alkyl has 1 to 12 carbon atoms
- “(C2-C5)”means that the alkyl has 2 to 5 carbon atoms.
- “(Ca-Cb),” which means the number of carbon atomsis sometimes written as "Ca-Cb” without parentheses. So, for example, the "C1-C6" in “C1-C6 alkyl” means that the alkyl has 1 to 6 carbon atoms.
- alkylis intended to include both straight and branched chains, such as butyl and tert-butyl, while the specific term “butyl,” for example, means straight chain “normal butyl” and not branched chain “tert-butyl,” and branched chain isomers such as “tert-butyl” are specifically referred to when intended.
- halogen atomsinclude fluorine atoms, chlorine atoms, bromine atoms and iodine atoms.
- (C1-C12) alkylmeans straight or branched chain alkyl having 1 to 12 carbon atoms.
- Examples of (C1-C12)include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, 2-ethylhexyl, etc.
- (C1-C6)alkylmeans straight or branched chain alkyl having 1 to 6 carbon atoms. Examples of (C1-C6)alkyl include appropriate examples of (C1-C12)alkyl listed above.
- (C3-C8)cycloalkylmeans cycloalkyl having 3 to 8 carbon atoms.
- Examples of (C3-C8)cycloalkylare cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- (C2-C6)alkenylmeans straight or branched alkenyl having 2 to 6 carbon atoms.
- Examples of (C2-C6)alkenylinclude, but are not limited to, vinyl, 1-propenyl, isopropenyl, 2-propenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 1-hexenyl, etc.
- (C2-C6)alkynylmeans straight or branched alkynyl having 2 to 6 carbon atoms.
- Examples of (C2-C6)alkynylinclude, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, etc.
- (C6-C12)arylrefers to an aromatic hydrocarbon group having 6 to 12 carbon atoms.
- Examples of (C6-C12)arylare phenyl, biphenyl, 1-naphthyl, and 2-naphthyl.
- the carbon atoms on the aromatic ringmay be substituted with one or more substituents.
- (C6-C10)arylrefers to an aromatic hydrocarbon group having 6 to 10 carbon atoms.
- Examples of (C6-C10)arylare phenyl, 1-naphthyl, and 2-naphthyl.
- the carbon atoms on the aromatic ringmay be substituted with one or more substituents.
- a heterocyclyl grouprefers to a non-aromatic heterocycle containing, in addition to carbon atoms, one or more atoms selected from oxygen atoms, nitrogen atoms, sulfur atoms, and boron atoms.
- a heterocyclyl grouprefers to a non-aromatic heterocycle containing, in addition to carbon atoms, one or more atoms selected from oxygen atoms, nitrogen atoms, sulfur atoms, and boron atoms.
- itis a 3- to 8-membered or 3- to 6-membered non-aromatic heterocycle.
- atoms on the heterocyclemay be substituted with one or more substituents.
- Heteroarylrefers to a 5-12-membered monocyclic or fused bicyclic aromatic heterocycle containing, in addition to carbon atoms, one or more heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms.
- monocyclic aromatic heterocyclesinclude pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl, and tetrazolyl groups.
- fused bicyclic heterocyclesinclude a C8- or 12-membered monocyclic group and a phenyl ring, or a C8- or 12-membered heteroaromatic monocyclic group and a phenyl ring.
- Fused bicyclic moieties formed by condensing to form a C10 bicyclic groupinclude indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolinyl, quinolinyl, benzothiazolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridyl, triazolopyridyl, triazolopyrimidinyl, quinazolinyl, quinoxalinyl, or cinnolinyl, where the atoms on the heterocycle may be substituted with one or more substituents.
- (C1-C6)haloalkylmeans straight or branched alkyl having 1 to 6 carbon atoms, substituted with 1 to 13 identical or different halogen atoms, wherein the halogen atoms have the same meaning as defined above.
- Examples of (C1-C6)haloalkylinclude, but are not limited to, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, and the like.
- (C1-C6) haloalkyl which is optionally substituted with one or more substituentsmeans that in the (C1-C6) alkyl portion, one or more positions which are not substituted with halogen atoms may be substituted with a substituent other than a halogen atom.
- (C1-C6)alkoxymeans (C1-C6)alkyl-O- (wherein the (C1-C6)alkyl moiety has the same meaning as defined above, and the same applies in the following explanations).
- Examples of (C1-C6)alkoxyinclude, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, and the like.
- (C1-C6)alkoxy optionally substituted with one or more substituentsmeans that the (C1-C6)alkyl portion of the alkoxy group may be substituted with a substituent at one or more positions.
- the phrase "optionally substituted with one or more substituents" in the following descriptionis to be understood in the same way.
- Examples of (C1-C6)alkoxycarbonylinclude, but are not limited to, methoxycarbonyl and ethoxycarbonyl.
- a "carbamoyl which may be substituted by one or more substituents”is a carbamoyl group represented by -CONH2 in which one or two hydrogen atoms of the nitrogen atom are substituted by a substituent.
- An example of the substituentis (C1-C6) alkyl, and a more specific example is methyl or ethyl.
- (C6-C12)aryloxyrefers to a (C6-C12 aryl)-O- group, such as a phenoxy group, a naphthalene-1-yloxy group, or a naphthalene-2-yloxy group.
- arylexamples include the above-mentioned examples of (C6-C12)aryl.
- the cyclic hydrocarbon groups as defined or exemplified abovemay include non-fused cyclic (e.g., monocyclic or spirocyclic) and fused cyclic groups, if possible.
- the cyclic hydrocarbon groups as defined or exemplified abovemay be unsaturated, partially saturated or saturated, if possible.
- the cyclic hydrocarbon groups as defined or exemplified aboveare also called carbocyclic groups.
- a carbocycleis a ring that corresponds to a cyclic hydrocarbon group as defined or exemplified above.
- carbocyclesinclude, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, adamantane, etc.
- substituentsexamples of “one or more substituents” in the phrase “optionally substituted with one or more substituents” include, but are not limited to, one or more substituents (preferably 1 to 3 substituents) independently selected from the following group of substituents (a):
- the substituent group (a)is a group consisting of halogen atoms, nitro, cyano, hydroxy, amino, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C8) cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, carbamoyl, (C1-C6) haloalkyl, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylaminocarbonyl, phenyl, phenoxy, benzoyl, heterocyclyl, and a hydrocarbon ring group.
- one or more substituents (preferably 1 to 3 substituents) independently selected from the group of substituents (a)may each be independently substituted with one or more substituents (preferably 1 to 3 substituents) independently selected from the group of substituents (b).
- the group of substituents (b)is the same as the group of substituents (a).
- (C1-C12) alkyl optionally substituted by one or more substituentsinclude, but are not limited to, (C1-C12) haloalkyl, (C1-C12) hydroxyalkyl, and (C1-C4) alkyl optionally substituted by 1 to 9 fluorine atoms. Other groups not defined herein are defined as per usual.
- substituentse.g., R1 , R2 , R3 , R4 , R5 , X, Z, etc.
- substituentse.g., R1 , R2 , R3 , R4 , R5 , X, Z, etc.
- the compounds of the present inventionwhich are indole derivatives represented by formula (I) and/or tetrahydrocarbazole derivatives represented by formulas (II) to (VII), or their salts or solvates, include not only the compounds of the present invention which are indole derivatives represented by formula (I) and/or tetrahydrocarbazole derivatives represented by formulas (II) to (VII), but also their salts (preferably pharma- ceutically acceptable salts), various hydrates and solvates thereof, and substances having crystalline polymorphism, and substances which are prodrugs of these substances.
- saltspreferably pharma- ceutically acceptable salts
- various hydrates and solvates thereofand substances having crystalline polymorphism, and substances which are prodrugs of these substances.
- compounds having an asymmetric carbon atomnot only racemic bodies but also optically active bodies are included.
- acceptable salts of the indole derivative represented by formula (I) and/or the tetrahydrocarbazole derivative represented by formula (II) to formula (VII) of the present inventioninclude acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g., methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.) when the compound is treated as a basic compound.
- inorganic acidse.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
- organic acidse.g., methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.
- examples of acceptable salts of the compoundinclude inorganic salts (e.g., sodium salts, potassium salts, lithium salts, barium salts, calcium salts, magnesium salts, etc.) when the compound is treated as an acidic compound.
- inorganic saltse.g., sodium salts, potassium salts, lithium salts, barium salts, calcium salts, magnesium salts, etc.
- Solvates of the compounds of the present inventionwhich are the indole derivatives represented by formula (I) and/or the tetrahydrocarbazole derivatives represented by formulas (II) to (VII) and their salts, include hydrates and various solvates (for example, solvates with alcohols such as ethanol).
- the hydrogen atom or the group represented by -COOR9 or -CONHR10 in R1is preferably -COOR9 or -CONHR10 , and more preferably -COOR9 .
- R 9 and R 10are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents, and preferred examples of R 9 are a hydrogen atom, ethyl, or ethyl, and preferred examples of R 10 are ethyl or methyl.
- the hydrogen atom or the phenoxy group which may be substituted with one or more substituents in R2is preferably a hydrogen atom.
- a preferred example of the phenoxy group which may be substituted with one or more substituentsis a phenoxy group.
- the hydrogen atom, the (C1-C12) alkyl which may be substituted by one or more substituents, the (C3-C8) cycloalkyl which may be substituted by one or more substituents, or the (C6-C10) aryl which may be substituted by one or more substituents in R 3is preferably a hydrogen atom or a (C1-C12) alkyl which may be substituted by one or more substituents, more preferably a hydrogen atom.
- a preferred example of the (C1-C12) alkyl which may be substituted by one or more substituentsis an unsubstituted (C1-C12) linear or branched alkyl.
- (C1-C12) alkylwhich may be substituted by one or more substituents are 2-ethylhexyl, methyl, ethyl, propyl, 2-methylbutyl, cyclohexylmethyl, or oxiran-2yl-methyl, and a preferred specific example is 2-ethylhexyl.
- R 4 and R 5are each independently a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C6-C10) aryl which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a carboxy, or a (C1-C6) alkoxycarbonyl which may be substituted by one or more substituents; R 4 and R 5 may be bonded together to form a hydrocarbon ring with adjacent carbon atoms,
- More preferred examplesare ( C1 -C12) alkyl, each of which may be substituted with one or more substituents, where R 4 and R 5 are bonded together to form a hydrocarbon ring with adjacent carbon atoms.
- Preferred examples of the hydrocarbon ring formed by R 4 and R 5 bonded together to adjacent carbon atomsare cyclopentene which may be substituted with one or more substituents, hexene which may be substituted with one or more substituents, cycloheptene which may be substituted with one or more substituents, or cyclooctene which may be substituted with one or more substituents, more preferred examples are cyclohexene which may be substituted with one or more substituents, and even more preferred examples are cyclohexene that has no substituents.
- R4 and R5are bonded to each other and do not form a hydrocarbon ring together with the adjacent carbon atom
- preferred examples of R4 and R5are a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents, more preferably a hydrogen atom, methyl, ethyl, propyl, butyl, pentyl, phenyl, or a halo-substituted aryl, and even more preferably a hydrogen atom, methyl, ethyl, propyl, pentyl, phenyl, or fluorophenyl.
- R 6 to R 8each independently represent a hydrogen atom, a (C1-C12) alkyl which may be substituted with one or more substituents, a (C1-C6) alkoxy which may be substituted with one or more substituents, a hydroxyl or a halogen atom, and are preferably a hydrogen atom.
- R 11 (n)means 0 to 8 substituents which may be present on the cyclohexene ring portion of the tetrahydrocarbazole ring.
- examples of the maximum 8 substituentsare, independently of one another, groups independently selected from the group consisting of (C1-C12) alkyl which may be substituted with one or more substituents, (C3-C8) cycloalkyl which may be substituted with one or more substituents, carbamoyl which may be substituted with one or more substituents, (C1-C6) alkoxy which may be substituted with one or more substituents, hydroxy, and a halogen atom.
- preferred examples of the (C1-C12) alkyl which may be substituted by one or more substituentsare the (C3-C8) cycloalkyl which may be substituted by one or more substituents, the carbamoyl which may be substituted by one or more substituents, the (C1-C6) alkoxy which may be substituted by one or more substituents, the hydroxyl and the halogen atom are the (C1-C12) alkyl which may be substituted by one or more substituents, the (C3-C8) cycloalkyl which may be substituted by the above substituents and the carbamoyl which may be substituted by one or more substituents. More preferred examples of these are methyl, ethyl, propyl, tert-butyl, cyclopentyl, N-methylcarbamoyl and hydroxymethyl.
- X, R4 and R9are as defined in formula (I) and formula (II), respectively, and preferred examples thereof are also as given as preferred examples in formula (I) and formula (II).
- the group represented by R11 (n)(where n is an integer of 0 to 8) is as defined in formula (II). Preferred examples thereof are also as given as preferred examples in formula (II).
- C—R 12 or N in Zis preferably C—R 12 .
- R 12 to R 16each represent a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, a (C6-C12) aryloxy which may be substituted by one or more substituents, a (C6-C12) arylcarbonyl which may be substituted by one or more substitu
- X, Z and R 12 to R 16are each as defined in formula (IV), and preferred examples thereof are also the same as those given as preferred examples in formula (IV).
- Z and R 12 to R 16are each as defined in formula (IV), and preferred examples thereof are also the same as those given as preferred examples in formula (IV).
- R 12 to R 16are each as defined in formula (IV), and preferred examples thereof are also the same as those given as preferred examples in formula (IV).
- HCV Inhibitory ActivityThe effect of the compounds of the present invention can be confirmed by in vitro experiments in a cell-free system, for example, using as an indicator the inhibitory activity against the interaction between NS2 and SPCS1 (FIG. 1).
- the suppressive effect on the number of HCV genome copies contained in HCV-infected cellscan be confirmed by experiments using cultured cells.
- itcan also be appropriately confirmed by administration experiments on HCV-infected individuals (humans or model animals such as chimpanzees) on the premise that an ethically appropriate process is followed.
- HuH7.5.1 cellshuman hepatocellular carcinoma-derived cells
- Total RNAis prepared from the collected cells by a conventional method, and the RNA copy number of HCV is determined by quantitative RT-PCR.
- the test compoundis added at 0.63, 1.25, 2.5, 5, 10 or 20 ⁇ M.
- the test compoundis added at 0.1, 1.0, or 10 ⁇ M, or in other cases, the test compound is added at 1.0, 3.0, or 10 ⁇ M.
- quantitative RT-PCRcan be performed using, for example, a kit such as TaqMan (registered trademark) Fast Virus 1-Step Multiplex Master Mix for qPCR (manufactured by Thermo Fisher).
- the primers for detecting the HCV genomeare as follows: HCV-F: 5'-GAGTGTCGTGCAGCCTCCA-3' (SEQ ID NO: 1) HCV-R: 5'-CACTCGCAAGCACCCTATCA-3' (SEQ ID NO: 2)
- the TaqMan® probe (FAM/ZEN/3IABkFQ labeled probe) used for HCV-Tcontained the following sequence: HCV-T:5'-56FAM/CCCGCAAGA/ZEN/CTGCTAGCCGAGTAGTGTTGG/3IABkFQ/-3'
- the base sequence of 5'-CTGCTAGCCGAGTAGTGTTGG-3' in the HCV-T probeis set as SEQ ID NO:3.
- the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells treated with 10 ⁇ M of a test compoundis calculated when the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells not treated with the compound is set to 1, thereby evaluating the HCV inhibitory activity of the test compound.
- test compound XFor example, if the calculated value for test compound X is 0.41, this means that "addition of 10 ⁇ M of test compound X inhibits HCV production by 59%.”
- the compounds of the present inventionhave significant HCV inhibitory activity, and exhibit a value calculated by the above-mentioned evaluation method of 0.86 or less, preferably 0.7 or less, more preferably 0.6 or less, even more preferably 0.5 or less, and even more preferably 0.4 or less.
- Another method for evaluating the HCV inhibitory activity of a test compoundcan be performed by determining the EC 50 value. For example, as described above, tests are performed in parallel in which the test compound is added at 0.63, 1.25, 2.5, 5, 10 or 20 ⁇ M, and the amount of HCV (the number of HCV RNA copies) produced by HuH7.5.1 cells is determined in each case. The relationship between the concentration of the test compound and the determined amount of HCV is then plotted on a graph, and the concentration of the test compound that reduces the amount of HCV produced by untreated HuH7.5.1 cells by 50% is calculated, and this concentration is taken as the EC 50 value ( ⁇ M) of the test compound (here, EC 50 may also be referred to as IC 50 ).
- the EC 50 value ( ⁇ M)can also be determined by tests in which the test compound is added at 0.1, 1.0 or 10 ⁇ M, or tests in which the test compound is added at 1.0, 3.0 or 10 ⁇ M.
- the compounds of the present inventionhave significant HCV inhibitory activity, and exhibit an EC50 value calculated by the above-mentioned evaluation method of 20 ⁇ M or less, preferably 15 ⁇ M or less, more preferably 10 ⁇ M or less, even more preferably 5 ⁇ M or less, and most preferably 2 ⁇ M or less.
- this experimental systemby measuring the cell number and the amount of total RNA after culturing the virus-producing cells, it is also possible to evaluate whether or not the test compound has cytotoxicity.
- the compounds represented by formulas (I) to (VII)will now be described.
- the indole derivatives represented by general formula (I) and the tetrahydrocarbazole derivatives represented by general formulas (II) to (VII) of the present inventioncan all be produced by methods and techniques known to those skilled in the art. For example, they can be produced by the method shown below or a method similar thereto.
- the synthesized compoundscan also be confirmed by known means such as NMR.
- Compound J6-032One example of a compound of the present invention that has Hepatitis C virus inhibitory activity is compound J6-032, which has the structure shown below.
- Compound J6-032can be synthesized using known materials and conventional methods according to the route shown below.
- Compound J4-026One example of a compound of the present invention that has Hepatitis C virus inhibitory activity is compound J4-026, which has the structure shown below.
- Compound J4-026can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K7-025One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K7-025, which has the structure shown below.
- Compound K7-025can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K6-001One example of a compound of the present invention having hepatitis C virus inhibitory activity is compound K6-001, which has the structure shown below.
- Compound K6-001can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K7-034One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K7-034, which has the structure shown below.
- Compound K7-034can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K9-030can be synthesized using known materials and conventional methods according to the route shown below.
- compound K9-030can also be synthesized by amidating the following ester compound.
- Compound K24-023One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K24-023, which has the structure shown below.
- Compound K24-023can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K25-012One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K25-012, which has the structure shown below.
- Compound K25-012can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K25-013One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K25-013, which has the structure shown below.
- Compound K25-013can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K25-018One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K25-018, which has the structure shown below.
- Compound K25-018can be synthesized using known materials and conventional methods according to the route shown below.
- the compound represented by formula (IV)can be produced through the following steps: In addition, the steps shown for the compound K7-025 and the like can be referred to for the production.
- Compound K28-039One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K28-039, which has the structure shown below.
- Compound K28-039can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-013One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-013, which has the structure shown below.
- Compound K29-013can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-026One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-026, which has the structure shown below.
- Compound K29-026can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-027One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-027, which has the structure shown below.
- Compound K29-027can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-030One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-030, which has the structure shown below.
- Compound K29-030can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-035One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-035, which has the structure shown below.
- Compound K29-035can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-036One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-036, which has the structure shown below.
- Compound K29-036can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K30-031One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K30-031, which has the structure shown below.
- Compound K30-031can be synthesized using known materials and conventional methods according to the route shown below.
- Compound K24-037One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K24-037, which has the structure shown below.
- Compound K24-037can be synthesized using known materials and conventional methods according to the route shown below.
- a hepatitis C virus inhibitor(a preventive and/or therapeutic agent for hepatitis C) containing, as an active ingredient, a compound which is an indole derivative and/or a tetrahydrocarbazole derivative represented by formula (I) to (VII) of the present invention, or a salt or solvate thereof.
- the compound represented by formula (I) or formula (II) to (VI) of the present invention which is an active ingredientmay be, of course, an indole derivative and/or a tetrahydrocarbazole derivative represented by formula (I) or formula (II) to (VII) itself, or a compound in the form of a salt or solvate thereof.
- the saltis not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; organic base salts such as ammonium salts and trialkylamine salts; mineral acid salts such as hydrochlorides and sulfates; and organic acid salts such as acetates.
- alkali metal saltssuch as sodium salts and potassium salts
- alkaline earth metal saltssuch as calcium salts and magnesium salts
- organic base saltssuch as ammonium salts and trialkylamine salts
- mineral acid saltssuch as hydrochlorides and sulfates
- organic acid saltssuch as acetates.
- examples of the solvateinclude hydrates, alcohol solvates (eg, ethanol solvates), and the like.
- the route of administration of the preventive and/or therapeutic agent for hepatitis C (hepatitis C virus inhibitor) containing the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulae (II) to (VII) of the present invention as an active ingredientis not particularly limited, and the agent may be an oral or parenteral agent.
- the formulationmay be in the form of an oral preparation such as a tablet, capsule, granule, powder, or syrup.
- the formulationmay also be in the form of a parenteral preparation such as an injection, eye drops, nasal drops, ointment, cream, lotion, gel, or spray. These preparations may be produced by known methods.
- the formulationwhen it is for oral administration, it may be produced by appropriately combining and formulating solubilizers such as gum tragacanth, gum arabic, sucrose fatty acid ester, lecithin, olive oil, soybean oil, and PEG400; excipients such as starch, mannitol, and lactose; binders such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose; disintegrants such as crystalline cellulose and calcium carboxymethylcellulose; lubricants such as talc and magnesium stearate; and flow improvers such as light anhydrous silicic acid.
- solubilizerssuch as gum tragacanth, gum arabic, sucrose fatty acid ester, lecithin, olive oil, soybean oil, and PEG400
- excipientssuch as starch, mannitol, and lactose
- binderssuch as methylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose
- disintegrantssuch as crystalline cellulose
- a dried product or a stock solution of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present inventionwhich has been stored in a sterile manner, can be dissolved or diluted with physiological saline or a buffer solution for intravenous injection to prepare the preparation.
- indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present inventionWhen it is desired to increase the solubility of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention, known methods can be appropriately used, such as changing the solvent, forming the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention into ultrafine particles, or including the derivative in cyclodextrins.
- Subcutaneous, intramuscular and intravenous injectionscan be prepared by adding a pH regulator, a buffer, a stabilizer, an isotonicity agent, a local anesthetic, etc.
- pH adjusters and buffersinclude sodium citrate, sodium acetate, sodium phosphate, etc.
- stabilizersinclude sodium pyrosulfite, EDTA (sodium edetate), thioglycolic acid, thiolactic acid, etc.
- local anestheticsinclude procaine hydrochloride, lidocaine hydrochloride, etc.
- isotonicity agentsinclude sodium chloride, glucose, etc.
- the effective dosage of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention, which is the active ingredient of the preventive and/or therapeutic agent for hepatitis C of the present invention,is appropriately changed depending on various circumstances such as the condition and symptoms of the patient.
- the daily dosage of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present inventioncan be administered once a day or in several divided doses. Conversely, it is also possible to administer the dosage for several days at once, so that the administration pace is once every two or more days.
- the dosage of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention in the case of systemic administration as an injectioncan be administered once a day, or in several divided doses. Conversely, the dosage can be administered every two or more days by injecting several days' worth of the dose at once.
- a parenteral agentsuch as an ointment, lotion, cream, gel, or spray
- the amount of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention in the pharmaceutical composition as an external medicinecan be appropriately adjusted.
- administrationdoes not necessarily have to be performed continuously or periodically, and can be performed at appropriate intervals depending on changes in symptoms. If a single administration results in cure or remission, there is no need to administer multiple times. Administration may be resumed when symptoms recur or worsen.
- the method of administration of the preventive and/or therapeutic agent for hepatitis C containing the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulae (II) to (VII) of the present invention as an active ingredientis not particularly limited.
- the administration periodcan be adjusted as appropriate depending on the patient's condition.
- the dosage during the administration periodcan be adjusted as appropriate, but examples of the dosage form include continuous administration of a fixed amount, or administration of a relatively high dose only at the beginning of administration, followed by administration of a lower maintenance dose.
- the indole derivatives and/or tetrahydrocarbazole derivatives represented by formula (I) or formulas (II) to (VII) of the present inventioncan be used in combination with other medicines for the prevention and/or treatment of hepatitis C.
- An example of the combination partneris interferon.
- Another example of the combination partneris ribavirin.
- Yet another example of the combination partneris DAA.
- the number of medicines to be combinedis any number of two or more.
- the dosage and administration modecan be the same as those when each medicine is used alone, but can also be changed appropriately in consideration of the combined use.
- the combined medicinesmay be administered simultaneously or at different times.
- a combined drug for combined administrationmay be prepared and used, or drugs prepared separately may be used.
- an injection or infusion liquid in which the multiple medicines are mixed before administrationmay be prepared and used.
- a kit containing multiple medicines intended for the prevention and/or treatment of hepatitis Ccan also be prepared.
- the kitmay further include instructions or package inserts for such use.
- HCV NS2is a three-transmembrane protein, and since it is not easy to purify it, it is difficult to construct an experimental system in a test tube, which has been an obstacle to high-throughput screening of inhibitors. Therefore, the present inventors have used a cell-free protein synthesis system that also enables the preparation of active membrane proteins to construct an in vitro NS2-SPCS1 binding assay system, as shown in Fig. 2, and have realized screening of HCV inhibitors by applying test compounds contained in a compound library to the assay system.
- the luminescence at 520-620 nm in response to irradiation with 680 nm excitation lightis attenuated (compared to a control in the absence of the test compound), and thus compounds having inhibitory activity against the interaction were selected using the attenuation of luminescence as an index.
- a number of compounds, including compound A, which is a tetrahydrocarbazole derivative,were selected.
- the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells treated with 10 ⁇ M of a test compoundwas calculated when the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells not treated with a compound was set to 1, and the HCV inhibitory activity of the test compound was evaluated (hereinafter, the value calculated by the above-mentioned method is referred to as the "inhibitory activity value" of the test compound).
- the amount of HCV(the number of HCV RNA copies) was reduced by 59% in the presence of the tetrahydrocarbazole derivative, Compound A, and the inhibitory activity value of Compound A was 0.41. Furthermore, a test was also carried out in which the test compound was added at 0.63, 1.25, 2.5, 5, 10, or 20 ⁇ M, and the amount of HCV (the number of HCV RNA copies) produced by HuH7.5.1 cells was measured in each case, and the concentration of the compound added that reduced the amount of HCV produced by untreated HuH7.5.1 cells by 50%, i.e., the EC50 value ( ⁇ M), was calculated, and the EC50 value ( ⁇ M) of Compound A was 8.87.
- the samecan be expected when a clear decrease in the number of HCV RNA copies is observed in the presence of 10 ⁇ M (for example, an inhibitory activity value of 0.86 or less, preferably 0.7 or less, more preferably 0.6 or less, even more preferably 0.5 or less, and even more preferably 0.4 or less).
- the compoundsare comparable in any way to existing anti-HCV drugs such as DAA, and are expected to be practical medicines that provide new treatment options.
- the number of cells after culturing the virus-producing cells and the amount of total RNAwere measured to evaluate whether the test compound had cytotoxicity.
- Compound Adid not cause a significant decrease in the number of cells or the amount of total RNA within the tested concentration range of 0.63 to 20 ⁇ M, and no substantial cytotoxicity was observed for Compound A within the above concentration range. As a result, it can be said that Compound A can be a new hepatitis C virus inhibitor from the viewpoint of safety as well.
- tetrahydrocarbazole derivatives and indole derivativesthat are highly structurally similar to compound A may be compounds that inhibit NS2-SPCS1 binding and may serve as active ingredients in hepatitis C virus inhibitors. Therefore, the inventors decided to use compound A as a lead compound and to design and synthesize a large number of compounds by adding various structural mutations, and to measure the HCV particle production inhibitory activity of the synthesized compounds using the above-mentioned method.
- Example 1In the present examples, the compounds were produced by applying the procedures specifically shown below as well as known technical means.
- the analytical methodssuch as NMR, infrared (IR) spectrum, low resolution (LRMS) and high resolution (HRMS) mass spectrum used to confirm the synthesis of the compounds were performed under the conditions described in the "Characteristic Data" section above.
- Compound J6-032was synthesized according to the route and method shown below.
- J6-0324-((1,2,3,4-tetrahydrocyclopenta[b]indole)-7-sulfonamido)benzoic acid (J6-032; compound 5): To a solution of the ester compound (compound 1) in methanol (2.5 mL) was added 2N sodium hydroxide, and the mixture was stirred at room temperature until the reaction was complete. The mixture was quenched with 1N hydrochloric acid, extracted with ethyl acetate, and dried over Na2SO4 . Concentration under reduced pressure gave J6-032 (compound 5) as a red-brown solid (34.8 mg, 0.099 mmol, 98% yield) without purification . The synthesis of compound J6-032 was confirmed by NMR and HRMS.
- Compound J4-026was synthesized according to the route shown below, with reference to the above method for synthesizing J6-032.
- Compound K7-025was synthesized using known materials and conventional methods according to the route shown below.
- Compound K6-001was synthesized by standard methods according to the route shown below. The yield was 55%.
- K7-034was synthesized by standard methods according to the route shown below.
- Compound K9-030was synthesized by standard methods according to the route shown below. The yield was 74%.
- Compound K24-023was synthesized using known materials and conventional methods according to the route shown below.
- Compound K25-012was synthesized using known materials and conventional methods according to the route shown below.
- Compound K25-013was synthesized using known materials and conventional methods according to the route shown below.
- Compound K25-018was synthesized using known materials and conventional methods according to the route shown below.
- Compound K28-039was synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-013was synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-026was synthesized using known materials and conventional methods along the route shown below.
- Compound K29-027was synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-030was synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-035was synthesized using known materials and conventional methods according to the route shown below.
- Compound K29-036was synthesized using known materials and conventional methods according to the route shown below.
- Compound K30-031was synthesized using known materials and conventional methods along the route shown below.
- Compound K24-037was synthesized using known materials and conventional methods along the route shown below.
- Example 2Measurement of HCV production inhibitory activity of the compound of the present invention
- the HCV production inhibitory activity of the compound of the present inventionwas measured.
- the materials and methods for the measurementare described in the present specification under the heading "Confirmation of HCV inhibitory activity” as "An example of a specific method for confirming HCV inhibitory activity” and in the section “Confirmation of Hepatitis C virus inhibitory activity of compounds with inhibitory activity against NS2-SPCS1 interaction” (the administration concentration of the test compound was 10 ⁇ M).
- the results (average inhibitory activity value)are specifically shown below.
- the results (average inhibitory activity value)are specifically shown below.
- the compounds of the present inventionwhich are indole derivatives or tetrahydrocarbazole derivatives, have HCV inhibitory activity. Therefore, the compounds of the present invention and compositions containing them are expected to be useful as HCV inhibitors and agents for the prevention and/or treatment of hepatitis C.
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Abstract
Description
Translated fromJapanese本発明は、Ｃ型肝炎ウイルスに対する阻害活性を有する化合物及び当該化合物を含む医薬に関する。より具体的には、本発明は、インドール誘導体及び／又はテトラヒドロカルバゾール誘導体であるＣ型肝炎ウイルスに対する阻害活性を有する化合物及び当該化合物を含むＣ型肝炎ウイルス阻害剤に関する。The present invention relates to a compound having inhibitory activity against hepatitis C virus and a medicine containing said compound. More specifically, the present invention relates to a compound having inhibitory activity against hepatitis C virus, which is an indole derivative and/or a tetrahydrocarbazole derivative, and a hepatitis C virus inhibitor containing said compound.
Ｃ型肝炎は、Ｃ型肝炎ウイルス（ＨＣＶ：hepatitis C virus）の感染によって引き起こされる肝疾患（慢性肝炎、肝硬変、肝細胞癌）の総称である。ＨＣＶは、1989年、米国のChooらによって発見され、従来、非Ａ非Ｂ型肝炎と診断されていた症例の９０％以上、アルコール性肝障害と診断されていた症例の半数以上がＨＣＶによる肝障害であることが明らかとなった。最近の推定によれば、ＨＣＶキャリアは全世界で５８００万人、わが国で９０万～１３０万人存在する。ＨＣＶ感染が一旦成立すると、健康成人への感染であっても、急性の経過で治癒するものは約３０％であり、感染例の約７０％でＨＣＶ感染が持続し、慢性肝炎へと移行する。慢性化した場合、ウイルスの自然排除は年率０．２％とまれであり、ＨＣＶ感染による炎症の持続により肝線維化が惹起され、肝硬変や肝細胞癌へと進展する（非特許文献１）。Hepatitis C is a general term for liver diseases (chronic hepatitis, cirrhosis, and hepatocellular carcinoma) caused by infection with the hepatitis C virus (HCV). HCV was discovered in 1989 by Choo et al. in the United States, and it was revealed that more than 90% of cases previously diagnosed as non-A, non-B hepatitis and more than half of cases previously diagnosed as alcoholic liver disease were due to HCV-induced liver damage. According to recent estimates, there are 58 million HCV carriers worldwide, and 900,000 to 1.3 million in Japan. Once HCV infection is established, only about 30% of healthy adults are cured after an acute course, and in about 70% of infected cases, HCV infection persists and progresses to chronic hepatitis. When chronic, natural clearance of the virus is rare, at 0.2% per year, and persistent inflammation due to HCV infection induces liver fibrosis, which progresses to cirrhosis and hepatocellular carcinoma (Non-Patent Document 1).
Ｃ型肝炎治療の目標は、ＨＣＶ持続感染によって惹起される慢性肝疾患の長期予後の改善、すなわち、肝発癌ならびに肝疾患関連死を抑止することにある。この目標を達成するため抗ウイルス治療を行い、ＨＣＶの排除を目指す。事実、インターフェロン（interferon；ＩＦＮ）治療によってＨＣＶ ＲＮＡの排除に成功した症例では、肝炎が鎮静化することが示されている。The goal of hepatitis C treatment is to improve the long-term prognosis of chronic liver disease caused by persistent HCV infection, in other words, to prevent the development of liver cancer and deaths related to liver disease. To achieve this goal, antiviral treatment is administered with the aim of eliminating HCV. In fact, it has been shown that in cases where HCV RNA has been successfully eliminated through interferon (IFN) treatment, hepatitis subsides.
Ｃ型肝炎の治療法として従来、インターフェロン投与による化学療法が中心であったが、ウイルス因子を直接標的とした抗ＨＣＶ薬（ＤＡＡ； direct acting antivirals）が2011年に実用化された。わが国では、インターフェロンを使わない、直接型抗ウイルス薬 であるＤＡＡだけの治療、いわゆる「インターフェロンフリー」治療が２０１４年から始まり、近年ではＣ型肝炎の抗ウイルス治療の主流となっている。Traditionally, chemotherapy involving the administration of interferon has been the main treatment for hepatitis C, but anti-HCV drugs (DAA; direct acting antivirals) that directly target viral factors were put into practical use in 2011. In Japan, treatment using only DAA, a direct acting antiviral drug that does not use interferon, so-called "interferon-free" treatment, began in 2014 and has become the mainstream antiviral treatment for hepatitis C in recent years.
ＨＣＶは、プラス一本鎖ＲＮＡウイルスで、フラビウイルス科ヘパシウイルス属に属する。ＨＣＶ１～６までの６種の遺伝子型に分類される。さらにそれらの遺伝子型がいくつかのサブタイプに分類される。これまでにＨＣＶの複数の遺伝子型についてゲノム全長の塩基配列が決定されている。Ｃ型肝炎ウイルスのゲノムは約９６００ヌクレオチド長であり、約３０００アミノ酸の単一の大きなポリタンパク質をコードする単一のオープンリーディングフレーム（ＯＲＦ）を有する。感染した細胞において、このポリタンパク質は、ウイルスのプロテアーゼにより複数部位で切断されて、構造および非構造（ＮＳ）タンパク質を生じる。このうちウイルス粒子に取り込まれない非構造タンパク質は、ＮＳ２、ＮＳ３、ＮＳ４Ａ、ＮＳ４Ｂ、ＮＳ５ＡおよびＮＳ５Ｂに分けられている。現在、ＤＡＡの標的となっているのはこのうちＮＳ３／４Ａ、ＮＳ５Ａ、ＮＳ５Ｂ領域であり、それぞれプロテアーゼ活性、ウイルスゲノム複製複合体形成機能、ＲＮＡ依存性ＲＮＡポリメラーゼ活性を有している。HCV is a positive single-stranded RNA virus belonging to the Hepacivirus genus of the Flaviviridae family. It is classified into six genotypes, HCV1 to 6. These genotypes are further classified into several subtypes. The full-length genome sequences of several HCV genotypes have been determined. The genome of the hepatitis C virus is approximately 9,600 nucleotides long and has a single open reading frame (ORF) that encodes a single large polyprotein of approximately 3,000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by the viral protease to generate structural and nonstructural (NS) proteins. Of these, the nonstructural proteins that are not incorporated into viral particles are divided into NS2, NS3, NS4A, NS4B, NS5A, and NS5B. Currently, the NS3/4A, NS5A, and NS5B regions are targeted by DAA, and each of these regions has protease activity, viral genome replication complex formation function, and RNA-dependent RNA polymerase activity.
これまでに、ＮＳ３／４Ａプロテアーゼ阻害剤、ＮＳ５Ａ阻害剤、ＮＳ５Ｂ ＲＮＡポリメラーゼ阻害剤がそれぞれ複数種類承認されている。より具体的には、２０２２年５月までに、ＮＳ３／４Ａプロテアーゼ阻害薬としてはテラプレビル、シメプレビル、アスナプレビル、バニプレビル、パリタプレビル、グラゾプレビル、グレカプレビルの７種、ＮＳ５Ａ複製複合体阻害薬としてはダクラタスビル、レジパスビル、オムビタスビル、エルバスビル、ピブレンタスビル、ベルパタスビルの６種、さらにＮＳ５Ｂポリメラーゼ阻害薬として核酸型のソホスブビル、非核酸型のベクラブビルが承認されている。ただし、ＮＳ３／４Ａプロテアーゼ阻害薬は、バニプレビル、テラプレビル、シメプレビル、パリタプレビル、アスナプレビル及びグラゾプレビルの製造販売は中止されており、グレカプレビルが供給されるのみとなっている。To date, multiple types of NS3/4A protease inhibitors, NS5A inhibitors, and NS5B RNA polymerase inhibitors have been approved. More specifically, by May 2022, seven types of NS3/4A protease inhibitors (telaprevir, simeprevir, asunaprevir, vaniprevir, paritaprevir, grazoprevir, and glecaprevir) have been approved, six types of NS5A replication complex inhibitors (daclatasvir, ledipasvir, ombitasvir, elbasvir, pibrentasvir, and velpatasvir) have been approved, and the NS5B polymerase inhibitors sovosbuvir (nucleoside type) and beclabuvir (non-nucleoside type) have been approved. However, the manufacture and sale of the NS3/4A protease inhibitors vaniprevir, telaprevir, simeprevir, paritaprevir, asunaprevir, and grazoprevir have been discontinued, and only glecaprevir is being supplied.
現在、ソホスブビル（ＮＳ５Ｂ阻害剤）・レジパスビル（ＮＳ５Ａ阻害剤）配合錠（ハーボニー）による治療、グレカプレビル（ＮＳ３／４Ａ阻害剤）・ピブレンタスビル（ＮＳ５Ａ阻害剤）配合錠（マヴィレット）による治療、ソホスブビル・ベルパタスビル（ＮＳ５Ａ阻害剤）配合錠（エプクルーサ）による治療が、ウイルスの遺伝子型や肝炎の進行度や過去の治療歴の有無などを元に選択して投与されている。これにより、慢性肝炎から代償性肝硬変までの初回治療の場合、９５％以上の人で血中ウイルスを検出限界以下まで低下させることが可能となっている。これらは主に先進国での治療成績であるが、国や地域によって流行するウイルス遺伝子型が異なっている。最近、ＤＡＡに低感受性のウイルスが存在することが知られつつあり、例えばアフリカや中国に流布するＨＣＶ遺伝子３，４に対する治療で、５０％程度しか奏功しない例が報告された。これまで想定されていた以上にＨＣＶ遺伝子型間でＤＡＡ感受性の多様性が存在する可能性がある。また、先進国においても、現在の治療法に抵抗性、低感受性の患者は確実に存在している。治療不成功例で見られる薬剤耐性変異が多剤耐性になりうるなどＤＡＡ既治療例での薬剤耐性株の出現も報告されている。他方、市場縮小が見込まれることもあり、製薬企業における抗ＨＣＶ薬の新規開発は基本的に打ち止めの方針であるとされているため、治療不成功例などに対する新たな治療選択肢が供給されにくい情勢となっており、ＨＣＶに対する社会的ニーズは十分に満たされていない。Currently, treatment with sovosbuvir (NS5B inhibitor)/ledipasvir (NS5A inhibitor) combination tablets (Harvoni), treatment with glecaprevir (NS3/4A inhibitor)/pibrentasvir (NS5A inhibitor) combination tablets (Maviret), and treatment with sovosbuvir/velpatasvir (NS5A inhibitor) combination tablets (Epclusa) are selected and administered based on the genotype of the virus, the progression of hepatitis, and the presence or absence of a history of past treatment. As a result, in the case of initial treatment from chronic hepatitis to compensated cirrhosis, it is possible to reduce the blood virus to below the detection limit in more than 95% of people. These are mainly treatment results in developed countries, but the prevalent virus genotypes differ depending on the country and region. Recently, it has become known that there are viruses that are low sensitive to DAA, and for example, cases have been reported in which treatment for HCV genotypes 3 and 4 circulating in Africa and China was only effective in about 50% of cases. There is a possibility that there is more diversity in DAA sensitivity between HCV genotypes than previously assumed. Even in developed countries, there are certainly patients who are resistant or have low sensitivity to current treatments. There have been reports of the emergence of drug-resistant strains in patients who have already been treated with DAA, such as drug-resistant mutations seen in treatment failure cases that can lead to multidrug resistance. On the other hand, with the market expected to shrink, pharmaceutical companies are essentially halting the development of new anti-HCV drugs, making it difficult to provide new treatment options for treatment failure cases, and the social needs for HCV are not being fully met.
ＮＳ３／４Ａ、ＮＳ５Ａ、ＮＳ５Ｂ以外のＨＣＶタンパク質を標的とした阻害剤が開発されれば、既存のＤＡＡとの組み合わせにより、新たな治療選択肢に発展する可能性がある。想定される標的の一つであるＨＣＶ ＮＳ２は、ウイルス前駆体ポリタンパク質の切断に働くシステインプロテアーゼ活性を有するとともに粒子形成過程にも重要であることが変異解析から示されている。一時、製薬企業等でＮＳ２プロテアーゼ活性阻害を指標とする創薬研究が進められたが成功に至らず、ＮＳ２を標的とし、ＨＣＶ阻害剤の有効成分となり得る化合物はまだ開発されていない。If inhibitors targeting HCV proteins other than NS3/4A, NS5A, and NS5B are developed, they could potentially develop into new treatment options in combination with existing DAAs. One of the possible targets, HCV NS2, has cysteine protease activity that acts to cleave the viral precursor polyprotein, and mutation analysis has shown that it is also important in the particle formation process. At one time, pharmaceutical companies and others conducted drug discovery research using inhibition of NS2 protease activity as an indicator, but this was unsuccessful, and no compound that targets NS2 and could serve as an active ingredient in an HCV inhibitor has yet been developed.
本発明は、ＮＳ２を標的とし、ＨＣＶに対する阻害活性を有する化合物及び当該化合物を含む組成物の提供を課題とする。The objective of the present invention is to provide a compound that targets NS2 and has inhibitory activity against HCV, and a composition containing said compound.
かかる現状に鑑み、本発明者らは、Ｃ型肝炎ウイルスの粒子形成におけるＮＳ２の役割を解析し、ＮＳ２が宿主因子signal peptidase subunit 1（ＳＰＣＳ１）との結合を介してエンベロープＥ２と会合することが粒子のエンベロープ化に重要であることを見出した。また、本発明者らは、ＳＰＣＳ１との相互作用に重要なＮＳ２領域はＨＣＶの遺伝子型間でよく保存されていることを見出した。そして、これらの知見を基盤として、ＮＳ２を標的とした新規抗ＨＣＶ薬を探索を目指すこととした。しかしながら、ＨＣＶ ＮＳ２は３回膜貫通型のタンパク質で、精製が容易でないことから試験管内の実験系の構築が難しく、阻害剤のハイスループットスクリーニングの障害となっていた。そこで、本発明者らは、活性型の膜タンパク質の調製も可能にした無細胞タンパク質合成系を駆使してin vitroのＮＳ２－ＳＰＣＳ１ 結合アッセイ系を構築し、阻害剤スクリーニングを実現することに成功した。そして、ＮＳ２－ＳＰＣＳ１結合アッセイ系を使用して低分子化合物ライブラリーに対するスクリーニングを実施した結果、ＮＳ２－ＳＰＣＳ１結合阻害性を有するいくつかの化合物を選抜した。発明者らは、候補化合物の中から、ＨＣＶ粒子産生阻害活性を有するproof-of-concept化合物としてテトラヒドロカルバゾール誘導体である化合物Ａを同定した。また、当該化合物の細胞傷害性が低いことを確認することができた。さらに、本発明者らは、化合物Ａの構造に注目し、化合物Ａの部分構造を有する類縁化合物を多数設計、合成して更なるスクリーニングを行った結果、抗ＨＣＶ活性が高いインドール誘導体及び／又はテトラヒドロカルバゾール誘導体化合物を取得するに至り、本発明を完成させた。本発明を通じて発見された化合物は、既存のＤＡＡとは異なり、ＨＣＶのウイルス粒子形成に対する阻害活性を有するという特徴を有する。In light of this situation, the present inventors analyzed the role of NS2 in the particle formation of hepatitis C virus and found that the association of NS2 with envelope E2 through binding to the host factor signal peptidase subunit 1 (SPCS1) is important for particle envelope formation. The present inventors also found that the NS2 region important for interaction with SPCS1 is well conserved among HCV genotypes. Based on these findings, we aimed to search for a novel anti-HCV drug targeting NS2. However, HCV NS2 is a three-transmembrane protein that is difficult to purify, making it difficult to construct an experimental system in a test tube, which has been an obstacle to high-throughput screening of inhibitors. Therefore, the present inventors made full use of a cell-free protein synthesis system that also enables the preparation of active membrane proteins to construct an in vitro NS2-SPCS1 binding assay system and succeeded in realizing inhibitor screening. Then, a small molecule compound library was screened using the NS2-SPCS1 binding assay system, and several compounds were selected that have NS2-SPCS1 binding inhibitory properties. From among the candidate compounds, the inventors identified Compound A, a tetrahydrocarbazole derivative, as a proof-of-concept compound that has HCV particle production inhibitory activity. They were also able to confirm that the compound has low cytotoxicity. Furthermore, the inventors focused on the structure of Compound A, designed and synthesized a number of analogous compounds having a partial structure of Compound A and further screened them, resulting in the acquisition of indole derivatives and/or tetrahydrocarbazole derivative compounds with high anti-HCV activity, and thus completing the present invention. The compounds discovered through the present invention are characterized by having inhibitory activity against HCV virus particle formation, unlike existing DAA.
すなわち、本発明は、式（Ｉ）または（ＩＶ）の構造を有する化合物、当該化合物を含む組成物等に関する。式（Ｉ）または（ＩＶ）の構造を有する化合物は、ＮＳ２－ＳＰＣＳ１結合を阻害し、ＨＣＶのウイルス粒子形成を阻害する抗ＨＣＶ活性を示すため、本発明の一態様は、当該化合物を含むＨＣＶ阻害剤又はＣ型肝炎治療剤に関する。より具体的には、本発明は、次の［１］～［４９］に関する。In other words, the present invention relates to a compound having the structure of formula (I) or (IV), a composition containing said compound, etc. Since a compound having the structure of formula (I) or (IV) exhibits anti-HCV activity of inhibiting NS2-SPCS1 binding and inhibiting HCV virus particle formation, one aspect of the present invention relates to an HCV inhibitor or a hepatitis C therapeutic agent containing said compound. More specifically, the present invention relates to the following [1] to [49].
［１］
次の式（Ｉ）で示される化合物、若しくはその塩又はそれらの溶媒和物：[1]
A compound represented by the following formula (I), or a salt thereof, or a solvate thereof:
式（Ｉ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ１は、水素原子又は－ＣＯＯＲ９若しくは－ＣＯＮＨＲ１０で表される基であり；
ここでＲ９及びＲ１０は、互いに独立して、水素原子又は１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルであり；
Ｒ２は、水素原子又は１以上の置換基により置換されていても良いフェノキシ基であり；
Ｒ３は、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル又は１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリールであり；
Ｒ４及びＲ５は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、カルボキシ、又は、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニルであり；ここでＲ４及びＲ５は互いに結合して隣接する炭素原子と共に炭化水素環を形成してもよく；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ１はエトキシカルボニル基又はカルボキシ基であり、Ｒ２及びＲ３は水素原子であり、Ｒ４及びＲ５は互いに結合して隣接する炭素原子と共に置換基を有しないシクロヘキセン環を形成し、かつＲ６～Ｒ８がいずれも水素原子である場合を除くものである。
［２］
次の式（ＩＩ）で示される、［１］に記載の化合物、若しくはその塩又はそれらの溶媒和物：In formula (I),
X is S(=O)2 or C(=O);
R1 is a hydrogen atom or a group represented by -COOR9 or -CONHR10 ;
wherein R9 and R10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
R2 is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
R3 is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
R4 and R5 are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloalkyl optionally substituted by one or more substituents, a (C2-C6) alkenyl optionally substituted by one or more substituents, a (C2-C6) alkynyl optionally substituted by one or more substituents, a (C6-C10) aryl optionally substituted by one or more substituents, a (C1-C6) haloalkyl optionally substituted by one or more substituents, a (C1-C6) alkoxy optionally substituted by one or more substituents, a carboxy, or a (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents; wherein R4 and R5 may be bonded to each other to form a hydrocarbon ring together with the adjacent carbon atoms;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
Here, X is S(=O)2 ,R1 is an ethoxycarbonyl group or a carboxy group,R2 andR3 are hydrogen atoms,R4 andR5 are bonded to each other together with the adjacent carbon atom to form an unsubstituted cyclohexene ring, and all ofR6 toR8 are hydrogen atoms.
[2]
The compound according to [1], or a salt thereof, or a solvate thereof, represented by the following formula (II):
式（ＩＩ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ３、及びＲ６～Ｒ９は、それぞれ式（Ｉ）で定義されるとおりであり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ３、及びＲ６～Ｒ８はいずれも水素原子であり、Ｒ９はエチルであり、かつ、Ｒ１１（ｎ）においてｎ＝０である場合を除くものである。
［３］
次の式（ＩＩＩ）で示される、［２］に記載の化合物、若しくはその塩又はそれらの溶媒和物：In formula (II),
X is S(=O)2 or C(=O);
R3 and R6 to R9 are each as defined in formula (I);
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
Here, X is S(=O)2 ,R3 andR6 toR8 are all hydrogen atoms,R9 is ethyl, and the case where n=0 inR11 (n) is excluded.
[3]
The compound according to [2], represented by the following formula (III), or a salt thereof, or a solvate thereof:
式（ＩＩＩ）において、
Ｘ、Ｒ３、Ｒ９及びＲ１１はそれぞれ式（ＩＩ）で定義されるとおりであり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ３は水素原子であり、Ｒ９はエチルであり、かつ、Ｒ１１（ｎ）においてｎ＝０である場合を除くものである。
［４］
ＸはＳ（＝Ｏ）２である、［１］に記載の化合物、若しくはその塩又はそれらの溶媒和物。
［５］
Ｒ１は、－ＣＯＯＲ９あって、ここでＲ９は、水素原子、メチル又はエチルである、［１］に記載の化合物、若しくはその塩又はそれらの溶媒和物。
［６］
式（Ｉ）で示される化合物が以下のいずれかである、［１］に記載の化合物、若しくはその塩又はそれらの溶媒和物：In formula (III),
X, R3 , R9 and R11 are each as defined in formula (II);
Here, X is S(=O)2 ,R3 is a hydrogen atom,R9 is ethyl, andR11 (n) does not necessarily have to be 0.
[4]
The compound according to [1], wherein X is S(=O)2 , or a salt or solvate thereof.
[5]
The compound according to [1], or a salt or solvate thereof, wherein R1 is -COOR9 , where R9 is a hydrogen atom, methyl or ethyl.
[6]
The compound according to [1], wherein the compound represented by formula (I) is any one of the following, or a salt thereof, or a solvate thereof:
［７］
次の式（ＩＶ）で示される化合物、若しくはその塩又はそれらの溶媒和物：[7]
A compound represented by the following formula (IV), or a salt thereof, or a solvate thereof:
式（ＩＶ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
ＺはＣ－Ｒ１２又はＮであり；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールオキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールカルボニル、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルアミノカルボニル、カルボキシ、カルバモイル、シアノ、ヒドロキシ、アミノ、又はニトロで表される基である。
［８］
Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良いヘテロシクリル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、カルボキシ、又はニトロで表される基である、
［７］に記載の化合物、若しくはその塩又はそれらの溶媒和物。
［９］
次の式（Ｖ）に示される、［７］に記載の化合物、若しくはその塩又はそれらの溶媒和物：In formula (IV),
X is S(=O)2 or C(=O);
Z is C-R or N;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, and (C6-C12) aryloxy, (C6-C12) arylcarbonyl optionally substituted by one or more substituents, heterocyclyl group optionally substituted by one or more substituents, (5-12) heteroaryl optionally substituted by one or more substituents, (C1-C6) alkylcarbonyl optionally substituted by one or more substituents, (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents, (C1-C6) alkylaminocarbonyl optionally substituted by one or more substituents, carboxy, carbamoyl, cyano, hydroxy, amino, or nitro.
[8]
R12 to R16 are each independently a group represented by a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, a heterocyclyl which may be substituted by one or more substituents, a (C1-C6) alkoxycarbonyl which may be substituted by one or more substituents, a carboxy, or a nitro.
The compound according to [7], or a salt thereof, or a solvate thereof.
[9]
The compound according to [7], or a salt thereof, or a solvate thereof, represented by the following formula (V):
式（Ｖ）において、Ｘ、Ｚ、及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである。
［１０］
次の式（ＶＩ）に示される、［７］に記載の化合物、若しくはその塩又はそれらの溶媒和物：In formula (V), X, Z, and R12 to R16 are each as defined in formula (IV).
[10]
The compound according to [7], or a salt thereof, or a solvate thereof, represented by the following formula (VI):
式（ＶＩ）において、Ｚ、及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである。
［１１］
次の式（ＶＩＩ）に示される、［７］又は［８］に記載の化合物、若しくはその塩又はそれらの溶媒和物：In formula (VI), Z and R12 to R16 are each as defined in formula (IV).
[11]
A compound according to [7] or [8], or a salt thereof, or a solvate thereof, represented by the following formula (VII):
式（ＶＩＩ）において、Ｒ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである。
［１２］
ＸはＳ（＝Ｏ）２である、［７］に記載の化合物、若しくはその塩又はそれらの溶媒和物。
［１３］
式（ＩＶ）で示される化合物が以下のいずれかである、［７］に記載の化合物、若しくはその塩又はそれらの溶媒和物：In formula (VII), R12 to R16 are each as defined in formula (IV).
[12]
The compound according to [7], wherein X is S(=O)2 , or a salt or solvate thereof.
[13]
The compound according to [7], wherein the compound represented by formula (IV) is any one of the following, or a salt thereof, or a solvate thereof:
［１４］
［１］～［１３］のいずれか１に記載の化合物、若しくはその塩又はそれらの溶媒和物、および薬学的に許容される担体を含む、組成物。
［１５］
［１］～［１３］のいずれか１に記載の化合物、若しくはその塩又はそれらの溶媒和物、および薬学的に許容される担体を含む、Ｃ型肝炎ウイルス阻害剤。
［１６］
［１］～［１３］のいずれか１に記載の化合物、若しくはその塩又はそれらの溶媒和物、および薬学的に許容される担体を含む、Ｃ型肝炎の予防及び／又は治療剤。
［１７］
Ｃ型肝炎が、慢性肝炎、肝硬変及び肝細胞癌からなる群から選択される、Ｃ型肝炎ウイルス（ＨＣＶ：hepatitis C virus）の感染によって引き起こされる肝疾患である、［１６］に記載の予防及び／又は治療剤。
［１８］
経口投与剤である、［１７］に記載の予防及び／又は治療剤。
［１９］
非経口投与剤である、［１７］に記載の予防及び／又は治療剤。
［２０］
非経口投与剤が注射剤である、［１９］に記載の予防及び／又は治療剤。[14]
A composition comprising the compound according to any one of [1] to [13], or a salt thereof, or a solvate thereof, and a pharma- ceutically acceptable carrier.
[15]
A hepatitis C virus inhibitor comprising the compound according to any one of [1] to [13], or a salt thereof, or a solvate thereof, and a pharma- ceutically acceptable carrier.
[16]
A prophylactic and/or therapeutic agent for hepatitis C, comprising the compound according to any one of [1] to [13], or a salt thereof, or a solvate thereof, and a pharma- ceutically acceptable carrier.
[17]
The preventive and/or therapeutic agent according to [16], wherein the hepatitis C is a liver disease caused by infection with hepatitis C virus (HCV) selected from the group consisting of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma.
[18]
The prophylactic and/or therapeutic agent according to [17], which is an orally administered agent.
[19]
The prophylactic and/or therapeutic agent according to [17], which is a parenteral administration agent.
[20]
The preventive and/or therapeutic agent according to [19], wherein the parenteral administration agent is an injection.
［２１］
次の式（Ｉ）で示される化合物、若しくはその塩又はそれらの溶媒和物を投与する工程を含むＣ型肝炎ウイルスの阻害方法：[21]
A method for inhibiting hepatitis C virus, comprising the step of administering a compound represented by the following formula (I), or a salt thereof, or a solvate thereof:
式（Ｉ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ１は、水素原子又は－ＣＯＯＲ９若しくは－ＣＯＮＨＲ１０で表される基であり；
ここでＲ９及びＲ１０は、互いに独立して、水素原子又は１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルであり；
Ｒ２は、水素原子又は１以上の置換基により置換されていても良いフェノキシ基であり；
Ｒ３は、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル又は１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリールであり；
Ｒ４及びＲ５は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、カルボキシ、又は、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニルであり；ここでＲ４及びＲ５は互いに結合して隣接する炭素原子と共に炭化水素環を形成してもよく；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ１はエトキシカルボニル基であり、Ｒ２及びＲ３は水素原子であり、Ｒ４及びＲ５は互いに結合して隣接する炭素原子と共に置換基を有しないシクロヘキセン環を形成し、かつＲ６～Ｒ８がいずれも水素原子である場合を除くものである。
［２２］
次の式（ＩＶ）で示される化合物、若しくはその塩又はそれらの溶媒和物を投与する工程を含むＣ型肝炎ウイルスの阻害方法：In formula (I),
X is S(=O)2 or C(=O);
R1 is a hydrogen atom or a group represented by -COOR9 or -CONHR10 ;
wherein R9 and R10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
R2 is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
R3 is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
R4 and R5 are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloalkyl optionally substituted by one or more substituents, a (C2-C6) alkenyl optionally substituted by one or more substituents, a (C2-C6) alkynyl optionally substituted by one or more substituents, a (C6-C10) aryl optionally substituted by one or more substituents, a (C1-C6) haloalkyl optionally substituted by one or more substituents, a (C1-C6) alkoxy optionally substituted by one or more substituents, a carboxy, or a (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents; wherein R4 and R5 may be bonded to each other to form a hydrocarbon ring together with the adjacent carbon atoms;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
Here, X is S(=O)2 ,R1 is an ethoxycarbonyl group,R2 andR3 are hydrogen atoms,R4 andR5 are bonded to each other and together with the adjacent carbon atom form an unsubstituted cyclohexene ring, and all ofR6 toR8 are hydrogen atoms.
[22]
A method for inhibiting hepatitis C virus, comprising the step of administering a compound represented by the following formula (IV), or a salt thereof, or a solvate thereof:
式（ＩＶ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
ＺはＣ－Ｒ１２又はＮであり；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールオキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールカルボニル、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルアミノカルボニル、カルボキシ、カルバモイル、シアノ、ヒドロキシ、アミノ、又はニトロで表される基である。In formula (IV),
X is S(=O)2 or C(=O);
Z is C-R or N;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, and (C6-C12) aryloxy, (C6-C12) arylcarbonyl optionally substituted by one or more substituents, heterocyclyl group optionally substituted by one or more substituents, (5-12) heteroaryl optionally substituted by one or more substituents, (C1-C6) alkylcarbonyl optionally substituted by one or more substituents, (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents, (C1-C6) alkylaminocarbonyl optionally substituted by one or more substituents, carboxy, carbamoyl, cyano, hydroxy, amino, or nitro.
［２３］
次の式（Ｉ）で示される化合物、若しくはその塩又はそれらの溶媒和物を対象に投与する工程を含む、Ｃ型肝炎の予防及び／又は治療方法：[23]
A method for preventing and/or treating hepatitis C, comprising the step of administering to a subject a compound represented by the following formula (I), or a salt thereof, or a solvate thereof:
式（Ｉ）において、 ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ１は、水素原子又は－ＣＯＯＲ９若しくは－ＣＯＮＨＲ１０で表される基であり；
ここでＲ９及びＲ１０は、互いに独立して、水素原子又は１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルであり；
Ｒ２は、水素原子又は１以上の置換基により置換されていても良いフェノキシ基であり；
Ｒ３は、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル又は１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリールであり；
Ｒ４及びＲ５は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、カルボキシ、又は、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニルであり；ここでＲ４及びＲ５は互いに結合して隣接する炭素原子と共に炭化水素環を形成してもよく；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ１はエトキシカルボニル基であり、Ｒ２及びＲ３は水素原子であり、Ｒ４及びＲ５は互いに結合して隣接する炭素原子と共に置換基を有しないシクロヘキセン環を形成し、かつＲ６～Ｒ８がいずれも水素原子である場合を除くものである。
［２４］
式（Ｉ）で示される化合物が、以下の式（ＩＩ）で示される化合物である、［２３］に記載のＣ型肝炎の予防及び／又は治療方法：In formula (I), X is S(=O)2 or C(=O);
R1 is a hydrogen atom or a group represented by -COOR9 or -CONHR10 ;
wherein R9 and R10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
R2 is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
R3 is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
R4 and R5 are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloalkyl optionally substituted by one or more substituents, a (C2-C6) alkenyl optionally substituted by one or more substituents, a (C2-C6) alkynyl optionally substituted by one or more substituents, a (C6-C10) aryl optionally substituted by one or more substituents, a (C1-C6) haloalkyl optionally substituted by one or more substituents, a (C1-C6) alkoxy optionally substituted by one or more substituents, a carboxy, or a (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents; wherein R4 and R5 may be bonded to each other to form a hydrocarbon ring together with the adjacent carbon atoms;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
Here, X is S(=O)2 ,R1 is an ethoxycarbonyl group,R2 andR3 are hydrogen atoms,R4 andR5 are bonded to each other and together with the adjacent carbon atom form an unsubstituted cyclohexene ring, and all ofR6 toR8 are hydrogen atoms.
[24]
The method for preventing and/or treating hepatitis C according to [23], wherein the compound represented by formula (I) is a compound represented by the following formula (II):
式（ＩＩ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ３、及びＲ６～Ｒ９は、それぞれ式（Ｉ）で定義されるとおりであり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ３、及びＲ６～Ｒ８はいずれも水素原子であり、Ｒ９はエチルであり、かつ、Ｒ１１（ｎ）においてｎ＝０である場合を除くものである。
［２５］
式（ＩＩ）に示される化合物が、以下の式（ＩＩＩ）で示される化合物である、［２４］に記載のＣ型肝炎の予防及び／又は治療方法：In formula (II),
X is S(=O)2 or C(=O);
R3 and R6 to R9 are each as defined in formula (I);
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
Here, X is S(=O)2 ,R3 andR6 toR8 are all hydrogen atoms,R9 is ethyl, and the case where n=0 inR11 (n) is excluded.
[25]
The method for preventing and/or treating hepatitis C according to [24], wherein the compound represented by formula (II) is a compound represented by the following formula (III):
式（ＩＩＩ）において、
Ｘ、Ｒ４、Ｒ９及びＲ１１はそれぞれ式（ＩＩ）で定義されるとおりであり；
ここでＲ３ＸはＳ（＝Ｏ）２であり、Ｒ３は水素原子であり、Ｒ９はエチルであり、かつ、Ｒ１１（ｎ）においてｎ＝０である場合を除くものである。In formula (III),
X, R4 , R9 and R11 are each as defined in formula (II);
Here, R3 X is S(═O)2 , R3 is a hydrogen atom, R9 is ethyl, and R11 (n) does not necessarily have n=0.
［２６］
次の式（ＩＶ）で示される化合物、若しくはその塩又はそれらの溶媒和物を対象に投与する工程を含む、Ｃ型肝炎の予防及び／又は治療方法：[26]
A method for preventing and/or treating hepatitis C, comprising a step of administering to a subject a compound represented by the following formula (IV), or a salt thereof, or a solvate thereof:
式（ＩＶ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
ＺはＣ－Ｒ１２又はＮであり；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールオキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールカルボニル、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルアミノカルボニル、カルボキシ、カルバモイル、シアノ、ヒドロキシ、アミノ、又はニトロで表される基である。
［２７］
式（ＩＶ）で示される化合物が、以下の式（Ｖ）で示される化合物である、［２６］に記載のＣ型肝炎の予防及び／又は治療方法：In formula (IV),
X is S(=O)2 or C(=O);
Z is C-R or N;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, and (C6-C12) aryloxy, (C6-C12) arylcarbonyl optionally substituted by one or more substituents, heterocyclyl group optionally substituted by one or more substituents, (5-12) heteroaryl optionally substituted by one or more substituents, (C1-C6) alkylcarbonyl optionally substituted by one or more substituents, (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents, (C1-C6) alkylaminocarbonyl optionally substituted by one or more substituents, carboxy, carbamoyl, cyano, hydroxy, amino, or nitro.
[27]
The method for preventing and/or treating hepatitis C according to [26], wherein the compound represented by formula (IV) is a compound represented by the following formula (V):
式（Ｖ）において、
Ｘ、Ｚ、及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである。
［２８］
式（ＩＶ）に示される化合物が、以下の式（ＶＩ）で示される化合物である、［２６］に記載のＣ型肝炎の予防及び／又は治療方法：In formula (V),
X, Z, and R12 to R16 are each as defined in formula (IV).
[28]
The method for preventing and/or treating hepatitis C according to [26], wherein the compound represented by formula (IV) is a compound represented by the following formula (VI):
式（ＶＩ）において、Ｚ、及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである。
［２９］
式（ＩＶ）に示される化合物が、以下の式（ＶＩＩ）で示される化合物である、［２６］に記載のＣ型肝炎の予防及び／又は治療方法：In formula (VI), Z and R12 to R16 are each as defined in formula (IV).
[29]
The method for preventing and/or treating hepatitis C according to [26], wherein the compound represented by formula (IV) is a compound represented by the following formula (VII):
式（ＶＩＩ）において、Ｒ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである。
［３０］
対象がＣ型肝炎ウイルスに感染したヒトである、［２２］～［２９］のいずれか１に記載の予防及び／又は治療方法。In formula (VII), R12 to R16 are each as defined in formula (IV).
[30]
The preventive and/or therapeutic method according to any one of [22] to [29], wherein the subject is a human infected with hepatitis C virus.
［３１］
Ｃ型肝炎の予防及び／又は治療剤の製造のための、次の式（Ｉ）で示される化合物の使用：[31]
Use of a compound represented by the following formula (I) for the manufacture of a medicament for the prevention and/or treatment of hepatitis C:
式（Ｉ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ１は、水素原子又は－ＣＯＯＲ９若しくは－ＣＯＮＨＲ１０で表される基であり；
ここでＲ９及びＲ１０は、互いに独立して、水素原子又は１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルであり；
Ｒ２は、水素原子又は１以上の置換基により置換されていても良いフェノキシ基であり；
Ｒ３は、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル又は１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリールであり；
Ｒ４及びＲ５は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、カルボキシ、又は、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニルであり；ここでＲ４及びＲ５は互いに結合して隣接する炭素原子と共に炭化水素環を形成してもよく；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ１はエトキシカルボニル基であり、Ｒ２及びＲ３は水素原子であり、Ｒ４及びＲ５は互いに結合して隣接する炭素原子と共に置換基を有しないシクロヘキセン環を形成し、かつＲ６～Ｒ８がいずれも水素原子である場合を除くものである。In formula (I),
X is S(=O)2 or C(=O);
R1 is a hydrogen atom or a group represented by -COOR9 or -CONHR10 ;
wherein R9 and R10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
R2 is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
R3 is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
R4 and R5 are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloalkyl optionally substituted by one or more substituents, a (C2-C6) alkenyl optionally substituted by one or more substituents, a (C2-C6) alkynyl optionally substituted by one or more substituents, a (C6-C10) aryl optionally substituted by one or more substituents, a (C1-C6) haloalkyl optionally substituted by one or more substituents, a (C1-C6) alkoxy optionally substituted by one or more substituents, a carboxy, or a (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents; wherein R4 and R5 may be bonded to each other to form a hydrocarbon ring together with the adjacent carbon atoms;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
Here, X is S(=O)2 ,R1 is an ethoxycarbonyl group,R2 andR3 are hydrogen atoms,R4 andR5 are bonded to each other and together with the adjacent carbon atom form an unsubstituted cyclohexene ring, and all ofR6 toR8 are hydrogen atoms.
［３２］
Ｃ型肝炎の予防及び／又は治療剤の製造のための、次の式（ＩＶ）で示される化合物の使用：[32]
Use of a compound represented by the following formula (IV) for the manufacture of an agent for the prophylaxis and/or treatment of hepatitis C:
式（ＩＶ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
ＺはＣ－Ｒ１２又はＮであり；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールオキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールカルボニル、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルアミノカルボニル、カルボキシ、カルバモイル、シアノ、ヒドロキシ、アミノ、又はニトロで表される基である。In formula (IV),
X is S(=O)2 or C(=O);
Z is C-R or N;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, and (C6-C12) aryloxy, (C6-C12) arylcarbonyl optionally substituted by one or more substituents, heterocyclyl group optionally substituted by one or more substituents, (5-12) heteroaryl optionally substituted by one or more substituents, (C1-C6) alkylcarbonyl optionally substituted by one or more substituents, (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents, (C1-C6) alkylaminocarbonyl optionally substituted by one or more substituents, carboxy, carbamoyl, cyano, hydroxy, amino, or nitro.
［３３］
Ｃ型肝炎の予防及び／又は治療方法における使用のための、次の式（Ｉ）で示される化合物：[33]
A compound of formula (I) for use in a method for the prevention and/or treatment of hepatitis C:
式（Ｉ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ１は、水素原子又は－ＣＯＯＲ９若しくは－ＣＯＮＨＲ１０で表される基であり；
ここでＲ９及びＲ１０は、互いに独立して、水素原子又は１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルであり；
Ｒ２は、水素原子又は１以上の置換基により置換されていても良いフェノキシ基であり；
Ｒ３は、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル又は１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリールであり；
Ｒ４及びＲ５は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、カルボキシ、又は、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニルであり；ここでＲ４及びＲ５は互いに結合して隣接する炭素原子と共に炭化水素環を形成してもよく；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ１はエトキシカルボニル基であり、Ｒ２及びＲ３は水素原子であり、Ｒ４及びＲ５は互いに結合して隣接する炭素原子と共に置換基を有しないシクロヘキセン環を形成し、かつＲ６～Ｒ８がいずれも水素原子である場合を除くものである。
［３４］
式（Ｉ）で示される化合物が、以下の式（ＩＩ）で示される化合物である、［３３］に記載のＣ型肝炎の予防及び／又は治療方法における使用のための化合物：In formula (I),
X is S(=O)2 or C(=O);
R1 is a hydrogen atom or a group represented by -COOR9 or -CONHR10 ;
wherein R9 and R10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
R2 is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
R3 is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
R4 and R5 are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloalkyl optionally substituted by one or more substituents, a (C2-C6) alkenyl optionally substituted by one or more substituents, a (C2-C6) alkynyl optionally substituted by one or more substituents, a (C6-C10) aryl optionally substituted by one or more substituents, a (C1-C6) haloalkyl optionally substituted by one or more substituents, a (C1-C6) alkoxy optionally substituted by one or more substituents, a carboxy, or a (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents; wherein R4 and R5 may be bonded to each other to form a hydrocarbon ring together with the adjacent carbon atoms;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
Here, X is S(=O)2 ,R1 is an ethoxycarbonyl group,R2 andR3 are hydrogen atoms,R4 andR5 are bonded to each other and together with the adjacent carbon atom form an unsubstituted cyclohexene ring, and all ofR6 toR8 are hydrogen atoms.
[34]
The compound for use in the method for preventing and/or treating hepatitis C according to [33], wherein the compound represented by formula (I) is a compound represented by the following formula (II):
式（ＩＩ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ３、及びＲ６～Ｒ９は、それぞれ式（Ｉ）で定義されるとおりであり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ３、及びＲ６～Ｒ８はいずれも水素原子であり、Ｒ９はエチルであり、かつ、Ｒ１１（ｎ）においてｎ＝０である場合を除くものである。
［３５］
式（ＩＩ）に示される化合物が、以下の式（ＩＩＩ）で示される化合物である、［３４］に記載のＣ型肝炎の予防及び／又は治療方法における使用のための化合物：In formula (II),
X is S(=O)2 or C(=O);
R3 and R6 to R9 are each as defined in formula (I);
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
Here, X is S(=O)2 ,R3 andR6 toR8 are all hydrogen atoms,R9 is ethyl, and the case where n=0 inR11 (n) is excluded.
[35]
The compound for use in the method for preventing and/or treating hepatitis C according to [34], wherein the compound represented by formula (II) is a compound represented by the following formula (III):
式（ＩＩＩ）において、
Ｘ、Ｒ３、Ｒ９及びＲ１１はそれぞれ式（ＩＩ）で定義されるとおりであり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ３は水素原子であり、Ｒ９はエチルであり、かつ、Ｒ１１（ｎ）においてｎ＝０である場合を除くものである］
で示される化合物である。
［３６］
Ｃ型肝炎の予防及び／又は治療方法における使用のための、次の式（ＩＶ）で示される化合物：In formula (III),
X, R3 , R9 and R11 are each as defined in formula (II);
wherein X is S(=O)2 ,R3 is a hydrogen atom,R9 is ethyl, andR11 (n) does not necessarily have n=0.
It is a compound represented by the formula:
[36]
A compound represented by the following formula (IV) for use in a method for the prevention and/or treatment of hepatitis C:
式（ＩＶ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
ＺはＣ－Ｒ１２又はＮであり；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールオキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールカルボニル、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルアミノカルボニル、カルボキシ、カルバモイル、シアノ、ヒドロキシ、アミノ、又はニトロで表される基である。
［３７］
式（ＩＶ）で示される化合物が、以下の式（Ｖ）で示される化合物である、［３６］に記載のＣ型肝炎の予防及び／又は治療方法における使用のための化合物：In formula (IV),
X is S(=O)2 or C(=O);
Z is C-R or N;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, and (C6-C12) aryloxy, (C6-C12) arylcarbonyl optionally substituted by one or more substituents, heterocyclyl group optionally substituted by one or more substituents, (5-12) heteroaryl optionally substituted by one or more substituents, (C1-C6) alkylcarbonyl optionally substituted by one or more substituents, (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents, (C1-C6) alkylaminocarbonyl optionally substituted by one or more substituents, carboxy, carbamoyl, cyano, hydroxy, amino, or nitro.
[37]
The compound for use in the method for preventing and/or treating hepatitis C according to [36], wherein the compound represented by formula (IV) is a compound represented by the following formula (V):
式（Ｖ）において、Ｘ、Ｚ、及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである。
［３８］
式（ＩＶ）で示される化合物が、以下の式（ＶＩ）で示される化合物である、［３６］に記載のＣ型肝炎の予防及び／又は治療方法における使用のための化合物：In formula (V), X, Z, and R12 to R16 are each as defined in formula (IV).
[38]
The compound for use in the method for preventing and/or treating hepatitis C according to [36], wherein the compound represented by formula (IV) is a compound represented by the following formula (VI):
式（ＶＩ）において、Ｚ、及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである。
［３９］
式（ＩＶ）で示される化合物が、以下の式（ＶＩＩ）で示される化合物である、［３６］に記載のＣ型肝炎の予防及び／又は治療方法における使用のための化合物：In formula (VI), Z and R12 to R16 are each as defined in formula (IV).
[39]
The compound for use in the method for preventing and/or treating hepatitis C according to [36], wherein the compound represented by formula (IV) is a compound represented by the following formula (VII):
式（ＶＩＩ）において、Ｒ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである。In formula (VII), R12 to R16 are each as defined in formula (IV).
［４０］
インターフェロンと［１４］に記載の組成物を含む、キット。
［４１］
リバビリンをさらに含む、［４０］に記載のキット。
［４２］
ＤＡＡをさらに含む、［４０］又は［４１］に記載のキット。
［４３］
同時投与のための［４０］～［４２］のいずれか１に記載のキット。
［４４］
異時投与のための［４０］～［４２］のいずれか１に記載のキット[40]
A kit comprising an interferon and the composition according to [14].
[41]
The kit according to [40], further comprising ribavirin.
[42]
The kit according to [40] or [41], further comprising DAA.
[43]
The kit according to any one of [40] to [42], for simultaneous administration.
[44]
The kit according to any one of [40] to [42] for different time administration.
［４５］
ＤＡＡを含む組成物と［１４］に記載の組成物を含む、キット。
［４６］
リバビリンをさらに含む、［４５］に記載のキット。
［４７］
同時投与のための［４５］又は［４６］に記載のキット。
［４８］
異時投与のための［４５］又は［４６］に記載のキット
［４９］
Ｃ型肝炎の予防及び／又は治療を用途とするキットであって、当該用途のための取扱説明書又は添付文書をさらに含むものである、［４０］～［４８］のいずれか１に記載のキット。[45]
A kit comprising a composition containing DAA and the composition described in [14].
[46]
The kit according to [45], further comprising ribavirin.
[47]
The kit according to [45] or [46] for simultaneous administration.
[48]
[49] The kit according to [45] or [46] for administration at different times.
The kit according to any one of [40] to [48], which is intended for the prevention and/or treatment of hepatitis C, and further comprises an instruction manual or package insert for said use.
本発明により、式（Ｉ）又は（ＩＶ）の構造を有する化合物や当該化合物を含む組成物が提供される。また、本発明の化合物、組成物、Ｃ型肝炎ウイルス阻害剤、Ｃ型肝炎の予防及び／又は治療剤、医薬、治療方法、使用又はキットにより、Ｃ型肝炎ウイルスの低減が可能であり、Ｃ型肝炎及びＣ型肝炎炎に起因する疾患に対する新たな予防及び／又は治療を提供することができる。また、本発明の化合物は、μＭオーダー又はそれ以下の低用量で有意なＣ型肝炎ウイルス阻害活性を示すこと、及び／又は細胞傷害性が低いことから、本発明の治療剤、医薬、医薬組成物、治療方法、使用又は組合せにより、Ｃ型肝炎及びＣ型肝炎に起因する疾患に対する予防及び／又は治療を、副作用が小さく、安全性の高い形で提供することができる。The present invention provides a compound having the structure of formula (I) or (IV) or a composition containing the compound. In addition, the compound, composition, hepatitis C virus inhibitor, preventive and/or therapeutic agent, medicine, treatment method, use, or kit of the present invention can reduce hepatitis C virus, and provide a new prevention and/or treatment for hepatitis C and diseases caused by hepatitis C. In addition, since the compound of the present invention exhibits significant hepatitis C virus inhibitory activity at a low dose of the order of μM or less and/or has low cytotoxicity, the therapeutic agent, medicine, pharmaceutical composition, treatment method, use, or combination of the present invention can provide prevention and/or treatment for hepatitis C and diseases caused by hepatitis C in a form with few side effects and high safety.
ひとつの態様において、本発明は、式（Ｉ）In one embodiment, the present invention provides a compound of formula (I)
［式中：
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ１は、水素原子又は－ＣＯＯＲ９若しくは－ＣＯＮＨＲ１０で表される基であり；
ここでＲ９及びＲ１０は、互いに独立して、水素原子又は１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルであり；
Ｒ２は、水素原子又は１以上の置換基により置換されていても良いフェノキシ基であり；
Ｒ３は、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル又は１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリールであり；
Ｒ４及びＲ５は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、カルボキシ、又は、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニルであり；ここでＲ４及びＲ５は互いに結合して隣接する炭素原子と共に炭化水素環を形成してもよく；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ１はエトキシカルボニル基であり、Ｒ２及びＲ３は水素原子であり、Ｒ４及びＲ５は互いに結合して隣接する炭素原子と共に置換基を有しないシクロヘキセン環を形成し、かつＲ６～Ｒ８がいずれも水素原子である場合を除くものである］
で示される化合物、若しくはその塩又はそれらの溶媒和物である。
また、本発明の一態様は、当該化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。[In the formula:
X is S(=O)2 or C(=O);
R1 is a hydrogen atom or a group represented by -COOR9 or -CONHR10 ;
wherein R9 and R10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
R2 is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
R3 is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
R4 and R5 are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloalkyl optionally substituted by one or more substituents, a (C2-C6) alkenyl optionally substituted by one or more substituents, a (C2-C6) alkynyl optionally substituted by one or more substituents, a (C6-C10) aryl optionally substituted by one or more substituents, a (C1-C6) haloalkyl optionally substituted by one or more substituents, a (C1-C6) alkoxy optionally substituted by one or more substituents, a carboxy, or a (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents; wherein R4 and R5 may be bonded to each other to form a hydrocarbon ring together with the adjacent carbon atoms;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
where X is S(=O)2 ,R1 is an ethoxycarbonyl group,R2 andR3 are hydrogen atoms,R4 andR5 are bonded together with the adjacent carbon atom to form an unsubstituted cyclohexene ring, andR6 toR8 are all hydrogen atoms.
or a salt or solvate thereof.
Another aspect of the present invention is a hepatitis C virus inhibitor containing the compound, or a salt thereof, or a solvate of the compound or the salt.
別の態様において、本発明は、式（Ｉ）で示される化合物が、以下の式（ＩＩ）In another aspect, the present invention relates to a compound represented by formula (I) having the following formula (II):
［式中：
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ３、及びＲ６～Ｒ９は、それぞれ式（Ｉ）で定義されるとおりであり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ３、及びＲ６～Ｒ８はいずれも水素原子であり、Ｒ９はエチルであり、かつ、Ｒ１１（ｎ）においてｎ＝０である場合を除くものである］
で示される化合物、若しくはその塩又はそれらの溶媒和物である。
また、本発明の一態様は、上記式（ＩＩ）で示される化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。[In the formula:
X is S(=O)2 or C(=O);
R3 and R6 to R9 are each as defined in formula (I);
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
wherein X is S(=O)2 ,R3 andR6 toR8 are all hydrogen atoms,R9 is ethyl, and n=0 inR11 (n) is excluded.
or a salt or solvate thereof.
Another aspect of the present invention is a hepatitis C virus inhibitor containing a compound represented by the above formula (II), or a salt thereof, or a solvate of the compound or the salt.
別の態様において、本発明は、式（ＩＩ）で示される化合物が、以下の式（ＩＩＩ）In another aspect, the present invention relates to a compound represented by formula (II) having the following formula (III):
［式中：
Ｘ、Ｒ３、Ｒ９及びＲ１１はそれぞれ式（ＩＩ）で定義されるとおりであり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ３は水素原子であり、Ｒ９はエチルであり、かつ、Ｒ１１（ｎ）においてｎ＝０である場合を除くものである］
で示される化合物、若しくはその塩又はそれらの溶媒和物である。
また、本発明の一態様は、上記式（ＩＩＩ）で示される化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。[In the formula:
X, R3 , R9 and R11 are each as defined in formula (II);
wherein X is S(=O)2 ,R3 is a hydrogen atom,R9 is ethyl, andR11 (n) does not necessarily have n=0.
or a salt or solvate thereof.
Another aspect of the present invention is a hepatitis C virus inhibitor containing a compound represented by the above formula (III), or a salt thereof, or a solvate of the compound or the salt.
別の態様において、本発明は、式（Ｉ）～式（ＩＩＩ）のいずれか１で示される化合物、若しくはその塩又はそれらの溶媒和物であって、ＸはＳ（＝Ｏ）２である化合物、若しくはその塩又はそれらの溶媒和物である。
また、本発明の一態様は、上記式（Ｉ）～式（ＩＩＩ）のいずれか１で示される化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。In another aspect, the present invention relates to a compound represented by any one of formulas (I) to (III), or a salt thereof, or a solvate thereof, wherein X is S(=O)2 , or a salt thereof, or a solvate thereof.
Another aspect of the present invention is a hepatitis C virus inhibitor comprising a compound represented by any one of the above formulas (I) to (III), or a salt thereof, or a solvate of the compound or the salt.
別の態様において、本発明は、式（Ｉ）で示される化合物、若しくはその塩又はそれらの溶媒和物であって、Ｒ１は、－ＣＯＯＲ９あって、ここでＲ９は、水素原子、メチル又はエチルである化合物、若しくはその塩又はそれらの溶媒和物である。
また別の態様において、本発明は、式（Ｉ）で示される化合物、若しくはその塩又はそれらの溶媒和物であって、Ｒ１は、－ＣＯＯＲ９あって、ここでＲ９は、水素原子、メチル又はエチルである化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。In another embodiment, the present invention relates to a compound represented by formula (I), or a salt thereof, or a solvate thereof, in which R1 is -COOR9 , where R9 is a hydrogen atom, methyl or ethyl, or a salt thereof, or a solvate thereof.
In yet another aspect, the present invention relates to a hepatitis C virus inhibitor comprising a compound represented by formula (I), a salt thereof, or a solvate thereof, wherein R1 is -COOR9 , where R9 is a hydrogen atom, methyl, or ethyl, or a salt thereof, or a solvate thereof.
別の態様において、本発明は、式（ＩＩ）又は（ＩＩＩ）で示される化合物、若しくはその塩又はそれらの溶媒和物であって、ここでＲ９は、水素原子、メチル又はエチルである化合物、若しくはその塩又はそれらの溶媒和物である。
また別の態様において、本発明は、式（ＩＩ）又は（ＩＩＩ）で示される化合物、若しくはその塩又はそれらの溶媒和物であって、ここでＲ９は、水素原子、メチル又はエチルである化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。In another embodiment, the present invention relates to a compound represented by formula (II) or (III), or a salt thereof, or a solvate thereof, wherein R9 is a hydrogen atom, methyl or ethyl, or a salt thereof, or a solvate thereof.
In yet another aspect, the present invention relates to a hepatitis C virus inhibitor comprising a compound represented by formula (II) or (III), a salt thereof, or a solvate thereof, whereinR9 is a hydrogen atom, methyl, or ethyl, or a salt thereof, or a solvate thereof.
別の態様において、本発明は、式（Ｉ）で示される化合物、若しくはその塩又はそれらの溶媒和物であって、式（Ｉ）で示される化合物が以下のいずれかである化合物、若しくはその塩又はそれらの溶媒和物である：In another aspect, the present invention relates to a compound represented by formula (I), or a salt thereof, or a solvate thereof, wherein the compound represented by formula (I) is any one of the following:
もうひとつの態様において、本発明は、式（ＩＶ）In another aspect, the present invention provides a compound of formula (IV)
［ 式（ＩＶ）において、
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
ＺはＣ－Ｒ１２又はＮであり；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールオキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールカルボニル、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルアミノカルボニル、カルボキシ、カルバモイル、シアノ、ヒドロキシ、アミノ、又はニトロで表される基である］
で示される化合物、若しくはその塩又はそれらの溶媒和物である。
また、本発明の一態様は、当該化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。[In formula (IV),
X is S(=O)2 or C(=O);
Z is C-R or N;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, a (C6-C12)aryloxy group optionally substituted by one or more substituents, a (C6-C12)arylcarbonyl group optionally substituted by one or more substituents, a heterocyclyl group optionally substituted by one or more substituents, a (5-12)heteroaryl group optionally substituted by one or more substituents, a (C1-C6)alkylcarbonyl group optionally substituted by one or more substituents, a (C1-C6)alkoxycarbonyl group optionally substituted by one or more substituents, a (C1-C6)alkylaminocarbonyl group optionally substituted by one or more substituents, a carboxy group, a carbamoyl group, a cyano group, a hydroxy group, an amino group, or a nitro group.
or a salt or solvate thereof.
Another aspect of the present invention is a hepatitis C virus inhibitor containing the compound, or a salt thereof, or a solvate of the compound or the salt.
別の態様において、本発明は、式（ＩＶ）で示される化合物が、以下の式（Ｖ）In another aspect, the present invention relates to a compound represented by formula (IV) having the following formula (V):
［式（Ｖ）において、Ｘ、Ｚ、及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである］
で示される化合物で、若しくはその塩又はそれらの溶媒和物である。
また、本発明の一態様は、上記式（Ｖ）で示される化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。[In formula (V), X, Z, and R12 to R16 are each as defined in formula (IV)]
or a salt or solvate thereof.
Another aspect of the present invention is a hepatitis C virus inhibitor containing a compound represented by the above formula (V), or a salt thereof, or a solvate of the compound or the salt.
別の態様において、本発明は、式（ＩＶ）で示される化合物が、以下の式（ＶＩ）In another aspect, the present invention relates to a compound represented by formula (IV) having the following formula (VI):
［式（ＶＩ）において、Ｚ、及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである］
で示される化合物、若しくはその塩又はそれらの溶媒和物である。
また、本発明の一態様は、上記式（ＶＩ）で示される化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。[In formula (VI), Z and R12 to R16 are each as defined in formula (IV)]
or a salt or solvate thereof.
Another aspect of the present invention is a hepatitis C virus inhibitor containing a compound represented by the above formula (VI), or a salt thereof, or a solvate of the compound or the salt.
別の態様において、本発明は、式（ＩＶ）で示される化合物が、以下の式（ＶＩＩ）In another aspect, the present invention relates to a compound represented by formula (IV) having the following formula (VII):
［式（ＶＩＩ）において、Ｚ、及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりである］
で示される化合物、若しくはその塩又はそれらの溶媒和物である。
また、本発明の一態様は、上記式（ＶＩＩ）で示される化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。[In formula (VII), Z and R12 to R16 are each as defined in formula (IV)]
or a salt or solvate thereof.
Another aspect of the present invention is a hepatitis C virus inhibitor containing a compound represented by the above formula (VII), or a salt thereof, or a solvate of the compound or the salt.
別の態様において、本発明は、式（ＩＶ）～式（Ｖ）のいずれか１で示される化合物、若しくはその塩又はそれらの溶媒和物であって、ＸはＳ（＝Ｏ）２である化合物、若しくはその塩又はそれらの溶媒和物である。
また、本発明の一態様は、上記式（ＩＶ）～式（ＶＩＩ）のいずれか１で示される化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。In another aspect, the present invention relates to a compound represented by any one of formulas (IV) to (V), or a salt thereof, or a solvate thereof, wherein X is S(=O)2 , or a salt thereof, or a solvate thereof.
Another aspect of the present invention is a hepatitis C virus inhibitor comprising a compound represented by any one of the above formulas (IV) to (VII), or a salt thereof, or a solvate of the compound or the salt.
別の態様において、本発明は、式（ＩＶ）で示される化合物、若しくはその塩又はそれらの溶媒和物であって、Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、カルボキシ、又はニトロで表される基である化合物、若しくはその塩又はそれらの溶媒和物である。
また別の態様において、本発明は、式（ＩＶ）で示される化合物、若しくはその塩又はそれらの溶媒和物であって、Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、カルボキシ、又はニトロで表される基である化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。In another aspect, the present invention relates to a compound represented by formula (IV), or a salt or solvate thereof, in which R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, a heterocyclyl group which may be substituted by one or more substituents, a (5-12) heteroaryl which may be substituted by one or more substituents, a (C1-C6) alkoxycarbonyl which may be substituted by one or more substituents, carboxy, or nitro, or a salt or solvate thereof.
In yet another aspect, the present invention relates to a hepatitis C virus inhibitor comprising a compound represented by formula (IV), a salt thereof, or a solvate thereof, in which R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted with one or more substituents, a (C1-C6) alkoxy which may be substituted with one or more substituents, a (C6-C12) aryl which may be substituted with one or more substituents, a heterocyclyl group which may be substituted with one or more substituents, a (5-12) heteroaryl which may be substituted with one or more substituents, a (C1-C6) alkoxycarbonyl which may be substituted with one or more substituents, carboxy, or a group represented by nitro, or a salt thereof, or a solvate thereof.
別の態様において、本発明は、式（Ｖ）又は（ＶＩ）で示される化合物、若しくはその塩又はそれらの溶媒和物であって、ここでＺはＣ－Ｒ１２であり、Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、カルボキシ、又はニトロで表される基である化合物、若しくはその塩又はそれらの溶媒和物である。
また別の態様において、本発明は、式（Ｖ）又は（ＶＩ）で示される化合物、若しくはその塩又はそれらの溶媒和物であって、ここでＺはＣ－Ｒ１２であり、Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、カルボキシ、又はニトロで表される基である化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤である。In another aspect, the present invention relates to a compound represented by formula (V) or (VI), or a salt or solvate thereof, wherein Z is C-R12 , and R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl optionally substituted with one or more substituents, a (C1-C6) alkoxy optionally substituted with one or more substituents, a (C6-C12) aryl optionally substituted with one or more substituents, a heterocyclyl group optionally substituted with one or more substituents, a (5-12) heteroaryl optionally substituted with one or more substituents, a (C1-C6) alkoxycarbonyl optionally substituted with one or more substituents, carboxy, or nitro, or a salt or solvate thereof.
In yet another aspect, the present invention relates to a hepatitis C virus inhibitor comprising a compound represented by formula (V) or (VI), or a salt or solvate thereof, wherein Z is C-R12 , and R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted with one or more substituents, a (C1-C6) alkoxy which may be substituted with one or more substituents, a (C6-C12) aryl which may be substituted with one or more substituents, a heterocyclyl group which may be substituted with one or more substituents, a (5-12) heteroaryl which may be substituted with one or more substituents, a (C1-C6) alkoxycarbonyl which may be substituted with one or more substituents, carboxy, or a group represented by nitro, or a salt or solvate thereof.
別の態様において、本発明は、式（ＩＶ）で示される化合物、若しくはその塩又はそれらの溶媒和物であって、式（ＩＶ）で示される化合物が以下のいずれかである化合物、若しくはその塩又はそれらの溶媒和物である：In another aspect, the present invention relates to a compound represented by formula (IV), or a salt thereof, or a solvate thereof, wherein the compound represented by formula (IV) is any one of the following, or a salt thereof, or a solvate thereof:
本発明の化合物の例としては、次の化合物が挙げられるが、これらに限定されるものではない。
4-((9-(2-ethylhexyl)-2,3,4,9-tetrahydro-1H-carbazole)-6-sulfonamido)benzoic acid；
ethyl 4-(1,2,3,4-tetrahydrocyclopenta[b]indole-7-sulfonamido)benzoate；
ethyl 4-(5,6,7,8,9,10-hexahydrocyclohepta[b]indole-2-sulfonamido)benzoate；
ethyl 4-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indole-2-sulfonamido)benzoate；4-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indole-2-sulfonamido)benzoic acid；
4-(5,6,7,8,9,10-hexahydrocyclohepta[b]indole-2-sulfonamido)benzoic acid；
4-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indole-2-sulfonamido)benzoic acid；
ethyl 4-(3-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoate；
ethyl 4-(2-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoate；
ethyl 4-(2,3,4,9-tetrahydrospiro[carbazole-1,1’-cyclopentane]-6-sulfonamido)benzoate；
ethyl 4-(3-(N-methyl-carbamoyl)-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoate；
ethyl 4-(3-hydroxymethyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoate；
4-(3-propyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoic acid；
4-(3-tert-butyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoic acid；
4-(2,2,4-trimethyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoic acid；ethyl 4-(2-methyl-1H-indole-5-sulfonamido)benzoate；
ethyl 4-(2,3-dimethyl-1H-indole-5-sulfonamido)benzoate；
ethyl 4-(3-ethyl-2-propyl-1H-indole-5-sulfonamido)benzoate：
4-(3-ethyl-2-propyl-1H-indole-5-sulfonamido)benzoic acid；
ethyl 4-(2-phenyl-1H-indole-5-sulfonamido)benzoate；
ethyl 4-(2-phenyl-1H-indole-5-sulfonamido)benzoate；
ethyl 4-(3-methyl-2-(4-fluorophenyl)-1H-indole-5-sulfonamido)benzoate；
ethyl 4-(3-methyl-2-(4-fluorophenyl)-1H-indole-5-sulfonamido)benzoate；
4-[2-(4-fluorophenyl)-3-methyl-1H-indole-5-sulfonamido]benzoic acid；
N-[2-(2-methylphenoxy)phenyl]-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamide；
ethyl 4-[(2,3,4,9-tetrahydro-1H-carbazole-6-carbonyl)amino]benzoate；
4-[(2,3,4,9-tetrahydro-1H-carbazole-6-carbonyl)amino]benzoic acid；
N-methyl-4-(2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzamide；及び
4-(2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoic acid。Examples of compounds of the present invention include, but are not limited to, the following compounds:
4-((9-(2-ethylhexyl)-2,3,4,9-tetrahydro-1H-carbazole)-6-sulfonamido)benzoic acid;
ethyl 4-(1,2,3,4-tetrahydrocyclopenta[b]indole-7-sulfonamido)benzoate;
ethyl 4-(5,6,7,8,9,10-hexahydrocyclohepta[b]indole-2-sulfonamido)benzoate;
ethyl 4-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indole-2-sulfonamido)benzoate; 4-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indole-2-sulfonamido)benzoic acid;
4-(5,6,7,8,9,10-hexahydrocyclohepta[b]indole-2-sulfonamido)benzoic acid;
4-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indole-2-sulfonamido)benzoic acid;
ethyl 4-(3-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoate;
ethyl 4-(2-methyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoate;
ethyl 4-(2,3,4,9-tetrahydrospiro[carbazole-1,1'-cyclopentane]-6-sulfonamido)benzoate;
ethyl 4-(3-(N-methyl-carbamoyl)-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoate;
ethyl 4-(3-hydroxymethyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoate;
4-(3-propyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoic acid;
4-(3-tert-butyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoic acid;
4-(2,2,4-trimethyl-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoic acid; ethyl 4-(2-methyl-1H-indole-5-sulfonamido)benzoate;
ethyl 4-(2,3-dimethyl-1H-indole-5-sulfonamido)benzoate;
ethyl 4-(3-ethyl-2-propyl-1H-indole-5-sulfonamido)benzoate:
4-(3-ethyl-2-propyl-1H-indole-5-sulfonamido)benzoic acid;
ethyl 4-(2-phenyl-1H-indole-5-sulfonamido)benzoate;
ethyl 4-(2-phenyl-1H-indole-5-sulfonamido)benzoate;
ethyl 4-(3-methyl-2-(4-fluorophenyl)-1H-indole-5-sulfonamido)benzoate;
ethyl 4-(3-methyl-2-(4-fluorophenyl)-1H-indole-5-sulfonamido)benzoate;
4-[2-(4-fluorophenyl)-3-methyl-1H-indole-5-sulfonamido]benzoic acid;
N-[2-(2-methylphenoxy)phenyl]-2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamide;
ethyl 4-[(2,3,4,9-tetrahydro-1H-carbazole-6-carbonyl)amino]benzoate;
4-[(2,3,4,9-tetrahydro-1H-carbazole-6-carbonyl)amino]benzoic acid;
N-methyl-4-(2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzamide; and
4-(2,3,4,9-tetrahydro-1H-carbazole-6-sulfonamido)benzoic acid.
本明細書に記載された用語について説明する。 Explain the terms used in this specification.
用語「ニトロ」は置換基「－ＮＯ２」を意味する。
用語「シアノ」または「ニトリル」は置換基「－ＣＮ」を意味する。
用語「ヒドロキシ」は置換基「－ＯＨ」を意味する。
用語「カルボキシ」は置換基「－ＣＯＯＨ」を意味する。
用語「カルバモイル」は置換基「－ＣＯＮＨ２」を意味する。
用語「アミノ」は置換基「－ＮＨ２」を意味する。The term "nitro" refers to the substituent "--NO.sub.2 ."
The term "cyano" or "nitrile" refers to the substituent "-CN."
The term "hydroxy" refers to the substituent "-OH."
The term "carboxy" refers to the substituent "--COOH."
The term "carbamoyl" refers to the substituent "--CONH2 ".
The term "amino" refers to the substituent "-NH2 ".
（Ｃａ－Ｃｂ）は、炭素原子数がａ～ｂ個であることを意味する。例えば、「（Ｃ１－Ｃ１２）アルキル」の「（Ｃ１－Ｃ１２）」は、アルキルの炭素原子数が１～１２であることを意味し、「（Ｃ２－Ｃ５）」は、アルキルの炭素原子数が２～５であることを意味する。炭素原子数を意味する「（Ｃａ－Ｃｂ）」は括弧なしで「Ｃａ－Ｃｂ」と表記する場合がある。従って、例えば、「Ｃ１－Ｃ６アルキル」の「Ｃ１－Ｃ６」は、アルキルの炭素原子数が１～６であることを意味する。(Ca-Cb) means that the number of carbon atoms is a to b. For example, the "(C1-C12)" in "(C1-C12) alkyl" means that the alkyl has 1 to 12 carbon atoms, and "(C2-C5)" means that the alkyl has 2 to 5 carbon atoms. "(Ca-Cb)," which means the number of carbon atoms, is sometimes written as "Ca-Cb" without parentheses. So, for example, the "C1-C6" in "C1-C6 alkyl" means that the alkyl has 1 to 6 carbon atoms.
本明細書中、「アルキル」のような一般的用語は、ブチル及びｔｅｒｔ－ブチルのような直鎖及び分岐鎖の両方を含むと解釈する。一方で、例えば、具体的用語「ブチル」は、直鎖の「ノルマルブチル」を意味し、分岐鎖の「ｔｅｒｔ－ブチル」を意味しない。そして「ｔｅｒｔ－ブチル」のような分岐鎖異性体は、意図した場合に具体的に言及される。In this specification, general terms such as "alkyl" are intended to include both straight and branched chains, such as butyl and tert-butyl, while the specific term "butyl," for example, means straight chain "normal butyl" and not branched chain "tert-butyl," and branched chain isomers such as "tert-butyl" are specifically referred to when intended.
ハロゲン原子の例は、フッ素原子、塩素原子、臭素原子及びヨウ素を含む。Examples of halogen atoms include fluorine atoms, chlorine atoms, bromine atoms and iodine atoms.
（Ｃ１－Ｃ１２）アルキルは、１～１２個の炭素原子を有する直鎖又は分岐鎖のアルキルを意味する。（Ｃ１－Ｃ１２）の例は、それぞれ、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ－ブチル、イソブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル、２－エチルヘキシル等を含むが、これらに限定されない。(C1-C12) alkyl means straight or branched chain alkyl having 1 to 12 carbon atoms. Examples of (C1-C12) include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, 2-ethylhexyl, etc.
（Ｃ１－Ｃ６）アルキルは、１～６個の炭素原子を有する直鎖又は分岐鎖のアルキルを意味する。（Ｃ１－Ｃ６）アルキルの例は、上記の（Ｃ１－Ｃ１２）アルキルの例のうちの適切な例を含む。(C1-C6)alkyl means straight or branched chain alkyl having 1 to 6 carbon atoms. Examples of (C1-C6)alkyl include appropriate examples of (C1-C12)alkyl listed above.
（Ｃ３－Ｃ８）シクロアルキルは、３～８個の炭素原子を有するシクロアルキルを意味する。（Ｃ３－Ｃ８）シクロアルキルの例は、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルである。(C3-C8)cycloalkyl means cycloalkyl having 3 to 8 carbon atoms. Examples of (C3-C8)cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
（Ｃ２－Ｃ６）アルケニルは、２～６個の炭素原子を有する直鎖又は分岐鎖のアルケニルを意味する。（Ｃ２－Ｃ６）アルケニルの例は、ビニル、１－プロペニル、イソプロペニル、２－プロペニル、１－ブテニル、１－メチル－１－プロペニル、２－メチル－１－プロペニル、２－ブテニル、３－ブテニル、１，３－ブタジエニル、１－ペンテニル、１－ヘキセニル等を含むが、これらに限定されない。(C2-C6)alkenyl means straight or branched alkenyl having 2 to 6 carbon atoms. Examples of (C2-C6)alkenyl include, but are not limited to, vinyl, 1-propenyl, isopropenyl, 2-propenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 1-hexenyl, etc.
（Ｃ２－Ｃ６）アルキニルは、２～６個の炭素原子を有する直鎖又は分岐鎖のアルキニルを意味する。（Ｃ２－Ｃ６）アルキニルの例は、エチニル、１－プロピニル、２－プロピニル、１－ブチニル、１－メチル－２－プロピニル、２－ブチニル、３－ブチニル、１－ペンチニル、１－ヘキシニル等を含むが、これらに限定されない。(C2-C6)alkynyl means straight or branched alkynyl having 2 to 6 carbon atoms. Examples of (C2-C6)alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, etc.
（Ｃ６－Ｃ１２）アリールは、特に限定しない限り、炭素数が６～１２の芳香族炭化水素基を示す。（Ｃ６－Ｃ１２）アリールの例は、フェニル、ビフェニル、１－ナフチル、及び２－ナフチルである。ここで、芳香環上の炭素原子は、１以上の置換基により置換されていても良い。
（Ｃ６－Ｃ１０）アリールは、特に限定しない限り、炭素数が６～１０の芳香族炭化水素基を示す。（Ｃ６－Ｃ１０）アリールの例は、フェニル、１－ナフチル、及び２－ナフチルである。ここで、芳香環上の炭素原子は、１以上の置換基により置換されていても良い。Unless otherwise specified, (C6-C12)aryl refers to an aromatic hydrocarbon group having 6 to 12 carbon atoms. Examples of (C6-C12)aryl are phenyl, biphenyl, 1-naphthyl, and 2-naphthyl. Here, the carbon atoms on the aromatic ring may be substituted with one or more substituents.
Unless otherwise specified, (C6-C10)aryl refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples of (C6-C10)aryl are phenyl, 1-naphthyl, and 2-naphthyl. Here, the carbon atoms on the aromatic ring may be substituted with one or more substituents.
ヘテロシクリル基は、特に限定しない限り、炭素原子以外に酸素原子、窒素原子、硫黄原子及びホウ素原子から選択される原子を１個以上含む非芳香族ヘテロ環を示す。例えば、３員～８員又は３員～６員の非芳香族ヘテロ環である。具体的な例として、アジリジニル、オキシラニル、オキセタニル、チエタニル、テトラヒドロフラニル、テトラヒドロピラニル、アゼチジニル、ピロリジニル、ピペリジニル、ピぺラジニル、ジヒドロイソキサゾリル、ジオキサボロラニル、ジオキソラニル、ジオキサニル、又はモルホリニル等の基を挙げることができる。ここで、ヘテロ環上の原子は、１以上の置換基により置換されていても良い。Unless otherwise specified, a heterocyclyl group refers to a non-aromatic heterocycle containing, in addition to carbon atoms, one or more atoms selected from oxygen atoms, nitrogen atoms, sulfur atoms, and boron atoms. For example, it is a 3- to 8-membered or 3- to 6-membered non-aromatic heterocycle. Specific examples include aziridinyl, oxiranyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dihydroisoxazolyl, dioxaborolanyl, dioxolanyl, dioxanyl, or morpholinyl groups. Here, the atoms on the heterocycle may be substituted with one or more substituents.
（５－１２）ヘテロアリールは、特に限定しない限り、炭素原子の他に、窒素原子、酸素原子及び硫黄原子から選択されるヘテロ原子を１個以上含む５～１２員環の単環式または縮合二環式の芳香族ヘテロ環を示す。単環式芳香族ヘテロ環としては、例えば、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、トリアジニル、チエニル、フラニル、ピロリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、イミダゾリル、トリアゾリル、チアジアゾリル、オキサジアゾリル、又はテトラゾリル等の基を挙げることができ、縮合二環式ヘテロ環としては、単環式の基のうちの１つとフェニル環とを、またはヘテロ芳香族単環式の基のいずれかとを、Ｃ８－Ｃ１０二環式の基を形成するように縮合させることによって形成された縮合二環式部分、例えばインドリル、ベンゾイミダゾリル、インダゾリル、ベンゾトリアゾリル、イソキノリニル、キノリニル、ベンゾチアゾリル、ベンゾフラニル、ベンゾチエニル、ベンゾイソオキサゾリル、ピラゾロピリジル、ピラゾロピリミジニル、ピロロピリジル、トリアゾロピリジル、トリアゾロピリミジニル、キナゾリニル、キノキサリニル、又はシンノリニル等の基を挙げることができる。ここで、ヘテロ環上の原子は、１以上の置換基により置換されていても良い。(5-12) Heteroaryl, unless otherwise specified, refers to a 5-12-membered monocyclic or fused bicyclic aromatic heterocycle containing, in addition to carbon atoms, one or more heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms. Examples of monocyclic aromatic heterocycles include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl, and tetrazolyl groups. Examples of fused bicyclic heterocycles include a C8- or 12-membered monocyclic group and a phenyl ring, or a C8- or 12-membered heteroaromatic monocyclic group and a phenyl ring. Fused bicyclic moieties formed by condensing to form a C10 bicyclic group include indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolinyl, quinolinyl, benzothiazolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyridyl, triazolopyridyl, triazolopyrimidinyl, quinazolinyl, quinoxalinyl, or cinnolinyl, where the atoms on the heterocycle may be substituted with one or more substituents.
（Ｃ１－Ｃ６）ハロアルキルは、同一又は異なる１～１３個のハロゲン原子により置換されている、炭素原子数が１～６の直鎖又は分岐鎖のアルキルを意味する（ここで、ハロゲン原子は上記の定義と同じ意味を有する。）。（Ｃ１－Ｃ６）ハロアルキルの例は、フルオロメチル、クロロメチル、ブロモメチル、ジフルオロメチル、ジクロロメチル、トリフルオロメチル、トリクロロメチル等を含むが、これらに限定されるものではない。
「１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル」の「１以上の置換基により置換されていても良い」とは、（Ｃ１－Ｃ６）アルキル部分において、ハロゲン原子に置換されていない１以上の箇所において、ハロゲン原子以外の置換基により置換されていても良いことを意味する。(C1-C6)haloalkyl means straight or branched alkyl having 1 to 6 carbon atoms, substituted with 1 to 13 identical or different halogen atoms, wherein the halogen atoms have the same meaning as defined above. Examples of (C1-C6)haloalkyl include, but are not limited to, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, and the like.
The phrase "optionally substituted with one or more substituents" in "(C1-C6) haloalkyl which is optionally substituted with one or more substituents" means that in the (C1-C6) alkyl portion, one or more positions which are not substituted with halogen atoms may be substituted with a substituent other than a halogen atom.
（Ｃ１－Ｃ６）アルコキシは、（Ｃ１－Ｃ６）アルキル－Ｏ－を意味する（ここで、（Ｃ１－Ｃ６）アルキル部分は上記の定義と同じ意味を有する。以下の説明においても同様である。）。（Ｃ１－Ｃ６）アルコキシの例は、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、ｓｅｃ－ブトキシ、イソブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、ヘキシルオキシ等を含むが、これらに限定されない。
「１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ」とは、アルコキシ基における（Ｃ１－Ｃ６）アルキル部分において、１以上の箇所において、置換基により置換されていても良いことを意味する。以下の説明における「１以上の置換基により置換されていても良い」の語句も、同様に理解されるものである。(C1-C6)alkoxy means (C1-C6)alkyl-O- (wherein the (C1-C6)alkyl moiety has the same meaning as defined above, and the same applies in the following explanations). Examples of (C1-C6)alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, and the like.
"(C1-C6)alkoxy optionally substituted with one or more substituents" means that the (C1-C6)alkyl portion of the alkoxy group may be substituted with a substituent at one or more positions. The phrase "optionally substituted with one or more substituents" in the following description is to be understood in the same way.
（Ｃ１－Ｃ６）アルコキシカルボニルは、（Ｃ１－Ｃ６）アルキル－Ｏ－Ｃ（＝Ｏ）－を意味する。（Ｃ１－Ｃ６）アルコキシカルボニルの例は、メトキシカルボニル、エトキシカルボニルを含むが、これらに限定されない。(C1-C6)alkoxycarbonyl means (C1-C6)alkyl-O-C(=O)-. Examples of (C1-C6)alkoxycarbonyl include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.
（Ｃ１－Ｃ６）アルキルカルボニル基は、特に限定しない限り、（（Ｃ１－Ｃ６）アルキル）－Ｃ（＝Ｏ）－基を示し、例えば、アセチル、プロピオニル、２－メチルプロピオニル、２，２－ジメチルプロピオニル、ブタノイル、ピバロイル、２－メチルブタノイル、３－メチルブタノイル、２－エチルブタノイル、２，２－ジメチルブタノイル、２，３－ジメチルブタノイル、３，３－ジメチルブタノイル、ペンタノイル、２－メチルペンタノイル、３－メチルペンタノイル、４－メチルペンタノイル、又はヘキサノイル等の基を挙げることができる。Unless otherwise specified, the (C1-C6) alkylcarbonyl group refers to a ((C1-C6) alkyl)-C(=O)- group, and examples of such groups include acetyl, propionyl, 2-methylpropionyl, 2,2-dimethylpropionyl, butanoyl, pivaloyl, 2-methylbutanoyl, 3-methylbutanoyl, 2-ethylbutanoyl, 2,2-dimethylbutanoyl, 2,3-dimethylbutanoyl, 3,3-dimethylbutanoyl, pentanoyl, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, and hexanoyl.
（Ｃ１－Ｃ６）アルキルアミノカルボニルは、特に限定しない限り、（（Ｃ１－Ｃ６）アルキル）－ＮＨ－Ｃ（＝Ｏ）－基を示し、例えば、メチルアミノカルボニル、エチルアミノカルボニル、ｎ－プロピルアミノカルボニル、イソプロピルアミノカルボニル、ｎ－ブチルアミノカルボニル、イソブチルアミノカルボニル、ｓｅｃ－ブチルアミノカルボニル、ｔｅｒｔ－ブチルアミノカルボニル、ｎ－ペンチルアミノカルボニル、１－メチルブチルアミノカルボニル、２－メチルブチルアミノカルボニル、３－メチルブチルアミノカルボニル、１－エチルプロピルアミノカルボニル、１，１－ジメチルプロピルアミノカルボニル、１，２－ジメチルプロピルアミノカルボニル、２，２－ジメチルプロピルアミノカルボニル、又はｎ－ヘキシルアミノカルボニル等の基を挙げることができる。Unless otherwise specified, (C1-C6) alkylaminocarbonyl refers to a ((C1-C6) alkyl)-NH-C(=O)- group, and examples thereof include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, 1-methylbutylaminocarbonyl, 2-methylbutylaminocarbonyl, 3-methylbutylaminocarbonyl, 1-ethylpropylaminocarbonyl, 1,1-dimethylpropylaminocarbonyl, 1,2-dimethylpropylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, and n-hexylaminocarbonyl.
「１以上の置換基により置換されていても良いカルバモイル」の例は、－ＣＯＮＨ２で示されるカルバモイル基における窒素原子の１又は２の水素原子が置換基により置換されたものである。置換基の一例は（Ｃ１－Ｃ６）アルキルであり、より具体的な例はメチル又はエチルである。An example of a "carbamoyl which may be substituted by one or more substituents" is a carbamoyl group represented by-CONH2 in which one or two hydrogen atoms of the nitrogen atom are substituted by a substituent. An example of the substituent is (C1-C6) alkyl, and a more specific example is methyl or ethyl.
（Ｃ６－Ｃ１２）アリールオキシは、特に限定しない限り、（Ｃ６－Ｃ１２アリール）－Ｏ－基を示し、例えばフェノキシ基、ナフタレン－１－イルオキシ基、ナフタレン－２－イルオキシ基等の基を挙げることができる。Unless otherwise specified, (C6-C12)aryloxy refers to a (C6-C12 aryl)-O- group, such as a phenoxy group, a naphthalene-1-yloxy group, or a naphthalene-2-yloxy group.
（Ｃ６－Ｃ１２）アリールカルボニルは、特に限定しない限り、（Ｃ６－Ｃ１２アリール）－Ｃ（＝Ｏ）－基を示し、例えば、ベンゾイル、ビフェニルカルボニル、ナフタレン－１－イルカルボニル、又はナフタレン－２－イルカルボニル等の基を挙げることができる。Unless otherwise specified, (C6-C12)arylcarbonyl refers to a (C6-C12aryl)-C(=O)- group, and examples of such groups include benzoyl, biphenylcarbonyl, naphthalene-1-ylcarbonyl, and naphthalene-2-ylcarbonyl.
環式の炭化水素基は、環を構成する原子が全て炭素原子である、環式基を意味する。一つの態様では、環式の炭化水素基の例は、芳香族又は非芳香族の、単環式、二環式又は三環式の３～１４員（好ましくは５～１４員、より好ましくは５～１０員）の環式の炭化水素基を含むが、これらに限定されない。環式の炭化水素基の例は、シクロアルキル、アリール等を含むが、これらに限定されない。シクロアルキルの例は、上記の（Ｃ３－Ｃ８）シクロアルキルの例を含む。アリールは、上記で定義した通りの環式の炭化水素基のうち、芳香族の環式基である。アリールの例は、上記の（Ｃ６－Ｃ１２）アリールの例を含む。上記で定義又は例示した通りの環式の炭化水素基は、可能であれば、非縮合環式（例えば、単環式又はスピロ環式）及び縮合環式の環式基を包含してもよい。上記で定義又は例示した通りの環式の炭化水素基は、可能であれば、不飽和、部分飽和又は飽和のいずれでもよい。上記で定義又は例示した通りの環式の炭化水素基は炭素環基とも言う。炭素環は、上記で定義又は例示した通りの環式の炭化水素基に相当する環である。炭素環（炭化水素環）の例は、シクロプロパン、シクロブタン、シクロペンタン、シクロペンテン、シクロヘキサン、シクロヘキセン、シクロヘプタン、シクロヘプテン、シクロオクタン、シクロオクテン、アダマンタン等を含むが、これらに限定されない。A cyclic hydrocarbon group means a cyclic group in which all atoms constituting the ring are carbon atoms. In one embodiment, examples of cyclic hydrocarbon groups include, but are not limited to, aromatic or non-aromatic monocyclic, bicyclic or tricyclic 3- to 14-membered (preferably 5- to 14-membered, more preferably 5- to 10-membered) cyclic hydrocarbon groups. Examples of cyclic hydrocarbon groups include, but are not limited to, cycloalkyl, aryl, and the like. Examples of cycloalkyl include the above-mentioned examples of (C3-C8)cycloalkyl. Aryl is an aromatic cyclic group among the cyclic hydrocarbon groups defined above. Examples of aryl include the above-mentioned examples of (C6-C12)aryl. The cyclic hydrocarbon groups as defined or exemplified above may include non-fused cyclic (e.g., monocyclic or spirocyclic) and fused cyclic groups, if possible. The cyclic hydrocarbon groups as defined or exemplified above may be unsaturated, partially saturated or saturated, if possible. The cyclic hydrocarbon groups as defined or exemplified above are also called carbocyclic groups. A carbocycle is a ring that corresponds to a cyclic hydrocarbon group as defined or exemplified above. Examples of carbocycles (hydrocarbon rings) include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, adamantane, etc.
本明細書中、用語「１以上の置換基により置換されていても良い」における「置換基」については、それらが化学的に許容され、本発明の効果を示す限りは、特に制限はない。In this specification, there are no particular limitations on the "substituents" in the term "optionally substituted with one or more substituents" as long as they are chemically permissible and exhibit the effects of the present invention.
本明細書中、「１以上の置換基により置換されていても良い」との用語における「１以上の置換基」の例は、次の置換基群（ａ）から独立して選択される１以上の置換基（好ましくは１～３個の置換基）を含むが、これらに限定されない。In this specification, examples of "one or more substituents" in the phrase "optionally substituted with one or more substituents" include, but are not limited to, one or more substituents (preferably 1 to 3 substituents) independently selected from the following group of substituents (a):
置換基群（ａ）は、ハロゲン原子、ニトロ、シアノ、ヒドロキシ、アミノ、（Ｃ１－Ｃ６）アルキル、（Ｃ１－Ｃ６）ハロアルキル、（Ｃ３－Ｃ８）シクロアルキル、（Ｃ２－Ｃ６）アルケニル、（Ｃ２－Ｃ６）アルキニル、（Ｃ１－Ｃ６）アルコキシ、カルバモイル、（Ｃ１－Ｃ６）ハロアルキル、（Ｃ１－Ｃ６）アルキルカルボニル、（Ｃ１－Ｃ６）アルコキシカルボニル、（Ｃ１－Ｃ６）アルキルアミノカルボニル、フェニル、フェノキシ、ベンゾイル、ヘテロシクリル、及び炭化水素環基からなる群である。The substituent group (a) is a group consisting of halogen atoms, nitro, cyano, hydroxy, amino, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C8) cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, carbamoyl, (C1-C6) haloalkyl, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkylaminocarbonyl, phenyl, phenoxy, benzoyl, heterocyclyl, and a hydrocarbon ring group.
加えて、置換基群（ａ）から独立して選択される１以上の置換基（好ましくは１～３個の置換基）は、それぞれ独立して、置換基群（ｂ）から独立して選択される１以上の置換基（好ましくは１～３個の置換基）により置換されていても良い。ここで、置換基群（ｂ）は置換基群（ａ）と同じである。In addition, one or more substituents (preferably 1 to 3 substituents) independently selected from the group of substituents (a) may each be independently substituted with one or more substituents (preferably 1 to 3 substituents) independently selected from the group of substituents (b). Here, the group of substituents (b) is the same as the group of substituents (a).
「１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル」の例は、（Ｃ１－Ｃ１２）ハロアルキル、（Ｃ１－Ｃ１２）ヒドロキシアルキル、１～９個のフッ素原子により置換されていても良い（Ｃ１－Ｃ４）アルキルを含むが、これらに限定されない。
その他、ここに定義のない基については、通常の定義に従う。Examples of "(C1-C12) alkyl optionally substituted by one or more substituents" include, but are not limited to, (C1-C12) haloalkyl, (C1-C12) hydroxyalkyl, and (C1-C4) alkyl optionally substituted by 1 to 9 fluorine atoms.
Other groups not defined herein are defined as per usual.
本明細書中、置換基（例えば、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｘ、Ｚ等）に言及するときの用語「本明細書中に記載の通り」及び類似の用語は、本明細書中の置換基の全ての定義並びにもしあれば全ての例、好ましい例、より好ましい例、更に好ましい例及び特に好ましい例等を参照することにより取り込む。As used herein, the term "as described herein" and similar terms when referring to substituents (e.g.,R1 ,R2 ,R3 ,R4 ,R5 , X, Z, etc.) incorporates by reference all definitions of the substituents herein and all examples, preferred examples, more preferred examples, further preferred examples and particularly preferred examples, if any.
本明細書中、非限定的な用語「含む（comprise(s)/comprising）」は、限定的な語句「からなる（consist(s) of/consisting of）」にそれぞれ任意に置き換えることができる。In this specification, the open-ended terms "comprise(s)" and "comprising" may be optionally replaced with the restrictive phrase "consist(s) of" and "consisting of", respectively.
そうでないと明示しない限り、本明細書において用いられる全ての技術的および科学的用語は、本開示が属する当業者に通常理解されるものと同じ意味を有する。Unless otherwise expressly stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
別段に示されない限り、本明細書で使用される量、大きさ、濃度、反応条件などの特徴を表す数字は、用語「約」によって修飾されると理解される。いくつかの態様では、開示された数値は、報告された有効数字の桁数と、通常の丸め手法を適用して解釈される。いくつかの態様では、開示された数値は、それぞれの試験測定方法に見られる標準偏差から必然的に生じる誤差を含むと解釈される。Unless otherwise indicated, numbers expressing quantities, sizes, concentrations, reaction conditions, and the like used herein are understood to be modified by the term "about." In some aspects, the disclosed numerical values are to be construed based on the number of reported significant digits and by applying ordinary rounding techniques. In some aspects, the disclosed numerical values are to be construed to include errors necessarily resulting from the standard deviation found in their respective testing measurement methods.
本発明の式（Ｉ）で示されるインドール誘導体及び／又は式（ＩＩ）～式（ＶＩＩ）で示されるテトラヒドロカルバゾール誘導体である化合物、若しくはその塩又はそれらの溶媒和物としては、本発明の式（Ｉ）で示されるインドール誘導体及び／又は式（ＩＩ）～式（ＶＩＩ）で示されるテトラヒドロカルバゾール誘導体である化合物のみならず、その塩（好ましくは、薬学的に許容されるその塩）、それらの各種の水和物や溶媒和物、及び結晶多形を有する物質、及びこれらの物質のプロドラッグとなる物質を包含している。また、不斉炭素原子を有する場合には、ラセミ体のみならず、光学活性体が包含される。The compounds of the present invention which are indole derivatives represented by formula (I) and/or tetrahydrocarbazole derivatives represented by formulas (II) to (VII), or their salts or solvates, include not only the compounds of the present invention which are indole derivatives represented by formula (I) and/or tetrahydrocarbazole derivatives represented by formulas (II) to (VII), but also their salts (preferably pharma-ceutically acceptable salts), various hydrates and solvates thereof, and substances having crystalline polymorphism, and substances which are prodrugs of these substances. In addition, in the case of compounds having an asymmetric carbon atom, not only racemic bodies but also optically active bodies are included.
本発明の式（Ｉ）で示されるインドール誘導体及び／又は式（ＩＩ）～式（ＶＩＩ）で示されるテトラヒドロカルバゾール誘導体である化合物として許容される塩としては、具体的には、化合物を塩基性化合物として扱う場合は、無機酸（例えば、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等）や有機酸（例えば、メタンスルホン酸、エタンスルホン酸、ｐ－トルエンスルホン酸等）との酸付加塩等が挙げられる。一方、化合物を酸性化合物として扱う場合には、無機塩（例えば、ナトリウム塩、カリウム塩、リチウム塩、バリウム塩、カルシウム塩、マグネシウム塩等）等が挙げられる。Specific examples of acceptable salts of the indole derivative represented by formula (I) and/or the tetrahydrocarbazole derivative represented by formula (II) to formula (VII) of the present invention include acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g., methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.) when the compound is treated as a basic compound. On the other hand, examples of acceptable salts of the compound include inorganic salts (e.g., sodium salts, potassium salts, lithium salts, barium salts, calcium salts, magnesium salts, etc.) when the compound is treated as an acidic compound.
本発明の本発明の式（Ｉ）で示されるインドール誘導体及び／又は式（ＩＩ）～式（ＶＩＩ）で示されるテトラヒドロカルバゾール誘導体である化合物やその塩の溶媒和物としては、水和物や各種の溶媒和物（例えば、エタノールなどのアルコールとの溶媒和物）が挙げられる。Solvates of the compounds of the present invention, which are the indole derivatives represented by formula (I) and/or the tetrahydrocarbazole derivatives represented by formulas (II) to (VII) and their salts, include hydrates and various solvates (for example, solvates with alcohols such as ethanol).
一般式（Ｉ）及び（ＩＶ）中、ＸにおけるＳ（＝Ｏ）２又はＣ（＝Ｏ）として、好ましくはＳ（＝Ｏ）２である。In the general formulae (I) and (IV), S(=O)2 or C(=O) in X is preferably S(=O)2 .
一般式（Ｉ）中、Ｒ１における、水素原子又は－ＣＯＯＲ９若しくは－ＣＯＮＨＲ１０で表される基として、好ましくは－ＣＯＯＲ９若しくは－ＣＯＮＨＲ１０であり、より好ましくは－ＣＯＯＲ９である。In the general formula (I), the hydrogen atom or the group represented by-COOR9 or-CONHR10 inR1 is preferably-COOR9 or-CONHR10 , and more preferably-COOR9 .
前記Ｒ９及びＲ１０は、互いに独立して、水素原子又は１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルであり、ここでＲ９の好ましい例は水素原子、エチル又はエチルであり、Ｒ１０の好ましい例はエチル又はメチルである。R9 and R10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents, and preferred examples of R9 are a hydrogen atom, ethyl, or ethyl, and preferred examples of R10 are ethyl or methyl.
一般式（Ｉ）中、Ｒ２における、水素原子又は１以上の置換基により置換されていても良いフェノキシ基として、好ましくは水素原子である。また、１以上の置換基により置換されていても良いフェノキシ基の好ましい例は、フェノキシ基である。In the general formula (I), the hydrogen atom or the phenoxy group which may be substituted with one or more substituents inR2 is preferably a hydrogen atom. A preferred example of the phenoxy group which may be substituted with one or more substituents is a phenoxy group.
一般式（Ｉ）中、Ｒ３における、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル又は１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリールとして、好ましくは水素原子又は１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキルであり、より好ましくは水素原子である。また、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキルの好ましい例は、置換基を有しない（Ｃ１－Ｃ１２）直鎖又は分岐鎖アルキルである。１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキルの具体的な例は、２－エチルヘキシル、メチル、エチル、プロピル、２－メチルブチル、シクロヘキシルメチル、又はオキシラン－２イル－メチルであり、好ましい具体的な例は２－エチルヘキシルである。In the general formula (I), the hydrogen atom,the (C1-C12) alkyl which may be substituted by one or more substituents, the (C3-C8) cycloalkyl which may be substituted by one or more substituents, or the (C6-C10) aryl which may be substituted by one or more substituents in R 3 is preferably a hydrogen atom or a (C1-C12) alkyl which may be substituted by one or more substituents, more preferably a hydrogen atom. A preferred example of the (C1-C12) alkyl which may be substituted by one or more substituents is an unsubstituted (C1-C12) linear or branched alkyl. Specific examples of the (C1-C12) alkyl which may be substituted by one or more substituents are 2-ethylhexyl, methyl, ethyl, propyl, 2-methylbutyl, cyclohexylmethyl, or oxiran-2yl-methyl, and a preferred specific example is 2-ethylhexyl.
一般式（Ｉ）中、Ｒ４及びＲ５における、互いに独立して水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、カルボキシ、又は、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニルであり；ここでＲ４及びＲ５は互いに結合して隣接する炭素原子と共に炭化水素環を形成してもよいものとして、好ましくは１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、水素原子、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリール、又は１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキルが挙げられる。より好ましい例は、Ｒ４及びＲ５がそれぞれ１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキルであって、ここでＲ４及びＲ５は互いに結合して隣接する炭素原子と共に炭化水素環を形成するものである。Ｒ４及びＲ５は互いに結合して隣接する炭素原子と共に炭化水素環の好ましい例は、１以上の置換基により置換されていても良いシクロペンテン、１以上の置換基により置換されていても良いヘキセン、１以上の置換基により置換されていても良いシクロヘプテン又は１以上の置換基により置換されていても良いシクロオクテンであり、より好ましい例は１以上の置換基により置換されていても良いシクロヘキセンであり、さらに好ましい例は置換基を有しないシクロヘキセンである。
また、Ｒ４及びＲ５が互いに結合して隣接する炭素原子と共に炭化水素環を形成しない場合において、Ｒ４及びＲ５の好ましい例は、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、又は１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリールであり、より好ましくは水素原子、メチル、エチル、プロピル、ブチル、ペンチル、フェニル、又はハロ置換アリールであり、さらに好ましくは水素原子、メチル、エチル、プロピル、ペンチル、フェニル、又はフルオロフェニルである。In the general formula (I), R4 and R5 are each independently a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C6-C10) aryl which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a carboxy, or a (C1-C6) alkoxycarbonyl which may be substituted byone or more substituents;R 4 and R 5 may be bonded together to form a hydrocarbon ring with adjacent carbon atoms, and preferably include (C1-C12) alkyl which may be substituted with one or more substituents, hydrogen atom, (C6-C10) aryl which may be substituted with one or more substituents, or (C1-C6) haloalkyl which may be substituted with one or more substituents. More preferred examples are (C1 -C12) alkyl, each of which may be substituted with one or more substituents, where R4 and R5 are bonded together to form a hydrocarbon ring with adjacent carbon atoms. Preferred examples of the hydrocarbon ring formed byR4 and R5 bonded together to adjacent carbon atoms are cyclopentene which may be substituted with one or more substituents, hexene which may be substituted with one or more substituents, cycloheptene which may be substituted with one or more substituents, or cyclooctene which may be substituted with one or more substituents, more preferred examples are cyclohexene which may be substituted with one or more substituents, and even more preferred examples are cyclohexene that has no substituents.
In addition, whenR4 andR5 are bonded to each other and do not form a hydrocarbon ring together with the adjacent carbon atom, preferred examples ofR4 andR5 are a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents, more preferably a hydrogen atom, methyl, ethyl, propyl, butyl, pentyl, phenyl, or a halo-substituted aryl, and even more preferably a hydrogen atom, methyl, ethyl, propyl, pentyl, phenyl, or fluorophenyl.
一般式（Ｉ）及び（ＩＶ）中、Ｒ６～Ｒ８における、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子として、好ましくは水素原子である。In general formulas (I) and (IV), R6 to R8 each independently represent a hydrogen atom, a (C1-C12) alkyl which may be substituted with one or more substituents, a (C1-C6) alkoxy which may be substituted with one or more substituents, a hydroxyl or a halogen atom, and are preferably a hydrogen atom.
一般式（ＩＩ）中、Ｘ、Ｒ４、及びＲ６～Ｒ９は、それぞれ式（Ｉ）で定義されるとおりであり、それぞれにおいて好ましい例もまた、式（Ｉ）において好ましい例として挙げたとおりである。In general formula (II), X, R4 , and R6 to R9 are each as defined in formula (I), and preferred examples thereof are also the same as those given as preferred examples in formula (I).
一般式（ＩＩ）及び（ＩＶ）中、Ｒ１１（ｎ）として示される基（ここでｎは０～８の整数）とは、テトラヒドロカルバゾール環中のシクロヘキセン環部分に存在し得る０～８個の置換基を意味する。ここで最大８個の置換基の例は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基である。ここで、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子のうち好ましい例は、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、及び１以上の置換基により置換されていても良いカルバモイルである。これらのうちより好ましい例は、メチル、エチル、プロピル、ｔｅｒｔ－ブチル、シクロペンチル、Ｎ－メチルカルバモイル、及びヒドロキシメチルである。In general formulae (II) and (IV), the group represented by R11 (n) (wherein n is an integer of 0 to 8) means 0 to 8 substituents which may be present on the cyclohexene ring portion of the tetrahydrocarbazole ring. Here, examples of the maximum 8 substituents are, independently of one another, groups independently selected from the group consisting of (C1-C12) alkyl which may be substituted with one or more substituents, (C3-C8) cycloalkyl which may be substituted with one or more substituents, carbamoyl which may be substituted with one or more substituents, (C1-C6) alkoxy which may be substituted with one or more substituents, hydroxy, and a halogen atom. Here, preferred examples of the (C1-C12) alkyl which may be substituted by one or more substituents, the (C3-C8) cycloalkyl which may be substituted by one or more substituents, the carbamoyl which may be substituted by one or more substituents, the (C1-C6) alkoxy which may be substituted by one or more substituents, the hydroxyl and the halogen atom are the (C1-C12) alkyl which may be substituted by one or more substituents, the (C3-C8) cycloalkyl which may be substituted by the above substituents and the carbamoyl which may be substituted by one or more substituents. More preferred examples of these are methyl, ethyl, propyl, tert-butyl, cyclopentyl, N-methylcarbamoyl and hydroxymethyl.
一般式（ＩＩＩ）中、Ｘ、Ｒ４及びＲ９は、それぞれ式（Ｉ）及び式（ＩＩ）で定義されるとおりであり、それぞれにおいて好ましい例もまた、式（Ｉ）及び式（ＩＩ）において好ましい例として挙げたとおりである。また、一般式（ＩＩＩ）中、Ｒ１１（ｎ）として示される基（ここでｎは０～８の整数）は、式（ＩＩ）で定義されるとおりである。また、その好ましい例もまた、式（ＩＩ）において好ましい例として挙げたとおりである。In general formula (III), X,R4 andR9 are as defined in formula (I) and formula (II), respectively, and preferred examples thereof are also as given as preferred examples in formula (I) and formula (II). In general formula (III), the group represented byR11 (n) (where n is an integer of 0 to 8) is as defined in formula (II). Preferred examples thereof are also as given as preferred examples in formula (II).
一般式（ＩＶ）中、ＺにおけるＣ－Ｒ１２又はＮとして、好ましくはＣ－Ｒ１２である。In formula (IV), C—R12 or N in Z is preferably C—R12 .
一般式（ＩＶ）中、Ｒ１２～Ｒ１６における、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールオキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールカルボニル、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルアミノカルボニル、カルボキシ、カルバモイル、シアノ、ヒドロキシ、アミノ、又はニトロで表される基として、好ましくは、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、カルボキシ、又はニトロで表される基であり、より好ましくは水素原子、ハロゲン原子、メチル、エチル、メトキシ、ニトロ、カルボキシ、メトキシカルボニル、エトキシカルボニル、ピリジル、フェニル、モルホリニル、及びピペリジニルである。ここで、ハロゲン原子の好ましい例は、フッ素原子、臭素原子、塩素原子、及びヨウ素原子である。In general formula (IV), R12 to R16 each represent a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, a (C6-C12) aryloxy which may be substituted by one or more substituents, a (C6-C12) arylcarbonyl which may be substituted by one or more substituents, a heterocyclyl group which may be substituted by one or more substituents, a (5-12) heteroaryl which may be substituted by one or more substituents, a (C1-C6) alkylcarbo As the group represented by nyl, (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents, (C1-C6) alkylaminocarbonyl optionally substituted by one or more substituents, carboxy, carbamoyl, cyano, hydroxy, amino, or nitro, preferred are a hydrogen atom, a halogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C1-C6) alkoxy optionally substituted by one or more substituents, a (C6-C12) aryl optionally substituted by one or more substituents, a (5-12) heteroaryl optionally substituted by one or more substituents, a (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents, a carboxy, or nitro group, more preferred are a hydrogen atom, a halogen atom, methyl, ethyl, methoxy, nitro, carboxy, methoxycarbonyl, ethoxycarbonyl, pyridyl, phenyl, morpholinyl, and piperidinyl. Preferred examples of the halogen atom are a fluorine atom, a bromine atom, a chlorine atom, and an iodine atom.
一般式（Ｖ）中、Ｘ、Ｚ及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりであり、それぞれにおいて好ましい例もまた、式（ＩＶ）において好ましい例として挙げたとおりである。In formula (V), X, Z and R12 to R16 are each as defined in formula (IV), and preferred examples thereof are also the same as those given as preferred examples in formula (IV).
一般式（ＶＩ）中、Ｚ及びＲ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりであり、それぞれにおいて好ましい例もまた、式（ＩＶ）において好ましい例として挙げたとおりである。In general formula (VI), Z and R12 to R16 are each as defined in formula (IV), and preferred examples thereof are also the same as those given as preferred examples in formula (IV).
一般式（ＶＩＩ）中、Ｒ１２～Ｒ１６は、それぞれ式（ＩＶ）で定義されるとおりであり、それぞれにおいて好ましい例もまた、式（ＩＶ）において好ましい例として挙げたとおりである。In general formula (VII), R12 to R16 are each as defined in formula (IV), and preferred examples thereof are also the same as those given as preferred examples in formula (IV).
ＨＣＶ阻害活性の確認
本発明の化合物等による効果は、例えばＮＳ２とＳＰＣＳ１との相互作用に対する阻害活性を指標として、無細胞系のインビトロの実験により確認することができる（図１）。
別の例としては、後記実施例に示すように、ＨＣＶ感染細胞に含まれるＨＣＶゲノムコピー数の抑制効果として培養細胞系の実験により確認することができる。また、倫理的に適切なプロセスを経過することを前提として、ＨＣＶ感染個体（ヒト又はチンパンジーなどのモデル動物）に対する投与実験でも適宜確認できる。Confirmation of HCV Inhibitory Activity The effect of the compounds of the present invention can be confirmed by in vitro experiments in a cell-free system, for example, using as an indicator the inhibitory activity against the interaction between NS2 and SPCS1 (FIG. 1).
As another example, as shown in the Examples below, the suppressive effect on the number of HCV genome copies contained in HCV-infected cells can be confirmed by experiments using cultured cells. In addition, it can also be appropriately confirmed by administration experiments on HCV-infected individuals (humans or model animals such as chimpanzees) on the premise that an ethically appropriate process is followed.
ＨＣＶ阻害活性を確認するための具体的な手法の一例は、次のとおりである。
ＨｕＨ－７由来ＨＣＶ ＪＦＨ－１持続感染細胞（ＳＬ２ ｃｅｌｌｓ；発明者作製）を、ダルベッコ改変イーグル培地を含む２４穴プレートに播種（１ｘ１０５ｃｅｌｌｓ／ｍＬ）（Ｎ＝３）し、一晩培養する。その後、被験化合物を添加し、さらに３日間培養する。培養後、培養上清を回収し、ＨｕＨ７．５．１細胞（ヒト肝細胞癌由来細胞）を含む培地（３５０μＬ）に前記培養液を（１５０μＬ）添加し、３日間培養したのち、細胞を回収する。回収した細胞から全ＲＮＡを常法により調製し、ＨＣＶのＲＮＡコピー数を定量的ＲＴ－ＰＣＲ法により決定する。ここで、被験化合物は、０．６３、１．２５、２．５、５、１０又は２０μＭ添加する。被験化合物を、０．１、１．０、もしくは１０μＭ添加する場合、又は、被験化合物を、１．０、３．０、もしくは１０μＭ添加する場合もある。
ここで、定量的ＲＴ－ＰＣＲは、例えばキットであるＴａｑＭａｎ（登録商標） Ｆａｓｔ Ｖｉｒｕｓ １－Ｓｔｅｐ Ｍｕｌｔｉｐｌｅｘ Ｍａｓｔｅｒ Ｍｉｘ ｆｏｒ ｑＰＣＲ（Ｔｈｅｒｍｏ Ｆｉｓｈｅｒ社製）を使用することができる。
ＨＣＶゲノム検出用プライマーは、次のとおりである。
ＨＣＶ－Ｆ：５’－ＧＡＧＴＧＴＣＧＴＧＣＡＧＣＣＴＣＣＡ－３’ （配列番号１）
ＨＣＶ－Ｒ：５’－ＣＡＣＴＣＧＣＡＡＧＣＡＣＣＣＴＡＴＣＡ－３’ （配列番号２）ＴａｑＭａｎ（登録商標）プローブ（ＦＡＭ／ＺＥＮ／３ＩＡＢｋＦＱ 標識プローブ）は、以下の配列を含むＨＣＶ－Ｔを用いた。
ＨＣＶ－Ｔ：５’－５６ＦＡＭ／ＣＣＣＧＣＡＡＧＡ／ＺＥＮ／ＣＴＧＣＴＡＧＣＣＧＡＧＴＡＧＴＧＴＴＧＧ／３ＩＡＢｋＦＱ／－３’
ここで、ＨＣＶ－Ｔプローブ中、５’－ＣＴＧＣＴＡＧＣＣＧＡＧＴＡＧＴＧＴＴＧＧ－３’の塩基配列を配列番号３とする。An example of a specific method for confirming HCV inhibitory activity is as follows.
HuH-7-derived HCV JFH-1 persistently infected cells (SL2 cells; prepared by the inventor) are seeded (1x105 cells/mL) (N=3) in a 24-well plate containing Dulbecco's modified Eagle medium and cultured overnight. Then, a test compound is added and cultured for another 3 days. After culture, the culture supernatant is collected, and the culture solution (150 μL) is added to a medium (350 μL) containing HuH7.5.1 cells (human hepatocellular carcinoma-derived cells), and after culturing for 3 days, the cells are collected. Total RNA is prepared from the collected cells by a conventional method, and the RNA copy number of HCV is determined by quantitative RT-PCR. Here, the test compound is added at 0.63, 1.25, 2.5, 5, 10 or 20 μM. In some cases, the test compound is added at 0.1, 1.0, or 10 μM, or in other cases, the test compound is added at 1.0, 3.0, or 10 μM.
Here, quantitative RT-PCR can be performed using, for example, a kit such as TaqMan (registered trademark) Fast Virus 1-Step Multiplex Master Mix for qPCR (manufactured by Thermo Fisher).
The primers for detecting the HCV genome are as follows:
HCV-F: 5'-GAGTGTCGTGCAGCCTCCA-3' (SEQ ID NO: 1)
HCV-R: 5'-CACTCGCAAGCACCCTATCA-3' (SEQ ID NO: 2) The TaqMan® probe (FAM/ZEN/3IABkFQ labeled probe) used for HCV-T contained the following sequence:
HCV-T:5'-56FAM/CCCGCAAGA/ZEN/CTGCTAGCCGAGTAGTGTTGG/3IABkFQ/-3'
In this case, the base sequence of 5'-CTGCTAGCCGAGTAGTGTTGG-3' in the HCV-T probe is set as SEQ ID NO:3.
前記の手法により決定したＨＣＶのＲＮＡコピー数を用いて、化合物無処理ＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）を１とした時、１０μＭの被験化合物を処理したＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）の値を算出することにより、被験化合物のＨＣＶ阻害活性を評価する。
例えば、被験化合物Ｘについて算出した値が０．４１であれば、すなわち、「被験化合物Ｘを１０μＭ添加すると、ＨＣＶ産生は５９％阻害される」ということを意味する。
本発明の化合物は、有意なＨＣＶ阻害活性を有するものであり、前記の評価方法により算出した値として、０．８６以下、好ましくは０．７以下、より好ましくは０．６以下、さらに好ましくは０．５以下、さらに好ましくは０．４以下の値を示すものである。Using the HCV RNA copy number determined by the above-mentioned method, the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells treated with 10 μM of a test compound is calculated when the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells not treated with the compound is set to 1, thereby evaluating the HCV inhibitory activity of the test compound.
For example, if the calculated value for test compound X is 0.41, this means that "addition of 10 μM of test compound X inhibits HCV production by 59%."
The compounds of the present invention have significant HCV inhibitory activity, and exhibit a value calculated by the above-mentioned evaluation method of 0.86 or less, preferably 0.7 or less, more preferably 0.6 or less, even more preferably 0.5 or less, and even more preferably 0.4 or less.
被験化合物のＨＣＶ阻害活性を評価する別の方法は、ＥＣ５０の値を決定することにより行うことができる。たとえば、前記のように、被験化合物を０．６３、１．２５、２．５、５、１０又は２０μＭ添加する試験を並列して行い、それぞれにおいてＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）を決定する。そして、被験化合物の濃度と決定されたＨＣＶ量との関係をグラフ上にプロットし、化合物無処理ＨｕＨ７．５．１細胞から産生されるＨＣＶ量を５０％低下させる添加濃度を算出し、その濃度を被験化合物の、ＥＣ５０値（μＭ）とする（ここで、ＥＣ５０はＩＣ５０と言ってもよい。）。被験化合物を、０．１、１．０、もしくは１０μＭ添加する試験、又は、被験化合物を、１．０、３．０、もしくは１０μＭ添加する試験によっても、同様に、ＥＣ５０値（μＭ）を決定することができる。
本発明の化合物は、有意なＨＣＶ阻害活性を有するものであり、前記の評価方法により算出したＥＣ５０値として、２０μＭ以下、好ましくは１５μＭ以下、より好ましくは１０μＭ以下、さらに好ましくは５μＭ以下、最も好ましくは２μＭ以下の値を示すものである。
なお、本実験系において、ウイルス産生細胞の培養後の細胞数、及び全ＲＮＡ量を測定することで、被験化合物に細胞傷害性が認められるか否かも併せて評価することができる。Another method for evaluating the HCV inhibitory activity of a test compound can be performed by determining the EC50 value. For example, as described above, tests are performed in parallel in which the test compound is added at 0.63, 1.25, 2.5, 5, 10 or 20 μM, and the amount of HCV (the number of HCV RNA copies) produced by HuH7.5.1 cells is determined in each case. The relationship between the concentration of the test compound and the determined amount of HCV is then plotted on a graph, and the concentration of the test compound that reduces the amount of HCV produced by untreated HuH7.5.1 cells by 50% is calculated, and this concentration is taken as the EC50 value (μM) of the test compound (here, EC50 may also be referred to as IC50 ). The EC50 value (μM) can also be determined by tests in which the test compound is added at 0.1, 1.0 or 10 μM, or tests in which the test compound is added at 1.0, 3.0 or 10 μM.
The compounds of the present invention have significant HCV inhibitory activity, and exhibit anEC50 value calculated by the above-mentioned evaluation method of 20 μM or less, preferably 15 μM or less, more preferably 10 μM or less, even more preferably 5 μM or less, and most preferably 2 μM or less.
In this experimental system, by measuring the cell number and the amount of total RNA after culturing the virus-producing cells, it is also possible to evaluate whether or not the test compound has cytotoxicity.
式（Ｉ）～式（ＶＩＩ）に示される化合物について説明する。本発明の一般式（Ｉ）で表されインドール誘導体、一般式（ＩＩ）～（ＶＩＩ）で表されるテトラヒドロカルバゾール誘導体は、いずれも当業者にとって公知の方法と周知技術により製造することができる。例えば、以下に示す方法、あるいはこれに準じた方法により製造することができる。また、合成された化合物は、ＮＭＲ等、周知の手段により確認することができる。The compounds represented by formulas (I) to (VII) will now be described. The indole derivatives represented by general formula (I) and the tetrahydrocarbazole derivatives represented by general formulas (II) to (VII) of the present invention can all be produced by methods and techniques known to those skilled in the art. For example, they can be produced by the method shown below or a method similar thereto. The synthesized compounds can also be confirmed by known means such as NMR.
一般的な方法
空気または湿気に敏感な試薬を用いる反応はすべて、特に断りのない限り、市販の溶媒と試薬を用い、窒素雰囲気下の乾燥ガラス器具で行った。薄層クロマトグラフィー（ＴＬＣ）は、Ｍｅｒｃｋ ６０Ｆ２５４プレコートシリカゲルプレート上で行い、常法によって可視化した。フラッシュカラムクロマトグラフィーは、シリカゲル６０Ｎ（関東化学株式会社）を用いて行った。General Methods All reactions involving air- or moisture-sensitive reagents were carried out in dry glassware under a nitrogen atmosphere using commercially available solvents and reagents unless otherwise noted. Thin-layer chromatography (TLC) was performed on Merck 60F254 precoated silica gel plates and visualized by routine methods. Flash column chromatography was performed using Silica Gel 60N (Kanto Chemical Co., Ltd.).
特性データ
１Ｈ ＮＭＲ （４００ ＭＨｚ）および１３Ｃ ＮＭＲ （１００ ＭＨｚ）スペクトルはＢｒｕｋｅｒ Ｂｉｏｓｐｉｎ ＡＶＡＮＣＥ ＩＩＩ ＨＤを用いて記録した。
ケミカルシフトは、内部標準としてＭｅ４Ｓｉ（ＣＤＣｌ３中）に対するδ（ｐｐｍ）で報告される。赤外（ＩＲ）スペクトルはＪＡＳＣＯ ＦＴ／ＩＲ ６３００で記録され、波数（ｃｍ－１）で報告される。低分解能（ＬＲＭＳ）および高分解能（ＨＲＭＳ）の質量スペクトルは、Ｂｒｕｋｅｒ Ｄａｌｔｏｎｉｃｓ ｃｏｍｐａｃｔ （ＥＳＩ－ＭＳ）分光計を用い、ポジティブおよびネガティブ検出モードで記録した。Characteristic Data1 H NMR (400 MHz) and13 C NMR (100 MHz) spectra were recorded on a Bruker Biospin AVANCE III HD.
Chemical shifts are reported in δ (ppm) relative to Me4 Si (in CDCl3 ) as internal standard. Infrared (IR) spectra were recorded on a JASCO FT/IR 6300 and are reported in wavenumbers (cm−1 ). Low resolution (LRMS) and high resolution (HRMS) mass spectra were recorded on a Bruker Daltonics compact (ESI-MS) spectrometer in positive and negative detection mode.
式（Ｉ）に示される化合物について説明する。
式（Ｉ）に示される化合物は、概略、以下のような工程を通じて製造することができる。The compound represented by formula (I) will now be described.
The compound represented by formula (I) can be produced through the following steps.
化合物J6-032
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物J6-032である。Compound J6-032
One example of a compound of the present invention that has Hepatitis C virus inhibitory activity is compound J6-032, which has the structure shown below.
化合物J6-032は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound J6-032 can be synthesized using known materials and conventional methods according to the route shown below.
化合物J4-026
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物J4-026である。Compound J4-026
One example of a compound of the present invention that has Hepatitis C virus inhibitory activity is compound J4-026, which has the structure shown below.
化合物J4-026は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound J4-026 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K7-025
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K7-025である。Compound K7-025
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K7-025, which has the structure shown below.
化合物K7-025は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K7-025 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K6-001
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K6-001である。Compound K6-001
One example of a compound of the present invention having hepatitis C virus inhibitory activity is compound K6-001, which has the structure shown below.
化合物K6-001は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K6-001 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K7-034
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K7-034である。Compound K7-034
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K7-034, which has the structure shown below.
化合物K7-034は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K7-034 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K9-030
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K9-030である。Compound K9-030
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K9-030, which has the structure shown below.
化合物K9-030は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K9-030 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K9-030は、上記の経路とは別に、以下のエステル体化合物をアミド化することによっても合成することができる。In addition to the above route, compound K9-030 can also be synthesized by amidating the following ester compound.
化合物K24-023
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K24-023である。Compound K24-023
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K24-023, which has the structure shown below.
化合物K24-023は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K24-023 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K25-012
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K25-012である。Compound K25-012
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K25-012, which has the structure shown below.
化合物K25-012は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K25-012 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K25-013
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K25-013である。Compound K25-013
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K25-013, which has the structure shown below.
化合物K25-013は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K25-013 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K25-018
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K25-018である。Compound K25-018
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K25-018, which has the structure shown below.
化合物K25-018は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K25-018 can be synthesized using known materials and conventional methods according to the route shown below.
次に、式（ＩＶ）に示される化合物について説明する。
式（ＩＶ）に示される化合物は、概略、以下のような工程を通じて製造することができる。また、製造にあたり、上記の化合物K7-025等について示された工程を参照することもできる。Next, the compound represented by formula (IV) will be described.
The compound represented by formula (IV) can be produced through the following steps: In addition, the steps shown for the compound K7-025 and the like can be referred to for the production.
化合物K28-039
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K28-039である。Compound K28-039
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K28-039, which has the structure shown below.
化合物K28-039は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K28-039 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K29-013
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K29-013である。Compound K29-013
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-013, which has the structure shown below.
化合物K29-013は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K29-013 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K29-026
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K29-026である。Compound K29-026
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-026, which has the structure shown below.
化合物K29-026は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K29-026 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K29-027
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K29-027である。Compound K29-027
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-027, which has the structure shown below.
化合物K29-027は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K29-027 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K29-030
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K29-030である。Compound K29-030
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-030, which has the structure shown below.
化合物K29-030は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K29-030 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K29-035
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K29-035である。Compound K29-035
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-035, which has the structure shown below.
化合物K29-035は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K29-035 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K29-036
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K29-036である。Compound K29-036
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K29-036, which has the structure shown below.
化合物K29-036は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K29-036 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K30-031
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K30-031である。Compound K30-031
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K30-031, which has the structure shown below.
化合物K30-031は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K30-031 can be synthesized using known materials and conventional methods according to the route shown below.
化合物K24-037
Ｃ型肝炎ウイルス阻害活性を有する本発明の化合物の一つの例は、以下に示す構造を有する化合物K24-037である。Compound K24-037
One example of a compound of the present invention having Hepatitis C virus inhibitory activity is compound K24-037, which has the structure shown below.
化合物K24-037は、以下に示す経路に従い、公知の材料及び常法に従い、合成することができる。Compound K24-037 can be synthesized using known materials and conventional methods according to the route shown below.
本発明の式（Ｉ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体である化合物、若しくはその塩又はそれらの溶媒和物を有効成分として含有してなる、Ｃ型肝炎ウイルス阻害剤（Ｃ型肝炎の予防及び／又は治療剤）の調製
有効成分であるの本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩ）で示される化合物は、式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体それ自体はもちろんのこと、その塩若しくは溶媒和物の形態の化合物を用いることもできる。塩及び溶媒和物形態の化合物は常法により製造することができる。本明細書において単に、式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示される化合物と記載される場合であっても、式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示される化合物の塩や溶媒和物の化合物形態を使用する場合の発明が同等に含まれるものと解される。Preparation of a hepatitis C virus inhibitor (a preventive and/or therapeutic agent for hepatitis C) containing, as an active ingredient, a compound which is an indole derivative and/or a tetrahydrocarbazole derivative represented by formula (I) to (VII) of the present invention, or a salt or solvate thereof. The compound represented by formula (I) or formula (II) to (VI) of the present invention which is an active ingredient may be, of course, an indole derivative and/or a tetrahydrocarbazole derivative represented by formula (I) or formula (II) to (VII) itself, or a compound in the form of a salt or solvate thereof. Compounds in the form of salts and solvates can be produced by conventional methods. Even when a compound represented by formula (I) or formula (II) to (VII) is simply described in this specification, it is understood that the invention in which a compound represented by formula (I) or formula (II) to (VII) in the form of a salt or solvate is used is equivalently included.
前記の塩としては、薬学的に許容できるものであれば特に制限はないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アンモニウム塩、トリアルキルアミン塩等の有機塩基塩；塩酸塩、硫酸塩等の鉱酸塩；酢酸塩等の有機酸塩等が挙げられる。
前記の溶媒和物としては、水和物、アルコール和物（例えば、エタノール和物）等が挙げられる。The salt is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; organic base salts such as ammonium salts and trialkylamine salts; mineral acid salts such as hydrochlorides and sulfates; and organic acid salts such as acetates.
Examples of the solvate include hydrates, alcohol solvates (eg, ethanol solvates), and the like.
本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体を有効成分として含有してなる、Ｃ型肝炎の予防及び／又は治療剤（Ｃ型肝炎ウイルス阻害剤）の投与経路は特に限定されず、経口投与剤であっても、非経口投与剤であってもよい。
たとえば、錠剤、カプセル剤、顆粒剤、粉末剤、シロップ等の経口投与剤の剤型とすることができる。また、注射剤、点眼剤、点鼻剤、軟膏、クリーム、ローション、ゲル剤、スプレー剤などの非経口投与剤の剤型とすることもできる。これらの製剤は、公知の方法で製造することができる。例えば、経口投与用製剤とする場合には、トラガントガム、アラビアガム、ショ糖脂肪酸エステル、レシチン、オリーブ油、大豆油、ＰＥＧ４００等の溶解剤；澱粉、マンニトール、乳糖等の賦形剤；メチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース等の結合剤；結晶セルロース、カルボキシメチルセルロースカルシウム等の崩壊剤；タルク、ステアリン酸マグネシウム等の滑沢剤、軽質無水ケイ酸等の流動性向上剤等を適宜組み合わせて処方することにより製造することができる。また、注射用の製剤とする場合は、例えば、無菌的に保存した本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体の乾燥物又は保存溶液を、静脈注射用の生理食塩水又は緩衝液によって溶解又は希釈して調製することができる。本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体の溶解度を高めたい場合は、溶媒を変更したり、本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体を超微細粒子化したり、シクロデキストリン類に包接させるなど、公知の手法が適宜利用可能である。本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体とともにｐＨ調節剤、緩衝剤、安定化剤、等張化剤、局所麻酔剤等を添加し、常法を利用して、皮下、筋肉及び静脈内注射剤を製造することができる。
ｐＨ調製剤及び緩衝剤としては、クエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウム等が挙げられる。安定化剤としては、ピロ亜硫酸ナトリウム、ＥＤＴＡ（エデト酸ナトリウム）、チオグリコール酸、チオ乳酸等が挙げられる。局所麻酔剤としては、塩酸プロカイン、塩酸リドカイン等が挙げられる。等張化剤としては、塩化ナトリウム、ブドウ糖等が挙げられる。The route of administration of the preventive and/or therapeutic agent for hepatitis C (hepatitis C virus inhibitor) containing the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulae (II) to (VII) of the present invention as an active ingredient is not particularly limited, and the agent may be an oral or parenteral agent.
For example, the formulation may be in the form of an oral preparation such as a tablet, capsule, granule, powder, or syrup. The formulation may also be in the form of a parenteral preparation such as an injection, eye drops, nasal drops, ointment, cream, lotion, gel, or spray. These preparations may be produced by known methods. For example, when the formulation is for oral administration, it may be produced by appropriately combining and formulating solubilizers such as gum tragacanth, gum arabic, sucrose fatty acid ester, lecithin, olive oil, soybean oil, and PEG400; excipients such as starch, mannitol, and lactose; binders such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose; disintegrants such as crystalline cellulose and calcium carboxymethylcellulose; lubricants such as talc and magnesium stearate; and flow improvers such as light anhydrous silicic acid. In addition, when preparing a preparation for injection, for example, a dried product or a stock solution of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention, which has been stored in a sterile manner, can be dissolved or diluted with physiological saline or a buffer solution for intravenous injection to prepare the preparation. When it is desired to increase the solubility of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention, known methods can be appropriately used, such as changing the solvent, forming the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention into ultrafine particles, or including the derivative in cyclodextrins. Subcutaneous, intramuscular and intravenous injections can be prepared by adding a pH regulator, a buffer, a stabilizer, an isotonicity agent, a local anesthetic, etc. together with the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention, using a conventional method.
Examples of pH adjusters and buffers include sodium citrate, sodium acetate, sodium phosphate, etc. Examples of stabilizers include sodium pyrosulfite, EDTA (sodium edetate), thioglycolic acid, thiolactic acid, etc. Examples of local anesthetics include procaine hydrochloride, lidocaine hydrochloride, etc. Examples of isotonicity agents include sodium chloride, glucose, etc.
本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体を有効成分として含有してなる、Ｃ型肝炎の予防及び／又は治療剤（Ｃ型肝炎ウイルス阻害剤）の投与形態
本発明のＣ型肝炎の予防及び／又は治療剤の有効成分となる本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体の有効投与量は、患者の状態、症状など諸事情により適宜変更される。経口投与する場合における本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体の１日分の投与量は、これを１日１回投与するか、又は数回に分けて投与することができる。逆に数日分の用量を１回に投与することにより２日以上毎に１度の投与ペースとすることもできる。注射剤として全身投与する場合における本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体の投与量も、１日１回投与するか、又は１日分を数回に分けて投与することができる。逆に数日分の用量を１回に注射することにより２日以上毎の投与ペースとすることもできる。また、点滴等により継続的に投与することでも良い。軟膏、ローション、クリーム、ゲル剤、スプレー剤などの非経口投与剤を局所投与をする場合も、外用薬としての医薬組成物中の本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体の配合量、局所投与の頻度、及び塗布範囲などは適宜調整できる。いずれの場合も、投与は必ずしも継続的又は定期的に行う必要はなく、症状の変化などに応じて適宜間隔を空けて行うことが可能である。仮に単回の投与で治癒又は寛解すれば、複数回投与を行う必要はない。症状が再発乃至増悪した場合に投与を再開することでも良い。
本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体を有効成分として含有してなる、Ｃ型肝炎の予防及び／又は治療剤の投与方法としては、特に限定されるものではない。
投与期間は、患者の病状に応じて適宜調整できる。投与期間中の投与用量は適宜調整できるが、継続的に一定量を投与するか、又は投与当初のみ比較的高用量で投与した後により少ない維持量の一定投与に移行する投与形態とすることが例示される。Administration form of the preventive and/or therapeutic agent for hepatitis C (hepatitis C virus inhibitor) containing the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention as an active ingredient The effective dosage of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention, which is the active ingredient of the preventive and/or therapeutic agent for hepatitis C of the present invention, is appropriately changed depending on various circumstances such as the condition and symptoms of the patient. When orally administered, the daily dosage of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention can be administered once a day or in several divided doses. Conversely, it is also possible to administer the dosage for several days at once, so that the administration pace is once every two or more days. The dosage of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention in the case of systemic administration as an injection can be administered once a day, or in several divided doses. Conversely, the dosage can be administered every two or more days by injecting several days' worth of the dose at once. It may also be administered continuously by drip infusion or the like. In the case of local administration of a parenteral agent such as an ointment, lotion, cream, gel, or spray, the amount of the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulas (II) to (VII) of the present invention in the pharmaceutical composition as an external medicine, the frequency of local administration, and the application range can be appropriately adjusted. In either case, administration does not necessarily have to be performed continuously or periodically, and can be performed at appropriate intervals depending on changes in symptoms. If a single administration results in cure or remission, there is no need to administer multiple times. Administration may be resumed when symptoms recur or worsen.
The method of administration of the preventive and/or therapeutic agent for hepatitis C containing the indole derivative and/or tetrahydrocarbazole derivative represented by formula (I) or formulae (II) to (VII) of the present invention as an active ingredient is not particularly limited.
The administration period can be adjusted as appropriate depending on the patient's condition. The dosage during the administration period can be adjusted as appropriate, but examples of the dosage form include continuous administration of a fixed amount, or administration of a relatively high dose only at the beginning of administration, followed by administration of a lower maintenance dose.
本発明の式（Ｉ）、又は式（ＩＩ）～（ＶＩＩ）で示されるインドール誘導体及び／又はテトラヒドロカルバゾール誘導体は、Ｃ型肝炎の予防及び／又は治療を目的として、他の医薬と組み合わせて使用することもできる。組合せ相手の一例は、インターフェロンである。組合せ相手の別の一例は、リバビリンである。組合せ相手のまた別の一例は、ＤＡＡである。これらの医薬を組み合わせて使用する場合、組み合わせる医薬の数は２以上の任意の数である。投与量、投与態様はそれぞれの医薬を単独で使用する場合の投与量、投与態様が適用できるが、組み合わせ使用を考慮して適宜変更することもできる。組合せ医薬は、同時投与でも異時投与でも良い。同時投与であって、組み合わせ投与される複数の医薬のいずれもが経口投与剤として調製されるものである場合、組み合わせ投与用の合剤を調製して使用しても良く、別々に調製された剤を使用しても良い。同時投与であって、組み合わせ投与される複数の医薬のいずれもが注射剤又は点滴として投与される場合、複数の医薬が投与前に予め混合された注射剤又は点滴用液剤を調製し、使用しても良い。複数の医薬を組み合わせて投与するために、Ｃ型肝炎の予防及び／又は治療を用途とする複数の医薬を含むキットを調製することもできる。キットは、当該用途のための取扱説明書又は添付文書をさらに含むものとしても良い。The indole derivatives and/or tetrahydrocarbazole derivatives represented by formula (I) or formulas (II) to (VII) of the present invention can be used in combination with other medicines for the prevention and/or treatment of hepatitis C. An example of the combination partner is interferon. Another example of the combination partner is ribavirin. Yet another example of the combination partner is DAA. When these medicines are used in combination, the number of medicines to be combined is any number of two or more. The dosage and administration mode can be the same as those when each medicine is used alone, but can also be changed appropriately in consideration of the combined use. The combined medicines may be administered simultaneously or at different times. When the multiple medicines to be administered in combination are administered simultaneously and all of them are prepared as oral preparations, a combined drug for combined administration may be prepared and used, or drugs prepared separately may be used. When the multiple medicines to be administered in combination are administered simultaneously and all of them are administered as injections or infusions, an injection or infusion liquid in which the multiple medicines are mixed before administration may be prepared and used. In order to administer multiple medicines in combination, a kit containing multiple medicines intended for the prevention and/or treatment of hepatitis C can also be prepared. The kit may further include instructions or package inserts for such use.
以下、実施例により本発明を更に詳細に説明するが、本発明はこれら実施例によって何ら限定されない。The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples in any way.
＜ＮＳ２とＳＰＣＳ１との相互作用を阻害する化合物の探索＞
ＨＣＶ ＮＳ２は、図１に模式的に示されるとおり、３回膜貫通型のタンパク質であり、精製が容易でないことから試験管内の実験系の構築が難しく、阻害剤のハイスループットスクリーニングの障害となってきた。そこで本発明者らは、活性型の膜タンパク質の調製も可能にした無細胞タンパク質合成系を利用して、図２で模式的に示されるin vitroのＮＳ２－ＳＰＣＳ１ 結合アッセイ系を構築し、当該アッセイ系に化合物ライブラリーに含まれる被験化合物を適用することにより、ＨＣＶ阻害剤スクリーニングを実現した。
より具体的には、被験化合物の存在下でＮＳ２とＳＰＣＳ１との相互作用が阻害されると、６８０ ｎｍの励起光照射に対する５２０－６２０ ｎｍの発光が（被験化合物非存在下の対照と比して）減弱するため、発光の減弱を指標として前記相互作用に対して阻害活性を有する化合物の選抜を実施した。その結果、テトラヒドロカルバゾール誘導体である化合物Ａを含む、複数の化合物が選抜された。<Screening for compounds that inhibit the interaction between NS2 and SPCS1>
As shown in Fig. 1, HCV NS2 is a three-transmembrane protein, and since it is not easy to purify it, it is difficult to construct an experimental system in a test tube, which has been an obstacle to high-throughput screening of inhibitors. Therefore, the present inventors have used a cell-free protein synthesis system that also enables the preparation of active membrane proteins to construct an in vitro NS2-SPCS1 binding assay system, as shown in Fig. 2, and have realized screening of HCV inhibitors by applying test compounds contained in a compound library to the assay system.
More specifically, when the interaction between NS2 and SPCS1 is inhibited in the presence of a test compound, the luminescence at 520-620 nm in response to irradiation with 680 nm excitation light is attenuated (compared to a control in the absence of the test compound), and thus compounds having inhibitory activity against the interaction were selected using the attenuation of luminescence as an index. As a result, a number of compounds, including compound A, which is a tetrahydrocarbazole derivative, were selected.
＜ＮＳ２－ＳＰＣＳ１相互作用に対する阻害活性化合物の、Ｃ型肝炎ウイルス阻害活性の確認＞
インビトロの無細胞アッセイ系により選抜されたＮＳ２－ＳＰＣＳ１相互作用に対する阻害活性化合物が、実際にＣ型肝炎ウイルスのウイルス粒子産生に対して有意な阻害活性を有し、Ｃ型肝炎ウイルス阻害剤として使用し得るものか、以下の細胞培養系において試験を行った。
ＨｕＨ－７由来ＨＣＶ ＪＦＨ－１持続感染細胞（ＳＬ２ ｃｅｌｌｓ；発明者作製）を、ダルベッコ改変イーグル培地を含む２４穴プレートに播種（１ｘ１０５ｃｅｌｌｓ／ｍＬ）（Ｎ＝３）し、一晩培養した。その後、被験化合物を添加し、さらに３日間培養した。培養後、培養上清を回収し、ＨｕＨ７．５．１細胞（ヒト肝細胞癌由来細胞）を含む培地（３５０μＬ）に前記培養液を（１５０μＬ）添加し、３日間培養したのち、細胞を回収した。回収した細胞から全ＲＮＡを常法により調製し、ＨＣＶのＲＮＡコピー数を定量的ＲＴ－ＰＣＲ法により決定した。ここで、被験化合物は、１０μＭ添加した。
定量的ＲＴ－ＰＣＲは、ＴａｑＭａｎ（登録商標） Ｆａｓｔ Ｖｉｒｕｓ １－Ｓｔｅｐ Ｍｕｌｔｉｐｌｅｘ Ｍａｓｔｅｒ Ｍｉｘ ｆｏｒ ｑＰＣＲ（Ｔｈｅｒｍｏ Ｆｉｓｈｅｒ社製）を使用して実施した。使用したプライマー及びプローブは上述のとおりである。<Confirmation of Hepatitis C Virus Inhibitory Activity of Compounds Inhibiting NS2-SPCS1 Interaction>
The compounds with inhibitory activity against the NS2-SPCS1 interaction selected by the in vitro cell-free assay system were tested in the following cell culture system to determine whether they actually have significant inhibitory activity against the production of virus particles by Hepatitis C virus and can be used as Hepatitis C virus inhibitors.
HuH-7-derived HCV JFH-1 persistently infected cells (SL2 cells; prepared by the inventor) were seeded (1x105 cells/mL) (N=3) in a 24-well plate containing Dulbecco's modified Eagle medium and cultured overnight. Then, a test compound was added and cultured for another 3 days. After culture, the culture supernatant was collected, and the above culture solution (150 μL) was added to a medium (350 μL) containing HuH7.5.1 cells (human hepatocellular carcinoma-derived cells), and after culturing for 3 days, the cells were collected. Total RNA was prepared from the collected cells by a conventional method, and the RNA copy number of HCV was determined by quantitative RT-PCR. Here, the test compound was added at 10 μM.
Quantitative RT-PCR was performed using TaqMan (registered trademark) Fast Virus 1-Step Multiplex Master Mix for qPCR (Thermo Fisher). The primers and probes used were as described above.
前記の手法により決定したＨＣＶのＲＮＡコピー数を用いて、化合物無処理ＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）を１とした時、１０μＭの被験化合物を処理したＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）の値を算出することにより、被験化合物のＨＣＶ阻害活性を評価した（以下、前記手法により算出した値を、被験化合物の「阻害活性値」と言う。）。
その結果、前記テトラヒドロカルバゾール誘導体である化合物Ａの存在下でＨＣＶ量（ＨＣＶのＲＮＡコピー数）は５９％低下することが確認され、当該化合物Ａの阻害活性値は０．４１であった。さらに、被験化合物を０．６３、１．２５、２．５、５、１０又は２０μＭ添加する試験も行い、それぞれにおいてＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）を測定すると共に、化合物無処理ＨｕＨ７．５．１細胞から産生されるＨＣＶ量を５０％低下させる添加濃度、すなわちＥＣ５０値（μＭ）を算出したところ、化合物ＡのＥＣ５０値（μＭ）は８．８７であった。Using the HCV RNA copy number determined by the above-mentioned method, the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells treated with 10 μM of a test compound was calculated when the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells not treated with a compound was set to 1, and the HCV inhibitory activity of the test compound was evaluated (hereinafter, the value calculated by the above-mentioned method is referred to as the "inhibitory activity value" of the test compound).
As a result, it was confirmed that the amount of HCV (the number of HCV RNA copies) was reduced by 59% in the presence of the tetrahydrocarbazole derivative, Compound A, and the inhibitory activity value of Compound A was 0.41. Furthermore, a test was also carried out in which the test compound was added at 0.63, 1.25, 2.5, 5, 10, or 20 μM, and the amount of HCV (the number of HCV RNA copies) produced by HuH7.5.1 cells was measured in each case, and the concentration of the compound added that reduced the amount of HCV produced by untreated HuH7.5.1 cells by 50%, i.e., theEC50 value (μM), was calculated, and theEC50 value (μM) of Compound A was 8.87.
化合物Ａについて、１０μＭの存在下でＨＣＶのＲＮＡコピー数の明確な低下が認められ、１０μＭを下回るＥＣ５０値が確認された。その結果、ＮＳ２－ＳＰＣＳ１結合を阻害する化合物が実際にＨＣＶ粒子産生阻害活性を有することを初めて見出すことができた。
１０μＭを下回るＥＣ５０値を示す化合物であれば、細胞培養系のみならず、インビボにおいても有意なＣ型肝炎ウイルス阻害活性が発揮されるものと期待できる。１０μＭの存在下でＨＣＶのＲＮＡコピー数の明確な低下が認められる場合（例えば、阻害活性値が０．８６以下、好ましくは０．７以下、より好ましくは０．６以下、さらに好ましくは０．５以下、さらに好ましくは０．４以下の値）においても、同様の期待ができる。また、ＤＡＡなど既存の抗ＨＣＶ薬と比しても何ら遜色なく、新たな治療選択肢を与える実用性のある医薬となることが期待できる。
さらに、本実験系において、ウイルス産生細胞の培養後の細胞数、及び全ＲＮＡ量を測定することで、被験化合物に細胞傷害性が認められるか否かも併せて評価したところ、化合物Ａは試験した０．６３～２０μＭの濃度範囲内で有意な細胞数の減少や全ＲＮＡ量の低下をもたらすことはなく、当該化合物Ａには前記濃度範囲内で実質的な細胞傷害性が認められなかった。この結果、化合物Ａは安全性の面からも新たなＣ型肝炎ウイルス阻害剤となり得るものと言える。For compound A, a clear decrease in the number of HCV RNA copies was observed in the presence of 10 μM, and anEC50 value of less than 10 μM was confirmed. As a result, it was found for the first time that a compound that inhibits NS2-SPCS1 binding actually has an activity of inhibiting HCV particle production.
Compounds showing anEC50 value of less than 10 μM are expected to exhibit significant hepatitis C virus inhibitory activity not only in cell culture systems but also in vivo. The same can be expected when a clear decrease in the number of HCV RNA copies is observed in the presence of 10 μM (for example, an inhibitory activity value of 0.86 or less, preferably 0.7 or less, more preferably 0.6 or less, even more preferably 0.5 or less, and even more preferably 0.4 or less). In addition, the compounds are comparable in any way to existing anti-HCV drugs such as DAA, and are expected to be practical medicines that provide new treatment options.
Furthermore, in this experimental system, the number of cells after culturing the virus-producing cells and the amount of total RNA were measured to evaluate whether the test compound had cytotoxicity. Compound A did not cause a significant decrease in the number of cells or the amount of total RNA within the tested concentration range of 0.63 to 20 μM, and no substantial cytotoxicity was observed for Compound A within the above concentration range. As a result, it can be said that Compound A can be a new hepatitis C virus inhibitor from the viewpoint of safety as well.
これら結果を受けて、化合物Ａと構造上の類似性の高いテトラヒドロカルバゾール誘導体やインドール誘導体には、ＮＳ２－ＳＰＣＳ１結合を阻害し、Ｃ型肝炎ウイルス阻害剤の有効成分となり得る化合物が存在するものと期待された。そこで、本発明者らは、化合物Ａをリード化合物として、様々な構造上の変異を加えて多数の化合物を設計、合成すると共に、合成された化合物のＨＣＶ粒子産生阻害活性を上記の手法に沿って測定することにした。In light of these results, it was anticipated that tetrahydrocarbazole derivatives and indole derivatives that are highly structurally similar to compound A may be compounds that inhibit NS2-SPCS1 binding and may serve as active ingredients in hepatitis C virus inhibitors. Therefore, the inventors decided to use compound A as a lead compound and to design and synthesize a large number of compounds by adding various structural mutations, and to measure the HCV particle production inhibitory activity of the synthesized compounds using the above-mentioned method.
［実施例１］
化合物の製造
本実施例において、化合物の製造は、以下に具体的に示す手順の他、公知の技術的手段を適用することにより実施された。化合物の合成の確認のために適用したＮＭＲ、赤外（ＩＲ）スペクトル、低分解能（ＬＲＭＳ）および高分解能（ＨＲＭＳ）の質量スペクトルといった解析手法は、前記「特性データ」の項目に記載の条件が適用された。[Example 1]
In the present examples, the compounds were produced by applying the procedures specifically shown below as well as known technical means. The analytical methods such as NMR, infrared (IR) spectrum, low resolution (LRMS) and high resolution (HRMS) mass spectrum used to confirm the synthesis of the compounds were performed under the conditions described in the "Characteristic Data" section above.
［実施例１－１］
化合物J6-032の製造[Example 1-1]
Preparation of compound J6-032
化合物J6-032は、以下に示す経路及び手法に従い合成した。Compound J6-032 was synthesized according to the route and method shown below.
エチル ４－（（２，３，４，９－テトラヒドロ－１Ｈ－カルバゾール）－６－スルホンアミド）ベンゾエート （化合物１）：
フェニルヒドラジン塩酸塩（１５９０．６ｍｇ， １１．０ ｍｍｏｌ）の酢酸（４０ ｍＬ）溶液にシクロヘキサノン （化合物２）（１．０ ｍＬ， １０．０ ｍｍｏｌ）を加え、１５０℃で１時間撹拌した。析出物を濾過し、ＭｅＯＨ で再結晶し、１，２，３，４－テトラヒドロカルバゾールを褐色固体として得た（１０６４．９ ｍｇ， ６．２ ｍｍｏｌ， 収率６２％）。
１，２，３，４－テトラヒドロカルバゾール（１７１２．０ ｍｇ， １０．０ ｍｍｏｌ）を０℃で入れた丸底フラスコにＣｌＳＯ３Ｈ（２０．０ ｍＬ）を滴下し、室温で一晩撹拌した。ＴＬＣチェック後、混合物をアイスバスに滴下した。反応混合物をＣＨ２Ｃｌ２で抽出し、Ｎａ２ＳＯ４上で乾燥した。減圧下で濃縮して黄色のアモルファスを得、これを精製せずに次のステップで直ちに使用した。ＣＨ２Ｃｌ２（２８．４ ｍＬ）中のカルバゾール中間体（１９１１．９ｍｇ， ７．１ｍｍｏｌ）の溶液に、窒素下０℃でエチル－４－アミノ安息香酸（２３４５．３ｍｇ， １４．２ｍｍｏｌ）およびトリエチルアミン（３．０ｍＬ， ２１．３ ｍｍｏｌ）を加えた。ＴＬＣで確認しながら反応が完了するまで撹拌した後、反応混合物を１Ｎ－塩酸でクエンチし、酢酸エチルで抽出した。抽出液をブラインで洗浄し、Ｎａ２ＳＯ４上で乾燥した。減圧下での濃縮後、ｎ－ヘキサン－ＥｔＯＡｃ（＝３：２～１：１）を用いたシリカゲル上のフラッシュクロマトグラフィーにより、化合物１を白色固体として得た（１６３０．０ ｍｇ， １４．１ ｍｍｏｌ， ２段階で収率４１％）
上記反応経路において化合物１として図示される中間体化合物の合成は、ＮＭＲ及びＨＲＭＳにより確認した。Ethyl 4-((2,3,4,9-tetrahydro-1H-carbazole)-6-sulfonamido)benzoate (Compound 1):
Cyclohexanone (compound 2) (1.0 mL, 10.0 mmol) was added to a solution of phenylhydrazine hydrochloride (1590.6 mg, 11.0 mmol) in acetic acid (40 mL), and the mixture was stirred at 150° C. for 1 hour. The precipitate was filtered and recrystallized from MeOH to obtain 1,2,3,4-tetrahydrocarbazole as a brown solid (1064.9 mg, 6.2 mmol, yield 62%).
ClSO3 H (20.0 mL) was added dropwise to a round bottom flask containing 1,2,3,4-tetrahydrocarbazole (1712.0 mg, 10.0 mmol) at 0° C. and stirred at room temperature overnight. After checking with TLC, the mixture was added dropwise to an ice bath. The reaction mixture was extracted with CH2 Cl2 and dried over Na2 SO4. Concentration under reduced pressure gave a yellow amorphous solid, which was used immediately in the next step without purification. To a solution of the carbazole intermediate (1911.9 mg, 7.1 mmol) in CH2 Cl2 (28.4 mL) was added ethyl-4-aminobenzoate (2345.3 mg, 14.2 mmol) and triethylamine (3.0 mL, 21.3 mmol) at 0° C. under nitrogen. After stirring until the reaction was complete as confirmed by TLC, the reaction mixture was quenched with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried over Na2 SO4. After concentration under reduced pressure, flash chromatography on silica gel with n-hexane-EtOAc (=3:2 to 1:1) afforded compound 1 as a white solid (1630.0 mg, 14.1 mmol, 41% yield for two steps).
The synthesis of the intermediate compound depicted as compound 1 in the above reaction scheme was confirmed by NMR and HRMS.
化合物１：1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.61 (s, 1H), 7.90 (s, 1H), 7.75 - 7.81 (m, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.21 - 7.25 (m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 2.66 (dt, J = 23.2, 5.4 Hz, 4H), 1.80 (q, J = 8.4 Hz, 4H), 1.25 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.7, 143.5, 138.1, 137.9, 130.9, 129.0, 126.9, 124.5, 118.9, 118.1, 117.7, 111.5, 110.1, 60.8, 23.1, 23.0, 20.7, 14.6; HRMS (ESI), m/z calcd for C21H23N2O4S [M+H]+ 399.1373, found 399.1373.Compound 1:1 H NMR (400 MHz, DMSO-d6 ) δ 11.25 (s, 1H), 10.61 (s, 1H), 7.90 (s, 1H), 7.75 - 7.81 (m, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.21 - 7.25 (m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 2.66 (dt, J = 23.2, 5.4 Hz, 4H), 1.80 (q, J = 8.4 Hz, 4H), 1.25 (t, J = 7.1 Hz, 3H);13C {1H } NMR (100 MHz, DMSO-d6 ) δ 165.7, 143.5, 138.1, 137.9, 130.9, 129.0, 126.9, 124.5, 118.9, 118.1, 117.7, 111.5, 110.1, 60.8, 23.1, 23.0, 20.7, 14.6; HRMS (ESI), m/z calcd for C21 H23 N2 O4 S [M+H]+ 399.1373, found 399.1373.
４－（（１，２，３，４－テトラヒドロシクロペンタ［ｂ］インドール）－７－スルホンアミド）安息香酸 （J6-032；化合物５）：
メタノール（２．５ｍＬ）中のエステル化合物（化合物１）の溶液に２規定の水酸化ナトリウムを加え、混合物を反応が完了するまで室温で撹拌した。混合物を１規定の塩酸でクエンチし、酢酸エチルで抽出し、Ｎａ２ＳＯ４上で乾燥した。減圧下で濃縮し、精製せずにJ6-032（化合物５）を赤褐色固体として得た（３４．８ ｍｇ， ０．０９９ ｍｍｏｌ，収率９８ ％）
化合物J6-032の合成は、ＮＭＲ及びＨＲＭＳにより確認した。4-((1,2,3,4-tetrahydrocyclopenta[b]indole)-7-sulfonamido)benzoic acid (J6-032; compound 5):
To a solution of the ester compound (compound 1) in methanol (2.5 mL) was added 2N sodium hydroxide, and the mixture was stirred at room temperature until the reaction was complete. The mixture was quenched with 1N hydrochloric acid, extracted with ethyl acetate, and dried overNa2SO4 . Concentration under reduced pressure gave J6-032 (compound 5) as a red-brown solid (34.8 mg, 0.099 mmol, 98% yield) without purification.
The synthesis of compound J6-032 was confirmed by NMR and HRMS.
1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 11.25 (s, 1H), 10.57 (s, 1H), 7.90 (s, 1H), 7.74 - 7.80 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.18 - 7.25 (m, 2H), 2.66 (dt, J = 23.4, 5.4 Hz, 4H), 1.80 (qt, J = 10.1, 5.5 Hz, 4H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 167.3, 143.1, 138.1, 137.9, 131.1, 129.1, 126.9, 125.4, 118.9, 118.1, 117.7, 111.5, 110.1, 23.1, 23.0, 21.5, 21.2, 20.7, 14.6.; HRMS (ESI), m/z calcd for C19H19N2O4S [M+H]+ 371.1060, found 371.1060.1 H NMR (400 MHz, DMSO-d6 ) δ 12.55 (s, 1H), 11.25 (s, 1H), 10.57 (s, 1H), 7.90 (s, 1H), 7.74 - 7.80 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.18 - 7.25 (m, 2H), 2.66 (dt, J = 23.4, 5.4 Hz, 4H), 1.80 (qt, J = 10.1, 5.5 Hz, 4H);13 C{1 H} NMR (100 MHz, DMSO-d6 ) δ 167.3, 143.1, 138.1, 137.9, 131.1, 129.1, 126.9, 125.4, 118.9, 118.1, 117.7, 111.5, 110.1, 23.1, 23.0, 21.5, 21.2, 20.7, 14.6.; HRMS (ESI), m/z calcd for C19 H19 N2 O4 S [M+H]+ 371.1060, found 371.1060.
［実施例１－２］
化合物J4-026の製造[Example 1-2]
Preparation of compound J4-026
化合物J4-026は、J6-032の合成に関する上記の手法を参考に、以下に示す経路に従い合成した。Compound J4-026 was synthesized according to the route shown below, with reference to the above method for synthesizing J6-032.
化合物J4-026のLRMSによる分子量分析: 432.54, LRMS (ESI) [M+H]+: 433.1538Molecular weight analysis of compound J4-026 by LRMS: 432.54, LRMS (ESI) [M+H]+: 433.1538
［実施例１－３］
化合物K7-025の製造[Examples 1-3]
Preparation of compound K7-025
化合物K7-025は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K7-025 was synthesized using known materials and conventional methods according to the route shown below.
４－（（９－（２－エチルヘキシル）－２，３，４，９－テトラヒドロ－１Ｈ－カルバゾール）－６－スルホンアミド）安息香酸 （K7-025；化合物８）：
ＮａＨ （１７４．５ ｍｇ， ５５％， ４．０ ｍｍｏｌ）の乾燥ＤＭＦ（１３．３ ｍＬ）溶液に０℃で１，２，３，４－テトラヒドロカルバゾールの乾燥ＤＭＦ（２．０ ｍＬ）溶液を滴下した。０℃で３０分間撹拌した後、１－ブロモ－２－エチルヘキサンを滴下し、反応混合物を室温で一晩撹拌した。ＴＬＣチェック後、混合物を０℃でＨ２Ｏでクエンチした。混合物をジエチルエーテルで抽出し、ブラインで洗浄した。抽出液をＮａ２ＳＯ４上で乾燥し、減圧下濃縮した。粗生成物をｎ－ヘキサン－ＥｔＯＡｃ（＝４９：１）を用いたフラッシュクロマトグラフィーで精製し、化合物７を無色オイルとして得た（４５０．３ ｍｇ， ７９％）。
化合物７（２５９ ｍｇ， ０．４５ ｍｍｏｌ，収率８０ ％ ｉｎ ２ ｓｔｅｐｓ）から上図に示される手順に従って化合物K7-025（化合物８）を調製した。
化合物K7-025の合成は、ＮＭＲ及びＨＲＭＳにより確認した。4-((9-(2-ethylhexyl)-2,3,4,9-tetrahydro-1H-carbazole)-6-sulfonamido)benzoic acid (K7-025; compound 8):
A solution of 1,2,3,4-tetrahydrocarbazole in dry DMF (2.0 mL) was added dropwise to a solution of NaH (174.5 mg, 55%, 4.0 mmol) in dry DMF (13.3 mL) at 0° C. After stirring at 0° C. for 30 min, 1-bromo-2-ethylhexane was added dropwise and the reaction mixture was stirred at room temperature overnight. After checking with TLC, the mixture was quenched with H2 O at 0° C. The mixture was extracted with diethyl ether and washed with brine. The extract was dried over Na2 SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using n-hexane-EtOAc (=49:1) to give compound 7 as a colorless oil (450.3 mg, 79%).
Compound K7-025 (compound 8) was prepared from compound 7 (259 mg, 0.45 mmol, yield 80% in 2 steps) according to the procedure shown in the above diagram.
The synthesis of compound K7-025 was confirmed by NMR and HRMS.
1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.94 - 7.88 (m, 2H), 7.58 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.13 - 7.20 (m, 2H), 3.85 (dd, J = 7.5, 3.3 Hz, 2H), 2.68 (q, J = 7.0 Hz, 4H), 1.82 - 1.97 (m, 4H), 1.73 - 1.82 (m, 1H), 1.23 (dqd, J = 24.3, 13.3, 5.0 Hz, 10H), 0.84 (dt, J = 9.6, 7.0 Hz, 7H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.9, 142.5, 138.8, 138.8, 131.7, 127.8, 126.8, 124.3, 118.9, 118.8, 118.2, 111.3, 109.5, 47.5, 40.3, 30.8, 28.7, 24.1, 23.1, 23.0, 22.8, 22.6, 20.8, 14.0, 10.9; HRMS (ESI), m/z calcd for C27H35N2O4S [M+H]+ 483.2312, found 483.2312.1 H NMR (400 MHz, CDCl3 ) δ 8.07 (s, 1H), 7.94 - 7.88 (m, 2H), 7.58 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.13 - 7.20 (m, 2H), 3.85 (dd, J = 7.5, 3.3 Hz, 2H), 2.68 (q, J = 7.0 Hz, 4H), 1.82 - 1.97 (m, 4H), 1.73 - 1.82 (m, 1H), 1.23 (dqd, J = 24.3, 13.3, 5.0 Hz, 10H), 0.84 (dt, J = 9.6, 7.0 Hz, 7H);13 C{1 H} NMR (100 MHz, CDCl3 ) δ 170.9, 142.5, 138.8, 138.8, 131.7, 127.8, 126.8, 124.3, 118.9, 118.8, 118.2, 111.3, 109.5, 47.5, 40.3, 30.8, 28.7, 24.1, 23.1, 23.0, 22.8,22.6 ,20.8 , 14.0, 10.9; [M+H]+ 483.2312, found 483.2312.
［実施例１－４］
化合物K6-001の製造[Examples 1 to 4]
Preparation of compound K6-001
化合物K6-001は、以下に示す経路に従い、常法により合成した。収率は５５％だった。Compound K6-001 was synthesized by standard methods according to the route shown below. The yield was 55%.
化合物K6-001のデータは次のとおりである。
Molecular weight: 362.43, LRMS (ESI) [M+H]+: 363.1763The data for compound K6-001 are as follows:
Molecular weight: 362.43, LRMS (ESI) [M+H]+ : 363.1763
［実施例１－５］
化合物K7-034の製造[Examples 1 to 5]
Preparation of compound K7-034
K7-034は、以下に示す経路に従い、常法により合成した。K7-034 was synthesized by standard methods according to the route shown below.
化合物K7-034のデータは次のとおりである。
Molecular weight: 334.38, LRMS (ESI) [M+H]+: 335.1340The data for compound K7-034 are as follows:
Molecular weight: 334.38, LRMS (ESI) [M+H]+ : 335.1340
［実施例１－６］
化合物K9-030の製造[Examples 1 to 6]
Preparation of compound K9-030
化合物K9-030は、以下に示す経路に従い、常法により合成した。収率は７４％だった。Compound K9-030 was synthesized by standard methods according to the route shown below. The yield was 74%.
化合物K9-030のデータは次のとおりである。
Molecular weight: 383.466
1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 10.36 (s, 1H), 8.19 (q, J = 4.4 Hz, 1H), 7.85 (s, 1H), 7.60 - 7.66 (m, 2H), 7.41 (dd, J = 8.8, 2.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.10 - 7.16 (m, 2H), 2.70 (d, J = 4.4 Hz, 4H), 2.58 - 2.69 (m, 4H), 1.74 - 1.87 (m, 4H).The data for compound K9-030 are as follows:
Molecular weight: 383.466
1 H NMR (400 MHz, DMSO-d6 ) δ 11.22 (s, 1H), 10.36 (s, 1H), 8.19 (q, J = 4.4 Hz, 1H), 7.85 (s, 1H), 7.60 - 7.66 (m, 2H), 7.41 (dd, J = 8.8, 2.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.10 - 7.16 (m, 2H), 2.70 (d, J = 4.4 Hz, 4H), 2.58 - 2.69 (m, 4H), 1.74 - 1.87 (m, 4H).
［実施例１－７］
化合物K24-023の製造[Examples 1 to 7]
Preparation of compound K24-023
化合物K24-023は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K24-023 was synthesized using known materials and conventional methods according to the route shown below.
化合物K24-023の合成は、ＮＭＲにより確認した。The synthesis of compound K24-023 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 1.6 Hz, 1H), 7.89 - 7.95 (m, 2H), 7.54 - 7.61 (m, 1H), 7.21 - 7.29 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.13 - 7.18 (m, 2H), 3.92 - 4.01 (m, 2H), 2.64 - 2.73 (m, 4H), 1.80 - 1.98 (m, 4H), 1.60 - 1.73 (m, 2H), 1.17 - 1.34 (m, 10H), 0.77 - 0.91 (m, 3H).1 H NMR (400 MHz, CDCl3 ) δ 8.06 (d, J = 1.6 Hz, 1H), 7.89 - 7.95 (m, 2H), 7.54 - 7.61 (m, 1H), 7.21 - 7.29 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.13 - 7.18 (m, 2H), 3.92 - 4.01 (m, 2H), 2.64 - 2.73 (m, 4H), 1.80 - 1.98 (m, 4H), 1.60 - 1.73 (m, 2H), 1.17 - 1.34 (m, 10H), 0.77 - 0.91 (m, 3H).
［実施例１－８］
化合物K25-012の製造[Examples 1 to 8]
Preparation of compound K25-012
化合物K25-012は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K25-012 was synthesized using known materials and conventional methods according to the route shown below.
化合物K25-012の合成は、ＮＭＲにより確認した。The synthesis of compound K25-012 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.89 - 7.95 (m, 2H), 7.55 - 7.60 (m, 1H), 7.08 - 7.21 (m, 4H), 4.07 - 3.95 (m, 2H), 2.61 - 2.77 (m, 4H), 1.99 - 2.10 (m, 7H), 1.80 - 1.90 (m, 6H), 1.46 - 1.69 (m, 6H), 1.23 - 1.35 (m, 2H). 1 H NMR (400 MHz, CDCl3 ) δ 8.05 (s, 1H), 7.89 - 7.95 (m, 2H), 7.55 - 7.60 (m, 1H), 7.08 - 7.21 (m, 4H), 4.07 - 3.95 (m, 2H), 2.61 - 2.77 (m, 4H), 1.99 - 2.10 (m, 7H), 1.80 - 1.90 (m, 6H), 1.46 - 1.69 (m, 6H), 1.23 - 1.35 (m, 2H).
［実施例１－９］
化合物K25-013の製造[Examples 1 to 9]
Preparation of compound K25-013
化合物K25-013は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K25-013 was synthesized using known materials and conventional methods according to the route shown below.
化合物K25-013の合成は、ＮＭＲにより確認した。The synthesis of compound K25-013 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 1.6 Hz, 1H), 7.89 - 7.95 (m, 2H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 3.74 (s, 2H), 2.60 - 2.77 (m, 4H), 1.89 - 2.09 (m, 14H), 1.55 - 1.64 (m, 2H), 1.49 - 1.54 (m, 4H).1 H NMR (400 MHz, CDCl3 ) δ 8.04 (d, J = 1.6 Hz, 1H), 7.89 - 7.95 (m, 2H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 3.74 (s, 2H), 2.60 - 2.77 (m, 4H), 1.89 - 2.09 (m, 14H), 1.55 - 1.64 (m, 2H), 1.49 - 1.54 (m, 4H).
［実施例１－１０］
化合物K25-018の製造[Examples 1-10]
Preparation of compound K25-018
化合物K25-018は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K25-018 was synthesized using known materials and conventional methods according to the route shown below.
化合物K25-018の合成は、ＮＭＲにより確認した。The synthesis of compound K25-018 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 2.0 Hz, 1H), 7.90 - 7.95 (m, 2H), 7.52 (dd, J = 8.8, 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.13 - 7.17 (m, 2H), 7.02 (s, 1H), 3.80 - 3.92 (m, 2H), 2.82 - 2.88 (m, 4H), 2.49 - 2.59 (m, 2H), 1.77 - 1.86 (m, 1H), 1.15 - 1.34 (m, 8H), 0.78 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 8.02 (d, J = 2.0 Hz, 1H), 7.90 - 7.95 (m, 2H), 7.52 (dd, J = 8.8, 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.13 - 7.17 (m, 2H), 7.02 (s, 1H), 3.80 - 3.92 (m, 2H), 2.82 - 2.88 (m, 4H), 2.49 - 2.59 (m, 2H), 1.77 - 1.86 (m, 1H), 1.15 - 1.34 (m, 8H), 0.78 - 0.92 (m, 6H).
［実施例１－１１］
化合物K28-039の製造[Examples 1-11]
Preparation of compound K28-039
化合物K28-039は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K28-039 was synthesized using known materials and conventional methods according to the route shown below.
化合物K28-039の合成は、ＮＭＲにより確認した。The synthesis of compound K28-039 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.80 - 7.85 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.48 - 7.54 (m, 2H), 7.39 - 7.45 (m, 2H), 7.32 - 7.36 (m, 1H), 7.21 - 7.25 (m, 2H), 3.75 - 3.91 (m, 2H), 2.59 - 2.75 (m, 4H), 1.70 - 1.96 (m, 5H), 1.09 - 1.36 (m, 8H), 0.72 - 0.91 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.45 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.80 - 7.85 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.48 - 7.54 (m, 2H), 7.39 - 7.45 (m, 2H), 7.32 - 7.36 (m, 1H), 7.21 - 7.25 (m, 2H), 3.75 - 3.91 (m, 2H), 2.59 - 2.75 (m, 4H), 1.70 - 1.96 (m, 5H), 1.09 - 1.36 (m, 8H), 0.72 - 0.91 (m, 6H).
［実施例１－１２］
化合物K29-013の製造[Examples 1-12]
Preparation of compound K29-013
化合物K29-013は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K29-013 was synthesized using known materials and conventional methods according to the route shown below.
化合物K29-013の合成は、ＮＭＲにより確認した。The synthesis of compound K29-013 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 7.96 - 7.92 (m, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.33 - 7.45 (m, 4H), 7.22 (d, J = 8.8 Hz, 1H), 6.90 - 6.97 (m, 2H), 6.84 (s, 1H), 3.81 - 3.93 (m, 2H), 2.61 - 2.74 (m, 4H), 1.75 - 1.99 (m, 5H), 1.11 - 1.36 (m, 8H), 0.75 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 7.96 - 7.92 (m, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.33 - 7.45 (m, 4H), 7.22 (d, J = 8.8 Hz, 1H), 6.90 - 6.97 (m, 2H), 6.84 (s, 1H), 3.81 - 3.93 (m, 2H), 2.61 - 2.74 (m, 4H), 1.75 - 1.99 (m, 5H), 1.11 - 1.36 (m, 8H), 0.75 - 0.92 (m, 6H).
［実施例１－１３］
化合物K29-026の製造[Example 1-13]
Preparation of compound K29-026
化合物K29-026は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K29-026 was synthesized using known materials and conventional methods along the route shown below.
化合物K29-026の合成は、ＮＭＲにより確認した。The synthesis of compound K29-026 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.0 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 6.41 (dd, J = 9.2, 2.4 Hz, 1H), 3.82 - 3.91 (m, 2H), 3.80 (t, J = 5.2 Hz, 4H), 3.27 (t, J = 5.2 Hz, 4H), 2.62 - 2.73 (m, 4H), 1.74 - 1.96 (m, 5H), 1.13 - 1.34 (m, 8H), 0.75 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.60 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.0 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 6.41 (dd, J = 9.2, 2.4 Hz, 1H), 3.82 - 3.91 (m, 2H), 3.80 (t, J = 5.2 Hz, 4H), 3.27 (t, J = 5.2 Hz, 4H), 2.62 - 2.73 (m, 4H), 1.74 - 1.96 (m, 5H), 1.13 - 1.34 (m, 8H), 0.75 - 0.92 (m, 6H).
［実施例１－１４］
化合物K29-027の製造[Examples 1-14]
Preparation of compound K29-027
化合物K29-027は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K29-027 was synthesized using known materials and conventional methods according to the route shown below.
化合物K29-027の合成は、ＮＭＲにより確認した。The synthesis of compound K29-027 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.07 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 2.0 Hz, 1H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 3.78 - 3.93 (m, 2H), 2.62 - 2.75 (m, 4H), 1.74 - 1.98 (m, 5H), 1.13 - 1.35 (m, 8H), 0.77 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.38 (s, 1H), 8.07 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 2.0 Hz, 1H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 3.78 - 3.93 (m, 2H), 2.62 - 2.75 (m, 4H), 1.74 - 1.98 (m, 5H), 1.13 - 1.35 (m, 8H), 0.77 - 0.92 (m, 6H).
［実施例１－１５］
化合物K29-030の製造[Example 1-15]
Preparation of compound K29-030
化合物K29-030は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K29-030 was synthesized using known materials and conventional methods according to the route shown below.
化合物K29-030の合成は、ＮＭＲにより確認した。The synthesis of compound K29-030 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 8.8, 2.0 Hz, 1H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.03 (s, 2H), 3.82 - 3.94 (m, 2H), 2.88 - 2.96 (m, 1H), 2.64 - 2.75 (m, 4H), 2.42 - 2.52 (m, 2H), 1.75 - 1.98 (m, 5H), 1.17 - 1.35 (m, 14H), 0.98 - 1.06 (m, 12H), 0.76 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.37 (s, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 8.8, 2.0 Hz, 1H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.03 (s, 2H), 3.82 - 3.94 (m, 2H), 2.88 - 2.96 (m, 1H), 2.64 - 2.75 (m, 4H), 2.42 - 2.52 (m, 2H), 1.75 - 1.98 (m, 5H), 1.17 - 1.35 (m, 14H), 0.98 - 1.06 (m, 12H), 0.76 - 0.92 (m, 6H).
［実施例１－１６］
化合物K29-035の製造[Example 1-16]
Preparation of compound K29-035
化合物K29-035は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K29-035 was synthesized using known materials and conventional methods according to the route shown below.
化合物K29-035の合成は、ＮＭＲにより確認した。The synthesis of compound K29-035 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.96 - 8.03 (m, 2H), 7.59 - 7.60 (m, 1H), 7.55 (dd, J = 8.8, 2.0 Hz, 2H), 7.19 (d, J = 8.8 Hz, 1H), 6.89 (s, 2H), 6.75 - 6.81 (m, 2H), 3.78 - 3.92 (m, 2H), 2.59 - 2.76 (m, 4H), 2.33 (s, 3H), 1.72 - 1.97 (m, 11H), 1.11 - 1.37 (m, 8H), 0.77 - 0.91 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.48 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.96 - 8.03 (m, 2H), 7.59 - 7.60 (m, 1H), 7.55 (dd, J = 8.8, 2.0 Hz, 2H), 7.19 (d, J = 8.8 Hz, 1H), 6.89 (s, 2H), 6.75 - 6.81 (m, 2H), 3.78 - 3.92 (m, 2H), 2.59 - 2.76 (m, 4H), 2.33 (s, 3H), 1.72 - 1.97 (m, 11H), 1.11 - 1.37 (m, 8H), 0.77 - 0.91 (m, 6H).
［実施例１－１７］
化合物K29-036の製造[Example 1-17]
Preparation of compound K29-036
化合物K29-036は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K29-036 was synthesized using known materials and conventional methods according to the route shown below.
化合物K29-036の合成は、ＮＭＲにより確認した。The synthesis of compound K29-036 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 7.98 - 8.05 (m, 2H), 7.66 (d, J = 1.6 Hz, 1H), 7.51 - 7.56 (m, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.02 (s, 2H), 6.87 (dd, J = 8.0, 1.6 Hz, 1H), 3.78 - 3.92 (m, 2H), 2.88 - 2.99 (m, 1H), 2.55 - 2.72 (m, 4H), 2.31 - 2.44 (m, 2H), 1.71 - 1.96 (m, 5H), 1.12 - 1.35 (m, 14H), 0.90 - 1.05 (m, 12H), 0.77 - 0.91 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.51 (s, 1H), 7.98 - 8.05 (m, 2H), 7.66 (d, J = 1.6 Hz, 1H), 7.51 - 7.56 (m, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.02 (s, 2H), 6.87 (dd, J = 8.0, 1.6 Hz, 1H), 3.78 - 3.92 (m, 2H), 2.88 - 2.99 (m, 1H), 2.55 - 2.72 (m, 4H), 2.31 - 2.44 (m, 2H), 1.71 - 1.96 (m, 5H), 1.12 - 1.35 (m, 14H), 0.90 - 1.05 (m, 12H), 0.77 - 0.91 (m, 6H).
［実施例１－１８］
化合物K30-031の製造[Example 1-18]
Preparation of compound K30-031
化合物K30-031は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K30-031 was synthesized using known materials and conventional methods along the route shown below.
化合物K30-031の合成は、ＮＭＲにより確認した。The synthesis of compound K30-031 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 2.0 Hz, 1H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 3.79 - 3.92 (m, 2H), 2.64 - 2.74 (m, 4H), 1.73 - 1.96 (m, 5H), 1.13 - 1.36 (m, 18H), 0.75 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.36 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 2.0 Hz, 1H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 3.79 - 3.92 (m, 2H), 2.64 - 2.74 (m, 4H), 1.73 - 1.96 (m, 5H), 1.13 - 1.36 (m, 18H), 0.75 - 0.92 (m, 6H).
［実施例１－１９］
化合物K24-037の製造[Example 1-19]
Preparation of compound K24-037
化合物K24-037は、以下に示す経路に沿って、公知の材料及び常法に従い、合成した。Compound K24-037 was synthesized using known materials and conventional methods along the route shown below.
化合物K24-037の合成は、ＮＭＲにより確認した。The synthesis of compound K24-037 was confirmed by NMR.
1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.92 (s, 1H), 7.68 - 7.75 (m, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 3.78 - 3.92 (m, 2H), 2.62 - 2.75 (m, 4H), 1.73 - 1.97 (m, 5H), 1.12 - 1.35 (m, 8H), 0.85 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.35 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.92 (s, 1H), 7.68 - 7.75 (m, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 3.78 - 3.92 (m, 2H), 2.62 - 2.75 (m, 4H), 1.73 - 1.97 (m, 5H), 1.12 - 1.35 (m, 8H), 0.85 (m, 6H).
［実施例１－２０］～［実施例１－］
上記の合成例と同様に、以下のインドール誘導体又はテトラヒドロカルバゾール誘導体である本発明の化合物についても合成を行った。[Example 1-20] to [Example 1-]
In the same manner as in the above synthesis examples, the following indole derivatives or tetrahydrocarbazole derivatives, which are compounds of the present invention, were also synthesized.
［実施例１－２０］
化合物K1-032の製造[Example 1-20]
Preparation of compound K1-032
Molecular weight: 384.45, LRMS (ESI) [M+H]+: 385.1165Molecular weight: 384.45, LRMS (ESI) [M+H]+ : 385.1165
［実施例１－２１］
化合物K2-004の製造[Example 1-21]
Preparation of compound K2-004
Molecular weight: 412.504
1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 10.60 (s, 1H), 7.92 (s, 1H), 7.75 - 7.80 (m, 2H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.20 - 7.25 (m, 2H), 4.22 (q, J = 7.2 Hz, 2H), 2.72 - 2.83 (m, 4H), 1.81 - 1.84 (m, 2H), 1.60 - 1.76 (m, 5H), 1.25 (t, J = 7.2 Hz, 3H)Molecular weight: 412.504
1 H NMR (400 MHz, DMSO-d6 ) δ 11.27 (s, 1H), 10.60 (s, 1H), 7.92 (s, 1H), 7.75 - 7.80 (m, 2H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.20 - 7.25 (m, 2H), 4.22 (q, J = 7.2 Hz, 2H), 2.72 - 2.83 (m, 4H), 1.81 - 1.84 (m, 2H), 1.60 - 1.76 (m, 5H), 1.25 (t, J = 7.2 Hz, 3H)
［実施例１－２２］
化合物K1-036の製造[Example 1-22]
Preparation of compound K1-036
Molecular weight: 426.53, LRMS (ESI) [M+Na]+: 449.2808 Molecular weight: 426.53, LRMS (ESI) [M+Na]+ : 449.2808
［実施例１－２３］
化合物K4-036の製造[Example 1-23]
Preparation of compound K4-036
Molecular weight: 356.396
1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 10.56 (s, 1H), 7.86 (s, 1H), 7.74 - 7.77 (m, 2H), 7.43 (dd, J = 8.8, 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.16 - 7.21 (m, 2H), 2.78 (m, 4H), 2.44 - 2.50 (m, 2H).Molecular weight: 356.396
1 H NMR (400 MHz, DMSO-d6 ) δ 11.40 (s, 1H), 10.56 (s, 1H), 7.86 (s, 1H), 7.74 - 7.77 (m, 2H), 7.43 (dd, J = 8.8, 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.16 - 7.21 (m, 2H), 2.78 (m, 4H), 2.44 - 2.50 (m, 2H).
［実施例１－２４］
化合物K4-038の製造[Example 1-24]
Preparation of compound K4-038
Molecular weight: 384.45
1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 11.27 (s, 1H), 10.55 (s, 1H), 7.91 (s, 1H), 7.72 - 7.78 (m, 2H), 7.42 (dd, J = 8.8, 2.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.16 - 7.22 (m, 2H), 2.72 - 2.82 (m, 4H), 1.81 - 1.84 (m, 2H), 1.66 - 1.70 (m, 4H).Molecular weight: 384.45
1 H NMR (400 MHz, DMSO-d6 ) δ 12.62 (s, 1H), 11.27 (s, 1H), 10.55 (s, 1H), 7.91 (s, 1H), 7.72 - 7.78 (m, 2H), 7.42 (dd, J = 8.8, 2.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.16 - 7.22 (m, 2H), 2.72 - 2.82 (m, 4H), 1.81 - 1.84 (m, 2H), 1.66 - 1.70 (m, 4H).
［実施例１－２５］
化合物K5-010の製造[Example 1-25]
Preparation of compound K5-010
Molecular weight: 398.477
1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.52 (s, 1H), 7.91 (s, 1H), 7.72 - 7.78 (m, 2H), 7.42 (dd, J = 8.8, 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.17 - 7.23 (m, 2H), 2.74 - 2.85 (m, 4H), 1.56 - 1.74 (m, 4H), 1.26 - 1.43 (m, 4H).Molecular weight: 398.477
1 H NMR (400 MHz, DMSO-d6 ) δ 11.26 (s, 1H), 10.52 (s, 1H), 7.91 (s, 1H), 7.72 - 7.78 (m, 2H), 7.42 (dd, J = 8.8, 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.17 - 7.23 (m, 2H), 2.74 - 2.85 (m, 4H), 1.56 - 1.74 (m, 4H), 1.26 - 1.43 (m, 4H).
［実施例１－２６］
化合物K2-011の製造[Example 1-26]
Preparation of compound K2-011
Molecular weight: 412.50, LRMS (ESI) [M+H]+: 413.1516Molecular weight: 412.50, LRMS (ESI) [M+H]+ : 413.1516
［実施例１－２７］
化合物K2-017の製造[Example 1-27]
Preparation of compound K2-017
Molecular weight: 412.50, LRMS (ESI) [M+H]+: 413.2653Molecular weight: 412.50, LRMS (ESI) [M+H]+: 413.2653
［実施例１－２８］
化合物K9-033の製造[Example 1-28]
Preparation of compound K9-033
Molecular weight: 452.57, LRMS (ESI) [M+H]+: 453.1757Molecular weight: 452.57, LRMS (ESI) [M+H]+ : 453.1757
［実施例１－２９］
化合物K8-004の製造[Example 1-29]
Preparation of compound K8-004
Molecular weight: 455.53, LRMS (ESI) [M+H]+: 456.1575Molecular weight: 455.53, LRMS (ESI) [M+H]+ : 456.1575
［実施例１－３０］
化合物K9-036の製造[Example 1-30]
Preparation of compound K9-036
Molecular weight: 428.50, LRMS (ESI) [M+H]+: 429.1399Molecular weight: 428.50, LRMS (ESI) [M+H]+ : 429.1399
［実施例１－３１］
化合物K5-024の製造[Example 1-31]
Preparation of compound K5-024
Molecular weight: 412.504
1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.54 (s, 1H), 7.88 (s, 1H), 7.72 - 7.77 (m, 2H), 7.44 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.16 - 7.21 (m, 2H), 2.78 (td, J = 13.8, 5.8 Hz, 2H), 2.71 (d, J = 7.4 Hz, 3H), 2.19 (dd, J = 15.6, 9.6 Hz, 1H), 1.90 - 2.01 (m, 2H), 1.64 - 1.80 (m, 2H), 1.34 - 1.53 (m, 8H), 0.87 - 0.98 (m, 5H).Molecular weight: 412.504
1 H NMR (400 MHz, DMSO-d6 ) δ 11.24 (s, 1H), 10.54 (s, 1H), 7.88 (s, 1H), 7.72 - 7.77 (m, 2H), 7.44 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.16 - 7.21 (m, 2H), 2.78 (td, J = 13.8, 5.8 Hz, 2H), 2.71 (d, J = 7.4 Hz, 3H), 2.19 (dd, J = 15.6, 9.6 Hz, 1H), 1.90 - 2.01 (m, 2H), 1.64 - 1.80 (m, 2H), 1.34 - 1.53 (m, 8H), 0.87 - 0.98 (m, 5H).
［実施例１－３２］
化合物K5-026の製造[Example 1-32]
Preparation of compound K5-026
Molecular weight: 426.531
1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 10.52 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.73 - 7.77 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.16 - 7.21 (m, 2H), 2.60 - 2.86 (m, 3H), 2.24 - 2.38 (m, 1H), 2.01 - 2.12 (m, 1H), 0.98 (s, 9H).Molecular weight: 426.531
1 H NMR (400 MHz, DMSO-d6 ) δ 11.22 (s, 1H), 10.52 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.73 - 7.77 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.16 - 7.21 (m, 2H), 2.60 - 2.86 (m, 3H), 2.24 - 2.38 (m, 1H), 2.01 - 2.12 (m, 1H), 0.98 (s, 9H).
［実施例１－３３］
化合物K5-025の製造[Example 1-33]
Preparation of compound K5-025
Molecular weight: 412.504
1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.89 - 7.95 (m, 2H), 7.55 - 7.60 (m, 1H), 7.08 - 7.21 (m, 4H), 4.07 - 3.95 (m, 2H), 2.61 - 2.77 (m, 4H), 1.99 - 2.10 (m, 7H), 1.80 - 1.90 (m, 6H), 1.46 - 1.69 (m, 6H), 1.23 - 1.35 (m, 2H).Molecular weight: 412.504
1 H NMR (400 MHz, CDCl3 ) δ 8.05 (s, 1H), 7.89 - 7.95 (m, 2H), 7.55 - 7.60 (m, 1H), 7.08 - 7.21 (m, 4H), 4.07 - 3.95 (m, 2H), 2.61 - 2.77 (m, 4H), 1.99 - 2.10 (m, 7H), 1.80 - 1.90 (m, 6H), 1.46 - 1.69 (m, 6H), 1.23 - 1.35 (m, 2H).
［実施例１－３４］
化合物K2-002の製造[Example 1-34]
Preparation of compound K2-002
Molecular weight: 358.41
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 10.62 (s, 1H), 7.96 (s, 1H), 7.74 - 7.79 (m, 2H), 7.45 (dd, J = 8.4, 1.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.18 - 7.24 (m, 2H), 6.30 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 2.38 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).Molecular weight: 358.41
1 H NMR (400 MHz, DMSO-d6 ) δ 11.46 (s, 1H), 10.62 (s, 1H), 7.96 (s, 1H), 7.74 - 7.79 (m, 2H), 7.45 (dd, J = 8.4, 1.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.18 - 7.24 (m, 2H), 6.30 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 2.38 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).
［実施例１－３５］
化合物K2-003の製造[Example 1-35]
Preparation of compound K2-003
Molecular weight: 372.44
1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.60 (s, 1H), 7.91 (s, 1H), 7.74 - 7.80 (m, 2H), 7.43 (dd, J = 8.8, 2.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.20 - 7.25 (m, 2H), 4.22 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.16 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).Molecular weight: 372.44
1 H NMR (400 MHz, DMSO-d6 ) δ 11.25 (s, 1H), 10.60 (s, 1H), 7.91 (s, 1H), 7.74 - 7.80 (m, 2H), 7.43 (dd, J = 8.8, 2.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.20 - 7.25 (m, 2H), 4.22 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.16 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).
［実施例１－３６］
化合物K6-023の製造[Example 1-36]
Preparation of compound K6-023
Molecular weight: 414.52, LRMS (ESI) [M+H]+: 415.1659 Molecular weight: 414.52, LRMS (ESI) [M+H]+ : 415.1659
［実施例１－３７］
化合物K7-004の製造[Example 1-37]
Preparation of compound K7-004
Molecular weight: 384.466
1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.98 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 2.70 (t, J = 7.6 Hz, 4H), 1.67 (t, J = 7.8 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H).Molecular weight: 384.466
1 H NMR (400 MHz, CDCl3 ) δ 8.07 (s, 1H), 7.98 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 2.70 (t, J = 7.6 Hz, 4H), 1.67 (t, J = 7.8 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H).
［実施例１－３８］
化合物K3-013の製造[Example 1-38]
Preparation of compound K3-013
Molecular weight: 420.48, LRMS (ESI) [M+H]+: 421.1238 Molecular weight: 420.48, LRMS (ESI) [M+H]+ : 421.1238
［実施例１－３９］
化合物K6-022の製造[Example 1-39]
Preparation of compound K6-022
Molecular weight: 490.62, LRMS (ESI) [M+H]+: 491.1965Molecular weight: 490.62, LRMS (ESI) [M+H]+ : 491.1965
［実施例１－４０］
化合物K5-014-2の製造[Example 1-40]
Preparation of compound K5-014-2
Molecular weight: 452.50, LRMS (ESI) [M+H]+: 453.1276Molecular weight: 452.50, LRMS (ESI) [M+H]+ : 453.1276
［実施例１－４１］
化合物K7-003の製造[Example 1-41]
Preparation of compound K7-003
Molecular weight: 462.56, LRMS (ESI) [M+H]+: 463.1611Molecular weight: 462.56, LRMS (ESI) [M+H]+ : 463.1611
［実施例１－４２］
化合物K5-028の製造[Example 1-42]
Preparation of compound K5-028
Molecular weight: 424.446
1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.62 (s, 1H), 8.08 (s, 1H), 7.74 - 7.79 (m, 2H), 7.73 - 7.65 (m, 3H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 7.34 - 7.39 (m, 2H), 7.19 - 7.25 (m, 2H), 2.39 (s, 3H).Molecular weight: 424.446
1 H NMR (400 MHz, DMSO-d6 ) δ 11.75 (s, 1H), 10.62 (s, 1H), 8.08 (s, 1H), 7.74 - 7.79 (m, 2H), 7.73 - 7.65 (m, 3H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 7.34 - 7.39 (m, 2H), 7.19 - 7.25 (m, 2H), 2.39 (s, 3H).
［実施例１－４３］
化合物K18-036の製造[Example 1-43]
Preparation of compound K18-036
Molecular weight: 412.50 Molecular weight: 412.50
［実施例１－４４］
化合物K18-037の製造[Example 1-44]
Preparation of compound K18-037
Molecular weight: 426.53, LRMS (ESI) [M+H]+: 427.1589Molecular weight: 426.53, LRMS (ESI) [M+H]+ : 427.1589
［実施例１－４５］
化合物K20-010の製造[Example 1-45]
Preparation of compound K20-010
Molecular weight: 440.56, LRMS (ESI) [M+H]+: 441.1747Molecular weight: 440.56, LRMS (ESI) [M+H]+ : 441.1747
［実施例１－４６］
化合物K19-034の製造[Example 1-46]
Preparation of compound K19-034
Molecular weight: 454.59, LRMS (ESI) [M+H]+: 455.1884Molecular weight: 454.59, LRMS (ESI) [M+H]+ : 455.1884
［実施例１－４７］
化合物K19-033の製造[Example 1-47]
Preparation of compound K19-033
Molecular weight: 494.65, LRMS (ESI) [M+H]+: 495.2184Molecular weight: 494.65, LRMS (ESI) [M+H]+ : 495.2184
［実施例１－４８］
化合物K20-016-3の製造[Example 1-48]
Preparation of compound K20-016-3
Molecular weight: 454.54, LRMS (ESI) [M+H]+: 455.1532Molecular weight: 454.54, LRMS (ESI) [M+H]+ : 455.1532
［実施例１－４９］
化合物K19-037の製造[Example 1-49]
Preparation of compound K19-037
Molecular weight: 384.45, LRMS (ESI) [M+H]+: 385.1123Molecular weight: 384.45, LRMS (ESI) [M+H]+ : 385.1123
［実施例１－５０］
化合物K19-038の製造[Example 1-50]
Preparation of compound K19-038
Molecular weight: 398.48, LRMS (ESI) [M+H]+: 399.1278Molecular weight: 398.48, LRMS (ESI) [M+H]+ : 399.1278
［実施例１－５１］
化合物K20-022の製造[Example 1-51]
Preparation of compound K20-022
Molecular weight: 412.50, LRMS (ESI) [M+H]+: 413.1417Molecular weight: 412.50, LRMS (ESI) [M+H]+ : 413.1417
［実施例１－５２］
化合物K20-013の製造[Example 1-52]
Preparation of compound K20-013
Molecular weight: 426.53, LRMS (ESI) [M+H]+: 427.1585Molecular weight: 426.53, LRMS (ESI) [M+H]+ : 427.1585
［実施例１－５３］
化合物K20-012の製造[Example 1-53]
Preparation of compound K20-012
Molecular weight: 466.60, LRMS (ESI) [M+H]+: 467.1883Molecular weight: 466.60, LRMS (ESI) [M+H]+ : 467.1883
［実施例１－５４］
化合物K21-004の製造[Example 1-54]
Preparation of compound K21-004
1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.08 (d, J = 8.8 Hz, 2H), 8.04 (s, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 3.84 - 3.97 (m, 2H), 2.68 - 3.96 (m, 4H), 1.80 - 2.01 (m, 5H), 1.40 - 1.18 (m, 8H), 0.87 - 0.94 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 8.38 (s, 1H), 8.08 (d, J = 8.8 Hz, 2H), 8.04 (s, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 3.84 - 3.97 (m, 2H), 2.68 - 3.96 (m, 4H), 1.80 - 2.01 (m, 5H), 1.40 - 1.18 (m, 8H), 0.87 - 0.94 (m, 6H).
［実施例１－５５］
化合物K27-015の製造[Example 1-55]
Preparation of compound K27-015
1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.54 (d, J = 8.8, Hz, 1H), 7.48 (d, J = 9.2, Hz, 1H), 7.24 (d, J = 8.8 Hz, 4H), 3.79 - 3.92 (m, 2H), 2.65 - 2.74 (m, 4H), 1.83 - 1.97 (m, 4H), 1.74 - 1.82 (m, 1H), 1.19 - 1.35 (m, 8H), 0.80 - 0.91 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 9.83 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.54 (d, J = 8.8, Hz, 1H), 7.48 (d, J = 9.2, Hz, 1H), 7.24 (d, J = 8.8 Hz, 4H), 3.79 - 3.92 (m, 2H), 2.65 - 2.74 (m, 4H), 1.83 - 1.97 (m, 4H), 1.74 - 1.82 (m, 1H), 1.19 - 1.35 (m, 8H), 0.80 - 0.91 (m, 6H).
［実施例１－５６］
化合物K27-020の製造[Example 1-56]
Preparation of compound K27-020
1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 8.08 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 8.8, 8.4 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.01 (dd, J = 8.4, 8.0 Hz, 1H), 3.77 - 3.90 (m, 2H), 2.68 (dt, J = 14.8, 6.0 Hz, 4H), 1.81 - 1.92 (m, 4H), 1.75 - 1.80 (m, J 1H), 1.10 - 1.35 (m, 8H), 0.76 - 0.91 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.43 (s, 1H), 8.08 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 8.8, 8.4 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.01 (dd, J = 8.4, 8.0 Hz, 1H), 3.77 - 3.90 (m, 2H), 2.68 (dt, J = 14.8, 6.0 Hz, 4H), 1.81 - 1.92 (m, 4H), 1.75 - 1.80 (m, J 1H), 1.10 - 1.35 (m, 8H), 0.76 - 0.91 (m, 6H).
［実施例１－５７］
化合物K27-029の製造[Example 1-57]
Preparation of compound K27-029
1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 3.80 - 3.92 (m, 2H), 2.69 (dt, J = 14.0, 6.0 Hz, 4H), 1.81 - 1.96 (m, 5H), 1.76 - 1.81 (m, 1H), 1.17 - 1.31 (m, 8H), 0.78 - 0.93 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.39 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 3.80 - 3.92 (m, 2H), 2.69 (dt, J = 14.0, 6.0 Hz, 4H), 1.81 - 1.96 (m, 5H), 1.76 - 1.81 (m, 1H), 1.17 - 1.31 (m, 8H), 0.78 - 0.93 (m, 6H).
［実施例１－５８］
化合物K27-035の製造[Example 1-58]
Preparation of compound K27-035
1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.02 (s, 1H), 7.76 (dd, J = 9.2, 4.8 Hz, 1H), 7.62 (dd, J = 88, 3.2 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.17 - 7.24 (m, 2H), 3.78 - 3.91 (m, 2H), 2.68 (q, J = 7.2 Hz, 4H), 1.75 - 1.94 (m, 5H), 1.14 - 1.34 (m, 8H), 0.84 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.13 (s, 1H), 8.02 (s, 1H), 7.76 (dd, J = 9.2, 4.8 Hz, 1H), 7.62 (dd, J = 88, 3.2 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.17 - 7.24 (m, 2H), 3.78 - 3.91 (m, 2H), 2.68 (q, J = 7.2 Hz, 4H), 1.75 - 1.94 (m, 5H), 1.14 - 1.34 (m, 8H), 0.84 (m, 6H).
［実施例１－５９］
化合物K30-013の製造[Example 1-59]
Preparation of compound K30-013
1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.49 (dd, J = 8.8, 2.0 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.07 (dd, J = 9.2, 3.2 Hz, 1H), 3.81 - 3.87 (m, 2H), 3.77 (s, 3H), 2.67 (q, J = 6.4 Hz, 4H), 1.72 - 1.93 (m, 5H), 1.11 - 1.34 (m, 8H), 0.78 - 0.91 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 9.96 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.49 (dd, J = 8.8, 2.0 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.07 (dd, J = 9.2, 3.2 Hz, 1H), 3.81 - 3.87 (m, 2H), 3.77 (s, 3H), 2.67 (q, J = 6.4 Hz, 4H), 1.72 - 1.93 (m, 5H), 1.11 - 1.34 (m, 8H), 0.78 - 0.91 (m, 6H).
［実施例１－６０］
化合物K22-013の製造[Example 1-60]
Preparation of compound K22-013
1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.8, 2.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.49 (dd, J = 8.4, 2.4 Hz, 1H), 6.30 (s, 1H), 3.82 - 3.92 (m, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 2.68 (q, J = 6.4 Hz, 4H), 1.74 - 1.98 (m, 5H), 1.13 - 1.36 (m, 8H), 0.86 (tt, J = 7.2, 6.8 Hz, 6H).1 H NMR (400 MHz, CDCl3 ) δ 7.91 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.8, 2.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.49 (dd, J = 8.4, 2.4 Hz, 1H), 6.30 (s, 1H), 3.82 - 3.92 (m, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 2.68 (q, J = 6.4 Hz, 4H), 1.74 - 1.98 (m, 5H), 1.13 - 1.36 (m, 8H), 0.86 (tt, J = 7.2, 6.8 Hz, 6H).
［実施例１－６１］
化合物K23-007の製造[Example 1-61]
Preparation of compound K23-007
1H NMR (400 MHz, CDCl3) δ 8.99 (d, J = 2.0 Hz, 1H), 8.15 (dd, J = 9.2, 2.4 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 3.79 - 3.93 (m, 5H), 2.70 (tt, J = 13.4, 6.1 Hz, 4H), 1.73 - 1.98 (m, 5H), 1.12 - 1.36 (m, 8H), 0.79 - 0.91 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 8.99 (d, J = 2.0 Hz, 1H), 8.15 (dd, J = 9.2, 2.4 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 3.79 - 3.93 (m, 5H), 2.70 (tt, J = 13.4, 6.1 Hz, 4H), 1.73 - 1.98 (m, 5H), 1.12 - 1.36 (m, 8H), 0.79 - 0.91 (m, 6H).
［実施例１－６２］
化合物K23-008の製造[Example 1-62]
Preparation of compound K23-008
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.4, 1.6 Hz, 1H), 7.71 (dd, J = 8.0 Hz, 1H), 7.65 (dd, J = 10.8, 2.0 Hz, 1H), 7.57 (dd, J = 8.8, 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H), 3.79 - 3.92 (m, 2H), 2.69 (tt, J = 12.4, 6.4 Hz, 4H), 1.71 - 1.97 (m, 5H), 1.12 - 1.36 (m, 10H), 0.77 - 0.92 (m, 7H).1 H NMR (400 MHz, CDCl3 ) δ 8.05 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.4, 1.6 Hz, 1H), 7.71 (dd, J = 8.0 Hz, 1H), 7.65 (dd, J = 10.8, 2.0 Hz, 1H), 7.57 (dd, J = 8.8, 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H), 3.79 - 3.92 (m, 2H), 2.69 (tt, J = 12.4, 6.4 Hz, 4H), 1.71 - 1.97 (m, 5H), 1.12 - 1.36 (m, 10H), 0.77 - 0.92 (m, 7H).
［実施例１－６３］
化合物K27-007の製造[Example 1-63]
Preparation of compound K27-007
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 1.6 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.59 (dd, J = 8.0, 1.2 Hz, 1H), 7.41 (dd, J = 8.4, 2.0 Hz, 1H), 7.15 - 7.23 (m, 2H), 6.61 (s, 1H), 3.81 - 3.93 (m, 2H), 2.67 (tt, J = 11.2, 5.6 Hz, 4H), 2.24 (s, 3H), 1.76 - 1.97 (m, 5H), 1.12 - 1.35 (m, 8H), 0.89 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 7.89 (d, J = 1.6 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.59 (dd, J = 8.0, 1.2 Hz, 1H), 7.41 (dd, J = 8.4, 2.0 Hz, 1H), 7.15 - 7.23 (m, 2H), 6.61 (s, 1H), 3.81 - 3.93 (m, 2H), 2.67 (tt, J = 11.2, 5.6 Hz, 4H), 2.24 (s, 3H), 1.76 - 1.97 (m, 5H), 1.12 - 1.35 (m, 8H), 0.89 - 0.92 (m, 6H).
［実施例１－６４］
化合物K27-008の製造[Example 1-64]
Preparation of compound K27-008
1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.11 (dd, J = 8.8, 2.0 Hz, 1H), 3.79 - 3.92 (m, 2H), 2.63 - 2.78 (m, 4H), 1.72 - 1.97 (m, 5H), 1.12 - 1.35 (m, 8H), 0.77 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 10.46 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.11 (dd, J = 8.8, 2.0 Hz, 1H), 3.79 - 3.92 (m, 2H), 2.63 - 2.78 (m, 4H), 1.72 - 1.97 (m, 5H), 1.12 - 1.35 (m, 8H), 0.77 - 0.92 (m, 6H).
［実施例１－６５］
化合物K27-010の製造[Example 1-65]
Preparation of compound K27-010
1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.0, 2.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 8.8, 2.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 3.67 - 3.80 (m, 2H), 2.66 (s, 3H), 2.54 (tt, J = 11.6, 6.0 Hz, 4H), 1.63 - 1.80 (m, 5H), 1.06 - 1.35 (m, 8H), 0.75 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 8.25 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.0, 2.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 8.8, 2.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 3.67 - 3.80 (m, 2H), 2.66 (s, 3H), 2.54 (tt, J = 11.6, 6.0 Hz, 4H), 1.63 - 1.80 (m, 5H), 1.06 - 1.35 (m, 8H), 0.75 - 0.92 (m, 6H).
［実施例１－６６］
化合物K27-011の製造[Example 1-66]
Preparation of compound K27-011
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.4, 2.0 Hz, 1H), 7.77 (s, 1H), 7.49 - 7.57 (m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 6.73 (s, 1H), 3.78 - 3.93 (m, 2H), 2.63 - 2.75 (m, 4H), 2.11 (s, 3H), 1.73 - 1.98 (m, 5H), 1.11 - 1.35 (m, 8H), 0.77 - 0.93 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 8.01 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.4, 2.0 Hz, 1H), 7.77 (s, 1H), 7.49 - 7.57 (m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 6.73 (s, 1H), 3.78 - 3.93 (m, 2H), 2.63 - 2.75 (m, 4H), 2.11 (s, 3H), 1.73 - 1.98 (m, 5H), 1.11 - 1.35 (m, 8H), 0.77 - 0.93 (m, 6H).
［実施例１－６７］
化合物K23-019の製造[Example 1-67]
Preparation of compound K23-019
1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.0, 2.0 Hz, 1H), 7.57 (dd, J = 8.8, 2.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 3.80 - 3.92 (m, 2H), 2.69 (tt, J = 12.8, 6.4 Hz, 4H), 1.74 - 1.97 (m, 5H), 1.13 - 1.35 (m, 8H), 0.76 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 8.42 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.0, 2.0 Hz, 1H), 7.57 (dd, J = 8.8, 2.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 3.80 - 3.92 (m, 2H), 2.69 (tt, J = 12.8, 6.4 Hz, 4H), 1.74 - 1.97 (m, 5H), 1.13 - 1.35 (m, 8H), 0.76 - 0.92 (m, 6H).
［実施例１－６８］
化合物K27-024の製造[Example 1-68]
Preparation of compound K27-024
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.8, 2.0 Hz, 1H), 7.35 (s, 1H), 7.20 - 7.26 (m, 2H), 7.07 (dd, J = 8.8, 2.4 Hz, 1H), 3.80 - 3.93 (m, 2H), 2.70 (tt, J = 12.0, 6.0 Hz, 4H), 1.72 - 1.98 (m, 5H), 1.12 - 1.35 (m, 8H), 0.75 - 0.94 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 8.06 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.8, 2.0 Hz, 1H), 7.35 (s, 1H), 7.20 - 7.26 (m, 2H), 7.07 (dd, J = 8.8, 2.4 Hz, 1H), 3.80 - 3.93 (m, 2H), 2.70 (tt, J = 12.0, 6.0 Hz, 4H), 1.72 - 1.98 (m, 5H), 1.12 - 1.35 (m, 8H), 0.75 - 0.94 (m, 6H).
［実施例１－６９］
化合物K27-025の製造[Example 1-69]
Preparation of compound K27-025
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 8.4, 2.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.8, 2.0 Hz, 1H), 7.41 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.80 - 3.92 (m, 2H), 2.69 (tt, J = 12.6, 6.4 Hz, 4H), 1.74 - 1.97 (m, 5H), 1.12 - 1.35 (m, 8H), 0.75 - 0.93 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 8.05 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 8.4, 2.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.8, 2.0 Hz, 1H), 7.41 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.80 - 3.92 (m, 2H), 2.69 (tt, J = 12.6, 6.4 Hz, 4H), 1.74 - 1.97 (m, 5H), 1.12 - 1.35 (m, 8H), 0.75 - 0.93 (m, 6H).
［実施例１－７０］
化合物K27-026の製造[Example 1-70]
Preparation of compound K27-026
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 8.8, 2.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.80 - 3.92 (m, 2H), 2.69 (tt, J = 12.4, 6.0 Hz, 4H), 1.73 - 1.78 (m, 5H), 1.12 - 1.35 (m, 8H), 0.75 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 8.12 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 8.8, 2.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.80 - 3.92 (m, 2H), 2.69 (tt, J = 12.4, 6.0 Hz, 4H), 1.73 - 1.78 (m, 5H), 1.12 - 1.35 (m, 8H), 0.75 - 0.92 (m, 6H).
［実施例１－７１］
化合物K30-036の製造[Example 1-71]
Preparation of compound K30-036
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 1.6 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 7.23 - 7.29 (m, 1H), 7.19 (d, J = 8.8 Hz, 1H), 3.77 - 3.90 (m, 2H), 3.07 - 3.21 (m, 4H), 2.67 (q, J = 6.4 Hz, 4H), 1.74 - 1.94 (m, 9H), 1.11- 1.36 (m, 8H), 0.78 - 0.92 (m, 6H).1 H NMR (400 MHz, CDCl3 ) δ 8.00 (d, J = 1.6 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 7.23 - 7.29 (m, 1H), 7.19 (d, J = 8.8 Hz, 1H), 3.77 - 3.90 (m, 2H), 3.07 - 3.21 (m, 4H), 2.67 (q, J = 6.4 Hz, 4H), 1.74 - 1.94 (m, 9H), 1.11- 1.36 (m, 8H), 0.78 - 0.92 (m, 6H).
［実施例２］
本発明の化合物の、ＨＣＶ産生阻害活性の測定
本発明の化合物のＨＣＶ産生阻害活性の測定を行った。測定に係る材料と方法については、本明細書において「ＨＣＶ阻害活性の確認」の項目において「ＨＣＶ阻害活性を確認するための具体的な手法の一例」として記載し、また、本実施例中に「ＮＳ２－ＳＰＣＳ１相互作用に対する阻害活性化合物の、Ｃ型肝炎ウイルス阻害活性の確認」の項目において記載したとおりである（被験化合物の投与濃度は１０μＭ）。また、実施例１で製造した化合物のうち、いくつか例については、複数の投与濃度（具体的には、０．６３、１．２５、２．５、５及び１０μＭ；０．１、１及び１０μＭ；又は１、３及び１０μＭ；各濃度について、Ｎ＝３）について試験を行い、ＨＣＶ産生阻害活性に関するＥＣ５０値（μＭ）を決定した。
＜結果＞
本発明の化合物のＨＣＶ産生阻害活性を評価するために、前述のとおり、無処理ＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）を１とした時、１０μＭの本発明の化合物（実施例１で製造されたもの）を処理したＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）の値（阻害活性値）を算出した（各化合物について、Ｎ＝３）。以下にその結果（阻害活性値の平均値）を具体的に示した。[Example 2]
Measurement of HCV production inhibitory activity of the compound of the present invention The HCV production inhibitory activity of the compound of the present invention was measured. The materials and methods for the measurement are described in the present specification under the heading "Confirmation of HCV inhibitory activity" as "An example of a specific method for confirming HCV inhibitory activity" and in the section "Confirmation of Hepatitis C virus inhibitory activity of compounds with inhibitory activity against NS2-SPCS1 interaction" (the administration concentration of the test compound was 10 μM). In addition, for some examples of the compounds produced in Example 1, tests were performed at multiple administration concentrations (specifically, 0.63, 1.25, 2.5, 5 and 10 μM; 0.1, 1 and 10 μM; or 1, 3 and 10 μM; N=3 for each concentration), and the EC50 value (μM) for the HCV production inhibitory activity was determined.
<Results>
In order to evaluate the HCV production inhibitory activity of the compound of the present invention, as described above, the amount of HCV (HCV RNA copy number) produced from untreated HuH7.5.1 cells was set to 1, and the value (inhibitory activity value) of the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells treated with 10 μM of the compound of the present invention (produced in Example 1) was calculated (N=3 for each compound). The results (average inhibitory activity value) are specifically shown below.
また、０．６３～１０μＭの濃度範囲で投与した試験の結果、化合物K7-025のＥＣ５０値は０．４９μＭ、化合物J4-026のＥＣ５０値は４．１９μＭであった。なお、これらの濃度範囲の投与において、実質的な細胞傷害性は認められなかった。In addition, as a result of the test in which the compounds were administered in the concentration range of 0.63 to 10 μM, theEC50 value of compound K7-025 was 0.49 μM, and theEC50 value of compound J4-026 was 4.19 μM. Furthermore, no substantial cytotoxicity was observed when the compounds were administered in these concentration ranges.
本発明の以下の化合物について、ＨＣＶ産生阻害活性を評価するために、無処理ＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）を１とした時、０．１、１又は１０μＭの本発明の化合物（実施例１で製造されたもの）を処理したＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）の値（阻害活性値）を算出した（各化合物について、Ｎ＝３）。以下にその結果（阻害活性値の平均値）を具体的に示した。To evaluate the HCV production inhibitory activity of the following compounds of the present invention, the amount of HCV (HCV RNA copy number) produced from untreated HuH7.5.1 cells was set to 1, and the value (inhibitory activity value) of the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells treated with 0.1, 1, or 10 μM of the compound of the present invention (manufactured in Example 1) was calculated (N=3 for each compound). The results (average inhibitory activity value) are specifically shown below.
本発明の以下の化合物について、ＨＣＶ産生阻害活性を評価するために、無処理ＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）を１とした時、１、３又は１０μＭの本発明の化合物（実施例１で製造されたもの）を処理したＨｕＨ７．５．１細胞から産生されるＨＣＶ量（ＨＣＶのＲＮＡコピー数）の値（阻害活性値）を算出した（各化合物について、Ｎ＝３）。以下にその結果（阻害活性値の平均値）を具体的に示した。To evaluate the HCV production inhibitory activity of the following compounds of the present invention, the amount of HCV (HCV RNA copy number) produced from untreated HuH7.5.1 cells was set to 1, and the value (inhibitory activity value) of the amount of HCV (HCV RNA copy number) produced from HuH7.5.1 cells treated with 1, 3, or 10 μM of the compound of the present invention (manufactured in Example 1) was calculated (N=3 for each compound). The results (average inhibitory activity value) are specifically shown below.
以上のとおり、インドール誘導体又はテトラヒドロカルバゾール誘導体である本発明の化合物はＨＣＶ阻害活性を有することが確認された。よって、本発明の化合物やそれを含む組成物は、ＨＣＶ阻害剤やＣ型肝炎の予防及び／又は治療剤として有用であることが期待できるものである。As described above, it has been confirmed that the compounds of the present invention, which are indole derivatives or tetrahydrocarbazole derivatives, have HCV inhibitory activity. Therefore, the compounds of the present invention and compositions containing them are expected to be useful as HCV inhibitors and agents for the prevention and/or treatment of hepatitis C.
式（Ｉ）～式（ＶＩＩ）の構造を有する化合物はＨＣＶ阻害活性を有するため、本発明の化合物、組成物、ＨＣＶ阻害剤、Ｃ型肝炎の予防及び／又は治療剤、医薬、治療方法、使用又はキットはＣ型肝炎の予防／治療に有用であり、産業上の利用可能性を有する。Since compounds having the structures of formulas (I) to (VII) have HCV inhibitory activity, the compounds, compositions, HCV inhibitors, preventive and/or therapeutic agents, medicines, treatment methods, uses or kits for hepatitis C of the present invention are useful for the prevention/treatment of hepatitis C and have industrial applicability.
Claims (21)
Translated fromJapaneseＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ１は、水素原子又は－ＣＯＯＲ９若しくは－ＣＯＮＨＲ１０で表される基であり；
ここでＲ９及びＲ１０は、互いに独立して、水素原子又は１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルであり；
Ｒ２は、水素原子又は１以上の置換基により置換されていても良いフェノキシ基であり；
Ｒ３は、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル又は１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリールであり；
Ｒ４及びＲ５は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１０）アリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、カルボキシ、又は、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニルであり；ここでＲ４及びＲ５は互いに結合して隣接する炭素原子と共に炭化水素環を形成してもよく；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ１はエトキシカルボニル基であり、Ｒ２及びＲ３は水素原子であり、Ｒ４及びＲ５は互いに結合して隣接する炭素原子と共に置換基を有しないシクロヘキセン環を形成し、かつＲ６～Ｒ８がいずれも水素原子である場合を除くものである］
で示される化合物、若しくはその塩又はそれらの溶媒和物を含有する、Ｃ型肝炎ウイルス阻害剤。Formula (I)
X is S(=O)2 or C(=O);
R1 is a hydrogen atom or a group represented by -COOR9 or -CONHR10 ;
wherein R9 and R10 are each independently a hydrogen atom or a (C1-C6) alkyl group optionally substituted by one or more substituents;
R2 is a hydrogen atom or a phenoxy group which may be substituted by one or more substituents;
R3 is a hydrogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, or a (C6-C10) aryl which may be substituted by one or more substituents;
R4 and R5 are each independently a hydrogen atom, a (C1-C12) alkyl optionally substituted by one or more substituents, a (C3-C8) cycloalkyl optionally substituted by one or more substituents, a (C2-C6) alkenyl optionally substituted by one or more substituents, a (C2-C6) alkynyl optionally substituted by one or more substituents, a (C6-C10) aryl optionally substituted by one or more substituents, a (C1-C6) haloalkyl optionally substituted by one or more substituents, a (C1-C6) alkoxy optionally substituted by one or more substituents, a carboxy, or a (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents; wherein R4 and R5 may be bonded to each other to form a hydrocarbon ring together with the adjacent carbon atoms;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
where X is S(=O)2 ,R1 is an ethoxycarbonyl group,R2 andR3 are hydrogen atoms,R4 andR5 are bonded together with the adjacent carbon atom to form an unsubstituted cyclohexene ring, andR6 toR8 are all hydrogen atoms.
2. A hepatitis C virus inhibitor comprising a compound represented by the following formula:
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
Ｒ３、及びＲ６～Ｒ９は、それぞれ式（Ｉ）で定義されるとおりであり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ３、及びＲ６～Ｒ８はいずれも水素原子であり、Ｒ９はエチルであり、かつ、Ｒ１１（ｎ）においてｎ＝０である場合を除くものである］
で示される化合物である、請求項１に記載Ｃ型肝炎ウイルス阻害剤。The compound represented by formula (I) is represented by the following formula (II):
X is S(=O)2 or C(=O);
R3 and R6 to R9 are each as defined in formula (I);
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
wherein X is S(=O)2 ,R3 andR6 toR8 are all hydrogen atoms,R9 is ethyl, and n=0 inR11 (n) is excluded.
The hepatitis C virus inhibitor according to claim 1, which is a compound represented by the following formula:
Ｘ、Ｒ３、Ｒ９及びＲ１１はそれぞれ式（ＩＩ）で定義されるとおりであり；
ここでＸはＳ（＝Ｏ）２であり、Ｒ３は水素原子であり、Ｒ９はエチルであり、かつ、Ｒ１１（ｎ）においてｎ＝０である場合を除くものである］
で示される化合物である、請求項２に記載のＣ型肝炎ウイルス阻害剤。The compound represented by formula (II) is represented by the following formula (III):
X, R3 , R9 and R11 are each as defined in formula (II);
wherein X is S(=O)2 ,R3 is a hydrogen atom,R9 is ethyl, andR11 (n) does not necessarily have n=0.
The hepatitis C virus inhibitor according to claim 2, which is a compound represented by the formula:
ＸはＳ（＝Ｏ）２又はＣ（＝Ｏ）であり；
ＺはＣ－Ｒ１２又はＮであり；
Ｒ６～Ｒ８は、互いに独立して、水素原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ又はハロゲン原子であり；
Ｒ１１（ｎ）において、ｎは０～８の整数であり、Ｒ１１は、互いに独立して、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良いカルバモイル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、ヒドロキシ及びハロゲン原子からなる群から独立に選択される基であり；
Ｒ１２～Ｒ１６は、互いに独立して、水素原子、ハロゲン原子、１以上の置換基により置換されていても良い（Ｃ１－Ｃ１２）アルキル、１以上の置換基により置換されていても良い（Ｃ３－Ｃ８）シクロアルキル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルケニル、１以上の置換基により置換されていても良い（Ｃ２－Ｃ６）アルキニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシ、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）ハロアルキル、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリール、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールオキシ、１以上の置換基により置換されていても良い（Ｃ６－Ｃ１２）アリールカルボニル、１以上の置換基により置換されていても良いヘテロシクリル基、１以上の置換基により置換されていても良い（５－１２）ヘテロアリール、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルコキシカルボニル、１以上の置換基により置換されていても良い（Ｃ１－Ｃ６）アルキルアミノカルボニル、カルボキシ、カルバモイル、シアノ、ヒドロキシ、アミノ、又はニトロで表される基である。A compound represented by the following formula (IV), or a salt thereof, or a solvate thereof:
X is S(=O)2 or C(=O);
Z is C-R or N;
R6 to R8 are each independently a hydrogen atom, a (C1-C12) alkyl group which may be substituted by one or more substituents, a (C1-C6) alkoxy group which may be substituted by one or more substituents, a hydroxyl group, or a halogen atom;
In R11 (n), n is an integer of 0 to 8, and R11 are each independently a group independently selected from the group consisting of (C1-C12) alkyl optionally substituted by one or more substituents, (C3-C8) cycloalkyl optionally substituted by one or more substituents, carbamoyl optionally substituted by one or more substituents, (C1-C6) alkoxy optionally substituted by one or more substituents, hydroxy, and a halogen atom;
R12 to R16 are each independently a hydrogen atom, a halogen atom, a (C1-C12) alkyl which may be substituted by one or more substituents, a (C3-C8) cycloalkyl which may be substituted by one or more substituents, a (C2-C6) alkenyl which may be substituted by one or more substituents, a (C2-C6) alkynyl which may be substituted by one or more substituents, a (C1-C6) alkoxy which may be substituted by one or more substituents, a (C1-C6) haloalkyl which may be substituted by one or more substituents, a (C6-C12) aryl which may be substituted by one or more substituents, and (C6-C12) aryloxy, (C6-C12) arylcarbonyl optionally substituted by one or more substituents, heterocyclyl group optionally substituted by one or more substituents, (5-12) heteroaryl optionally substituted by one or more substituents, (C1-C6) alkylcarbonyl optionally substituted by one or more substituents, (C1-C6) alkoxycarbonyl optionally substituted by one or more substituents, (C1-C6) alkylaminocarbonyl optionally substituted by one or more substituents, carboxy, carbamoyl, cyano, hydroxy, amino, or nitro.
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| JP2006517536A (en)* | 2003-01-22 | 2006-07-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Viral polymerase inhibitor |
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| JP2006517536A (en)* | 2003-01-22 | 2006-07-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Viral polymerase inhibitor |
Non-Patent Citations (3)
| Title |
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| DATABASE REGISTRY 27 April 2007 (2007-04-27), ANONYMOUS : "Benzoic acid,4-[[(6,7,8,9,10,11-hexahydro-5H-cyclooct[b]indol-2- yl)sulfonyl]amino]-,ethyl ester", XP093322111, retrieved from STN Database accession no. 932978-77-3* |
| ZHU DENG-JIE, DING WEN, WANG DONG-HUI, XUE MIN, YANG YONG: "One-pot, highly efficient, cavity controllable synthesis and binding properties of carbazole-based macrocycles with sulfonamide linkages", ORGANIC CHEMISTRY FRONTIERS, vol. 5, no. 15, 1 January 2018 (2018-01-01), pages 2345 - 2348, XP093322115, ISSN: 2052-4129, DOI: 10.1039/C8QO00538A* |
| 岸川 聖 ほか, Ｃ型肝炎ウイルスの感染粒子形成を阻害するテトラヒドロカルバゾール系化合物の構造活性相関研究, 日本薬学会年会要旨集第144年会, 05 March 2024, 30P-am118S, (KISHIKAWA, Hijiri et al., Structure-Activity Relationship Study of Tetrahydrocarbazole Derivatives Inhibiting HCV Particle Formation), non-official translation (Abstracts of the 144th Annual Meeting of the Pharmaceutical Society of Japan)* |
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