Brief Description of Drawings
Figure 1 is a graph showing the effect of compound a on transendothelial electrical resistance (TEER) recovery. Human vascular endothelial cell cultures were grown to confluence as measured by transendothelial cell resistance (TEER). The cell culture was then incubated under nitrogen atmosphere and allowed to hypoxia for 30 minutes. Cells were then treated with 0.1% DMSO or 5nM compound a with 0.1% DMSO. Statistical significance was noted on all data points after drug treatment. N-10 groups of cells.
FIG. 2 is a graph showing the effect of Compound A on the recovery of ATP levels. Human microvascular endothelial cells (adult) (HMVEC-AD) were grown to confluence. The cells were then treated with nitrogen for 30 minutes and returned to normal oxygen. ATP levels were monitored at defined time points using a luciferin-luciferase assay system (ATPLite, Perkin Elmer). ATP levels are expressed as relative luminescence. N-6 groups of cells (time points).
FIG. 3 is a drawing showing a scheme for preparing a compound (6)1H-NMR(200MHz，CDCl3) Figure, obtained from the following synthetic example 2.
FIG. 4 shows a scheme for preparing a compound (6)13C-NMR(50MHz，CDCl3) Figure, obtained from the following synthetic example 2.
FIG. 5 is a drawing showing a scheme of Compound (9)1H-NMR(200MHz，CDCl3) Figure, obtained from the following synthetic example 3.
FIG. 6 is a drawing showing a scheme for preparing a compound (9)13C-NMR(50MHz，CDCl3) Figure, obtained from the following synthetic example 3.
FIG. 7 shows a scheme for preparing a compound (12)1H-NMR(200MHz，CDCl3) FIG. 4 is obtained from the following Synthesis example 4.
FIG. 8 is a drawing showing a scheme for preparing a compound (12)13C-NMR(50MHz，CDCl3) FIG. 4 is obtained from the following Synthesis example 4.
FIG. 9 is a drawing of Compound (15)1H-NMR(200MHz，CDCl3) FIG. 5 is obtained from the following Synthesis example.
FIG. 10 shows a scheme for preparing a compound (15)13C-MR(50MHz，CDCl3) FIG. 5 is obtained from the following Synthesis example.
FIG. 11 is a photograph of Compound (18)1H-NMR(200MHz，CDCl3) FIG. 6 is obtained from the following Synthesis example.
FIG. 12 shows a scheme for preparing Compound (18)13C-NMR(50MHz，CDCl3) FIG. 6 is obtained from the following Synthesis example.
FIG. 13 is a photograph of Compound (21)1H-NMR(200MHz，CDCl3) FIG. 7, obtained from the following Synthesis example.
FIG. 14 shows a preparation of Compound (21)13C-NMR(50MHz，CDCl3) FIG. 7, obtained from the following Synthesis example.
FIG. 15 shows a scheme for preparing Compound (23)1H-NMR(200MHz，CDCl3) FIG. 8 is obtained from the following Synthesis example.
FIG. 16 shows a scheme for preparing Compound (23)13C-NMR(50MHz，CDCl3) FIG. 8 is obtained from the following Synthesis example.
FIG. 17 is a photograph of compound (25)1H-MR(200MHz，CDCl3) FIG. 9 is obtained from the following Synthesis example 9.
FIG. 18 is compound (25)) Is/are as follows13C-NMR(50MHz，CDCl3) FIG. 9 is obtained from the following Synthesis example 9.
FIG. 19 is of Compound (34)1H-NMR(200MHz，CDCl3) FIG. 10 is obtained from the following Synthesis example 10.
FIG. 20 is a drawing of Compound (34)13C-NMR(50MHz，CDCl3) FIG. 10 is obtained from the following Synthesis example 10.
Detailed Description
In the present invention, the "11-deoxy-prostaglandin compound" (hereinafter also referred to as "11-deoxy-PG compound") may include derivatives or analogs (including substituted derivatives) of any compound having no substituent at the 11-position of the prostanoic acid skeleton, regardless of the configuration of the five-membered ring, the number of double bonds, the presence or absence of a substituent, or any other modification on the α chain or the ω chain.
The formula (A) shows a basic skeleton of C-20 carbon atoms, but the present invention is not limited to compounds having the same number of carbon atoms. In the formula (A), the number of carbon atoms constituting the basic skeleton of the PG compound is from the carboxylic acid (number 1), the number of carbon atoms in the alpha chain is from 2 to 7 in the direction of the five-membered ring, the number of carbon atoms in the ring is from 8 to 12, and the number of carbon atoms in the omega chain is from 13 to 20. When the number of carbon atoms in the alpha chain is reduced, the numbering is deleted in sequence from the 2-position; and when the number of carbon atoms in the alpha chain increases, the compounds are named as substituted compounds having a corresponding substituent at the 2-position instead of the carboxyl group (C-1). Similarly, when the number of carbon atoms in the ω chain decreases, the numbering is sequentially absent from position 20; when the number of carbon atoms in the ω -chain increases, the carbon atoms other than the 20-position are named as substituents. Unless otherwise specified, the stereochemistry of the compounds is the same as that of formula (a) above.
As mentioned above, the nomenclature of 11-deoxy-PG compounds is based on the prostanoic acid skeleton. However, in the case where the compound has a similar partial structure to that of prostaglandin, the abbreviation "PG" may be used. Thus, an 11-deoxy-PG compound in which the alpha chain is extended by two carbon atoms (i.e., having 9 carbon atoms in the alpha chain) is named as a 2-decarboxylated-2- (2-carboxyethyl) -11-deoxy-PG compound. Likewise, an 11-deoxy-PG compound having 11 carbon atoms in the α chain is named as a 2-decarboxylated-2- (4-carboxybutyl) -11-deoxy-PG compound. Further, an 11-deoxy-PG compound in which the ω -chain extends by two carbon atoms (i.e., has 10 carbon atoms in the ω -chain) is named as an 11-deoxy-20-ethyl-PG compound. However, these compounds may also be named according to IUPAC nomenclature.
Examples of the analog (including substituted derivative) or derivative include 11-deoxy-PG compounds in which a carboxyl group at the end of the α chain is esterified; a compound in which the alpha chain is extended; a physiologically acceptable salt thereof; compounds having a double bond in positions 2 to 3 or a triple bond in positions 5 to 6, compounds having substituents in positions 3,5, 6, 16, 17, 18, 19 and/or 20; and compounds having a lower alkyl group or a hydroxy (lower) alkyl group at the position 9 in place of the hydroxy group.
Preferred substituents in positions 3, 17, 18 and/or 19 according to the invention include alkyl groups having 1 to 4 carbon atoms, especially methyl and ethyl. Preferred substituents at position 16 include lower alkyl groups (e.g., methyl and ethyl), hydroxy groups, halogen atoms (e.g., chlorine and fluorine), and aryloxy groups (e.g., trifluoromethylphenoxy). Preferred substituents at position 17 include lower alkyl groups (e.g., methyl and ethyl), hydroxy groups, halogen atoms (e.g., chlorine and fluorine), and aryloxy groups (e.g., trifluoromethylphenoxy). Preferred substituents at position 20 include saturated or unsaturated lower alkyl (e.g. C1-4 alkyl), lower alkoxy (e.g. C1-4 alkoxy) and lower alkoxyalkyl (e.g. C1-4 alkoxy-C1-4 alkyl). Preferred substituents at position 5 include halogen atoms such as chlorine and fluorine. Preferred substituents at position 6 include oxo which forms a carbonyl group. The stereochemistry of PG having a hydroxy, lower alkyl or hydroxy (lower) alkyl substituent at position 9 may be α, β or a mixture thereof.
Further, the above-mentioned analog or derivative may be a compound having an alkoxy group, a cycloalkyl group, a cycloalkoxy group, a phenoxy group, or a phenyl group at the end of the ω -chain, which is shorter than that of the original prostaglandin.
The nomenclature of the 11-deoxy-PG compounds used herein is based on the numbering system of the prostanoic acid represented by formula (A) above.
The following formula (I) represents preferred compounds for use in the present invention:
wherein L and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, wherein the five-membered ring may optionally contain at least one double bond;
a is-CH3、-CH2OH、-COCH2OH, -COOH or a functional derivative thereof;
R1is a saturated or unsaturated divalent lower or medium aliphatic hydrocarbon which is unsubstituted or substituted by: halogen, alkyl, hydroxy, oxo, aryl or heterocyclyl, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur;
R0is a saturated or unsaturated lower or medium aliphatic hydrocarbon residue which is unsubstituted or substituted by: halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkoxy, aryl, aryloxy, heterocyclic group or heterocyclic oxy group; lower alkoxy; a lower alkanoyloxy group; cyclo (lower) alkyl; cyclo (lower) alkoxy; an aryl group; an aryloxy group; a heterocyclic group; heterocyclic oxy, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen, or sulfur.
The following formula (II) represents more preferred compounds for use in the present invention:
wherein L and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, wherein the five-membered ring may optionally contain at least one double bond;
a is-CH3、-CH2OH、-COCH2OH, -COOH or a functional derivative thereof;
b is a single bond, -CH2-CH2-、-CH＝CH-、-C≡C-、-CH2-CH2-CH2-、-CH＝CH-CH2-、-CH2-CH＝CH-、-C≡C-CH2-or-CH2-C≡C-；
Z is
Or
Wherein R is4And R5Is hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl, wherein R is4And R5Not simultaneously being hydroxyl and lower alkoxy;
R1is a saturated or unsaturated divalent lower or medium aliphatic hydrocarbon which is unsubstituted or substituted by: halogen, alkyl, hydroxy, oxo, aryl or heterocyclyl, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur:
ra is a saturated or unsaturated lower or medium aliphatic hydrocarbon residue which is unsubstituted or substituted by: halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkoxy, aryl, aryloxy, heterocyclic group or heterocyclic oxy group; lower alkoxy; a lower alkanoyloxy group; cyclo (lower) alkyl; cyclo (lower) alkoxy; an aryl group; an aryloxy group; a heterocyclic group; heterocyclic oxy, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen, or sulfur.
The following formula (III) represents a particularly preferred group of compounds from the above group:
wherein L is hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, and wherein the five-membered ring may optionally contain at least one double bond;
a is-CH3、-CH2OH、-COCH2OH, -COOH or a functional derivative thereof;
b is a single bond, -CH2-CH2-、-CH＝CH-、-C≡C-、-CH2-CH2-CH2-、-CH＝CH-CH2-、-CH2-CH＝CH-、-C≡C-CH2-or-CH2-C≡C-；
Z is:
or
Wherein R is4And R5Is hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl, wherein R is4And R5Not simultaneously being hydroxyl and lower alkoxy;
X1and X2Is hydrogen, lower alkyl or halogen;
R1is a saturated or unsaturated divalent lower or medium aliphatic hydrocarbon which is unsubstitutedOr substituted with: halogen, alkyl, hydroxy, oxo, aryl or heterocyclyl, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur;
R2is a single bond or lower alkylene;
R3is lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkoxy, aryl, aryloxy, heterocyclic group or heterocyclic oxy group, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen or sulfur.
The present invention also relates to a compound represented by the following formula (IV):
wherein L is hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, wherein the five-membered ring may optionally contain at least one double bond;
a is-CH3、-CH2OH、-COCH2OH, -COOH or a functional derivative thereof;
b is a single bond, -CH2-CH2-、-CH＝CH-、-C≡C-、-CH2-CH2-CH2-、-CH＝CH-CH2-、-CH2-CH＝CH-、-C≡C-CH2-or-CH2-C≡C-；
Z is
Or
Wherein R is4And R5Is hydrogen or hydroxyHalogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl, wherein R4And R5Not simultaneously being hydroxyl and lower alkoxy;
X1' and X2' are the same or different halogen atoms;
R1is a saturated or unsaturated divalent lower or medium aliphatic hydrocarbon which is unsubstituted or substituted by: halogen, alkyl, hydroxy, oxo, aryl or heterocyclyl, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur;
R2is a single bond or lower alkylene;
R3is lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkoxy, aryl, aryloxy, heterocyclic group or heterocyclic oxy group, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen or sulfur;
with the proviso that the compound of formula (IV) is not 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGE1。
In the above formulae, R1And Ra means that at least one or more double and/or triple bonds are present between the backbone and/or side chain carbon atoms either individually, separately or in succession. According to common nomenclature, the unsaturated bond between two consecutive positions is represented by a number indicating the smaller of the two positions, and the unsaturated bond between two distal positions is represented by a number indicating the two positions.
The term "lower or medium aliphatic hydrocarbon" means a straight or branched chain hydrocarbon group having 1 to 14 carbon atoms (for a side chain, preferably 1 to 3 carbon atoms); and for R1Preferably 1 to 10 carbon atoms, particularly preferably 6 to 10 carbon atoms; for Ra, it is from 1 to 10 carbon atoms, in particular from 1 to 8 carbon atoms.
The term "halogen" includes fluorine, chlorine, bromine and iodine.
The term "lower" in this specification is intended to include groups having 1 to 6 carbon atoms unless otherwise specified.
The term "lower alkyl" refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.
The term "lower alkoxy" refers to lower alkyl-O-, wherein lower alkyl is as defined above.
The term "hydroxy (lower) alkyl" refers to a lower alkyl group as defined above substituted with at least one hydroxy group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxyethyl.
The term "lower alkanoyloxy" refers to a group represented by the formula RCO-O-, wherein RCO-is an acyl group formed by oxidation of a lower alkyl group as defined above, for example, an acetyl group.
The term "cyclo (lower) alkyl" refers to a cyclic group formed by cyclization of a lower alkyl group as defined above but containing three or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "cyclo (lower) alkoxy" means a cyclo (lower) alkyl-O-, wherein cyclo (lower) alkyl is as defined above.
The term "aryl" may include unsubstituted or substituted aromatic hydrocarbon rings (preferably monocyclic groups), such as phenyl, tolyl, xylyl. Examples of the substituent are a halogen atom and a halo (lower) alkyl group, wherein the halogen atom and the lower alkyl group are as defined above.
The term "aryloxy" refers to a group represented by the formula ArO-, wherein Ar is aryl as defined above.
The term "heterocyclyl" may include mono-to tricyclic, preferably monocyclic, heterocyclyl groups which are 5 to 14, preferably 5 to 10, membered rings having optionally substituted carbon atoms and 1 to 4, preferably 1 to 3, atoms selected from nitrogen, oxygen atomsOne or both types of heteroatoms of the group and sulfur atoms. Examples of heterocyclic groups include furyl, thienyl, pyrrolyl,Azolyl radical, isoOxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, indolyl, benzothienyl, quinolinyl, isoquinolinyl, purinyl, quinazolinyl, carbazolyl, acridinyl, phenanthridinyl, benzimidazolyl, benzimidazolinyl, benzothiazolyl, phenothiazinyl. Examples of the substituent in this case include halogen and halogen-substituted lower alkyl, wherein the halogen atom and lower alkyl are as described above.
The term "heterocyclyloxy" refers to a gene represented by the formula HcO-, wherein Hc is a heterocyclic group as described above.
The term "functional derivative" of a includes salts (preferably pharmaceutically acceptable salts), ethers, esters and amides.
Suitable "pharmaceutically acceptable salts" include non-toxic salts conventionally used; for example, salts with inorganic bases such as alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), ammonium salts; or a salt with an organic base, for example, an amine salt (e.g., methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethyl amino) ethane salt, monomethyl-monoethanolamine salt, procaine salt and caffeine salt), an alkaline amino acid salt (e.g., arginine salt and lysine salt), a tetraalkylammonium salt and the like. These salts can be prepared in a conventional manner, for example from the corresponding acids and bases or by salt exchange.
Examples of ethers include alkyl ethers such as: lower alkyl ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, tert-butyl ether, pentyl ether and 1-cyclopropylethyl ether; medium or higher alkyl ethers such as octyl ether, diethylhexyl ether, lauryl ether and cetyl ether; unsaturated ethers such as oleyl ether and linolenyl ether (linolenylether); lower alkenyl ethers such as vinyl ether, allyl ether; lower alkynyl ethers such as ethynyl ether and propynyl ether; hydroxy (lower) alkyl ethers such as hydroxyethyl ether and hydroxyisopropyl ether; lower alkoxy (lower) alkyl ethers such as methoxymethyl ether and 1-methoxyethyl ether; optionally substituted aryl ethers such as phenyl ether, tosyl ether, t-butylphenyl ether, salicyl ether, 3, 4-dimethoxyphenyl ether and benzamidophenyl ether; and aryl (lower) alkyl ethers such as benzyl ether, trityl ether and benzhydryl ether.
Examples of the ester include aliphatic esters such as lower alkyl esters, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester and 1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester and allyl ester; lower alkynyl esters such as acetylene ester and propynyl ester; hydroxy (lower) alkyl esters such as hydroxyethyl ester; lower alkoxy (lower) alkyl esters such as methoxymethyl ester and 1-methoxyethyl ester; and optionally substituted aryl esters such as phenyl ester, tolyl ester, tert-butyl phenyl ester, salicyl ester, 3, 4-dimethoxyphenyl ester, and benzamide phenyl ester; and aryl (lower) alkyl esters such as benzyl ester, trityl ester and diphenylmethyl ester.
The amide of a means a group represented by the formula-CONR 'R ", wherein R' and R" are each a hydrogen atom, a lower alkyl group, an aryl group, an alkylsulfonyl group, an arylsulfonyl group, a lower alkenyl group, and a lower alkynyl group, and includes, for example, lower alkylamides such as formamide, acetamide, dimethylamide, and diethylamide; arylamides such as anilide and toluidine; and alkylsulfonamides or arylsulfonylamides such as methylsulfonylamide, ethylsulfonylamide, and tolylsulfonylamide.
Examples of preferred L include hydroxy or oxo, which mainly constitute a 5-membered ring structure of the so-called PGF type or PGE type.
Examples of preferred a are-COOH, a pharmaceutically acceptable salt, ester or amide thereof.
An example of preferred B is-CH2-CH2This provides the so-called 13, 14-dihydro-type structure.
Preferably X1And X2Examples of (a) are hydrogen or at least one of them is halogen, more preferably both of them are halogen, especially fluorine, which provides the so-called 16, 16-difluoro type structure.
Preferred X1' and X2' is a difluoro atom.
Preferred R1Is a hydrocarbon group containing 1 to 10 carbon atoms, preferably 6 to 10 carbon atoms. Further, at least one carbon atom in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen or sulfur.
R1Examples of (b) include, for example, the following groups:
-CH2-CH2-CH2-CH2-CH2-CH2-，
-CH2-CH＝CH-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-CH＝CH-，
-CH2-C≡C-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-CH(CH3)-CH2-，
-CH2-CH2-CH2-CH2-O-CH2-，
-CH2-CH＝CH-CH2-O-CH2-，
-CH2-C≡C-CH2-O-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-，
-CH2-CH＝CH-CH2-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH＝CH-，
-CH2-C≡C-CH2-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-，
-CH2-CH＝CH-CH2-CH2-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH2-CH＝CH-，
-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-。
preferred Ra are hydrocarbons containing from 1 to 10 carbon atoms, more preferably from 1 to 8 carbon atoms. Ra may have one or two side chains containing one carbon atom.
Preferred R2Is a single bond, preferably R3Is a lower alkyl group. R3May have one orTwo side chains containing one carbon atom.
The configuration of the rings and the α chain and/or ω chain in the above formula (I), formula (II), formula (III) and formula (IV) may be the same as or different from that of the original PG. However, the present invention also includes mixtures of compounds having a pristine configuration with compounds having a non-pristine configuration.
Typical examples of compounds of the invention are 11-deoxy-13, 14-dihydro-16, 16-difluoro-PGE or PGF compounds, 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGE or PGF compounds, 2-decarboxylated-2- (2-carboxyethyl) -11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGE or PGF compounds, or 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-20-methyl or ethyl-PGE or PGF compounds and derivatives or analogues thereof.
A preferred example of a compound of the invention is 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGE111-deoxy-13, 14-dihydro-16, 16-difluoro-PGE111-deoxy-13, 14-dihydro-15-oxo-16, 16-difluoro-PGE1Isopropyl ester, 2-decarboxylated-2- (2-carboxyethyl) -11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGE1Isopropyl ester, 2-decarboxylated-2- (2-carboxyethyl) -11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGE111-deoxy-13, 14-dihydro-15-oxo-16, 16-difluoro-20-methyl-PGE1Isopropyl ester, 11-deoxy-13, 14-dihydro-15-oxo-16, 16-difluoro-20-methyl-PGE111-deoxy-13, 14-dihydro-15-oxo-16, 16-difluoro-20-ethyl-PGE111-deoxy-13, 14-dihydro-15-oxo-16, 16-difluoro-PGE1Methyl ester, 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-20-ethyl-PGE1Isopropyl ester or 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGF1αAn isopropyl ester.
In the present invention, any isomer such as a single tautomer, a mixture of tautomers, an optical isomer, a mixture of optical isomers, a racemic mixture, and other stereoisomers may be used for the same purpose.
Certain compounds used in the present invention can be prepared by the methods disclosed in U.S. Pat. Nos. 5,073,569, 5,166,174, 5,221,763, 5,212,324, 5,739,161, and 6,242,485 (all of these references cited are incorporated herein by reference).
In accordance with the present invention, the present invention may treat a mammalian subject by administering a compound for use in the present invention. The subject may be any mammalian subject, including humans. The compounds may be used systemically or locally. In general, the compounds may be administered by oral administration, intravenous injection (including infusion), subcutaneous injection, intrarectal administration, intravaginal administration, transdermal administration, and the like.
The dosage will depend on the animal species, age, weight, condition to be treated, desired therapeutic effect, route of administration, period of treatment, and the like. Satisfactory results can be obtained by systemic administration 1 to 4 times per day or by continuous administration in an amount of 0.00001 to 500mg/kg, more preferably 0.0001 to 100mg/kg per day.
Preferred compounds may be formulated into pharmaceutical compositions suitable for administration by conventional means. The composition may be a composition suitable for oral administration, injection or infusion, or may be a preparation for external use, a suppository or pessary.
The composition of the invention may also comprise physiologically acceptable additives. The additives may include ingredients used with the compounds of the present invention, such as excipients, diluents, fillers, solvents, lubricants, adjuvants, binders, disintegrants, coatings, encapsulants, ointment bases, suppository bases, aerosols, emulsifiers, dispersants, suspending agents, thickeners, tonicity agents, buffers, demulcents, preservatives, antioxidants, flavorants, seasonings, colorants, functional materials such as cyclodextrins, biodegradable polymers, and stabilizers. Additives are well known in the art and may be selected from additives in the usual pharmaceutical reference books.
The amount of the above compound in the composition of the present invention may vary depending on the dosage form of the composition, and may be generally 0.000001 to 10.0%, more preferably 0.00001 to 5.0%, and most preferably 0.0001 to 1%.
Examples of solid compositions for oral administration include tablets, troches, sublingual tablets, capsules, pills, powders, granules and the like. Solid compositions may be prepared by mixing one or more active ingredients with at least one inactive diluent. The composition may also contain additives other than inactive diluents, such as lubricants, disintegrants, and stabilizers. Tablets and pills may also be coated with an enteric coating film or a gastrointestinal coating film, if desired.
The composition may comprise two or more coatings. They may also be adsorbed on slow release materials, or may be microencapsulated. Alternatively, the composition may be encapsulated in a material that is readily degradable (e.g., gelatin). They may also be dissolved in suitable solvents, for example fatty acids or their mono-, di-or triglycerides, to give soft capsules. Where quick acting properties are desired, sublingual tablets may be used.
Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups, elixirs and the like. The composition may further comprise a conventional inactive diluent, such as purified water or ethanol. The compositions may also contain additives other than inactive diluents, such as wetting and suspending agents, sweetening, flavoring, perfuming and preservative agents and the like as adjuvants.
The compositions of the invention may be in the form of a spray, containing one or more active ingredients, and may be prepared by known methods.
Examples of the parenterally administrable injectable compositions of the present invention include sterile aqueous or sterile nonaqueous solutions, suspensions and emulsions.
Diluents in aqueous solutions or suspensions may include, for example, distilled water for injection, physiological saline, and ringer's solution.
Non-aqueous diluents in solutions and suspensions may include, for example, propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), alcohols (e.g., ethanol), and polysorbates. The composition may further comprise additives such as preservatives, wetting agents, emulsifying agents, dispersing agents and the like. They can be sterilized by the following methods: filtration (e.g., bacterial filters), mixing with a bactericide, or sterilization by gas sterilization or radioisotope radiation.
Injectable compositions may also be provided in the form of sterile powder injection compositions which are dissolved in a sterile solvent for injection immediately prior to use.
The external preparation of the present invention may be any form of external preparation for skin site and ear-nose-throat site, including ointment, cream, lotion and spray.
Another form of the composition is a suppository or pessary, which can be prepared by mixing the active ingredient into a conventional base such as cocoa butter, which softens at body temperature, and a nonionic surfactant having a suitable softening temperature, and can be used for improving absorbability.
The term "treatment" as used herein includes, for example, any controlled means of preventing, curing, alleviating and preventing the progression of a disorder.
The term "central nervous system disease" as used herein includes any central nervous system disease involving or associated with any type of condition and/or disease, or any central nervous system disease caused by: ischemia, trauma, infection, inflammation, tumor, edema, hypotension, hypoxemia, blood clot (thrombus), enzyme activation, arterial occlusion (embolus), arteriosclerosis, metabolic disorder, degeneration, aging, drug, medicine or surgery.
Examples of "central nervous system diseases" include, but are not limited to, cerebrovascular diseases such as cerebral apoplexy and cerebral infarction (e.g., cerebral thrombosis, cerebral arterial embolism, cerebral lacunar infarction, asymptomatic cerebral infarction); vasospasm due to intracerebral hemorrhage or subarachnoid hemorrhage; cerebrovascular dementia; neuronal diseases such as alzheimer's disease, Parkinson's disease, Huntington's chorea, dementia, Pick's disease, spinocerebellar degeneration, chorea, AIDS encephalopathy, hepatic encephalopathy, amyotrophic lateral sclerosis, peripheral neuropathy induced by anticancer drugs, diabetic neuropathy, traumatic neuropathy and multiple sclerosis; cerebral edema, hypernatremic encephalopathy, and brain tumors; ischemic diseases such as cerebral ischemia due to vascular disease, Transient Ischemic Attack (TIA), Reversible Ischemic Neurological Disorder (RIND), cerebral ischemia due to migraine or cocaine abuse, cerebral ischemia (including epilepsy or epileptic psychotic symptoms), cerebral ischemia during surgery (ischemic tissue injury), cerebral ischemia due to head injury, cerebral ischemia due to hypotension, cerebral ischemia due to hypoxemia or dyspnea, and cerebral ischemia due to cardiac arrest; inflammatory brain diseases such as chronic relapsing multiple sclerosis, encephalomyelitis, meningitis, traumatic brain injury; neonatal asphyxia and secondary complications of these diseases.
According to the present invention, the compounds used herein have a significant effect on restoring the barrier function of cerebrovascular endothelial cells, particularly the barrier function of the blood brain barrier, and thus are also useful for protecting cerebrovascular endothelial cells.
The pharmaceutical composition of the present invention may contain other pharmacological ingredients as long as they do not conflict with the object of the present invention.
The formulations of the present invention may contain a single active ingredient or a combination of two or more active ingredients. In the combination of the various active ingredients, their respective amounts may be appropriately increased or decreased in consideration of their therapeutic effects and safety.
In addition, the preparation of the present invention may contain other pharmacologically active ingredients as long as they do not conflict with the object of the present invention.
The present invention will be described in detail with reference to the following examples, but this does not limit the scope of the present invention.
Example 7
< method >
Human microvascular endothelial cells (adult) (HMVEC-AD) were grown to confluence. The cells were then treated with nitrogen for 30 minutes and returned to normal oxygen. The periluciferin-luciferase assay system (ATPLite, Perkin Elmer) monitors ATP levels at defined time points.
< results >
As shown in FIG. 2, ATP levels decreased when the cells were exposed to a nitrogen atmosphere for 30 minutes. ATP levels recovered faster in 5nM compound a-treated cells compared to cells treated with 0.01% DMSO alone.
The results indicate that compound a is useful for treating central nervous system disorders.
Synthesis example 1
16, 16-difluoro-PGA1Synthesis of benzyl ester (2)
Mixing 16, 16-difluoro-PEE1Benzyl ester (1) (457.8mg, 0.95mmol) in acetic acid
(13.7ml, 0.24mol) the solution was stirred at 80 ℃ for 18 h. The reaction mixture was allowed to cool to room temperature. 10ml of toluene was added to the solution, and concentrated under reduced pressure. This operation was repeated 5 times to remove acetic acid. The residue was purified by silica gel column chromatography (silica gel: FL60D (70g), FujiSilysia, hexane/ethyl acetate (2: 1)) to give compound (2) as a yellow oil. Yield: 391.6mg (88.9%).
11-deoxy-13, 14-dihydro-16, 16-difluoro-PGE1(3) Synthesis of (2)
In the presence of 10% palladium-carbon (57.4mg, wetted with 50% (w/w) water) at room temperature under atmospheric pressure, 16-difluoro-PGA was reacted1Benzyl ester (compound (2)) (382.5 mg, 0.83mmol) was hydrogenated in ethyl acetate (10ml) for 2 hours. The reaction mixture was filtered through a pad of celite, and the filter cake was washed with ethyl acetate, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel BW-300SP (50g, humidified with 50% (w/w) water), Fuji Silysia, hexane/ethyl acetate (1: 1)) to give crude compound (3) (298.5mg, 95.7%).
The crude compound (3) is mixed with a number of other crude compounds. Thus, a total of about 350mg of crude compound was purified by preparative HPLC (YMC-Pack D-SIL-5-0620X 250mm, hexane/2-propanol/acetic acid (250: 5: 1), 20 ml/min) to give compound (3) as a colorless oil. Yield: 297.3mg (HPLC purification recovery: 83.5%).
1H-NMR(200MHz，CDCl3)δ
0.94(3H，t，J＝7.1Hz)，1.22-2.29(28H，m)，2.34(2H，t，J＝7.3Hz)，3.65-3.81(1H，m)
13C-NMR(50MHz，CDCl3)δ
13.70，22.40，23.25，24.32，26.28，26.63)，27.18，27.58，28.49，29.09，30.39，31.77(t，J＝24.4Hz)，33.67，37.63，41.05，54.76，72.73(t，J＝29.0Mz)，124.09(t，J＝244.3Hz)，179.07，220.79.
Synthesis example 2
By the above two-step reaction in a similar manner to that described in Synthesis example 1, 11-deoxy-13, 14-dihydro-15-oxo-16, 16-difluoro-PGE was obtained1Isopropyl ester (compound (6)) was a colorless oil. Yield: 0.285g (first step: 96.2%, second step: 97.6%, HPLC purification: 81.0% recovery). Process for producing Compound (6)1H-NMR (200MHz，CDCl3) And13C-NMR(50MHz，CDCl3) As shown in fig. 3 and 4, respectively.
Synthesis example 3
According to a similar manner to that described in synthetic example 1, 2-decarboxylation-2- (2-carboxyethyl) -11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGE was obtained1Isopropyl ester (compound (9)) was a colorless oil. Yield: 0.402g (first step: 94.9%, second step: 92.2%, HPLC purification: recovery 83.1%). Process for producing Compound (9)1H-NMR(200MHz，CDCl3) And13C-NMR（50MHz，CDCl3) As shown in fig. 6, respectively.
Synthesis example 4
According to a similar manner to that described in Synthesis example 1, 2-decarboxylation-2- (2-carboxyethyl) -11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGE was obtained1(Compound (12)): as a colorless oil. Yield: 0.696g (first step: 95.6%, second step: 99.3%, HPLC purification: recovery: 87.4%). Process for producing Compound (12)1H-NMR(200MHz，CDCl3) And13C-NMR（50MHz，CDCl3) As shown in fig. 7 and 8, respectively.
Synthesis example 5
Following a similar procedure as described in synthetic example 1, 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-20-methyl-PGE was obtained1Isopropyl ester (compound (15)) was a colorless oil. Yield: 0.271g (first step: 91.4%, second step: 97.3%, HPLC purification: recovery: 79.0%). Process for producing Compound (15)1H-NMR(200MHz，CDCl3) And13C-NMR(150MHz，CDCl3) As shown in fig. 9 and 10, respectively.
Synthesis example 6
Following a similar procedure as described in synthetic example 1, 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-20-methyl-PGE was obtained1(Compound (18)) was a colorless oil. Yield: 0.637g (first step: 93.3%, second step: 96.6%, HPLC purification: recovery: 73.9%). Process for production of Compound (18)1H-NMR(200MHz，CDCl3) And13C-NMR(50MHz，CDCl3) As shown in figures 11 and 12, respectively.
Synthesis example 7
Following a similar procedure to that described in synthetic example 1, 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-20-ethyl-PGE was obtained1(Compound (21)) was a colorless oil. Yield: 0.401g (first step: 90.6%, second step: 92.7%, HPLC purification: recovery: 29.2%). Process for producing Compound (21)1H-NMR(200MHz，CDCl3) And13C-NMR(50MHz，CDCl3) As shown in fig. 13 and 14, respectively.
Synthesis example 8
Esterification of Compound (22) with diazomethane to give 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGE1The methyl ester (compound (23)) was a colorless oil. Yield: 0.860g (72.9%, after purification by silica gel column chromatography). Process for producing Compound (23)1H-NMR(200MHz，CDCl3) And13C-NMR(50MHz，CDCl3) As shown in fig. 15 and 16.
Synthesis example 9
Compound (24) (0.67g, 1.66mmol) was dissolved in DMF (13ml), and K was added2CO3(460.1mg, 3.33mmol) and 2-iodopropane (831. mu.l, 8.32 mmol). SolutionThe solution was stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, to which were added water (10ml) and brine, followed by extraction with ethyl acetate (30 ml). The organic layer was washed with brine (10ml), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel FL60D (50g), FujiSilysia, hexane/ethyl acetate (5: 1)) to give crude 11-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-20-ethyl-PGE1Isopropyl ester (compound (25)) (0.70g, 94.6%). The crude compound (25) was purified by preparative HPLC to give compound (25) as a colorless oil. Yield 245.8mg (35.1%). Process for production of Compound (25)1H-NMR(200MHz，CDCl3) And13C-NMR(50MHz，CDCl3) As shown in fig. 17 and 18, respectively.
Synthesis example 10
Compound (26) (8.71g, 20.0mmol) was dissolved in 1, 2-dichloroethane (70ml), and 1, 1' -thiocarbonyldiimidazole (5.41g, 30.3mmol) was added. The solution was stirred at 70 ℃ for 1 hour. The melons were mixed and discarded to room temperature, then concentrated under reduced pressure. The dead residue was purified by silica gel column chromatography (silica gel BW-300SP (650G), Fuji Silysia, ethane/ethyl acetate (1: 1)) to give compound (27) as a pale yellow oil (10.61G, 97.0%).
Bu is put into3SnH (11.21g, 38.5mmol) was dissolved in toluene (224ml) and refluxed by heating. A solution of compound (27) (10.41g, 19.2mmol) in toluene (208ml) was added dropwise to the reaction mixture at reflux temperature over 70 minutes. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give crude compound (28) as a pale yellow oil.
The crude compound (28) (19.2mmol) was dissolved in THF (52ml) and TBAF solution (1.0M THF, 38.5ml, 38.5mmol) was added dropwise over 10 min. After 1 h, TBAF solution (1.0M in THF, 19.2ml, 19.2mmol) was added dropwise to the solution. After stirring for a total of 3.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel BW-300SP (1,000g), Fuji Silysia, hexane/ethyl acetate (1: 1)) to give compound (29) as a yellow oil (4.01g, 69.3%).
Compound (31) was obtained from compound (29) by Swern oxidation and introduction of the ω chain.
Compound (31) (807.4mg, 1.88mmol) was hydrogenated in ethyl acetate (8ml) in the presence of 10% palladium-carbon at room temperature for 2 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give crude compound (32) as a light brown oil.
The crude compound (32) (1.88mmol) was dissolved in EtOH (8 ml). To the solution was added dropwise 1N NaOH solution (7.4ml, 7.4mol) at room temperature over 10 minutes. The reaction mixture was stirred at room temperature for 10 hours, and then cooled with ice. 1N HCl (7.1ml) was added dropwise to the reaction mixture to adjust the pH to about 3-4. The reaction mixture was then extracted with TBME (30 ml). The organic layer was washed with water (10ml) and brine (10ml), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: FL-60D (80g) containing 15% water, Fuji Silysia, hexane/ethyl acetate (2: 1)) to give compound (33) as a pale yellow oil (481.4mg, 68.8%).
By a similar method to that described in Synthesis example 9, 11-deoxy-13, 14-dihydro-15-oxo-16, 16-difluoro-PGF was obtained from Compound (33)1αIsopropyl ester (compound (34)) was a colorless oil. Yield: 166.6mg (reaction step 91.9%: HPLC purification: recovery: 55.4%). Process for producing Compound (34)1H-NMR(200MHz，CDCl3) And13C-NMR(50MHz，CDCl3) As shown in fig. 19 and 20, respectively.