Summary of The Invention
The present invention relates to 3H- [1, 2, 3] triazolo [4, 5-d ] pyrimidine derivatives for use in the treatment of cell proliferative diseases, for the treatment of disorders associated with MET activity, and for the inhibition of the tyrosine kinase MET receptor. The compounds of the present invention can be illustrated by formula I and formula II:
Detailed Description
The compounds of the invention, or pharmaceutically acceptable salts thereof, are useful for inhibiting the receptor tyrosine kinase MET and are illustrated by compounds of formula I or formula II or partially deuterated formula I or formula II:
wherein
R1Independently selected from: -O (CH)2)nOR11、-C(O)R11、-C(O)OR11、-C(O)NR11R12、C3-C8Cycloalkyl, 3-8 membered heteroalicyclic- (3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6Alkynyl, wherein C3-C8Cycloalkyl, 3-8 membered heteroalicyclic, 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6The alkynyl group is optionally substituted with one or more moieties selected from the group consisting of: br, Cl, F, - (CH)2)nCH(OR11)CH3、-(CH2)nOR11、-(CH2)nC(CH3)2OR11、-C(O)R11、-C(O)OR11、-(CR11R12)nC(O)OR11、-C(O)NR11R12、-(CR11R12)nC(O)NR11R12、-(CH2)nNR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-(CH2)nNR11C(O)NR11R12、-(CH2)nNR11C(O)OR12、-NR11C(O)R12、-NR11C(O)OR12、-NR11S(O)2R12、-CN、-NO2Oxo, C1-C6Alkyl radical, C3-C8Cycloalkyl, - (CH)2)n(3-to 8-membered heteroalicyclic group), - (CH)2)n(5-7 membered heteroaryl), - (CH)n(C6-C10Aryl group), C2-C6Alkenyl and C2-C6An alkynyl group;
R1' is independently selected from: hydrogen, I, Br, Cl, F, -O (CH)2)nCH3、-(CH2)nOR11、-(CR13R14)nNR11R12、-NR11C(O)OR13、-NR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-NR11C(O)NR11R12、-NR11C(O)R12、-NR11S(O)2R12、-N(CH2)n(C3-C8Cycloalkyl), -CN, -NO2、C1-C6Alkyl, or R1As defined above;
R2is H, halogen or C1-C6An alkyl group;
R3and R4Independently selected from: H. f, CF3、C1-C6An alkyl group;
or R3And R4May be taken together to form C3-C5A cycloalkyl ring;
R5is a moiety of the formula:
wherein R is6、R7、R8、R9And R10Independently selected from hydrogen, Br, Cl, F, - (CH)2)nOR11、-C(O)R11、-C(O)OR11、-C(O)NR11R12、-NR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-NR11C(O)NR11R12、-NR11C(O)R12、-NR11SO2R12、-CN、-NO2、C1-C6Alkyl radical, C3-C8Cycloalkyl, 3-8 membered heteroalicyclic, 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6Alkynyl, wherein C1-C6Alkyl radical, C3-C8Cycloalkyl, 3-8 membered heteroalicyclic, 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6The alkynyl group is optionally substituted with one or more moieties selected from the group consisting of: br, Cl, F, - (CH)2)nOR11、-C(O)R11、-C(O)OR11、-C(O)NR11R12、-NR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-NR11C(O)NR11R12、-NR11C(O)R12、-NR11S(O)2R12、-CN、-NO2Oxo, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C3-C8Heteroalicyclic, 5-7 membered heteroaryl, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6An alkynyl group; or
R8And R9Or R is9And R10Combine to form a ring selected from: saturated C4-C8Cycloalkyl, unsaturated C5-C8Cycloalkyl, 3-8 membered heteroalicyclic, 5-7 membered heteroaryl and C6-C10Aryl, wherein the ring is optionally substituted with one or more moieties selected from the group consisting of: br, Cl, F, - (CH)2)nOR11、-C(O)R11、-C(O)OR11、-C(O)NR11R12、-NR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-NR11C(O)NR11R12、-NR11C(O)R12、-NR11S(O)2R12、-CN、-NO2Oxo, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C3-C8Heteroalicyclic, 5-7 membered heteroaryl, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6An alkynyl group;
wherein if m is greater than 1, then each R6Independently selected from hydrogen, Br, Cl, F, - (CH)2)nOR11、-C(O)R11、-C(O)OR11、-C(O)NR11R12、-NR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-NR11C(O)NR11R12、-NR11C(O)R12、-NR11SO2R12、-CN、-NO2、C1-C6Alkyl radical, C3-C8Cycloalkyl, 3-8 membered heteroalicyclic, 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6Alkynyl, wherein C1-C6Alkyl radical, C3-C8Cycloalkyl, 3-8 membered heteroalicyclic, 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6The alkynyl group is optionally substituted with one or more moieties selected from the group consisting of: br, Cl, F, - (CH)2)nOR11、-C(O)R11、-C(O)OR11、-C(O)NR11R12、-NR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-NR11C(O)NR11R12、-NR11C(O)R12、-NR11S(O)2R12、-CN、-NO2Oxo, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C3-C8Heteroalicyclic, 5-7 membered heteroaryl, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6An alkynyl group;
R11and R12Independently selected from: H. - (CH)2)nOR13、-(CH2)nC(CH3)2OR13、-CHR13(CH2)nOR14、-C(O)OR13、-(CH2)nCHR13OR14、-C(CH3)2(CH2)nOR13、-CH2CF2H、-(CH2)nC(CH3)2NR13R14、-(CH2)nNR13R14、-(CH2)nCHOR13(CH2)nOR14、-(CH2)n(NR13R14)C(O)NR13R14、-(CH2)nS(O)2R13、-(CH2)nC(O)NR13R14、-NR13(CH2)n(5-7 membered heteroaryl), -NR13(CH2)n(3-to 8-membered heterocycle), - (CH)2)n(8-10 membered heterobicyclic group), - (CH)2)n(3-to 8-membered heteroalicyclic group), C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6Alkynyl, wherein the 5-7 membered heteroaryl, 3-8 membered heterocycle, and 8-10 membered heterobicyclic group are optionally substituted with one or more moieties selected from the group consisting of: - (CH)2)nOR13、C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C10Aryl radical, C2-C6Alkenyl, 3-8 membered heteroalicyclic and C2-C6Alkynyl, or when R is11And R12When bound to the same atom, R11And R12Optionally combined to form a 3-8 membered heteroalicyclic ring;
R13and R14Independently selected from: H. c1-C6Alkyl, -C (O) CH3、C3-C8Cycloalkyl radical, C6-C10Aryl radical, C2-C6Alkenyl, 5-7 membered heteroaryl and C2-C6Alkynyl, wherein the 5-7 membered heteroaryl is optionally substituted with one or more moieties selected from the group consisting of: c1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6Alkynyl, or when R is13And R14When bound to the same atom, R13And R14Optionally combined to form a 3-8 membered heteroalicyclic ring;
each n is independently 0,1, 2,3 or 4;
m is 0,1, 2,3, 4 or 5.
Except where inconsistencies may arise in describing the present invention, the present invention encompasses each of the following embodiments alone or in combination with any other embodiments described herein. Based on this disclosure, one of ordinary skill in the art will readily appreciate why these inconsistencies may be.
In another embodiment, R1' is independently selected from: hydrogen, I, Cl, -O (CH)2)nCH3、-(CH2)nOR11、-(CR13R14)nNR11R12、-NR11C(O)OR13、-NR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-NR11C(O)NR11R12、-NR11C(O)R12、-NR11S(O)2R12、-N(CH2)n(C3-C8Cycloalkyl), -CN, -NO2、C1-C6Alkyl, or R1As defined above;
in another embodiment, R1' is R1Wherein R is1As defined above.
In another embodiment, R1Independently selected from: -C (O) NR11R123-8 membered heteroalicyclic, 3-8 membered heteroalicyclic- (3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10Aryl and C2-C6Alkenyl, wherein 3-8 membered heteroalicyclic, 3-8 membered heteroalicyclic- (3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10Aryl and C2-C6The alkenyl group is optionally substituted with one or more moieties selected from the group consisting of: br, Cl, F, - (CH)2)nCH(OR11)CH3、-(CH2)nOR11、-(CH2)nC(CH3)2OR11、-(CH2)n(3-8 membered heterocycloaliphatic), -C (O) R11、-C(O)OR11、-(CR11R12)nC(O)OR11、-C(O)NR11R12、-(CR11R12)nC(O)NR11R12、-(CH2)nNR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-(CH2)nNR11C(O)NR11R12、-(CH2)nNR11C(O)OR12、-NR11C(O)R12、-NR11C(O)OR12、-NR11S(O)2R12、-CN、-NO2Oxo, C1-C6Alkyl radical, C3-C8Cycloalkyl, - (CH)2)n(3-to 8-membered heteroalicyclic group), - (CH)2)n(5-7 membered heteroaryl), - (CH)2)n(C6-C10Aryl group), C2-C6Alkenyl and C2-C6Alkynyl.
In another embodiment, R1Independently selected from: 3-8 membered heteroalicyclic, 3-8 membered heteroalicyclic- (3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10Aryl and C2-C6Alkenyl, wherein 3-8 membered heteroalicyclic, 3-8 membered heteroalicyclic- (3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C6-C10Aryl and C2-C6The alkenyl group is optionally substituted with one or more moieties selected from the group consisting of: br, Cl, F, - (CH)2)nCH(OR11)CH3、-(CH2)nOR11、-(CH2)nC(CH3)2OR11、-(CH2)n(3-8 membered heterocycloaliphatic), -C (O) R11、-C(O)OR11、-(CR11R12)nC(O)OR11、-C(O)NR11R12、-(CR11R12)nC(O)NR11R12、-(CH2)nNR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-(CH2)nNR11C(O)NR11R12、-(CH2)nNR11C(O)OR12、-NR11C(O)R12、-NR11C(O)OR12、-NR11S(O)2R12、-CN、-NO2Oxo, C1-C6Alkyl radical, C3-C8Cycloalkyl, - (CH)2)n(3-to 8-membered heteroalicyclic group), - (CH)2)n(5-7 membered heteroaryl), - (CH)2)n(C6-C10Aryl group), C2-C6Alkenyl and C2-C6Alkynyl.
In another embodiment, R1Selected from: 8-10 membered heterobicyclic group, 5-7 membered heteroaryl group, C6-C10Aryl and C2-C6Alkenyl, wherein 8-10 membered heterobicyclic group, 5-7 membered heteroaryl group, C6-C10Aryl and C2-C6The alkenyl group is optionally substituted with one or more moieties selected from the group consisting of: br, Cl, F, - (CH)2)nCH(OR11)CH3、-(CH2)nOR11、-(CH2)nC(CH3)2OR11、-(CH2)n(3-8 membered heterocycloaliphatic), -C (O) R11、-C(O)OR11、-(CR11R12)nC(O)OR11、-C(O)NR11R12、-(CR11R12)nC(O)NR11R12、-(CH2)nNR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-(CH2)nNR11C(O)NR11R12、-(CH2)nNR11C(O)OR12、-NR11C(O)R12、-NR11C(O)OR12、-NR11S(O)2R12、-CN、-NO2Oxo, C1-C6Alkyl radical, C3-C8Cycloalkyl, - (CH)2)n(3-to 8-membered heteroalicyclic group), - (CH)2)n(5-7 membered heteroaryl), - (CH)2)n(C6-C10Aryl group), C2-C6Alkenyl and C2-C6Alkynyl.
In another embodiment, R1Is a 5-7 membered heteroaryl optionally substituted with one or more moieties selected from the group consisting of: br, Cl, F, - (CH)2)nCH(OR11)CH3、-(CH2)nOR11、-(CH2)nC(CH3)2OR11、-(CH2)n(3-8 membered heterocycloaliphatic), -C (O) R11、-C(O)OR11、-(CR11R12)nC(O)OR11、-C(O)NR11R12、-(CR11R12)nC(O)NR11R12、-(CH2)nNR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-(CH2)nNR11C(O)NR11R12、-(CH2)nNR11C(O)OR12、-NR11C(O)R12、-NR11C(O)OR12、-NR11S(O)2R12、-CN、-NO2Oxo, C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,C3-C8Cycloalkyl, - (CH)2)n(3-to 8-membered heteroalicyclic group), - (CH)2)n(5-7 membered heteroaryl), - (CH)2)n(C6-C10Aryl group), C2-C6Alkenyl and C2-C6Alkynyl.
In another embodiment, R8And R9Combine to form a ring selected from: saturated C4-C8Cycloalkyl, unsaturated C5-C8Cycloalkyl, 3-8 membered heteroalicyclic, 5-7 membered heteroaryl and C6-C10Aryl, wherein the ring is optionally substituted with one or more moieties selected from the group consisting of: br, Cl, F, - (CH)2)nOR11、-C(O)R11、-C(O)OR11、-C(O)NR11R12、-NR11R12、-S(O)2R11、-S(O)R11、-S(O)2NR11R12、-CF3、-CF2H、-NR11C(O)NR11R12、-NR11C(O)R12、-NR11S(O)2R12、-CN、-NO2Oxo, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C3-C8Heteroalicyclic, 5-7 membered heteroaryl, C6-C10Aryl radical, C2-C6Alkenyl and C2-C6Alkynyl.
In a further embodiment, R10Is H. In another embodiment, R2Is H. In another embodiment, R3And R4Independently selected from H, F, CF3、CH3. In another embodiment, R3And R4Is H. In another embodiment, R3And R4Is F. In another embodiment, R3Is H, R4Is CH3. In some embodiments, R3Is CH3And R is4Is H. In a further embodiment, R3And R4Can be oneForm C3-C5A cycloalkyl ring; in another embodiment, R6And R7Is H.
In another embodiment, R5Selected from:
in another embodiment, R5The method comprises the following steps:
in another embodiment, R5The method comprises the following steps:
in another embodiment, R5The method comprises the following steps:
in another embodiment, the invention relates to a compound selected from the group consisting of: 6- ((5-chloro-3H- [1, 2, 3] triazolo [4, 5-d ] pyrimidin-3-yl) methyl) quinoline, 3- (quinolin-6-ylmethyl) -3H- [1, 2, 3] triazolo [4, 5-d ] pyrimidin-5-amine, 6- ((5-iodo-3H- [1, 2, 3] triazolo [4, 5-d ] pyrimidin-3-yl) methyl) quinoline, 6- ((5- (1-methyl-1H-pyrazol-4-yl) -3H- [1, 2, 3] triazolo [4, 5-d ] pyrimidin-3-yl) methyl) quinoline, 2- (4- (3- (quinolin-6-ylmethyl) -3H- [1, 2, 3] triazolo [4, 5-d ] pyrimidin-5-yl) -1H-pyrazol-1-yl) ethanol or a pharmaceutically acceptable salt thereof.
In a further aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In a further aspect, the invention relates to the use of a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a c-Met related disorder in a mammal.
In a further aspect, the present invention relates to the use of a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a mammal.
In a further aspect, the invention relates to the use of a compound of formula I or formula II, wherein the cancer is selected from breast cancer, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, glioma, liver cancer, stomach cancer, head cancer, neck cancer, melanoma, kidney cancer, leukemia, myeloma and sarcoma.
In a further aspect, the invention relates to a method of treating a mammal having a c-Met related disorder comprising administering to the mammal a therapeutically effective amount of a compound of formula I or formula II or a pharmaceutically acceptable salt thereof.
In a further aspect, the invention relates to a method of treating a mammal having cancer comprising administering to the mammal a therapeutically effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof.
In a further aspect, the invention relates to a method of treating cancer, wherein the cancer is selected from breast cancer, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, glioma, liver cancer, stomach cancer, head cancer, neck cancer, melanoma, renal cancer, leukemia, myeloma and sarcoma. In a further embodiment, the mammal is a human. In a further embodiment, the mammal is a canine.
Definition of
"pharmaceutically acceptable salt" refers to a salt that retains the biological effects and properties of the parent compound. These salts include: acid addition salts obtained by reacting the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid and the like or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid or malonic acid and the like, preferably hydrochloric acid or (L) -malic acid; or salts formed when an acid proton present in the parent compound is optionally substituted with a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or with organic bases such as ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like.
"pharmaceutically acceptable excipient" or "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
"pharmaceutical composition" refers to a mixture of one or more of the compounds described herein or a physiologically acceptable salt thereof with other chemical components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compound to an organism.
As used herein, "physiologically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
The term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.
As used herein, the term "modulation" or "modulating" refers to a change in the catalytic activity of c-Met. In particular, modulation refers to the activation of the catalytic activity of c-Met, preferably the activation or inhibition of the catalytic activity of c-Met, depending on the concentration of the compound or salt to which c-Met is exposed, more preferably the inhibition of the catalytic activity of c-Met.
As used herein, the term "contacting" refers to bringing together a compound of the invention and c-Met in the following manner: the compounds may influence the catalytic activity of c-Met either directly, i.e. by interacting with c-Met itself, or indirectly, i.e. by interacting with other molecules on which the catalytic activity of c-Met depends. This "contacting" can be done in vitro, i.e. in a test tube, a petri dish or the like. In vitro, the contacting may include only compound and c-Met or it may include all cells. Cells may also be maintained or cultured in cell culture dishes and contacted with compounds in that environment. In this context, the ability of a particular compound to affect c-Met related disorders, i.e., the IC of the compound defined below, can be determined before attempting to use the compound in more complex living organisms50. For cells outside of the organism, there are a variety of methods of contacting c-Met with the compound, including, but not limited to, direct cell microinjection and a variety of transmembrane vector methods, and are known to those skilled in the art.
The term "deuteration" refers to the replacement of hydrogen with deuterium.
"in vitro" refers to procedures performed in an artificial environment, such as, but not limited to, in a test tube or culture medium. Those skilled in the art will understand that: for example, the isolated c-Met may be contacted with a modulator in an in vitro environment. Alternatively, the isolated cells may be contacted with a modulator in an in vitro environment.
As used herein, "in vivo" refers to procedures performed in a living organism such as, but not limited to, a mouse, rat, rabbit, ungulate, cow, horse, pig, dog, cat, primate, or human.
As used herein, "c-Met related disorder" refers to a condition characterized by inappropriate c-Met catalytic activity, i.e., insufficient activity or, more generally, excessive activity. "c-Met associated disorders" also refers to such disorders: where there may be mutations in the gene that produce c-Met, which in turn produce c-Met with increased or decreased catalytic activity of c-Met.
Inappropriate catalytic activity may arise due to: (1) c-Met expression in cells that do not normally express c-Met, (2) increased c-Met expression resulting in undesired cell proliferation, differentiation and/or growth or (3) reduced c-Met expression resulting in undesired cell proliferation, differentiation and/or growth. Excessive activity of c-Met refers to the amplification of the gene encoding c-Met or resulting in a level of c-Met activity, which may be associated with cell proliferation, differentiation and/or growth disorders (i.e., as the level of c-Met increases, the severity of one or more symptoms of the cellular disorder increases). Of course, insufficient activity is the opposite, wherein the severity of one or more symptoms of the cellular disorder increases with decreasing levels of c-Met activity.
As used herein, the terms "treatment", "treating" and "treatment" refer to a method of reducing or eliminating a c-Met mediated cellular disorder and/or its attendant symptoms. In particular with respect to cancer, these terms simply mean that the life span of an individual affected by cancer will be increased, or one or more symptoms of the disease will be reduced.
The term "organism" refers to a living entity comprising at least one cell. A living organism may be simple, such as for example a single eukaryotic cell, or complex, such as a mammal. In a preferred aspect, the organism is a mammal. In a particularly preferred aspect, the mammal is a human.
As used herein, the term "therapeutically effective amount" refers to an amount of a compound administered that will alleviate one or more symptoms of the condition being treated to some extent. With reference to the treatment of cancer, a therapeutically effective amount refers to an amount that has the following effects: (1) reducing the size of the tumor, (2) inhibiting (i.e., reducing to some extent, preferably stopping) tumor metastasis, (3) inhibiting (i.e., reducing to some extent, preferably stopping) tumor growth to some extent, and/or (4) alleviating (or, preferably, eliminating) to some extent one or more symptoms associated with the cancer.
By "monitoring" is meant observing or detecting the effect of contacting the compound with cells expressing c-Met. The observed or detected effect may be a change in the phenotype of the cell, a change in the catalytic activity of c-Met or a change in the interaction between c-Met and the natural binding partner. Techniques for observing or detecting these effects are well known in the art. For example, the catalytic effect of c-Met can be observed by determining the rate or amount of phosphorylation of the target molecule.
"cellular phenotype" refers to the appearance of a cell or tissue, or the biological function of a cell or tissue. Examples of cellular phenotypes are, without limitation, cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. These phenotypic characteristics can be measured by methods well known in the art.
"Natural binding partner" refers to a polypeptide that binds c-Met in a cell. Natural binding partners may play a role in the transmission of signals during c-Met-mediated signal transduction. Changes in the interaction of the natural binding partner with c-Met can manifest themselves as increased or decreased concentrations of the c-Met/natural binding ligand complex and produce observable changes in the ability of c-Met to mediate signal transduction.
As used herein, "administration" or "administering" refers to the delivery of a compound or salt of the invention or a pharmaceutical composition comprising a compound or salt of the invention to an organism for the purpose of preventing or treating a c-Met-related disorder. The terms "abnormal cell growth" and "hyperproliferative disorder" are used interchangeably in this application.
As used herein, "abnormal cell growth" refers to cell growth that does not rely on normal regulatory mechanisms (e.g., loss of contact inhibition), including abnormal growth of normal cells and growth of abnormal cells. This includes, but is not limited to, abnormal growth of: (1) benign and malignant tumor cells (tumors), expressing activated Ras oncogenes; (2) benign and malignant tumor cells, in which Ras protein is activated due to oncogenic mutation in another gene; (3) benign and malignant cells in other proliferative diseases, in which abnormal Ras activation occurs. Examples of such benign proliferative diseases are psoriasis, benign prostatic hypertrophy, human papilloma virus ((HPV) and restenosis. "abnormal cell growth" also refers to and includes abnormal growth of benign and malignant cells resulting from the activity of the enzyme farnesyl protein transferase.
"alkyl" is meant to include straight or branched chain saturated aliphatic hydrocarbons. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever a numerical range is specified herein, such as "1-20," it means a group, in which case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). More preferably, it is an intermediate size alkyl group having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 6 carbon atoms. Alkyl groups may be substituted or unsubstituted. When substituted, each substituent is preferably one or more substituents independently selected from: halogen, -hydroxy, -COR ', -COOR', -OCOR ', -CONRR', -RNCOR ', -NRR', -CN, -NO2、-CF3-SR′、-SOR′、-SO2R′、-SO2OR′、-SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclic, heteroaryl, and aryl. R and R' may independently be: H. alkyl or aryl, wherein the alkyl or aryl may be substituted with halogen, (CH)2)nN(R″)2、(CH2)nCO2R″、(CH2)nOR″、(CH2)nOC (O) R', hydrocarbyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, heteroalicyclic ring, aryl, hydrocarbyloxy, -OCF3Aryloxy group, C (O) NH2Or heteroaryl further substituted. R' may be H, alkyl or aryl. n is 0 to 3.
"alkenyl" refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight, branched, or cyclic groups having at least one carbon-carbon double bond. Preferably, an alkenyl group has 2 to 20 carbon atoms (whenever a numerical range is specified herein, such as "2-20," it means a group, in which case the alkenyl group may contain 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). More preferably, it is an alkenyl group having an intermediate size of 2 to 10 carbon atoms. Most preferably, it is a lower alkenyl group having 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, 1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted. When substituted, each substituent is preferably one or more substituents independently selected from: halogen, -hydroxy, -COR ', -COOR', -OCOR ', -CONRR', -RNCOR ', -NRR', -CN, -NO2、-CF3、-SR′、-SOR′、-SO2R′、-SO2OR′、-SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclic, heteroaryl, and aryl. Wherein R and R' are defined herein.
"alkynyl" refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight, branched, or cyclic groups having at least one carbon-carbon triple bond. Preferably, the alkynyl group has 2 to 20 carbon atoms (whenever a numerical range is specified herein, such as "2-20", this means a group, in which case the alkynyl group may contain 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). More preferably, it is a toolWith an intermediate size alkynyl group of 2 to 10 carbon atoms. Most preferably, it is a lower alkynyl group having 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, 1-propynyl, 1-butynyl, 2-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted. When substituted, each substituent is preferably one or more substituents independently selected from: halogen, -hydroxy, -COR ', -COOR', -OCOR ', -CONRR', -RNCOR ', -NRR', -CN, -NO2、-CF3、-SR′、-SOR′、-SO2R′、-SO2OR′、-SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclic, heteroaryl, and aryl. Wherein R and R' are defined herein.
"cycloalkyl" or "alicyclic group" refers to an all-carbon monocyclic or fused ring (i.e., rings that share adjacent pairs of carbon atoms) group in which one or more of the rings does not have a completely conjugated pi-electron system. Preferably, the cyclic hydrocarbon group has 3 to 8 carbon atoms in the ring. Examples of cycloalkyl groups are, but not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene. The cycloalkyl group may be substituted or unsubstituted. When substituted, each substituent is preferably one or more substituents independently selected from: halogen, -hydroxy, -COR ', -COOR', -OCOR ', -CONRR', -RNCOR ', -NRR', -CN, -NO2、-CF3、-SR′、-SOR′、-SO2R′、-SO2OR′、-SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclic, heteroaryl, and aryl. Wherein R and R' are defined herein.
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., co-cyclic) ring having a fully conjugated pi-electron systemRings sharing adjacent pairs of carbon atoms). Preferably, the aryl group has 6 to 12 carbon atoms in the ring. Examples of aryl groups are, but not limited to, phenyl, naphthyl, and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, each substituent is preferably one or more substituents selected from: halogen, -hydroxy, alkoxy, aryloxy, -COR ', -COOR', -OCOR ', -CONRR', -RNCOR ', -NRR', -CN, -NO2、-CF3、-SR′、-SOR′、-SO2R′、-SO2OR′、-SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclic, heteroaryl, and aryl. Wherein R and R' are defined herein.
As used herein, "heteroaryl" refers to a monocyclic ring having one or more atoms in the ring selected from the group consisting of nitrogen, oxygen, and sulfur, provided that the present invention does not contemplate inclusion of a highly labile heteroatom arrangement such as O-O, O-O and the like. One of ordinary skill in the art will recognize labile groups not encompassed by the present invention. Furthermore, heteroaryl groups have a fully conjugated pi-electron system. Preferably, the heteroaryl group has 5 to 7 ring atoms. Examples of typical monocyclic heteroaryls include, but are not limited to:
pyrrolofuranthiophene pyrazolimidazole
(pyrrolyl) (furanyl) (thienyl) (pyrazolyl) (imidazolyl)
Isoxazole oxazole isothiazolyl 1, 2, 3-triazoles
(isoxazolyl) (oxazolyl) (isothiazolyl) (thiazolyl) (1, 2, 3-triazolyl)
1, 3, 4-triazole 1-oxa-2, 3-diazole 1-oxa-2, 4-diazole 1-oxa-2, 5-diazole
(1, 3, 4-triazolyl) (1-oxa-2, 3-oxadiazolyl) (1-oxa-2, 4-oxadiazolyl) (1-oxa-2, 5-oxadiazolyl)
1-oxa-3, 4-diazole 1-thia-2, 3-diazole 1-thia-2, 4-diazole 1-thia-2, 5-diazoles
(1-oxa-3, 4-oxadiazolyl) (1-thia-2, 3-oxadiazolyl) (1-thia-2, 4-oxadiazolyl) (1-thia-2, 5-oxadiazolyl)
1-thia-3, 4-diazoles tetrazole pyridiniopyridazines
(1-thia-3, 4-oxadiazolyl) (tetrazolyl) (pyridinyl) (pyridazinyl) (pyrimidinyl)
When substituted, each substituent is preferably one or more selected from: halogen, hydroxy, -COR ', -COOR', -OCOR′、-CONRR′、-RNCOR′、-NRR′、-CN、-NO2、-CF3-SR′、-SOR′、-SO2R′、-SO2OR′、-SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclic, heteroaryl, and aryl. Wherein R and R' are defined herein.
"heteroalicyclic" or "heterocyclic" refers to a monocyclic group having one or more atoms in the ring selected from the group consisting of nitrogen, oxygen, and sulfur. The rings may be saturated or may have one or more double bonds (i.e., partially unsaturated). However, the ring may not have a completely conjugated pi-electron system. Preferably, the heteroalicyclic comprises 3 to 8 ring atoms. Examples of suitable saturated heteroalicyclic groups include, but are not limited to:
oxirane thietane aziridine Oxirane Epipropane Epithiobutane tetrahydrofuran
(epoxy (thia (aziridinyl) (epoxy (episulfide (azacyclo (tetrahydrofuranyl)) group)
Ethyl) propyl) butyl)
Tetrahydrothienylpyrrolidine tetrahydropyran tetrahydrothiopyrans
(Tetrahydrothienyl) (pyrrolidinyl) (tetrahydropyranyl) (tetrahydrothiopyranyl)
Piperidine 1, 4-dioxane 1, 4-oxathiirane 1, 4-dithiane
(piperidinyl) (1, 4-dioxanyl) (1, 4-oxathia (morpholinyl) (1, 4-dithianyl)
Six ring base)
Piperazine 1, 4-azathiane oxepane thiacycloheptane azacycloheptane
(piperazinyl) (1, 4-azathialkyl) (oxacycloheptyl) (azepanyl)
Alkyl)
Examples of partially unsaturated heterocyclic groups include, but are not limited to:
3, 4-dihydro-2H-pyran 5, 6-dihydro-2H-pyran
(3, 4-dihydro-2H-pyranyl) (5, 6-dihydro-2H-pyranyl) (2H-pyranyl)
1, 2,3, 4-tetrahydropyridine 1, 2,5, 6-tetrahydropyridine
(1, 2,3, 4-tetrahydropyridinyl) (1, 2,5, 6-tetrahydropyridinyl)
The above groups derived from the compounds listed above may be C-linked or N-linked where the linkage is possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). The heteroalicyclic can be substituted or unsubstituted. A heteroalicyclic ring may comprise one or more oxo groups. When substituted, the substituents are preferably selected from one or more of the following: halogen, -hydroxy, -COR ', -COOR', -OCOR ', -CONRR', -RNCOR ', -NRR', -CN, -NO2、-CF3、-SR′、-SOR′、-SO2R′、-SO2OR′、-SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclic, heteroaryl, and aryl. Wherein R and R' are defined herein.
"3-8 membered heteroalicyclic- (3-8 membered heteroalicyclic)" means having two 3-8 membered heteroalicyclic groups covalently linked to each other through a single ring atom of each ring. The 3-8 membered heteroalicyclic can be any heteroalicyclic as defined above. Furthermore, as defined above, the heteroalicyclic can be substituted or unsubstituted.
"heterobicyclic" or "heterobicyclic" refers to a fused ring (i.e., a ring sharing a contiguous pair of atoms) group having one or more atoms in the ring selected from the group consisting of nitrogen, oxygen, and sulfur, and additionally having one or more double bonds of a fully conjugated pi-electron system (i.e., -an aromatic heterobicyclic) or not yielding a fully conjugated pi-electron system, with the proviso that: heterobicyclyl radicals containing highly labile heteroatom arrays such as O-O, O-O-O and the like are not encompassed by the present invention. One of ordinary skill in the art will recognize labile groups not encompassed by the present invention. Preferably, the heterobicyclic group contains 8 to 10 ring atoms. The heterobicyclic ring can be substituted or unsubstituted. The heterobicyclic ring may comprise one or more oxo groups. Examples of suitable fused ring aromatic heterobicyclic groups include, but are not limited to:
benzofuran benzothiophene indole benzimidazole indazoles
(benzofuranyl) (benzothienyl) (indolyl) (benzimidazolyl) (indazolyl)
Benzotriazolepyrrolo [2, 3-b ] pyridepyrrolo [2, 3-c ] pyridepyrrolo [3, 2-c ] pyridine
(Benzotriazolyl) (pyrrolo [2, 3-b ] pyridinyl) (pyrrolo [2, 3-c ] pyridinyl) (pyrrolo [3, 2-c ] pyridinyl)
Pyrrolo [3, 2-b ] pyridylimidazo [4, 5-c ] pyridylpyrazolo [4, 3-d ] pyridines
(pyrrolo [3, 2-b ] pyridinyl) (imidazo [4, 5-c ] pyridinyl) (pyrazolo [4, 3-d ] pyridinyl)
Pyrazolo [4, 3-c ] pyridylpyrazolo [3, 4-b ] pyridylisoindole
(pyrazolo [4, 3-c ] pyridyl) (pyrazolo [3, 4-b ] pyridyl) (isoindolyl)
Indazole purine indolizine imidazo [1, 2-a ] pyridine imidazo [1, 5-a ] pyridine
(indazolyl) (purinyl) (indolizinyl) (imidazo [1, 2-a ] pyridinyl) (imidazo [1, 5-a ] pyridinyl)
Pyrazolo [1, 5-a ] pyridylpyrrolo [1, 2-b ] pyridazineimidazo [1, 2-c ] pyrimidinethienopyrimidines
(pyrazolo [1, 5-a ] pyridinyl) (pyrrolo [1, 2-b ] pyridazinyl) (imidazo [1, 2-c ] pyrimidinyl) (thienopyrimidinyl)
Quinolinoisoquinolinolincinnolinoquinazolines
(quinolinyl) (isoquinolinyl) (cinnolinyl) (azaquinazoline)
Quinoxalin phthalazine 1, 6-naphthyridine 1, 7-naphthyridine
(quinoxalinyl) (phthalazinyl) (1, 6-naphthyridinyl) (1, 7-naphthyridinyl)
1, 8-naphthyridine 1, 5-naphthyridine 2, 6-naphthyridine 2, 7-naphthyridine
(1, 8-naphthyridinyl) (1, 5-naphthyridinyl) (2, 6-naphthyridinyl) (2, 7-naphthyridinyl)
Pyrido [3, 2-d ] pyrimido [4, 3-d ] pyrimido [3, 4-d ] pyrimidines
(pyrido [3, 2-d ] pyrimidinyl) (pyrido [4, 3-d ] pyrimidinyl) (pyrido [3, 4-d ] pyrimidinyl)
Pyrido [2, 3-d ] pyrimido [2, 3-b ] pyrazino [3, 4-b ] pyrazino
(pyrido [2, 3-d ] pyrimidinyl) (pyrido [2, 3-b ] pyrazinyl) (pyrido [3, 4-b ] pyrazinyl)
Examples of suitable fused ring heterobicyclic groups include, but are not limited to:
indolineisoindoline 2, 3-dihydrobenzofuran 1, 3-dihydroisobenzofuran
(indolinyl) (isoindolinyl) (2, 3-dihydrobenzofuranyl) (1, 3-dihydroisobenzofuranyl)
1, 2,3, 4-tetrahydroquinoxalin 3, 4-dihydro-2H-chromene 2, 3-dihydrobenzo [ b ] [1, 4] dioxine
(1, 2,3, 4-tetrahydroquinoxalinyl) (3, 4-dihydro-2H-chromenyl) 2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl)
4H-benzo [ d ] [1, 3] dioxine 2H-chromene 4H-chromene
(4H-benzo [ d ] [1, 3] dioxinyl) (2H-chromenyl) (4H-chromenyl)
1, 2-dihydroquinazolin 1H-isoindole 3H-indoles
(1, 2-dihydroquinazolyl) (1H-isoindolyl) (3H-indolyl)
When substituted, the substituents are preferably selected from one or more of the following: halogen, -hydroxy, -COR ', -COOR', -OCO R ', -CONRR', -RNCOR ', -NRR', -CN, -NO2、-CF3、-SR′、-SOR′、-SO2R′、-SO2OR′、-SO2NRR', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroalicyclic, heteroaryl, and aryl. Wherein R and R' are defined herein.
When used herein, substituents having two or more R groups on different atoms such as- (CH)2)n(NR13R14)C(O)NR13R14or-NR11C(O)NR11R12The R groups in (A) may be the same or different. Specifically, in an exemplary substituent-NR11C(O)NR11R12In two, R11The radicals may be identical or different from one another, and likewise two R11The group may be with R12The groups may be the same or different. For example, in- (CH)2)n(NR13R14)C(O)NR13R14In two, R13The radicals may be identical or different from one another, and likewise two R14The groups may be the same or different from each other. Likewise, two R13The radicals may be substituted with two R14The groups may be the same or different. In addition, where a single atom is substituted with more than one group, the groups on that atom may be the same or different. Thus, in-NR11C(O)NR11R12In (1), R on the same nitrogen11And R12May be the same or different from each other.
An "oxo" group refers to a carbonyl moiety, such that an alkyl group substituted with an oxo group refers to a ketone group.
A "hydroxy" group refers to an-OH group.
"hydrocarbyloxy" group refers to-O-alkyl and-O-cycloalkyl groups, as defined herein.
"Hydroxycarbonyl" group refers to-C (O) OR.
The "aminocarbonyl" group refers to-C (O) NRR'.
An "aryloxycarbonyl" group refers to-C (O) O-aryl.
An "aryloxy" group refers to the group-O-aryl and-O-heteroaryl, as defined herein.
An "arylalkyl" group refers to an-alkylaryl group, wherein alkyl and aryl are defined herein.
"arylsulfonyl" radical means-SO2And (4) an aryl group.
"alkylsulfonyl" radical means-SO2An alkyl group.
A "heteroaryloxy" group refers to a heteroaryl-O group containing a heteroaryl group as defined herein.
"Heteroaliphatic epoxy" group refers to a heteroalicyclic-O group containing a heteroalicyclic as defined herein.
A "carbonyl" group refers to — C (═ O) R.
An "aldehyde" group refers to a carbonyl group wherein R is hydrogen.
A "thiocarbonyl" group refers to a-C (═ S) -R group.
"Trihaloalkylcarbonyl" radical means X3A CC (O) group, wherein X is halogen.
A "C-carboxy" group refers to a-C (O) OR group.
An "O-carboxy" group refers to an RC (O) O group.
A "carboxylic acid" group refers to a C-carboxyl group wherein R is hydrogen.
"halo" or "halogen" groups all refer to fluoro, chloro, bromo, or iodo.
"Trihalomethyl" group means-CX3A group.
The "trihalomethanesulfonyl" group means X3CS(O)2A group.
"Trihaloalkanesulfonamido" radicals mean X3CS(O)2An NR-group.
A "sulfinyl" group refers to the group-S (O) R.
The "sulfonyl" group means-S (O)2And R group.
The "S-sulfonylamino" group means-S (O)2An NR-group.
The "N-sulfonylamino" group means-NR-S (O)2And R group.
The "O-carbamoyl" group refers to the-OC (O) NRR' group.
The "N-carbamoyl" group refers to the ROC (O) NR-group.
An "O-thiocarbamoyl" group refers to the-OC (S) NRR' group.
An "N-thiocarbamoyl" group refers to the ROC (S) NR' group.
An "amino" group refers to-NH2Or a-NRR' group.
A "C-amido" group refers to a-C (O) NRR' group.
An "N-acylamino" group refers to an R' C (O) NR group.
The "nitro" group means-NO2A group.
A "cyano" group refers to a-CN group.
The "silyl" group means-Si (R)3A group.
A "phosphoryl" group refers to-P (═ O) (OR)2A group.
An "aminoalkyl" group refers to an-alkyl NRR' group.
An "alkylaminoalkyl" group refers to an-alkyl-NR-alkyl group.
"Dialkylaminoalkyl" refers to-alkyl N- (alkyl)2A group.
"perfluoroalkyl" refers to an alkyl group in which all hydrogen atoms have been replaced with fluorine atoms.
Compounds that have the same molecular formula but differ in the nature or sequence of their bonding of the atoms or the spatial arrangement of their atoms are referred to as "isomers". Isomers that differ in the arrangement of atoms in space are referred to as "stereoisomers". Stereoisomers that are non-mirror images of each other are referred to as "diastereomers" and those that are non-overlapping mirror images of each other are referred to as "enantiomers". When the compound has an asymmetric center, for example, it is attached to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the R-and S-ordering rules of Cahn and Prelog, or by the manner in which molecules rotate the plane of polarized light and are designated dextrorotatory or levorotatory (i.e., the (+) or (-) -isomers, respectively). The chiral compounds may exist as individual enantiomers or mixtures thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures". The formulae mentioned herein may show phenomena of tautomerism and structural isomerism. The present invention encompasses any tautomer or structural isomeric form and mixtures thereof, which have the ability to modulate c-Met activity and are not limited to any one tautomeric or structural isomeric form.
The compounds of the invention may have one or more asymmetric centers; these compounds can thus be prepared as single (R) -or (S) -stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include individual enantiomers and mixtures, racemic or other mixtures thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion of chapter 4 of "Advanced Organic chemistry", 4 th edition, j. march, John Wiley and Sons, New York, 1992). Thus, the present invention also encompasses any stereoisomeric form, their corresponding enantiomers (d-and l-or (+) and (-) isomers) and diastereomers thereof, and mixtures thereof, which have the ability to modulate the activity of c-Met and are not limited to any one stereoisomeric form.
The compounds of formula I or formula II may exhibit phenomena of tautomerism and structural isomerism. For example, the compounds described herein may adopt the E or Z configuration with respect to the double bond, or they may be a mixture of E and Z. The present invention encompasses any tautomer or structural isomeric form and mixtures thereof, which have the ability to modulate c-Met activity and are not limited to any one tautomeric or structural isomeric form.
It should be noted that: the compounds of formula I or formula II will be metabolized by enzymes in an organism such as a human to produce metabolites that can modulate c-Met activity. These metabolites fall within the scope of the present invention.
Those compounds of formula I or formula II, which are acidic in nature, are capable of forming base salts with a variety of pharmacologically acceptable cations. Examples of such salts include: alkali metal salts or alkaline earth metal salts and, in particular, sodium salts and potassium salts.
The compounds of the invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. The present invention relates to the use of all optical isomers and stereoisomers of the compounds of the invention and mixtures thereof, and to all pharmaceutical compositions and methods of treatment in which they may be used or which comprise them. The compounds of formula I or formula II may also exist as tautomers. The present invention relates to the use of all these tautomers and mixtures thereof.
The invention also includes pharmaceutical compositions containing compounds of formula I or formula II and methods of treating proliferative disorders or abnormal cell growth by administering prodrugs of compounds of formula I or formula II. Compounds of formula I or formula II having a free amino, amido, hydroxyl or carboxyl group can be converted into prodrugs. Prodrugs include compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked through an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of a compound of formula I or formula II. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly represented by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine. Other types of prodrugs are also included. For example, the free carboxyl groups may be derivatized as amides or alkyl esters. Free hydroxyl groups can be derivatized using groups including, but not limited to hemisuccinate, phosphate, dimethylaminoacetate, and phosphoryloxymethoxymethoxycarbonyl, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Also included are carbamate prodrugs of hydroxy and amino groups, as are carbonate prodrugs, sulfonates and sulfates of hydroxy groups. Derivatization of the hydroxyl group into (acyloxy) methyl ethers and (acyloxy) ethyl ethers, wherein the acyl group may be an alkyl ester optionally substituted with functional groups including, but not limited to, ether, amine, and carboxylic acid, or wherein the acyl group is an amino acid ester as defined above, is also included. This type of prodrug is described in j.med.chem.1996, 39, 10. The free amine may also be derivatized as an amide, sulfonamide or phosphoramide. All of these prodrug moieties may be incorporated into groups including, but not limited to, ether, amine, and carboxylic acid functional diagrams.
Use of
The compounds of the present invention find use in a variety of applications. As understood by those skilled in the art, the kinase activity of MET can be modulated in a variety of ways, i.e., one can influence the phosphorylation/activation of MET by modulating the initial phosphorylation of proteins or by modulating the autophosphorylation of other active sites of proteins. Alternatively, the kinase activity of MET can be modulated by affecting binding of a MET phosphorylation substrate.
The compounds of the invention are useful for binding to and/or modulating the activity of receptor tyrosine kinases. In one embodiment, the receptor tyrosine kinase is a member of the MET subfamily. In further embodiments, MET is human MET, but the activity of receptor tyrosine kinases from other organisms may also be modulated by the compounds of the invention. In the present context, modulation means increasing or decreasing the kinase activity of MET. In one embodiment, the compounds of the invention inhibit the kinase activity of MET.
The compounds of the invention are useful for treating or preventing cell proliferative disorders. Disease states that can be treated by the methods and compositions provided herein include, but are not limited to, cancer (discussed further below), autoimmune diseases, arthritis, transplant rejection, inflammatory bowel disease, medical procedures including, but not limited to, surgery, angioplasty, and the like, induced proliferation. It will be appreciated that in some cases the cells may not be in a state of hyperproliferation or low proliferation (abnormal state) and still require treatment. Thus, in one embodiment, the invention includes application to a cell or individual suffering from, or ultimately suffering from, any of these conditions or states.
The compounds, compositions and methods provided herein are particularly recognized for the treatment and prevention of cancer, including solid tumors such as skin cancer, breast cancer, brain cancer, cervical cancer, testicular cancer, and the like. In one embodiment, the present compounds are used to treat cancer. In particular, cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to:heart:sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;lung (lung): bronchial carcinomas (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, hamartoma, mesothelioma;gastrointestinal tract:esophagus (squamous cell carcinoma, adenocarcinomaLeiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, sugioenterotoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Karposi sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenocarcinoma, villous adenoma, hamartoma, leiomyoma);genitourinary:kidney (adenocarcinoma, Wilm tumor [ nephroblastoma ]]Lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);liver:liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteoochronofroma) (osteochondral exostosis), benign chondroma, chondroblastoma, chondrmucomyxomatoid fibroma, osteoid osteoma, and giant cell tumor;the nervous system:skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma (menningosarcoma), glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [ pinealoma]Glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);the gynecology:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma [ serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma)]Follicle-membrane cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (striated muscle of the peri-foetal tract)Tumor]Fallopian tubes (cancer);blood:blood (myelogenous leukemia [ acute and chronic)]Acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [ malignant lymphoma ]](ii) a Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi sarcoma, moles, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; andadrenal gland:neuroblastoma. Thus, the term "cancerous cell" as provided herein includes cells afflicted by any one of the above-identified conditions. In another embodiment, the compounds of the invention are useful for the treatment or prevention of a cancer selected from the group consisting of: histiocytic lymphoma, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, liver cancer, stomach cancer, colon cancer, multiple myeloma, glioblastoma and breast cancer. In yet another embodiment, the compounds of the invention are used for the treatment of a cancer selected from the group consisting of: histiocytic lymphoma, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, liver cancer, stomach cancer, colon cancer, multiple myeloma, glioblastoma and breast cancer. In another embodiment, the compounds of the invention are used to prevent or modulate cancer cells and cancer metastasis. In particular, the compounds of the invention are useful for preventing or modulating the following metastases: ovarian cancer, childhood hepatocellular carcinoma, metastatic head and neck squamous cell carcinoma, gastric cancer, breast cancer, colorectal cancer, cervical cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, glioblastoma, and sarcoma.
The compounds of the present invention may be administered to a mammal, preferably a human, alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, according to standard pharmaceutical practice. The compounds may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the preparation of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically advantageous and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known methods to mask the unpleasant taste of the drug or to delay disintegration and absorption in the gastrointestinal tract and thereby provide a longer lasting effect. For example, water soluble taste masking materials such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose, or time delay materials such as ethyl cellulose, cellulose acetate butyrate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; the disintegrant or wetting agent may be a naturally occurring phosphatide, for example lecithin or a concentrated product of an alkylene oxide and a fatty acid, for example polyoxyethylene stearate, or a concentrated product of ethylene oxide and a long chain aliphatic alcohol, for example heptadecaethylene oxide cetyl alcohol (heptadecaethylene oxide), or a concentrated product of ethylene oxide and a partial ester derived from a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a concentrated product of ethylene oxide and a partial ester derived from a fatty acid and hexitol anhydride, for example polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those listed above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous suspension formulation by the addition of water provide the active ingredient in admixture with a dispersing and wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical composition of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifiers may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening agents, flavouring agents, preservatives and antioxidants.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain demulcents, preservatives, flavouring and colouring agents and antioxidants.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution.
The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into the water and glycerin mixture and processed to form a microemulsion.
The injectable solution or microemulsion may be introduced into the patient's bloodstream by local intravenous bolus injection. Alternatively, it may be advantageous to apply the solution or microemulsion in such a way as to maintain a constant circulating concentration of the present compounds. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is Deltec CADD-PLUSTMModel 5400 intravenous pump.
The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. Such suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of formula I or formula II may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug with suitable non-irritating excipients which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. These materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of formula I or formula II are used. (for purposes of this application, topical applications will include mouth washes and rinses.)
The compounds of the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes using those forms of transdermal patches well known to those of ordinary skill in the art. For administration in the form of a transdermal delivery system, the dosage administration will of course be continuous rather than intermittent throughout the dosage regimen. The compounds of the invention may also be delivered as suppositories using bases such as cocoa butter, glycerogelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycols. When a compound according to the invention is administered into a human subject, the daily dose will generally be determined by the prescribing physician, and the dose will generally vary according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.
In one exemplary application, a suitable amount of the compound is administered to a mammal undergoing cancer treatment. The administration is in an amount of between about 0.1mg/kg body weight per day to about 60mg/kg body weight per day, preferably between 0.5mg/kg body weight per day to about 40mg/kg body weight per day.
The compounds are also useful in combination with known therapeutic and anticancer agents. For example, the present compounds are useful in combination with known anti-cancer agents. It is within the scope of the present invention to combine the presently disclosed compounds with other anti-cancer agents or therapeutic agents. Examples of such agents are found in Cancer Principles and Practice of Oncology, v.t. devita and s.hellman (eds.), 6 th edition (2.15.2001), Lippincott Williams & Wilkins Publishers. One of ordinary skill in the art will be able to discern which combinations of agents will be useful based on the particular characteristics of the drug and the cancer involved. Such anti-cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins/cytostatics, antiproliferatives, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducers, and agents that interfere with cell cycle checkpoints. The present compounds are particularly useful when co-administered with radiation therapy.
In one embodiment, the present compounds are also useful in combination with known anti-cancer agents, including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HTV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
"Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LYl 17081, toremifene, fulvestrant, 4- [7- (2, 2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy ] phenyl ] -2H-1-benzopyran-3-yl ] -phenyl-2, 2-dimethylpropionate, 4' -dihydroxybenzophenone-2, 4-dinitrophenyl-hydrazone, and SH 646.
"androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include: finasteride and other 5 α -reductase inhibitors, nilutamide, flutamide, bicalutamide, liazole and abiraterone acetate.
"retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include: bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α -difluoromethyl ornithine, ILX23-7553, trans-N- (4' -hydroxyphenyl) retinoamide (retinamide), and N-4-carboxyphenyl retinoamide.
"cytotoxin/cytostatic agents" refer to compounds that cause cell death or inhibit cell proliferation or inhibit or interfere with cell mitosis (mytosis) primarily by directly interfering with cell function, including alkylating agents, tumor necrosis factors, intercalating agents, hypoxia-activatable compounds (hypoxia activatable compounds), microtubule inhibitors/microtubule stabilizers, mitotic kinesin inhibitors, histone deacetylase inhibitors, kinase inhibitors involved in mitotic processes, antimetabolites; biological response modifiers, hormone/anti-hormone therapeutics, hematopoietic growth factors, monoclonal antibody targeted therapeutics, topoisomerase inhibitors, protease inhibitors, and ubiquitin ligase inhibitors.
Examples of cytotoxic agents include, but are not limited to: sertenef, cachectin, ifosfamide, tasolinamine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ramustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, eproufenon tosylate, trofosfamide, nimustine, dibromospiro-ammonium chloride, purepypeperiside, lobaplatin, satraplatin, mitomycin, cisplatin, elovin, dexifosfamide, cis-aminodichloro (2-methylpyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans ) -bis- μ - (hexane-1, 6-diamine) - μ - [ diamine-platinum (II) ] bis [ diamine (chloro) platinum (II) ] tetrachloro, diarizinylspermine, diarsenarsine, 1- (11-dodecylamino-10-hydroxyundecyl) -3, 7-dimethylxanthine, levorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, naproxen-tebucin, valrubicin, amrubicin, anticancer peptides, 3 '-desamino-3' -morpholino-13-deoxy-10-hydroxycarminomycin, anthracycline, garrubicin, eletrinafide, MEN10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032).
An example of a hypoxia activatable compound is tirapazamine.
Examples of proteasome inhibitors include, but are not limited to, lactacystin and bortezomib.
Examples of microtubule inhibitors/microtubule stabilizing agents include: paclitaxel, vindesine sulfate, 3 ', 4' -didehydro-4 '-deoxy-8' -norvinblastine (norvinceeukeukobtaine), docetaxel, rhizomycin, dolastatin, mitobutrine isethionate, auristatin, cimadrol, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3, 4,5, 6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N, N-dimethyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-tert-butanamide, TDX258, epothilones (see, e.g., U.S. Pat. nos. 6,284,781 and 6,288,237), and BMS 188797.
Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4' -O-oxo (exo) -benzylmethylozoenin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3, 4, 5-kl ] acridine-2- (6H) propylamine, 1-amino-9-ethyl-5-fluoro-2, 3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [ de ] pyrano [3 ', 4': b, 7] -indolino [1, 2b ] quinoline-10, 13(9H, 15H) dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl ] - (20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobozolone, 2 '-dimethylamino-2' -deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl ] -9-hydroxy-5, 6-dimethyl-6H-pyrido [4, 3-b ] carbazole-1-carboxamide, asulamine, (5a, 5aB, 8aa, 9b) -9- [2- [ N- [2- (dimethylamino) ethyl ] -N-methylamino ] ethyl ] -5- [ 4-hydroxy-3, 5-dimethoxyphenyl ] -5, 5a, 6,8, 8a, 9-hexahydrofuro (3 ', 4': 6, 7) naphtho (2, 3-d) -1, 3-dioxol-6-one, 2, 3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [ c ] -phenanthridinium salt (phenanthridinium), 6, 9-bis [ (2-aminoethyl) amino ] benzo [ g ] isoquinoline (isogenine) -5, 10-dione, 5- (3-aminopropylamino) -7, 10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4, 5, 1-de ] acridin-6-one, N- [1- [2 (diethylamino) ethylamino ] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl ] carboxamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6- [ [2- (dimethylamino) ethyl ] amino ] -3-hydroxy-7H-indeno [2, 1-c ] quinolin-7-one and dimesna.
Examples of mitotic kinesin inhibitors, and in particular human mitotic kinesin KSP, are described in: PCT publications WO 01/30768, WO 01/98278, WO03/050,064, WO03/050,122, WO 03/049,527, WO 03/049,679, WO 03/049,678 and WO03/39460 and pending applications PCT application Nos. US03/06403 (filed 3/4/2003), US03/15861 (filed 5/19/2003), US03/15810 (filed 5/19/2003), US03/18482 (filed 6/12/2003) and US03/18694 (filed 6/12/2003). In one embodiment, inhibitors of mitotic kinesins include, but are not limited to, KSP inhibitors, MKLP1 inhibitors, CENP-E inhibitors, MCAK inhibitors, Kifl4 inhibitors, Mphoshl inhibitors, and Rab6-KIFL inhibitors.
Examples of "histone deacetylase inhibitors" include, but are not limited to, SAHA, TSA, oxamflatin, PXD101, MG98, valproic acid, and scriptaid. Further citations for other histone deacetylase inhibitors can be found in the following references: miller, t.a. et al, j.med.chem.46 (24): 5097-5116(2003).
"kinase inhibitors involved in mitotic progression" include, but are not limited to, aurora kinase inhibitors, Polo-like kinase inhibitors (PLKs), particularly PLK-1 kinase inhibitors, bub-1 inhibitors, and bub-R1 inhibitors.
"antiproliferative agents" include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine octadecyl sodium phosphate (cytarabine ocfosfate), fosetadine sodium hydroxide, raltitrexed, palitexid, ethimidin, thifluzaline, decitabine, nolatrexed, pemetrexed, nelarabine (nelrazbine), 2 ' -deoxy-2 ' -methylenecytosine nucleoside, 2 ' -fluoromethylene-2 ' -deoxycytidine cytidine, N- [5- (2, 3-dihydro-benzofuranyl) sulfonyl ] -N ' - (3, 4-dichlorophenyl) urea, N6- [ 4-deoxyn- [2- [2 (E30032), 4(E) -tetradecadienoylglycylamino (tetradecadienyljglycylaminol) -L-glycerol-B-L-manno-heptapyranosyladenine (heptapyranosylJadenine), aplidine, tazone, 4- [ 2-amino-4-oxo-4, 6,7, 8-tetrahydro-3H-pyrimido [5, 4-B ] [1, 4] thiazin-6-yl- (S) -ethyl ] -2, 5-thiophenyl-L-glutamic acid, aminopterin, 5-fluorouracil, aragonin, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1, 11-diazepitetracyclo (7.4.1.0.0) -deca-2, 4, 6-trien-9-yl acetate, swainsonine, lometrexol, dexrazoxane, methioninase, 2 '-cyano-2' -deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and 3-aminopyridine-2-carbaldehyde thiosemicarbazide.
Examples of monoclonal antibody-targeted therapeutic agents include those having cytotoxic agents or radioisotopes attached to a cancer cell-specific or target cell-specific monoclonal antibody. Examples include Bexxar.
"HMG-CoA reductase inhibitor" refers to an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include, but are not limited to: lovastatin (See U.S. Pat. Nos. 4,231,938, 4,294,926, and 4,319,039), simvastatin (simvastatinSee U.S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (pravastatin: (A)See U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (F:)See U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896) and atorvastatin(s) ((R) ()See U.S. patent nos. 5,273,995, 4,681,893, 5,489,691, and 5,342,952). The structural formulae of these and additional HMG-CoA reductase inhibitors that may be used in the present methods are described in M.Yalpani, "Cholesterol Power Drugs," Chemistry&Industry, page 87, pages 85-89 (1996, 2/5), and U.S. Pat. Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open acid forms (i.e., wherein the lactone ring is open to form the free acid) as well as the salt and ester forms of compounds having HMG-CoA reductase inhibitory activity and thus the use of these salt, ester, open acid and lactone forms is included within the scope of the present invention.
"prenyl protein transferase inhibitor" refers to a compound that inhibits any one or any combination of prenyl protein transferases, including farnesyl-protein transferase (FPT enzyme), geranylgeranyl-protein transferase type I (GGPT enzyme-I), and geranylgeranyl-protein transferase type II (GGPT enzyme-II, also known as Rab GGPT enzyme).
Examples of prenyl protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat. No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S. Pat. No. 5,602,098, European patent publication 0618221, European patent publication 0675112, European patent publication 0604181, European patent publication 0696593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436 and us patent No. 5,532,359. For example, see European J.of Cancer, Vol.35, 9, pp.1394-1401 (1999).
"angiogenesis inhibitors" refers to compounds that inhibit neovascularization without regard to mechanism. Examples of angiogenesis inhibitors include, but are not limited to: tyrosine kinase inhibitors, such as tyrosine kinase receptor FIt-1(VEGFR1) and Flk-1/KDR (VEGFR2) inhibitors, epidermal derived, fibroblast derived or platelet derived growth factor inhibitors, MMP (matrix metalloproteinase) inhibitors, integrin blockers, interferon- α, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, and selective cyclooxygenase 2 inhibitors, such as Cofferso et al (PNAS, Vol.89, p.7384 (1992); JNCI, Vol.69, p.475 (1982); Arch Opthallmo, Vol.108, p.573 (1990); Anch. Rec Vol.238, p.68 (1994); FEBS Letters, Vol.372, p.83 (Clin, Orthop.313, p.1995; J.76. endo.16, page 107 (1996); jpn.j.pharmacol, volume 75, page 105 (1997); cancer res, volume 57, page 1625 (1997); cell, volume 93, page 705 (1998); intl.j.mol.med., volume 2, page 715 (1998); biol. chem., vol. 274, page 9116 (1999)), steroidal anti-inflammatory drugs (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylprednisolone, betamethasone), carboxamidotriazole, combretastatin a-4, squalamine, 6-O-chloroacetyl-carbonyl) -fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al, j.lab.clin.med.105: 141-145(1985)) and anti-VEGF antibodies (see Nature Biotechnology, vol.17, p.963-968 (10 months 1999); kim et al, Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).
Other therapeutic agents that modulate or inhibit angiogenesis and that may also be used in combination with the compounds of the present invention include agents that modulate or inhibit the coagulation and fibrinolytic systems (for review in clin. chem. la. med. 38: 679-692 (2000)). Examples of such agents that modulate or inhibit the coagulation pathway and the fibrinolysis pathway include, but are not limited to, heparin (see Thromb. Haemost.80: 10-23(1998)), low molecular weight heparin and carboxypeptidase U inhibitors (also known as active thrombin-activated fibrinolysis inhibitors [ TAFIa ]) (see Thrombosis Res.101: 329-354 (2001)). TAFIa inhibitors have been described in PCT publication WO 03/013,526 and U.S. sequence No. 60/349,925 (filed 1/18 of 2002).
"agent that interferes with a cell cycle checkpoint" refers to a compound that inhibits a protein kinase that transduces a cell cycle checkpoint signal, thereby sensitizing cancer cells to DNA damaging agents. These agents include ATR, ATM, Chk1 and Chk2 kinase inhibitors as well as cdk and cdc kinase inhibitors, and specific examples are 7-hydroxystearicin, fusidic acid (flavopiridol), CYC202 (Cyclel) and BMS-387032.
"inhibition of cell proliferation and survival signaling pathways" refers to the inhibition of cell surface receptors and agents downstream of the signaling cascade of these surface receptors. These agents include: EGFR inhibitors (e.g., gefitinib and erlotinib), ERB-2 inhibitors (e.g., trastuzumab), IGFR inhibitors, cytokine receptor inhibitors, MET inhibitors, PBK inhibitors (e.g., LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064, WO02/083139, WO 02/083140 and WO 02/083138), Raf kinase inhibitors (e.g., BAY-43-9006), MEK inhibitors (e.g., CI-1040 and PD-098059) and mTOR inhibitors (e.g., Wyeth CCI-779). These agents include small molecule inhibitor compounds and antibody antagonists.
"apoptosis-inducing agents" include activators of TNF receptor family members, including TRAIL receptors.
The present invention also includes combinations with NSAIDs that are selective COX-2 inhibitors. For purposes of this specification, NSAIDs that are COX-2 selective inhibitors are defined as those compounds having a specificity of inhibiting COX-2 over COX-1 by at least 100-fold as assessed by cellular or microsomal assays for IC of COX-250IC over COX-150The ratio of (A) to (B). These compounds include, but are not limited to, those disclosed in U.S. patent 5,474,995, U.S. patent 5,861,419, U.S. patent 6,001,843, U.S. patent 6,020,343, U.S. patent 5,409,944, U.S. patent 5,436,265, U.S. patent 5,536,752, U.S. patent 5,550,142, U.S. patent 5,604,260, U.S. patent 5,698,584, U.S. patent 5,710,140, WO 94/15932, U.S. patent 5,344,991, U.S. patent 5,134,142, U.S. patent 5,380,738, U.S. patent 5,393,790, U.S. patent 5,466,823, U.S. patent 5,633,272, and U.S. patent 5,932,598.
COX-2 inhibitors that are particularly useful in the present treatment method are: 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone and 5-chloro-3- (4-methylsulfonyl) -phenyl-2- (2-methyl-5-pyridyl) pyridine; or a pharmaceutically acceptable salt thereof.
Has been describedCompounds that are COX-2 specific inhibitors and therefore are useful in the present invention include, but are not limited to: parecoxib,Andor a pharmaceutically acceptable salt thereof.
Other examples of angiogenesis inhibitors include, but are not limited to: endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4- [ 2-methyl-3- (3-methyl-2-butenyl) epoxyethyl ] -1-oxaspiro [2, 5] oct-6-yl (chloroacetyl) carbamate, acetyldinanaline, 5-amino-1- [ [3, 5-dichloro-4- (4-chlorobenzoyl) -phenyl ] methyl ] -1H-1, 2, 3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate (sulfated mannopentaose phosphate), 7- (carbonyl-bis [ imino-N-methyl-4, 2-pyrrolocarbonylimino [ N-methyl-4, 2-pyrrole ] -carbonylimino ] -bis- (1, 3-naphthalenedisulfonate) and 3- [ (2, 4-dimethylpyrrol-5-yl) methylene ] -2-indolone (SU 5416).
As used above, "integrin blocker" refers to a means of selectively antagonizing, inhibiting, or counteracting a physiological ligand and αvβ3Integrin binding compounds, meaning selective antagonism, inhibition or antagonism of physiological ligands and alphavβ5Integrin binding compounds, meaning selective antagonism, inhibition or antagonism of physiological ligands and alphavβ3Integrins and alphavβ5Integrin binding compounds, and refers to activities that antagonize, inhibit, or antagonize specific integrins expressed on capillary epidermal cells. The term also refers to alphavβ6、αvβ8、α1β1、α2β1、α5β1、α6β1And alpha6β4Antagonists of integrins. The term also refers to alphavβ3、αvβ5、αvβ6、αvβ8、α1β1、α2β1、α5β1、α6β1And alpha6β4Antagonists of any combination of integrins.
Some specific examples of tyrosine kinase inhibitors include: n- (trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide, 3- [ (2, 4-dimethylpyrrol-5-yl) methylene) indol-2-one, 17- (allylamino) -17-demethoxygeldanamycin, 4- (3-chloro-4-fluorophenylamino) -7-methoxy-6- [3- (4-morpholinyl) propoxy ] quinazoline, N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) -4-quinazolinamine, BIBX1382, 2,3, 9, 10, 11, 12-hexahydro-10- (hydroxymethyl) -10-hydroxy-9-methyl-9, 12-epoxy-1H-diindolo [1, 2, 3-fg: 3 ', 2', 1 '-kl ] pyrrolo [3, 4-i ] [1, 6] benzodiazepin-1-one, SH268, genistein, imatinib (STI571), CEP2563, 4- (3-chlorophenylamino) -5, 6-dimethyl-7H-pyrrolo [2, 3-d ] pyrimidine methanesulfonate, 4- (3-bromo-4-hydroxyphenyl) amino-6, 7-dimethoxyquinazoline, 4- (4' -hydroxyphenyl) amino-6, 7-dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4- (4-pyridylmethyl) -1-phthalazinamine and EMD 121974.
Combinations with compounds other than anticancer compounds are also included in the present methods. For example, combinations of the presently claimed compounds with PPAR-gamma (i.e., PPAR-gamma) agonists and PPAR-delta (i.e., PPAR-delta) agonists are useful in the treatment of certain malignancies. PPAR- γ and PPAR- δ are nuclear peroxisome proliferator-activated receptors γ and δ. The expression of PPAR- γ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J.Cardiovasc.Pharmacol.1998; 31: 909-. More recently, PPAR-gamma antagonists have been shown to inhibit angiogenic responses to VEGF in vitro, and troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice. (Arch. Ophthamol.2001; 119: 709-. Examples of PPAR-gamma agonists and PPAR-gamma/alpha agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2- [ (5, 7-dipropyl-3-trifluoromethyl-1, 2-benzisoxazol-6-yl) oxy ] -2-methylpropanoic acid (disclosed in USSN 09/782,856), and 2(R) -7- (3- (2-chloro-4- (4-fluorophenoxy) phenoxy) propoxy) -2-ethylchroman (cliromane) -2-carboxylic acid (disclosed in USSN60/235,708 and 60/244,697).
Another embodiment of the invention is the use of the presently disclosed compounds for the treatment of cancer in combination with gene therapy. For a summary of genetic strategies for the treatment of Cancer see Hall et al (Am J Hum Genet 61: 785-789, 1997) and Kufe et al (Cancer Medicine, 5 th edition, pp. 876-889, BCDecker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressor gene. Examples of such genes include, but are not limited to: p53 that can be delivered via recombinant virus-Mediated Gene transfer (see, e.g., U.S. Pat. No. 6,069,134), a uPA/uPAR Antagonist ("Adenoviral-Mediated Delivery of a uPA/uPAR Antagonist supressures Angiogenesis-Dependent Tumor Growth and Dissemination in Mice (Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist in Mice inhibits Angiogenesis-Dependent Tumor Growth and Dissemination)," Gene Therapy, 8 months 1998; 5 (8): 1105-13) and interferon γ (J Immunol 2000; 164: 217-222).
The compounds of the invention may also be administered in combination with inhibitors of self-multidrug resistance (MDR), particularly MDR associated with high levels of carrier protein expression. These MDR inhibitors include P-glycoprotein (P-gp) inhibitors such as LY335979, XR9576, OC144-093, R101922, VX853, and PSC833 (valcepta).
The compounds of the invention may be used in combination with an anti-emetic to treat nausea or vomiting, including acute, delayed, late and early onset emesis, as a result of the use of the compounds of the invention alone or in combination with radiation therapy. For the prevention or treatment of emesis, the compounds of the present invention may be used in combination with other anti-emetics, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists such as ondansetron, granisetron, tropisetron and zatosetron, GABAB receptor antagonists such as baclofen, corticosteroids such as dicarbalone (dexamethasone), cangle, triamcinolone, pinocembrine, Preferid, Benecorten or others, such as those disclosed in U.S. Pat. nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,749,712, anti-dopamine agents such as phenothiazines (e.g., prochlorperazine, fluphenazine, thioridazine and mesoridazine), chloromethopram or cannabinol. In one embodiment, the anti-emetic is selected from: neurokinin-1 receptor antagonists, 5HT3 receptor antagonists and corticosteroids administered as an adjuvant for the treatment or prevention of emesis that may result from administration of the present compounds. Neurokinin-1 receptor antagonists useful in conjunction with the compounds of the present invention are fully disclosed in, for example: U.S. patent nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; european patent publications nos. EP 0360390, 0394989, 0428434, 0429366, 0430771, 0436334, 0443132, 0482539, 0498069, 0499313; PCT international patent publication nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and british patent publication nos. 2266529, 2268931, 2269170, 2269590, 2271774, 2292144, 2293168, 2293169 and 2302689. The preparation of these compounds is described in the aforementioned patents and publications, which are incorporated herein by reference.
In one embodiment, the neurokinin-1 receptor antagonist used in conjunction with the compounds of the present invention is selected from: 2- (R) - (1- (R) - (3, 5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluorophenyl) -4- (3- (5-oxo-1H, 4H-1, 2, 4-triazolo) methyl) morpholine or a pharmaceutically acceptable salt thereof, which is described in U.S. patent No. 5,719,147.
The compounds of the invention may be used in the treatment or prevention of cancer, including bone cancer, in combination with bisphosphonates, understood to include bisphosphonates (biphosphonates), diphosphonates (diphosphonates), bisphosphonic acids (bisphosphonic acids) and bisphosphonates (diphosphonic acids). Examples of bisphosphonates include, but are not limited to: 1-hydroxy-ethylene-1, 1-diphosphonate (Didronel), pamidronate (Alda), vitamin D alendronate (Forkinam), incadronate (Actonel), zoledronic acid (Zomet), ibandronate (Boniva), incadronate or sodium incadronate (cimadronate), clodronate, EB-1053, minodronate, neridronate, [2- (2-pyridyl) ethylene ] -1, 1-diphosphonate (piridronate), and tiludronate, including any and all pharmaceutically acceptable salts, derivatives, hydrates, and mixtures thereof.
The compounds of the present invention may also be administered with agents for the treatment of anemia. Such anemia therapeutics are, for example, sustained erythropoiesis receptor activators (such as epoetin alpha).
The compounds of the present invention may also be administered with agents useful in the treatment of neutropenia. Such a neutropenia therapeutic agent is, for example, a hematopoietic growth factor, which regulates the production and function of neutrophils such as human granulocyte colony stimulating factor (G-CSF). Examples of G-CSF include fegerastine.
The compounds of the invention may also be administered with immune enhancing drugs such as levamisole, isoprinosine and hydrangeae.
The compounds of the present invention may also be used in combination with aromatase inhibitors for the treatment or prevention of breast cancer. Examples of aromatase inhibitors include, but are not limited to: anastrozole, letrozole, and exemestane.
The compounds of the invention may also be used in combination with siRNA therapeutics for the treatment or prevention of cancer.
Accordingly, the scope of the present invention includes the use of the instantly claimed compounds in combination with a second compound selected from the group consisting of: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins/cytostatic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HTV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, PPAR-gamma agonists, PPAR-delta agonists, inhibitors of automultidrug resistance, anti-emetic agents, agents for treating anemia, agents for treating neutropenia, immunopotentiating agents, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents, bisphosphonates, aromatase inhibitors, siRNA therapeutics, and agents that interfere with the cell cycle.
In one embodiment, the angiogenesis inhibitor used as the second compound is selected from: an antibody to a tyrosine kinase inhibitor, an epidermal derived growth factor inhibitor, a fibroblast derived growth factor inhibitor, a platelet derived growth factor inhibitor, an MMP (matrix metalloenzyme protein) inhibitor, an integrin blocker, interferon- α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin a-4, squalamine, 6-0-chloroacetyl-carbonyl) -fumagillol, thalidomide, angiostatin, myogenin-1, or VEGF. In one embodiment, the estrogen receptor modulator is tamoxifen or raloxifene.
Also included within the scope of the claims is a method of treating cancer comprising administering a therapeutically effective amount of a compound of formula I or formula II in combination with radiation therapy and/or in combination with a compound selected from the group consisting of: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins/cytostatic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HTV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, PPAR-gamma agonists, PPAR-delta agonists, inhibitors of multidrug resistance per se, anti-emetic agents, agents for treating anemia, agents for treating neutropenia, immunopotentiators, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents, bisphosphonates, aromatase inhibitors, siRNA checkpoint therapeutics, and agents that interfere with the cell cycle.
Yet another embodiment of the present invention is a method of treating cancer comprising administering a therapeutically effective amount of a compound of formula I or formula II in combination with paclitaxel or trastuzumab. The invention further includes a method of treating or preventing cancer comprising administering a therapeutically effective amount of a compound of formula I or formula II in combination with a COX-2 inhibitor.
The invention also includes a pharmaceutical composition for treating or preventing cancer comprising a therapeutically effective amount of a compound of formula I or formula II and a compound selected from the group consisting of: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins/cytostatics, antiproliferatives, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HTV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, PPAR-gamma agonists, PPAR-delta agonists, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, and agents that interfere with cell cycle checkpoints.
These and other aspects of the invention will be apparent in light of the teachings contained herein.
General reaction scheme
In addition to other standard procedures known in the literature or exemplified in experimental procedures, the compounds of the present invention can also be prepared by employing the reactions shown in the following schemes. Thus, for purposes of illustration, the following illustrative schemes are not limited by the compounds listed or any specific substituents employed. The substituent numbering shown in the schemes does not necessarily correlate to the numbering used in the claims, and generally for clarity purposes, a single substituent is shown attached to a compound where multiple substituents are allowed under the definition of formula I or formula II above.
Those skilled in the art will recognize that this general scheme can be modified and still result in the compounds of the present invention. As shown in scheme 1, 2, 4-dichloropyrimidin-5-amine III, suitably substituted under acidic (chem. pharm. Bull.1987, 35(12), 4972-4976) and basic conditions, is reacted with propylamine IV to give 2-chloropyrimidin-4, 5-diamine V. Can be prepared by heating in a suitable solvent,in nitrites such as NaNO2Cyclization of intermediate 2-chloropyrimidine-4, 5-diamine V to 5-chloro-3H- [1, 2, 3-diamine V in the presence of a suitable acid, e.g., hydrochloric acid and/or acetic acid and the like, and optionally in the presence of amyl nitrite]Triazolo [4, 5-d]Pyrimidine VI. With NH in a suitable solvent, such as ethanol3Treatment of 5-chloro-3H- [1, 2,3]Triazolo [4, 5-d]Pyrimidine VI to give 3H- [1, 2,3]Triazolo [4, 5-d]Pyrimidine-5-amines VII. 3H- [1, 2, 3] by treatment with isoamyl nitrite in diiodomethane or dibromomethane (chem. pharm. Bull.1991, 39(11), 3037-Bull. 3040)]Triazolo [4, 5-d]Conversion of the amino group in the 5-position of pyrimidine VII to iodine or bromine to give 5-iodo or bromo-3H- [1, 2,3]Triazolo [4, 5-d]Pyrimidine VIII. 5-chloro-3H- [1, 2,3]Triazolo [4, 5-d]Pyrimidine VI or 5-iodo or bromo-3H- [1, 2,3]Triazolo [4, 5-d]Pyrimidine VIII with suitably substituted bromic acid, bromate, zincate or stannane R1Cross-coupling of Y under Suzuki (Miyaura, N., Suzuki, A., chem.Rev.1995, 95, 2457), Negishi (J.Org.chem.1977, 42, 1821) or Stille conditions (Agnew. chem., int.Ed.Engl.1986, 25, 508 and references therein) catalyzed by transition metals gives the coupled product, 5-substituted-3H- [1, 2,3]Triazolo [4, 5-d]Pyrimidines I and II.
Scheme 1
Scheme 1
Scheme 2 illustrates an alternative route to the intermediate 2-chloropyrimidine-4, 5-diamine V. Reaction of 2, 4-dichloro-5-nitropyrimidine IX with the appropriate amine IV in the presence of N-diisopropylethylamine affords intermediate X. At H2Reduction of intermediate X in the presence of a suitable catalyst such as platinum or palladium on carbon, a suitable catalyst poison such as thiophene solution and a suitable solvent such as methanol affords intermediate 2-chloropyrimidine-4, 5-diamine V. Alternatively, it may be in the presence of Fe and ammonium chloride solution or in the presence of SnCl2And an alcoholic solution to give the same intermediate V.
Scheme 2
Scheme 2
Scheme 3 further illustrates that multiple modifications of 5-chloro-3H- [1, 2, 3] triazolo [4, 5-d ] pyrimidine VI with O-, N-, and S-nucleophiles (chem. pharm. Bull.1989, 37(7), 1731-1734) can yield various 5-substituted 3H- [1, 2, 3] triazolo [4, 5-d ] pyrimidines XI, XII, and XIII.
Scheme 3
Scheme 3