Indole compounds useful for the treatment of cancer
AssigneeThe Regents of the University of California
InventorsDennis Carson, Howard Cottam, Lorenzo Leoni
Life of this patent
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Abstract
The present invention provides novel indole derivatives useful to inhibit cancer or sensitize cancer cells to chemotherapeutic agents, radiation or other anti-cancer treatments.
Claims32
A compound of formula (I):
- wherein R1 is lower alkyl, lower alkenyl, (hydroxy)lower alkyl, lower alkynyl, phenyl, benzyl or 2-thienyl,
- R2, R3, R4 and R5 are the same or different and are each hydrogen or lower alkyl;
- each R6 is independently hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro or halo, n is 1-3,
- R7 is hydrogen, lower alkyl or lower alkenyl;
- X is oxy or thio,
- Y is (CH2)1-3, or (CH2)1-3SO2;
- Z is (ω-(4-pyridyl)(C2-C4alkoxy), (ω-((R8)(R9)amino)(C2-C4 alkoxy), an amino acid ester of (ω-(HO)(C2-C4))alkoxy, N(R8)CH(R8)CO2H, 1′-D-glucuronyloxy, OH, (C2-C4)acyloxy, SO3H, PO4H2, N(NO)(OH), SO2NH2, PO(OH)(NH2), OCH2CH2N(CH3)3+, amino, lower alkylamino, di(lower alkyl)amino, phenylamino, or tetrazolyl;
- wherein R8 and R9 are each H, (C1-C3)alkyl or together with N, are a 5- or 6-membered heterocyclic ring having 1-3 N(R8), S or nonperoxide O;
- or
- Y-Z is (CH2)1-3R10 wherein R10 is OH, (C2-C4)acyloxy, SO3H, PO4H2, N(NO)(OH), SO2NH2, PO(OH)NH2,
- provided that when n is 1, R6 is hydrogen, and R1 is methyl, then-Y-Z is not —CH2CH2—OH, —CH2—OH, —CH2CH2—OC(O)CH3, or —CH2—OC(O)CH3;
- or tetrazolyl;
- and when n is 1, R6 is 8-ethyl, and R1 is ethyl, then —Y-Z is not —CH2CH2—OH, or —CH2CH2—OC(O)CH3;
- or a pharmaceutically acceptable salt thereof.
A therapeutic method comprising:
- (a) evaluating the level of at least one of PPAR-γ, in cancer cells isolated from a patient afflicted with prostate cancer to determine if said level is sufficiently high so that said cells would be susceptible to inhibition by a compound of formula (I):
- wherein R1 is lower alkyl, lower alkenyl, (hydroxy)lower alkyl, lower alkynyl, phenyl, benzyl or 2-thienyl,
- R2, R3, R4 and R5 are the same or different and are each hydrogen or lower alkyl;
- each R6 is individually hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro or halo, n is 1-3,
- R7 is hydrogen, lower alkyl or lower alkenyl,
- X is oxy or thio,
- Y is carbonyl, (CH2)1-3, (CH2)1-3SO2 or (CH2)1-3C(O), and
- Z is (ω-(4-pyridyl)(C2-C4alkoxy), (ω-((R8)(R9)amino)(C2-C4 alkoxy), an amino acid ester of (ω-(HO)(C2-C4))alkoxy, N(R8)CH(R8)CO2H, 1′-D-glucuronyloxy, OH, (C2-C4)acyloxy, SO3H, PO4H2, N(NO)(OH), SO2NH2, PO(OH)(NH2), OCH2CH2N(CH3)3+, amino, lower alkylamino, di(lower alkyl)amino, phenylamino, or tetrazolyl;
- wherein R8 and R9 are each H, (C1-C3)alkyl or together with N, are a 5- or 6-membered heterocyclic ring having 1-3 N(R8), S or nonperoxide O;
- or
- Y-Z is (CH2)1-3R10 wherein R10 is OH, (C2-C4)acyloxy, SO3H, PO4H2, N(NO)(OH), SO2NH2, PO(OH)NH2, or tetrazolyl;
- and
- (b) administering to said patient an amount of a compound of formula (I) effective to inhibit said cells or to sensitize said cells to inhibition by administration of a chemotherapeutic agent.
A method for determining the ability of a test agent to inhibit prostate cancer cells comprising contacting a population prostate cancer cells that express PPAR-γ with said agent and determining whether the agent increases the expression of PPAR-γ in said cells.
A method for determining the ability of a test agent to inhibit cancer comprising determining whether or not the agent competitively inhibits the receptor-mediated binding of radiolabeled etodolac to cancer cells.
A method for determining the susceptibility of prostate cancer to treatment by a compound that activates PPAR-γ expression in prostate cancer cells comprising:
- (a) isolating prostate cancer cells from a human subject;
- and
- (b) evaluating whether or not said cells express PPAR-γ at a level sufficient to render them subject to inhibition by said compound.
Dependencies are inferred from the claim text.