Patent Application
20090018145
Approximately twenty percent of deaths from all causes in the United States are cancer-related. Although chemotherapy is a principal means of cancer treatment, the rate at which effective new drugs have become available for use in cancer chemotherapy has not increased (Horowitz et al., Journal of Clinical Oncology, Vol. 6, No. 2, pp 308-314 (1988)). Despite many years of promising new therapies, cancer remains a major cause of morbidity and mortality (Bailar et al., N. Engl. J. Med. 336:1569-1574, 1997). Accordingly, there is a substantial need for new drugs that are effective in inhibiting the growth of tumors.
The present invention provides novel compounds and pharmaceutical compositions thereof, as well as methods for using the compounds and pharmaceutical compositions for treating tumors. Examples of specific tumor types that the compounds may be used to treat include, but are not limited to sarcomas, melanomas, neuroblastomas, carcinomas (including but not limited to lung, renal cell, ovarian, liver, bladder, and pancreatic carcinomas), and mesotheliomas. In one aspect, the present invention provides compounds according to the general formula I:
wherein
In another aspect the present invention provides pharmaceutical compositions, comprising one or more compounds according to the invention, and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides methods for treating a subject with a tumor, comprising administering to the subject an amount effective of a compound according to formula I.
All references cited herein are incorporated by reference in their entirety.
In one aspect, the present invention provides novel compounds according the general formula I:
wherein
The invention also relates to compounds of formula Ia:
wherein R2, R3, R4, R10 and Z are as defined above for formula I.
In an embodiment, the invention relates to compounds of formula Ia wherein R2, R3 and R4 are hydrogen.
The invention also relates to compounds of formula Ib:
wherein R1, R2, R3, R4, R6, R10 , R12, R12′, R12″, R12′″, R13, R13′, R13″, R 13′″ and R″″ are as defined above for formula I.
In an embodiment, the invention relates to compounds of formula Ib wherein R1 is hydrogen, chloro or methyl, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Ib wherein R12′ is hydrogen or halo, and R12, R12′ and R12′″ are hydrogen.
In still another embodiment, the invention relates to compounds of formula Ib wherein R13, R13′ and R13″ are hydrogen.
The invention also relates to compounds of formula Ic:
wherein R1, R2, R3, R4, R10, R12, R12′, R12″, R12′″, R13′, R13″, R13′″ and R13″″ are as defined above for formula I.
In an embodiment, the invention relates to compounds of formula Ic wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Ic wherein R12, R12′, R12″ and R12′″ are hydrogen.
In still another embodiment, the invention relates to compounds of formula Ic wherein R13′, R13″, R13′″ and R13″″ are hydrogen.
The invention also relates to compounds of formula Id:
wherein R1, R2, R3, R4, R10, R12, R12′, R12″, R12′″, R13, R13′, R13″ and R13′″ are as defined above for formula I.
In an embodiment, the invention relates to compounds of formula Id wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Id wherein R12, R12′, R12″ and R12′″ are hydrogen.
In still another embodiment, the invention relates to compounds of formula Id wherein R13, R13′, R13″ and R13′″ are hydrogen.
The invention also relates to compounds of formula Ie:
wherein R1, R2, R3, R4, R10, R12, R12′, R12″, R12′″, R13, R13 ′ and R13″ are as defined above for formula I.
In an embodiment, the invention relates to compounds of formula Ie wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Ie wherein R12, R12′, R12″ and R12′″ are hydrogen.
In still another embodiment, the invention relates to compounds of formula Ie wherein R13, R13′ and R13″ are hydrogen.
The invention also relates to compounds of formula If:
wherein R1, R2, R3, R4, R10, R12, R12″, R12′″, R13, R13′, R13″, R13′″ and R13″″ are as defined above for formula I.
In an embodiment, the invention relates to compounds of formula If wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula If wherein R12, R12″ and R12′″ are hydrogen.
In still another embodiment, the invention relates to compounds of formula If wherein R13, R13′, R13″, R13′″ and R13″″ are hydrogen.
The invention also relates to compounds of formula Ig:
wherein R1, R2, R3, R4, R10, R12, R12′, R12″, R12′″, R13, R13′, R13″, R13′″ and R13″″ are as defined above for formula I.
In an embodiment, the invention relates to compounds of formula Ig wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Ig wherein R12, R12′, R12″ and R12′″ are hydrogen.
In still another embodiment, the invention relates to compounds of formula Ig wherein R13, R13′, R13″, R13′″ and R13″″ are hydrogen.
The invention also relates to compounds of formula Ih:
wherein R1, R2, R3, R4, R10, R12, R12′, R12″ and R12′″ are as defined above for formula I, and W is —OH, —C(O)OR or —C(O)NHR′.
In an embodiment, the invention relates to compounds of formula Ih wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Ih wherein R12, R12′, R12″ and R12′″ are hydrogen.
In still another embodiment, the invention relates to compounds of formula Ih wherein R10 is pyridine-2-yl optionally substituted with one or two groups selected from lower alkyl, lower alkoxy or halo.
The invention also relates to compounds of formula Ii:
wherein R1, R2, R3, R4, R10, R12, R12′, R12″, R12′″, R13, R13′, R13″ and R13′″ are as defined above for formula I.
In an embodiment, the invention relates to compounds of formula Ii wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Ii wherein R12, R12′, R12 ″ and R12′″ are hydrogen.
In still another embodiment, the invention relates to compounds of formula Ii wherein R13, R13″ and R13′″ are hydrogen, and R13′ is selected from hydrogen, aminoalkyl, monoalkylaminoalkyl, dialkyaminoalkyl or lower alkoxy.
The invention also relates to compounds of formula Ij:
wherein R1, R2, R3, R4, R10, R12, R12′, R12″ and R12′″ are as defined above for formula I, and X is halo.
In an embodiment, the invention relates to compounds of formula Ih wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Ih wherein R12, R12′, R12″ and R12′″ are hydrogen.
In still another embodiment, the invention relates to compounds of formula Ih wherein X is bromo.
The invention also relates to compounds of formula Ik:
wherein R1, R2, R3, R4 and Z are as defined above for formula I and R22, R22′, R22″ and R22′″ are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R; or aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one to three groups selected from lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R.
In an embodiment, the invention relates to compounds of formula Ik wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Ik wherein R22, R22′, R22″ and R22′″ are selected from hydrogen, halo, lower alkyl, lower alkoxy or optionally substituted heterocyclyl.
The invention also relates to compounds of formula Il:
wherein A is —CH or N, and R1, R2, R3, R4 and Z are as defined above for formula I and R22 and R22′ are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R; or aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one to three groups selected from lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R.
In an embodiment, the invention relates to compounds of formula Il wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Il wherein R22 and R22′ are selected from hydrogen, halo, lower alkyl and lower alkoxy.
The invention also relates to compounds of formula Im:
wherein the — — — bonds are both present or both absent, and R1, R2, R3, R4 and Z are as defined above for formula I and R22, R22′ and R22″ are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R; or aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one to three groups selected from lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R.
In an embodiment, the invention relates to compounds of formula Im wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Im wherein R22 and R22′ are selected from hydrogen, halo, lower alkyl and lower alkoxy.
The invention also relates to compounds of formula In:
wherein A is —CH or N, and R1, R2, R3, R4 and Z are as defined above for formula I and R22 and R22′ are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R; or aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one to three groups selected from lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R.
In an embodiment, the invention relates to compounds of formula In wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula In wherein R22 and R22′ are selected from hydrogen, halo, lower alkyl and lower alkoxy.
The invention also relates to compounds of formula Io:
wherein A is —CH or N, and R1, R2, R3, R4 and Z are as defined above for formula I and R22 is as independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R; or aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one to three groups selected from lower alkyl, lower alkenyl, lower alkynyl, trifluoromethyl, lower alkoxy, hydroxyl, halo, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, —CN, oxo, —C(O)OR, —NH—C(O)—R′, —C(O)—NHR′, —SR, —SO2R, —CO2R.
In an embodiment, the invention relates to compounds of formula Io wherein R1 is chloro, and R2, R3 and R4 are hydrogen.
In another embodiment, the invention relates to compounds of formula Io wherein R22 and R22′ are selected from hydrogen, halo, lower alkyl, lower alkoxy and optionally substituted aryl.
A family of specific compounds of particular interest within formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows (all compounds are named via the structure naming plug-in to either ChemDraw Ultra 6.0 or 8.0, or ACDLabs version 6.0, all versions using IUPAC rules):
6-chloro-N-(tetrahydrofuran-2-ylmethyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(2-furylmethyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-chloropyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(4,5-dihydro-1,3-thiazol-2-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(2-pyrrolidin-1-ylethyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(5-chloropyrimidin-2-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(3-methylisoxazol-5-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-[6-(methylsulfonyl)-1,3-benzothiazol-2-yl]-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-1,2,4-triazin-3-yl-1,1′:4′,1″-terphenyl-3-carboxamide;
methyl 3-{[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]amino}benzoate;
6-chloro-N-(5-phenyl-1,3,4-oxadiazol-2-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-[3-(2-methyl-1,3-dioxolan-2-yl)phenyl]-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(4-methoxyphenyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
(2aR,6R,9S, 12S,12bS)-6,12b-bis(acetyloxy)-9-{[3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-12-yl benzoate;
6-chloro-N-quinolin-6-yl-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-pyrazin-2-yl-1,1′:4′,1″-terphenyl-3-carboxamide;
1-[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]pyrrolidin-3-amine;
N-(5-bromopyridin-2-yl)-6-chloro-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-fluoropyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(5-chloropyridin-2-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-pyridin-2-ylbiphenyl-3-carboxamide;
6-chloro-3′-fluoro-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-pyridin-4-ylbiphenyl-3-carboxamide;
6-chloro-N-(4-methylphenyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(3-fluoro-4-methoxyphenyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-pyrimidin-5-ylbiphenyl-3-carboxamide;
6-chloro-N-[2-(dimethylamino)ethyl]-N-pyridin-3-yl-1,1′:4′,1″-terphenyl-3-carboxamide;
N-(2-pyrrolidin-1-ylethyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-morpholin-4-ylpyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
4-chloro-N-(6-methoxypyridin-3-yl)-3-(6-phenylpyridin-3-yl)benzamide;
6-chloro-N-[6-(methylthio)pyridin-3-yl]-1,1′:4′,1″-terphenyl-3-carboxamide;
1,4-dihydroxy-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)anthra-9,1 0-quinone dihydrochloride;
6-chloro-N-(5-methoxypyrazin-2-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-[2-(methylthio)pyrimidin-5-yl]-1,1′:4′,1″-terphenyl-3-carboxamide
6-chloro-N-(2-methoxypyrimidin-5-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
methyl [5-(2-thienylcarbonyl)-1H-benzimidazol-2-yl]carbamate;
6-chloro-N-(6-methylpyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-oxo-1,6-dihydropyridin-3-yl)-4′-pyridin-2-ylbiphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-(2-methyl-2H-tetrazol-5-yl)biphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-1,1′:3′,1″-terphenyl-3-carboxamide;
N-(6-methoxypyridin-3-yl)-6-methyl-1,1′:4′,1″-terphenyl-3-carboxamide;
5-biphenyl-4-yl-6-chloro-N-(6-methoxypyridin-3-yl)nicotinamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-pyridin-2-ylbiphenyl-3-carboxamide;
6-chloro-3″-formyl-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-3″-[(dimethylamino)methyl]-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-3″-(hydroxymethyl)-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-4′-[(dimethylamino)methyl]-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
6-chloro-4″-[(dimethylamino)methyl]-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-4″-(hydroxymethyl)-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-3″-(methylsulfonyl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-pyridin-3-ylbiphenyl-3-carboxamide;
4″-(aminomethyl)-6-chloro-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-(methylsulfonyl)biphenyl-3-carboxamide;
4′-(benzyloxy)-6-chloro-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
4″-(benzyloxy)-6-chloro-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
2′-chloro-5′-{[(6-methoxypyridin-3-yl)amino]carbonyl}biphenyl-3-carboxylic acid;
6-chloro-4′-[5-(hydroxymethyl)pyridin-3-yl]-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
4′-bromo-6-chloro-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
4′-bromo-6-chloro-N-pyrazin-2-ylbiphenyl-3-carboxamide;
6-chloro-N3-(6-methoxypyridin-3-yl)biphenyl-3,3′-dicarboxamide;
6-chloro-N3-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3,3″-dicarboxamide;
6-chloro-3′-hydroxy-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
6-chloro-3″-hydroxy-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-4″-hydroxy-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-4′-{5-[(dimethylamino)methyl]pyridin-3-yl}-N-(6-methoxypyridin-3-5yl)biphenyl-3-carboxamide;
5-fluoro-N-(6-methoxypyridin-3-yl)-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-{3-[(morpholin-4-ylacetyl)amino]phenyl}-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-1,1′:4′,1″-terphenyl-3-carboxamide;
6-chloro-N-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}-1,1′:4′,1″-terphenyl-3-carboxamide;
4′-acetyl-6-chloro-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
6-chloro-N-(6-methoxypyridin-3-yl)-4′-(methylsulfinyl)biphenyl-3-carboxamide;
6-chloro-4′-[hydroxy(oxido)amino]-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
6-chloro-4′-[(dimethylamino)sulfonyl]-N-(6-methoxypyridin-3-yl)biphenyl-3-carboxamide;
6-chloro-N-[6-(hydroxymethyl)pyridin-3-yl]-1,1′:4′,1″-terphenyl-3-carboxamide;
2′-chloro-5′-{[(6-methoxypyridin-3-yl)amino]carbonyl}biphenyl-4-yl 4-methylpiperazine-1-carboxylate;
2″-chloro-5″-{[(6-methoxypyridin-3-yl)amino]carbonyl}-1,1′:4′,1″-terphenyl-4-yl 4-methylpiperazine-1-carboxylate;
6-chloro-4′-(methylsulfonyl)-N-pyrazin-2-ylbiphenyl-3-carboxamide;
(8S,10S)-10-((2R)-4-amino-tetrahydro-5-hydroxy-6-methyl-2H-pyran-2-yloxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxytetracene-5,12-dione;
2-{[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]amino}indane-2-carboxylic acid;
2-{[(2′,4′,6-trichlorobiphenyl-3-yl)carbonyl]amino}indane-2-carboxylic acid;
N-[4-chloro-3-(phenylethynyl)benzoyl]-3-(3a,7a-dihydro-1H-indol-3-yl)-L-alanine;
(2S)-2-{[4-chloro-3-(phenylethynyl)benzoyl]amino}-4-cyclohexa-2,4-dien-1-ylbutanoic acid;
N-[(4′,6-dichlorobiphenyl-3-yl)carbonyl]-3-(3a,7a-dihydro-1H-indol-3-yl)-L-alanine;
(4S)-3-[(4′,6-dichlorobiphenyl-3-yl)carbonyl]-1,3-thiazolidine-4-carboxylic acid;
3-cyclohexyl-N-[(5′,6-dichloro-2′-methoxybiphenyl-3-yl)carbonyl]-D-alanine;
3-cyclohexyl-N-[(2′,4′,6-trichlorobiphenyl-3-yl)carbonyl]-D-alanine;
2-{[4-chloro-3-(phenylethynyl)benzoyl]amino}indane-2-carboxylic acid;
N-[(6-chloro-4′-methoxybiphenyl-3-yl)carbonyl]-3-cyclohexyl-D-alanine;
(4S)-3-[4-chloro-3-(phenylethynyl)benzoyl]-1,3-thiazolidine-4-carboxylic acid;
N-[4-chloro-3-(phenylethynyl)benzoyl]-3-cyclopropyl-D-alanine;
3-cyclopropyl-N-[(4′,6-dichlorobiphenyl-3-yl)carbonyl]-D-alanine;
(4S)-3-[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]-1,3-thiazolidine-4-carboxylic acid;
N-[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]-D-methionine;
4-[4-(3-{1-[(5-bromo-6-chloropyridin-3-yl)sulfonyl]piperidin-4-yl}propyl)piperidin-1-yl]-3-chloro-N-(pyridin-2-ylmethyl)benzenesulfonamide;
2-[(2S)-2-amino-3-biphenyl-4-yl-1-oxopropyl]-N-(2-furylmethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(2S)-3-cyclohexyl-2-({(2S)-4-phenyl-2-[(quinolin-3-ylcarbonyl)amino]butanoyl}amino)propanoic acid;
N-[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]-3-cyclopropyl-D-alanine;
N-[(6-chloro-1,1′:4′,1″-terphenyl-3-yl)carbonyl]-3-(7,7a-dihydro-1H-indol-3-yl)-D-alanine;
N-(4-{[2-(3-chlorophenyl)ethyl]amino}-2,5-difluorobenzoyl)-3-cyclohexylalanine;
N-(4-{[2-(4-bromophenyl)ethyl]amino}-2,5-difluorobenzoyl)-D-alanine;
N-(4-{[2-(4-bromophenyl)ethyl]amino}-2,5-difluorobenzoyl)-3-cyclohexylalanine;
4-{[2-(2-chlorophenyl)ethyl]amino}-N-[2-cyclohexyl-1-(hydroxymethyl)ethyl]-2,5-difluorobenzamide;
N-(4-{[2-(2,4-dichlorophenyl)ethyl]amino}-2,5-difluorobenzoyl)-D-alanine;
N-(2,5-difluoro-4-{[2-(1H-indol-3-yl)ethyl]amino}benzoyl)-D-alanine;
N-(4-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-2,5-difluorobenzoyl)-D-alanine; and
N-(4-{[2-(4-aminophenyl)ethyl]amino}-2,5-difluorobenzoyl)-3-cyclohexylalanine.
By “alkyl” and “lower alkyl” in the present invention, either alone or within other terms such as “alkylamino”, is meant straight or branched chain alkyl groups having 1-12 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. It is understood that in cases where an alkyl chain of a substituent (e.g. of an alkyl, alkoxy or alkenyl group) is within a distinct range, it will be so indicated in the second “C” as, for example, “C1-C6” indicates a maximum of 6 carbons. The alkyl groups herein may be substituted in one or more substitutable positions with various groups. For example, such alkyl groups may be optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl or ═O.
By “alkoxy” and “lower alkoxy” in the present invention is meant straight or branched chain alkyl groups having 1-12 carbon atoms, attached through at least one divalent oxygen atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and 3-methylpentoxy. The alkoxy groups herein may be substituted in one or more substitutable positions with various groups. For example, such alkoxy groups may be optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl or ═O.
The term “alkenyl” or “lower alkyenyl” embraces linear or branched radicals having at least one carbon-carbon double bond of two to twelve atoms. More preferred alkenyl radicals are those radicals having two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, 2-propenyl, allyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. The alkenyl groups herein may be alkenyl groups may be optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl or ═O.
The term “alkynyl” embraces linear or branched radicals having at least one carbon-carbon triple bond of two to twelve carbon atoms. More preferred alkynyl radicals are those radicals having two to about four carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, and 4-methylbutynyl. The alkynyl groups herein may be substituted in one or more substitutable positions with various groups. For example, such alkynyl groups may be optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl or ═O.
The term “halo” or “halogen” means halogens such as fluorine, chlorine, bromine or iodine atoms.
By “aryl” is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. More preferred aryl is phenyl. The aryl groups herein may be substituted in one or more substitutable positions with various groups. For example, such aryl groups may be optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl or ═O.
By “heteroaryl” is meant a single ring, multiple rings, or multiple condensed rings in which at least one is aromatic, wherein such rings may be attached together in a pendent manner or may be fused. The ring systems contain of from between 9-15 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Examples include, but are not limited to, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl. The heteroaryl groups herein may be substituted in one or more substitutable positions with various groups. For example, such heteroaryl groups may be optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl or ═O.
As used herein, the term “cycloalkyl” refers to saturated carbocyclic radicals having three to twelve carbon atoms. The cycloalkyl can be monocyclic, or a polycyclic fused or spiro system, and can optionally contain a double bond. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such cycloalkyl groups may be optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, oxo, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl or di(C1-C6)alkylamino(C1-C6)alkyl.
By “heterocycle” or “heterocycloalkyl” is meant one or more carbocyclic ring systems which includes fused and spiro ring systems of 9-15 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. The heterocycle may optionally contain a double bond. Examples of heterocycles of the present invention include morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahyiropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. The heterocycle groups herein may be substituted in one or more substitutable positions with various groups. For example, such heterocycle groups may be optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl or ═O.
Any term that includes two radicals such as, for example, “arylalkyl”, denotes the first radical, or aryl as in the example, attached to the concluding radical, or alkyl as in the example. The concluding radical is attached to the substituent in question.
The compounds of the invention can be synthesized by procedures known in the art. A representative example is depicted below in Scheme 1.
According to scheme 1, the amide 3 can be prepared by coupling the acid 1 with the amine 2 under standard coupling conditions, such as, for example, (3-dimethylamino-propyl)-ethyl-carbodiimide-HCl salt (EDAC) and 1-hydroxybenzotriazole (HOBT) and optionally in the presence of a base such as diisopropylethylamine in an appropriate solvent. Next, the amide 3 can be coupled to a 4-halo-aryl- or heteroaryl-boronic acid 4 with a catalyst, including but not limited to, tetrakis(triphenylphosphine)palladium, optionally in the presence of base, for example, potassium carbonate, in a solvent such as dioxane or tetrahydrofuran (THF). The resulting 4-halo-bicyclic-4-benzoic acid 5 can subsequently be coupled to a tributylstannylaryl or heteroaryl 6 under similar, but not necessarily the exact, conditions described above in the previous step, to afford the tricyclic compound 7.
Compounds of the present invention can possess, in general, one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. Unless otherwise indicated, the compounds of the present invention, as depicted or named, may exist as the racemate, a single enantiomer, or any uneven (i.e. non 50/50) mixture of enantiomers. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column, such as, for example, a CHIRAL-AGP column, optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
The compounds of the invention include pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, including but not limited to carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term “salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, arid the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like—(See, for example, Berge S. M. et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6 alkyl esters, wherein the alkyl group is a straight or branched, substituted or unsubstituted, C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl and triphenylmethyl. C1-C4 alkyl esters are preferred, such as methyl, ethyl, 2,2,2-trichloroethyl, and tert-butyl. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines, wherein the alkyl groups are straight or branched. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods. The term “prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.
These compounds can be administered individually or in combination, usually in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Accordingly, a further aspect of the present invention includes pharmaceutical compositions comprising as one or more compounds of the invention disclosed above, associated with a pharmaceutically acceptable carrier. For administration, the compounds are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
In another aspect, the present invention provides methods for treating a subject with a tumor, comprising administering to the subject an amount effective of a compound according to formula I and formulas Ia-Io.
Non-limiting examples of specific tumor types that the compounds may be used to treat include, but are not limited to sarcomas, melanomas, neuroblastomas, carcinomas (including but not limited to lung, renal cell, ovarian, liver, bladder, and pancreatic carcinomas), and mesotheliomas
As used herein, the term “amount effective” means a dosage sufficient to produce a desired result. The desired result can be subjective or objective improvement in the recipient of the dosage; a decrease in tumor size, time to progression of disease, and/or survival; inhibiting an increase in tumor size; reducing or preventing metastases; and/or limiting or preventing recurrence of the tumor in a subject that has previously had a tumor.
In one embodiment, the methods of the invention can be used in combination with surgery on the subject, wherein surgery includes primary surgery for removing one or more tumors, secondary cytoreductive surgery, and palliative secondary surgery.
In a further embodiment, the methods of the invention further comprise treating the subject with chemotherapy and/or radiation therapy. One benefit of such a method if that use of the compounds permits a reduction in the chemotherapy and/or radiation dosage necessary to inhibit tumor growth and/or metastasis. As used herein, “radiotherapy” includes but is not limited to the use of radio-labeled compounds targeting tumor cells. Any reduction in chemotherapeutic or radiation dosage benefits the patient by resulting in fewer and decreased side effects relative to standard chemotherapy and/or radiation therapy treatment. In this embodiment, the one or more compounds may be administered prior to, at the time of, or shortly after a given round of treatment with chemotherapeutic and/or radiation therapy. In a preferred embodiment, the one or more compounds is administered prior to or simultaneously with a given round of chemotherapy and/or radiation therapy. In a most preferred embodiment, the one or more compounds is administered prior to or simultaneously with each round of chemotherapy and/or radiation therapy. The exact timing of compound administration will be determined by an attending physician based on a number of factors, but the compound is generally administered between 24 hours before a given round of chemotherapy and/or radiation therapy and simultaneously with a given round of chemotherapy and/or radiation therapy.
The methods of the invention are appropriate for use with chemotherapy using one or more cytotoxic agent (ie: chemotherapeutic), including, but not limited to, cyclophosphamide, taxol, 5-fluorouracil, adriamycin, cisplatinum, methotrexate, cytosine arabinoside, mitomycin C, prednisone, vindesine, carbaplatinum, and vincristine. The cytotoxic agent can also be an antiviral compound which is capable of destroying proliferating cells. For a general discussion of cytotoxic agents used in chemotherapy, see Sathe, M. et al., Cancer Chemotherapeutic Agents: Handbook of Clinical Data (1978), hereby incorporated by reference. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The methods of the invention are also particularly suitable for those patients in need of repeated or high doses of chemotherapy and/or radiation therapy.
The actual compound dosage range for administration is based on a variety of factors, including the age, weight, sex, medical condition of the individual, the severity of the condition, and the route of administration. Thus, the dosage regimen may vary widely, but can be determined by a physician using standard methods. An effective amount of the one or more compounds that can be employed ranges generally between 0.01 μg/kg body weight and 10 mg/kg body weight, preferably ranging between 0.05 μg/kg and 5 mg/kg body weight, more preferably between 1 μg/kg and 5 mg/kg body weight, and even more preferably between about 10 μg/kg and 5 mg/kg body weight.
The compounds may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions). The compounds of the invention may be applied in a variety of solutions and may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. The compounds of the invention may be administered by any suitable route, including orally, parentally, by inhalation or rectally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjutants, and vehicles, including liposomes. The term parenteral as used herein includes, subcutaneous, intravenous, intraarterial, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques, intracavity, or intraperitoneally.
In yet further aspects, the invention provides an article of manufacture comprising packaging material and the above pharmaceutical compositions.
The instant invention may be embodied in other forms or carried out in other ways without departing from the spirit or essential characteristics thereof. The present disclosure and enumerated examples are therefore to be considered as in all respects illustrative and not restrictive, and all equivalency are intended to be embraced therein. One of ordinary skill in the art would be able to recognize equivalent embodiments of the instant invention, and be able to practice such embodiments using the teaching of the instant disclosure and only routine experimentation.
4-Chloro-3-iodo-N-(6-methoxy-pyridin-3-yl)-benzamide (3a)
To a solution of 4-chloro-3-iodobenzoic acid (20 g, 70.8 mmol), EDC•HCl (15 g 78.2 mmol) and HOBt (11 g, 78 mmol) in 500 mL of dry dichloromethane was added DIEA (27 mL, 156 mmol). The mixture was stirred for 15 minutes at which time 5-amino-2-methoxy pyridine (10 g, 79 mmol) was added. The reaction stirred at room temperature for 12 hours. The reaction was washed with 600 mL of water. The DCM layer was separated, and the product precipitated out of solution. Pure product 3a was obtained upon filtration and dried in a vacuum oven at 50° C. to yield 21 g (78%) of a white solid.
4-Bromo-6-chloro-biphenyl-3-carboxylic Acid (6-methoxy-pyridine-3-yl)-amide (5a)
To a solution of 4-chloro-3-iodo-N-(6-methoxy-pyridin-3-yl)-benzamide (3a) (10 g, 25.77 mmol) and 4-bromophenylboronic acid (10.35 g 51.5 mmol) in 200 mL dry dioxane was added Pd2(PPh3)4 (5 g, 15 mol %) and potassium carbonate (8 g, 58 mmol). The solution was heated to 50° C. for 12 hours, reaction completion was determined by TLC and LC/MS. The solution was cooled to room temperature and reduced to dryness. After chromatography eluting with (4-1) to (2-1) heptanes/ethyl acetate pure product as a white solid (5a), 7.3 g (70%) was obtained.
6-Chloro-4-pyridine-2-yl-biphenyl-3-carboxylic Acid (6-methoxy-pyridin-3-yl)-amide (7a)
To a solution of 4-bromo-6-chloro-biphenyl-3-carboxylic acid (6-methoxy-pyridine-3-yl)-amide (7.3 g 17.5 mmol) and 2-tributylstannylpyridine (7 g, 19 mmol) in 100 mL dry dioxane was added Pd2(PPh3)4 (5 g, 20 mol %). The solution was heated to 80° C. for 12 hours, the reaction was monitored by TLC and LC/MS; After 6 hours, another equivalent of 2-tributylstannylpyridine and ˜10 mol % Pd2(PPh3)4 were added. Upon completion, the reaction was cooled to room temperature and reduced to a dark solid. The product was purified via chromatography eluting with (4-1) to (2-1) heptanes/ethyl acetate to afford target 7a (4 g, 60%) as a white solid.
1H NMR (400 MHz, DMSO-d6) ζ ppm 3.82 (s, 3 H) 6.82 (d, J=8.98 Hz, 1 H) 7.33-7.40 (m, 1 H) 7.63 (d, J=8.40 Hz, 2 H) 7.74 (d, J=8.40 Hz, 1 H) 7.83-7.92 (m, 2 H) 7.95-8.05 (m, 3 H) 8.08 (d, J=2.15 Hz, 1 H) 8.21 (d, J=8.59 Hz, 2 H) 8.50 (d, J=2.54 Hz, 1 H) 8.66-8.71 (m, 1 H) 10.38 (s, 1 H).
Bi-phenyl compounds according to the present invention were initially identified based on potential anti-microbial activity. A representative compound was subsequently tested and found to possess gyrase-inhibitory activity. Such activity suggested that the compound might also possess topoisomerase inhibitory activity.
In order to verify whether these compounds might have anti-topo activity, CP5017808 inhibition of topoisomerase II was assayed by monitoring the appearance of 2.5 kilobase DNA from eukaryotic topoII decatenation of kinetoplast DNA via agarose gel electrophoresis. All reagents were purchased from Topogen, Inc, Port Orange, Fla., unless otherwise noted. Reactions contained 1 uL of titrated CP5017808 in DMSO, 0.1 ug of kinetoplast DNA, 2 units of eukaryotic topoisomerase II, and 1× topoII reaction buffer (50 mM Tris-HCl pH 8, 120 mM KCl, 10 mM MgCl2, 0.5 mM each of dithiothreitol, ATP and 30 ug BSA/mL), in a final volume of 25 uL. Reactions were incubated in a 37° C. water bath for 15 minutes and terminated with 5 uL of stop buffer (5% sarkosyl, 0.025% bromophenol blue, 50% glycerol). 25 uL of the reaction products were analyzed on a 1% agarose gel. Electrophoresis analysis of the reaction products were performed using standard agarose gel electrophoresis units (Biorad, Hercules, Calif.). Gels were run at 100 volts, allowing the bromophenol blue dye front to migrate 75% down the gel. Following electrophoresis, gels were stained with 0.5 ug ethidium bromide/mL for 30 minutes and then photographed using a Gel Doc 2000 imaging system (Biorad, Hercules, Calif.). The resulting data confirmed that CP5017808 possessed anti-topoisomerase activity, suggesting it and other compounds according to the present invention may be cytotoxic to tumor cells, and thus useful for treating tumors. Further studies demonstrated that CP5017808 inhibits microtubule polymerization, further suggesting its potential use as an anti-tumor agent.
Raji cells (lymphoblastoid) or MCF-7 (breast carcinoma) cells were seeded at 5,000 to 10,000 cells per will, incubated for 3 days at 37° C. with compounds according to the invention. Alamar Blue (Accumed International, Westlake Ohio) was then added to the cells at 1/10 the volume of the well, and the cells were further incubated at 37° C. for various times. Alamar Blue dye measures cellular re-dox reactions (ie: cellular mitochrondrial respiration) whereby a spectral shift occurs upon reduction of the dye. (Excitation 530 nm; emission 590 nm). IC50 determinations were made from these readings.
Subsequently, a large number of candidate compounds were analyzed for anti-tumor activity in a cell line assay versus NCI-H460 (lung carcinoma cells).
For screening of anti-tumor activity versus primary human sarcoma tumor cells, excess tissue specimens obtained from freshly at the time of surgery were sent for pathological testing. For diagnosis and grading of tissue samples (ie: prior to processing), hematoxylin and eosin stained tissue sections were examined by a pathologist. If the diagnosis and grading of the tissue concurred with the determination made by the surgical pathologist that provided the tissue, then the tissue was used in the screen. If there was no agreement, then two additional pathologists served as referees. If no consensus was reached, then the tissue was discarded. The remaining tissue was used to prepare cell suspensions. The tissue was initially treated enzymatically via standard methods until only undigested material remained. The digested cell suspension was filtered through one or more screens of between 40 micron and 100 micron porosity. The resulting cell suspension was further purified via isokinetic density centrifugation.
Additional normal cells were removed from the cell suspension by negative immunoselection with a combination of monoclonal antibodies linked to magnetic beads (Dynal) that were used according to the manufacturers' instructions. The remaining cells were placed into appropriate medium, frozen down in 1.0 mL aliquots, and stored until use.
After tissue processing, the relative purity of the resulting cell suspension was determined by cytological examination after pap staining. Only those cell preparations greater than 80% tumor cells were used for testing of candidate compounds. If there was any doubt about the percentage of tumor cells in the cell preparation, additional pathologists served as referees to make a determination.
Cell preparations that passed histological and cytological examination for diagnosis, grading, and cell purity were thawed at 37° C. and resuspended in tissue culture medium designed to maintain the cells during the incubation period. The live and dead cells were counted and the cells were diluted in culture medium to 1.0×103 live tumor cells/test well.
The cells were added to microtiter plates and incubated at 37° C. overnight with 10 μM of the candidate compounds that were added at 1/10th the volume of the cell suspension. Alamar Blue (Accumed International, Westlake Ohio) was then added to the cells at 1/10 the volume of the well, and the cells were further incubated at 37° C. for various times. Alamar Blue dye measures cellular re-dox reactions (ie: cellular respiration) whereby a spectral shift occurs upon reduction of the dye. (Excitation 530 nm; emission 590 nm)
The kinetics of cellular re-dox reactions were subsequently measured at various times, for example at 3 hours, 3 days, and 5 days post-dye addition. These measurements, in comparison with control cells (untreated with compound) and media controls (test wells without cells) provide the IC50 determinations.
Compounds according to the present invention with activity against at least one tumor type tested are presented in
T=Tumor
Cytotoxic: The compound showed activity at one, or more concentrations, but an IC50 was not determined; these compounds are considered “active.”
These data clearly show that the compounds of the invention can be used as an anti-tumor agent against a variety of tumor types.
The in vivo anti-tumor activity of CP5017808 was evaluated against A375 human melanoma xenografts and ovarian carcinoma. The data presented below show that CP5017808 possesses significant anticancer activity.
CP5017808 was dissolved with heat and sonication in a 1:1 mixture of absolute ethanol and CREMAPHOR™ equivalent to 20% of the final desired volume, and then brought to a final volume with 40% hydroxypropyl-β-cyclodextin in water. CP5017808 produced a fine suspension with a pH of 6.2.
Female NCr nu/nu mice (Charles River Laboratory) were used for the study. They were 5-6 weeks old on Day 1 of the experiment. The animals were fed Rodent Diet 5010 (LabDiet™) and water ad libitum. The mice were housed in Thoren™ microisolator caging with Bed-O'Cobs™ bedding. All treatments, body weight determinations, and tumor measurements were carried out in laminar down flow cabinets. The environment was controlled to a temperature range of 70-78° F. and a humidity range of 30-70%. Test animals were implanted subcutaneously on day 0 with 30 to 60 mg tumor fragments using a 12-gauge trocar needle. All animals were observed for clinical signs at least once daily. Animals with tumors in excess of 1 g or with ulcerated tumors were euthanized, as were those found in obvious distress or in a moribund condition.
Treatments began when the tumors were approximately 100 mg. In the present study, treatment began on Day 12 when the mean estimated tumor mass for all groups in the experiment was 116 mg (range, 111-121 mg). All animals weighed >18 g at the initiation of therapy. Mean group body weights at first treatment were well-matched (range, 21-22.5 g). All animals were dosed according to individual body weight on the day of treatment (0.2 ml/20 g).
Body weights and tumor measurements were recorded three times weekly. Tumor burden (mg) was estimated from caliper measurements by the formula for the volume of a prolate ellipsoid assuming unit density as: Tum burden (mg)=(L×W2)/2, where L and W are the respective orthogonal tumor length and width measurements (mm). The primary endpoints used to evaluate efficacy were study day 26 T/C values, complete and partial tumor responses, tumor growth delay, and the number of tumor-free survivors at the end of the study. T/C values were calculated by dividing the treated median tumor mass by the median control tumor mass and multiplying by 100. The USA National Cancer Institute (NCI) considers a compound which produces a %T/C value of 42 of less is active. Complete response (CR) is defined as a decrease in tumor mass to an undetectable size (<50 mg), and a partial response (PR) is defined as a ≧50% decrease in tumor mass from that at first treatment. PRs are exclusive of CRs, as are Tumor-Free Survivors (TFS). Tumor Growth Delay (T-C) was also used to quantify efficacy. Tumor growth delay for this experiment was expressed as a T-C value, where T and C are the median times in days required for the treatment and control group tumors, respectively, to grow to a selected evaluation size, 750 mg.
All animals were observed for clinical signs at least once daily. Animals were weighed on each day of treatment and 3×/week thereafter. Treatment related weight loss in excess of 15% is generally considered unacceptably toxic. As used in this example, a dose is described as tolerated if treatment related weight loss (during and two weeks after treatment) was <15% and lethality during this period in the absence of potentially lethal tumor burdens was <10%. Upon death or euthanasia, all animals were necropsied to provide a general assessment of potential cause of death and perhaps target organs for toxicity. The presence or absence of metastases was also noted.
The time for individual tumors to reach evaluation size, time to fold growth, and tumor volume doubling times were analyzed by a single factor ANOVA. Frankly, toxic dose levels were excluded from this analysis. If the ANOVA analysis indicated no significant differences, no additional analyses were performed. If the ANOVA analysis indicated significant differences between the study groups, the data ware then analyzed to determine if the data within each treatment group were drawn from a normal distribution using the Kolmogrov-Smirnov test for normality. Finally, a least significant difference analysis was applied to determine exactly which treatment groups were significantly different from the control group. The “within mean sum of squares” term and degrees of freedom from the single factor ANOVA were used as the common variance and degrees of freedom, respectively, in this analysis. Statistical significance was determined using built-in Microsoft Excel data analysis tools and R (R Project for Statistical Computing).
The mean estimated tumor burden for all groups in the experiment on the first day of treatment was 116 mg and all of the groups in the experiment were well-matched (range, 111-121 mg). All animals weighed >18 grams at the initiation of therapy. Mean group body weights at first treatment were also well-matched (range, 21-22.5 g). 750 mg was chosen as the evaluation size for the experiment. The median control tumor reached evaluation size on Day 25, and the tumor volume doubling time for the control group was 4.6 days. Control animals experienced 0.5 g mean weight loss during the treatment regimen. There were no spontaneous regressions in the control group. Based on historical data for this model, the biology of the control group was judged to be within the normal range. The median mouse in the control group surpassed a mass of 1-gram size on study day 26, the day used for %T/C calculations. Treatment with 30 mg/kg of docetaxel, the positive control compound for this experiment, produced a %T/C value of 32% on study day 26 and produced a 10 day tumor growth delay. This was consistent with expected activity.
CP5017808 was toxic at 100 mg/kg; producing 100% treatment related deaths. Six out of the 8 mice were found dead within four treatments, with common necropsy findings of mottled liver and red intestines. The remaining two mice died several days later with similar necropsy observations. CP5017808 was tolerated at 60 and 36 mg/kg, producing 13 and 0% treatment related deaths, respectively. The 60 mg/kg group experienced one death, which occurred on study day 27. This mouse was too decomposed to necropsy. Minimal weight loss, 6 and 3.8%, respectively was observed in these dosage groups, both maximal on study day 15. The weight loss induced by the 60 mg/kg treatment was recovered within 13 days and the weight loss related to the 36 mg/kg treatment was recovered within 3.6 days. All animals were necropsied as they left the study due to tumor burden with no remarkable findings to report.
CP5017808 was significantly active at 60 mg/kg producing a %T/C value of 34% on study day 26, which is well below the NCI-designated threshold for meaningful anti-tumor activity of 42% (ie: 42% or lower represents meaningful activity). This treatment produced a tumor growth delay of 6.1 days. CP7808 was less active at 36 mg/kg producing a %T/C value of 66%, and a tumor growth delay of 4.7 days. Neither value was statistically significant compared to the control group. Neither dose level produced complete or partial regressions or tumor free survivors.
Under experimental conditions similar to those in Example 4, CP5017808 was active at 60 mg/kg against A2780 human ovarian adenocarcinoma xenografts. A positive control (Taxol®) was included in the experiment to ensure the responsiveness of the tumor model to taxanes.
Test animals were implanted subcutaneously on day 0 with 30 to 60 mg A2780 tumor fragments. The primary endpoints used to evaluate efficacy were day 19 T/C values, complete and partial tumor responses, and the number of tumor-free survivors at the end of the study. Tumor mass on day 19 was analyzed by a single factor ANOVA.
The mean estimated tumor burden for all groups in the experiment on the first day of treatment was 100 mg and all of the groups in the experiment were well-matched (range 90-108 mg). All animals weighed >16.9 grams at the initiation of therapy. Mean group body weights at first treatment were also well-matched (range, 19.6-22.1 g). 750 mg was chosen as the evaluation size for the experiment. The median control tumor reached evaluation size on Day 17, and the tumor volume doubling time for the control group was 2.4 days (Table 1). Vehicle only (negative control) treated animals experienced a 1.1 g mean weight loss during the treatment regimen. There were no spontaneous regressions in the control group. Based on historical data for this model, the biology of the control group was judged to be within the normal range. The median mouse in the control group surpassed a mass of 1-gram size on Day 19, which was used for all %T/C calculations. The positive control compound for this experiment, Taxol® at 15 mg/kg, produced a %T/C value of 15 on the last day of the study (Day 19). This is consistent with expected activity.
CP5017808 was tolerated at all dose levels (60, 36, and 21.6 mg/kg) tested. Treatment at the highest dose tested, 60 mg/kg, produced an 11.2% weight loss and one death (17%). Although 17% mortality is usually considered to reflect unacceptable toxicity, the unusual behavior of this animal compared to its group mates, prompted the study leader to include this dose level in the analyses for anticancer activity. CP5017808 at 36 and 21.6 mg/kg produced 16.7% and 8.3% weight losses, respectively and no treatment-related deaths. All of the animals in these dose groups had large red livers and full gall bladders at necropsy on day 20. Other organs appeared normal and no drug deposits were present in the peritoneal cavity.
CP5017808 was active at the highest dose tested, 60 mg/kg, producing a day 19 T/C value of 29%. Treatment at 36 and 21.6 mg/kg was ineffective producing day 19 T/C values of 81 and 94% respectively. There were no complete or partial regressions and no tumor free survivors at any dose level.
This application claims priority to U.S. provisional patent application Ser. No. 60/620,042 filed Oct. 19, 2004, which is incorporated by reference herein in its entirety.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US05/37618 | 10/18/2005 | WO | 00 | 7/23/2008 |
| Number | Date | Country | |
|---|---|---|---|
| 60620045 | Oct 2004 | US |
