US 2003/0195173 A1Published application

Colchinol derivatives as angiogenesis inhibitors

AssigneeAngiogene Pharmaceuticals Ltd.

InventorJean Claude Arnould

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Abstract

The invention related to colchinol derivatives of the formula (I): Wherein: R1, R2 and R3 are each independently hydroxy, phosphoryloxy (—OPO3H2), C1-4alkoxy or an in vivo hydrolysable ester of hydroxy, with the proviso that at least 2 of R1, R2 and R3 are C1-4alkoxy; A is —CO—, —C(O)O—, —CON(R8)— (wherein R8 is hydrogen, C1-4alkyl, C1-3alkoxyC1-3alkyl, aminoC1-3alkyl or hydroxyC1-3alkyl); a is an integer from 1 to 4 inclusive; Ra and Rb are independently selected from hydrogen, hydroxy and amino; B is —O—, —CO—, N(R9)CO—, —CON(R9)—, —N(R9)C(O)O—, —N(R9)CON(R10)—, —N(R9)SO2—, —SO2N(R9)— or a direct single blond (wherein R9 and R10 are independently selected from hydrogen, C1-4alkyl, C1-3alkoxyC1-3alkyl,aminoC1-3alkyl and hydroxyC1-3alkyl); b is O or an integer from 1 to 4 inclusive, (provided that when bis O, B is a single direct bond); D is carboxy, sulpho, tetrazolyl, imidazolyl, phosphoryloxy, hydroxy, amino, N-(C1-4alkyl)amino, N,N-di(C1-3alkyl)amino, or of the formula-Y1(CH2)0R11 or —NHCH(R12)COOH;[wherein Y1 is a direct single bond, —O—, —C(O)—, —N(R13)C(O)— or —C(O)N(R13)— (wherein R13 is hydrogen, C1-4alkyl,C1-3alkoxyC2-3alkyl, aminoC2-3alkyl or hydroxyC2-3alkyl); e is O or an integer from 1 to 4 inclusive.

Claims17

Dependent claims

A compound of the formula (I):

22
wherein:
R1, R2 and R3 are each independently hydroxy, phosphoryloxy (—OPO3H2), C1-4alkoxy or an in vivo hydrolysable ester of hydroxy, with the proviso that at least 2 of R1, R2 and R3 are C1-4alkoxy;
A is —CO—, —C(O)O—, —CON(R8)—, —SO2— or —SO2N(R8)— (wherein R8 is hydrogen, C1-4alkyl, C1-3alkoxyC1-3alkyl, aminoC1-3alkyl or hydroxyC1-3alkyl);
a is an integer from 1 to 4 inclusive;
Ra and Rb are independently selected from hydrogen, hydroxy and amino;
B is —O—, —CO—, —N(R9)CO—, —CON(R9)—, —C(O)O—, —N(R9)—, —N(R9)C(O)O—, —N(R9)CON(R10)—, —N(R9)SO2—, —SO2N(R9)— or a direct single bond (wherein R9 and R10 are independently selected from hydrogen, C1-4alkyl, C1-3alkoxyC1-3alkyl, aminoC1-3alkyl and hydroxyC1-3alkyl);
b is 0 or an integer from 1 to 4 inclusive, (provided that when b is 0, B is a single direct bond);
D is carboxy, sulpho, tetrazolyl, imidazolyl, phosphoryloxy, hydroxy, amino, N-(C1-4alkyl)amino, N,N-di(C1-3alkyl)amino or of the formula —Y1—(CH2)cR11 or —NHCH(R12)COOH;
[wherein Y1 is a direct single bond, —O—, —C(O)—, —N(R13)—, —N(R13)C(O)— or —C(O)N(R13)— (wherein R13 is hydrogen, C1-4alkyl, C1-3alkoxyC2-3alkyl, aminoC2-3alkyl or hydroxyC2-3alkyl);
c is 0 or an integer from 1 to 4 inclusive;
R11 is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) containing 1 or 2 ring heteroatoms, selected independently from O, S and N, or a 5-6-membered unsaturated or partially unsaturated heteroaryl group (linked via carbon or nitrogen) containing 1 or 2 ring heteroatoms, selected independently from O, S and N, which heterocyclic group or heteroaryl group may bear 1 or 2 substituents selected from:
oxo, hydroxy, halogeno, C1-4alkyl, C2-4alkanoyl, carbamoyl, N-(C1-4alkyl)carbamoyl, N,N-di-(C1-4alkyl)carbamoyl, hydroxyC1-4alkyl, C1-4alkoxy, cyanoC1-3alkyl, carbamoylC1-3alkyl, carboxyC1-4alkyl, aminoC1-4alkyl, N-C1-4alkylaminoC1-4alkyl, di-N,N-(C1-4alkyl)aminoC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4alkylsulphonylC1-4alkyl and R14 (wherein R14 is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) containing 1 or 2 ring heteroatoms, selected independently from O, S and N, which heterocyclic group is optionally substituted by 1 or 2 substituents selected from:
oxo, hydroxy, halogeno, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl and C1-4alkylsulphonylC1-4alkyl);
R12 is an amino acid side chain;
R5 is C1-4alkoxy;
R4 and R6 are each independently selected from:
hydrogen, fluoro, nitro, amino, N-C1-4alkylamino, N,N-di-(C1-4alkyl)amino, hydroxy, C1-4alkoxy and C1-4alkyl;
R7 is hydrogen, C1-4alkyl, C1-3alkoxyC1-3alkyl, aminoC1-3alkyl or hydroxyC1-3alkyl;
or a pharmaceutically acceptable salt, solvate or pro-drug thereof.

17 more elements

A compound of formula (III):

24
wherein:
R1, R2 and R3 are each independently hydroxy, phosphoryloxy (—OPO3H2), C1-4alkoxy or an in vivo hydrolysable ester of hydroxy, with the proviso that at least 2 of R1, R2 and R3 are C1-4alkoxy;
A is —CO—, —C(O)O—, —CON(R8)—, —SO2— or —SO2N(R8)— (wherein R8 is hydrogen, C1-4alkyl, C1-3alkoxyC2-3alkyl, aminoC2-3alkyl or hydroxyC2-3alkyl);
a is an integer from 1 to 4 inclusive;
Ra and Rb are independently selected from hydrogen, hydroxy and amino;
B is —O—, —CO—, —N(R9)CO—, —CON(R9)—, —C(O)O—, —N(R9)—, —N(R9)C(O)O—, —N(R9)CON(R10)—, —N(R9)SO2—, —SO2N(R9)— or a direct single bond (wherein R9 and R10 are independently selected from hydrogen, C1-4alkyl, C1-3alkoxyC2-3alkyl, aminoC2-3alkyl and hydroxyC2-3alkyl);
b is 0 or an integer from 1 to 4 inclusive;
D is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) containing 1 or 2 ring heteroatoms, selected independently from O and N, which heterocyclic group may bear 1 or 2 substituents selected from:
oxo, hydroxy, halogeno, C1-4alkyl, C2-4alkanoyl, carbamoyl, N-(C1-4alkyl)carbamoyl, N,N-di-(C1-4alkyl)carbamoyl, hydroxyC1-4alkyl, C1-4alkoxy, cyanoC1-3alkyl, carbamoylC1-3alkyl, carboxyC1-4alkyl, aminoC1-4alkyl, N-C1-4alkylaminoC1-4alkyl, di-N,N-(C1-4alkyl)aminoC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4alkylsulphonylC1-4alkyl and R14 (wherein R14 is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) containing 1 or 2 ring heteroatoms, selected independently from O and N, which heterocyclic group is optionally substituted by 1 or 2 substituents selected from:
oxo, hydroxy, halogeno, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl and C1-4alkylsulphonylC1-4alkyl);
R5 is C1-4alkoxy;
R4 and R6 are each independently selected from:
hydrogen, halogeno, nitro, amino, N-C1-4alkylamino, N,N-di-(C1-4alkyl)amino, hydroxy, C1-4alkoxy and C1-4alkyl;
R7 is hydrogen, C1-4alkyl, C1-3alkoxyC1-3alkyl, aminoC1-3 alkyl or hydroxyC1-3alkyl;
or a pharmaceutically acceptable salt, solvate or pro-drug thereof.

13 more elements

A compound selected from:

N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]-2-[2-aminoacetylamino]acetamide;
4-oxo-4-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]amino]butyl disodium phosphate;
N-{N-[2-(imidazol-1-yl)ethyl]carbamoyl}-5(S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-ylamine;
and
2-{N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]carbamoyloxy}ethyl disodium phosphate;
2-morpholinoethyl N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]carbamate;
3-(1-methylpiperazin-4-yl)propyl N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a,c]cyclohepten-5-yl]carbamate;
N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]-2-[2-aminoacetylamino]acetamide;
2-(1-acetylpiperazin-4-yl)ethyl-N-[(5S)-3,9,10,11-tetramethoxy-6-7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]carbamate;
N-[(5S)-3,9,10,11-tetramethoxy-6-7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]-4-(1-methylpiperazin-4-yl)-4-oxobutan-1-amide;
4-oxo-4-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]amino]butyl disodium phosphate;
N-{N-[2-(imidazol-1-yl)ethyl]carbamoyl}-5(S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-ylamine;
3-(1-acetylpiperazin-4-yl) propyl-N-[(5S)-3,9,10,11-tetramethoxy-6-7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]carbamate;
N-1-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]carbamoyloxy]ethyl disodiumphosphate;
4-morpholino-4-oxobutyl-N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a-c]cyclohepten-5-yl]carbamate;
and
4-(1-methylpiperazin-4-yl)-4-oxobutyl-N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cylcohepten-5-yl]carbamate;
and pharmaceutically-acceptable salts, solvates or pro-drugs thereof.

15 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/332,271Filed 7 Jan 2003
Priority: EP 00401977.47 Jul 2000
Published: 16 Oct 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 295/185
Radicals derived from carboxylic acids: from aliphatic carboxylic acids
A61P 35/00
Antineoplastic agents
C07C 217/74
Having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms…:…
C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…