US2003125317A1PendingUtilityA1
Vitronectin receptor antagonists
Est. expiryOct 2, 2016(expired)· nominal 20-yr term from priority
Inventors:James Francis CallahanRussell Donovan CousinsRichard M. KeenanChet KwonWilliam Henry MillerIrene N. Uzinskas
A61K 33/243C07D 223/16C07D 401/12A61K 45/06A61K 31/55C07D 417/12C07D 403/12
57
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Claims
Abstract
Compounds having a benzodiazepinyl core structure are disclosed which are vitronectin receptor antagonists useful in the treatment of osteoporosis, angiogenesis, tumor growth and metastasis, atherosclerosis, restenosis and inflammation.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound according to formula (I):
wherein:
R 1 is R 7 , or A-C 0-4 alkyl, A-C 2-4 alkenyl, A-C 2-4 alkynyl, A-C 3-4 oxoalkenyl, A-C 3-4 oxoalkynyl, A-C 1-4 aminoalkyl, A-C 3-4 aminoalkenyl, A-C 3-4 aminoalkynyl, optionally substituted by any accessible combination of one or more of R 10 or R 7 ;
A is H, C 3-6 cycloalkyl, Het or Ar;
R 7 is —COR 8 , —COCR′ 2 R 9 , —C(S)R 8 , —S(O) m OR′, —S(O) m NR′R″, —PO(OR′), —PO(OR′) 2 , —NO 2 , or tetrazolyl;
each R 8 independently is —OR′, —NR′R″, —NR′SO 2 R′, —NR′OR′, or —OCR′ 2 CO(O)R′;
R 9 is —OR′, —CN, —S(O) r R′, —S(O) m NR′ 2 , —C(O)R′, C(O)NR′ 2 , or —CO 2 R′;
R 10 is H, halo, —OR 11 , —CN, —NR′R 11 , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R′, —CONR′ 2 , A-C 0-6 alkyl-, A-C 1-6 oxoalkyl-, A-C 2-6 alkenyl-, A-C 2-6 alkynyl-, A-C 0-6 alkyloxy-, A-C 0-6 alkylamino- or A-C 0-6 alkyl-S(O) r —;
R 11 is R′, —C(O)R′, —C(O)NR′ 2 , —C(O)OR′, —S(O) m R′, or —S(O) m NR′ 2 ;
W is —(CHR g ) a —U—(CHR g ) b —;
U is absent or CO, CR g 2 , C(═CR g 2 ), S(O) k , O, NR g , CR g OR g , CR g (OR k )CR g 2 , CR g 2 CR g (OR k ), C(O)CR g 2 , CR g 2 C(O), CONR i , NR i CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR g , NR g C(S), S(O) 2 NR 9 , NR g S(O) 2 N═N, NR g NR g , NR g CR g 2 , CR g 2 NR g , CR g 2 O, OCR g 2 , C≡C or CR g ═CR g ;
G is NR e , S or O;
R g is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl or Ar—C 0-6 alkyl;
R k is R g , —C(O)R g , or —C(O)OR f ;
R i is is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, or C 1-6 alkyl substituted by one to three groups chosen from halogen, CN, NR g 2 , OR g , SR g , CO 2 R g , and CON(R g ) 2 ;
R f is H, C 1-6 alkyl or Ar—C 0-6 alkyl;
R e is H. C 1-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl, or (CH 2 ) k CO 2 R g ;
R b and R c are independently selected from H, C 1-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, or C 3-6 cycloalkyl-C 0-6 alkyl, halogen, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f ) 2 , CH 2 N(R f ) 2 , or R b and R e are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from halogen, CF 3 , C 1-4 alkyl, OR f , S(O) k R f , COR f F, CO 2 R f , OH, NO 2 , N(R f ) 2 , CO(NR f ) 2 , and CH 2 N(R f ) 2 ; or methylenedioxy;
Q 1 , Q 2 , Q 3 and Q 4 are independently N or C—R y , provided that no more than one of Q 1 , Q 2 , Q 3 and Q 4 is N;
R′ is H, C 1-6 alkyl, Ar—C 0-6 alkyl or C 3-6 cycloalkyl-C 0-6 alkyl;
R″ is R′, —C(O)R′ or —C(O)OR′;
R′″ is H, C 1-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, or C 3-6 cycloalkyl-C 0-6 alkyl, halogen, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f ) 2 , CH 2 N(R f ) 2 ;
R y is H, halo, —OR g , —SR g , —CN, —NR g R k , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R g , —COR g or —CONR g 2 , or C 1-6 alkyl optionally substituted by halo, —OR g , —SR g , —CN, —NR g R″, —NO 2 , —CF 3 , R′S(O) r —, —CO 2 R g , —COR g or —CONR g 2 ;
a is 0, 1 or 2;
b is 0, 1 or 2;
k is 0, 1 or 2;
m is 1 or 2;
r is 0, 1 or 2;
s is 0, 1 or 2;
u is 0 or 1; and
v is 0 or 1;
or a pharmaceutically acceptable salt thereof.
2 . A compound according to claim 1 in which R 2 is
wherein Q 1 , Q 2 , and Q 3 are each CR y , Q 4 is CRY or N and u is 0.
3 . A compound according to claim 2 in which each R′ is H, R″ is H, C 1-6 alkyl, —C(O)C 1-6 alkyl, C(O)OC 1-6 alkyl, —C(O)CO 6alkyl-Ar, or C(O)OC 0-6 alkyl-Ar, W is —CH 2 —CH 2 —, and R y is H, halo, —OR g , —SR g , —CN, —NR g R k , —NO 2 , —CF 3 , CF 3 S(O)C, —CO 2 R g , —COR g —CONR g 2 , or C 1-6 alkyl.
4 . A compound according to claim 1 in which R 2 is
wherein Q 1 , Q 2 , and Q 3 are each CH and u is 0.
5 . A compound according to claim 4 in which each R′ is H, R″ is H or C 1-4 alkyl, v is 0 and W is —CH 2 —CH 2 —.
6 . A compound according to claim 1 in which R 2 is
wherein G is NH and R b and R c are each H.
7 . A compound according to claim 6 in which W is —NR g —(CHR g ) b —.
8 . A compound according to claim 1 in which R 2 is
wherein G is NH and R b and R c are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from halogen, CF 3 , C 1-4 alkyl, OR f , S(O) k R f , COR f , CO 2 R f , OH, NO 2 , N(R f ) 2 , CO(NR f ) 2 , and CH 2 N(R f ) 2 ; or methylenedioxy.
9 . A compound according to claim 8 in which R b and R c are joined together to form a six membered aromatic carbocyclic ring.
10 . A compound according to claim 9 in which W is —CH 2 —CH 2 —.
11 . A compound according to claim 8 in which R b and R c are joined together to form a six membered aromatic heterocyclic ring.
12 . A compound according to claim 11 in which W is —CH 2 —CH 2 —.
13 . A compound according to claim 1 in which R 2 is
wherein each R′ is H, R″ is H or C 1-4 alkyl, R g is H or C 1-4 alkyl and s is 0, 1 or 2.
14 . A compound according to claim 13 in which W is —CH 2 —CH 2 —.
15 . A compound according to claim 1 in which R 1 is H, C 1-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, —CH 2 CF 3 , —(CH 2 ) 1-2 C(O)OR′, or —(CH 2 ) 2 OR′, in which R′ is H or C 1-4 alkyl.
16 . A compound according to claim 15 in which R 1 is H, C 1-4 alkyl, Ph-C 0-4 alkyl, —CH 2 CF 3 , —(CH 2 ) 1-2 C(O)OR′, or —(CH 2 ) 2 OR′, in which R′ is H or C 1-4 alkyl.
17 . A compound according to claim 16 in which R 1 is —CH 2 CF 3 .
18 . A compound according to claim 1 which is:
(±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[3-(4-amino-2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-]H-2-benzazepine-4-acetic acid;
(±)-8-[3-(4-methoxy-2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[3-(2-pyridylamino)-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[3-(2-imidazolylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[3-[2-(1,4,5,6-tetrahydropyrimidinyl)amino]-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[3-(6-amino-2-pyridylamino)-1-propylaxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[2-(2-benzimidazolyl)ethoxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[2-(4-aza-2-benzimidazolyl)ethoxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[2-(benzimidazol-2-yl)-1-ethoxy]-3-oxo-2,3,4,5-tetrahydro-11H-2-benzazepine-4-acetic acid;
(±)-8-[3-(4-aminopyridin-2-ylamino)-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-(pyrimidin-2-ylamino)-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(R)-8-[3-(4-aminopyridin-2-ylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-[(1,4,5,6-tetrahydropyrimidin-2-yl)amino]-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(S)-8-[3-(4-aminopyridin-2-ylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[3-[N-(1-oxopyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-2-methyl-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(methyl)amino)]-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-2-benzyl-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-2-(carboxymethyl)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-2-(4-aminobenzyl)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(benzoyl)amino]-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[3-(2-imidazolin-2-ylamino)-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[2-(2-aminothiazol-4-yl)-1-ethoxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[3-(4,6-dimethylpyridin-2-ylamino)-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-8-[3-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-ylamino)-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butylacetyl)amino]-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(isobutoxycarbonyl)amino]-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(S)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-(4-methylpyridin-2-ylamino)-1-propyloxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(methyl)amino)]-1-propyloxy]-2-[4-(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(S)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(R)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(S)-8-[3-(4-methylpyridin-2-ylamino)-1-propyloxy]-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(S)-3-oxo-8-[3-(1,4,5,6-tetrahydropyrimid-2-ylamino)-1-propyloxy]-2-[4-(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(S)-3-oxo-2-(2-phenylethyl)-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(S)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
(S)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid; or
(S)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-[4-(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;
or a pharmaceutically acceptable salt thereof.
19 . A compound according to claim 1 which is (S)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof.
20 . A compound according to claim 1 which is (S)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2.2,2-trifluoroethyl)-2.3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof.
21 . A compound according to claim 1 which is (S)-8-[3-(4-methylpyridin-2-ylamino)-1-propyloxy]-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof.
22 . A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier.
23 . A pharmaceutical composition which comprises a compound according to claim 1 , an antineoplastic agent and a pharmaceutically acceptable carrier.
24 . The pharmaceutical composition according to claim 23 wherein the antineoplastic agent is topotecan.
25 . The pharmaceutical composition according to claim 23 wherein the antineoplastic agent is cisplatin.
26 . A pharmaceutical composition which comprises a compound according to claim 1 , an inhibitor of bone resorption and a pharmaceutically acceptable carrier.
27 . A method of treating a disease state in which antagonism of the α V β 3 receptor is indicated which comprises administering to a subject in need thereof a compound according to claim 1 .
28 . A method of treating a disease state in which antagonism of the α V β 5 receptor is indicated which comprises administering to a subject in need thereof a compound according to claim 1 .
29 . A method of treating osteoporosis which comprises administering to a subject in need thereof a compound according to claim 1 .
30 . A method for inhibiting angiogenesis which comprises administering to a subject in need thereof a compound according to claim 1 .
31 . A method for inhibiting tumor growth or tumor metastasis which comprises administering to a subject in need thereof a compound according to claim 1 .
32 . A method of treating atherosclerosis or restenosis which comprises administering to a subject in need thereof a compound according to claim 1 .
33 . A method of treating inflammation which comprises administering to a subject in need thereof a compound according to claim 1 .
34 . A method of inhibiting tumor growth which comprises administering stepwise or in physical combination a compound according to claim 1 and an antineoplastic agent.
35 . The method according to claim 34 wherein the antineoplastic agent is topotecan.
36 . The method according to claim 34 wherein the antineoplastic agent is cisplatin.
37 . A method of treating osteoporosis or inhibiting bone loss which comprises administering stepwise or in physical combination a compound according to claim 1 and an inhibitor of bone resorption.
38 . A compound according to formula (II):
wherein:
R 1 is R 7 , or A-C 0-4 alkyl, A-C 2-4 alkenyl, A-C 2-4 alkynyl, A-C 3-4 oxoalkenyl, A-C 3-4 oxoalkynyl, A-C 1-4 aminoalkyl, A-C 3-4 aminoalkenyl, A-C 3-4 aminoalkynyl, optionally substituted by any accessible combination of one or more of R 10 or R 7 ;
A is H, C 3-6 cycloalkyl, Het or Ar;
R 7 is —COR 8 , —COCR′ 2 R 9 , —C(S)R 8 , —S(O) m OR′, —S(O) m NR′R″, —PO(OR′), —PO(OR′) 2 , —NO 2 , or tetrazolyl;
each R g independently is —OR′, —NR′R″, —NR′SO 2 R′, —NR′OR′, or —OCR′ 2 CO(O)R′;
R 9 is —OR′, —CN, —S(O) r R′, —S(O) m NR′ 2 , —C(O)R′, C(O)NR′ 2 , or —CO 2 R′;
R 10 is H, halo, —OR 11 , —CN, —NR′R 11 , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R′, —CONR′ 2 , A-C 0-6 alkyl-, A-C 1-6 oxoalkyl-, A-C 2-6 alkenyl-, A-C 2-6 alkynyl-, A-C 0-6 alkyloxy-, A-C 0-6 alkylamino- or A-C 0-6 alkyl-S(O) r —;
R 11 is R′, —C(O)R′, —C(O)NR′ 2 , —C(O)OR′, —S(O) m R′, or —S(O) m NR′ 2 ;
W is —(CHR g ) a —U—(CHR g ) b —;
U is absent or CO, CR g 2 , C(═CR g 2 ), S(O) k , O, NR g , CR g OR g , CR g (OR k )CR g 2 , CR g 2 CR g (OR k ), C(O)CR g 2 , CR g 2 C(O), CONR i , NR i CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR g , NR g C(S), S(O) 2 NR g , NR g S(O) 2 N═N, NR g NR g , NR g CR g 2 , CR g 2 NR g , CR g 2 O, OCR g 2 , C≡C or CR g ═CR g ;
G is NR e , S or O;
R g is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl or Ar—C 0-6 alkyl;
R k is R g , —C(O)R g , or —C(O)OR f ;
R i is is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, or C 1-6 alkyl substituted by one to three groups chosen from halogen, CN, NR g 2 , OR g , SR g , CO 2 R g , and CON(R g ) 2 ;
R f is H, C 1-6 alkyl or Ar—C 0-6 alkyl;
R e is H, C 1-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl, or (CH 2 ) k CO 2 R g ;
R b and R c are independently selected from H, C 1-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, or C 3-6 cycloalkyl-C 0-6 alkyl, halogen, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f ) 2 , CH 2 N(R f ) 2 , or R b and R c are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from halogen, CF 3 , C 1-4 alkyl, OR f , S(O) k R f , COR f , CO 2 R f , OH, NO 2 , N(R f ) 2 , CO(NR f ) 2 , and CH 2 N(R f ) 2 ; or methylenedioxy;
Q 1 , Q 2 , Q 3 and Q 4 are independently N or C—R y , provided that no more than one of Q 1 , Q 2 , Q 3 and Q 4 is N;
R′ is H, C 1-6 alkyl, Ar—C 0-6 alkyl or C 3-6 cycloalkyl-C 0-6 alkyl;
R″ is R′, —C(O)R′ or —C(O)OR′;
R′″ is H, C 1-6 alkyl, Ar—C 0-6 alkyl, Het-C 0-6 alkyl, or C 3-6 cycloalkyl-C 0-6 alkyl, halogen, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f ) 2 , CH 2 N(R f ) 2 ;
R y is H, halo, —OR g , —SR g , —CN, —NR g R k , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R g , —COR g or —CONR g 2 , or C 1-6 alkyl optionally substituted by halo, —OR g , —SR g , —CN, —NR g R″, —NO 2 , —CF 3 , R′S(O) r —, —CO 2 R g , —COR g or —CONR g 2 ;
a is 0, 1 or 2;
b is 0, 1 or 2;
k is 0, 1 or 2;
m is 1 or 2;
r is 0, 1 or 2;
s is 0, 1 or 2;
u is 0 or 1; and
v is 0 or 1;
or a pharmaceutically acceptable salt thereof.
39 . A compound according to claim 38 which is:
methyl (±)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate; or
ethyl (±)-8-[3-(4-aminopyridin-2-ylamino)-1-propyloxy]-3-oxo-2,3,4.5-tetrahydro-1H-2-benzazepine-4-acetate;
or a pharmaceutically acceptable salt thereof.
40 . A compound according to formula (III):
R 1 is R 7 , or A-C 0-4 alkyl, A-C 2-4 alkenyl, A-C 2-4 alkynyl, A-C 3-4 oxoalkenyl, A-C 3-4 oxoalkynyl, A-C 1-4 aminoalkyl, A-C 3-4 aminoalkenyl, A-C 3-4 aminoalkynyl, optionally substituted by any accessible combination of one or more of R 10 or R 7 ;
A is H, C 3-6 cycloalkyl, Het or Ar;
R 7 is —COR 8 , —COCR′ 2 R 9 , —C(S)R 8 , —S(O) m OR′, —S(O) m NR′R″, —PO(OR′), —PO(OR′) 2 , —NO 2 , or tetrazolyl;
each R 8 independently is —OR′, —NR′R″, —NR′SO 2 R′, —NR′OR′, or —OCR 12 CO(O)R′;
R 9 is —OR′, —CN, —S(O) r R′, —S(O) m NR′ 2 , —C(O)R′, C(O)NR′ 2 , or —CO 2 R′;
R 10 is H, halo, —OR 11 , —CN, —NR′R 11 , —NO 2 , —CF 3 , CF 3 S(O) r , —CO 2 R′, —CONR′ 2 , A-C 0-6 alkyl-, A-C 1-6 oxoalkyl-, A-C 2-6 alkenyl-, A-C 2-6 alkynyl-, A-C 0-6 alkyloxy-, A-C 0-6 alkylamino- or A-C 0-6 alkyl-S(O) r —;
R 11 is R′, —C(O)R′, —C(O)NR′ 2 , —C(O)OR′, —S(O) m R′, or —S(O) m NR′ 2 ;
W is —(CHR g ) a —U—(CHR g ) b —;
U is absent or CO, CR g 2 , C(═CR g 2 ), S(O) k , O, NR g , CR g OR g , CR g (OR k )CR g 2 , CR g 2 CR g (OR k ), C(O)CR g 2 , CR g 2 C(O), CONR i , NR i CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR g , NR g C(S), S(O) 2 NR g , NR g S(O) 2 N═N, NR g NR g , NR g CR g 2 , CR g 2 NR g , CR g 2 O, OCR g 2 , C≡C or CR g =CR g ;
R g is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl or Ar—C 0-6 alkyl;
R k is R g , —C(O)R g , or —C(O)OR f ;
R i is is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl, Ar—C 0-6 alkyl, or C 1-6 alkyl substituted by one to three groups chosen from halogen, CN, NR g 2 , OR g , SR g , CO 2 R g , and CON(R g ) 2 ;
R f is H, C 1-6 alkyl or Ar—C 6 alkyl;
Q 1 , Q 2 , Q 3 and Q 4 are independently N or C—R y , provided that no more than one of Q 1 , Q 2 , Q 3 and Q 4 is N;
R′ is H, C 1-6 alkyl, Ar—C 0-6 alkyl or C 3-6 cycloalkyl-C 0-6 alkyl;
R″ is R′, —C(O)R′ or —C(O)OR′;
R y is H, halo, —OR g , —SR g , —CN, —NR g R k , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R g , —COR g or —CONR g 2 , or C 1-6 alkyl optionally substituted by halo, —OR g , —SR g , —CN, —NR g R″, —NO 2 , —CF 3 , R′S(O) r —, —CO 2 R g , —COR g or —CONR g 2 ;
a is 0, 1 or 2;
b is 0, 1 or 2:
m is 1 or 2; and
r is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
41 . A process for preparing a compound of the formula (I) as defined in claim 1 , which process comprises reacting a compound of formula (IV) with a compound of formula (V):
wherein R 1 and R 2 are as defined in formula (I), with any reactive functional groups protected, and L 1 is OH or halo;
and thereafter removing any protecting groups, and optionally forming a pharmaceutically acceptable salt.
42 . A process for preparing a compound of the formula (I) as defined in claim 1 , which process comprises reacting a compound of formula (IV) with a compound of formula (VI):
wherein R 1 , R′, R″, W, Q 1 , Q 2 , Q 3 and Q 4 are as defined in formula (I), with any reactive functional groups protected;
and thereafter removing any protecting groups, and optionally forming a pharmaceutically acceptable salt.
43 . A process for preparing a compound of the formula (I) as defined in claim 1 , which process comprises reacting a compound of formula (IV) with a compound of formula (VII):
wherein R 1 , R′, R″, W, Q 1 , Q 2 , Q 3 and v are as defined in formula (I), with any reactive functional groups protected;
and thereafter removing any protecting groups, and optionally forming a pharmaceutically acceptable salt.
44 . A compound according to any one of claims 1 to 21 for use as a medicament.
45 . The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the treatment of diseases in which antagonism of the α V β 3 receptor is indicated.
46 . The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the treatment of diseases in which antagonism of the α V β 5 receptor is indicated.
47 . The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the treatment of osteoporosis.
48 . The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the inhibition of angiogenesis.
49 . The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the inhibition of tumor growth or tumor metastasis.
50 . The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the treatment of atherosclerosis or restenosis.
51 . The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the treatment of inflammation.
52 . The use of a compound of the formula (I) as defined in claim 1 and an antineoplastic agent in the manufacture of a medicament for the inhibition of tumor growth in physical combination or for stepwise administration.
53 . The use according to claim 52 wherein the antineoplastic agent is topotecan.
54 . The use according to claim 52 wherein the antineoplastic agent is cisplatin.
55 . The use of a compound of the formula (I) as defined in claim 1 and an inhibitor of bone resorption in the manufacture of a medicament for the treatment of osteoporosis in physical combination or for stepwise administration.Join the waitlist — get patent alerts
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