Patent EA-002419-B1 (EA)
Title: Vitronectin receptor antagonists
Inventor: CALLAHAN JAMES FRANCIS
IPC: A61K33/243
Filed: 1997-10-01
Abstract: 1. A compound according to formula (I):   wherein: R is R<7>, or A-C0-4alkyl, A-C2-4alkenyl, A-C2-4alkynyl, A-C3-4oxoalkenyl, A-C3-4oxoalkynyl, A-C1-4aminoalkyl, A-C3-4aminoalkenyl,A-C3-4aminoalkynyl, optionally substituted by any accessible combination of one or more of R<10> or R<7>; A is H, C3-6cycloalkyl, Het or Ar; R<7> is -COR<8>, -COCR'2R<9>, -C(S)R<8>, -S(O)mOR', -S(O)mNR'R", -PO(OR'), -PO(OR')2, -NO2, or tetrazolyl; each R<8> independently is -OR', -NR'R", -NR'SO2R', -NR'OR', or -OCR'2CO(O)R'; R<9> is -OR', -CN, -S(O)rR', -S(O)mNR'2, -C(O)R', C(O)NR'2, or -CO2R'; R<10> is H, halo, -OR<11>, -CN, -NR'R<11>, -NO2, -CF3, CF3S(O)r-, -CO2R', -CONR'2, A-C0-6alkyl-, A-C1-6oxoalkyl-, A-C2-6alkenyl-, A-C2-6alkynyl-, A-C0-6alkyloxy-, A-C0-6alkylamino- or A-C0-6alkyl-S(O)r-; R<11> is R', -C(O)R', -C(O)NR'2, -C(O)OR', -S(O)mR', or -S(O)mNR'2; R<2> is     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>2CR<g>(OR<k>), C(O)CR<g>2, CR<g>2C(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)2NR<g>, NR<g>S(O)2N=N, NR<g>NR<g>, NR<g>CR<g>2, CR<g>2NR<g>, CR<g>2O, OCR<g>2, C [triple bond] C or CR<g>=CR<g>; G is NR<e>,S or O; R<g> is H, C1-6alkyl, Het-C0-6alkyl, C3-7cycloalkyl-C0-6alkyl or Ar-C0-6alkyl; R<k> is R<g>, -C(O)R<g>, or-C(O)OR<f>; R<i> is H, C1-6alkyl, Het-C0-6alkyl, C3-7cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, or C1-6alkyl substituted by one to three groups chosen from halogen, CN, NR<g>2, OR<g>, SR<g>, CO2R<g>, and CON(R<g>)2; R<f> is H, C1-6alkyl or Ar-C0-6alkyl; R<e> is H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, C3-7cycloalkyl-C0-6alkyl, or (CH2)kCO2R<g>; R<b> and R<c> are independently selected from H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, or C3-6cycloalkyl-C0-6alkyl, halogen, CF3, OR<f>, S(O)kR<f>, COR<f>, NO2, N(R<f>)2, CO(NR<f>)2, CH2N(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, CF3, C1-4alkyl, OR<f>, S(O)kR<f>, COR<f>, CO2R<f>, OH, NO2, N(R<f>)2, CO(NR<f>)2, and CH2N(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, C1-6alkyl, Ar-C0-6alkyl or C3-6cycloalkyl-C0-6alkyl; R" is R', -C(O)R' or -C(O)OR'; R"' is H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, or C3-6cycloalkyl-C0-6alkyl, halogen, CF3, OR<f>, S(O)kR<f>, COR<f>, NO2, N(R<f>)2, CO(NR<f>)2, CH2N(R<f>)2; R<Y> is H, halo, -OR<g>, -SR<g>, -CN, -NR<g>R<k>, -NO2, -CF3, CF3S(O)r-, -CO2R<g>, -COR<g> or -CONR<g>2, or C1-6alkyl optionally substituted by halo, -OR<g>, -SR<g>, -CN, -NR<g>R", -NO2, -CF3, R'S(O)r-, -CO2R<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; wherein Het, or heterocycle, is optionally substituted five- or six membered monocyclic ring or nine- or ten membered bicyclic ring, comprising one to three heteroatoms selected from the group, consisting from nitrogen, oxygen and sulfur; 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 CR<Y> or N and u is O, each R' is H, R"is H, C1-6alkyl, -C(O)C1-6alkyl, C(O)OC1-6alkyl, -C(O)C0-6alkyl-Ar, or C(O)OC0-6alkyl-Ar, W is -CH2-CH2-, and R<Y> is H, halo, -OR<g>, -SR<g>, -CN, -NR<g>R<k>, -NO2, -CF3, CF3S(O)r-, -CO2R<g>, -COR<g>, -CONR<g>2, or C1-6alkyl, or   wherein Q<1>, Q<2>, and Q<3> are each CH and u is 0, each R' is H, R" is H or C1-4alkyl, v is 0 and W is -CH2-CH2-, or   wherein G is NH, and R<b> and R<c> are each H and W is -NR<g>-(CHR<g>)b-, or   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, CF3, C1-4alkyl, OR<f>, S(O)kR<f>, COR<f>, CO2R<f>, OH, NO2, N(R<f>)2, CO(NR<f>)2, and CH2N(R<f>)2; or methylenedioxy; and W is -CH2-CH2-, or   wherein each R' is H, R" is H or C1-4alkyl, R<g> is H or C1-4alkyl and s is 0, 1 or 2 and W is -CH2-CH2-. 3. A compound according to Claim 1 in which R<1> is H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, C3-6cycloalkyl-C0-6alkyl, -CH2CF3, -(CH2)1-2C(O)OR', or -(CH2)2OR', in which R<1> is H or C1-4alkyl. 4. A compound according to Claim 3 in which R<1> is -CH2CF3. 5. A compound 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-1H-2-benzazepine-4-acetic acid; (+-)-8-[3-(4-methoxy-2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-terahydro-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-(1,4,5,6,-tetrahydropyrimidinyl)amino]-1-pyropyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid; (+-)-8-[2-(2-benzimidazolyl)ethoxy]-3-oxo-2,3,4,5-terahydro-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-1H-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-1H-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-isobutoxycarbonylamino]-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-tetrahyropyrimid-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. 6. A pharmaceutical composition, which comprises a compound according to any of Claims 1-5 and a pharmaceutically acceptable carrier. 7. 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 (1), with any reactive functional groups protected, and L<1> is OH or halo; and thereafter removing any protecting groups, and optionally forming a pharmaceutically a