Patent EA-002822-B1 (EA)
Title: Integrin receptor antagonists
Inventor: ASKEW BEN C
IPC: A61K31/4427
Filed: 1998-12-14
Abstract: 1. A compound of the formula   wherein X is selected from the group consisting of   Y is selected from the group consisting of (CH2)m, (CH2)m-S-(CH2)n and (CH2)m-NR<4>-(CH2)n, wherein any methylene (CH2) carbon atom in Y, other than in R<4>, can be substituted by one or two R<3> substituents, with proviso, that when Y is -(CH2)m-NR<4>-(CH2)n- and n=1, then R<3> substituent on carbon atom of methylene group in -(CH2)m-, adjacent to nitrogen atom, can not be oxo; Z is selected from the group consisting of   -CH2CH2-, wherein any carbon atom can be substituted by one or two R<3> substituents; R<1> is selected from the group consisting of hydrogen, halogen, C1-10alkyl, C3-8cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl C1-6 alkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, (C1-6alkyl)pamino, (C1-6alkyl)pamino C1-8alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-3 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C1-6 alkyloxy C1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1-8 alkyl-S(O)p, (C1-8 alkyl)paminocarbonyl, C1-8 alkyloxycarbonylamino, (C1-8 alkyl)paminocarbonyloxy, (aryl C1-8 alkyl)pamino, (aryl)pamino, aryl Cl-8alkylsulfonylamino, and C1-8 alkylsulfonylamino; or two R<1> substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; each R<3> is independently selected from the group consisting of hydrogen, fluoro; trifluoromethyl, C1-8 alkyl, aryl C1-6 alkyl, hydroxy, oxo, arylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aminocarbonyl, and aminocarbonyl C1-6 alkyl, each R<4> is independently selected from the group consisting of hydrogen, aryl, C3-8 cycloalkyl, C1-8 alkyl, C1-8 alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, arylC1-6 alkylsulfonyl, arylC1-6 alkylcarbonyl, C1-8 alkylaminocarbonyl, aryl C1-5 alkylaminocarbonyl, aryl C1-8 alkyloxycarbonyl, and C1-8 alkyloxycarbonyl, R<5> and R<6> are each independently selected from the group consisting of hydrogen, aryl; C1-8alkyl, aryl-C [triple bond] C-(CH2)t-, arylC1-6 alkyl; CH2=CH-(CH2)t- and HC [triple bond] C-(CH2)t-; R<7> and R<8> are each independently selected from the group consisting of hydrogen, aryl; C1-8 alkylcarbonylamino, C1-8 alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, C1-8 alkylsulfonylamino C1-6 alkyl, arylsulfonylamino C1-6 alkyl, aryl C1-6 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino C1-6 alkyl, C1-8 alkoxycarbonylamino, C1-8alkoxycarbonylamino C1-8alkyl, aryloxycarbonylamino C1-8 alkyl, aryl C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino C1-8 alkyl, C1-8 alkylcarbonylamino C1-6 alkyl, arylcarbonylamino C1-6 alkyl, aryl C1-6 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino C1-6 alkyl, aminocarbonylaminoC1-6 alkyl, (C1-8alkyl)paminocarbonylamino, (C1-8alkyl)paminocarbonylamino C1-6alkyl, (aryl)paminocarbonylamino C1-6 alkyl, arylaminocarbonylamino, (aryl Cl-8 alkyl)paminocarbonylamino; (aryl Cl-8 alkyl)paminocarbonylamino C1-6 alkyl, aminosulfonylamino C1-6 alkyl, (C1-8alkyl)paminosulfonylamino, (C1-8alkyl)paminosulfonylamino C1-6alkyl, (aryl)paminosulfonylamino C1-6 alkyl, (aryl Cl-8 alkyl)paminosulfonylamino, (aryl Cl-8 alkyl)paminosulfonylamino C1-6alkyl, C1-6 alkylthiocarbonylamino, C1-6 alkylthiocarbonylamino C1-6 alkyl, arylthiocarbonylamino C1-6 alkyl, aryl C1-6 alkylthiocarbonylamino, aryl C1-6 alkylthiocarbonylamino C1-6 alkyl, and C7-20 polycyclyl C0-8 alkylsulfonylamino, R<9> is selected from the group consisting of hydrogen, C1-8 alkyl, aryl, aryl C1-8 alkyl, C1-8 alkylcarbonyloxy C1-4 alkyl, aryl C1-8 alkylcarbonyloxy C1-4 alkyl, C1-8 alkylaminocarbonylmethylene, and C1-8 dialkylaminocarbonylmethylene; wherein each m is independently an integer from 0 to 6; each n is independently an integer from 0 to 6; each p is independently an integer from 0 to 2; each t is independently an integer from 0 to 3; or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1, wherein R<6>, R<7> and R<8> each represents hydrogen and R<5> is selected from the group, consisting of hydrogen, aryl, C1-8alkyl, aryl-C [triple bond] C-(CH2)t-, aryl C1-6alkyl, CH2=CH-(CH2)t- and HC [triple bond] C-(CH2)t-. 3. The compound according to Claim 2 wherein R<9> is selected from the group consisting of hydrogen, methyl, and ethyl. 4. The compound according to Claim 3 wherein R<9> is hydrogen. 5. The compound of Claim 1 wherein R<5>, R<6>, and R<8> are each hydrogen and R<7> is selected from the group consisting of hydrogen, aryl, C1-8 alkylcarbonylamino, aryl C1-6 alkylcarbonylamino, arylcarbonylamino, C1-8 alkylsulfonylamino, aryl C1-6 alkylsulfonylamino, arylsulfonylamino, C1-8 alkoxycarbonylamino, aryl C1-8 alkoxycarbonylamino, arylaminocarbonylamino, (C1-8 alkyl)paminocarbonylamino, (aryl C1-8 alkyl)paminocarbonylamino, (C1-8 alkyl)paminosulfonylamino and (aryl C1-8 alkyl)paminosulfonylamino. 6. The compound according to Claim 5 wherein R<9> is selected from the group consisting of hydrogen, methyl, and ethyl. 7. The compound according to Claim 6 wherein R<9> is hydrogen. 8. The compound of Claim 1 selected from the group consisting of: 3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)propionic acid; 3(S)-(pyridin-3-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid; 3(S)-(5,6,7,8-tetrahydroquinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)propionic acid (trifluoroacetate); 2(S)-benzenesulfonylamino-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid trifluoroacetate; 3(S)-(quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid; 3(R)-(quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid; 3-(quinolin-3-yl)-3-(7-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)heptanoylamino)propionic acid bis (trifluoroacetate); 3-(quinolin-3-yl)-3-(6-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)hexanoylamino)propionic acid; 3(S)-(3-fluorophenyl)-3-(4-(5,6,7,8-tetrahydro[1,8]naphthyridin-2ylamino)butyrylamino)propionic acid bis (trifluoroacetate); 3(S)-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)-pent-4-enoic acid; 3(S)-(3-fluorophenyl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid; 2-(3-fluorophenyl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid trifluoroacetate salt; 3(S)-(benzo[1,3]dioxol-5-yl)-3-(5-(5,6,7,8-tetrahydro-[l,8]naphthyridin-2-yl)pentanoylamino)propionic acid; 3(S)-(2,3-dihydrobenzofuran-6-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid; 3(S)-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid trifluoroacetate; 3(S)-(3-fluorophenyl)-3-{3-[(5,6,7,8-tetrahydro[1,8]naphthyridin-2ylmethyl)amino]propionylamino}propionic acid; 3(S)-(3-fluorophenyl)-3-(2-{propyl[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]amino}acetylamino)propionic acid trifluoroacetate; 3(S)-(3-fluorophenyl)-3-(2-{phenethyl-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]amino}acetylamino)propionic acid trifluoroacetate; 3(S)-(3-fluorophenyl)-3-{3(S)-[(5,6,7,8-tetrahydro[1,8]naphthyridin-2ylmethyl)amino]pent-4-ynoylamino}propionic acid; 3(S)-(3-fluorophenyl)-3-{3(S)-(3-fluorophenyl)-3-[(5,6,7,8-tetrahydro[1,8]naphthyridin-2-ylmethyl)amino]propionylamino}-propionic acid bis (trifluoroacetate); 3(S)-(3-fluoro-4-phenylphenyl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid trifluoroacetate; 2(S)-(2-thienylsulfonylamino)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid trifluoroacetate; 3(S)-(3-fluorophenyl)-3-{3-methyl-3-{(5,6,7,8-tetrahydro[1,8]naphthyridin-2-ylmethyl)amino]propionylamino}propionic acid; 3(S)-(3-fluorophenyl)-3-{2-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethylamino]acetylamino}propionic acid; 3(S)-(3-fluorophenyl)-3-{[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl]ureido}propionic acid; 2(S)-(methanesulfonylamino)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)pentanoylamino)propionic acid; 3(S)-(2,3-dihydrobenzofuran-6-yl)-3-[3-(1,2,3,4,6,7,8 (R or S), 9-octahydrobenzo[b] [1,8]naphthyridin-8-yl)propionylamino]propionic acid; 3(S)-(2,3-dihydrobenzofuran-6-yl)-3-[3-(1,2,3,4,6,7,8 (S or R), 9-octahydrobenzo [b][1,8]naphthylridin-8-yl)propionylamino]propionic acid; 3(S)-(6-methoxypyridin-3-yl)-3-[N-methyl-3-(1,2,3,4,6,7,8,9-octahydrobenzo [b] [1,8]naphthyridin-8-ylpropionyl)amino] propionic acid; 3(S)-(2,3-dihydrobenzofuran-6-yl)-3-[3-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-ylmethylsulfanyl)propionylamino]propionic acid bis (trifluoroacetate); 3-(quinolin-3-yl)-7-[(5,6,7,8-tetrahydro[1,8]naphthyridin-2-ylmethyl)amino]heptanoic acid; 3-(quinolin-3-yl)-7-[acetyl-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-ylmethyl)amino]heptanoic acid; 3-(quinolin-3-yl)-7-[methanesulfonyl(5,6,7,8-tetrahydro[1,8]naphthyridin-2-ylmethyl) amino]heptanoic acid; 3-[5-(2-aminopyrimidin-4-yl)pentanoylamino]-3(S)-(quinolin-3-yl)propionic acid; 9-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)nonanoic acid; 2-(benzenesulfonylamino)-9-(5,6,7,8-tetrahydro[1,8]-naphthyridin-2-yl)non-4-enoic acid bis (trifluoroacetate); 2(S)-(benzenesulfonylamino)-9-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl) nonanoic acid; 2(R)-(benzenesulfonylamino)-9-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl) nonanoic acid; 2(S)-(benzenesulfonylamino)-10-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl) decanoic acid; 2(S)-(benzenesulfonylamino)-8-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl) octanoic acid; 2(S)-(cyclohexylmethanesulfonylamino)-9-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl) nonanoic acid hydrochloride; 2(S)-(7,7-dimethyl-2-oxobicyclo [2.2.1]hept-1(S)-ylmethanesulfonylamino)-9-(5,6,7,8-tetrahydro[1,8]naphthyr