Patent ID: 6593346
Filing Date: 2003-07-15
Classification: C07D,Y02P

Abstract:
A method of treating graft rejection, reperfusion injury, or cytokine-induced toxicity which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt or individual diastereomer thereof: wherein: X is selected from: â€”(C0-6 alkyl)-Y-(C0-6 alkyl)-, â€”(C0-6 alkyl)-C3-8 cycloalkyl-(C0-6 alkyl)-, C2-10 alkenyl, and C2-10 alkynyl, where the alkyl is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from: (a) halo, (b) hydroxy, (c) â€”Oâ€”C1-3 alkyl, and (d) trifluoromethyl, and where Y is selected from: a single bond, â€”Oâ€”, â€”SO2â€”, â€”NR10â€”, â€”NR10â€”, â€”SO2â€”SO2â€”NR10â€”, â€”Sâ€”, and â€”SOâ€”, and where R10 is independently selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C5-6 cycloalkyl, benzyl, phenyl, and C1-6 alkyl-C3-6 cycloalkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl; R1 is selected from: (1) â€”CO2H, (2) â€”NO2, (3) -tetrazolyl, (4) -hydroxyisoxazole, (5) â€”SO2NHCOâ€”(C0-3 alkyl)-R9, wherein R9 is independently selected from: hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl, and (6) â€”P(O)(OH)2; R3 is selected from the group consisting of: phenyl and heterocycle, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from: (a) halo, (b) trifluoromethyl, (c) hydroxy, (d) C1-3 alkyl, (e) â€”Oâ€”C1-3 alkyl, (f) â€”CO2R9, (g) â€”NR9R10, and (h) â€”CONR9R10; R4, R5 and R6 are independently selected from: hydrogen, C1-10 alkyl, C3-8 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, phenyl, â€”(C1-6 alkyl)-phenyl, â€”(C1-6 alkyl)-C3-8 cycloalkyl, naphthyl, biphenyl, and heterocycle, which is unsubstituted or substituted with 1-7 of R11 where R11 is independently selected from: (a) halo, (b) trifluoromethyl, (c) hydroxy, (d) C1-3 alkyl, (e) â€”Oâ€”C1-3 alkyl, (f) â€”CO2R9, (g) â€”NR9R10, and (h) â€”CONR9R10, or where R4 and R5 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11, or where R5 and R6 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11; R7 is selected from: (1) hydrogen, (2) C1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from: hydroxy, cyano, and halo, (3) hydroxy, and (4) halo; R8 is selected from: hydrogen, C3-8 cycloalkyl, phenyl, naphthyl, biphenyl, and heterocycle, which is unsubstituted or substituted with 1-7 of R12 where R12 is independently selected from: (a) halo, (b) cyano, (c) hydroxy, (d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13 where R13 is independently selected from: halo, cyano, hydroxy, C1-6 alkoxy, â€”CO2H, â€”CO2(C1-6 alkyl), trifluoromethyl, and â€”NR9R10, (e) â€”Oâ€”C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13, (f) â€”CF3, (g) â€”CHF2, (h) â€”CH2F, (i) â€”NO2, (j) C0-6 alkyl-phenyl or C0-6 alkyl-heterocycle, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from: (i) halo, (ii) hydroxy, (iii) C1-6 alkyl, unsubstituted or substituted with 1-5 substituents, each of which is independently selected from halo, cyano, hydroxy, C1-6 alkoxy,â€”CO2H, â€”CO2(C1-6 alkyl), trifluoromethyl, and â€”NR9R10, (iv) â€”Oâ€”C1-6 alkyl, (v) â€”CF3, (vi) â€”OCF3, (vii) â€”NO2, (viii) â€”CN, (ix) â€”SO2â€”C1-6 alkyl, (x) â€”CO2R9, (xi) â€”NR9R10, (xii) â€”CONR9R10, (xiii) â€”SO2â€”NR9R10, (xiv) â€”NR9â€”SO2â€”R10, (xv) â€”C3-8 cycloalkyl, (xvi) â€”C3-8 cycloalkyl, and (xvii) phenyl; (k) â€”CO2R9, (l) tetrazolyl, (m) â€”NR9R10, (n) â€”NR9â€”COR10, (o) â€”NR9â€”CO2R10, (p) â€”COâ€”NR9R10, (q) â€”OCOâ€”NR9R10, (r) â€”NR9COâ€”NR9R10, (s) â€”S(O)mâ€”R9, wherein m is an integer selected from 0, 1 and 2, (t) â€”S(O)2â€”NR9R10, (u) â€”NR9S(O)2â€”R10, (v) â€”NR9S(O)2â€”NR9R10, (w) C1-6 alkyl substituted with â€”C3-8 cycloalkyl, and (x) â€”C3-8 cycloalkyl; n is an integer selected from 1, 2, 3 and 4; x is an integer selected from 0, 1 and 2, and y is an integer selected from 0, 1 and 2, with the proviso that the sum of x and y is 2.