Patent ID: 6251921
Filing Date: 2001-06-26
Classification: A61K,A61P,C07D

Abstract:
A method of inhibiting thrombin in a mammal comprising administering to a mammal in need thereof an effective amount of a thrombin inhibiting compound of formula I (or a pharmaceutically acceptable salt thereof) ##STR700##whereinA is O or S;A.sup.2 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the L,- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear a hydroxymethyl, benzyloxymethyl, (1-3C)alkyl, (1-2C)alkoxy, hydroxy or halo substituent;A.sup.3 is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6- relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-) relationship and which divalent radical may bear one or two substituents independently selected from dimethylamino, (1-4C)alkyl, halo, trifluoromethyl, (1-2C)alkoxy, hydroxy, cyano, aminomethyl, nitro, --NHCH.sub.2 R.sup.f, --NHC(O)R.sup.f or --NHS(O).sub.2 R.sup.g in which R.sup.f is hydrogen or (1-2C)alkyl and R.sup.g is (1-2C)alkyl or phenyl; provided that A.sup.2 and A.sup.3 are not both para-phenylene;R.sup.1 denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;X.sup.1 is O, S, methylene, carbonyl or ethene-1,1-diyl;(a) X.sup.2 is imino, a direct bond, methylene, O or S; j is 0; k is 0; m is 5, 1, 2, 3 or 4; provided that when m is 1, then X.sup.2 is a direct bond; and R.sup.a and R.sup.b are independently hydrogen or (1-3C)alkyl or the group NR.sup.a R.sup.b is 1-imidazolyl, 1-pyrazolyl, N-(1,2,4-triazolyl), neopentylamino, (cyclohexylmethyl)amino, benzylamino, (3-pyridylmethyl)amino, (2,3-dihydroxypropyl)amino, (1-iminoethyl)amino, 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, 2-methyl-1-piperidinyl, morpholino or hexamethyleneimino; or(b) X.sup.2 is imino, O or S; j is 1; k is 1; m is 1; R.sup.2 is hydroxy; and R.sup.a and R.sup.b are independently hydrogen or (1-3C)alkyl or the group NR.sup.a R.sup.b is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or(c) X.sup.2 is imino, O or S; j is 1; k is 1; m is 0; R.sup.2 is methyl, carboxy, hydroxymethyl or methoxycarbonyl; and R.sup.a and R.sup.b are independently hydrogen or (1-3C)alkyl; or(d) X.sup.2 is imino, O or S; j is 0, 1, 2 or 3; k is 1; m is 0 or 1; provided that j and m are not both 0; R.sup.2 and R.sup.a together form a diradical --(CH.sub.2).sub.n -- in which n is 2, 3 or 4 and the sum of m and n is 3 or 4; and R.sup.b is hydrogen or (1-3C)alkyl; or(e) X.sup.2 is --NH--C(O)--; j is 0; k is 0; m is 1; and R.sup.a and R.sup.b are independently hydrogen or (1-3C)alkyl or the group NR.sup.a R.sup.b is 1,1-dioxothiomorpholin-4-yl, pyrrolidino, piperidino, morpholino or hexamethyleneimino; and(1) X.sup.3 is a direct bond, methylene, imino, 0 or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X.sup.3 is a direct bond; each R.sup.3 is hydrogen or the two R.sup.3 groups together form a divalent radical --(CH.sub.2).sub.s -- in which s is 3 or 4; or q and r are each 1 and the group --(CHR.sup.3 --CHR.sup.3)-- is propane-2,2-diyl; and R.sup.c and R.sup.d are independently hydrogen or (1-4C)alkyl or the group NR.sup.c R.sup.d is 1-pyrazolyl, 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, morpholino, hexamethyleneimino, 1-imidazolyl or 4,5-dihydro-1-imidazolyl; or(2) X.sup.3 is imino, O or S; q is 0; r is 1; one R.sup.3 group is (1-5C)alkyl and the other R.sup.3 group is independently hydrogen or (1-5C)alkyl; and R.sup.c and R.sup.d are independently hydrogen or (1-3C)alkyl or the group NR.sup.c R.sup.d is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or(3) X.sup.3 is imino, O or S; q is 0, 1 or 2; r is 1; one R.sup.3 group is hydrogen and the other R.sup.3 group together with the group R.sup.c forms a divalent radical --(CH.sub.2).sub.t -- in which t is 2, 3 or 4 such that the resulting ring is a pyrrolidine or piperidine; and R.sup.d is hydrogen or (1-3C)alkyl; or(4) X.sup.3 is --N(R.sup.h)--; q is 0; r is 1; the R.sup.3 group on the carbon bonded to X.sup.3 and the group R.sup.h together form a diradical --(CH.sub.2).sub.3 --; the other R.sup.3 group is hydrogen; and R.sup.c and R.sup.d are independently (1-3C)alkyl or the group NR.sup.c R.sup.d is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or(5) X.sup.3 is ethene-1,2-diyl or ethyne-1,2-diyl; q is 1; r is 0; and R.sup.c and R.sup.d are independently (1-3C)alkyl or the group NR.sup.c R.sup.d is pyrrolidino, piperidino, morpholino or hexamethyleneimino.