Patent NZ-333774-A (NZ)
Title: Bicyclic pyrimidine derivatives and their use as anti-coagulants
Inventor: MORRISSEY MICHAEL M
IPC: C07D498/04
Filed: 1997-08-14
Abstract: Compounds of the formulae above are inhibitors of factor Xa. A is O, N(R5), or S(O)n; Z1 and Z2 are independently O, N(R5) or OCH2; R1 and R4 are each independently hydrogen, halo, alkyl, OR8, C(O)OR8, C(O)N(R8)R9, N(R8)R9, N(R8)C(O)R9, or N(H)S(O)2 R11; R2 is C(NH)NH2, C(NH)N(H)OR8, C(NH)N(H)C(O)OR11, C(NH)N(H)C(O)R8, C(NH)N(H)S(O)2 R11, or C(NH)N(H)C(O)N(H)R8;  R3 is halo, alkyl, haloalkyl, haloalkoxy, cyano, ureido, guanidino, OR8, C(NH)NH2, C(NH)N(H)OR8, C(O)N(R8)R9, R10C(O)N(R8)R9, CH(OH)C(O)N(R8)R9, N(R8)R9, R10 N(R8)R9, C(O)OR8, R10C(O)OR8, N(R8)C(O)R8, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl); R5 is hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R6 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, C(O)OR8, R10C(O)OR8, R10C(O)N(R8)R9, C(O)R10N(R8)R9, R10C(O)R8, R10C(O)N(R8)N(R8)R9, R10C(R)8)(OR9)R10N(R8)(R9), C(R8)(OR8)C(O)OR9, R10C(R8)(C(O)OR9)2, C(R8)(N(R8)R9)C(O)OR8, R10C(R8)(N(R8)R9)C(O)OR8, C(R8)(OR8)R9, R10N(R8)R9, R10N(R8)C(O)OR11, R10N(R8)C(O)R9, R10N(R8)C(NR8)R11, R10N(R8)S(O)2R11, R10N(R8)C(O)N(R8)R9, R10N(R8)C(NR8)N(R8)R9, R10N(R8)C(NR8)N(R8)N(R8)R9, R10N(R8)R10C(R8)(N(R8)R9)C(O)OR8, R10N(R8)S(O)R9, R10OR8, R10ON(R8)C(NR8)N(R8)R9, R10OS(O)2OR8, R10P(O)(OR8)R9, R10OP(O)(OR8)2, R10P(O)(OR8)2, R10SR8, R10SR10C(O)OR8, R10SR10N(R8)R9, R10SR10C(R8)N(R8)R9)C(O)OR8, R10SR10N(R8)C(O)OR8,  R10SSR10C(R8)N(R8)R9)C(O)OR8, R10SC(O) N(R8)R9, R10SC(S)N(R8)R9, R10 S(O)R8, R10 S(O)2 R11, R10 S(O)OR8, R10S(O)2OR8, R10S(O)2N(R8)R9, R10S(O)(NR8)R9; or R6 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, OR8, SR8, N(R8)R9, C(O)OR8, C(O)N(R8)R9, S(O)2OR8 and OP(O)(OR8)2); or R6 is aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, OR8, SR8, N(R8)R9, C(O)OR8, C(O)N(R8)R9, S(O)2OR8 and OP(O)(OR8)2); or R6 is heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, aralkyl, OR8, C(O)OR8, N(R8)R9, C(O)N(R8)R9, S(O)2OR8 and OP(O)(OR8)2); or R6 is heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, aralkyl, OR8, SR8, C(O)OR8, N(R8)R9, C(O)N(R8)R9), S(O)2OR8 and OP(O)(OR8)2); or R6 is adamantyl (optionally substituted by alkyl, halo, haloalkyl, haloalkoxy, OR8, SR8, C(O)OR8, N(R8)R9, C(O)N(R8)R9, S(O)2OR8 and OP(O)(OR8)2); or R6 is adamantylalkyl (where the adamantyl radical is optionally substituted by alkyl, halo, haloalkyl, haloalkoxy, OR8, SR8, C(O)OR8, N(R8)R9, C(O)N(R8)R9, S(O)2OR8 and OP(O)(OR8)2); R7 is hydrogen, alkyl, cycloalkyl, aralkyl or aryl; R8 and R9 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R10 is a straight or branched alkylene chain; and R11 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl). The compounds can be used to treat disease-states characterised by thrombotic activity.  Examples of applications include the prophylaxis for long term risk following myocardial infarction and the prohylaxis for deep vein thrombosis.  The compounds can be used in the treatment of thrombotic complications, such as with promyelocytic leukemia, diabetes, multiple myelomas, purpura fulminanas or disseminated intravascular coagulation associated with septic shock.   In addition the compounds are useful as in vitro diagnostic agents for selectively inhibiting factor Xa.