Patent NZ-333895-A (NZ)
Title: Purine derivatives and their use as anti-coagulants
Inventor: MORRISSEY MICHAEL M
IPC: C07D473/00
Filed: 1997-08-14
Abstract: Compounds of the formulae (I) to (IV) are inhibitors of factor Xa. Z1 and Z2 are O, N(R10) or CH2O; R1 and R4 are each independently hydrogen, halo, alkyl, OR10, C(O)OR10, C(O)N(R10)R11, N(R10)R11, N(R10)C(O)R10, or N(H)S(O)2 R13 ; R2 is C(NH)NH2, C(NH)N(H)OR10, C(NH)N(H)C(O)OR13, C(NH)N(H)C(O)R10, C(NH)N(H)S(O)2R13, or C(NH)N(H)C(O)N(H)R10 R3 is halo, alkyl, haloalkyl, haloalkoxy, ureido, cyano, guanidino, OR10, C(NH)NH2, C(NH)N(H)OR10, C(O)N(R10)R11, R12C(O)N(R10)R11, CH(OH)C(O)N(R10)R11, N(R10)R11, R12N(R10)R11, C(O)OR10, R12C(O)OR10, N(R10)C(O)R10, (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, halo, alkyl, cycloalkyl, haloakyl, aryl, aralkyl, alkylthio, hydroxy, mercapto, alkoxy, or N(R10)R11 ; R6 is (C(R7)(R8))n R9 (where n is 1 to 4), 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); R7 is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, C(O)OR10, R12C(O)OR10, R12C(O) N(R10)R11, C(O)R12N(R10)R11, R12C(O)R10, R12C(O)N(R10)N (R10)R11, R12C(R10)(OR10)R12N(R10)(R11), C(R10)(OR10)C(O)OR11, R12C(R10)(C(O)OR10)2, C(R10)(N(R10)R11)C(O)OR10, R12C(R10) (N(R10)R11)C(O)OR10, C(R10)(OR10)R11, R12N(R10)R11, R12N(R10) C(O)OR13, R12N(R10)C(O)R11, R12N(R10)C(NR10)R13, R12N(R10) S(O)2R13, R12N(R10)C(O)N(R10)R11, R12N(R10)C(NR10)N(R10)R11, R12N(R10)C(NR10)N(R10)N(R10)R11, R12N(R10)R12C(R10)(N(R10) R11)C(O)OR10, R12N(R10)S(O)R11, R12OR10, R12ON(R10)C (NR10)N(R10)R11, R12OS(O)2OR10, R12P(O)(OR10)R11, R12OP(O) (OR10)2, R12P(O)(OR10)2, R12SR10, R12SR12C(O)OR10, R12SR12N (R10)R11, R12SR12C(R10)(N(R10)R11)C(O)OR10, R12SR12N(R10) C(O)OR10, R12SR12N(R10)C(O)R10, R12SSR12C(R10)(N(R10) R11)C(O)OR10, R12SC(O)N(R10)R11, R12SC(S)N(R10)R11, R12S(O) R10, R12S(O)2R13, R12S(O)OR10, R12S(O)2OR10, R12S(O)2 N(R10)R11,R12S(O)(NR10)R11, or R7 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, OR10, SR10, N(R10)R11, C(O)OR10, C(O)N(R10)R11, S(O)2OR10  and P(O)(OR10)2), or R7 is aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, OR10, SR10, N(R10)R11, C(O)OR10, C(O)N(R10)R11, S(O)2 OR10 and OP(O)(OR10)2), or R7 is heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, aralkyl, OR10, C(O)OR10, N(R10)R11, C(O)N(R10)R11, S(O)2OR10 and OP(O)(OR10)2), or R7 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, OR10, SR10, C(O)OR10, N(R10)R11, C(O)N(R10)R11), S(O)2 OR10 and OP(O)(OR10)2), or R7 is adamantyl (optionally substituted by alkyl, halo, haloalkyl, haloalkoxy, OR10, SR10, C(O)OR10, N(R10)R11, C(O)N(R10)R11, S(O)2OR10 and OP(O)(OR10)2), or each R7 is adamantylalkyl (where the adamantyl radical is optionally substituted by alkyl, halo, haloalkyl, haloalkoxy, OR10, SR10, C(O)OR10, N(R10)R11, C(O)N(R10)R11, S(O)2OR10 and OP(O)(OR10)2); R8 is independently hydrogen, alkyl, cycloalkyl, or aryl; R9 is C(O)OR10 or C(O)N(R10)R11 ; R10 and R11 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); R12 is a straight or branched alkylene chain; and R13 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.