Benzamidine derivatives and their use as anti-coagulants
AssigneeBerlex Laboratories, Inc.
InventorsBrad O. Buckman, David D. Davey, William J. Guilford, Michael M. Morrissey, Howard P. Ng, Gary B. Phillips, Shung C. Wu, Wei Xu
Life of this patent
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Abstract
This invention is directed to benzamidine derivatives which are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.
Claims11
A compound selected from the group consisting of the following formulae:
- ##STR12## wherein A is --N.dbd.;
- Z.sup.1 and Z.sup.2 are independently --O-- or --S--;
- R.sup.1 and R.sup.3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, --N(R.sup.8)R.sup.9, or --C(O)N(R.sup.8)R.sup.9 ;
- R.sup.2 is hydrogen, halo, alkyl, haloalkoxy, --OR.sup.8, --N(R.sup.8)R.sup.9, or --N(R.sup.8)(CH.sub.2).sub.n C(O)OR.sup.8 (where n is 1 to 3);
- R.sup.4 and R.sup.7 are independently hydrogen, halo, alkyl, nitro, --OR.sup.8, --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9, --N(R.sup.8)R.sup.9, --N(H)C(O)R.sup.8, or --N(H)S(O).sub.2 R.sup.8 ;
- R.sup.5 is --C(NH)NH.sub.2, --C(NH)NHOR.sup.8, --C(NH)N(H)C(O)OR.sup.8, or --C(NH)N(H)C(O)R.sup.8 ;
- R.sup.6 is (1,2)-imidazolyl (optionally substituted by alkyl) or (1,2)-imidazolinyl (optionally substituted by alkyl);
- and
- each R.sup.8 and R.sup.9 are independently hydrogen, alkyl, aryl, or aralkyl;
- or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition useful in treating a human having a disease-state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- ##STR15## wherein A is --N.dbd.;
- Z.sup.1 and Z.sup.2 are independently --O-- or --S--;
- R.sup.1 and R.sup.3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, --N(R.sup.8)R.sup.9, or --C(O)N(R.sup.8)R.sup.9 ;
- R.sup.2 is hydrogen, halo, alkyl, haloalkoxy, --OR.sup.8, --N(R.sup.8)R.sup.9, or --N(R.sup.8)(CH.sub.2).sub.n C(O)OR.sup.8 (where n is 1 to 3);
- R.sup.4 and R.sup.7 are independently hydrogen, halo, alkyl, nitro, --OR.sup.8, --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9, --N(R.sup.8)R.sup.9, --N(H)C(O)R.sup.8, or --N(H)S(O).sub.2 R.sup.8 ;
- R.sup.5 is --C(NH)NH.sub.2, --C(NH)NHOR.sup.8, --C(NH)N(H)C(O)OR.sup.8, or --C(NH)N(H)C(O)R.sup.8 ;
- R.sup.6 is (1,2)-imidazolyl (optionally substituted by alkyl) or (1,2)-imidazolinyl (optionally substituted by alkyl);
- and
- each R.sup.8 and R.sup.9 are independently hydrogen, alkyl, aryl, or aralkyl;
- or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.
A method of treating a human having a disease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- ##STR16## wherein A is --N.dbd.;
- Z.sup.1 and Z.sup.2 are independently --O-- or --S--;
- R.sup.1 and R.sup.3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, --N(R.sup.8)R.sup.9, or --C(O)N(R.sup.8)R.sup.9 ;
- R.sup.2 is hydrogen, halo, alkyl, haloalkoxy, --OR.sup.8, --N(R.sup.8)R.sup.9, or --N(R.sup.8)(CH.sub.2).sub.n C(O)OR.sup.8 (where n is 1 to 3);
- R.sup.4 and R.sup.7 are independently hydrogen, halo, alkyl, nitro, --OR.sup.8, --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9, --N(R.sup.8)R.sup.9, --N(H)C(O)R.sup.8, or --N(H)S(O).sub.2 R.sup.8 ;
- R.sup.5 is --C(NH)NH.sub.2, --C(NH)NHOR.sup.8, --C(NH)N(H)C(O)OR.sup.8, or --C(NH)N(H)C(O)R.sup.8 ;
- R.sup.6 is (1,2)-imidazolyl (optionally substituted by alkyl) or (1,2)-imidazolinyl (optionally substituted by alkyl);
- and
- each R.sup.8 and R.sup.9 are independently hydrogen, alkyl, aryl, or aralkyl;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.