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US 5,849,759 AGranted
Naphthyl-substituted benzimidazole derivatives as anti-coagulants
AssigneeBerlex Laboratories, Inc.
InventorsDamian O. Arnaiz, Brian D. Griedel, Steven T. Sakata, Kenneth J. Shaw, Zuchun Zhao
Life of this patent
Estimating the term…
Abstract
Compounds of formula (I): ##STR1## wherein: n, A, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 have meanings as defined herein, or a pharmaceutically acceptable salt thereof, are useful as anti-coagulants.
Claims14
A compound of formula (I):
- ##STR15## wherein:
- n is 0 or 1;
- A is alkylene;
- R.sup.1 is --OR.sup.5 or --N(R.sup.5)R.sup.6 ;
- R.sup.2 is independently nitro, alkyl (optionally substituted by --C(O)OR.sup.8), --OR.sup.5, --N(R.sup.7)R.sup.9, --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9 or piperidinyl optionally substituted by --C(O)OR.sup.8 or --R.sup.10 --C(O)OR.sup.8 ;
- R.sup.3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, --C(O)OR.sup.8, or --C(O)N(R.sup.8)R.sup.9 ;
- R.sup.4 is --C(NH)NH.sub.2 ;
- each R.sup.5 is independently:
- hydrogen;
- or
- alkyl optionally substituted by one or more substituents selected from the group consisting of --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9 and phenyl (optionally substituted by --C(O)OR.sup.8);
- or
- piperidinyl or pyrrolidinyl, each optionally substituted by 1-iminoalkyl, --C(NH)N(R.sup.8)R.sup.9, --R.sup.10 --C(O)OR.sup.8 or --SO.sub.3 H;
- R.sup.6 is hydrogen, alkyl, benzyl (optionally substituted by --C(O)OR.sup.8), --R.sup.10 --C(O)OR.sup.8, --R.sup.10 --C(O)N(R.sup.8)R.sup.9 or --C(O)R.sup.7 ;
- R.sup.7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of --C(O)OR.sup.8 and aryl (optionally substituted by --C(O)OR.sup.8);
- each R.sup.8 and R.sup.9 is independently hydrogen or alkyl;
- and
- each R.sup.10 is independently a branched or straight chain alkylene,
- or a pharmaceutically acceptable salt thereof.
16 more elements
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 of formula (I):
- ##STR16## wherein:
- n is 0 or 1;
- A is alkylene;
- R.sup.1 is --OR.sup.5 or --N(R.sup.5)R.sup.6 ;
- R.sup.2 is independently nitro, alkyl (optionally substituted by --C(O)OR.sup.8), --OR.sup.5, --N(R.sup.7)R.sup.9, --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9 or piperidinyl optionally substituted by --C(O)OR.sup.8 or --R.sup.10 --C(O)OR.sup.8 ;
- R.sup.3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, --C(O)OR.sup.8, or --C(O)N(R.sup.8)R.sup.9 ;
- R.sup.4 is --C(NH)NH.sub.2 ;
- each R.sup.5 is independently:
- hydrogen;
- or
- alkyl optionally substituted by one or more substituents selected from the group consisting of --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9 and phenyl (optionally substituted by --C(O)OR.sup.8);
- or
- piperidinyl or pyrrolidinyl, each optionally substituted by 1-iminoalkyl, --C(NH)N(R.sup.8)R.sup.9, --R.sup.10 --C(O)OR.sup.8 or --SO.sub.3 H;
- R.sup.6 is hydrogen, alkyl, benzyl (optionally substituted by --C(O)OR.sup.8), --R.sup.10 --C(O)OR.sup.8, --R.sup.10 --C(O)N(R.sup.8)R.sup.9 or --C(O)R.sup.7 ;
- R.sup.7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of --C(O)OR.sup.8 and aryl (optionally substituted by --C(O)OR.sup.8);
- each R.sup.8 and R.sup.9 is independently hydrogen or alkyl;
- and
- each R.sup.10 is independently a branched or straight chain alkylene, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.
15 more elements
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 of formula (I):
- ##STR17## wherein:
- n is 0 or 1;
- A is alkylene;
- R.sup.1 is --OR.sup.5 or --N(R.sup.5)R.sup.6 ;
- R.sup.2 is independently nitro, alkyl (optionally substituted by --C(O)OR.sup.8), --OR.sup.5, --N(R.sup.7)R.sup.9, --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9 or piperidinyl optionally substituted by --C(O)OR.sup.8 or --R.sup.10 --C(O)OR.sup.8 ;
- R.sup.3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, --C(O)OR.sup.8, or --C(O)N(R.sup.8)R.sup.9 ;
- R.sup.4 is --C(NH)NH.sub.2 ;
- each R.sup.5 is independently:
- hydrogen;
- or
- alkyl optionally substituted by one or more substituents selected from the group consisting of --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9 and phenyl (optionally substituted by --C(O)OR.sup.8);
- or
- piperidinyl or pyrrolidinyl, each optionally substituted by 1-iminoalkyl, --C(NH)N(R.sup.8)R.sup.9, --R.sup.10 --C(O)OR.sup.8 or --SO.sub.3 H;
- R.sup.6 is hydrogen, alkyl, benzyl (optionally substituted by --C(O)OR.sup.8), --R.sup.10 --C(O)OR.sup.8, --R.sup.10 --C(O)N(R.sup.8)R.sup.9 or --C(O)R.sup.7 ;
- R.sup.7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of --C(O)OR.sup.8 and aryl (optionally substituted by --C(O)OR.sup.8);
- each R.sup.8 and R.sup.9 is independently hydrogen or alkyl;
- and
- each R.sup.10 is independently a branched or straight chain alkylene, or a pharmaceutically acceptable salt thereof.
15 more elements
A method of treating a human having a disease-state alleviated by the inhibition of factor Xa, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (I):
- ##STR18## wherein:
- n is 0 or 1;
- A is alkylene;
- R.sup.1 is --OR.sup.5 or --N(R.sup.5)R.sup.6 ;
- R.sup.2 is independently nitro, alkyl (optionally substituted by --C(O)OR.sup.8), --OR.sup.5, --N(R.sup.7)R.sup.9, --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9 or piperidinyl optionally substituted by --C(O)OR.sup.8 or --R.sup.10 --C(O)OR.sup.8 ;
- R.sup.3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, --C(O)OR.sup.8, or --C(O)N(R.sup.8)R.sup.9 ;
- R.sup.4 is --C(NH)NH.sub.2 ;
- each R.sup.5 is independently:
- hydrogen;
- or
- alkyl optionally substituted by one or more substituents selected from the group consisting of --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9 and phenyl (optionally substituted by --C(O)OR.sup.8);
- or
- piperidinyl or pyrrolidinyl, each optionally substituted by 1-iminoalkyl, --C(NH)N(R.sup.8)R.sup.9, --R.sup.10 --C(O)OR.sup.8 or --SO.sub.3 H;
- R.sup.6 is hydrogen, alkyl, benzyl (optionally substituted by --C(O)OR.sup.8), --R.sup.10 --C(O)OR.sup.8, --R.sup.10 --C(O)N(R.sup.8)R.sup.9 or --C(O)R.sup.7 ;
- R.sup.7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of --C(O)OR.sup.8 and aryl (optionally substituted by --C(O)OR.sup.8);
- each R.sup.8 and R.sup.9 is independently hydrogen or alkyl;
- and
- each R.sup.10 is independently a branched or straight chain alkylene, or a pharmaceutically acceptable salt thereof.
15 more elements
A method of inhibiting human factor Xa in vitro by the administration of a compound of formula (I):
- ##STR19## wherein:
- n is 0 or 1;
- A is alkylene;
- R.sup.1 is --OR.sup.5 or --N(R.sup.5)R.sup.6 ;
- R.sup.2 is independently nitro, alkyl (optionally substituted by --C(O)OR.sup.8), --OR.sup.5, --N(R.sup.7)R.sup.9, --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9 or piperidinyl optionally substituted by --C(O)OR.sup.8 or --R.sup.10 --C(O)OR.sup.8 ;
- R.sup.3 is hydrogen or alkyl optionally substituted by one or more substituents selected from the group consisting of halo, --C(O)OR.sup.8, or --C(O)N(R.sup.8)R.sup.9 ;
- R.sup.4 is --C(NH)NH.sub.2 ;
- each R.sup.5 is independently:
- hydrogen;
- or
- alkyl optionally substituted by one or more substituents selected from the group consisting of --C(O)OR.sup.8, --C(O)N(R.sup.8)R.sup.9 and phenyl (optionally substituted by --C(O)OR.sup.8);
- or
- piperidinyl or pyrrolidinyl, each optionally substituted by 1-iminoalkyl, --C(NH)N(R.sup.8)R.sup.9, --R.sup.10 --C(O)OR.sup.8 or --SO.sub.3 H;
- R.sup.6 is hydrogen, alkyl, benzyl (optionally substituted by --C(O)OR.sup.8), --R.sup.10 --C(O)OR.sup.8, --R.sup.10 --C(O)N(R.sup.8)R.sup.9 or --C(O)R.sup.7 ;
- R.sup.7 is a branched or straight chain alkylene substituted by one or more substituents selected from the group consisting of --C(O)OR.sup.8 and aryl (optionally substituted by --C(O)OR.sup.8);
- each R.sup.8 and R.sup.9 is independently hydrogen or alkyl;
- and
- each R.sup.10 is independently a branched or straight chain alkylene, or a pharmaceutically acceptable salt thereof.
15 more elements
Dependencies are inferred from the claim text.