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US 5,672,582 AGranted
Thrombin inhibitors
AssigneeMerck & Co., Inc.
InventorsDaniel F. Veber, S. Dale Lewis, Jules A. Shafer, Dong-Mei Feng, Ruth F. Nutt, Stephen F. Brady
Life of this patent
Estimating the term…
Abstract
4-substituted cyclohexylamine derivatives which are thrombin catalytic site inhibitors and which are useful as anticoagulants. These compounds show selectivity for thrombin over other trypsin-like enzymes and have oral bioavailability. They have the formula ##STR1## for example ##STR2##
Claims22
Compounds of the formula ##STR40## wherein:
- m=0 or 1;
- n=0,1, or 2;
- X=O or H.sub.2 ;
- R=arylsulfonyl, aminoacyl, acylaminoacyl, N-C.sub.1-3 alkyl aminoacyl, acyl-N-C.sub.1-3 alkylaminoacyl, arylacyl, arylC.sub.1-3 alkanoyl, hydroxyacyl, aryloxycarbonyl,
- C.sub.1-3 alkyloxycarbonyl, or ##STR41## where p is 0, 1, or 2;
- R"=aryl, heteroaryl, C.sub.5-11 carbomonocyclic, or
- C.sub.5-11 carbobicyclic;
- R.sup.1 =H or CH.sub.3 ;
- R.sup.2 =H or CH.sub.3 ;
- R.sup.3 =H, C.sub.1-3 alkyl, hydroxyC.sub.1-3 alkyl, carboxyC.sub.1-3 alkyl, aminoC.sub.1-3 alkyl, guanidoC.sub.1-3 alkyl, aryl or substituted aryl, arylmethyl, C.sub.3-8 cycloalkylmethyl, or C.sub.3-8 cycloalkyl;
- Y=CONR.sup.5 R.sup.6, COCO.sub.2 R.sup.4, COCH.sub.2 H, or COCO--Q,
- wherein
- Q= ##STR42## NR.sup.5 R.sup.6, or ##STR43## where q is 0, 1 or 2;
- R.sup.4 =C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- R.sup.5 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- R.sup.6 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- R.sup.7 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- and
- R.sup.8 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl,
- and pharmaceutically acceptable salts thereof.
17 more elements
Compounds of the formula ##STR55## wherein:
- m=0 or 1;
- n=0, 1, or 2;
- X=O or H.sub.2 ;
- R=arylsulfonyl, aminoacyl, acylaminoacyl, N-C.sub.1-3 alkyl aminoacyl, acyl-N-C.sub.1-3 alkylaminoacyl, arylacyl, aryl C.sub.1-3 alkanoyl, hydroxyacyl, aryloxycarbonyl, C.sub.1-3 alkyloxycarbonyl, or ##STR56## where p is 0, 1, or 2;
- R"=aryl, heteroaryl, C.sub.5-11 carbomonocyclic, or
- C.sub.5-11 carbobicyclic;
- R.sup.1 =H or CH.sub.3 ;
- R.sup.2 =H or CH.sub.3 ;
- Y=CONR.sup.5 R.sup.6, COCO.sub.2 R.sup.4, COCO.sub.2 H, or COCO--Q,
- wherein
- Q= ##STR57## NR.sup.5 R.sup.6, or ##STR58## where q is 0, 1 or 2;
- R.sup.4 =C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- R.sup.5 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- R.sup.6 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- R.sup.7 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- and
- R.sup.8 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl,
- and pharmaceutically acceptable salts thereof.
15 more elements
Compounds of the formula ##STR59## wherein:
- m=0 or 1;
- n=0, 1, or 2;
- X=O or H.sub.2 ;
- R=arylsulfonyl, aminoacyl, acylaminoacyl, N-C.sub.1-3 alkyl aminoacyl, acyl-N-C.sub.1-3 alkylaminoacyl, arylacyl, aryl C.sub.1-3 alkanoyl, hydroxyacyl, aryloxycarbonyl, C.sub.1-3 alkyloxycarbonyl;
- R.sup.1 =H or CH.sub.3 ;
- R.sup.2 =H or CH.sub.3 ;
- Y=CONR.sup.5 R.sup.6, COCO.sub.2 R.sup.4, COCO.sub.2 H, or COCO--Q,
- wherein ##STR60## NR.sup.5 R.sup.6, or ##STR61## where q is 0, 1 or 2;
- R.sup.4 =C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- R.sup.5 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- R.sup.6 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- R.sup.7 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl;
- and
- R.sup.8 =H, C.sub.1-3 alkyl or arylC.sub.1-3 alkyl,
- and pharmaceutically acceptable salts thereof.
12 more elements
Dependencies are inferred from the claim text.