Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-06-05
1998-12-22
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514422, 514317, 514343, 548540, 548527, 546208, 5462791, A61K 3140, A61K 31445, C07D20700, C07D40100
Patent
active
058520511
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/E95/04646 filed Nov. 25, 1995.
The present invention relates to dipeptide p-amidinobenzylamides with N-terminal sulfonyl or aminosulfonyl radicals, to the preparation thereof and to the use thereof as thrombin inhibitors.
EP 601 459 describes heterocyclic thrombin inhibitors which have a sulfonamide group.
The present invention relates to compounds of the formula I ##STR2## and their stereoisomers and their salts with physiologically tolerated acids, in which the substituents have the following meanings: -C.sub.8 -cycloalkyl, aryl-C.sub.1 -C.sub.10 -alkyl, aryl, hetaryl, OH or R.sup.3 R.sup.2 N where R.sup.2 and R.sup.3 are identical or different and are hydrogen, C.sub.1 -C.sub.10 -alkyl, aryl, aryl-C.sub.1 -C.sub.10 -alkyl or together are a C.sub.2 -C.sub.7 -alkylene chain to which an aryl or hetaryl radical can be fused or which can contain a hetero atom (O, S, NH or substituted N), ##STR3## where R.sup.4 is hydrogen, C.sub.1 -C.sub.8 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, aryl or aryl-C.sub.1 -C.sub.3 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1-3 -alkyl, aryl, aryl-C.sub.1 -C.sub.3 -alkyl, di(C.sub.3 -C.sub.7 -cycloalkyl)-methyl or diphenylmethyl or--if R.sup.4 =H--a C.sub.1 -C.sub.8 -alkyl radical in which one hydrogen atom is replaced by OR.sup.6 or CO--OR.sup.6 (R.sup.6 =hydrogen, C.sub.1 -C.sub.8 -alkyl or aryl-C.sub.1-C.sub.3 -alkyl), or may contain a fused-on aryl radical, ##STR4## where m is 2, 3 or 4, and one hydrogen on the ring can be replaced by a hydroxyl or C.sub.1 -C.sub.3 -alkyl group and--if m=3 or 4--a CH.sub.2 group in the ring can be replaced by oxygen, sulfur, NH-- or N-C.sub.1 -C.sub.4 -alkyl and/or two adjacent hydrogen atoms can be replaced by a double bond.
The following four groups of compounds are preferred:
1. Compounds of the formula I, in which the substituents have the following meanings: or different and are hydrogen, C.sub.1 -l.sub.0 -alkyl, aryl, aryl-C.sub.1 -C.sub.10 -alkyl or together are a C.sub.2 -C.sub.7 -alkylene chain to which an aryl or hetaryl radical may be fused or which may contain a hetero atom (O, S, NH or substituted N), ##STR5## where R.sup.4 is hydrogen, C.sub.1 -C.sub.8 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, aryl or aryl-C.sub.1-C.sub.3 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1-3 -alkyl, aryl, aryl-C.sub.1 -C.sub.3 -alkyl, di(C.sub.3 -C.sub.7 -cycloalkyl)-methyl or diphenylmethyl or--if R.sup.4 =H--a C.sub.1 -C.sub.8 -alkyl radical in which one hydrogen atom is replaced OR.sup.6 or CO--OR.sup.6 (R.sup.6 =hydrogen, C.sub.1 -C.sub.8 -alkyl or aryl-C.sub.1 -C.sub.3 -alkyl), or may contain a fused-on aryl radical, ##STR6## where m is 2, 3 or 4, and one hydrogen atom on the ring can be replaced by a hydroxyl or C.sub.1 -C.sub.3 -alkyl group and --if m=3 or 4--one CH.sub.2 group in the ring can be replaced by oxygen, sulfur, NH-- or N-C.sub.1 -C.sub.4 -alkyl and/or two adjacent hydrogen atoms can be replaced by a double bond.
2. Compounds of the formula I in which the substituents have the following meanings: -C.sub.8 -cycloalkyl, aryl-C.sub.1 -C.sub.10 -alkyl, aryl or hetaryl, ##STR7## where R.sup.4 is C.sub.1 -C.sub.8 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, aryl or aryl-C.sub.1 -C.sub.3 -alkyl, -C.sub.7 -cycloalkyl-C.sub.1-3 -alkyl, aryl, aryl-C.sub.1 -C.sub.3 -alkyl, di(C.sub.3 -C.sub.7 -cycloalkyl)-methyl or diphenylmethyl or may contain a fused-on aryl radical, ##STR8##
3. Compounds of the formula I in which the substituents have the following meanings: -C.sub.8 -cycloalkyl, aryl-C.sub.1 -C.sub.10 -alkyl, aryl, hetaryl or OH, ##STR9## where R.sup.5 is a C.sub.1 -C.sub.8 -alkyl radical in which one hydrogen atom is replaced by OR.sup.6 or CO--OR.sup.6 (R.sup.6 =hydrogen, C.sub.1 -C.sub.8 -alkyl or aryl-C.sub.1 -C.sub.3 -alkyl), ##STR10##
4. Compounds of the formula I in which the substituents have the following meanings: -C.sub.8 -cycloalkyl, aryl-C.sub.1 -C.sub.10 -alkyl, aryl, hetaryl or OH, ##STR11## where R.sup.5 a C.sub.1 -C.sub.8 -alkyl radical in which one hydrogen atom is replaced by OR.sup.6 or CO--OR.sup.6 (R.s
Bohm Hans-Joachim
Hoffken Hans Wolfgang
Hornberger Wilfried
Koser Stefan
Mack Helmut
BASF - Aktiengesellschaft
Lambkin Deborah C.
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