Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-07-30
1999-08-03
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514317, 514343, 514354, 514423, 540 1, 546192, 5462784, 546332, 548537, C07D23914, A61K 3855
Patent
active
059325674
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to p-amidinobenzylamides of peptides with N-terminal sulfonyl or aminosulfonyl radicals, to the preparation thereof and to the use thereof as thrombin inhibitors.
EP 601 459, EP 672 658, WO 94/29336 and WO 95/23609 describe peptide thrombin inhibitors.
The present invention relates to thrombin inhibitors of the formula I ##STR2## and the stereoisomers thereof and the salts thereof with physiologically tolerated acids, where the amidine functionality can be in mono- or diprotected form and in which the substituents have the following meanings: C.sub.3 -C.sub.8 -cycloalkyl, aryl-C.sub.1 -C.sub.10 -alkyl, aryl, hetaryl, R.sup.2 OOC--(CH.sub.2).sub.n 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), and n is 1, 2, 3 or 4, ##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, or C.sub.3 -C.sub.7 -cycloalkyl-CH.sub.2 --, it being possible for a CH.sub.2 group in the ring to be replaced by O, S, NR.sup.6, or (CH.sub.3).sub.3 Si--C.sub.1 -C.sub.4 -alkyl, aryl or aryl-C.sub.1 -C.sub.3 -alkyl, hetaryl or hetaryl-C.sub.1 -C.sub.3 -alkyl, if R.sup.4 is H, a C.sub.1 -C.sub.8 -alkyl radical in which a hydrogen atom is replaced by SR.sup.6, OR.sup.6, 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 CONR.sup.7 R.sup.8 (R.sup.7, R.sup.8 are identical or different and are H, C.sub.1 -C.sub.4 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl or together are a C.sub.3 -C.sub.6 -alkylene chain), or may contain a fused-on aryl radical, ##STR4## where m is 2, 3 or 4, and a hydrogen on the ring can be replaced by a hydroxyl or C.sub.1 -C.sub.3 -alkyl group and, if m is 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 vicinal hydrogen atoms can be replaced by a double bond or by a fused-on aromatic system or a methylene chain with 4-6 carbon atoms, ##STR5## where R.sup.9 is F, Cl, Br, NO.sub.2, R.sup.15 O, R.sup.15 OOC, R.sup.15 OCH.sub.2, R.sup.15 NH, R.sup.15 CONH, R.sup.15 NH--CO or R.sup.15 OOCCH.sub.2 O, where R.sup.15 is H, C.sub.1 -C.sub.6 -alkyl, benzyl or phenyl, R.sup.9 and R.sup.10 or R.sup.11 may together form a fused-on phenylene ring or an alkylene chain consisting of 3 to 5 carbon atoms, in which one or two carbon atoms can be replaced by oxygen, R.sup.15 CO, CF.sub.3 CO, C.sub.2 F.sub.5 CO, R.sup.15 OCH.sub.2, R.sup.15 OOC, R.sup.15 OCH.sub.2 CO, R.sup.15 OOCCO or R.sup.15 NHCOCO, R.sup.15 OOC, R.sup.15 OCH.sub.2, R.sup.15 NH, R.sup.15 CONH, R.sup.15 NH--CO or R.sup.15 OOCCH.sub.2 O, and and the ring in VI can be substituted by 1 or 2 of the following radicals: C.sub.1 -C.sub.4 -alkyl, OH, O--C.sub.1 -C.sub.4 -alkyl, CF.sub.3, F, Cl, Br, S--C.sub.1 -C.sub.4 -alkyl, O(CH.sub.2).sub.n COOR.sup.6 (n=1-4).
The term "aryl" everywhere means mono- or bicyclic aromatic groups which contain 6 to 10 carbon atoms in the ring system, eg. phenyl or naphthyl, and which can be provided with up to three identical or different substituents.
The term "hetaryl" everywhere refers to 5- or 6-membered aromatic rings which may contain 1 or 2 hetero atoms such as N, O or S and to which an aryl ring, for example a phenyl ring, can be fused.
The term "cycloalkyl" means saturated cyclic hydrocarbon radicals with 3 to 7 carbon atoms, eg. cyclopentyl, cyclohexyl, cycloheptyl, it being possible for the rings to be substituted by halogen, C.sub.1 -C.sub.4 -alkyl and O--C.sub.1 -C.sub.4 -alkyl.
The following compound groups Ia to Ig are preferred: ##STR6##
Herein, the substituents R and the fragments A and B have the following meanings: naphthyl, phenyl-C.sub.1 -C.sub.4 -alkyl (especially benzyl and phenethyl), naphthyl-C.sub.1 -C.sub.4 -alkyl, pyridyl, isoquinolyl, NH.sub.2, C.sub.1
Bohm Hans-Joachim
Hoffken Hans Wolfgang
Hornberger Wilfried
Koser Stefan
Mack Helmut
BASF - Aktiengesellschaft
Davis Zinna Northington
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