Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-12-28
1996-02-06
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540362, 540463, 540527, 546216, 546164, 546146, 548546, 514210, 514211, 514212, 5142288, 5142352, 514307, 514311, 514327, 514408, 5142355, A61K 31395, C07D40312
Patent
active
054895839
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel 2-substituted 3-(4-amidinophenyl)propionic acid derivatives, the preparation thereof and the use thereof for controlling diseases.
Thrombin belongs to the group of serine proteases and plays a central part in the blood coagulation cascade as terminal enzyme. Both the intrinsic and the extrinsic coagulation cascade lead via several intensification states to the production of thrombin from prothrombin. The thrombin-catalyzed cleavage of fibrinogen then initiates blood coagulation and thus also possible thrombus formation. Thrombin additionally stimulates the aggregation of platelets which in turn, owing to the formation of platelet factor 3 and coagulation factor XIII as well as a whole series of highly active mediators, intensify thrombin formation.
The formation and action of thrombin are central events in the development both of white, arterial and of red, venous thrombi, and therefore potentially effective sites of attack of drugs. Thrombin inhibitors are, in contrast to heparin, able completely to inhibit, independently of cofactors, simultaneously the actions of thrombin both in the coagulation cascade and on platelets. They are able in the acute phase to prevent thromboembolic events after percutaneous transluminal coronary angioplasty (PCTA) and lysis and to act as anticoagulants in extracorporeal circulation (heart-lung machine, hemodialysis). They can also be used generally for thrombosis prophylaxis, for example after surgical interventions.
Two classes of compounds have to date been described as low molecular weight thrombin inhibitors, namely
FR 2,593,812, FR 2,593,813, EP 236,164 and C.A. 113, (1990) 6182j) and EP 293,881, EP 185,390).
We have now found that 2-substituted 3-(4-amidinophenyl)propionic acid derivatives of the formula ##STR2## where A is ##STR3## or --OR.sup.3 in which R.sup.1 and R.sup.2, which can be identical or different, are each hydrogen, saturated or unsaturated alkyl with up to 6 carbons or aralkyl or aryl, or R.sup.1 and R.sup.2 together with the nitrogen to which they are bonded are a 5- to 7-membered saturated ring which is unsubstituted or substituted by alkyl radicals with up to 4 carbons and can contain an oxygen atom, where the nitrogen and oxygen atoms are in the 1,2 or 1,4 positions, carbons, cycloalkyl or aralkyl, ##STR4## (where n is 1, 2, 3, 4 or 5) or ##STR5## Ar is phenyl or .alpha.- or .beta.-naphthyl which is unsubstituted or substituted by one or more halogen atoms, nitro groups, amino groups, C.sub.1-4 -mono- or bisalkylamino groups, hydroxyl groups, C.sub.1-4 -alkyl radicals, C.sub.1-4 -alkoxy groups, a methylenedioxy or ethylenedioxy radical, or Ar is pyridyl, quinolyl or isoquinolyl which is unsubstituted or substituted by one or more C.sub.1-4 -alkyl groups or C.sub.1-4 -alkoxy groups, action.
Preferred compounds are those where B is a pyrrolidinone, a piperidinone or a piperidone group, A is --NR.sup.1 R.sup.2 where R.sup.1 and R.sup.2 together with the nitrogen atom are a 5- to 7-membered ring which may be substituted by C.sub.1-4 -alkyl radicals, and Ar is .beta.-naphthyl which is substituted by one or more C.sub.1-4 -alkoxy radicals.
Particularly preferred compounds are those where A and B have the abovementioned meanings and Ar is .beta.-naphthyl which is substituted by 1 or 2 methoxy groups in position 4, 5, 6, 7 and/or 8 or by a methylenedioxy or ethylenedioxy group in these positions.
The novel compounds have one or two asymmetric centers. They may be in the form either of the racemates or of the antipodes with respect to the two asymmetric centers. Compounds which have the R configuration and the phenylalanine moiety are preferred.
The novel compounds can, if required, be in the form of their salts with physiologically tolerated acids. Examples of suitable physiologically tolerated acids are: hydrochloric acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, malonic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, ascorbic acid, malic acid, methanesulfonic acid,
REFERENCES:
Voigt et al. "Pharmazie" vol. 41 (1986) pp. 233-235.
Boehm Hans-Joachim
Hoeffken Hans W.
Hornberger Wilfried
Mack Helmut
Pfeiffer Thomas
BASF - Aktiengesellschaft
Bond Robert T.
LandOfFree
2-substituted 3-(4-amidinophenyl)propionic acid derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 2-substituted 3-(4-amidinophenyl)propionic acid derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2-substituted 3-(4-amidinophenyl)propionic acid derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2175227