6-Amidino-2-naphthyl 4-guanidinobenzoate derivatives and pharmac

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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514218, 514256, 514275, 514535, 540553, 544332, 548315, 560 34, A61K 31415, A61K 31505, C07D23350, C07D23388

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active

047771828

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE ART

The present invention relates to amidine compounds having anti-trypsin, anti-plasmin, anti-kallikrein, anti-thrombin and anti-complement activities.


BACKGROUND OF THE ART

Compounds having anti-trypsin, anti-plasmin, anti-kallikrein, anti-thrombin and anti-complement activities have already been known from British Pat. No. 2,083,818.
The present compounds are stronger in enzyme inhibitory activities and anti-complement activity, and more effective in oral administration than the above prior compounds.


DISCLOSURE OF THE INVENTION

The present invention relates to novel amidine compounds of formula (I) ##STR4## wherein R.sub.1 and R.sub.2 represent each a hydrogen atom, or a straight or branched chain alkyl group of 1 to 6 carbon atoms; R.sub.3 represents a straight or branched chain alkyl group of 1 to 6 carbon atoms, or a group of the formula R.sub.4 --B--(CH.sub.2).sub.n -- wherein n is 1 to 2, B is --O-- or --NH-- and R.sub.4 is a hydrogen atom, R.sub.5 --CO-- or ##STR5## R.sub.5 is a straight or branched chain alkyl group of 1 to 15 carbon atoms; and R.sub.1 and R.sub.3 taken together via 2 to 4 carbon atoms may form a ring optionally containing double bonds and straight or branched chain alkyl groups of 1 to 4 carbon atoms as substituents, and the pharmaceutically acceptable acid addition salts thereof.
An object of the present invention is to provide pharmaceutically useful novel amidine compounds and pharmaceutically acceptable acid addition salts thereof.
Another object of the present invention is to provide a process for producing said novel amidine compounds.
A still another object of the present invention is to provide anti-trypsin, anti-plasmin, anti-kallikrein, anti-thrombin and anti-complement agents which may be administered orally.
The compound (I) of the present invention can be produced by the reaction between a carboxylic acid compound of formula (II) or a reactive intermediate thereof and 6-amidino-2-naphthol of formula (III) or preferably an acid addition salt thereof. ##STR6## R.sub.1, R.sub.2 and R.sub.3 are as defined above. The reactive intermediates, as herein referred to, include acid halides and acid anhydrides commonly used in the dehydration condensation and the reactive intermediates formed by reacting dicyclohexylcarbodiimide (DCC), diphenyl phosphorylazide (DPPA), or the like with a carboxylic acid derivative.
The process for producing the present compound is described below in detail.
The present compound (I) can be prepared by dissolving or suspending a carboxylic acid compound (II) in an organic solvent such as dimethylformamide, pyridine, or the like, then allowing the compound (II) to react with a carboxylic acid activator such as dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), or the like, which is usually used as dehydration-condensation agent, and adding 6-amidino-2-naphthol (III) or preferably an acid addition salt thereof to the reaction product.
For instance, when DCC is used as the dehydration-condensation agent, a carboxylic acid derivative (II) is added to a solvent such as pyridine, then 6-amidino-2-naphthol (III) is added, and the mixture is stirred at a temperature between -30.degree. and 80.degree. C., preferably at room temperature, for 3 to 5 hours to complete the reaction, though it is not objectionable to continue the reaction overnight. Dicyclohexylurea (DCU) precipitates out of the reaction mixture, while the present compound (I) either precipitates with DCU or remains dissolved in the solvent. In the former case, both precipitates are collected by filtration, then suspended in a suitable solvent such as dimethylformamide or the like and the mixture is filtered to remove insoluble DCU. After adding to the filtrate a solvent such as ethyl ether, ethyl acetate, acetone or the like, the precipitate is collected by filtration to obtain the present compound (I). Alternatively, the combined precipitate of DCU and the present compound (I) is collected by filtration, then added to a suitable solvent such as dimethylforma

REFERENCES:
patent: 4420619 (1983-12-01), Marxer
patent: 4454338 (1984-06-01), Fujii et al.
patent: 4532255 (1985-07-01), Fujii et al.
patent: 4598077 (1986-07-01), Fujii et al.
Webster's New Int'l Dictionary, Second Edition, (1961), p. 562, "Congestion".
Dorland's Illustrated Medical Dictionary, Twenty-Sixth Edition, (1981), p. 298, "Congestion".
Animal and Clinical Pharmacologic Techniques in Drug Evaluation, Edited by Nodine & Siegler, Chapter 7.
"Stages of Drug Evaluation in Man; General Principals of Experimental Design", by John H. Nodine, M.D., pp. 89-95, esp. p. 90, published 1964, Yearbook Medical Publishers, Inc., Chicago.

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