Guanidine derivatives as inhibitors of Na.sup.+ /H.sup.+ exchan

Details Guanidine derivatives as inhibitors of Na.sup.+ /H.sup.+ exchan Guanidine derivatives as inhibitors of Na.sup.+ /H.sup.+ exchan

1995-11-09

1998-10-20

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514256, 514357, 514364, 514365, 514381, 514427, 514429, 514438, 514471, 544141, 544335, 546332, 548143, 548204, 548253, 548560, 548561, 548563, 548577, 549 61, 549 77, 549474, 549493, A61K 3134, A61K 3138, A61K 3140, A61K 31535

Patent

active

058246916

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP94/00786, filed May 12, 1994.


TECHNICAL FIELD

This invention relates to new guanidine derivatives and a pharmaceutically acceptable salts thereof which are useful as a medicament.


DISCLOSURE OF INVENTION

This invention relates to new guanidine derivatives. More particularly, this invention relates to new guanidine derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities, processes for preparation thereof, a pharmaceutical composition comprising the same and a use of the same.
Accordingly, one object of this invention is to provide the new and useful guanidine derivatives and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on Na.sup.+ /H.sup.+ exchange in cells.
Another object of this invention is to provide processes for preparation of the guanidine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said guanidine derivatives or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said guanidine derivatives or a pharmaceutically acceptable salt thereof as a medicament for the treatment and/or prevention of cardiovascular diseases, cerebrovascular diseases, renal diseases, arteriosclerosis, shock and the like in human being and animals.
The object guanidine derivatives of the present invention are novel and can be represented by the following general formula (I): ##STR2## wherein Y is N or C--R.sup.1 lower alkoxy, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, amino(lower)alkyl, protected amino(lower)alkyl, carboxy(lower)alkoxy, protected carboxy(lower)alkoxy, hydroxy(lower)alkoxy, protected hydroxy(lower)alkoxy, acyl, aryl or heterocyclic group), mono(or di or tri)halo(lower)alkyl, acyl, heterocyclic group which may have suitable substituent(s) or heterocyclic(lower)alkyl, heterocyclic group, or ##STR3## (in which R.sup.8 is hydrogen or lower alkyl, ##STR4## (in which R.sup.5 is hydrogen or lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, amino, protected amino, cyano, lower alkoxy(lower)alkyl, carboxy(lower)alkenyl, protected carboxy(lower)alkenyl, hydroxy, protected hydroxy, di(lower)alkylamino(lower)alkyl, amino(lower)alkyl, protected amino(lower)alkyl, hydroxy(lower)alkoxy, protected hydroxy(lower)alkoxy, hydroxyimino(lower)alkyl, heterocyclic group, heterocyclic(lower)alkyl which may have suitable substituent(s) or acyl), and hydroxy).
The object compound (I) of the present invention can be prepared by the following process. ##STR5## wherein R.sup.2, R.sup.3, W, Y and Z are each as defined above.
The starting compound (II) can be prepared by the following processes or Preparations mentioned below, or similar manners thereto. ##STR6## wherein defined above, ##STR7## is amidated carboxy, and X.sup.1, X.sup.2 and X.sup.3 are each a leaving group.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, isethionate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration

REFERENCES:
patent: 3574527 (1971-04-01), Walz et al.
patent: 4251545 (1981-02-01), Resnick
patent: 5364868 (1994-11-01), Englert et al.
Chemical Abstract 121:133971 for Chinese Patent 1075960 (Sep. 8, 1993).
Englert, Chemical Abstract 120:106777 for EP 556672 (Aug. 25, 1993).
Englert, Chemical Abstract 115:71158 for DE 3929582 (Mar. 7, 1991).

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