Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Reduced antigenicity – reduced ability to bind complement – or...
Patent
1981-10-19
1984-01-10
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Reduced antigenicity, reduced ability to bind complement, or...
2601125R, 548201, 548533, C07C10352, A61K 3702
Patent
active
044253338
DESCRIPTION:
BRIEF SUMMARY
This invention relates to sulfur-containing acylamino acids and related salts and antihypertensive compositions containing these compounds as main ingredients, which have the following formula ##STR2## wherein Q.sup.1 and Q.sup.2 are methylene or sulfur atom, but at least one of them is methylene; phenyl, furyl, thienyl, pyridyl or naphthyl, which may be substituted by 1 to 3 groups selected from lower alkyl, hydroxy, R.sup.2 --S--, lower alkoxy, halogen, nitro, amino, lower alkylamino, lower alkanoylamino, aroylamino, lower alkanoyloxy, aroyloxy, lower alkylenedioxy, carboxy, sulfamoyl, lower alkylaminosulfamoyl or cyano, but when R.sup.1 is hydrogen, Q.sup.1 and Q.sup.2 are not methylene at the same time; higher alkanoyl, phenyl-lower alkanoyl, substituted phenyl-lower alkanoyl, benzoyl, substituted benzoyl, pyridylcarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, R.sup.6 --S--; or the specified R.sup.1 groups other than hydrogen; with R.sup.3 or thiazolidine ring formed with R.sup.3, which may be substituted by hydroxy, lower alkanoyloxy, aroyloxy, aralkyloxy, lower alkoxy, amino, guanidino, carboxy, lower alkoxycarbonyl, phenoxycarbonyl, aralkyloxycarbonyl, carbamoyl, mercapto, lower alkylthio, aralkylthio, lower alkanoylmercapto, aroylmercapto, imidazolyl or indolyl; alkanoyloxy-lower alkyl, imido-lower alkyl, aralkyl or phenyl; specified R.sup.1 groups other than hydrogen; the same shall be applied hereinafter.
The compounds of this invention are synthesized by such methods as the following A, B and C.
(A) The active derivatives of compounds represented by the formula ##STR3## wherein R.sup.7 is groups excluded hydrogen from the above-mentioned R.sup.2 ; ##STR4## are condensed by a general method such as mixed anhydride method, etc. in synthesizing peptides to give the compounds of this invention represented by the formula. ##STR5## The resulting compounds are acidified with hydrochloric acid, trifluoroacetic acid, etc., alkalified with sodium hydroxide, ammonia, etc., or treated by catalytic hydrogenation with palladium-carbon, electrolytic reduction, or reduction with complex metal hydride such as sodium borohydride or with metal to give the compounds of this invention wherein R.sup.2 is hydrogen and/or wherein R.sup.5 is hydroxy. The diastereoisomers of the products can be separated and purified by a general method such as fractional recrystallization, chromatography, etc.
(B) The compounds represented by the formula ##STR6## by a general method such as Schotten-Baumann reaction, etc. to give the products represented by the formula. ##STR7## The products react with salt of benzylmercaptan, thioacetic acid or thiobenzoic acid such as potassium salt, etc. to give the compounds [IV] of this invention.
(C) The compounds represented by the formula aralkyl such as benzyl, etc., X--CO--Z--S-- or R.sup.6 --S--react with the above-mentioned compounds [VI] by the above method A or B to give the compounds of this invention represented by the formula ##STR8## wherein R.sup.9 is groups excluded hydrogen from the above mentioned R.sup.2.
The compounds of this invention represented by the formula [II] synthesized by the above mentioned A, B or C can form the conventional salts to be generally used as medicine such as sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, diethylamine salt, triethanolamine salt, etc. The compounds [I] of this invention have the stereoisomers because they have one or more asymmetric carbon atoms. These stereoisomers are also within the limit of this invention. Examples are shown below, although this invention is not limited to these ones.
EXAMPLE 1
N-[2R,4R)-[3-(S-Acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazoli dinyl]carbonyl]glycine
To the solution of 1.78 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidin ecarboxylic acid dissolved in 30 ml of dry tetrahydrofuran (It is abbreviated to THF hereinafter.) 0.51 g of N-methylmorpholine is added. To the reaction mixture 0.68 g of isobutyl chlorocarbonate is added a
REFERENCES:
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patent: 4248883 (1981-02-01), Sawayama
patent: 4282235 (1981-08-01), Ondetti
patent: 4283328 (1981-08-01), Stammer
145975k "Pharmaceutical Composition Containing a Proline Derivative and a Diuretic" Horovitz et al.; Pharmaceuticals, vol. 91, 1979.
2281-x "Amides of Cyclic Amino Acids" Wiskott, Erik; Chemical Abstracts, vol 92, 1980.
Iso Tadashi
Iwao Jun-ichi
Oya Masayuki
Gerstl Robert
Santen Pharmaceutical Co. Ltd.
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