Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-10-29
1993-04-27
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142368, 514255, 514326, 514342, 544133, 544369, 546277, 546209, 548200, C07D27704, C07D41706, C07D41712, A61K 31425
Patent
active
052062546
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to .beta.-carbonylcarboxyamides of 2-substituted thiazolidines, to a method for their preparation and to pharmaceutical compositions containing them.
3-acyl-2-substituted-thiazolidines, sharing both antitussive and mucus-regulating activities have been disclosed in EP-A-169,581.
The mucus-regulating activity is common to all the compounds of said EP application, while the antitussive activity depends on the N-acyl substituent of the 1,3-thiazolidine ring: when the N-acyl-substituents are oxalic, succinic, glutaric and cyclopropyl carboxylic acid residues, antitussive activity is lost.
It has now been surprisingly found, that 3-acyl-2-substituted-1,3-thiazolidines whose N-acyl-substituent is that of a .beta.-carbonyl acid, for example a malonic acid residue, are endowed with potent and selective antitussive activity.
The present invention relates to .beta.-carbonyl-carboxyamides of formula (I) ##STR2## wherein R is hydrogen, a linear or branched C.sub.1 -C.sub.4 -alkyl, allyl or propargyl; hydroxy, --O--(CH.sub.2).sub.n Ra, --NRbRc, --NH--(CH.sub.2)m-NRbRc; p-methoxy-phenyl, 3,4,5-trimethoxy-phenyl, .beta.-pyridyl, cyclopentyl or cyclohexyl; or branched C.sub.1 -C.sub.4 -alkyl, cyclohexyl, cyclopentyl, benzyl, hexahydrobenzyl, .alpha., .beta., .gamma.-pyridylmethyl, or Rb and Rc taken together with the nitrogen atom to which they are linked, form a morpholine, piperidine or piperazine residue of formula Rd--N(CH.sub.2 CH.sub.2).sub.2 N-- wherein Rd is hydrogen, linear or branched C.sub.1 -C.sub.4 -alkyl, benzyl, hexahydrobenzyl, (C.sub.6 H.sub.5).sub.2 CH--, (p--F--C.sub.6 H.sub.4).sub.2 CH-- or .beta.-pyridylmethyl;
Compounds of formula (I) have at least a chiral carbon atom and have therefore more than one enantiomer. The invention includes all said enantiomers and the mixtures thereof, racemates included. Moreover, since compounds of formula (I) may contain acid or basic groups, also salts with pharmaceutically acceptable acids or bases are included in the present invention.
Pharmaceutically acceptable salts of the compounds of formula (I) with pharmaceutically acceptable bases are salts with either organic bases such as, for example, methylamine, dimethylamine, trimethylamine, lysine, arginine, N-methyl-N-cyclohexylamine, ethylamine, diisopropylamine, tromethamine, N,N-dimethylethanolamine, N,N-diethylethanolamine or .beta.-phenylethylamine, morpholine, piperidine, piperazine, galactosime, N-methylglucamine or inorganic bases such as, for example, alkaline or alkaline-earth hydroxides as well as zinc or aluminum hydroxydes.
Pharmaceutically acceptably salts of the compounds of formula (I) with pharmaceutically acceptable acids are salts with either organic acids such as, for example, acetic, formic, propionic, fumaric, maleic, malic, malonic, tartaric, benzoic, salicyclic, methanesulphonic, lactic, asparatic, glutammic, L or D-2-phenylthiazolidinecarboxylic acids, N-acetyl-crysteine or inorganic acids such as, for example, nitric, phosphoric, hydrochloric, hydrobromic acids.
Specific examples of compounds of the invention are the following: thiazolidine; 1,3-thiazolidine; idine; N'-[(R,S)-2-(2-methoxy-phenoxymethyl)-1,3-thiazolidine]-malondiamide; N'[(+)-2-(2-methoxy-phenoxymethyl-1,3-thiazolidine]-malondiamide; N'-[(-)-2-(2-methoxy-phenoxymethyl)-1,3-thiazolidine]-malondiamide; N'-[(R,S)-2-(2-allyloxy-phenoxymethyl)-1,3-thiazolidine)-malondiamide; N'-[(R,S)-2-(2-propargyloxyphenoxymethyl)-1,3-thiazolidine]-malondiamide; N'-[(R,S)-2-2-(2-methoxy-phenylthiomethyl)-1,3-thiazolidine]-malondiamide; N'-[(R,S)-2-(2-methoxy-phenyl)ethyl-1,3-thiazolidine]-malondiamide; de; olidine]-malondiamide; lidine]-malondiamide; ndiamide; mide.
The compounds of the invention are prepared by a process comprising the reaction of a compound of formula (II) ##STR3## wherein R and X are as above defined, with an acid or with an activated species of an acid of formula (III) ##STR4## wherein R'.sub.1 is as above defined for R.sub.1, or is a group convertible into R.sub.1, and if desired, converting a
REFERENCES:
patent: 4798898 (1989-01-01), Gandolfi
patent: 4857643 (1989-08-01), Gandolfi
Fieser, Reagents for Organic Synthesis, p. 209 (1967).
R.N. 119637-67-1 Moguisteine.
Di Domenico Roberto
Gallico Licia
Gandolfi Carmelo A.
Lumachi Bruno
Spinelli Silvano
Boehringer Mannheim Italia S.p.A.
Gerstl Robert
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