Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-06-27
1993-04-20
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5483351, 5483451, 5483114, 514397, A61K 31415, C07D23356
Patent
active
052043649
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new N-imidazolyl and N-imidazolylmethyl derivatives of bicyclic compounds, in particular to N-imidazolyl and N-imidazolylmethyl derivatives of 3,4-dihydro-2H-1-benzopyran, 2H-1-benzopyran, 3,4-dihydro-2H-1-benzothiopyran, 2H-1-benzothiopyran, 1,2,3,4-tetrahydronaphthalene and 1,2-dihydronaphthalene, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents.
The present invention provides novel compounds having the general formula (I) ##STR2## wherein A is a .gtoreq.CR.sub.3 or >CHR.sub.3 group, in which R.sub.3 is hydrogen or C.sub.1 -C.sub.6 alkyl, or a >C=CR.sub.4 R.sub.5 group, in which each of --CH.dbd.CH--COOR', in which each of R' and R" independently is hydrogen or C.sub.1 -C.sub.6 alkyl, and the pharmaceutically acceptable salts thereof; and wherein: then Z is --CH.sub.2 --, --0-- or --S--; then n is one; and is --CH.sub.2 --, n is one and R.sub.2 is --COOR' wherein R' is as defined above, then at least one of R and R.sub.1 is other than hydrogen.
The above proviso a) excludes from formula (I) compounds wherein n is zero and Z is --S--, that are not obtainable according to the processes herein described. The proviso b) excludes the compounds previously disclosed by U.S. Pat. Nos. 4,510,149 and 4,602,022; and proviso c) excludes those disclosed by E.P.-A-135177.
The invention also includes within its scope all the possible isomers, stereoisomers and their mixtures and the metabolites and the metabolic precursors or bio-precursors of the compounds of formula (I). A C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.5 alkyl group is preferably a C.sub.1 -C.sub.4 alkyl group, in particular methyl, ethyl, propyl and isopropyl, more preferably methyl and ethyl.
The substituent R.sub.2 can be linked to any of the carbon atoms of the benzene moiety.
Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts, with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulfuric, perchloric and phosphoric acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids, and salts with inorganic, e.g. alkali metal, especially sodium or potassium, bases or alkaline-earth metal, especially calcium or magnesium, bases, or with organic bases, e.g. alkylamines, preferably triethyl-amine.
As stated above the present invention also includes within its scope pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I). Preferred compounds of the invention are the compounds of formula (I), wherein, subject to the above provisos, -C.sub.4 alkyl, or a >C.dbd.CHR.sub.4 group in which R.sub.4 hydrogen or C.sub.1 -C.sub.4 alkyl; Z is --CH.sub.2 --, --0-- or --S--; --CH.dbd.CH--COOR', in which each of R' and R" independently is hydrogen or C.sub.1 -C.sub.4 alkyl; and the pharmaceutically acceptable salts thereof.
More preferred compounds of the invention are the compounds of formula (I), wherein, subject to the above provisos, or a >C.dbd.CH.sub.2 group; --CONH.sub.2 ; and the pharmaceutically acceptable salts thereof.
Examples of preferred compounds of formula (I) are the following: acid; lic acid; 5,6-dihydro-7-(1H-imidazol-1-ylmethyl)-8-methyl-2-naphthalenecarboxylate; acid; and acid;
The compounds of the invention and the salts thereof can be prepared by the process comprising: ##STR3## wherein R, R.sub.1, R.sub.2, R.sub.3, n and Z are as defined above the M represents hydrogen or an acyl group, thus obtaining a compound of formula (I), wherein A is a .gtoreq.C--R.sub.3 group, in which R.sub.3 is as defined above; or ##STR4## wherein R, R.sub.1, R.sub.2, Z and n are as defined above, thus obtaining a compound of formula (I) in which A is a >C.dbd.CR.su
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Carganico Germano
Cozzi Paolo
Ferti Corrado
Pillan Antonio
Salvati Patricia
Farmitalia Carlo Erba S.r.l.
Lee Mary C.
Miltenberger Lenora Ava
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