1,4-disubstituted piperazines useful in the therapy of the asthm

Details 1,4-disubstituted piperazines useful in the therapy of the asthm 1,4-disubstituted piperazines useful in the therapy of the asthm

1995-03-28

1997-03-04

Grumbling, Matthew V.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514242, 514245, 514252, 544113, 544121, 544122, 544212, 544295, 544364, 544372, A61K 31495, A61K 3140, C07D40300, C07D40302

Patent

active

056079303

DESCRIPTION:

BRIEF SUMMARY
This is a national stage entry application of International PCT Application Serial PCT/EP93/02264, filed on Aug. 24, 1993 and published as WO94/07856 on Apr. 14, 1994.
The present invention relates to heterocyclic amines, a process for the preparation thereof and pharmaceutical compositions containing them.
More particularly, the invention relates to compounds of formula (I). ##STR2## the single enantiomeric and diastereomeric forms thereof, the mixtures thereof and the salts thereof with pharmaceutically acceptable acids and bases, wherein: --CH.sub.2 NHCS-- group; substituted with 1 or 2 amino, mono-C.sub.1 -C.sub.6 -alkylamino, mono-C.sub.3 -C.sub.7 -alkenyl- or mono-C.sub.3 -C.sub.7 alkynylamino, di -C.sub.1 -C.sub.6 -alkylamino, (C.sub.1 -C.sub.6)alkyl (C.sub.3 C.sub.7)alkenylamino, piperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl groups; carbon atom they are linked to, they form a C.sub.3 -C.sub.6 -cycloalkyl group;
Examples of C.sub.1 -C.sub.3 or C.sub.1 -C.sub.6 -alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl.
Examples of 5- or 6-membered heterocyclic groups with 1-3 nitrogen atoms, optionally substituted with 1-2amino groups, are: [2,6-bis(diethylamino)-4-pyrimidinyl], [2,6-bis(allylamino)-4-pyrimidinyl], [2,6-bis(amino)-4-pyrimidinyl], [2,6-bis(pyrrolidin-1-yl)-4-pyrimidinyl], [4,6-bis(allylamino)-1,3,5-triazin-2-yl], [4,6-bis(diethylamino)-1,3,5-triazin-2-yl], [4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl], [3,6-bis(diethylamino)pyridin-2-yl], [3,6-bis(pyrrolidin-1-yl)pyridin-2-yl], [3,6-bis(allylamino)pyridin-2-yl], [3,6-bis(propargylamino)pyridin-2-yl], [3,6-bis(N-ethyl-N-allylamino)pyridin-2-yl], [3-ethylaminopyridin-2-yl].
Examples of mono-C.sub.1 -C.sub.6 -alkylamino groups are methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, t-butylamino.
Examples of mono-C.sub.3 -C.sub.6 -alkenyl- or mono-alkynylamino groups are allylamino, propargylamino.
Examples of di -C.sub.1 -C.sub.6 -alkylamino groups are dimethylamino, diethylamino, methylethylamino, methylpropylamino, methylisopropylamino, diisopropylamino, methyl n-butylamino.
Examples of (C.sub.1 -C.sub.6)alkyl-(C.sub.3 -C.sub.7)alkenylamino groups are methylallylamino, ethylallylamino, propylallylamino, isopropylallylamino.
Ra and Rb are preferably hydrogen, methyl, ethyl or, if taken together with the carbon atom they are linked to, are a cyclopropyl, cyclopentyl or cyclohexyl group.
Particularly preferred compounds (I) are those in which B is a --CO-- or --CH.sub.2 OCO-- group; D is an heterocycle selected from the group consisting of [2,6-bis(pyrrolidin-1-yl)-4-pyrimidinyl], [4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl], [3,6-bis(diethylamino)-pyridin-2-yl ]and [3-ethylaminopyridin-2-yl ]; Ra, which is the same as Rb, is hydrogen or methyl and n is 1.
The acid and basic groups can be salified respectively with pharmaceutically acceptable bases and acids. The non toxic salts thus obtained fall within the scope of the invention, as well as the single enantiomers, diastereomers, diastereomeric mixtures and racemates of the compounds of formula (I). Compounds (I) can be salified with both inorganic and organic acids which are pharmaceutically acceptable, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric or sulfuric, acetic, ossalic, tartaric, citric, benzoic, glycolic, gluconic, glucuronic, succinic, maleic, fumaric acids, etc. The carboxy group can be salified with bases of various nature, with the only proviso that the salts are pharmaceutically acceptable. Examples of said salts comprise those with: ammonium, sodium, potassium, calcium, magnesium, aluminium, iron, zinc, copper, or salts with pharmaceutically acceptable organic bases such as arginine, lysine, histidine, methylamine, ethylamine, dimethylamine, dibenzylamine, morpholine, phenylglycin and D-glucosamine.
Prolinamides with piperazinquinazoline are described to be ACE-inhibitors (Sankyo Co., JP 82 91,987; C.A., 97:198218w, 1982). N-Carbamoylprolinamides with N-methylpiperazine are known to be

REFERENCES:
patent: 5453423 (1995-09-01), Long et al.

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