Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-03-15
1996-05-28
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514 63, 5142328, 514293, 544126, 544361, 544139, 544370, 546 14, 546 82, 546278, 546159, 548110, 5483147, 5483151, 5483171, A61K 31495, A61K 31435, C07D47104
Patent
active
055211879
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
A number of substituted imidazo[4,5-b]quinolin-2-ones are known from BE-904,671; DE-A-3,717,291; U.S. Pat. No. 4,701,459 and U.S. Pat. No. 4,943,573 as phosphodiesterase and blood platelet aggregation inhibitors which are useful as inotropic cardiotonics and antithrombotics.
In U.S. Pat. No. 5,043,327 which corresponds to EP-A-0,406,958, published Jan. 9, 1991, there are described positive inotropic and lusitropic 3,5-dihydro-imidazo[2,1-b]quinazolin-2(1H)-one derivatives.
DESCRIPTION OF THE INVENTION
The present invention is concerned with novel 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives having the formula ##STR2## the pharmaceutically acceptable addition salts thereof and the stereochemically isomeric forms thereof, wherein R is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl optionally substituted with from 1 to 3 substituents each independently selected from halo, hydroxy, C.sub.1-6 alkyloxy, C.sub.5-6 cycloalkyloxy, C.sub.1-6 alkyl or trifluoromethyl; pyridinyl; thienyl optionally substituted with halo or C.sub.1-6 alkyl; optionally substituted with COOH, COOC.sub.1-4 alkyl, CONR.sup.3 R.sup.4 or COOCH.sub.2 CONR.sup.5 R.sup.6 ; CONR.sup.5 R.sup.6 or C.sub.1-6 alkyl optionally substituted with COOH, COOCl.sub.1-4 alkyl, CONR.sup.3 R.sup.4 or COOCH.sub.2 CONR.sup.5 R.sup.6 ; alkyloxyC.sub.1-4 alkyl, hydroxycarbonylC.sub.1-4 alkyl, C.sub.1-4 alkyloxycarbonylC.sub.1-4 alkyl; cycloalkyl, phenyl, thienyl or pyridinyl; or attached may form a pyrrolidinyl, morpholinyl or piperazinyl ring, said piperazinyl ring being optionally substituted on the nitrogen atom with C.sub.1-4 alkyl, (C.sub.3-7 cycloalkyl)C.sub.1-4 alkyl, phenylC.sub.1-4 alkyl or C.sub.1-6 alkyl substituted with one, two, three, four or five hydroxy groups; and alkyloxyC.sub.1-4 alkyl, hydroxycarbonylC.sub.1-4 alkyl, C.sub.1-4 alkyloxycarbonylC.sub.1-4 alkyl; cycloalkyl, phenyl, thienyl or pyridinyl; or attached may form a pyrrolidinyl, morpholinyl or piperazinyl ring, said piperazinyl ring being optionally substituted on the nitrogen atom with C.sub.1-4 alkyl, (C.sub.3-7 cycloalkyl)C.sub.1-4 alkyl, phenylC.sub.1-4 alkyl or C.sub.1-6 alkyl substituted with one, two, three, four or five hydroxy groups.
In the foregoing definitions the term halo defines fluoro, chloro, bromo and iodo; C.sub.1-4 alkyl defines straight and branched saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl; C.sub.1-6 alkyl defines C.sub.1-4 alkyl and the higher homologs thereof such as, for example, pentyl, hexyl and the like; C.sub.3-7 cycloalkyl defines cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Tri(C.sub.1-6 alkyl)silyl in particular may be trimethylsilyl, triethylsilyl, tert. butyldimethylsilyl and the like.
Pharmaceutically acceptable addition salts as mentioned hereinabove comprise the therapeutically active non-toxic addition salt forms which the compounds of formula (I) are able to form. Said salt forms can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) containing acidic protons may also be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with ap
REFERENCES:
patent: 4701459 (1987-10-01), Meanwell et al.
patent: 4943573 (1990-07-01), Meanwell
patent: 5043327 (1991-08-01), Freyne et al.
patent: 5342842 (1994-08-01), Cheng
Beavo et al, Tips 11, pp. 150-155 (1990).
Nicholson et al., Tips 121 (1991), pp. 19-27.
Meanwell et al, J. Med. Chem. 35, pp. 2672-2687 (Jul. 10, 1992).
De Chaffoy De Courcelles Didier R. G. G.
Freyne Eddy J. E.
Raeymaekers Alfons H. M.
Bernhardt Emily
Janssen Pharmaceutica N.V.
Metz Charles J.
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