Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-11-29
1997-02-11
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514292, 544295, 544361, 544372, 546 84, 546208, 546210, 548546, 548547, A01N 4338, A01N 4342, C07D47102
Patent
active
056021348
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT Application Ser. No. PCT/EP 94/01960, filed Jun. 15, 1994, which claims priority from European Patent Application Ser. No. 93.201.771.8, filed on Jun. 21, 1993.
EP-0,406,958 describes imidazoquinazolinone derivatives having positive inotropic and lusitropic properties. GB-2,190,676 and EP-0,426,180 disclose a number of imidazoquinolinones as c-AMP phosphodiesterase inhibitors. U.S. Pat. No. 5,196,428 describes imidazoquinolinones having an inhibitory effect on the ADP induced blood platelet aggregation in human platelet-rich plasma.
Perkin and Robinson, J. Chem. Soc., 103, 1973 (1913) describe the preparation of 1,3-dihydro-2H-pyrrolo[2,3-b]quinolin-2-one. However, according to Tanaka et al., J. Het. Chem., 9, 135 (1972) the procedure of Perkin and Robinson did not produce the above pyrroloquinolinone compound, but rather some plain quinoline derivatives.
Vogel et al., Helv. Chim. Acta., 52(7), 1929 (1969) and U.S. Pat. No. 3,974,165 describe the preparation of some partially hydrogenated pyrrolo[2,3-b]quinolin-2-one derivatives.
The compounds of the present invention differ structurally from the cited art-known compounds by the particular substitution of the pyrroloquinolinone moiety and by their favorable positive inotropic and lusitropic properties.
The present invention is concerned with novel 1,3-dihydro-2H-pyrrolo[2,3-b]-quinolin-2-one derivatives having the formula ##STR2##
the pharmaceutically acceptable addition salts thereof and the stereochemically isomeric forms thereof, wherein
L is a radical of formula --O-Alk-(NH).sub.p -C(.dbd.O)-R.sup.1, wherein
Alk is C.sub.1-6 alkanediyl;
p is 0 or 1; and
R.sup.1 is hydroxy, C.sub.1-4 alkyloxy or --NR.sup.2 R.sup.3, wherein
R.sup.2 is hydrogen or C.sub.1-4 alkyl; and
R.sup.3 is C.sub.3-7 cycloalkyl or piperidinyl, which is optionally substituted with C.sub.1-4 alkyl, phenylmethyl or C.sub.3-7 cycloalkylmethyl;
R.sup.2 and R.sup.3 may also be joined together to form piperazinyl, optionally substituted with C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylmethyl, C.sub.1-6 alkyl optionally substituted with one or two hydroxy groups, 2,2-dimethyl-1,3-dioxcilanylmethyl, benzyl, halophenylmethyl, (cyclopentyloxy)(methoxy)phenylmethyl, diphenylC.sub.1-4 alkyl, pyridinyl, pyrimidinyl or phenyl optionally substituted with C.sub.1-4 alkyloxy or halo; or
R.sup.2 and R.sup.3 are joined together to form piperidinyl, optionally substituted with imidazolylcarbonyl.
In the foregoing definitions halo is generic to fluoro, chloro, bromo and iodo; the term 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; C.sub.1-6 alkanediyl defines straight and branch chained bivalent hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,1-ethanediyl, 1,1-propanediyl, 1,2-propanediyl 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, tier 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-p
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patent: 4943573 (1990-07-01), Meanwell et al.
patent: 5196428 (1993-03-01), Meanwell et al.
patent: 5220023 (1993-06-01), Freyne
Evans et al., Screening and Determination of Kinetic Parameters of Aromatase inhibitors using Human Genital Skin Fibroblasts, Journal of Enzyme Inhibition, 1993, vol. 7, pp. 203-212 1993.
Freyne Eddy J. E.
Raeymaekers Alfons H. M.
Janssen Pharmaceutica N.V.
Metz Charles J.
Rao Deepak
Shah Mukund J.
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