Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-01-06
2000-05-02
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546101, A61K 31473, C07D40112
Patent
active
060573341
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel benzo[g]quinoline derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
More particularly the present invention provides a compound of formula I ##STR2## wherein A and B are each H or form together an additional bond, CH.sub.2 or O--CH.sub.2, and ##STR3## wherein R.sub.1 is defined above, R.sub.2 is H or trifluoromethyl, Z.sub.1 is O, S or NH and Z.sub.2 is CH or N, free bond is adjacent to the nitrogen and R.sub.2 is H, then A and B are not H, in free base or acid addition salt form.
The above-defined alkyl groups preferably represent methyl.
The compounds of the invention possess asymmetrical centers in positions 3, 4a and 10a, and possibly in the X--Y--R substituent. They may therefore appear in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixture are part of the present invention.
In a group of compounds of formula I, A and B are each hydrogen, X is CH.sub.2, Y is O or S and R is of formula (b) or (c).
In a further group of compounds of formula I, A and B form together an additional bond, X is CH.sub.2, Y is O or S and R is of formula (a) or (e).
In still a further group, A and B and X are as defined above, Y is O, S, NR.sub.1 [R.sub.1 being H or (C.sub.1-4)alkyl], CH.sub.2, or O--CH.sub.2, and R is of formula (a), (b), (c), (d), or (g), wherein R.sub.1 is as defined above and R.sub.2 is H, or of formula (e) or (f), wherein R.sub.1 is H, Z.sub.1, is O or S and Z.sub.2 is CH.
When A and B are each H, the X--Y--R substituent preferably presents the configuration 3R.
In a further aspect the invention provides a process for the production of the compounds of formula I and their acid addition salts, whereby in a compound of formula II ##STR4## wherein A, B, X, Y and R are as defined above and R.sub.2 is (C.sub.1-4)alkyl, the alkoxy group is converted into a hydroxy group, and the compounds of formula I thus obtained are recovered in free base or acid addition salt form.
The reaction can be effected according to known methods, e.g. using hydrobromide acid or boron tribromide. In formula II, R.sub.2 is preferably methyl.
Working up the reaction mixtures obtained according to the above process and purification of the compounds thus obtained may be carried out in accordance to known procedures.
Acid addition salts may be produced from the free bases in known manner, and vice versa. Suitable acid addition salts for use in accordance with the present invention include for example the hydrochloride.
The starting compounds of formula II wherein A and B are each H may be produced from the corresponding compounds of formula III.sub.a ##STR5## wherein R.sub.2 is as defined above, for example as described in Example 1.
The compounds of formula III.sub.a are known or may be produced in analogous manner to known procedures.
The starting compounds of formula II wherein A and B together form an additional bond may be produced from the corresponding compounds of formula Ill.sub.b ##STR6##
wherein R.sub.2 is as defined above, for example as described in Example 24.
The compounds of formula III.sub.b may be produced from compounds of formula X according to the following reaction scheme: ##STR7##
All the reactions in this scheme may be carried out according to known procedures.
The compounds of formula X are k n own or may be produced in analogous manner to known procedures.
The compounds of formula I and their physiologically acceptable acid addition salts, referred to hereinafter as agents of the invention, exhibit valuable pharmacological properties in animal tests and are therefore useful as pharmaceuticals.
In particular, the agents according to the invention effect a decrease on the intraocular pressure in rabbits, at doses of 0.1 to 100 .mu.mol. Male rabbits of ca. 3 to 6 kg are fixed in cages leaving their heads free. The solutions with the compound to be tested are applied to the right eye and the placebo soluti
REFERENCES:
patent: 4565818 (1986-01-01), Nordmann et al.
patent: 5262422 (1993-11-01), Gull et al.
P. Luvone et al., Investigative Ophthamology & Visual Science, vol. 32, No. 5, pp. 1674-1677 (1991). *
Chemical Abstracts 127:76436.
Chemical Abstracts 126:198252.
Chemical Abstracts 125:265927.
Chemical Abstracts 125:48966.
Derwent Abstract 96-343937.
Gull Peter
Markstein Rudolf
Seiler Max Peter
Balasubramanian V.
Gorman, Jr. Robert J.
Meece R. Scott
Novartis AG
Shah Mukund J.
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