Imidazolinobenzodiazepines

Details Imidazolinobenzodiazepines Imidazolinobenzodiazepines

1996-05-06

1998-11-10

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540559, 540562, A61K 31395, C07D48704

Patent

active

058344640

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The benzodiazepine class of compounds has been widely exploited as therapeutic agents, especially as central nervous system drugs, such as anxiolytics. They exhibit strong binding to "benzodiazepine receptors" and some exhibit binding to CCK-B or gastrin receptors. None of the compounds known to be a CCK-B antagonist is of the imidazolinobenzodiazepine type shown as structure I, below.


SUMMARY OF THE INVENTION

This invention is concerned with novel compounds of structure I: ##STR2## which are antagonists of CCK-B. They are useful in the treatment and prevention CCK-B related disorders of the central nervous systems of animals, preferably mammals and especially humans.
The invention is also concerned with pharmaceutical formulations of the novel compounds, processes for their preparation and the use of the novel compounds as anxiolytic agents.


DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention have structural formula: ##STR3## or a pharmaceutically acceptable salt thereof, wherein R is bromo or fluoro, or C.sub.1-3 alkyl, with C.sub.1-3 alkyl, hydroxy-C.sub.1-3 alkyl, --COOH ##STR4## R.sup.4 is C.sub.1-6 alkyl, CF.sub.3, cyclopropyl, 2,2-dimethylcyclopropyl, 2,2-di-fluorocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or mono- or di-substituted phenyl CF.sub.3, OCH.sub.3, or NH.sub.2.
One embodiment of the novel compounds of this invention is that wherein R.sup.1 is ##STR5##
Specific compounds representative of this embodiment are those depicted in the following table:


______________________________________ A R R.sup.2 ______________________________________ CH.sub.2 CH .sub.2 phenyl 3-CH.sub.3 ##STR6## phenyl 3-CH.sub.3 ##STR7## phenyl 3-CH.sub.3 ##STR8## cyclohexyl 3-CH.sub.3 ##STR9## phenyl 3-CH.sub.3 CH.sub.2 CH.sub.2 CH .sub.2 pheyl 3-CH.sub.3 ##STR10## phenyl 4-Cl ##STR11## phenyl 3-Cl ##STR12## phenyl 4-CF.sub.3 ##STR13## phenyl 3-CH.sub.3 ##STR14## phenyl 3-CH.sub.3 ##STR15## phenyl 3-CH.sub.3 ##STR16## phenyl 3-CH.sub.3 ##STR17## phenyl 3-CH.sub.3 CHCH phenyl 3-CH.sub.3 ##STR18## phenyl 3-CH.sub.3 ______________________________________
This invention is meant to include the individual diastereomers where such exist and mixtures thereof and enantiomers and mixtures of the enantiomers.
The pharmaceutically acceptable salts of the compounds of Formulas I include the conventional non-toxic salts or the quarternary ammonium salts of the compounds of Formula I formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combination of solvents.
The ability of the novel compounds to antagonize CCK-B makes these compounds useful as pharmaceutical agents for mammals, especially humans for the treatment and prevention of disorders wherein CCK-B is involved such as anxiety.
The compounds of Formula I may be administered to a human subject either alone or, preferably, in combination with pharmaceutically-acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally o

REFERENCES:
patent: 4847248 (1989-07-01), Freidinger
patent: 5439906 (1995-08-01), Bock et al.

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