4,5,6,11-tetrahydrobenzo [6,7] cycloocta [1,2-b]thiophen-6,11-im

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

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540581, C07D51322, A61K 3138

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active

052603091

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,414,154 refers to compounds of the formula ##STR2##
The compounds are said to be useful as anticonvulsants, anxiolytics and antidepressants. The foregoing compounds do not have a thiophene ring as part of the tricyclic ring system.
U.S. Pat. No. 4,252,810 refers to compounds of the formula ##STR3## The compounds are said to be useful as antianxiety agents and as muscle relaxants. The compounds of the '810 patent have a different orientation of the thiophene ring than the compounds of the present invention as well as a cyclohepta-rather than a cycloocta-ring as part of the bridged tricyclic ring system.


SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR4## wherein the broken line represents an optional double bond, R.sup.1 and R.sup.4 are independently selected from hydrogen and C.sub.1 to C.sub.6 alkyl, and R.sup.2 and R.sup.3 are independently selected from hydrogen, C.sub.1 to C.sub.6 alkyl, halogen (e.g., fluoro, chloro, bromo and iodo), C.sub.1 to C.sub.6 alkoxy and C.sub.1 to C.sub.6 alkylthio, and pharmaceutically acceptable salts thereof.
Preferred compounds are compounds of the Formula I wherein R.sup.1 equals hydrogen. More preferably, R.sup.1 equals hydrogen and R.sup.4 equals methyl.
Specific preferred compounds of the present invention are the following:
11-methyl-4,5,6,11-tetrahydrobenzo[6,7]cycloocta[2-b]thiophen-6,11-imine;
8-fluoro-11-methyl-4,5,6,11-tetrahydrobenzo[6,7]-cycloocta[1,2-b]thiophen-6 ,11-imine; and
8,11-dimethyl-4,5,6,11-tetrahydrobenzo[6,7]-cycloocta[1,2-b]thiophen-6,11-i mine.
The (+) isomer of 11-methyl-4,5,6,11-tetrahydrobenzo[6,7]cycloocta[1,2,-b]thiophen-6,11-imin e is particularly preferred.
The present invention also relates to a pharmaceutical composition for the treatment of cerebral ischemia, Alzheimer's disease or convulsions comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof that is effective in preventing neuronal damage following cerebral ischemia or during the progression of Alzheimer's disease or in preventing convulsions and a pharmaceutically acceptable carrier. Preferred compositions of the present invention contain the foregoing preferred and specific preferred compounds.
The present invention also relates to a method for the treatment of cerebral ischemia, Alzheimer's disease or convulsions, comprising administering an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof that is effective in preventing neuronal damage following cerebral ischemia or during the progression of Alzheimer's disease or in preventing convulsions.
The present invention also relates to a process for the preparation of formula I and pharmaceutically acceptable salts thereof.
The present invention also relates to novel intermediates in the preparation of formula I. Such intermediates are compounds of the formula ##STR5## wherein R.sup.4 equals hydrogen or methyl, R.sup.3 equals hydrogen, fluorine or methyl and R.sup.1 is a protecting group such as CO.sub.2 CH.sub.2 CCl.sub.3.


DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may be prepared as shown in the reaction scheme set forth below: ##STR6##
The first step in the sequence involves dilithiation of the appropriate N-silyl benzenemethanamine derivative of Formula II by treatment of Formula II with at least 2 equivalents of an alkyl lithium reagent, preferably commercial n-butyl lithium sold as a solution in hexane. Suitable solvents include anhydrous dialkyl ethers, tetrahydrofuran, saturated hydrocarbons or any combination thereof. To facilitate the lithiation, 0.5 to 1.0 equivalents of tetramethylethylenediamine may be used as a co-solvent. The lithiation process is generally carried out at temperatures ranging from about 0.degree. C. to the boiling point of the solvent being used, although temperatures down to minus 78.degree. C. may be used if desired. When the reaction is carried out at room temperature, a period of about 2 hours is g

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