1,4-Cycloalkano-oxazepines, salts thereof and analgesic uses the

Details 1,4-Cycloalkano-oxazepines, salts thereof and analgesic uses the 1,4-Cycloalkano-oxazepines, salts thereof and analgesic uses the

1980-06-26

1982-06-22

Milestone, Norma S.

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

2603308, C07D26714, C07D26712, A61K 31395

Patent

active

043362630

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The invention relates to novel 1,4-cycloalkano-oxazepines, processes for their preparation and their use in combating pain (algias).


PRIOR ART

German Pat. No. 1,620,198 discloses that certain benzoxazocines have an analgesic action. The best-known of these compounds is Nefopam (5-methyl-1-phenyl-3,4,5,6-tetrahydro-1H-benz[f]-2,5-oxazocine).


DESCRIPTION OF INVENTION

We have found compounds which are substantially more active than Nefopam.
The present invention relates to 1,4-cycloalkano-oxazepines of the general formula I ##STR2## where R.sup.1 is hydrogen, hydroxyl or alkoxy or acyloxy of 1 to 4 carbon atoms, R.sup.2 is a hydrocarbon radical of 1 to 3 carbon atoms, n is 1, 2 or 3 and x is 0 or 1, and of their salts with physiologically acceptable acids. The invention also relates to a process for the preparation of the 1,4-cycloalkano-oxazepines of the general formula I, wherein a compound of the general formula II ##STR3## where R.sup.3 is hydrogen or alkoxy of 1 to 4 carbon atoms and R.sup.4 is a hydrocarbon radical of 1 to 3 carbon atoms or is benzyl, is reduced, after which, where appropriate, alkoxy is replaced by hydroxyl or acyloxy and/or benzyl is replaced by a hydrocarbon radical and, if desired, the resulting compound is converted to a salt with a physiologically acceptable acid.
Finally, the invention also relates to pharmaceuticals containing 1,4-cycloalkano-oxazepines of the general formula I and to the use of the novel substances in combating pain (algias).
The compounds I contain two asymmetric carbon atoms, so that they can in principle form two diastereomeric series. The present invention only relates to those compounds in which the two rings are cis-linked to one another. The novel compounds can be prepared in the form of their racemates and in the form of their antipodes.
A strong reducing agent, eg. diborane or, preferably, lithium aluminum hydride, is required for reducing a compound II. Particularly suitable solvents are tetrahydrofuran, dimethoxyethane, dioxane and ether.
The reduction takes place at an elevated temperature, preferably at the boiling point of the solvent.
A benzyl radical in the 4-position can easily be removed by catalytic hydrogenation. The hydrogenation may be carried out in an alcohol, eg. methanol or ethanol, or in acetic acid as the solvent, preferably at room temperature, and using a noble metal of main group 8 of the periodic table, preferably Pd/charcoal, as the catalyst.
The resulting secondary amine can be alkylated by means of an alkyl halide in the presence of an acid acceptor, such as an alkali metal carbonate, alkali metal hydroxide or tertiary amine, in a solvent such as methyl isobutyl ketone, at about 0.degree.-150.degree. C., preferably at about 80.degree. C. The alkylation can also be effected by reaction with a carboxylic acid followed by reduction of the C.dbd.O group with lithium aluminum hydride.
The replacement of methoxy by hydroxyl may be carried out with, for example, sodium methylmercaptide, in a dipolar aprotic solvent, eg. hexamethylphosphorotriamide, dimethylsulfoxide or dimethylformamide, at 50.degree.-200.degree. C., preferably 80.degree.-150.degree. C.
Virtually all conventional methods may be employed for acylating the free hydroxyl groups. The simplest method is to react such groups with an acid anhydride or acid halide at an elevated temperature.
The starting materials of the general formula II, required for the preparation of the novel compounds, have not previously been described. They may be prepared as follows:
A Mannich compound of the formula III is prepared from a cycloalkanone, formaldehyde and a secondary benzylamine derivative (cf. Organic Reactions I (1942), British Pat. No. 615,136, J. Chem. Soc. 1950, 1512 and J. Org. Chem. 24, (1959), 1069): ##STR4## Reaction of III with an appropriate Grignard compound gives the compound IV (cf. J. Am. Chem. Soc. 71 (1949), 2050, British Pat. No. 997,399, German Pat. No. 1,199,764 and Arzneim. Forsch. 28 (1978), 107): ##STR5## from which the benzyl radical is

REFERENCES:
patent: 3598808 (1971-08-01), Szmuszkovicz
patent: 3830803 (1974-08-01), Klohs et al.

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