Isoxazole derivatives

Details Isoxazole derivatives Isoxazole derivatives

1981-04-14

1983-08-09

Bond, Robert T.

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

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

424251, 424263, 424267, 424272, 544300, 544344, 546187, 546193, 546194, 546199, 546209, 546256, 546275, 546 17, 546 20, 548240, 548247, A61K 31495, C07D47120

Patent

active

043978533

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD AND DISCLOSURE OF THE INVENTION

This invention relates to novel isoxazole derivatives having spontaneous locomotor suppressing activity, anti-apomorphine activity, and like activity useful as drugs such as psychotropic agents and antiemetic agents and are represented by the general formula ##STR2## and pharmaceutically acceptable acid addition salts thereof. The invention also relates to a process for preparing these compounds.
In the foregoing formula, Ar represents a phenyl group optionally containing a lower alkoxy group or a halogen atom as a substituent, or a pyridyl group, R.sup.1 represents a hydrogen atom, a lower alkyl group or a group represented by Ar, R.sup.2 represents a hydrogen atom or alternatively R.sup.1 and R.sup.2 are bound together and form a carbon-carbon bond, and Am represents an amino residue selected from the group consisting of the following residues: ##STR3## wherein R.sup.3 represents a hydrogen atom or a lower alkyl group, X.sup.1 and X.sup.2 each represent a hydrogen atom, a halogen atom or a trifluoromethyl group, and Y represents O or S.
The term "halogen" herein includes fluorine, chlorine, bromine, etc. The term "lower alkoxy" herein represents a methoxy, ethoxy, propoxy, butoxy, etc. The term "lower alkyl" herein represents methyl, ethyl, propyl, butyl, etc.
The compounds of the formula (I) may be prepared by reacting a compound of the formula ##STR4## wherein Ar, R.sup.1 and R.sup.2 are defined as above and Z represents a halogen atom or an organic sulfonyloxy group (e.g. tosyloxy, mesyloxy, etc.), with a compound of the formula
The reaction may be carried out usually in a solvent such as methanol, ethanol, isopropanol, benzene, toluene, xylene, dimethylformamide, chloroform, dichloroethane, acetone, methyl ethyl ketone, etc., at a temperature between room temperature and 140.degree. C., preferably between 50.degree. C. and 110.degree. C., in the presence of potassium carbonate, sodium carbonate, triethylamine or like acid acceptor, for 1 to 48 hours, preferably 4 to 18 hours. The reaction may be accelerated by the use of a catalyst. Examples of such catalyst are potassium iodide, sodium iodide, etc.
The compound of the formula (I) may be converted into an acid addition salt. Typical examples of such an acid addition salt which is pharmaceutically acceptable are salts formed with use of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, maleic acid, oxalic acid, succinic acid, fumaric acid, acetic acid, lactic acid and citric acid.
The experiments carried out for demonstrating anti-apomorphine activity of the compounds of this invention in mice will be described below.
Groups of 5 male dd-mice (20-25 g body weight) each were used. Apomorphine hydrochloride (0.5 mg/kg) was subcutaneously administered 60 minutes after oral administration of test compound. Immediately after the apomorphine treatment, motor activity was determined for 20 minutes by animex. For the control groups, 0.5% methylcellulose solution was administered instead of test compound. The ED.sub.50, a dose which inhibited the motor activity by 50% as compared with the control, was determined.


______________________________________ Anti-apomorphine activity Compound ED.sub.50 (mg/kg, p.o.) ______________________________________ A 1.7 B 2.1 C 3.4 Clozapine 10 ______________________________________ A:1-[5(4-Fluorophenyl)-4,5-dihydroisoxazol-3-ylmethyl4-(2-oxo-1-benzimida olinyl)piperidine fumarate B:1[5(4-Fluorophenyl)-4,5-dihydroisoxazol-3-ylmethyl4-(5-fluoro-2-oxo-1-b nzimidazolinyl)piperidine maleate C:1[5(4-Fluorophenyl)-4,5-dihydroisoxazol-3-ylmethyl4-(4-chlorophenyl)-4- ydroxypiperidine fumarate
The compounds of the formula (II) are novel and may be prepared, for example, by reducing a compound of the formula ##STR5## wherein Ar, R.sup.1 and R.sup.2 are as defined above and R represents a lower alkyl group, with use of sodium borohydride etc., and reacting the resulting compound of the formula ##STR6## wherein Ar, R.sup.1 and

REFERENCES:
patent: 3890323 (1975-06-01), Yamamoto et al.

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