Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-01-07
1999-08-10
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514316, 546187, 546189, 546191, 546208, A61K 31445, C07D40106
Patent
active
059359749
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to diphenylmethylene piperidine derivatives, pharmaceutical compositions containing the same, a method of production thereof, and a method of treatment and prophylaxis of psychotic disorders.
BACKGROUND OF THE INVENTION
Related diphenylmethylene piperidine derivatives are known in the art. Notably, related compounds are disclosed in U.S. Pat. No. 4,540,780, and in a divisional thereof U.S. Pat. No. 4,666,905, mentioning diphenylmethylene piperidine derivatives which are useful as anti-emetic, anti-histamine, pulmonary, and antispasmodic agents.
SUMMARY OF THE INVENTION
The present invention relates to diphenylmethylene piperidine derivatives of the formula ##STR2## wherein n is 1 or 2; or a pharmaceutically acceptable salt thereof.
With more preference the diphenylmethylene piperidine derivatives of the invention have both fluorine atoms attached to the para position of the benzene rings.
A preferred compound is the diphenylmethylene piperidine derivative having the formula ##STR3## or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The diphenylmethylene piperidine derivatives of the invention are dopamine receptor antagonists which have strong antipsychotic activity, as is demonstrated in vivo in the apomorphine climbing test (ACT). The ability of dopamine receptor antagonists to inhibit the behavioural effects in rodents caused by dopamine agonists such as apomorphine is a well established criterion for predicting the antipsychotic efficacy of these drugs in man (see e.g. W. C. Bowman and M. J. Rand, Textbook of Pharmacology, 2nd ed., 1980, 15, 6). A particularly relevant test in this respect is the ACT which measures the ability of a dopamine antagonist to inhibit the climbing behaviour in mice, induced by the subcutaneous administration of apomorphine. Activity in this test has been widely used as a predictor of antipsychotic activity i.e anti-schizophrenic activity (see e.g. J. T. Strupczewski et al., J. Med. Chem., 1995, 38, 1119).
The compounds of this invention (entries 1 and 2) were compared with various related diphenylmethylene piperidine derivatives according to U.S. Pat. No. 4,540,780 (entries 3-15), and results are given in the following table:
TABLE I ______________________________________
1 #STR4##
Entry R.sub.1
m X Y n R.sub.2
ACT (sc)
______________________________________
THIS INVENTION
1 F 3 O C 1 H 0.5
2 F 3 O C 2 H 0.5
COMPOUNDS ACCORDING TO U.S. Pat. No. 4,540,780
3 H 3 O C 1 H 2.1
4 H 3 O C 2 H 1.1
5 F 4 O C 1 H 3.7
6 H 2 O C 2 H >22
7 H 4 O C 2 H 3.6
8 H 5 O C 2 H 7.4
9 H 3 O O 2 H 5
10 F 3 O C 2 OH 6.8
11 H 4 O C 2 (CH.sub.3).sub.2
>22
12 H 3 O C 2 (CH.sub.3).sub.2
>22
13 F 3 H.sub.2
C 2 H >22
14 H 3 H.sub.2
C 1 H >22
15 H 3 H.sub.2
C 2 H >22
______________________________________
The five compounds of Table I which have the highest activity after subcutaneous administration, were tested in the ACT after oral administration. The results are given in Table II.
TABLE II ______________________________________
Entry ACT (sc) ACT (po)
______________________________________
1 0.5 2.8
2 0.5 1.4
3 2.1 47
4 1.1 22
7 3.6 33.8
______________________________________
As demonstrated in Table II, the compounds of this invention have good oral activity in comparison with the diphenylmethylene piperidine derivatives according to U.S. Pat. No. 4,540,780. Moreover, the instantly claimed compounds do not exhibit catalepsy, which predicts that they are devoid of unwanted extrapyramidal side effects.
The compounds of the invention can be prepared by methods known in the art, for instance by methods analogous to the preparation as disclosed in U.S. Pat. No. 4,540,780. A suitable method of production is the condensation of 4-bis-(2-, 3-, or 4-fluorophenyl)methylene piperidine or a salt thereof (for instance the hydrochloride), the synthesis of which is disclosed in U.S. Pat. No. 4,540,780, with 1-(4-halo-1-oxobutyl)pyrrolidine (n=1) or 1-(4-halo-1-oxobutyl)
REFERENCES:
patent: 3922276 (1975-11-01), Duncan et al.
patent: 4180583 (1979-12-01), Carr et al.
patent: 4540780 (1985-09-01), Downs et al.
patent: 4666905 (1987-05-01), Downs
Jaap David Robert
Rae Duncan Robertson
Akzo Nobel N.V.
Chang Ceila
Sullivan Michael G.
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