Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-30
2004-12-07
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S368000
Reexamination Certificate
active
06828325
ABSTRACT:
The invention relates to novel phenylpiperazine derivatives of the formula (1):
wherein:
R is a group of the formula (a) or (b)
and salts thereof.
It has been found that the compounds according to the invention show high affinity for both the dopamine D
2
receptor and the serotonin reuptake site. This combination is useful for the treatment of psychotic disorders like schizophrenia (treating both positive and negative symptoms), and other psychiatric disorders.
The compounds show activity as (partial) agonists which makes them suited as well for the treatment of Parkinson's disease.
The compounds show antagonist activity at dopamine D
2
receptors as they antagonize apomorphine-induced climbing behaviour in mice. The compounds also show activity as inhibitors of serotonin reuptake as they potentiate 5-HTP induced behaviour in mice.
The compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g. the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61-67) and antidepressants or anxiolytics (e.g. suppression of stress-induced vocalization; van der Poel et al., Psychopharmacology, 1989, 97: 147-148).
The compounds are active in clinically relevant models for Parkinson's disease (e.g. turning rat behaviour; U. Ungerstedt, Acta Physiol. Scand., 1971, 82 (suppl. 367): 69-93).
In contrast to clinically relevant dopamine D
2
receptor antagonists the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyrimidal side effects than existing antipsychotic agents.
The inhibitory activity of serotonin reuptake inherent in these compounds may be responsible for the therapeutic effects observed in behavioural models sensitive to either antidepressants or anxiolytics.
The compounds can be used for the treatment of affections or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotonergic systems, for example: aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, Parkinson's disease and in schizophrenia and other psychotic disorders.
Pharmacologically acceptable acids with which the compounds of the invention can form suitable acid addition salts are for example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphthalene sulphonic acid.
The compounds and their acid addition salts can be brought into forms suitable for administration by means of suitable processes using auxiliary substances such as liquid and solid carrier materials.
The compounds having formula (1) can be prepared by reaction of a compound of the formula
under basic conditions with a compound of the formula
L−(a) or L−(b)
in which formulae (a) and (b) have the meanings given above, and L is a so-called leaving group such as a halogen atom or a mesylate group.
The piperazine compound having formula (2) can be obtained as described in EP 0189612.
The starting materials of the formula L−(a) can be obtained according to the following scheme:
Compound 1p2 can be obtained from 1p1 in the same manner as compound 2p4, i.e. compound L−(b) wherein L is the mesylate group, from compound 2p3 (see Scheme B below).
The invention is illustrated by means of the following Examples.
REFERENCES:
patent: 0 900 792 (1999-03-01), None
patent: WO 99 67237 (1999-12-01), None
patent: WO 00 23441 (2000-04-01), None
patent: 01/14330 (2001-03-01), None
patent: 03/068207 (2003-08-01), None
Robichaud et al, Annual Reports in Medicinal Chemistry, vol. 35,p. 11-20 (2000).*
TenBrink et al., Annual Reports in Medicinal Chemistry, vol. 29, p. 43-51 (1994).
Feenstra Roelof W.
Kruse Cornelis G.
McCreary Andrew C.
Ronken Eric
van Scharrenburg Gustaaf J. M.
Bernhardt Emily
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Solvay Pharmaceuticals B.V.
LandOfFree
Phenylpiperazines does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Phenylpiperazines, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Phenylpiperazines will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3271840