Indian Patents. 222625:PHENYLPIPERAZINE DERIVATIVE & A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

Title of Invention	PHENYLPIPERAZINE DERIVATIVE & A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
Abstract	Phenylpiperazine derivative & a pharmaceutical composition comprising the same The present invention relates to a phenylpiperazine derivative of the formula I and to a phyrmaceutical composition comprising the pheylpiperazine derivative ands at least one pharmaceuticeuically acceptable auxiliary substance.

Full Text	The invention relates to the novel phenylpiperazine derivative of the formula (I): Patent application wO 01/14330 relates a group of novel phenyl piperazines. The compounds of that group show high affinity for both the dopamine D2 receptor and the serotonin reuptake site. This combination is useful for the treatment of schizophrenia and other psychotic disorders which enables a more complete treatment of all disease symptoms (e.g. positive symptoms and negative symptoms). The compounds show activity as antagonists at dopamine D2 receptors as they potentially antagonize apomorphine-induced climbing behaviour in mice. The compounds also show activity as inhibitors of serotonin reuptal^e, 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). In contrast to clinically relevant dopamine D2 receptor antagonists the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramidal 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 particular schizophrenia and other psychotic disorders. It has now been found that the mesylate of the above formula has particularly favourable properties In comparison with the free base (I.e. compound no. 89 of EP 99202710.2). This mesylate compound is much better soluable in water than the free base resulting in a good bio- availability. The compound has a centre of chirality; both the racemic mixture and the individual enantiomers belong to the Invention. The compound can be brought into forms suitable for administration by means of suitable processes using auxiliary substances such as liquid and solid carrier materials. The free base of compounds can be prepared as described in EP 99202710.2 The free base can be converted into the mesylate according to processes known per se for salt formation. The invention is illustrated by means of the following Example. Example 2.0 g (4.7 mmol) of the free base obtainable as described in EP 99202710.2 (compound no. 89) is suspended in 40 ml of methanol. The suspension Is warmed to 60 °C, and a solution of 0.45 g (4.7 mmol) of methanesulfonic acid In 10 ml of methanol is added in about two minutes. A clear solution is obtained. After stirring for 5 minutes at 60 °C the crystallization begins. The solution is cooled slowly in 60 minutes to 20 °C. and stinred at that temperature for 30 minutes. Further cooling to 0 °C in 60 minutes and stirring for 90 minutes is carried out. The solid material is isolated by means of filtration, washed with 5 ml of methanol and dried during a night at 50 °C under reduced pressure. Yield 2.17 g (88%) of white coloured mesylate. WE CLAIM: 1. A phenylpiperazine derivative of the formula I 2. A pharmaceutical composition comprising the compound of claim 1, and at least one pharmaceutically acceptable auxiliary substance.

Full Text

The invention relates to the novel phenylpiperazine derivative of the formula (I):

Patent application wO 01/14330 relates a group of novel phenyl piperazines. The compounds of that group show high affinity for both the
dopamine D2 receptor and the serotonin reuptake site. This combination is useful for the treatment of schizophrenia and other psychotic disorders which enables a more complete treatment of all disease symptoms (e.g. positive symptoms and negative symptoms).
The compounds show activity as antagonists at dopamine D2 receptors as they potentially antagonize apomorphine-induced climbing behaviour in mice. The compounds also show activity as inhibitors of serotonin reuptal^e, 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).
In contrast to clinically relevant dopamine D2 receptor antagonists the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramidal 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 particular schizophrenia and other psychotic disorders.
It has now been found that the mesylate of the above formula has particularly favourable properties In comparison with the free base (I.e. compound no. 89 of EP 99202710.2).
This mesylate compound is much better soluable in water than the free base resulting in a good bio- availability.
The compound has a centre of chirality; both the racemic mixture and the individual enantiomers belong to the Invention.
The compound can be brought into forms suitable for administration by means of suitable processes using auxiliary substances such as liquid and solid carrier materials.
The free base of compounds can be prepared as described in EP 99202710.2
The free base can be converted into the mesylate according to processes known per
se for salt formation.
The invention is illustrated by means of the following Example.
Example
2.0 g (4.7 mmol) of the free base obtainable as described in EP 99202710.2 (compound no. 89) is suspended in 40 ml of methanol. The suspension Is warmed to 60 °C, and a solution of 0.45 g (4.7 mmol) of methanesulfonic acid In 10 ml of methanol is added in about two minutes. A clear solution is obtained. After stirring for 5 minutes at 60 °C the crystallization begins. The solution is cooled slowly in 60 minutes to 20 °C. and stinred at that temperature for 30 minutes. Further cooling to 0

°C in 60 minutes and stirring for 90 minutes is carried out. The solid material is isolated by means of filtration, washed with 5 ml of methanol and dried during a night at 50 °C under reduced pressure. Yield 2.17 g (88%) of white coloured mesylate.

WE CLAIM:
1. A phenylpiperazine derivative of the formula I
2. A pharmaceutical composition comprising the compound of claim 1, and at least one pharmaceutically acceptable auxiliary substance.

Documents:

1281-chenp-2003 abstract duplicate.pdf

1281-chenp-2003 claims duplicate.pdf

1281-chenp-2003 description (complete) duplicate.pdf

1281-chenp-2003-abstract.pdf

1281-chenp-2003-claims.pdf

1281-chenp-2003-correspondnece-others.pdf

1281-chenp-2003-correspondnece-po.pdf

1281-chenp-2003-description(complete).pdf

1281-chenp-2003-form 1.pdf

1281-chenp-2003-form 26.pdf

1281-chenp-2003-form 3.pdf

1281-chenp-2003-form 5.pdf

1281-chenp-2003-other documents.pdf

1281-chenp-2003-pct.pdf

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Patent Number

222625

Indian Patent Application Number

1281/CHENP/2003

PG Journal Number

47/2008

Publication Date

21-Nov-2008

Grant Date

20-Aug-2008

Date of Filing

14-Aug-2003

Name of Patentee

SOLVAY PHARMACEUTICALS B.V.

Applicant Address

C.J. van Houtenlaan 36, NL-1381 CP Weesp,

Inventors:

#	Inventor's Name	Inventor's Address
1	BAKKER, Cornelis	C.J. van Houtenlaan 36, NL-1381 CP Weesp,

PCT International Classification Number

C07D413/12

PCT International Application Number

PCT/EP2002/001795

PCT International Filing date

2002-02-19

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	01200610.2	2001-02-21	EUROPEAN UNION