Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-02
2002-07-02
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S238000
Reexamination Certificate
active
06413966
ABSTRACT:
The present invention relates to the preparation of new arylpiperazinylalkyl-3(2H)-pyridazinones and their addition salts. The new compounds present serotonergic and central dopaminergic activity, which makes them useful as antipsychotics.
The most widely accepted theory explaining the biochemical bases of schizophrenia holds that the dopaminergic activity in the mesolimb system of the brain is increased and, accordingly, the pharmacological power of classic antipsychotics is correlated with their affinity for D
2
receptors (Science 1976, 1982, 481-483). It has further been proposed (J. Pharm. Exp. Ther., 1989, 251, 238-246) that the high affinity for 5HT
1A
receptors is responsible for the beneficial effects of the pharmacological profile of atypical antipsychotics. It has moreover been found (J. Neurol. Transm., 1983, 57, 255) that
5
HT
1A
agonists are capable of inverting haloperidol-induced catalepsy. Consequently, many compounds composite affinity for 5HT
1A
, 5HT
2
and D
2
receptors, claimed as atypical antipsychotics (Advances in Med. Chem., 3, 1995, 1-55).
Antipsychotic compounds heretofore described belong in several chemical families, which are only sometimes interrelated, with structures differing essentially from the 3(2H)-pyridazinones subject of this invention.
European Patent EP 0329168 describes a number of 1,4-disubstituted piperazines with psychotropic activity, in which the 1-substituent is a bicyclic heterocycle which incorporates an amide or imide function and the 4-substituent is another heterocycle, which differ from those described herein, wherein the alkyl-3(2H)-pyridazinone fragment is the 1-substituent and a non-heterocyclic cyclic system is the 4-substituent.
J. Med. Chem. 1994, 37, 1060-1062 describes a number of phenylpiperazines having a high affinity for D
2
, D
3
, 5HT
1A
and &agr;
1A
receptors, providing them with interesting antipsychotic properties, moreover presenting a low potential for causing extrapyramidal effects. These phenylpiperazines are clearly distinguished from those described herein in the fragment bound to piperazine.
Patent WO 93/16073 claims arylpiperidines and arylpiperazines with D
2
and 5HT
2
receptor antagonist properties, useful in the treatment of psychosis, though said compounds are characterised by having a heterobycyclic system at the 4-position of piperazine or piperidine, which clearly distinguishes them from the compounds described in the present invention.
Patent ES 9700812 (C.A.: 129:343506) finally describes a number of naphthylpiperazines having a high affinity for 5HT
1A
, 5HT
2
and D
2
receptors, potentially useful as antipsychotics, containing a phthalazinone rest in their structure which characterises them as to their chemical structure and distinguishes them from those described herein.
In existing reference works a number of 1-aminoalkyl-3(2H)-pyridazinones carrying a [1,4]-benzodioxanylmethylamine or phenoxyalkylamine group can also be found, as contained in Eur. J. Med. Chem. 1992, 27, 107-114, although they are described as blocking &agr;-adrenoreceptors and having antihypertensive activity, distinguishing them pharmacologically from those described herein, since those claimed in the present invention have affinity for dopamine and serotonin receptors, with respect to the central nervous system. Furthermore, these pyridazinones are structurally different from those described in the present invention, due to the presence of the benzodioxanylmethylamine or phenoxyalkylamine fragment, whereas those described herein carry a diversely substituted arylpiperazinoalkyl fragment.
The compounds described in the present invention are essentially different from all those referred to in the above-mentioned publications. due to the presence of the 3(2H)-pyridazinone grouping, which pharmacologically characterises them and provides them with a great affinity for serotonin 5HT
1A
and 5HT
2
receptors as well as dopamine D
2
receptors, and they are therefore useful as atypical antipsychotics.
DESCRIPTION
The present invention relates to the preparation of new arylpiperazinylalkyl-3(2H)-pyridazinones of formula (I) and their addition salts with pharmaceutically acceptable acids,
in which R
1
is a methyl or phenyl group,
R
2
is a hydrogen atom or a methyl group
n takes values between 2 and 4
and R
3
is a naphthyl radical or a phenyl radical which may be substituted by a radical such as methoxyl, chlorine, trifluoromethyl.
The preparation of compounds of formula (I) can be carried out along various synthetic routes, using conventional methods:
Condensation of a compound of formula (II)
in which R
1
, R
2
and n have the meaning specified for formula (I) and Z is chlorine or bromine, with a piperazine of formula (III)
The reaction is carried out in an inert solvent, in the presence of a base, and at a temperature ranging between 20° C. and the boiling point of the reaction mixture.
The solvent used is dichloromethane, chloroform, acetonitrile, dimethylformamide or tetrahydrofurane.
The base used can be an alkaline carbonate or bicarbonate, such as K
2
CO
3
, KHCO
3
, Na
2
CO
3
, NaHCO
3
or a tertiary amine such as pyridine or triethylamine.
The reaction rate may be increased by adding catalytic amounts of an alkaline iodide, such as KI to the reaction mixture.
The piperazines of formula (III) are commercially available, when R
3
is phenyl or phenyl-substituted, and are prepared by reacting bis (2-chloroethyl)amine with the conveniently substituted naphthylamine., when R
3
is naphthyl or naphthyl-substituted.
The compounds of general formula (II) used at the previous condensation stage are prepared by reactin compound of general formula (IV)
in which R
1
and R
2
have been previously defined, with an alkyl dihalide in the presence of a strong base, such as NaH in an aprotic solvent such as dimethylformamide or tetrahydrofurane, or solid potassium hydroxide in dimethylformamide, at a temperature ranging between room temperature and 100° C.
The compounds of general formula (IV) are commercially available or are prepared by reacting suitable 2-benzoylpropionic acids with hydrazine hydrate.
Alternately, compounds of general formula (II) can be prepared by means of a substitution of the hydroxyl group with chlorine or bromine in compounds of formula (V), obtained in accordance with the method described in Chimie Therapeutique, 1967, 2, 250-253.
The substitution reaction can be carried out by treatment of (V) with hydrogen chloride, hydrogen bromide, with organic or inorganic acid halides, such as oxalyl chloride or thionyl chloride, in an inert solvent such as chloroform, dichloromethane, or toluene, or using the acid chloride as a solvent, at a temperature ranging between 0° C. and the boiling point of the reaction mixture.
Pharmacological Studies
As noted hereinbefore, the new compounds of general formula (I), in accordance with the present invention, show SNC activity, more specifically at the 5HT
1A
, 5HT
2
and D
2
receptor levels.
Binding studies of the compounds described in the present invention have been carried out to ascertain the affinity of the compounds for 5HT
1A
, 5HT
2
and D
2
receptors.
5HT
1A
Receptor
Cerebral cortex taken from both male and female Wistar rats was homogenised in saccharose buffer 0.32 M (1:10 g/mL) and centrifuged at 900 g (10 min, 4° C. ). The supernatant was collected and centrifuged at 48000 g (25 min, 4° C. ). The sediment thus obtained was re-suspended in cold TRIS buffer 50 mM (pH 7.5, 1:10, g/mL), homogenised, incubated at 37° C. for 15 min and centrifuged again at 48000 g (25 min, 4° C. ). The final sediment was re-suspended in cold SNAYDER buffer (1:4, g/mL), homogenised and kept at −70° C. in 5 mL containers.
For the displacement trial, 100 &mgr;L of radioligand (2 nM, final conc.), 100 &mgr;L of the different tested concentrations of the displacing product and 750 &mgr;L of a suspension of membranes 1:32 in SNAYDER with pargilin were used. The volume was topped up to 1 mL with 50 &mgr;L of SNAYDER. Serotonin (5HT) 10 &mgr;M was used t
Garcia-Dominguez Neftali
Orjales Venero Aurelio
Bernhardt Emily
FAES, Fabrica Espanola de Productos Quimicos y Farmaceuticos, S.
Lackenbach & Siegel LLP
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