Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1996-12-09
2003-02-04
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...
C514S341000, C514S254050, C546S207000, C546S208000, C546S209000, C546S210000, C546S274400, C544S370000
Reexamination Certificate
active
06514993
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a novel series of 4-phenylpiperazines, 4-phenylpiperidines and 4-phenyl-1,2,3,6-tetrahydropyridines. Having effects on both central serotonin 5-HT
1A
and dopamine D
2
receptors, the novel compounds are useful in the treatment of certain psychic and neurologic disorders.
BACKGROUND OF THE INVENTION
In International patent publication No. WO 92/03426, a class of piperazine derivatives having phenyl, naphtyl or quinolyl in the 4-position and an N-aryl substituted carbamoyl alkyl group or an N-aryl substituted ureido alkyl group in the 1-position is described. Said compounds are claimed to exhibit affinity for various receptors, including 5-HT
2
, 5-HT
1A
, alpha and dopamine receptors.
EP A1 0376607 relates to certain 1-[4-(3-indolyl)butyl]-4-(2-oxyphenyl)piperazine compounds being partial 5-HT
1A
agonists.
EP A1 0526434 among a number of other compounds, describes 1-[(4-phenylpiperazin-1-yl)-C
2-6
alkyl]-benzimidazol-2-one compounds said to show 5-HT
1A
agonistic activity and 5-HT
2A
antagonistic activity.
U.S. Pat. No. 3,374,237 discloses a class of 1-phenyl-3-(4-phenyl-1-piperazinyl-C
2-4
alkyl)-2-imidazolidinones claimed to be useful as tranquilizers. No test data at all are presented. FR Patents Nos 1.394.708 and 1.513.604, respectively, describe similar compounds without a phenyl substituent in the 4-position of the piperazinyl group and said to possess tranquilizing and psychopharmachodynamic properties, respectively.
AU Patent No 15658/83 discloses 3-(4-phenyl-1-piperazinyl-C
2-4
alkyl)hydantoin compounds having antihypertensive effects.
WO 92/00282 relates to a subgroup of the compounds of U.S. Pat. No. 3,374,237 which are 1-phenyl-3-[4-(4-phenyl-1-piperazinyl)-1-butyl]-2-imidazolidinones having an optional chloro atom in the 2-position of the phenyl substituent in 1-position of the imidazolidinone ring and a methoxy or ethoxy substituent in the 2- and/or 3-position of the other phenyl substituent. The compounds show dopaminergic effects.
Clinical studies of known 5-HT
1A
partial agonists such as e.g. buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione, gepirone, 4,4-dimethyl-1-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-2,6-piperidinedione, and ipsapirone, 2-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3(2H)-one-1,1-dioxide, have shown that 5-HT
1A
partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R.,
Drugs
1991, 41, 11). Preclinical studies indicate that also full agonists are useful in the treatment of the above mentioned anxiety related disorders (Schipper,
Human Psychopharmacol
., 1991, 6, S53).
There is also evidence, both clinical and preclinical, in support of the beneficial effect of 5-HT
1A
agonists in the treatment of depression, impulse control disorders and alcohol abuse (van Hest,
Psychopharmacol
., 1992, 107, 474; Schipper et al,
Human Psychopharmacol
., 1991, 6, S53; Cervo et al,
Eur. J. Pharmacol
., 1988, 158, 53; Glitz, D. A., Pohl, R.,
Drugs
1991, 41, 11; Grof et al.,
Int. Clin.Psychopharmacol
. 1993, 8, 167-172; Ansseau et al.,
Human Psychopharmacol
. 1993, 8, 279-283).
5-HT
1A
agonists and partial agonists inhibit isolation-induced aggression in male mice indicating that these compounds are useful in the treatment of aggression (Sanchez et al.,
Psychopharmacology
, 1993, 110, 53-59).
Furthermore, 5-HT
1A
agonists have been reported to show antipsychotic effect in animal models (Wadenberg and Ahlenius,
J. Neural. Transm
., 1991, 83, 43; Ahlenius,
Pharmacol
.&
Toxicol
., 1989, 64, 3; Lowe et al.,
J. Med. Chem
., 1991, 34, 1860; New et al.,
J. Med. Chem
., 1989, 32, 1147; and Martin et al.,
J. Med. Chem
., 1989, 32, 1052) and recent studies also indicate that 5-HT
1A
receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks,
Life Science
1990, 47, 1609, Wadenberg et al.
Pharmacol. Biochem
. &
Behav
. 1994, 47, 509-513) suggesting that 5-HT
1A
agonists are useful in the treatment of the extrapyramidal side effects (EPS) induced by conventional antipsychotic agents such as haloperidol.
Damping of dopamine (DA) overactivity by the use of DA receptor blocking drugs is today the most important principle in the treatment of schizophrenia, in particular the positive symptoms thereof, and other psychoses. “Classical neuroleptics” such as haloperidol, cis(Z)-flupentixol and chlorpromazine are believed to induce antipsychotic effect via DA receptor blockade. Unfortunately, these classical neuroleptics also induce EPS, which seem to be correlated to the propensity of these compounds to induce catalepsy in rodents (Arnt et al.
Neuropharmacology
, 1981, 20, 1331-1334). A combination of 5-HT
1A
receptor agonism which may prevent EPS in man (cf. above) and dopamine receptor blockade to treat the positive symptoms of schizophrenia would thus be very advantageous.
Furthermore, 5-HT
1A
agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn,
Eur. J. Pharm
. 1991, 203, 213).
Pharmacological studies have been presented which indicate that 5-HT
1A
antagonists are useful in the treatment of senile dementia (Bowen et al,
Trends Neur. Sci
. 1992, 15, 84).
Both in animal models and in clinical trials, it has been shown that 5-HT
1A
agonists exert antihypertensive effects via a central mechanism (Saxena and Villalón,
Trends Pharm. Sci
. 1990, 11, 95; Gillis et al,
J. Pharm. Exp. Ther
. 1989, 248, 851. 5-HT
1A
ligands may, therefore, be beneficial in the treatment of cardiovascular disorders.
Accordingly, agents acting both on the 5-HT
1A
receptor, including agonists, partial agonists and antagonists, and at the same time blocking the dopamine D
2
receptor are believed to be of potential use in the therapy of such conditions, in particular in the treatment of psychosis, and thus being highly desired.
SUMMARY OF THE INVENTION
It has now been found that a novel series of phenylpiperazines, 4-phenylpiperidines and 4-phenyl-1,2,3,6-tetrahydropyridines posseses both central serotonergic 5-HT
1A
and antidopaminergic D
2
activity.
Accordingly, the present invention relates to novel 4-phenylpiperazine, 4-phenylpiperidine and 4-phenyl-1,2,3,6-tetrahydropyridine compounds of general Formula I:
wherein A is a spacer group selected from branched or straight chain C
3-8
alkylene, C
3-8
alkenylene and C
3-8
alkynylene, and C
3-7
cycloalkylene, said spacer group being optionally substituted with lower alkyl, aryl or hydroxy;
R
1
is a branched C
3-10
alkyl, C
3-10
alkenyl or C
3-10
alkynyl group, cycloalk(en)yl, cycloalk(en)yl-lower alk(en/yn)yl, trifluoromethylsulfonyl, or lower alkylsulfonyl,
R
2
-R
5
are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, lower alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy, cycloalkyl, cycloalkyl-lower alkyl, nitro, lower alkylamino, di-lower-alkylamino and trifluoromethylthio;
R
9
and R
10
are independently hydrogen, lower alkyl or they may be linked together, thereby forming an ethylene or propylene bridge;
W is O or S;
V is O, S, CR
6
R
7
, or NR
8
wherein R
6
, R
7
, and R
8
are independently chosen among hydrogen or lower alkyl or lower alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl-lower-alkyl or aryl, or R
6
and R
7
are linked together to constitute a 3-7 membered spirojoined ring;
Z is —(CH
2
)
m
—, m being 2 or 3 or Z is —CH═CH—;
the dotted line, emanating from X, indicates an optional bond and when it does not indicate a bond X is N or CH and when it indicates a bond X is C;
any alkyl, cycloalkyl or cycloalkylalkyl group present being op
Moltzen Ejner Knud
Perregaard Jens Kristian
Bernhardt Emily
Darby & Darby
H. Lundbeck A/S
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