Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-03
2001-06-26
Bernhardt, Emily (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S373000
Reexamination Certificate
active
06251908
ABSTRACT:
The invention relates to piperazine derivatives of the formula I
in which
R
1
is an indol-3-yl radical which is unsubstituted or mono- or disubstituted by Hal, CN, A, AO, OH, CONH
2
, CONHA, CONA
2
, COOH, COOA, CH
2
OH, CH
2
OA, CH
2
NH
2
, CH
2
NHA and/or CH
2
NA
2
,
R
2
is 2-oxo-2H-1-benzopyran-6-yl or 2-oxo-2H-1-benzopyran-4-yl, which is unsubstituted or mono- or disubstituted by A, AO, OH, Hal, CN, NO
2
, NH
2
, NHA, NA
2
, COA, CONH
2
, CONHA, CONA
2
, CH
2
OH, CH
2
OA, CH
2
NH
2
, CH
2
NHA, CH
2
NA
2
, COOH and/or COOA,
Hal is F, Cl, Br or I,
A is straight-chain or branched alkyl having 1-10 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms, or is cycloalkyl having 3-10 C atoms,
m is 2, 3 or 4
and their physiologically acceptable salts.
The invention was based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their physiologically acceptable acid addition salts have valuable pharmacological properties. The compounds of the formula I affect serotonin-ergic transmission. Since the compounds also inhibit serotonin reuptake, they are suitable, in particular, as antidepressants and anxiolytics. The compounds exhibit serotonin-agonistic and -antagonistic properties ties. They inhibit the binding of tritiated serotonin ligands to hippocampal receptors (Cossery et al., European J. Pharmacol. 140 (1987), 143-155) and inhibit synaptosomal serotonin reuptake (Sherman et al., Life Sci. 23 (1978), 1863-1870). Additionally, changes in DOPA accumulation in the striatum and 5-HT accumulation in various brain regions occur (Seyfried et al., European J. Pharmacol. 160 (1989), 31-41). The 5-HT
1A
-antagonistic action is demonstrated in vitro, for example, by inhibition of the abolition of the electrically induced contraction of the guinea-pig ileum caused by 8-OH-DPAT (Fozard and Kilb-nger, Br. J. Pharmacol. 86 (1985) 601P). Ex-vivo, the inhibition of the 5-HTP accumulation decreased by 8-OH-DPAT serves for the demonstration of the 5-HT
1A
antagonistic action (Seyfried et al., European J. Pharmacol. 160 (1989), 31-41) and the antagonism of the effects induced by 8-OH-DPAT in the ultrasonic vocalization test (DeVry, Dsychpharmacol. 121 (1995), 1-26). For the ex-vivo demonstration of serotonin reuptake inhibition, synaptosomal uptake inhibition (Wong et al., Neuropsychopharmacol. 8 (1993), 23-33) and p-chloro-amphetamine antagonism (Fuller et al., J. Pharmacol. Exp. Ther. 212 (1980), 115-119) are used. Furthermore, analgesic and hypotensive actions occur.
The compounds are therefore suitable for the treatment of schizophrenia, cognitive deficits, anxiety, depression, nausea, tardive dyskinesias, gastrointestinal tract disorders, learning disorders, age-dependent memory disorders, psychoses and for positively affecting obsessive-compulsive disorder (OCD) and eating disorders (e.g. bulimia). They exhibit actions on the central nervous system, especially additional 5-HT
1A
-agonistic and 5-HT-reuptake-inhibiting actions. They are also suitable for the prophylaxis and for the control of the sequelae of cerebral infarcts (cerebral apoplexy) such as stroke and cerebral ischaemias, and for the treatment of extrapyramidal motor side effects of neuroleptics and of Parkinson's disease.
The compounds of the formula I are therefore suitable both in veterinary and in human medicine for the treatment of functional disorders of the central nervous system and of inflammation. They can be used for the prophylaxis and for the control of the sequelae of cerebral infarcts (cerebral apoplexy) such as stroke and cerebral ischaemias and for the treatment of extrapyramidal/motor side effects of neuroleptics and of Parkinson's disease, for the acute and symptomatic therapy of Alzheimer's disease and for the treatment of amyotrophic lateral sclerosis. Likewise, they are suitable as therapeutics for the treatment of brain and spinal cord traumata. However, they are also suitable as pharmaceutical active compounds for anxiolytics, antidepressants, antipsychotics, neuroleptics, anti-hypertensives and/or for positively affecting obsessive-compulsive disorder, sleep disorders, tardive dyskinesias, learning disorders, age-dependent memory disorders, eating disorders such as bulimia and/or sexual function disorders.
The invention relates to piperazine derivatives of the formula I and to their physiologically acceptable acid addition salts.
The invention relates in particular to compounds of the formula I selected from the group
a) 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]butyl}indole-5-carbonitrile;
b) 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]butyl}-5-fluoroindole;
c) 3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinyl]butyl}indole-5-carbonitrile;
d) 3-{4-[4-(7-hydroxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]butyl}indole-5-carbonitrile;
and their physiologically acceptable salts.
For all radicals which occur several times, such as, for example, A, it is a condition that their meanings are independent of one another.
The radical A is alkyl and has 1 to 10, preferably 1, 2, 3, 4, 5 or 6, in particular 1 or 2, C atoms. Alkyl is therefore in particular, for example, methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl and further also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, and further also fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trichloroethyl or pentafluoroethyl.
Cycloalkyl is in particular, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 1-adamantyl.
OA is preferably methoxy, and further also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. NHA is preferably methylamino, and further ethylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino or tert-butylamino. NA
2
is preferably dimethylamino, and further N-ethyl-N-methylamino, diethylamino, di-n-propylamino, diisopropylamino or di-n-butylamino. As a result of this, CO-NHA iS preferably N-methylcarbamoyl or N-ethylcarbamoyl; CO-NA
2
is preferably N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl.
Hal is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine. k is 0 or 1, preferably 0. m is 1, 2, 3 or 4, in particular 3 or 4.
The radical R
1
is preferably 3-indolyl which is unsubstituted or mono- or disubstituted, but in particular monosubstituted, by Hal, CN, A, AO, OH, CONH
2
, CONHA, CONA
2
, COOH, COOA, CH
2
OH, CH
2
OA, CH
2
NH
2
, CH
2
NHA and/or CH
2
NA
2
. Preferably, the indole radical is substituted in the 5-position, and further also in the 6- or 7-position.
R
1
is therefore preferably 2- or 3-indolyl, 5- or 6-methylindol-2-yl, 5- or 6-methylindol-3-yl, 5- or 6-methoxyindol-2-yl, 5- or 6-methoxyindol-3-yl, 5- or 6-hydroxyindol-2-yl, 5- or 6-hydroxyindol-3-yl, 5- or 6-fluoroindol-2-yl, 5- or 6-fluoroindol-3-yl, 5- or 6-cyanoindol-2-yl, 5- or 6-cyanoindol-3-yl, 5- or 6-chloroindol-2-yl, 5- or 6-chloroindol-3-yl, 5- or 6-carboxyindol-2-yl, 5- or 6-carboxyindol-3-yl, 5- or 6-methoxycarbonylindol-2-yl, 5- or 6-methoxycarbonylindol-3-yl, 5- or 6-hydroxymethylindol-2-yl, 5- or 6-hydroxymethylindol-3-yl, 5- or 6-aminomethylindol-2-yl, 5- or 6-aminomethylindol-3-yl, and further 5- or 6-bromoindol-2-yl, 5- or 6-bromoindol-3-yl, 5- or 6-ethylindol-2-yl, 5- or 6-ethylindol-3-yl, 5- or 6-trifluoromethylindol-2-yl, 5- or 6-trifluoromethylindol-3-yl, 5- or 6-isopropylindol-2-yl, 5- or 6-isopropylindol-3-yl, 5- or 6-dimethylaminoindol-3-yl or 6-dimethylaminoindol-2-yl, 5- or 6-ethoxyindol-3-yl or 5- or 6-ethoxyindol-2-yl.
The radical R
2
is preferably 2-oxo-2H-1-benzopyran-6-yl or 2-oxo-2H-1-benzopyran-4-yl, which is unsubstituted or monosubsti
Bartoszyk Gerd
Bottcher Henning
Greiner Hartmut
Seyfried Christoph
Bernhardt Emily
Merck Patent Gesellschaft mit beschraenkter Haftung
Millen White Zelano & Branigan P.C.
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