Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-25
2002-10-08
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S638000, C514S657000, C546S201000, C558S411000
Reexamination Certificate
active
06462056
ABSTRACT:
The invention relates to compounds of the formula I
in which
R
1
is H, CN, Hal or OA,
R
2
, R
3
are each, independently of one another, H, CN, Hal or OA,
R
2
and R
3
together are also methylenedioxy,
A is H, CF
3
or alkyl with 1-6 C atoms and
Hal is F, Cl, Br, I,
and the salts thereof.
5-[(2-Oxobenzimidazolin-1-yl)piperidinomethyl]-oxazolidin-2-ones with effects on the central nervous system are disclosed, for example, in EP 0 443 197. Indolepiperidines N-alkylated by indolalkyl radicals are described, for example, in EP 0 683 16. 3-Phenyl-5-[(4-R-X-piperidino)alkyl]oxazolidin-2-one derivatives in which R is phenyl and X is —O—, —S—, —SO— or —SO
2
— and which have effects on the central nervous system are disclosed, for example, in EP 0 635 505. Indolepiperidine derivatives with a tricyclic radical and effects on the central nervous system are described, for example, in EP 0 722 942. 4-Aryl-1-(indan-, dihydrobenzofuran- or dihydrobenzothiophenemethyl)-piperidine derivatives with an effect on serotoninergic and dopaminergic transmission and with an inhibiting effect on 5-HT reuptake are described, for example, in WO 95/33721.
The invention was based on the object of finding novel compounds with valuable properties, in particular those which can be used to produce pharmaceuticals.
It has been found that, while being well tolerated, compounds of the formula I and their salts have particularly valuable pharmacological properties because they display effects on the central nervous system, in particular dopamine-antagonistic and 5-HT reuptake-inhibiting effects since they influence both serotoninergic and dopaminergic transmission. In particular, they have affinities for the 5-HT
1A
and/or 5-HT
2A
receptors.
The compounds of the formula I inhibit the binding of tritiated serotonin receptor 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). In particular, they bind to 5-HT
2A
and D
2
receptors. In addition, changes in DOPA accumulation in the striatum and 5-HTP accumulation in the raphe nuclei occur (Seyfried et al., European J. Pharmacol. 160 (1989), 31-41). The 5-HT
1A
-antagonistic effect is detected in vitro for example by inhibition of the abolition caused by 8-OH-DPAT in the electrically induced contraction of the guineapig ileum (Fozard and Kilbinger, Br. J. Pharmacol. 86 (1985) 601P). The 5-HT
1A
-antagonistic effect is detected ex vivo by the inhibition of 5-HTP accumulation reduced by 8-OH-DPAT (Seyfried et al., European J. Pharmacol. 160 (1989), 31-41).
Ex vivo inhibition of serotonin reuptake is detected by means of synaptosomal uptake inhibition (Wong et al., Neuropsychopharmacol. 8 (1993), 23-33) and p-chloroamphetamine antagonism (Fuller et al., J. Pharmacol. Exp. Ther. 212 (1980), 115-119). The pharmacological tests can moreover be carried out in analogy to the methods described in WO 95/33721.
The compounds of the formula I are therefore suitable both in veterinary medicine and in human medicine for treating central nervous system dysfunctions. They can be used for the prophylaxis and control of the sequelae of cerebral infarctions (apoplexia cerebri) such as stroke and cerebral ischaemias, and for the treatment of extrapyramidal motor side effects of neuroleptics, and of Parkinson's disease. However, they are particularly suitable as pharmaceutical active substances for anxiolytics, anti-depressants, antipsychotics and/or for the treatment of obsessive-compulsive disorder (OCD), anxiety states, panic attacks, depressions, psychoses, schizophrenia, delusional obsessions, Alzheimer's disease, migraine, anorexia, sleep disturbances, tardive dyskinesias, learning disorders, age-related memory impairments, eating disorders such as bulimia, substance abuse and/or sexual dysfunctions.
The compounds of the formula I and their physiologically acceptable acid addition salts can therefore be used as pharmaceutical active substances for anxiolytics, antidepressants, antipsychotics, neuroleptics and/or antihypertensives, and for beneficially influencing obsessive-compulsive disorder, eating disorders such as Bulimia, tardive dyskinesias, learning disorders and age-related memory impairments. They can furthermore be employed as intermediates for preparing other pharmaceutical active substances.
The invention thus relates to compounds of the formula I and to their physiologically acceptable acid addition salts.
The invention accordingly relates to the compounds of the formula I and to a process for preparing compounds of the formula I, characterized in that
a) a compound of the formula II
in which R
1
has the meaning stated in Claim 1, and L is Cl, Br, I or a free or reactively functionally modified OH group,
is reacted with a compound of the formula III
in which R
2
and R
3
have the meanings given in Claim 1, or
b) a compound of the formula IV
in which R
1
, R
2
and R
3
have the meanings stated in Claim 1,
is reacted with a compound of the formula V
in which L and L′ are each, independently of one another, Cl, Br, I or a free or reactively functionally modified OH group, or
c) a compound of the formula VI
in which R
1
, R
2
and R
3
have the meanings stated in Claim 1, is hydrogenated,
and/or in that a basic compound of the formula I is converted by treatment with an acid into one of its salts.
Hereinbefore and hereinafter, the radicals R
1
, R
2
, R
3
and L have the meanings stated for formulae I, II, III, IV and V unless expressly stated otherwise.
The invention likewise relates to pharmaceuticals of the formula I and their physiologically acceptable salts with 5-HT
1A
- and 5-HT
2A
-antagonistic and 5-HT reuptake-inhibiting effects.
The invention relates to the compounds of the formula I according to Claim 1 and to the enantiomers thereof and the salts thereof.
It applies to all radicals which occur more than once, such as, for example, A, that their meanings are independent of one another.
Alkyl has 1 to 10, preferably 1, 2, 3, 4, 5 or 6 C atoms. Alkyl is therefore in particular, for example, methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, 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, also fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trichloroethyl or pentafluoro-ethyl.
A—C— is hydroxyl or alkoxy, in particular, for example, methoxy, ethoxy, propoxy or butyloxy.
The compounds of the formula I, and the starting materials for preparing them, are moreover prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry] Georg-Thieme-Verlag, Stuttgart), specifically under reaction conditions known and suitable for the reactions mentioned. It is moreover possible to make use of variants which are known per se but which are not mentioned here in detail.
L in the compounds of the formula II, and L and L′ in the compounds of the formula V, are in each case independently of one another, Cl, Br, I or a free or reactive esterified OH group.
If L is a reactive esterified OH group, this is preferably trichloromethoxy, alkoxy such as, for example, methoxy, ethoxy, propoxy or butoxy, furthermore phenoxy, alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, also 2-naphthalenesulfonyloxy). L in the compounds of the formula V in particular is Cl, 1-imidazolyl, ethoxy, trichloromethoxy, phenoxy or nitrophenoxy.
The starting materials can, if required, also be formed in situ so that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the fo
Bartoszyk Gerd
Böttcher Henning
Greiner Hartmut
Prücher Helmut
Seyfried Christoph
Merck Patent Gesellschaft mit beschrankter Haftung
Millen White Zelano & Branigan P.C.
Solola T. A.
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