SULFONYLOXAZOLAMINES AND THEIR USE AS 5-HT6 LIGANDS The invention relates to sulfonyloxazolamines of the general formula I in which RllR2 each independently of one another are H, A, cycloalkyl having 3 to 8 C atoms,-(CH2) n-Ar, - (CH2) n-OA,- (CH2) n-NH2,- (CH2) n-NHA, -(CH2)n-NA2 or alkenyl having 2 to 6 C atoms, Ri and R2 together are also a mononuclear saturated heterocycle having 1 to 2 N, O and/or S atoms, Z, z1 or z2 in each case independently of one another is H, A, CF3, NO2, Hal, OH, OA, OCF3, SCF3, NH2, NHA or NA2, A is alkyl having 1 to 6 C atoms, Ar is phenyl which is mono-, di-or tri- substituted by Z, Hal is F, Cl, Br or I, n is 1,2,3 or 4, or their physiologically acceptable salts or solvates as therapeutic active compounds.

The invention furthermore relates to the use of the sulfonyloxazolamines of the general formula I as therapeutic active compounds.

The invention also relates to the use of the sulfonyloxazolamines of the general formula I for the production of pharmaceutical preparations in the control of disorders of the central nervous system.

The formula I includes known and novel compounds.

Some compounds of the general formula I are known from various earlier publications. Thus, the preparation of the compounds of the formula I in which Z is H or 4-CH3, Ar is unsubstituted phenyl, R1 is H and R2 is benzyl, R1 and R2 are methyl or R1 and R2 together are piperidino or morpholino is described in V. A.

Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57 (4), 415-418 or V. A. Chervonyi et al., Zh. Org.

Khim. 1988,24 (2), 453-4 corresponding to V. A.

Chervonyi et al., J. Org. Chem. USSR (Engl. transl.) 1988,24,401.

More detailed publications with respect to the pharmacological efficacy of the compounds of the formula I are not available in the prior art.

The invention was based on the object of finding novel useful properties of sulfonyloxazolamines, in particular those which confirm the compounds to be therapeutic active compounds and/or can lead to the use of the sulfonyloxazolamines as therapeutic active compounds and/or to the production of pharmaceutical preparations, and of preparing further novel sulfonyloxazolamines having these properties.

It has been found that both the known and the novel compounds of the formula I and their pharmacologically active salts surprisingly have a selective affinity for 5-HT6 receptors, together with good tolerability. They exhibit 5-HT6-antagonistic or 5-HT6 agonistic actions.

5-HT6 receptors form a subfamily of 5-HT receptors. The neurotransmitter 5-hydroxytryptamine (5-HT), also known as serotonin, is an important regulating neurotransmitter in the brain, whose actions are assisted by a family of receptors which, at the current level of knowledge, contain 13 G protein- coupled receptors and an ion channel.

The greatest density of the serotonin 5-HT6 receptors in the brain is found in the olfactory tubercle, in the nucleus accumbens, in the striatum, in the dentate gyrus and in the CA1-3 regions of the hippocampus. These regions are involved to a particular extent in psychiatric disorders such as, for example, schizophrenia or depression. Moreover, it is known from animal experiments that the administration of 5-HT6 antisense oligonucleotides causes a behavioural syndrome which corresponds to that of dopamine agonists. Furthermore, hyperactivity of the dopaminergic neurotransmitter system in schizophrenia (dopamine hypothesis of schizophrenia) is pathophysiologically confirmed. However, dysfunctions of the dopamine system in various forms of depression have been demonstrated. Of the established or alternatively newer therapeutics which are employed in clinical practice for the treatment of these psychiatric disorders, a large number moreover bind to the 5-HT6 receptor. The atypical neuroleptics (e. g. clozapine) and the tricyclic antidepressants (e. g. amitriptyline) may be mentioned here in particular.

Moreover, it was found in animal experimental investigations that 5-HT6 receptors in the brain control cholinergic neurotransmission. Cholinergics are employed in disorders with memory disturbances such as, for example, Alzheimer's disease.

For these reasons, it can be concluded that there is an involvement of the 5-HT6 receptor in psychiatric and neurological disorders such as, preferably, schizophrenia, depression and Alzheimer's.

The compounds of the formula I and their physiologically acceptable salts are therefore suitable as therapeutic active compounds for disorders of the central nervous system. The compounds of the formula I and their physiologically acceptable salts or solvates are particularly suitable for the treatment of psychoses, schizophrenia, manic depression (B. L. Roth et al., J. Pharmacol. Exp. Ther. 1994,268,1403-1410),

depression (D. R. Sibley et al., Mol. Pharmacol. 1993, 43,320-327), neurological disorders (A. Bourson et al., J. Pharmacol. Exp. Ther. 1995,274,173-180), memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease (A. J. Sleight et al., Neurotransmissions 1995, 11,1-5), bulimia, anorexia nervosa or other eating disorders, compulsive acts or of premenstrual syndrome.

The invention relates to the compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active compounds.

The invention relates to the use of compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active compounds.

The invention furthermore relates to the use of compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active compounds for disorders of the central nervous system.

The invention also relates to novel compounds of the formula Ia or their physiologically acceptable salts or solvates.

The invention relates to compounds of the formula Ib or their physiologically acceptable salts or solvates, and to a process for their preparation.

The invention relates to compounds of the formula Ic or their physiologically acceptable salts or solvates, and to a process for their preparation.

The invention relates to compounds of the formula Id or their physiologically acceptable salts or solvates, and to a process for their preparation.

The invention relates to compounds of the formula Ie or their physiologically acceptable salts or solvates, and to a process for their preparation.

Solvates of the compounds of the formula I are understood as meaning adducts of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual force of attraction.

Solvates are, for example, mono-or dihydrates or alcoholates.

For all radicals which occur more than once, such as, for example, Z or A, it holds true that their meanings are independent of one another.

Above and below, the radicals and parameters R1, R2, Z, z, Z2 and n have the meanings indicated in the formulae I to VII, if not expressly stated otherwise.

In the above formulae, A is alkyl, is linear or branched, and has 1 to 6, preferably 1,2,3 or 4, C atoms. A is preferably methyl, furthermore ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl or tert- butyl, in addition also pentyl, 1-, 2-or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl or hexyl. Methyl, ethyl, propyl, isopropyl or tert-butyl is particularly preferred.

Alkenyl is preferably allyl, 2-or 3-butenyl, isobutenyl, sec-butenyl, in addition is preferably 4-pentenyl, isopentenyl or 5-hexenyl. Allyl is particularly preferred for alkenyl.

Ar is preferably phenyl which is mono-, di or trisubstituted by Z, where Z can be H, A, CF3, N02, Hal, OH, OA, OCF3, SCF3, NH2, NHA or NA2.

Ar is therefore preferably phenyl, o-, m-or p- methylphenyl, o-, m-or p-ethylphenyl, o-, m-or p- propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p- tert-butylphenyl, o-, m-or p-aminophenyl, o-, m-or p- N, N-dimethylaminophenyl, o-, m-or p-nitrophenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-methoxyphenyl, o-, m-or p-ethoxyphenyl, o-, m-, p-trifluoromethylphenyl, o-, m-, p-trifluoromethoxyphenyl, o-, m-, p- trifluoromethylsulfanylphenyl, o-, m-or p- fluorophenyl, o-, m-or p-chlorophenyl, o-, m-or p- bromophenyl, o-, m-or p-iodophenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- dibromophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-

dimethoxyphenyl, 5-fluoro-2-methylphenyl, 3,4,5- trimethoxyphenyl or 2,4,5-trimethylphenyl.

Phenyl, o-or p-methylphenyl, p-tert- butylphenyl, o-or m-trifluoromethylphenyl, o-, m-or p-trifluoromethoxyphenyl, o-, m-or p- trifluoromethylsulfanylphenyl, p-fluorophenyl, o-or p- chlorophenyl, p-bromophenyl, m-iodophenyl, o-, m-or p- methoxyphenyl, o-ethoxyphenyl, 5-fluoro-2-methylphenyl or 2,4-dichlorophenyl is particularly preferred for Ar.

Cycloalkyl having 3 to 8 C atoms is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being particularly preferred.

In- (CH2)-Ar, Ar has one of the preferred meanings indicated beforehand, where n can be 1 or 2.

Benzyl, 4-methoxyphenylethyl, 3-methoxyphenylethyl, 2- methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2- ethoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-tert- butylbenzyl, 2-trifluoromethylbenzyl, 3-trifluoro- methylbenzyl, 4-fluorobenzyl, 3-iodobenzyl, 4- trifluoromethoxybenzyl, 3-trifluoromethoxybenzyl or 4- trifluoromethylsulfanylbenzyl is particularly preferred for-(CH2) n-Ar.

In-(CH2) n-OA, A has one of the preferred meanings indicated beforehand, where n can be 1, 2,3 or 4. Methoxypropyl or methoxyethyl is particularly preferred for- (CHZ) n-OA.

In- (CH2)-NA2, A has one of the preferred meanings indicated beforehand, where n can be 2,3 or 4. Dimethylaminopropyl or dimethylaminoethyl is particularly preferred for-(CH2) n-NA2.

Hal is preferably fluorine, chlorine, bromine or iodine.

Z, Z1 or Z2 are, in each case independently of one another, H, A, CF3, NO2, Hal, OH, OA, OCF3, SCF3, NH2, NHA or NA2, where A and Hal have one of the preferred meanings indicated beforehand. H, methyl, trifluoromethyl, fluorine, chlorine, bromine, ethoxy or methoxy is particularly preferred for Z in formula I.

Particularly preferably, zi is H or chlorine.

Particularly preferably Z2 is H. n is preferably 1,2,3 or 4, particularly preferably 1,2 or 3.

R1 and R2 are, independently of one another, H, A, cycloalkyl having 3 to 8 carbon atoms,- (CH2) n- <BR> <BR> <BR> Ar,-(CH2) n-OA/-(CH2) n-NH2,-(CH2) n-NHA/-(CH2) n-NA2 or alkenyl having 2 to 6 C atoms, where A, Ar, alkenyl, cycloalkyl and n have one of the preferred or particularly preferred meanings indicated beforehand.

In addition, R1 and R2 together are also a mononuclear saturated heterocycle having 1 to 2 N, O and/or S atoms.

R1 and R2 together are preferably tetrahydro-2- or-3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2-or-3- thienyl, 1-, 2-or 3-pyrrolidinyl, tetrahydro-1-,-2- <BR> <BR> <BR> or-4-imidazolyl, tetrahydro-1-,-3-or-4-pyrazolyl, 1-, 2-, 3-or 4-piperidinyl, 1-, 2-, 3-or 4-perhydroazepinyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-,-3-or-4-pyranyl, 1,4-dioxanyl, 1,3- dioxan-2-,-4-or-5-yl, hexahydro-1-,-3-or-4- pyridazinyl, hexahydro-1-,-2-,-4-or-5-pyrimidinyl or 1-, 2-or 3-piperazinyl. Piperidin-1-yl, piperazin- 1-yl or morpholin-4-yl is particularly preferred for and R2 together.

The compounds of the formula I include the following groups: a) compounds of the formula Ia

in which Rl/R2 each independently of one another are H, A, -(CH2) n-Ar or alkenyl having 2 to 6 C atoms, Ri and R2 together are also a mononuclear saturated heterocycle having 1 or 2 N, O and/or S atoms, Z is H, A, CF3, NO2, Hal, OH, OA, NH2, NHA or NH2, A is alkyl having 1 to 6 C atoms, Ar is phenyl which is mono-or disubstituted by Z, Hal is F, Cl, Br or I, n is 1 or 2, or their physiologically acceptable salts or solvates; b) compounds of the formula Ib in which Z is H, A, CF3, NO2, Hal, OH, OA, OCF3, SCF3, NH2, NHA or NA2, A is alkyl having 1 to 6 C atoms, Ar is phenyl which is mono-, di-or trisubstituted by Z, Hal is F, Cl, Br or I, n is 1,2 or 3 or their physiologically acceptable salts or solvates; c) compounds of the formula Ic z ( I s//0 1 c N Ic HN ° H-Nô Cydoatky)

in which Z is H, A, CF3, NO2, Hal, OH, OA, OCF3, SCF3, NH2, NHA or NA2, A is alkyl having 1 to 6 C atoms, Ar is phenyl which is. mono-, di-or trisubstituted by Z, Hal is F, Cl, Br or I, or their physiologically acceptable salts or solvates; d) compounds of the formula Id in which Z is H, A, CF3, NO2, Hal, OH, OA, OCF3, SCF3, NH2, NHA or NA2, A is alkyl having 1 to 6 C atoms, Ar is phenyl which is mono-, di-or trisubstituted by Z, Hal is F, C1, Br or I, n is 1,2,3 or 4,

or their physiologically acceptable salts or solvates; or e) compounds of the formula Ie in which R1,R2 each independently of one another are H, A, cycloalkyl having 3 to 8 C atoms,-(CH2) n- Ar,- (CH2)-OA,- (CH2) n-NH2,- (CH2) N-NHA,- (CH2) n-NA2 or alkenyl having 2 to 6 C atoms, Ri and R2 together are also a mononuclear saturated heterocycle having 1 or 2 N, O and/or S atoms, Z or Z1 in each case independently of one another are A, CF3, NO2, Hal, OH, OA, OCF3, SCF3, NH2, NHA or NA2, A is alkyl having 1 to 6 C atoms, Ar is phenyl which is mono-, di-or trisubstituted by Z, Hal is F, C1, Br or I, n is 1, 2,3 or 4 or their physiologically acceptable salts or solvates.

For the subject of the invention, of the therapeutic active compounds of the formula I, in particular of the formula Ia, or their physiologically acceptable salts or solvates, of the use of the compounds of the formula I, in particular of the formula Ia, or their physiologically acceptable salts or solvates as therapeutic active compounds or of the production of a pharmaceutical preparation for the

treatment of disorders of the central nervous system, those compounds of the formula I which correspond to the formula Ia are particularly preferred and in which at least one of the radicals mentioned has one of the preferred or particularly preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulae Iaa to Iac, which correspond to the formula Ia and in which the radicals not described in greater detail have the meaning indicated in the formula Ia, but in which in Iaa R1 and R2 in each case independently of one another are H, A,-(CH2) n-Ar or alkenyl having 2 to 6 C atoms, Z is H, A or Hal; alkenyl is allyl; Ar is phenyl, o-or p-methylphenyl, p-tert- butylphenyl, o-or m-trifluoromethylphenyl, o-, m-or p-trifluoromethoxyphenyl, p-tri- fluoromethylsulfanylphenyl, p-fluorophenyl, o- or p-chlorophenyl, p-bromophenyl, m-iodophenyl, o-, m-or p-methoxyphenyl, o-ethoxyphenyl, 5- fluoro-2-methylphenyl or 2,4-dichlorophenyl and -(CH2) n-Ar is benzyl, 4-methoxyphenylethyl, 3-methoxy- phenylethyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 2- methylbenzyl, 3-methylbenzyl, 4-tert-butyl- benzyl, 2-trifluoromethylbenzyl, 3-trifluoro- methylbenzyl, 4-fluorobenzyl, 3-iodobenzyl, 4- trifluoromethoxybenzyl, 3-trifluoromethoxy- benzyl or 4-trifluoromethylsulfanylbenzyl; in Iab Ri and R2 in formula I together are piperidin-1-yl or piperazin-1-yl; z is H, A or Hal and Ar is phenyl, o-or p-methylphenyl, p-tert- butylphenyl, o-or m-trifluoromethylphenyl, o-, m-or p-trifluoromethoxyphenyl, p-

trifluoromethylsulfanylphenyl, p-fluorophenyl, o-or p-chlorophenyl, p-bromophenyl, m- iodophenyl, o-, m-or p-methoxyphenyl, o- ethoxyphenyl, 5-fluoro-2-methylphenyl or 2,4- dichlorophenyl or in Iac R1 and R2 in formula I together are morpholin-4-yl; Z is H, A or Hal and Ar is phenyl, o-or p-methylphenyl, p-tert- butylphenyl, o-or m-trifluoromethylphenyl, o-, m-or p-trifluoromethoxyphenyl, p-trifluoro- methylsulfanylphenyl, p-fluorophenyl, o-or p- chlorophenyl, p-bromophenyl, m-iodophenyl, o-, m-or p-methoxyphenyl, o-ethoxyphenyl, 5- fluoro-2-methylphenyl or 2,4-dichlorophenyl.

In relation to formula Ia the following known compounds are particularly preferred for use according to Claim 1: <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> dimethyl- [2-phenyl-4- (toluene-4-sulfonyl) oxazol-5-yl]- amine; [2- (2, 4-dichlorophenyl)-4- (toluene-4-sulfonyl) oxazol-5- yl] dimethylamine ; <BR> <BR> <BR> <BR> benzyl- [2- (2, 4-dichlorophenyl)-4- (toluene-4-sulfonyl)- oxazol-5-yl] amine; methyl- [4- (toluene-4-sulfonyl)-2-p-tolyloxazol-5-yl]- amine; benzyl- [4- (4-chlorobenzenesulfonyl)-2- (2, 4- dichlorophenyl) oxazol-5-yl] amine;

(4-benzenesulfonyl-2-m-tolyloxazol-5-yl) benzylamine; [4- (4-chlorobenzenesulfonyl)-2-p-tolyloxazol-5-yl]- dimethylamine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) methylamine; <BR> <BR> benzyl- [4- (4-chlorobenzenesulfonyl)-2- (2-chlorophenyl)- oxazol-5-yl] amine ; [4-benzenesulfonyl-2- (2, 4-dichlorophenyl) oxazol-5-yl]- benzylamine; [4-benzenesulfonyl-2- (2, 4-dichlorophenyl) oxazol-5-yl]- dimethylamine; [4-benzenesulfonyl-2- (2-chlorophenyl) oxazol-5-yl]- dimethylamine; 1- [2- (2, 4-dichlorophenyl)-4- (toluene-4-sulfonyl)- oxazol-5-yl] piperidine ; 1- [4-benzenesulfonyl-2- (2, 4-dichlorophenyl) oxazol-5- yl] piperidine ; 1- [4-benzenesulfonyl-2- (2-chlorophenyl) oxazol-5-yl]- piperidine; 4- [4- (toluene-4-sulfonyl)-2-p-tolyloxazol-5-yl]- morpholine; 4- [4- (4-chlorobenzenesulfonyl)-2-p-tolyloxazol-5-yl]- morpholine; 4- [4- (4-chlorobenzenesulfonyl)-2-phenyloxazol-5-yl]- morpholine; <BR> <BR> 4- [4- (4-benzenesulfonyl)-2- (4-bromophenyl) oxazol-5-yl]- morpholine; 4- [4- (4-benzenesulfonyl)-2-m-tolyloxazol-5-yl]- morpholine; 4- [4- (4-benzenesulfonyl)-2- (4-methoxyphenyl) oxazol-5- yl] morpholine ; 4- [4- (4-benzenesulfonyl)-2-phenyloxazol-5-yl]- morpholine; allyl- (4-benzenesulfonyl-2-phenyloxazol-5-yl) amine; 4- [4-benzenesulfonyl-2- (2-chlorophenyl) oxazol-5-yl]- morpholine; (4-benzenesulfonyl-2-phenyloxazol-5-yl) dimethylamine; (4-benzenesulfonyl-2-m-tolyloxazol-5-yl) dimethylamine; benzyl- [2-phenyl-4- (toluene-4-sulfonyl) oxazol-5-yl]- amine and

benzyl- [4- (toluene-4-sulfonyl)-2-m-tolyloxazol-5-yl]- amine.

Preferred novel compounds of the formula Ia are the following compounds whose preparation is described in Examples 1 to 7: (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) methylamine; [4-benzenesulfonyl-2- (4-fluorophenyl) oxazol-5- yl] methylamine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) benzylamine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) propylamine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- [2- (4- methoxyphenyl) ethyl] amine ; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- methoxybenzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- methylbenzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (4- fluorobenzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- methoxybenzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- methylbenzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (4- trifluoromethoxybenzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- [2- (3- methoxyphenyl) ethyl] amine ; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- trifluoromethoxybenzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (4-tert- butylbenzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- (trifluoromethyl) benzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- (trifluoromethyl) benzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (4- (trifluoromethylsulfanyl) benzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- ethoxybenzyl) amine;

(4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- (trifluoromethoxy) benzyl) amine; [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] methylamine ; [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] propylamine ; <BR> <BR> <BR> benzyl- [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] amine ; [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5-yl]- (4- fluorobenzyl) amine; [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5-yl]- (2- methoxybenzyl) amine; <BR> <BR> <BR> [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5-yl]- [2- (4-methoxyphenyl) ethyl] amine; [4-benzenesulfonyl-2- (2- (trifluoromethyl) phenyl) oxazol- 5-yl] methylamine ; [4-benzenesulfonyl-2- (2- (trifluoromethyl) phenyl) oxazol- 5-yl] propylamine ; [4-benzenesulfonyl-2- (2- (trifluoromethyl) phenyl) oxazol- 5-yl] benzylamine ; [4-benzenesulfonyl-2- (2- (trifluoromethyl) phenyl) oxazol- 5-yl]- (4-fluorobenzyl) amine; [4-benzenesulfonyl-2- (2- (trifluoromethyl) phenyl) oxazol- 5-yl]- (4-methoxybenzyl) amine; [4-benzenesulfonyl-2- (2- (trifluoromethyl) phenyl) oxazol- 5-yl]- [2- (4-methoxyphenyl) ethyl] amine ; [4-benzenesulfonyl-2- (5-fluoro-2-methylphenyl) oxazol-5- yl]- [2- (4-methoxyphenyl) ethyl] amine ; [4-benzenesulfonyl-2- (5-fluoro-2-methylphenyl) oxazol-5- yl]-(2-methoxybenzyl)amine; [4-benzenesulfonyl-2- (5-fluoro-2-methylphenyl) oxazol-5- yl] methylamine ; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- iodobenzyl) amine; [4- (4-bromobenzenesulfonyl)-2- (5-fluoro-2- methylphenyl) oxazol-5-yl] methylamine ; benzyl- [4- (4-bromobenzenesulfonyl)-2- (5-fluoro-2- methylphenyl) oxazol-5-yl] amine ;

1- [4-benzenesulfonyl-2- (4-fluorophenyl) oxazol-5- yl] piperazine ; (4-benzenesulfonyl-2-phenyloxazol-5-yl) methylamine; (4-benzenesulfonyl-2-phenyloxazol-5-yl)benzylamine; (4-benzenesulfonyl-2-phenyloxazol-5-yl)- (4- fluorobenzyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) ethylamine; [4-benzenesulfonyl-2- (2- (trifluoromethyl) phenyl) oxazol- 5-yl] ethylamine ; [4-benzenesulfonyl-2- (2-ethoxyphenyl) oxazol-5- yl] methylamine ; [4-benzenesulfonyl-2- (2-ethoxyphenyl) oxazol-5- yl] ethylamine ; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) isopropylamine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (4- methoxybenzyl) amine; 1- (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) piperazine; (4-benzenesulfonyl-2-phenyloxazol-5-yl) ethylamine; methyl- [4- (toluene-4-sulfonyl)-2-o-tolyl-oxazol-5- yl] amine ; ethyl- [4- (toluene-4-sulfonyl)-2-o-tolyl-oxazol-5- yl] amine ; methyl- [2-phenyl-4- (toluene-4-sulfonyl) oxazol-5- yl] amine ; ethyl- [2-phenyl-4- (toluene-4-sulfonyl) oxazol-5- yl] amine; [2- (2-ethoxyphenyl)-4- (toluene-4-sulfonyl) oxazol-5- yl] methylamine ; [2- (2-ethoxyphenyl)-4- (toluene-4-sulfonyl) oxazol-5- yl] ethylamine ; [4-benzenesulfonyl-2- (4-chlorophenyl) oxazol-5- yl] methylamine and [4-benzenesulfonyl-2- (4- chlorophenyl) oxazol-5-yl] ethylamine.

In relation to formula Iaa, the novel compounds of the formula Ia mentioned beforehand without the two piperazine derivatives 1- [4-benzenesulfonyl-2- (4-fluorophenyl) oxazol-5- yl] piperazine and

1- (4-benzenesulfonyl-2-o-tolyl-oxazol-5-yl) piperazine, and in relation to formula Ia, the following known compounds are preferred for use as therapeutic active compounds: <BR> <BR> dimethyl- [2-phenyl-4- (toluene-4-sulfonyl) oxazol-5-yl]- amine; [2- (2, 4-dichlorophenyl)-4- (toluene-4-sulfonyl) oxazol-5- yl] dimethylamine ; benzyl- [2- (2, 4-dichlorophenyl)-4- (toluene-4-sulfonyl)- oxazol-5-yl] amine ; methyl- [4- (toluene-4-sulfonyl)-2-p-tolyloxazol-5-yl]- amine; benzyl- [4- (4-chlorobenzenesulfonyl)-2- (2, 4-dichloro- phenyl) oxazol-5-yl] amine ; (4-benzenesulfonyl-2-m-tolyloxazol-5-yl) benzylamine; [4- (4-chlorobenzenesulfonyl)-2-p-tolyloxazol-5-yl]- dimethylamine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) methylamine; benzyl- [4- (4-chlorobenzenesulfonyl)-2- (2-chlorophenyl)- oxazol-5-yl] amine ; [4-benzenesulfonyl-2- (2, 4-dichlorophenyl) oxazol-5-yl]- benzylamine; allyl- (4-benzenesulfonyl-2-phenyloxazol-5-yl) amine; (4-benzenesulfonyl-2-phenyloxazol-5-yl) dimethylamine; (4-benzenesulfonyl-2-m-tolyloxazol-5-yl) dimethylamine; benzyl-[2-phenyl-4-(toluene-4-sulfonyl) oxazol-5-yl]- amine; benzyl- [4- (toluene-4-sulfonyl)-2-m-tolyloxazol-5-yl]- amine ; [4-benzenesulfonyl-2- (2, 4-dichlorophenyl) oxazol-5- yl] dimethylamine and [4-benzenesulfonyl-2- (2-chlorophenyl) oxazol-5-yl]- dimethylamine.

In relation to formula Iab, the following known and novel compounds are preferred for use as therapeutic active compounds: 1- [4-benzenesulfonyl-2- (4-fluorophenyl) oxazol-5- yl] piperazine ;

1- (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) piperazine; 1- [2- (2, 4-dichlorophenyl)-4- (toluene-4-sulfonyl)- oxazol-5-yl] piperidine ; 1- [4-benzenesulfonyl-2- (2, 4-dichlorophenyl) oxazol-5- yl] piperidine and 1- [4-benzenesulfonyl-2- (2-chlorophenyl) oxazol-5-yl]- piperidine.

In relation to formula Iac, the following known compounds are preferred for use as therapeutic active compounds: 4- [4- (toluene-4-sulfonyl)-2-p-tolyloxazol-5-yl]- morpholine; 4- [4- (4-chlorobenzenesulfonyl)-2-p-tolyloxazol-5-yl]- morpholine; 4- [4- (4-chlorobenzenesulfonyl)-2-phenyloxazol-5-yl]- morpholine; 4- [4- (4-benzenesulfonyl)-2- (4-bromophenyl) oxazol-5- yl] morpholine ; 4- [4- (4-benzenesulfonyl)-2-m-tolyloxazol-5-yl]- morpholine; 4- [4-benzenesulfonyl-2- (2-chlorophenyl) oxazol-5-yl]- morpholine; 4- [4- (4-benzenesulfonyl)-2- (4-methoxyphenyl) oxazol-5- yljmorpholine and 4- [4- (4-benzenesulfonyl)-2-phenyloxazol-5-yl]- morpholine.

For the subject of the invention, of the novel compounds of the formula I, in particular of the formula Ib, or their physiologically acceptable salts or solvates, and of the use of the compounds of the formula I, in particular of the formula Ib, or their physiologically acceptable salts or solvates as therapeutic active compounds or of the production of a pharmaceutical preparation for the treatment of disorders of the central nervous system, those compounds of the formula Ib are particularly preferred which correspond to the formula Ib and in which at least one of the radicals mentioned has one of the

preferred or particularly preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulae Iba and Ibb, which correspond to the formula Ib and in which the radicals not designated in greater detail have the meaning indicated in the formula Ib, but in which in Iba Z is H, A or Hal or in Ibb Z is H, A or Hal and Ar is phenyl, o-or p-methylphenyl, p-tert- butylphenyl, o-or m-trifluoromethylphenyl, o-, m-or p-trifluoromethoxyphenyl, p- trifluoromethylsulfanylphenyl, p-fluoro- phenyl, o-or p-chlorophenyl, p-bromophenyl, m-iodophenyl, o-, m-or p-methoxyphenyl, o- ethoxyphenyl, 5-fluoro-2-methylphenyl or 2,4- dichlorophenyl.

Preferred compounds of the formula Ib are: (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- methoxypropyl) amine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- methoxyethyl) amine; [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5-yl]- (2- methoxyethyl) amine or [4-benzenesulfonyl-2- (5-fluoro-2-methylphenyl) oxazol-5- yl]- (2-methoxyethyl) amine.

For the subject of the invention, of the novel compounds of the formula I, in particular of the formula Ic, or their physiologically acceptable salts or solvates, and of the use of the compounds of the formula I, in particular of the formula Ic, or their physiologically acceptable salts or solvates as therapeutic active compounds or of the production of a pharmaceutical preparation for the treatment of disorders of the central nervous system, those compounds of the formula Ic are particularly preferred which correspond to the formula Ic and in which at

least one of the radicals mentioned has one of the preferred or particularly preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulae Ica and Icb, which correspond to the formula Ic and in which the radicals not designated in greater detail have the meaning indicated in the formula Ic, but in which in Ica Z is H, A or Hal; in Icb Z is H, A or Hal and Ar is phenyl, o-or p-methylphenyl, p-tert- butylphenyl, o-or m-trifluoromethylphenyl, o-, m-or p-trifluoromethoxyphenyl, p-trifluoro- methylsulfanylphenyl, p-fluorophenyl, o-or p- chlorophenyl, p-bromophenyl, m-iodophenyl, o-, m-or p-methoxyphenyl, o-ethoxyphenyl, 5- fluoro-2-methylphenyl or 2,4-dichlorophenyl.

Preferred compounds of the formula Ic are: (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) cyclopropylamine; (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) cyclopentylamine; (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) cyclobutylamine; [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] cyclopropylamine ; [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] cyclopentylamine ; [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] cyclohexylamine ; [4-benzenesulfonyl-2- (2- (trifluoromethyl) phenyl) oxazol- 5-yl] cyclopropylamine or [4-benzenesulfonyl-2- (5-fluoro-2-methylphenyl) oxazol-5- yl] cyclopropylamine.

For the subject of the invention, of the novel compounds of the formula I, in particular of the formula Id, or their physiologically acceptable salts

or solvates, and of the use of the compounds of the formula I, in particular of the formula Id, or their physiologically acceptable salts or solvates as therapeutic active compounds or of the production of a pharmaceutical preparation for the treatment of disorders of the central nervous system, those compounds of the formula Id are particularly preferred which correspond to the formula Id and in which at least one of the radicals mentioned has one of the preferred or particularly preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulae Ida and Idb, which correspond to the formula Id and in which the radicals not designated in greater detail have the meaning indicated in the formula Id, but in which in Ida Z is H, A or Hal or in Idb Z is H, A or Hal and Ar is phenyl, o-or p-methylphenyl, p-tert- butylphenyl, o-or m-trifluoromethylphenyl, o-, m-or p-trifluoromethoxyphenyl, p- trifluoromethylsulfanylphenyl, p-fluoro- phenyl, o-or p-chlorophenyl, p-bromophenyl, m-iodophenyl, o-, m-or p-methoxyphenyl, o- ethoxyphenyl, 5-fluoro-2-methylphenyl or 2,4- dichlorophenyl.

Preferred compounds of the formula Id are: N'- [4- (4-bromobenzenesulfonyl-2-o-tolyloxazol-5-yl]- N, N-dimethylethane-1, 2-diamine; N'- (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)-N, N- dimethylpropane-1, 3-diamine; N'- [4-benzenesulfonyl-2- (2- (trifluoromethyl) phenyl) oxazol-5-yl]-N, N- dimethylpropane-1, 3-diamine or N'- [4-benzenesulfonyl-2- (5-fluoro-2- methylphenyl) oxazol-5-yl]-N, N-dimethylpropane-1, 3- diamine.

For the subject of the invention, of the novel compounds of the formula I, in particular of the formula Ie, or their physiologically acceptable salts or solvates, and of the use of the compounds of the formula I, in particular of the formula Ie, or their physiologically acceptable salts or solvates as therapeutic active compounds or of the production of a pharmaceutical preparation for the treatment of disorders of the central nervous system, those compounds of the formula Ie are particularly preferred which correspond to the formula Ie and in which at least one of the radicals mentioned has one of the preferred or particularly preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulae Iea to Iec, which correspond to the formula Ie and in which the radicals not designated in greater detail have the meaning indicated in the formula Ie, but in which in Iea R, R in each case independently of one another are H, A, cycloalkyl having 3 to 8 C atoms, - (CH2) n-Ar,-(CH2) n ~ OA,-(CH2) n-NH2,-(CH2) n~ NHA, or- (CH2) n-NA2 ; in Ieb R, R2 in each case independently of one another are H, A, cycloalkyl having 3 to 8 C atoms, - (CH2) n-Ar,- (CH2) n~ OA or-(CH2) n-NA2 and Ar is phenyl, o-or p-methylphenyl, p-tert- butylphenyl, o-or m-trifluoromethylphenyl, o-, m-or p-trifluoromethoxyphenyl, p- trifluoromethylsulfanylphenyl, p-fluoro- phenyl, o-or p-chlorophenyl, p-bromophenyl, m-iodophenyl, o-, m-or p-methoxyphenyl, o- ethoxyphenyl, 5-fluoro-2-methylphenyl or 2,4- dichlorophenyl; in Iec

R, R in each case independently of one another are H, A, cycloalkyl having 3 to 8 C atoms, -(CH2) n-Ar,-(CH2) n-OA or-(CH2) n-NA2, Z, Z1 in each case are Hal and Ar is phenyl, o-or p-methylphenyl, p-tert- butylphenyl, o-or m- (trifluoromethyl) phenyl, o-, m-or p- (trifluoromethoxy) phenyl, p- (trifluoromethylsulfanyl) phenyl, p- fluorophenyl, o-or p-chlorophenyl, p- bromophenyl, m-iodophenyl, o-, m-or p- methoxyphenyl, o-ethoxyphenyl, 5-fluoro-2- methylphenyl or 2,4-dichlorophenyl.

Preferred compounds of the formula Ie are: [4- (3, 4- (dichloro) benzenesulfonyl)-2-o-tolyloxazol-5- yl] methylamine ; [4- (3, 4- (dichloro) benzenesulfonyl)-2-o-tolyloxazol-5- yl] propylamine ; [4- (3, 4- (dichloro) benzenesulfonyl)-2-o-tolyloxazol-5- yl]- (2-methoxyethyl) amine; benzyl- [4- (3, 4- (dichloro) benzenesulfonyl)-2-0- tolyloxazol-5-yl] amine ; [4- (3, 4- (dichloro) benzenesulfonyl)-2-o-tolyloxazol-5- yl]- (4-fluorobenzyl) amine; [4- (3, 4- (dichloro) benzenesulfonyl)-2-o-tolyloxazol-5- yl]- (2-methoxybenzyl) amine; [4- (3, 4- (dichloro) benzenesulfonyl)-2-o-tolyloxazol-5- yl]- [2- (4-methoxyphenyl) ethyl] amine ; cyclopropyl- [4- (3, 4- (dichloro) benzenesulfonyl)-2- (5- fluoro-2-methylphenyl) oxazol-5-yl] amine; [4- (3, 4- (dichloro) benzenesulfonyl)-2- (5-fluoro-2- methylphenyl) oxazol-5-yl]- (3-methylbenzyl) amine; [4- (2, 5- (dichloro) benzenesulfonyl)-2-o-tolyloxazol-5- yl] methylamine; benzyl- [4- (2, 5- (dichloro) benzenesulfonyl)-2-o- tolyloxazol-5-yl] amine ; [4- (2, 5- (dichloro) benzenesulfonyl)-2- (2- (trifluoromethyl) phenyl) oxazol-5-yl] methylamine ; benzyl- [4- (2, 5- (dichloro) benzenesulfonyl)-2- (2- (trifluoromethyl) phenyl) oxazol-5-yl] amine or

[4- (2, 5- (dichloro) benzenesulfonyl)-2- (2- (trifluoromethyl) phenyl) oxazol-5-yl]- (4- fluorobenzyl) amine.

The invention furthermore relates to the use of the following compounds, selected from the group a) dimethyl- [2-phenyl-4- (toluene-4-sulfonyl) oxazol-5- yl] amine, b) [2- (2, 4-dichlorophenyl)-4- (toluene-4-sulfonyl)- oxazol-5-yl] dimethylamine, c) benzyl- [4- (4-chlorobenzenesulfonyl)-2- (2- chlorophenyl) oxazol-5-yl] amine, d) (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- methylamine, e) benzyl- [2- (2, 4-dichlorophenyl)-4- (toluene-4- sulfonyl) oxazol-5-yl] amine, f) [4-benzenesulfonyl-2- (2, 4-dichlorophenyl) oxazol-5- yl] benzylamine, g) [4-benzenesulfonyl-2- (2, 4-dichlorophenyl) oxazol-5- yl] dimethylamine, h) allyl (4-benzenesulfonyl-2-phenyloxazol-5-yl) amine, i) [4-benzenesulfonyl-2- (4-fluorophenyl) oxazol-5- yl] methylamine, k) (4-benzenesulfonyl-2-phenyloxazol-5-yl) methylamine or 1) [4-benzenesulfonyl-2- (2-ethoxyphenyl) oxazol-5- yl] methylamine or one of their physiologically acceptable salts or solvates as therapeutic active compounds against disorders of the central nervous system.

The compounds of the formula I, in particular of the formula Ia, are in some cases commercially obtainable or can be synthesized according to the following synthesis scheme (for this cf. V. A.

Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57 (4), 415-418 or V. A. Chervonyi et al., Zh. Org.

Khim. 1988,24 (2), 453-4 corresponding to V. A.

Chervonyi et al., J. Org. Chem. USSR (Engl. transl.) 1988, 24,401).

Synthesis scheme:

In the synthesis scheme shown beforehand, the starting material of the formula II is reacted with trichloroacetate to give the compound III. The reaction with thionyl chloride and subsequently with the sodium sulfinate of the formula V generates an aryl vinyl sulfone of the formula VI, which cyclizes to give the sulfonyloxazolamines of the formula I by reaction with an amine of the formula VII. In this connection, the substituents Ar, Z, R1 and R2 of the formula II to VII have preferred or particularly preferred meanings as indicated beforehand.

The suitable reaction conditions of the reactions mentioned from the synthesis scheme are known from the references V. A. Chervonyi et al., Ukr. Khim.

Zh. (Russ. Ed.) 1991,57 (4), 415-418 or V. A. Chervonyi et al., Zh. Org. Khim. 1988,24 (2), 453-4 corresponding to V. A. Chervonyi et al., J. Org. Chem. USSR (Engl. transl.) 1988,24,401, or from standard works such as, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme- Verlag, Stuttgart. In this case, use can also be made of variants which are known per se, but not mentioned here in greater detail.

The novel compounds of the formulae Ib to Ie can be prepared analogously to the previous synthesis scheme.

The invention therefore furthermore relates to a process for the preparation of compounds of the formulae Ib to Ie, and of their salts and solvates, characterized in that a) for the preparation of the compounds of the formula Ib a compound of the formula VIa

in which Z and Ar have one of the meanings described beforehand in formula Ib, is reacted with a compound of the formula VIIb H2N- (CH2)-OA VIIB, in which A and n have one of the meanings described beforehand in formula Ib; or b) for the preparation of the compounds of the formula Ic a compound of the formula VIa in which Z and Ar have one of the meanings described beforehand in formula Ic, is reacted with a compound of the formula VIIc H2N-cycloalkyl VIIc, in which cycloalkyl has one of the meanings described beforehand in formula Ic ; or c) for the preparation of the compounds of the formula Id a compound of the formula VIa

in which Z and Ar have one of the meanings described beforehand in formula Id, is reacted with a compound of the formula VIId H2N-(CH2) n-NA2 VIId, in which A and n have one of the meanings described beforehand in formula Id; or d) for the preparation of the compounds of the formula Ie a compound of the formula IV in which Ar has one of the meanings described beforehand in formula Ie, is first reacted with a compound of the formula Ve in which Z and Z1 have one of the meanings described beforehand in formula Ie, and the resulting coupling product VIe

in which Ar, Z and Z1 have one of the meanings described beforehand in formula Ie, is reacted with a compound of the formula VII HNR1R2 VII, in which Rl and R2 have one of the meanings described beforehand in formula Ie; and/or a base or acid of the formulae Ia to Ie is converted into one of its salts.

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. For this reaction, suitable acids are in particular those which yield physiologically acceptable salts. Thus inorganic acids can be used, e. g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono-or polybasic carboxylic, sulfonic or sulfuric acids, e. g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane-or ethanesulfonic acid, p-toluenesulfonic acid, naphthalenemono-and disulfonic acids or lauryl

sulfuric acid. Salts with physiologically unacceptable acids, e. g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.

The binding of the compounds of the formula I to 5-HT6 receptors was determined as follows: The substances to be tested were dissolved in DMSO at a concentration of 1 mM and diluted to the desired concentrations (0.1 nM to 10 pM) using test buffer (20 mM HEPES, 0.1% ascorbic acid, adjusted to pH 7.4 using NaOH).

20 ul of the respective substance solution were incubated at 37°C for 1 hour with 80 pl of 3H-LSD solution (TRK-1041, Amersham Pharmacia, Freiburg, spec. act. 80-90 Ci/mMol, 1 nM in the batch) and 100 pu of membrane suspension (5-HT6 receptors, RB-HS6, Biotrend, Cologne, 25-30 ag of protein). The reaction mixture was filtered through GFB filters (Whatman) which had been pretreated with 0.1% aqueous polyethyleneimine solution for 1 hour. The filters were washed 3 times with 3 ml of test buffer, transferred to minivials and, after addition of Ultima Gold (Packard, Frankfurt), the radioactivity was determined in a liquid scintillation counter. The evaluation and IC50 determination was carried out by means of in-house programs in RS1 (BBN Software Corporation).

The compounds of the formula I have a selective affinity for 5-HT6 receptors having an inhibition constant ICso of less than 4 pmol/l.

The invention furthermore relates to the use of the compounds of the general formula I for the production of a pharmaceutical preparation for controlling disorders of the central nervous system.

The invention furthermore relates to the use of compounds of the general formula I for the production of a pharmaceutical preparation for the treatment of psychoses, schizophrenia, manic depression, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, bulimia, anorexia

nervosa or other eating disorders, compulsive acts or premenstrual syndrome.

The invention furthermore relates to pharmaceutical preparations for the control of disorders of the central nervous system, comprising at least one compound of the formula I or one of its physiologically acceptable salts or solvates.

These preparations can be used as pharmaceuticals in human or veterinary medicine.

Possible vehicles are organic or inorganic substances which are suitable for enteral (e. g. oral), or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, in particular, are used for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, in addition suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations.

The preparations indicated can be sterilized and/or can contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavourings and/or other active compounds, e. g. one or more vitamins.

The invention also relates to a process for the production of these pharmaceutical preparations, which is characterized in that a compound of the formula I or one of its physiologically tolerable salts or solvates is brought into a suitable dose form together with at least one solid, liquid or semiliquid vehicle or

excipient and, if appropriate, in combination with one or more other active compound.

The compounds of the formula I and their physiologically acceptable salts or solvates can be employed for the control of disorders of the central nervous system.

The substances according to the invention are as a rule administered here in a dose of preferably between approximately 1 and 500 mg, in particular between 5 and 100 mg, per dose unit. The daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight. The specific dose for each patient, however, depends on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.

Above and below, all temperatures are indicated in °C. In the following examples,"customary working- up"means : if necessary, water is added, if necessary, depending on the constitution of the final product, the mixture is adjusted to a pH of between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel, by preparative HPLC and/or by crystallization. m. p. denotes melting point.

Example 1: 0.5 mol of 4-fluorobenzamide is suspended in 100 ml of toluene and, after addition of 0.625 mol (92.2 g) of chloral (trichloroacetaldehyde), the mixture is heated at 110° for 1 hour. After cooling, the crystalline reaction product, 4-fluoro-N- (2, 2,2- trichloro-l-hydroxyethyl) benzamide is filtered off with suction, washed with cold water and dried in vacuo

(m. p. 131-133°). 0.2 mol of 4-fluoro-N- (2, 2,2- trichloro-1-hydroxyethyl) benzamide is suspended in toluene and heated with 0.3 mol of thionyl chloride at 100° with exclusion of moisture. Excess thionyl chloride is distilled off in vacuo. 4-fluoro-N- (1, 2,2,2-tetrachloroethyl) benzamide (m. p. 123-125°) is obtained. 0.01 mol of 4-fluoro-N- (1, 2,2,2- tetrachloroethyl) benzamide, 0.01 mol of sodium benzenesulfinate and 20 ml of anhydrous acetonitrile are heated at boiling temperature for 2.5 hours. The resulting sodium chloride is filtered off and washed with hot acetonitrile. The solvent is distilled off and the resulting residue is filtered through a silica gel column using ethyl acetate. 1.5 g of N- (1- benzenesulfonyl-2,2-dichlorovinyl)-4-fluorobenzamide (m. p. 160-164°) are obtained.

0.75 g of N- (1-benzenesulfonyl-2, 2- dichlorovinyl)-4-fluorobenzamide is dissolved in 40 ml of THF and 5.5 ml of 2.2 molar methylamine solution are stirred in at room temperature. After stirring overnight at room temperature, the solution is filtered off, the filtrate is evaporated and the residue is taken up with isopropanol. 100 mg of [4- benzenesulfonyl-2- (4-fluorophenyl) oxazol-5- yl] methylamine (m. p. 190°) crystallize from the isopropanol.

The following is obtained analogously by reaction of N- (l-benzenesulfonyl-2, 2-dichlorovinyl)-4- fluorobenzamide with piperazine 1- [4-benzenesulfonyl-2- (4-fluorophenyl) oxazol-5- yl] piperazine.

Analogously to Example 1, the following are obtained by stepwise reaction of 4-chlorobenzamide with chloral, thionyl chloride, sodium benzenesulfinate and with methylamine [4-benzenesulfonyl-2- (4-chlorophenyl) oxazol-5- yl] methylamine

and with ethylamine [4-benzenesulfonyl-2- (4-chlorophenyl) oxazol-5- yl] ethylamine.

Example 2: Analogously to Example 1, the following are obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium benzenesulfinate and with benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) benzylamine; with propylamine (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) propylamine; with 2- (4-methoxyphenyl) ethylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- [2- (4- methoxyphenyl) ethyl] amine ; with (2-methoxy) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- methoxybenzyl) amine; m. p. 131-134° ; with (3-methyl) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- methylbenzyl) amine; with (4-fluoro) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (4- fluorobenzyl) amine; with (3-methoxy) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- methoxybenzyl) amine; with (2-methyl) benzylamine

(4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- methylbenzyl) amine; with (4-trifluoromethoxy) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (4- trifluoromethoxybenzyl) amine; with 2- (3-methoxyphenyl) ethylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- [2- (3- methoxyphenyl) ethyl] amine; with (3-trifluoromethoxy) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- trifluoromethoxybenzyl) amine; with (4-tert-butyl) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (4-tert- butylbenzyl) amine; with (3-trifluoromethyl) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- trifluoromethylbenzyl) amine; with (2-trifluoromethyl) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- trifluoromethylbenzyl) amine; with (4-trifluoromethylsulfanyl) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (4- (trifluoromethylsulfanyl) benzyl) amine; with (2-ethoxy) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- ethoxybenzyl) amine; with (2-trifluoromethoxy) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- trifluoromethoxybenzyl) amine;

with (3-iodo) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- iodobenzyl) amine; with ethylamine (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) ethylamine; m. p. 167.7°; with isopropylamine (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) isopropylamine; with (4-methoxy) benzylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (4- methoxybenzyl) amine ; and with piperazine 1- (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) piperazine.

Example 3: Analogously to Example 1, the following are obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium (4- bromobenzene) sulfinate and with methylamine [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] methylamine ; with propylamine [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] propylamine ; with benzylamine [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] benzylamine ; m. p. 161-161.5°; with (4-fluoro) benzylamine

[4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5-yl]- (4-fluorobenzyl) amine; with (2-methoxy) benzylamine [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5-yl]- (2-methoxybenzyl) amine and with 2- (4-methoxyphenylethyl) amine [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5-yl]-<BR> [2- (4-methoxyphenyl) ethyl] amine.

The following are obtained analogously by stepwise reaction of 5-fluoro-2-methylbenzamide with chloral, thionyl chloride, sodium (4- bromobenzene) sulfinate and with methylamine [4- (4-bromobenzenesulfonyl)-2- (5-fluoro-2- methylphenyl) oxazol-5-yl] methylamine and with benzylamine [4- (4-bromobenzenesulfonyl)-2- (5-fluoro-2- methylphenyl) oxazol-5-yllbenzylamine.

Example 4: Analogously to Example 1, the following are obtained by stepwise reaction of 2-trifluoromethyl- benzamide with chloral, thionyl chloride, sodium benzenesulfinate and with methylamine [4-benzenesulfonyl-2- (2-trifluoromethylphenyl)- oxazol-5-yl] methylamine ; m. p. 146-146.5°; with propylamine [4-benzenesulfonyl-2- (2-trifluoromethylphenyl)- oxazol-5-yl] propylamine ; with benzylamine

[4-benzenesulfonyl-2- (2-trifluoromethylphenyl)- oxazol-5-yl] benzylylamine ; with (4-fluoro) benzylamine [4-benzenesulfonyl-2- (2-trifluoromethylphenyl)- oxazol-5-yl]- (4-fluorobenzyl) amine; m. p. 145.5- 146°; with (4-methoxy) benzylamine [4-benzenesulfonyl-2- (2- trifluoromethylphenyl) oxazol-5-yl]-(4- methoxybenzyl) amine; m. p. 146.5-147°; with 2- (4-methoxyphenylethyl) amine [4-benzenesulfonyl-2- (2- trifluoromethylphenyl) oxazol-5-yl]- [2- (4- methoxyphenyl) ethyl] amine and with ethylamine [4-benzenesulfonyl-2- (2-trifluoromethylphenyl)- oxazol-5-yl] ethylamine ; m. p. 136.5-137°.

Example 5: Analogously to Example 1, the following are obtained by stepwise reaction of 5-fluoro-2-methyl- benzamide with chloral, thionyl chloride, sodium benzenesulfinate and with 2- (4-methoxyphenylethyl) amine [4-benzenesulfonyl-2- (5-fluoro-2-methylphenyl)- oxazol-5-yl]- [2- (4-methoxyphenyl) ethyl] amine; with (2-methoxy) benzylamine [4-benzenesulfonyl-2- (5-fluoro-2-methylphenyl)- oxoazol-5-yl]-(2-methoxybenzyl) amine; m. p. 127-128° and with methylamine

(4-benzenesulfonyl-2- (5-fluoro-2-methylphenyl)- oxazol-5-yl) methylamine; m. p. 160.5-161.2° (decomposition).

Example 6: Analogously to Example 1, the following are obtained by stepwise reaction of benzamide with chloral, thionyl chloride, sodium benzenesulfinate and with methylamine (4-benzenesulfonyl-2-phenyloxazol-5- yl) methylamine; m. p. 171.5° (decomposition); with benzylamine (4-benzenesulfonyl-2-phenyloxazol-5- yl) benzylamine; with (4-fluoro) benzylamine [4-benzenesulfonyl-2-phenyloxazol-5-yl]- (4- fluorobenzyl) amine and with ethylamine (4-benzenesulfonyl-2-phenyloxazol-5-yl) ethylamine; m. p. 169.5-170.5°.

Example 7: Analogously to Example 1, the following are obtained by stepwise reaction of benzamide with chloral, thionyl chloride, sodium (4- methylbenzene) sulfinate and with methylamine methyl- [2-phenyl-4- (toluene-4-sulfonyl) oxazol-5- yl] amine ; m. p. 173° (decomposition) and with ethylamine ethyl- [2-phenyl-4- (toluene-4-sulfonyl) oxazol-5- yl] amine ; m. p. 197° (decomposition).

Analogously to Example 1, the following are obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium (4- methylbenzene) sulfinate and with methylamine methyl- [4- (toluene-4-sulfonyl)-2-o-tolyloxazol-5- yl) amine and with ethylamine ethyl- [4- (toluene-4-sulfonyl)-2-o-tolyloxazol-5- yl] amine ; m. p. 172.5° (decomposition).

Analogously to Example 1, the following are obtained by stepwise reaction of 2-ethoxybenzamide with chloral, thionyl chloride, sodium (4- methylbenzene) sulfinate and with methylamine [2- (2-ethoxyphenyl)-4- (toluene-4-sulfonyl) oxazol- 5-yl] methylamine ; m. p. 136° (decomposition) and with ethylamine [2- (2-ethoxyphenyl)-4- (toluene-4-sulfonyl) oxazol- 5-yl] ethylamine; m. p. 147-148°.

Analogously to Example 1, the following are obtained by stepwise reaction of 2-ethoxybenzamide with chloral, thionyl chloride, sodium benzenesulfinate and with methylamine [4-benzenesulfonyl-2- (2-ethoxyphenyl) oxazol-5- yl] methylamine ; m. p. 130° (decomposition) and with ethylamine [4-benzenesulfonyl-2- (2-ethoxyphenyl) oxazol-5- yl] ethylamine ; m. p. 144° (decomposition).

Example 8 : Analogously to Example 1, the following are obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium (3,4- dichlorobenzene) sulfinate and with methylamine [4- (3, 4-dichlorobenzenesulfonyl)-2-o-tolyloxazol- 5-yl] methylamine ; with propylamine [4- (3, 4-dichlorobenzenesulfonyl)-2-o-tolyloxazol- 5-yl] propylamine ; with benzylamine [4- (3, 4-dichlorobenzenesulfonyl)-2-o-tolyloxazol- 5-yl] benzylamine ; with (4-fluoro) benzylamine [4- (3, 4-dichlorobenzenesulfonyl)-2-o-tolyloxazol- 5-yl]- (4-fluorobenzyl) amine; with cyclopropylamine cyclopropyl [4- (3, 4-dichlorobenzenesulfonyl)-2-o- tolyloxazol-5-yl] amine ; with 2-methoxyethylamine [4- (3, 4-dichlorobenzenesulfonyl)-2-o-tolyloxazol- 5-yl]- (2-methoxyethyl) amine; with (2-methoxy) benzylamine [4- (3, 4-dichlorobenzenesulfonyl)-2-o-tolyloxazol- 5-yl]-(2-methoxybenzyl) amine and with 2- (4-methoxyphenylethyl) amine [4- (3, 4-dichlorobenzenesulfonyl)-2-o-tolyloxazol-<BR> 5-yl]- [2- (4-methoxyphenyl) ethyl] amine.

Analogously to Example 1, the following are obtained by stepwise reaction of 5-fluoro-2- methylbenzamide with chloral, thionyl chloride, sodium (3,4-dichlorobenzene) sulfinate and with cyclopropylamine cyclopropyl [4- (3, 4-dichlorobenzenesulfonyl)-2- (5- fluoro-2-methylphenyl) oxazol-5-yl] amine and with (3-methyl) benzylamine [4- (3, 4-dichlorobenzenesulfonyl)-2- (5-fluoro-2- methylphenyloxazol-5-yl]- (3-methylbenzyl) amine.

Analogously to Example 1, the following are obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium (2,5- dichlorobenzene) sulfinate and with methylamine [4- (2, 5-dichlorobenzenesulfonyl)-2-o-tolyloxazol- 5-yl] methylamine and with benzylamine [4- (2, 5-dichlorobenzenesulfonyl)-2-o-tolyloxazol- 5-yl] benzylamine.

Analogously to Example 1, the following are obtained by stepwise reaction of 2-trifluoromethyl- benzamide with chloral, thionyl chloride, sodium (2,5- dichlorobenzene) sulfinate and with methylamine [4- (2, 5-dichlorobenzenesulfonyl)-2- (2- trifluoromethylphenyl) oxazol-5-yl] methylamine ; with benzylamine [4- (2, 5-dichlorobenzenesulfonyl)-2- (2-trifluoro- methylphenyl) oxazol-5-yl] benzylamine and

with (4-fluoro) benzylamine [4- (2, 5-dichlorobenzenesulfonyl)-2- (2- trifluoromethylphenyl) oxazol-5-yl]-(4- fluorobenzyl) amine.

Example 9: Analogously to Example 1, the following are obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium benzenesulfinate and with 3-methoxypropylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (3- methoxypropyl) amine and with 2-methoxyethylamine (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)- (2- methoxyethyl) amine.

Analogously to Example 1, the following is obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium (4- bromobenzene) sulfinate and with 2-methoxyethylamine [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5-yl]- (2-methoxyethyl) amine.

Analogously to Example 1, the following is obtained by stepwise reaction of 5-fluoro-2- methylbenzamide with chloral, thionyl chloride, sodium benzenesulfinate and with 2-methoxyethylamine [4-benzenesulfonyl-2- (5-fluoro-2- methylphenyl) oxazol-5-yl]- (2-methoxyethyl) amine.

Example 10: Analogously to Example 1, the following are obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium benzenesulfinate and with cyclopropylamine (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) cyclopropylamine; with cyclopentylamine (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) cyclopentylamine and with cyclobutylamine (4-benzenesulfonyl-2-o-tolyloxazol-5- yl) cyclobutylamine; m. p. 168.5-169°.

Analogously to Example 1, the following are obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium (4- bromobenzene) sulfinate and with cyclopropylamine [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] cyclopropylamine ; with cyclopentylamine [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl] cyclopentylamine and with cyclohexylamine [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5-<BR> yl] cyclohexylamine.

Analogously to Example 1, the following is obtained by stepwise reaction of 2-trifluoromethyl- benzamide with chloral, thionyl chloride, sodium benzenesulfinate and

with cyclopropylamine [4-benzenesulfonyl-2- (2-trifluoromethylphenyl)- oxazol-5-yl] cyclopropylamine.

Analogously to Example 1, the following is obtained by stepwise reaction of 5-fluoro-2- methylbenzamide with chloral, thionyl chloride, sodium benzenesulfinate and with cyclopropylamine <BR> <BR> <BR> [4-benzenesulfonyl-2- (5-fluoro-2-<BR> <BR> <BR> <BR> <BR> methylphenyl) oxazol-5-yl] cyclopropylamine.

Example 11: Analogously to Example 1, the following is obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium (4- bromobenzene) sulfinate and with N1, Nl-dimethylethane-1, 2-diamine N'- [4- (4-bromobenzenesulfonyl)-2-o-tolyloxazol-5- yl]-N, N-dimethylethane-1, 2-diamine.

Analogously to Example 1, the following is obtained by stepwise reaction of 2- trifluoromethylbenzamide with chloral, thionyl chloride, sodium benzenesulfinate and with N1, Nl-dimethylpropane-1, 3-diamine N'- [4- (4-bromobenzenesulfonyl)-2- (2- trifluoromethylphenyl) oxazol-5-yl]-N, N- dimethylpropane-1, 3-diamine.

Analogously to Example 1, the following is obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodium benzenesulfinate and with N1, Nl-dimethylpropane-1, 3-diamine

N'- [4-benzenesulfonyl)-2-o-tolyloxazol-5-yl]-N, N- dimethylpropane-1, 3-diamine.

Analogously to Example 1, the following is obtained by stepwise reaction of 5-fluoro-2- methylbenzamide with chloral, thionyl chloride, sodium benzenesulfinate and with Nl, Nl-dimethylpropane-1, 3-diamine N'- [4-benzenesulfonyl-2- (5-fluoro-2- methylphenyl) oxazol-5-yl]-N, N-dimethylpropane-1, 3- diamine.

The following examples relate to pharmaceutical preparations: Example A: Injection vials A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 1 of double-distilled water using 2N hydrochloric acid, sterile-filtered, filled into injection vials, lyophilized under sterile conditions and aseptically sealed. Each injection vial contains 5 mg of active compound.

Example B: Suppositories A mixture of 20 g of an active compound of the formula I is fused with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active compound.

Example C: Solution A solution of 1 g of an active compound of the formula I, 9.38 g of NaH2PO42 H2O, 28.48 g of Na2HPO412 H20 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. It is adjusted to pH 6.8, made up to 1 1 and sterilized by irradiation.

This solution can be used in the form of eye drops.

Example D: Ointment 500 mg of an active compound of the formula 1 are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: Tablets A mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1. 2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is compressed to give tablets in a customary manner such that each tablet contains 10 mg of active compound.

Example F: Coated tablets Analogously to Example E, tablets are pressed and are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: Capsules 2 kg of active compound of the formula I are filled into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound.

Example H: Ampoules A solution of 1 kg of active compound of the formula I in 60 ml of double-distilled water is sterile-filtered, filled into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound.