Sulfonyloxazoleamines

Details Sulfonyloxazoleamines Sulfonyloxazoleamines

2002-05-28

2004-05-18

Desai, Rita (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S253010, C514S254020, C514S340000, C544S359000, C544S360000, C544S367000, C546S271400

Reexamination Certificate

active

06737426

ABSTRACT:

The invention relates to sulfonyloxazolamines of the general formula I and to their use as medicaments, and to a process for their preparation, to the intermediates employed in the preparation process and to a process for preparing the intermediates.
The sulfonyloxazolamines according to the invention are compounds of the general formula (I)
where
R
1
and R
2
independently of one another are H, —R
6
, —C
3
-C
8
-cycloalkyl, —(CH
2
)
n
—R
7
, —(CH
2
)
n
—O—R
6
, —(CH
2
)
n
—NH
2
, —(CH
2
)
n
—NHR
6
, —(CH
2
)—N(R
6
)
2
, C
2
-C
6
-alkenyl or, where appropriate, together form a mononuclear saturated heterocycle having one or two nitrogen, oxygen and/or sulfur atoms,
R
3
and R
4
independently of one another are H, —R
6
, —CF
3
, —NO
2
, —Hal, —OH, —O—R
6
, —NH
2
, —NH—R
6
or —N(R
6
)
2
,
R
5
is a 5- or 6-membered, saturated or unsaturated heterocycle having one or two nitrogen, oxygen and/or sulfur atoms which may be mono- or disubstituted by —R
6
, —CF
3
, —NO
2
, —Hal, —OH, —O—R
6
, —NH
2
, —NH—R
6
or —N(R
6
)
2
, and
R
6
is C
1
-C
6
-alkyl,
R
7
is R
3
- and/or R
4
-substituted phenyl,
n is 0 to 2,
and physiologically acceptable salts or solvates thereof.
Some sulfonyloxazolamines are known from various earlier publications: V. A. Chervonyi et al.,
Ukr. Khim. Zh
. (Russian Ed.) 1991, 57(4), 415-418 or V. A. Chervonyi et al.,
Zh. Org. Khirm
. 1988, 24(2), 453-4 corresponding to V. A. Chervonyi et al.,
J. Org. Chem. USSR
(Engl. transl.) 1988, 24, 401. The latter publication describes, for example, the preparation of 4-tolylsulfonyl-5-dimethylamino-2-phenyl-1,3-oxazole.
The invention was based on the object of finding sulfonyloxazolamines with valuable properties. In particular it was important to find pharmacologically active sulfonyloxazolamines.
The object is achieved by compounds of the general formula I described hereinbefore and physiologically acceptable salts or solvates thereof.
It was found that the compounds of the formula I and their pharmacologically active salts surprisingly have a selective affinity to 5-HT6 receptors, together with good tolerability, and they are therefore 5-HT6 receptor ligands. 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, contains 13 G protein-coupled receptors and an ion channel. The group of G protein-coupled receptors also includes the 5-HTG receptors. Some representatives have been cloned and to some extent histologically and biochemically investigated (see, for example, Kohen et al. (1996) J. Neurochem 66, 47-56; Ruart et al. (1993), 193, 268-76).
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, especially, 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 physiologically acceptable salts or solvates thereof 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.,
Neurotransmitters
1995, 11, 1-5), bulimia, anorexia nervosa or other eating disorders, compulsive acts or of premenstrual syndrome. 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 dehydrates or alcoholates.
For all radicals which occur one or more times it holds true that their meanings are independent of one another.
R
3
and R
4
are preferably and independently of one another methyl, methoxy, chlorine and bromine or hydrogen.
is 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- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, 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.
Particularly preferred for
is phenyl, o- or p-methylphenyl, o- or p-chlorophenyl, p-bromophenyl, p-methoxyphenyl or 2,4-dichlorophenyl.
—Hal is fluorine, chlorine or bromine.
R
1
and R
2
together may also form a mononuclear saturated heterocycle having from 1 to 2 N, O and/or S atoms.
This heterocycle is preferably tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- 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, 1-Piperidinyl or 4-morpholinyl is particularly preferred.
Compounds in which R
1
is H are preferred.
Furthermore, compounds of the general formula I in which R
2
is R
6
are preferred.
Moreover, R
3
and/or R
4
are preferably H.
R
5
is preferably 2-furyl, 2-thienyl or 3- or 4-pyridyl.
R
6
is linear or branched, and has 1 to 6, preferably 1, 2, 3 or 4, C atoms. R
6
is preferably methyl, furthermore ethyl, 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 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.
A base of the general formula I can be converted

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