Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-07-06
2001-04-10
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S484000, C540S553000
Reexamination Certificate
active
06214822
ABSTRACT:
The invention relates to substituted aza- and diazacycloheptane and -cyclooctane compounds and to the use of such compounds. Said compounds have valuable therapeutic properties and can be used in particular for treating disorders which respond to dopamine D
3
ligands.
Compounds of the type under discussion here and having physiological activity have in some cases been disclosed. Thus, DE 21 39 082 and DE 22 58 561 describe pyrimidine derivatives and pyrimidone derivatives with basic substituents as drugs for lowering blood pressure. These pyrimidine and pyrimidone derivatives have the formulae:
where in (A) X is, inter alia, a sulfur atom, A is a C
1
-C
6
-alkylene group, and R
1
, R
2
, R
3
and Z are various substituents. In (B), X and Y are an oxygen or sulfur atom, A is a C
2
-C
6
-alkylene group, W is a vinylene group and R and Z are various substituents.
EP-A-361271 describes pyridyl and pyrimidyl derivatives of the formula:
where R
1
is halogen or hydrogen, and R
2
is halogen; X is oxygen, sulfur or methylene; R
3
and R
4
, which are identical or different, are hydrogen or lower alkyl; n is 2 or 3; A is a 2-pyrimidyl group or a 2- or 3-pyridyl group, it being possible for these groups to be substituted.
These compounds can be used to treat mental disturbances.
EP-A-454498 describes compounds of the formula
where A is, inter alia, —(CH
2
)
m
— or —B—(CH
2
)
k
—, where B is O, S, an unsubstituted or substituted amino group, —CONH— or —COO—, R
1
and R
2
can, inter alia, together form an alkylene chain, R
3
and R
4
are a hydrogen atom or a lower alkyl group, and X
1
, X
2
and X
3
are various substituents. These compounds can be used to treat cardiac arrhythmias.
EP-A-452107 and EP-A-369627 describe structurally similar compounds which can likewise be used for treating cardiac arrhythmias.
In addition, BE-A-628 766 describes compounds of the formula
where X is a halogen atom or a lower alkyl radical, T is piperazine, methylpiperazine, homopiperazine or methylhomopiperazine; Z is alkylene or alkenylene; A is O or S; and Y is a naphthyl, halonaphthyl or an unsubstituted or mono- to trisubstituted phenyl radical. These compounds can be used to treat schistosomiasis.
Neurones obtain their information inter alia via G-protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of these is dopamine.
Confirmed information on the presence of dopamine and its physiological function as neurotransmitter is available. Cells responding to dopamine are connected with the etiology of schizophrenia and Parkinson's disease. These and other diseases are treated with drugs which interact with dopamine receptors.
Up to 1990, two subtypes of dopamine receptors had been clearly defined pharmacologically, mainly the D
1
and D
2
receptors.
More recently, a third subtype has been found, namely the D
3
receptor, which appears to mediate some of the effects of antipsychotics (J. C. Schwartz et al., The Dopamine D
3
Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144).
D
3
receptors are mainly expressed in the limbic system. It is therefore assumed that a selective D
3
antagonist is likely to have the antipsychotic properties of the D
2
antagonists but not their neurological side effects (P. Sokoloff et al., Localization and Function of the D
3
Dopamine Receptor,
Arzneim. Forsch./Drug Res.
42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D
3
) as a Target for Neuroleptics,
Nature,
347, 146 (1990)).
P. J. Murray et al., Bioorganic & Medicinal Chemistry Letters, Vol. 5, No. 3, 219-222 (1995), have described arylpiperazines of the formula
where R
1
and R
2
are H or CH
3
O, and X is Br, 4-acetylphenyl, 4-methylsulfonylphenyl or 4-aminophenyl, with higher affinity and selectivity for the dopamine D
3
receptor.
We have now found, surprisingly, that certain aza- and diazacycloheptane and -cyclooctane compounds have a high affinity for the dopamine D
3
receptor and a low affinity for the D
2
receptor. They are thus selective D
3
ligands.
The present invention therefore relates to the compounds of the general formula I:
Ar
1
—A—B—Ar
2
(I)
where
Ar
1
is
or a 5- or 6-membered heteroaromatic ring with 1, 2 or 3 heteroatoms which are selected, independently of one another, from O, N and S, where Ar
1
may have 1, 2, 3 or 4 substituents which are selected, independently of one another, from OR
1
, alkyl which is unsubstituted or substituted by OH, OC
1
-C
8
-alkyl or halogen, or C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, cycloalkyl, halogen, CN, CO
2
R
1
, NO
2
, NR
1
R
2
, SR
1
, CF
3
, CHF
2
, phenyl which is unsubstituted or substituted by C
1
-C
6
-alkyl, OC
1
-C
6
-alkyl, acyl, phenyl, amino, nitro, cyano or halogen, or phenoxy which is unsubstituted or substituted by C
1
-C
6
-alkyl, OC
1
-C
6
-alkyl or halogen, or C
1
-C
6
-alkanoyl or benzoyl;
R
1
is H, alkyl which is unsubstituted or substituted by OH, OC
1
-C
6
-alkyl, phenyl or halogen;
R
2
has the meanings stated for R
1
or is COR
1
or CO
2
R
1
;
A is a C
3
-C
15
-alkylene group when Ar
1
is C
6
H
5
CONH, or, when Ar
1
is a 5- or 6-membered heteroaromatic ring, is a C
4
-C
15
-alkylene group or a C
3
-C
15
-alkylene group which comprises at least one group Z which is selected from O, S, NR
1
, a double and a triple bond, where R
1
is as defined above,
B is a 7- or 8-membered saturated ring with one or two nitrogen heteroatoms, the nitrogen heteroatoms being located in the 1,4 or 1,5 position and the ring being bonded in position 1 to the radical A and in position 4 or 5 to the radical Ar
2
, and it additionally being possible for the ring to have a double bond in position 3 or 4 in the monoaza ring and in position 6 in the 1,4-diaza ring;
Ar
2
is phenyl, pyridyl, pyrimidinyl or triazinyl, it being possible for Ar
2
to have 1, 2, 3 or 4 substituents which are selected, independently of one another, from OR
1
, alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, alkoxyalkyl, haloalkyl, halogen, CN, CO
2
R
1
, NO
2
, SO
2
R
1
, NR
1
R
2
, SO
2
NR
1
R
2
, SR
1
, a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or 6-membered heterocyclic aromatic or non-aromatic ring with 1 to 3 heteroatoms which are selected from O, S and N, the carbocyclic or heterocyclic ring being unsubstituted or substituted by C
1
-C
8
-alkyl, phenyl, phenoxy, halogen, OC
1
-C
8
-alkyl, OH, NO
2
or CF
3
, where R
1
and R
2
have the abovementioned meanings, and Ar
2
may also be fused to a carbocyclic ring of the type defined above, and where Ar
2
cannot be a pyrimidinyl radical substituted by 2 hydroxyl groups, and the salts thereof with physiologically tolerated acids.
The compounds according to the invention are selective dopamine D
3
receptor ligands which intervene regioselectively in the limbic system and, because of their low affinity for the D
2
receptor, have fewer side effects than classical neuroleptics, which are D
2
receptor antagonists. The compounds can therefore be used to treat disorders which respond to dopamine D
3
receptor antagonists or agonists, eg. for treating disorders of the central nervous system, in particular schizophrenia, depression, neuroses and psychoses.
For the purpose of the present invention, the following terms have the meanings indicated thereafter:
alkyl (also in radicals such as alkoxy, alkylamino etc.) is a straight-chain or branched alkyl group with 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and, in particular, 1 to 4 carbon atoms. The alkyl group may have one or more substituents which are selected, independently of one another, from OH and OC
1
-C
8
-alkyl.
Examples of an alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl, etc.
Cycloalkyl is in particular C
3
-C
6
-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Alkylene is a straight-chain or branched radical with, preferably, 4 to 15 carbon atoms, particularly preferably
Blank Stefan
Starck Dorothea
Teschendorf Hans-Jurgen
Treiber Hans-Jorg
Unger Liliane
BASF - Aktiengesellschaft
Keil & Weinkauf
Shah Mukund J.
Sripada Pavanaram K
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