Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-27
2002-06-18
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S575000, C544S121000, C544S230000, C544S295000, C544S357000, C544S364000, C544S366000
Reexamination Certificate
active
06407106
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel 2-indolylmethyl-piperazine derivatives which are antagonistic to neurokinin receptors and which are substituted at a nitrogen of the piperazine parent structure by a triazolylmethyl radical. Furthermore, the invention relates to medicaments containing these novel N-triazolylmethyl-piperazine derivatives. Furthermore, the invention relates to a process for the preparation of the novel piperazine derivatives and also intermediate products of this process.
Compounds which are structurally similar to the compounds of the present invention are already known from WO 98/57954, which compounds are ascribed general properties which are antagonistic to tachykinin, neurokinin A or alternatively neurokinin B and which are capable of influencing the central nervous system (=CNS).
2-Indolylmethyl-piperazine derivatives having a different substitution pattern from the compounds of the present invention and which have properties which are antagonistic to neurokinin receptors are described in EP 0 899 270 A1.
Furthermore, additional 2-indolylmethyl-piperazine derivatives having a different substitution pattern from the compounds of the present invention are known from EP 0 655 442 A1 which are ascribed properties which generally are antagonistic to tachykinin, neurokinin A or alternatively neurokinin B and which are regarded as being suitable to influence the CNS.
SUMMARY OF THE INVENTION
It was an object of the present invention to provide novel active substances having properties antagonistic to neurokinin (=NK) receptors.
Another object of the invention was to provide compounds with neurokinin receptor antagonistic properties and an improved activity profile.
A further object of the invention was to provide compounds with neurokinin receptor antagonistic properties which are suitable for treating peripheral disturbances such as functional and inflammatory disturbances of the gastrointestinal tract.
These and other objects of the invention have been achieved by providing a compound corresponding to the formula I:
wherein
R
1
is hydrogen or lower alkyl,
R
2
is lower alkyl, di-lower-alkylamino lower alkyl, lower-alkoxycarbonyl lower alkyl; cyclo(hetero)alkyl having 5-6 ring atoms, which may optionally be substituted once or twice by lower alkyl and which optionally contains 1-2 double bonds; (hetero)phenyl lower alkyl optionally substituted once or twice in the (hetero)phenyl ring by halogen, lower alkyl and/or lower alkoxy, the lower-alkyl chain of which (hetero)phenyl lower alkyl is optionally substituted once or twice by lower alkyl or by spiro-C
4
-C
5
-alkylene; or phenyl lower alkoxy optionally substituted once or twice in the phenyl ring by halogen, lower alkyl and/or lower alkoxy, and
R
3
is lower alkyl, lower-alkoxycarbonyl lower alkyl or cyclo(hetero)alkyl with 5-6 ring atoms which is optionally substituted once or twice by lower alkyl, or
R
2
and R
3
, together with the nitrogen to which they are bonded, form a cyclic group of formula a:
wherein
A is nitrogen, oxygen, methylene or methylidene, the double bond of which, together with the adjacent carbon, is formed in position 3 of group a,
n is a whole number from 1 to 3,
R
4
is hydrogen, lower alkyl, lower-alkoxy lower alkyl, lower alkoxycarbonyl, lower-alkoxycarbonyl lower alkyl, di-lower-alkylamino lower alkyl; (hetero)phenyl optionally substituted once or twice by halogen, lower alkyl and/or lower alkoxy; (hetero)phenyl lower alkyl optionally substituted once or twice in the (hetero)phenyl ring by halogen, lower alkyl and/or lower alkoxy, the lower-alkyl chain of which (hetero)phenyl lower alkyl is optionally substituted once or twice by lower alkyl; cyclo(hetero)alkyl with 5-6 ring atoms, or cyclo(hetero)alkyl lower alkyl, the cyclo(hetero)alkyl group of which has 5-6 ring atoms, and
R
5
is hydrogen, lower alkyl or lower-alkoxy lower alkyl, or
R
4
and R
5
together are spiroethylenedioxy bonded to a carbon of group a; C
3
-C
4
-alkylene bonded to two adjacent atoms of group a; or phenyl fused via two adjacent carbons of group a, or
R
2
and R
3
, together with the nitrogen to which they are bonded, form a pyrrolidine ring which is substituted twice by C
4
-alkylene which is bonded each time via two adjacent carbon atoms;
or a physiologically compatible acid addition salts thereof.
It has now surprisingly been discovered that one group of novel N-triazolylmethyl-piperazine derivatives is distinguished by specific properties antagonistic to NK-1 receptors and exerts its action preferentially in the peripheral region. Accordingly, the group of compounds according to the invention appears particularly suitable for the treatment of peripheral disturbances induced by NK-1, in particular for the treatment of functional and inflammatory disturbances of the gastrointestinal tract.
The invention thus relates to new compounds corresponding to the formula I:
wherein
R
1
is hydrogen or lower alkyl,
R
2
is lower alkyl, di-lower-alkylamino lower alkyl, lower-alkoxycarbonyl lower alkyl; cyclo(hetero)alkyl having 5-6 ring atoms, which may optionally be substituted once or twice by lower alkyl and which optionally contains 1-2 double bonds; (hetero)phenyl lower alkyl optionally substituted once or twice in the (hetero)phenyl ring by halogen, lower alkyl and/or lower alkoxy, the lower-alkyl chain of which (hetero)phenyl lower alkyl is optionally substituted once or twice by lower alkyl or by spiro-C
4
-C
5
-alkylene; or phenyl lower alkoxy optionally substituted once or twice in the phenyl ring by halogen, lower alkyl and/or lower alkoxy, and
R
3
is lower alkyl, lower-alkoxycarbonyl lower alkyl or cyclo(hetero)alkyl with 5-6 ring atoms which is optionally substituted once or twice by lower alkyl, or
R
2
and R
3
, together with the nitrogen to which they are bonded, form a cyclic group of formula a:
wherein
A is nitrogen, oxygen, methylene or methylidene, the double bond of which, together with the adjacent carbon, is formed in position 3 of group a, n is a whole number from 1 to 3,
R
4
is hydrogen, lower alkyl, lower-alkoxy lower alkyl, lower alkoxycarbonyl, lower-alkoxycarbonyl lower alkyl, di-lower-alkylamino lower alkyl; (hetero)phenyl optionally substituted once or twice by halogen, lower alkyl and/or lower alkoxy; (hetero)phenyl lower alkyl optionally substituted once or twice in the (hetero)phenyl ring by halogen, lower alkyl and/or lower alkoxy, the lower-alkyl chain of which (hetero)phenyl lower alkyl is optionally substituted once or twice by lower alkyl; cyclo(hetero)alkyl with 5-6 ring atoms, or cyclo(hetero)alkyl lower alkyl, the cyclo(hetero)alkyl group of which has 5-6 ring atoms, and
5
is hydrogen, lower alkyl or lower-alkoxy lower alkyl, or
4
and
5
together are spiroethylenedioxy bonded to a carbon of group a, C
3
-C
4
-alkylene bonded to two adjacent atoms of group a, or phenyl fused via two adjacent carbons of group a; or
R
2
and R
3
, together with the nitrogen to which they are bonded, form a pyrrolidine ring which is substituted twice by C
4
-alkylene which is bonded each time via two adjacent carbon atoms, and physiologically compatible acid addition salts of compounds of Formula I.
Furthermore, the invention also relates to pharmaceutical compositions containing the compounds of Formula I.
In addition, the invention relates to a process for preparing the compounds of Formula I and intermediate products of this process.
Whenever in the compounds of Formula I the substituents are or contain lower alkyl or alkoxy groups, these may be straight-chain or branched and contain 1 to 4 carbon atoms.
Whenever the substituents contain halogen, in particular fluorine, chlorine or bromine, preferably fluorine or chlorine, are used.
Whenever the substituents of the compounds of Formula I are or contain cyclo(hetero)alkyl, this may be a pure carbocyclic group, or it may also represent carbocyclic compounds in which in each case 1 to 3 ring carbon atoms are replaced by nitrogen, oxygen and/or sulfur. Nitrogen and oxygen are pref
Brueckner Reinhard
Eeckhout Christian
Jasserand Daniel
Sann Holger
Schoen Uwe
Crowell & Moring LLP
Ramsuer Robert W.
Solvay Pharmaceuticals GmbH
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