1- (1,2-disubstituted piperidinyl) -4-substituted piperazine...

Details 1- (1,2-disubstituted piperidinyl) -4-substituted piperazine... 1- (1,2-disubstituted piperidinyl) -4-substituted piperazine...

1998-04-03

2001-03-06

Bernhardt, Emily (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S253010, C514S253090, C514S253100, C514S218000, C544S360000, C544S362000, C544S364000, C544S365000, C540S575000

Reexamination Certificate

active

06197772

ABSTRACT:

This invention concerns 1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives having tachykinin antagonistic activity, in particular substance P antagonistic activity, and their preparation, it further relates to compositions comprising them, as well as their use as a medicine.
Substance P is a naturally occurring neuropeptide of the tachykinin family. There are ample studies showing that substance P and other tachykinins are involved in a variety of biological actions, and therefore, play an essential role in various disorders (Regoli et al., Pharmacological Reviews 46(4), 1994, p: 551-599, “Receptors and Antagonists for Substance P and Related Peptides”). The development of tachykinin antagonists has led to date to a series of peptide compounds of which might be anticipated that they are metabolically too labile to be employed as pharmaceutically active substances (Longmore J. et al., DN&P 8(1), February 1995, p. 5-23. “Neurokinin Receptors”). The present invention concerns nonpeptide tachykinin antagonists, in particular nonpeptide substance-P antagonists, which in general are metabolically more stable, and hence, may be more appropriate as pharmaceutically active substances.
Several nonpeptide tachykinin antagonists are disclosed in the art. For instance, EP-0,532,456-A, published on Mar. 17, 1993 by Ciba-Geigy Corp., discloses 1-acylpiperidine compounds, in particular 2-arylalkyl-1-arylcarbonyl-4-piperidinamine derivatives, and their use as substance-P antagonists. EP-0,655,442-A, published on May 31, 1995 by Fujisawa Pharmaceutical Co. Ltd., discloses piperazine derivatives having tachykinin antagonistic activity.
The present compounds differ therefrom in that they invariably contain a 4-substituted-(piperazine or homopiperazine)-moiety in the 4-position of a piperidine- or homopiperidine group or in the 3-position of a pyrrolidine group, and by their favourable farmacological properties.
The present invention concerns compounds of formula
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
n is 0, 1 or 2;
m is 1 or 2, provided that if m is 2, then n is 1;
p is 1 or 2;
═Q is ═O or ═NR
3
;
X is a convalent bond or a bivalent radical of formula —O—, —S—, —NR
3
—;
R
1
is Ar
1
, Ar
1
C
1-6
alkyl or di(Ar
1
)C
1-6
alkyl, wherein each C
1-6
alkyl group is optionally substituted with hydroxy, C
1-4
alkyloxy, oxo or a ketalized oxo substituent of formula —O—CH
2
—CH
2
—O— or —O—CH
2
—CH
2
—CH
2
—O—;
R
2
is Ar
2
, Ar
2
C
1-6
alkyl, Het
1
or Het
1
C
1-6
alkyl;
R
3
is hydrogen or C
1-6
alkyl;
L is hydrogen, Ar
3
; C
1-6
alkyl; C
1-6
alkyl substituted with 1 or 2 substituents selected from hydroxy, C
1-6
alkyloxy, Ar
3
, Ar
3
C
1-6
alkyloxy and Het
2
; C
3-6
alkenyl; Ar
3
C
3-6
alkenyl; di(Ar
3
)C
3-6
alkenyl or a radical of formula
wherein each q independently is 2, 3 or 4;
each r is 0, 1, 2, 3 or 4;
each Y
1
independently is a covalent bond, —O— or NR
3
;
Y
2
is a covalent bond, C
1-4
alkanediyl or —C
1-4
alkylNR
3
—;
each —A═B— independently is a bivalent radical of formula —CH═CH—, —N═CH— or —CH═N—;
each R
4
independently is hydrogen, C
1-6
alkyl, Ar
2
or Ar
2
C
1-6
alkyl;
R
5
is hydrogen, C
1-6
alkyl or Ar
3
;
R
6
is C
1-6
alkyl, Ar
3
, Ar
3
C
1-6
alkyl, di(Ar
3
)C
1-6
alkyl, Ar
3
C
3-7
cycloalkyl, or indolyl;
R
7
is Ar
3
, Ar
3
C
1-6
alkyl; di(Ar
3
)C
1-6
alkyl; C
1-6
alkyl; C
3-7
cycloalkyl; C
3-7
cycloalkyl substituted with Ar
3
; oxazolyl; oxazolyl substituted with halo or C
1-6
alkyl; thiazolyl; thiazolyl substituted with halo or C
1-6
alkyl; imidazolyl; imidazolyl substituted with Ar
3
, C
1-6
alkyl, Ar
3
C
1-6
alkyl or halo; indolinyl; indolinyl substituted with C
1-4
alkyl; 2,3,4-trihydroquinolinyl; pyrrolidinyl or furanyl;
each R
8
independently is hydrogen, C
1-6
alkyl, C
3-7
cycloalkyl or a radical of formula
—Alk—R
11
  (b-1)
or
—Alk—Z—R
12
  (b-2);
wherein Alk is C
1-6
alkanediyl;
Z is a bivalent radical of formula —O—, —S— or —NR
3
—;
R
11
is phenyl; phenyl substituted with 1 or 2 substituents selected from halo, C
1-6
alkyl or C
1-6
alkyloxy; furanyl; furanyl substituted with 1 or 2 substituents selected from C
1-6
alkyl or hydroxyC
1-6
alkyl; thienyl; thienyl substituted with 1 or 2 substituents selected from halo or C
1-6
alkyl; oxazolyl; oxazolyl substituted with 1 or 2 C
1-6
alkyl substituents, thiazolyl; thiazolyl substituted with 1 or 2 C
1-6
alkyl substitutents; pyridinyl or pyridinyl substituted with 1 or 2 C
1-6
alkyl substituents;
R
12
is C
1-6
alkyl or C
1-6
alkyl substituted with hydroxy, carboxyl or C
1-6
alkyloxycarbonyl;
Ar
1
is phenyl; phenyl substituted with 1,2 or 3 substituents each independently selected from halo, C
1-4
alkyl, haloC
1-4
alkyl, cyano, aminocarbonyl, C
1-4
alkyloxy or haloC
1-4
alkyloxy;
Ar
2
is naphtalenyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from hydroxy, halo, cyano, nitro, amino, mono- or di(C
1-4
alkyl)amino, C
1-4
alkyl, haloC
1-4
alkyl, C
1-4
alkyloxy, halo C
1-4
alkyloxy, carboxyl, C
1-4
alkyloxycarbonyl, aminocarbonyl and mono- or di(C
1-4
alkyl)aminocarbonyl;
Ar
3
is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, amino, nitro, aminocarbonyl, C
1-6
alkyl, haloC
1-6
alkyl or C
1-6
alkyloxy;
Het
1
is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, C
1-4
alkyl or mono-, di or tri(halo)methyl; and
Het
2
is a heterocycle selected from 1,4-dihydro-5-oxo-tetrazol-1-yl, imidazo[1,2-a]-pyridinyl, oxazolyl or imidazolyl; each of said heterocycles may be substituted with 1 or where possible 2 substituents selected from C
1-4
alkyl and Ar
3
.
The heterocycles in the definition of Het
1
are preferably connected to the rest of the molecule, i.e. X, —C(═Q)— or C
1-6
alkyl, by a carbon atom.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
2-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as, for example, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C
1-4
alkyl is meant to include C
2-4
alkyl and methyl; C
1-5
alkyl is meant to include C
1-4
alkyl and the higher homologues thereof having 5 carbon atoms such as, for example, pentyl, 2-methylbutyl and the like; C
1-6
alkyl is meant to include C
1-5
alkyl and the higher homologues thereof having 6 carbon atoms such as, for example, hexyl, 2-methylpentyl and the like; C
1-4
alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, and the like; C
1-6
alkanediyl is meant to include C
1-4
alkanediyl and the higher homologues thereof having form 5 to 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like; C
3-6
alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propentyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like; and the carbon of said C
3-6
alkenyl connected to the nitrogen atom of the piperazine or homopiperazine preferably is saturated.
As used in the foregoing definitions and hereinafter, haloC
1-4
alkyl is defined as mono- or polyhalosubstituted C
1-4
alkyl, in particular C
1-4
alkyl substitutred with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl.
The pharmaceutically acceptable addition salts as men

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