Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-22
2003-02-18
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S249000, C514S252110, C514S252180, C514S252020, C514S253010, C514S253090, C514S253100, C514S253130, C514S253060, C544S236000, C544S238000, C544S295000, C544S357000, C544S353000, C544S355000, C544S360000, C544S362000, C544S363000, C544S364000, C544S365000
Reexamination Certificate
active
06521621
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 substances 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 covalent 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
—H
2
—H
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 1, 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 substituents; 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, haloC
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
alkyl-oxy;
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-propenyl, 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 substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl.
The pharmaceutically acceptable addition salts
Janssens Frans Eduard
Leenaerts Joseph Elisabeth
Sommen François Maria
Surleraux Dominique Louis Nestor Ghislaine
Van Roosbroeck Yves Emiel Maria
Appollina Mary
Bernhardt Emily
Janssen Pharmaceutica N.V.
LandOfFree
1-(1,2-disubstituted piperidinyl)-4-substituted piperazine... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 1-(1,2-disubstituted piperidinyl)-4-substituted piperazine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 1-(1,2-disubstituted piperidinyl)-4-substituted piperazine... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3130508