Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-13
2002-02-12
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S208000, C540S597000, C514S212010
Reexamination Certificate
active
06346540
ABSTRACT:
This invention concerns 1-(1,2-disubstituted piperidinyl)-4-substituted piperidine 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, discloses 1-acylpiperidine compounds, in particular 2-arylalkyl-1-arylcarbonyl-4-piperidinamine derivatives, and their use as substance P antagonists.
EP-0,151,824-A and EP-0,151,826-A disclose structurally related 1-(1-(carbonyl or imino)-4-piperidinyl)-4-piperidinamine derivatives as histamine- and serotonine antagonists.
The present compounds differ from the art compounds by their structure and by their favourable pharmacological properties.
The present invention concerns compounds of formula
the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and 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 0, 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
—CH
2
—CH
2
—O—;
R
2
is Ar
2
; Ar
2
C
1-6
alkyl; Het or HetC
1-6
alkyl;
R
3
is hydrogen or C
1-6
alkyl;
R
4
is hydrogen; C
1-4
alkyl; C
1-4
alkyloxyC
1-4
alkyl; hydroxyC
1-4
alkyl; carboxyl;
C
1-4
alkyloxycarbonyl or Ar
3
;
R
5
is hydrogen; hydroxy; Ar
3
; Ar
3
C
1-6
alkyloxy; di(Ar
3
)C
1-6
alkyloxy;
Ar
3
C
1-6
alkylthio; di(Ar
3
)C
1-6
alkylthio; Ar
3
C
1-6
alkylsulfoxy; di(Ar
3
)C
1-6
alkylsulfoxy;
Ar
3
C
1-6
alkylsulfonyl; di(Ar
3
)C
1-6
alkylsulfonyl; —NR
7
R
8
; C
1-6
alkyl substituted with —NR
7
R
8
; or a radical of formula
wherein
R
7
is hydrogen; C
1-6
alkyl; pyridinyl or Ar
3
;
R
8
is hydrogen; C
1-6
alkyl; Ar
3
C
1-6
alkyl; di(Ar
3
)C
1-6
alkyl; imidazolyl substituted with Ar
3
, C
1-6
alkyl or Ar
3
C
1-6
alkyl; benzoxazolyl or benzothiazolyl;
R
9
is hydrogen; hydroxy; C
1-6
alkyl; C
1-6
alkyloxy; Ar
3
; Ar
3
C
1-6
alkyl; di(Ar
3
)-C
1-6
alkyl; amino; mono- or di(C
1-6
alkyl)amino; imidazolyl; imidazolyl substituted with Ar
3
, C
1-6
alkyl or Ar
3
C
1-6
alkyl; pyrrolidinyl; piperidinyl; homopiperidinyl; morpholinyl or thiomorpholinyl;
R
10
is hydrogen or C
1-6
alkylcarbonyl;
R
11
is hydrogen; halo or mono-, di- or tri(halo)methyl;
Y is Y
1
or Y
2
,
wherein
Y
1
is a covalent bond; C
1-6
alkanediyl; —NR
7
— or
—C
1-6
alkanediyl-NR
7
—; or
Y
2
is —O—, provided that R
9
is other than hydroxy or C
1-6
alkyloxy;
R
4
and R
5
may also be taken together to form a bivalent radical of formula —O—CH
2
—CH
2
—O— or —C(═O)—NR
3
—CH
2
—NR
7
—;
R
6
is hydroxy; C
1-6
alkyloxy; C
1-6
alkyl or Ar
3
C
1-6
alkyl;
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
alkyloxy; and
Het 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.
The heterocycles in the definition of Het 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
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C
1-6
alkyl is meant to include C
1-4
alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, 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 from 5 to 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like.
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 as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The pharmaceutically acceptable addition salts as mentioned hereinabove are also meant to comprise the therapeutically active non-toxic base, in particular, the metal or amine addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the compounds of formula (I) containing acidic hydrogen atoms with appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabanine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid
Janssens Frans Eduard
Sommen François Maria
Surleraux Dominique Louis Nestor Ghislaine
Van Roosbroeck Yves Emiel Maria
Appollina Mary
Aulakh C. S.
Janssen Pharmaceutica N.V.
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