Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-06-22
2001-06-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S215000, C514S217000, C540S548000, C540S579000
Reexamination Certificate
active
06251894
ABSTRACT:
This invention concerns novel 1-(1,2-disubstituted piperidinyl)-4-(fused imidazole) 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.
WO 92/06981, published on Apr. 30, 1992, discloses 11-[4-substituted-(piperidinyl or piperidinylidene)]-imidazobenzazepines as agents useful in the treatment of asthma and other allergic diseases and in the treatment of inflammation. WO 92/22553, published on Dec. 23, 1992, discloses 10-(piperidinyl or piperidinylidene)-imidazo[1,2-a](pyrrolo, thieno and furano)[3,2-d]azepine derivatives having antiallergic activity. WO-94/13680, published on Jun. 23, 1994, discloses 10-(piperidinyl or piperidinylidene)-imidazo[1,2-a](pyrrolo, thieno and furano)[2,3-d]azepine derivatives having antiallergic activity. Further, WO 95/02600, published on Jan. 26, 1995, discloses other pipetidinyl- or piperidinylidene substituted imidazoazepine derivatives also having antiallergic activity.
The present compounds differ from the art compounds in that they invariably contain a 4-substituted-piperidine moiety in the 4-position of a 2-substituted-(piperidine- or homopiperidine) group or in the 3-position of a 2-substituted-pyrrolidine group, and by their favourable farmacological properties.
Hence, the present invention concerns novel 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;
═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;
L is a radical of formula
wherein the dotted line is an optional bond;
each —A—B— independently is a bivalent radical of formula
—Y—CR
7
═CH— (b-1);
—CH═CR
7
—Y— (b-2);
—CH═CH—CH═CH— (b-3);
—CH═CR
7
—CH═CH— (b-4);
—CH═CH—CR
7
═CH— (b-5);
or
—CH═CH—CH═CR
7
— (b-6);
wherein each Y independently is a bivalent radical of formula —O—, —S— or —NR
8
—;
each R
7
independently is C
1-6
alkyl; halo; ethenyl substituted with carboxyl or C
1-6
alkyloxycarbonyl; hydroxyC
1-6
alkyl; formyl; carboxyl or hydroxycarbonylC
1-6
alkyl; or
R
7
is hydrogen in case —A—B— is a radical of formula (b-1) or (b-2);
R
8
is hydrogen, C
1-6
alkyl or C
1-6
alkylcarbonyl;
each Z independently is Z
1
or Z
2
;
wherein Z
1
is a bivalent radical of formula —CH
2
—, —CH
2
—CH
2
— or CH═CH—; provided that when L is a radical of formula (a-1) and the dotted line is an extra bond, then Z
1
is other than —CH
2
—;
Z
2
is a bivalent radical of formula —CH
2
—CHOH—, CH
2
O—, —CH
2
—C(═O)— or —CH
2
—C(═NOH)—, provided that the —CH
2
— moiety of said bivalent radicals is connected to the nitrogen of the imidazole ring;
each R
4
independently is hydrogen; C
1-6
alkyl; halo; ethenyl substituted with carboxyl or C
1-6
alkyloxycarbonyl; C
1-6
alkyl substituted with carboxyl or C
1-6
alkyloxycarbonyl; hydroxyC
1-6
alkyl; formyl or carboxyl;
each R
5
independently is hydrogen, C
1-6
alkyl, hydroxyC
1-6
alkyl, Ar
1
or halo; or
R
4
and R
5
taken together may form a bivalent radical of formula
CH═CH—CH═CH— or —CH
2
—CH
2
—CH
2
—CH
2
;
each R
6
is hydrogen, C
1-6
alkyl or Ar
1
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; 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 form 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-tolu
Janssens Frans Eduard
Leenaerts Joseph Elisabeth
Van Roosbroeck Yves Emiel Maria
Appollina Mary
Janssen Pharmaceuticals N.V.
Raymond Richard L.
Truong Tamthom M.
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