2-substituted-1-piperidyl benzimidazole compounds as...

Details 2-substituted-1-piperidyl benzimidazole compounds as... 2-substituted-1-piperidyl benzimidazole compounds as...

1999-08-05

2001-01-09

Huang, Evelyn Mei (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S235800, C514S316000, C514S322000, C544S124000, C544S364000, C546S187000, C546S199000

Reexamination Certificate

active

06172067

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel 1-substituted-piperidin-4-yl 2-substituted benzimidazole compounds, and their salts, pharmaceutical compositions containing them, their medical uses, processes for preparing those compounds and intermediate compounds useful in the processes. The compounds of this invention have activity as selective ORL1-receptor agonists, and as such are useful in treating or preventing disorders or medical conditions selected from pain, inflammatory diseases and the like.
BACKGROUND ART
In spite of their usefulness as analgesics, usage of opioids such as morphine and heroin are strictly limited. This is because these drugs induce side effects such as euphoria, respiratory depression or constipation. Further, multiple dosage of the drugs cause addiction. Thus, there has been a long-felt need to provide analgesics with reduced side effects.
From the above point of view, considerable pharmacological and biochemical studies have been carried out to identify opioid receptors and their endogenous ligands to prepare peptide and non-peptide opioid ligands for the receptors. In the recent past, amino acid sequences of mu- (&mgr;-), delta (&dgr;-) and kappa (&kgr;-) opioid receptor subtypes have been identified and reported. Subsequently, a novel receptor subtype was identified and termed ORL1-receptor, and Meunier, J.-C et al. reported the isolation and structure of the endogenous agonist of the receptor (
Nature
, Vol. 377, pp. 532-535, Oct. 12, 1995). It is suggested that the agonist compounds for ORL1-receptor be effective in neurogenic inflammation (
Tips
, Vol. 18, pp. 293-300, August 1997). It is also suggested that the agonist compounds be potent analgesics having less psychological side effects and addiction (D. Julius,
Nature
, Vol. 377, p. 476, Oct. 12, 1995).
WO 97/40035 discloses a 2-substituted 1-piperidyl benzimidazolyl compound substituted with a cycloalkyl group at the nitrogen atom of the piperidine group.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or a salt thereof, wherein
R is selected from the group consisting of (C
3
-C
11
)cycloalkyl, (C
6
-C
16
)bicycloalkyl, (C
6
-C
16
)tricycloalkyl and (C
8
-C
16
)tetracyclyoalkyl, wherein said groups are partially saturated, fully saturated or fully unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C
1
-C
5
)alkyl and (C
3
-C
7
)cycloalkyl;
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C
1
-C
7
)alkyl, mono-, di, or tri-halo (C
1
-C
7
)alkyl, (C
2
-C
5
)alkenyl, (C
2
-C
5
)alkynyl, phenyl-(C
1
-C
5
)alkyl, aryl, and aromatic or non-aromatic heterocyclic comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms (i.e., O, S and N), and
said phenyl moiety in phenyl-(C
1
-C
5
)alkyl, aryl, or aromatic or non-aromatic heterocyclic being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C
1
-C
4
)alkyl, halo (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, halo (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl-CO—, phenyl, benzyl, —CHO, cyano, (C
1
-C
4
)alkyl-CO—, NH
2
—CO—, NH
2
—CH
2
—, amino, (C
1
-C
4
)alkyl-NH—, di((C
1
-C
4
)alkyl)-N—, (C
1
-C
4
)alkyl-CO—NH—, (C
1
-C
4
)alkyl-NH—CO—, hydrazino, azido, ureido, amidino, guanidino, oxo and ═N—OH;
Y is selected from the group consisting of hydrogen, halo, amino, mercapto, (C
1
-C
12
)alkyl-M—, (C
3
-C
7
)cycloalkyl-M—, (C
2
-C
6
)alkenyl-M—, aryl-M—, aromatic or non-aromatic heterocyclic-M—, aryl-(C
1
-C
5
)alkyl-M—, aromatic or non-aromatic heterocyclic-(C
1
-C
5
)alkyl-M—, said aromatic or non-aromatic heterocyclic moiety of said groups comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms (i.e., O, S and N), and M is selected from the group consisting of a covalent bond, O, S, SO, SO
2
, CO (i.e., C(═O)), NQ (i.e., N(Q)), NQCO (i.e., N(Q)C(═O)), and CONQ (i.e., C(═O)N(Q)), wherein Q is selected from the group consisting of hydrogen and (C
1
-C
6
)alkyl,
said (C
1
-C
12
)alkyl, (C
3
-C
7
)cycloalkyl or (C
2
-C
6
)alkenyl moiety in said groups being optionally substituted with up to three (preferably zero to two) substituents independently selected from the group consisting of halo, hydroxy, amino, (C
1
-C
4
)alkyl-NH—, di-(C
1
-C
4
)alkyl-N—, hydrazino, azido, ureido, amidino, guanidino, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl-S—, (C
1
-C
4
)alkyl-SO— and (C
1
-C
4
)alkyl-SO
2
—, and
said aryl, or aromatic or non-aromatic heterocyclic moiety of said groups being optionally substituted with up to three (preferably zero to two) substituents independently selected from the group consisting of halo, hydroxy, (C
1
-C
4
)alkyl, halo (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, halo (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl-CO—, phenyl, benzyl, —CHO, cyano, (C
1
-C
4
)alkyl-CO—, NH
2
—CO—, NH
2
—CH
2
—, amino, (C
1
-C
4
)alkyl-NH—, di(C
1
-C
4
alkyl)-N—, (C
1
-C
4
)alkyl-CO—NH—, (C
1
-C
4
)alkyl-NH—CO—, hydrazino, azido, ureido, amidino, guanidino, oxo and ═N—OH; and
Z
1
, Z
2
, Z
3
and Z
4
are each independently selected from the group consisting of hydrogen, halo, (C
1
-C
4
)alkyl, halo (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkylsulfonyl, (C
1
-C
4
)alkyl-CO—, carboxy, (C
1
-C
4
)alkyl-COO—, amino, NH
2
CO—, (C
1
-C
4
)alkyl-CO—NH—, (C
1
-C
4
)alkyl-SO
2
—NH—, phenyl and naphthyl.
This invention also relates to processes for preparing compounds of the formula (I) defined as above which comprises
(a) coupling compounds of formulae
wherein R, A and Z
1
to Z
4
are defined as above, and L is halo to give the compound of formula
(b) reducing the compound of formula (IX) to the compound of formula (X)
 by either reduction or hydrogenation; and
(c) subjecting the resulting compound of formula (X) to benzimidazole formation to give the compound of formula (I).
This invention also relates to an intermediate compound of formula
which is useful in the above-mentioned processes for preparing a compound of formula (I) wherein
R is selected from the group consisting of (C
3
-C
11
)cycloalkyl, (C
6
-C
16
)bicycloalkyl, (C
6
-C
16
)tricycloalkyl and (C
8
-C
16
)tetracyclyoalkyl, wherein said groups are partially saturated, fully saturated or fully unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C
1
-C
5
)alkyl and (C
3
-C
7
)cycloalkyl;
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C
1
-C
7
)alkyl, mono-, di, or tri-halo (C
1
-C
7
)alkyl, (C
2
-C
5
)alkenyl, (C
2
-C,)alkynyl, phenyl-(C
1
-C
5
)alkyl, aryl, and aromatic or non-aromatic heterocyclic comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms, and
said phenyl moiety in phenyl-(C
1
-C
5
)alkyl, aryl, or aromatic or non-aromatic heterocyclic being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C
1
-C
4
)alkyl, halo (C
1
-
4
)alkyl, (C
1
-C
4
)alkoxy, halo (C
1
-
4
)alkoxy, (C
1
-C
4
)alkyl-CO—, phenyl, benzyl, —CHO, cyano, (C
1
-C
4
)alkyl-CO—, NH
2
—CO—, NH
2
—CH
2
—, amino, (C
1
-C
4
)alkyl-NH—, di((C
1
-C
4
)alkyl)-N—, (C
1
-C
4
)alkyl-CO—NH—, (C
1
-C
4
)alkyl-NH—CO—, hydrazino, azido, ureido, amidino, guanidino, oxo and ═N—OH; and
Z
1
, Z
2
, Z
3
and Z
4
are independently selected from the group consisting of hydrogen, halo, (C
1
-C
4
)alkyl, halo (C
1
-C
4
)alkyl, (C
1
-
4
)alkoxy, (C
1
-
4
)alkylsulfonyl, (C
1
-C
4
)alkyl-CO—, carboxy, (C
1
-C
4
)alkyl-COO—, amino, NH
2
CO—, (C
1
-C
4
)alkyl-CO—NH—, (C
1
-C
4
)alkyl-SO
2
—NH—, phenyl and naphthyl.
This invention also relates to an intermediate compound of formula
which is useful in the above

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