4-(2-keto-1-benzimidazolinyl)piperidine compounds as...

Details 4-(2-keto-1-benzimidazolinyl)piperidine compounds as... 4-(2-keto-1-benzimidazolinyl)piperidine compounds as...

2000-03-06

2002-07-23

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S322000, C546S194000, C546S199000

Reexamination Certificate

active

06423725

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel 4-(2-keto-1-benzimidazolinyl)piperidine compounds or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of this invention have activity as ORL1-receptor (opioid receptor-like 1 receptor) agonists, and as such are useful as an analgesic, anti-inflammatory, diuretic, anesthetic, neuroprotective, anti-hypertensive, or an anti-anxiety agent, or as an agent for appetite control or hearing regulation.
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 or respiratory failure. Further, multiple dosage of the drugs cause addiction. Thus, there has been a long-felt need to provide less toxic analgesics.
Considerable pharmacological and biochemical studies have been carried out to identify opioid receptors and their endogenous ligands, and peptide and non-peptide opioid ligands have been discovered. In the recent past, amino acid sequences of &mgr;-, &dgr;- and &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 for ORL1-receptor be effective in neurogenic inflammation (
Tips
, Vol. 18, pp. 293-300, August 1997). It is also suggested that the agonist be a potent analgesic having less psychological side effects and addiction (D. Julius,
Nature
, Vol. 377, p. 476, Oct. 12, 1995).
WO 97/40035 and U.S. Pat. No. 3,318,900 disclose a series of benzimidazolinyl piperidines.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or the pharmaceutically acceptable salts thereof, wherein
R
1
and R
2
are independently C
1
-C
4
alkyl; or
R
1
and R
2
, taken together with the carbon atom to which they are attached, form a mono-, bi-, tri- or spiro-cyclig group having 6 to 13 carbon atoms, wherein the cyclic group is optionally substituted by one to five substituents independently selected from C
1
-C
4
alkyl, C
2
-C
4
alkylene, C
1
-C
4
alkoxy, hydroxy, oxo, ═CH
2
and ═CH—C
1
-C
4
and alkyl;
R
3
is C
1
-C
7
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, phenyl-C
1
-C
5
alkyl, phenyl optionally substituted by one to three substituents independently selected from fluorine, C
1
-C
3
alkyl and C
1
-C
3
alkoxy, or a heteroaryl group selected from furyl, thienyl, pyrrolyl and pyridyl, wherein said heteroaryl group is optionally substituted by one to three substituents independently selected from halo, C
1
-C
3
alkyl and C
1
-C
3
alkoxy, with the proviso that when both R
1
and R
2
are C
1
-C
4
alkyl, then R
3
is other than C
1
-C
7
alkyl, C
2
-C
5
alkenyl and C
2
-C
5
alkynyl;
R
4
is selected from:
1) hydrogen,
2) optionally mono- or di-substituted, C
1
-C
8
alkyl, C
3
-C
7
cycloalkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, C
1
-C
6
alkyl-Z—, C
1
-C
6
alkyl-Z—(C
1
-C
6
)alkyl, C
3
-C
7
cycloalkyl-Z—(C
1
-C
6
)alkyl, C
2
-C
6
alkenyl-Z—(C
1
-C
6
)alkyl or C
2
-C
6
alkynyl-Z—(C
1
-C
6
)alkyl, wherein Z is selected from O, S, SO, SO
2
, CO, CO
2
, OCO, NR, CONR and NRCO, wherein R is hydrogen or C
1
-C
6
alkyl, and the substituents to be attached to the alkyl, alkenyl, alkynyl or cycloalkyl moiety are independently selected from halo, hydroxy, carboxy, amino, mono- or di-(C
1
-C
4
alkyl)amino, hydrazino, azido, ureido, amidino and guanidino; or
3) optionally mono- or di-substituted, aryl, heterocyclic, aryl(C
1
-C
5
)alkyl, heterocyclic(C
1
-C
5
)alkyl, heterocyclic-heterocyclic(C
1
-C
5
)alkyl, aryl-heterocyclic(C
1
-C
5
)alkyl, heterocyclic-Z—(C
1
-C
5
)alkyl, aryl-Z—(C
1
-C
5
)alkyl, aryl(C
1
-C
5
)alkyl-Z—(C
1
C
5
)alkyl, or heterocyclic(C
1
-C
5
)alkyl-Z—(C
1
-C
5
)alkyl, wherein Z is selected from O, S, SO, SO
2
, CO, CO
2
, OCO, NR, CONR and NRCO, wherein R is hydrogen or C
1
-C
6
alkyl, and the substituents to be attached to the aryl or heterocyclic moiety are independently selected from halo, hydroxy, carboxy, C
1
-C
4
alkyl, halo C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkyl-CO—, amino(C
1
-C
4
)alkyl-CO—, phenyl, benzyl, amino, mono- or di-(C
1
-C
4
alkyl)amino, hydrazino, azido, ureido, amidino and guanidino;
R
5
is independently selected from halo, C
1
-C
3
alkyl, C
1
-C
3
alkoxy, C
1
-C
3
alkylsulfonyl, CF
3
, carboxy, hydroxy, amino, alkylamino, acylamino, arylcarbonyl, alkylcarbonyl and hydroxyalkyl; and
n is 0, 1, 2, 3 or 4.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term “alkoxy ”, as used herein, includes O-alkyl groups wherein “alkyl” is defined above.
The term “halo”, as used herein, refers to F, Cl, Br or I, preferably F or Cl.
The term “C
2
-C
4
alkylene” means a straight or branched radical formed from an unsaturated aliphatic hydrocarbon such as ethenyl, propenyl or butenyl.
The term “cycloalkyl”, as used herein, means a saturated carbocyclic radical including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term “aryl”, as used herein, means a monocyclic or bicyclic aromatic carbocyclic ring system of 6-11 carbon atoms including, but not limited to, phenyl, naphthyl, indanyl, (1,2,3,4)-tetrahydronaphthyl, indenyl, isoindenyl and the like.
The term “heterocyclic” means a monocyclic or bicyclic hydrocarbon ring system which has one or more hetero atoms in the ring, preferably has 4 to 10 carbon atoms and 1 to 3 heteroatoms including, but not limited to, piperidino, hexamethyleneimino, morpholino, thiamorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolyl, thiophenyl, pyrazinyl, pyridazinyl, aziridinyl and azetidinyl.
The term “bi- or tri-cyclic ring” means hydrocarbon cyclic groups of 6 to 16 carbon atoms, having two to three rings therein, including, but not limited to, decahydronaphthalene, bicyclo[2.2.1.]heptane, bicyclo[3.2.1]octane, bicyclo[3.3.1]nonane, adamantane and tricyclo[5.2.1.0
2,6
]decane.
The term “spirocyclic group” means a hydrocarbon spirocyclic group of 6 to 13 carbon atoms, including, but not limited to, spiro[5.5]undecanyl and spiro[4.5]decanyl.
The term “treating”, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment” as used herein refers to the act of treating, as “treating” is defined immediately above.
A preferred group of the compounds of the present invention includes the compound of Formula (I), wherein
R
1
and R
2
are independently C
1
-C
4
alkyl; or
R
1
and R
2
, taken together with the carbon atom to which they are attached, form a monocyclic group selected from cyclo-C
3
-C
14
alkyl and cyclo-C
4
-C
14
alkenyl, a bicyclic group selected from decahydronaphthalene, bicyclo[2.2.1.]heptane, bicyclo[4.3.0]nonane, bicyclo[3.2.1]octane, bicyclo[3.2.0]heptene and bicyclo[3.3.1]nonane, a tricyclic group selected from adamantane and tricyclo[5.2.1.0
2.6
]decane, or a spirocyclic group selected from spiro[5.5]undecanyl and spiro[4.5]decanyl, wherein the cyclic group is optionally substituted by one to three substituents independently selected from C
1
-C
4
alkyl, C
2
-C
4
alkylene, C
1
-C
4
alkoxy, hydroxy and oxo;
R
3
is C
1
-C
7
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, phenyl-C
1
-C
5
alkyl, phenyl optionally substituted by one to three

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