2-benzimidazolylamine compounds as ORL-1-receptor agonists

Details 2-benzimidazolylamine compounds as ORL-1-receptor agonists 2-benzimidazolylamine compounds as ORL-1-receptor agonists

2000-06-29

2002-01-22

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S322000, C514S253090, C514S258100, C546S199000, C544S364000, C544S129000, C544S256000

Reexamination Certificate

active

06340681

ABSTRACT:

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 failure, depression or constipation. Further, multiple dosage of the drugs may 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).
Neurosearch's WO 97/40035 discloses a 2-substituted 1-piperidyl benzimidazolyl compound substituted with a cycloalkyl group at the nitrogen atom of the piperidine group.
Novo Nordisk's WO 99/59997 discloses use of a small organic compound as an opioid receptor ligand for the treatment of a disease selected from migraine, non insulin dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence, vasomotor disturbances including the peripheral vasomotor effects such as hot flushes, and alleviating symptoms of drug withdrawal such as abstinence symptoms occurring during withdrawal from abusive drugs.
Schering Corporation's WO 00/06545 discloses use of a nociceptin receptor ORL1-agonist, alone or in combination with a second agent for treating pain, anxiety, asthma, depression, alcohol abuse, cough or allergy.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or a salt thereof wherein
R
3
and R
4
are independently selected from hydrogen;
halo(C
1
-C
10
)alkyl;
(C
1
-C
6
)alkyl optionally substituted with one to two substituents independently selected from hydroxy, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl-S—, phenoxy, amino, oxo, mono[(C
1
-C
4
)alkyl]amino, di[(C
1
-C
4
)alkyl]amino, N-[(C
7
-C
9
)cycloalkyl-(C
1
-C
4
)alkyl]-N-(C
1
-C
4
)alkyl-amino, (C
1
-C
4
)alkoxy-C(═O)—, aryl selected from phenyl and naphtyl wherein the aryl is optionally substituted with one to three substituents independently selected from halo, hydroxy, (C
1
-C
4
)alkoxy and trifluoro(C
1
-C
4
)alkoxy, and heterocyclyl selected from pyrrolidyl and piperidinyl wherein the heterocyclyl is optionally substituted with (C
1
-C
4
)alkyl;
(C
3
-C
8
)cycloalkyl optionally substituted with (C
1
-C
4
)alkyl;
(C
3
-C
8
)cycloalkenyl optionally substituted with (C
1
-C
4
)alkoxy-C(═O)—;
5- to 6-membered-heterocyclyl, 5- to 6-membered-heterocyclyl-C(═O)— and 5- to 6-membered-heterocyclyl-(C
1
-C
4
)alkyl, wherein each heterocyclyl contains in the ring one to three heteroatoms independently selected from oxygen, nitrogen and sulfur, is optionally fused to a phenyl ring, and is optionally substituted with one to two substituents independently selected from halo, (C
1
-C
4
)alkyl, benzyl and oxo;
phenyl optionally substituted with one to three substituents independently selected from halo, (C
1
-C
4
)alkyl, halo(C
1
-C
4
)alkyl and (C
1
-C
4
)alkoxy; and 5- to 6-membered heteroaryl-(C
1
-C
4
)alkyl wherein said heteroaryl contains one to four ring atoms independently selected from oxygen, nitrogen and sulfur and is optionally fused to a phenyl ring; or
R
3
and R
4
, together with the nitrogen atom to which they are attached, form a fully saturated, partially saturated or fully unsaturated 5- to 8-membered nitrogen containing heterocyclic ring wherein said heterocyclic ring optionally contains in the ring one or two additional heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally contains in the ring a group CR
6
R
7
wherein R
6
and R
7
taken together form an oxo group or a cyclic acetal, and optionally fused to a phenyl, naphthalene or (C
5
-C
8
)cycloalkyl ring, and optionally substituted with one to two substituents independently selected from halo; (C
1
-C
4
)alkyl; halo(C
1
-C
4
)alkyl; (C
1
-C
4
)alkoxy; hydroxy; carbonyl; benzhydryl; hydroxy-(C
1
-C
4
)alkyl; (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl-; amino; amino(C
1
-C
4
)alkyl-amino-; mercapto; (C
1
-C
4
)alkoxy-C(═O)—; pyrrolidino-(C
1
-C
4
)alkyl; amino-C(═O)—; (C
1
-C
4
)alkyl-C(═O)—; (C
1
-C
4
)alkoxy-C(═O)—amino-; piperidinyl optionally substituted with one or two substituents independently selected from amino, mono[(C
1
-C
4
)alkyl]amino-, di[(C
1
-C
4
)alkyl]amino-, benzylamino and di-(benzyl)amino; phenyl optionally substituted with one to three substituents independently selected from halo and (C
1
-C
4
)alkoxy, phenyl-(C
1
-C
4
)alkyl; phenyl-(C
1
-C
4
)alkenyl; phenyl-(C
1
-C
4
)alkoxy-C(═O)—; 1,3-benzodioxolyl-(C
1
-C
4
)alkyl-; trifluoromethyl; nitro; pyridyl optionally substituted with one to three substituents independently selected from halo and trifluoromethyl; quinolinyl optionally substituted with one to three substituents independently selected from halo and trifluoromethyl; pyrrolidinyl-(C
1
-C
4
)alkyl; and pyrrolidinyl-(CH
2
)
m
—CR
8
R
9
—(CH
2
)
n
— wherein m and n are independently 1, 2, 3 or 4, and R
8
and R
9
, taken together with the carbon atom to which they are attached, form (C
3
-C
6
)cycloalkyl; and
R
5
is phenyl or (C
4
-C
11
)cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halo, hydroxy, (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-C(═O)—, carboxy, (C
1
-C
4
)alkyl-C(═O)O—, amino, NH
2
—C(═O)—, (C
1
-C
4
)alkyl-C(═O)—NH—, (C
1
-C
4
)alkyl-SO
2
—NH—, phenyl and naphthyl.
This invention also relates to a pharmaceutical composition for the treatment of a disorder or condition mediated by ORL1-receptor and its endogenous ligands in a mammal including a human, or for anesthetizing a mammal including a human, which comprises an effective amount of the compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
This invention also relates to a method of treating a disorder or condition, or anesthetizing a mammal including a human, the treatment and anesthetization of which can be effected or facilitated by agonising ORL1-receptor in a mammal including a human, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The term “alkyl”, as used herein, means a straight or branched saturated monovalent hydrocarbon radical including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like.
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 “alkoxy”, as used herein, means an O-alkyl group wherein “alkyl” is defined above.
The term “halo”, as used herein, refers to F, Cl, Br or I, preferably F or Cl.
The term “heterocyclyl”, as used herein, unless otherwise indicated, includes a non-aromatic and optionally bridged heterocyclic-group having 5 to 8 atoms comprising 1 to 4 heteroatoms each selected from oxygen (O), sulfur (S) and nitrogen (N). Examples of the heterocyclic inc

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