Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-22
2002-10-15
Aulakh, Charanjit S. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S020000
Reexamination Certificate
active
06465478
ABSTRACT:
TECHNICAL FIELD
This invention relates to 1,3,8-triazaspiro[4.5]decanone compounds or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of this invention have activity as ORL1-receptor agonists, and are useful as an analgesic, anti-inflammatory, diuretic, anesthetic, neuroprotective, anti-hypertensive or 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 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 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).
European Patent Publication No. EP 856514 A1 discloses a series of 8-substituted-1,3,8-triazaspiro[4.5]decan-4-one compounds as agonists and/or antagonists of the Orphanin EQ (OFQ) receptor.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or its pharmaceutically acceptable salt, 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-cyclic group having 3 to 13 carbon atoms, wherein the cyclic group is optionally substituted by one to five substituents independently selected from halo, (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl, (C
1
-C
4
)alkoxy, hydroxy, oxo, ═CH
2
and ═CH—(C
1
-C
4
)alkyl, provided that the bi- or tri-cyclic group is not a benzo-fused ring;
A is (C
1
-C
7
)alkyl, (C
2
-C
5
)alkenyl, (C
2
-C
5
)alkynyl, phenyl-(C
1
-C
5
)alkyl, phenyl or heteroaryl selected from furyl, thienyl, pyrrolyl and pyridyl, wherein the phenyl and heteroaryl are optionally substituted by one to three substituents selected from halo, (C
1
-C
3
)alkyl and (C
1
-C
3
)alkoxy;
R is hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
7
)cycloalkyl, (C
1
-C
6
)alkanoyl, ((C
1
-C
4
)alkyl)-Z—(C
1
-C
6
)alkyl, ((C
3
-C
7
)cycloalkyl)-Z—(C
1
-C
6
)alkyl, heterocyclic-(C
1
-C
6
)alkyl, phenyl-(C
1
-C
6
)alkyl, heterocyclic-(C
1
-C
6
)alkyl-Z—(C
1
-C
6
)alkyl, phenyl-(C
1
-C
6
)alkyl-Z—(C
1
-C
6
)alkyl, heterocyclic-Z—(C
1
-C
6
)alkyl, ((C
3
-C
7
)cycloalkyl)-heterocyclic-(C
1
-C
6
)alkyl, heterocyclic-heterocyclic-Z—(C
1
-C
6
)alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic are optionally substituted by one to three substituents selected from halo, hydroxy, amino, guanizino, carboxy, amidino, ureido, (C
1
-C
3
)alkyl, (C
1
-C
3
)alkoxy, and mono- or di-(C
1
-C
4
)alkylamino, and wherein Z is O, S, SO, SO
2
, CO, C(═O)O, OC(═O), N(R), C(═O)N(R) or N(R)CO (preferred R in Z is hydrogen or (C
1
-C
4
)alkyl); and
X is phenyl, heterocyclic, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
3
-C
7
)cycloalkyl, (C
2
-C
7
)alkynyl, wherein the phenyl, heterocyclic, alkyl, alkenyl, cycloalkyl and alkynyl are optionally substituted by one to three substituents selected from halo, (C
1
-C
3
)alkyl and (C
1
-C
3
)alkoxy.
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 “cycloalkyl”, as used herein, means a saturated carbocyclic radical including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term “heterocyclic” means saturated, partially saturated or fully-unsaturated 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. Preferred heterocyclic includes, but not limited to, piperidino, piperidinyl, hexamethyleneimino, morpholino, thiamorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, isoquinolyl, quinolyl, thiophenyl, pyrazinyl, pyridazinyl, aziridinyl and azetidinyl.
The term “mono-, bi- or tri-cyclic ring” means hydrocarbon cyclic groups of 3 to 13 carbon atoms, having one to three rings therein, and optionally having a double bond therein, including, but not limited to, cycloalkyl, cycloalkenyl, 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 compounds 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 (C
3
-C
13
)cycloalkyl and (C
3
-C
13
)cycloalkenyl, wherein the monocyclic group is optionally substituted by one or two substituents independently selected from halo and (C
1
-C
4
)alkyl;
A is phenyl-(C
1
-C
5
)alkyl or phenyl optionally substituted by one to three substituents independently selected from halo, (C
1
-C
3
)alkyl and (C
1
-C
3
)alkoxy;
R is hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, heterocyclic-(C
1
-C
6
)alkyl or ((C
1
-C
4
)alkyl)-Z—(C
1
-C
6
)alkyl, wherein the alkyl, alkenyl and heterocyclic are optionally substituted by one to three substituents selected from halo, hydroxy, amino, guanizino, carboxy, amidino, ureido, (C
1
-C
3
)alkyl, (C
1
-C
3
)alkoxy, mono- and di-(C
1
-C
4
)alkylamino; and
X is phenyl, heterocyclic, (C
1
-C
6
)alkyl or (C
2
-C
6
)alkenyl, wherein the phenyl, heterocyclic, alkyl and alkenyl are optionally substituted by one to three substituents selected from halo, (C
1
-C
3
)alkyl and (C
1
-C
3
)alkoxy.
A more preferred group of this invention includes the compounds of Formula (I), wherein R
1
and R
2
, taken together with the carbon atom to which they are attached, form a monocyclic group selected from (C
5
-C
10
)cycloalkyl and (C
5
-C
10
)cycloalkenyl, wherein the monocyclic group is optionally substituted by one or two substituents independently selected from (C
1
-C
3
)alkyl; A is phenyl or benzyl; R is hydrogen, (C
1
-C
3
)alkyl, amino-(C
1
-C
6
)alkyl, heterocyclic-(C
1
-C
3
)alkyl wherein the heterocyclic is optionally substituted by amino or ((C
1
-C
4
)alkyl)-Z—(C
1
-C
6
)alkyl wherein Z is OC(═O); and X is (C
1
-C
3
)alkyl or phenyl.
A further preferred group
Ito Fumitaka
Ohashi Yoriko
Aulakh Charanjit S.
Ginsburg P. H.
Joran A. D.
Pfizer Inc.
Richardson P. C.
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