Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-05
2004-08-17
Desai, Rita (Department: 1625)
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
06777421
ABSTRACT:
The present invention is directed to novel 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful in the treatment of disorders and conditions mediated by the ORL-1 G-protein coupled receptor. More particularly, the compounds of the present invention are useful in the treatment of disorders and conditions such as anxiety, depression, substance abuse, neuropathic pain, acute pain, migraine, asthma, cough and for improved cognition.
BACKGROUND OF THE INVENTION
The ORL-1 (orphan opioid receptor) G-protein coupled receptor, also known as the nociceptin receptor, was first reported in 1994, and was discovered based on its homology with the classic delta-, mu-, and kappa-opioid receptors. The ORL-1 G-protein coupled receptor does not bind opioid ligands with high affinity. The amino acid sequence of ORL-1 is 47% identical to the opioid receptors overall, and 64% identical in the transmembrane domains. (
Nature
, 1995, 377, 532.)
The endogenous ligand of ORL-1, known as nociceptin, a highly basic 17 amino acid peptide, was isolated from tissue extracts in 1995. It was named both nociceptin, because it increased sensitivity to pain when injected into mouse brain, and orphanin FQ (OFQ) because of the terminal phenylalanine (F) and glutamine (O) residues that flank the peptide on either side. (WO97/07212)
Nociceptin binding to ORL-1 receptors causes inhibition of cAMP synthesis, inhibition of voltage-gated calcium channels, and activation of potassium conductance. In vivo, nociceptin produces a variety of pharmacological effects that at times oppose those of the opioids, including hyperalgesia and inhibition of morphine-induced analgesia. Mutant mice lacking nociceptin receptors show better performance in learning and memory tasks. These mutant mice also have normal responses to painful stimuli.
The ORL-1 receptor is widely distributed/expressed throughout the human body, including in the brain and spinal cord. In the spinal cord, the ORL-1 receptor exists in both the dorsal and ventral horns, and precursor mRNA has been found in the superficial lamina of the dorsal horn, where primary afferent fibers of nociceptors terminate. Therefore, the ORL-1 has an important role in nociception transmission in the spinal cord. This was confirmed in recent studies wherein nociceptin, when given to mice by i.c.v. injection, induced hyperalgesia and decreased locomotor activity. (
Brit. J. Pharmacol
. 2000, 129, 1261.)
Adam, et al., in U.S. Pat. No. 6,071,925 (and in EP 0856514) disclose 1,3,8-triazaspiro[4,5]decan-4-one derivatives, agonists and/or antagonists of the OFQ receptor. More recently, Higgins, et. al., in European Forum of Neuroscience 2000, Brighton, U.K., Jun. 24-28, 2000, Poster 077.22 disclosed, 8-[(1R,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one useful as a cognition enhancers. Adam et al., in EP 921125-A1 disclose 1,3,8-triazaspiro[4.5]decan-4-one derivatives, agonists and/or antagonists of the OFQ receptor.
Ito, et al., in EP 0997464 disclose 1,3,8-triazaspiro[4.5]decan-4-one compounds as ORL-1 receptor agonists.
Watson, et al., in WO 99/59997 disclose 1,3,8-triazaspiro[4.5]decan-4-ones with high affinity for opioid receptor subtypes, useful for the treatment of migraine, type II diabetes, sepsis, inflammation, incontinence and/or vasomotor disturbance.
JP2000169476, assigned to Banyu Pharmaceutical Co., Ltd, disclose 4-oxoimidazolidine-5-spiro-nitrogen containing heterocyclic compounds which inhibit binding of nociceptin to the ORL1 receptor.
We now describe novel small molecule modulators of the ORL-1 receptor, useful for the treatment of disorders and conditions mediated by the ORL-1 receptor, such as anxiety, depression, substance abuse, neuropathic pain, acute pain, migraine, asthma, cough and for improved cognition.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of the general formula
wherein
R
1
is selected from the group consisting of hydrogen, C
1-6
alkyl, aryl and aralkyl;
wherein the aryl or aralkyl group is optionally substituted with one to four substituents independently selected from halogen, C
1-6
alkyl, halogenated C
1-6
alkyl, C
1-6
alkoxy, nitro, amino, (C
1-6
alkyl)amino, di(C
1-6
alkyl)amino, C
1-6
alkylsulfonyl, amido, (C
1-6
alkyl)amido, di(C
1-6
alkyl)amido, sulfonyl, aminosulfonyl, (C
1-6
alkyl)aminosulfonyl, di(C
1-6
alkyl)aminosulfonyl or C
3-8
cycloalkyl;
R
2
is selected from the group consisting of hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, hydroxyaminoC
1-6
alkyl, aminocarbonylC
1-6
alkyl, C
1-6
alkoxycarbonylC
1-6
alkyl, aryl, C
3-8
cycloalkyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl, C
1-6
aralkyl, carbocyclylC
1-6
alkyl, heteroarylC
1-6
alkyl, heterocycloalkylC
1-6
alkyl and phthalimidoylC
1-6
alkyl;
wherein the alkyl group is optionally substituted with one to two substituents independently selected from hydroxy, carboxy, cyano, amino, C
1-6
alkylamino, di(C
1-6
alkyl)amino, hydroxyC
1-6
alkylamino, aminoC
1-6
alkylamino, C
1-6
alkylaminoC
1-6
alkylamino or di(C
1-6
alkyl)aminoC
1-6
alkylamino,
wherein the aryl, cycloalkyl, carbocyclyl, heteroaryl or heterocycloalkyl group is optionally substituted with one to four substituents independently selected from halogen, C
1-6
alkyl, halogenated C
1-6
alkyl, C
1-6
alkoxy, nitro, amino, (C
1-6
alkyl)amino, di(C
1-6
alkyl)amino, C
1-6
alkylsulfonyl, amido, (C
1-6
alkyl)amido, di(C
1-6
alkyl)amido, sulfonyl, aminosulfonyl, (C
1-6
alkyl)aminosulfonyl, di(C
1-6
alkyl)aminosulfonyl or C
1-4
alkoxycarbonyl;
a is an integer from 0 to 2;
R
3
is selected from the group consisting of C
1-4
alkyl and hydroxy C
1-4
alkyl;
n is an integer from 0 to 1;
X is selected from the group consisting of C
1-6
alkyl, C
2-6
alkenyl, C
2-4
alkyl-O and C
2-4
alkyl-S;
wherein the alkyl group is optionally substituted with one to two substituents independently selected from fluoro, C
1-6
alkyl, fluorinated C
1-6
alkyl, C
1-6
alkoxy, nitro, amino, (C
1-6
alkyl)amino, di(C
1-6
alkyl)amino, C
1-6
alkylsulfonyl, amido, (C
1-6
alkyl)amido, di(C
1-6
alkyl)amido, sulfonyl, aminosulfonyl, (C
1-6
alkyl)aminosulfonyl or di(C
1-6
alkyl)aminosulfonyl;
and wherein X is C
2-4
alkyl-O or C
2-4
alkyl-S, the X group is incorporated into the molecule such that the C
2-4
alkyl is bound directly to the piperidine portion of the molecule;
is selected from the group consisting of phenyl, a five membered heteroaryl and a six membered heteroaryl;
b is an integer from 0 to 1;
R
4
is selected from the group consisting of aryl, C
3-8
cycloalkyl, partially unsaturated carbocyclyl, heteroaryl and heterocycloalkyl;
c is an integer from 0 to 3;
R
5
is selected from the group consisting of halogen, C
1-6
alkyl, halogenated C
1-6
alkyl, C
1-6
alkoxy, nitro, amino, (C
1-6
alkyl)amino, di(C
1-6
alkyl)amino, C
1-6
alkylsulfonyl, amido, (C
1-6
alkyl)amido, di(C
1-6
alkyl)amido, sulfonyl, aminosulfonyl, (C
1-6
alkyl)aminosulfonyl or di(C
1-6
alkyl)aminosulfonyl;
m is an integer from 0 to 1;
Y is selected from the group consisting of C
1-4
alkyl, C
2-4
alkenyl, O, S, NH, N(C
1-4
alkyl), C
1-6
alkyl-O, C
1-6
alkyl-S, O—C
1-6
alkyl and S—C
1-6
alkyl-S;
R
6
is selected from the group consisting of aryl, partially unsaturated carbocyclyl, C
3-8
cycloalkyl, heteroaryl, heterocycloalkyl and benzoyloxyphenyl;
wherein the aryl, partially unsaturated carbocyclyl, C
3-8
cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one to four substituents independently selected from halogen, hydroxy, C
1-6
alkyl, halogenated C
1-6
alkyl, C
1-6
alkoxy, nitro, amino, (C
1-6
alkyl)amino, di(C
1-6
alkyl)amino, C
1-6
alkylsulfonyl, amido, (C
1-6
alkyl)amido, di(C
1-6
alkyl)amido, sulfonyl, aminosulfonyl, (C
1-6
alkyl)aminosulfonyl, di(C
1-6
alkyl)aminosulfonyl or triphenylmethyl;
provided that when a is 0, R
1
is phenyl, R
2
is hydrogen, n is 1, X is CH
2
,
is phenyl, b is 0, c is 0 and m is 0, then R
6
is selected from the group consisting of partially unsaturated carbocyclyl, C
3-8
cyclo
Jordan Alfonzo
Pan Kevin
Reitz Allen B.
Desai Rita
Ortho-McNeil Pharmaceutical , Inc.
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