Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-04
2001-10-23
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S233200, C514S253030, C514S256000, C544S127000, C544S335000, C544S362000, C546S124000, C546S125000, C546S126000
Reexamination Certificate
active
06306876
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to delta-opioid receptor modulators. More particularly, the present invention is directed to 4-[aryl(8-azabicyclo[3.2.1]octan-3-yl)]aminobenzoic acid derivatives which are delta-opioid receptor modulators useful as effective analgesics.
BACKGROUND OF THE INVENTION
WO 97/23466 discloses compounds described as having an analgesic effect, having a general and a typical preferred formula:
WO 98/28270 also discloses compounds described as having an analgesic effect, having a general and a typical preferred formula:
WO 98/28275 further discloses compounds described as having an analgesic effect, having a general and a typical preferred formula:
Isomeric 3-propananilidotropane are used as intermediates herein and have been published in Bagley, J. R., et al.,
J. Heterocycl. Chem
., 1977, 14(4), 599-602, having the following formulae:
Amide derivatives of 3-aminotropane are also used as intermediates herein and have been prepared and described as having potential pharmacological activity, Gutkowska, B., et al.,
Acta Pol. Pharm
., 1984, 41(6), 613-617, having the formula:
WO 93/15062 discloses compounds which have been described as delta-opioid and mu-opioid receptor agonists, having (approximately) the formula:
The foregoing reference compounds have been described as either delta- or mu-opioid receptor agonists or antagonists.
It is an object of the present invention to provide delta-opioid receptor modulators. It is another object of the present invention to provide delta-opioid receptor selective agonists as analgesics having reduced side-effects. It is also another object of the present invention to provide delta-opioid receptor antagonists as immunosuppressants, antiinflammatory agents, agents for the treatment of neurological and psychiatric conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases, having reduced side-effects. It is a further object of the present invention to provide a method for treating a disorder modulated by the delta-opioid receptor.
SUMMARY OF THE INVENTION
There are provided by the present invention delta-opioid receptor modulators of Formula (I):
wherein:
R
1
is a substituent selected from the group consisting of hydrogen, (C
1-8
)alkyl, (C
2-6
)alkenyl, (C
3-7
)cycloalkyl, (C
3-6
)cycloalkyl(C
1-3
)alkyl, (C
1-6
)alkoxy(C
1-3
)alkyl, 4-(C
1-4
)alkyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl(C
1-4
)alkyl, 2-thienyl(C
1-4
)alkyl, 3-thienyl(C
1-4
)alkyl, 2-furanyl(C
1-4
)alkyl, 3-furanyl(C
1-4
)alkyl, 2-pyrrolyl(C
1-4
)alkyl, 3-pyrrolyl(C
1-4
)alkyl, 2-pyridinyl(C
1-4
)alkyl, 3-pyridinyl(C
1-4
)alkyl, 4-pyridinyl(C
1-4
)alkyl, 3-pyrazolyl(C
1-4
)alkyl, 4-pyrazolyl(C
1-4
)alkyl, 5-pyrazolyl(C
1-4
)alkyl, 2-pyrimidinyl(C
1-4
)alkyl, 4-pyrimidinyl(C
1-4
)alkyl, 5-pyrimidinyl(C
1-4
)alkyl, 6-pyrimidinyl(C
1-4
)alkyl, 2-thiazolyl(C
1-4
)alkyl, 4-thiazolyl(C
1-4
)alkyl, 5-thiazolyl(C
1-4
)alkyl, 2-oxazolyl(C
1-4
)alkyl, 4-oxazolyl(C
1-4
)alkyl, 5-oxazolyl(C
1-4
)alkyl, phenyl(C
1-4
)alkyl and phenyl(C
2-4
)alkenyl; wherein the foregoing thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl and phenyl substituents are optionally substituted with one to three substituents independently selected from the group consisting of hydroxy, halogen, (C
1-3
)alkyl, (C
2-3
)alkenyl, (C
1-3
)alkoxy, (C
1-3
)acyl, (C
1-10
)acyloxy, cyano, amino, (C
1-3
)acylamino, (C
1-3
)alkylamino, di(C
1-3
)alkylamino, (C
1-3
)alkylthio, (C
1-3
)alkylsulfonyl, —OCH
2
O—, —O(CH
2
)
2
O—, trifluoromethyl and trifluoromethoxy;
R
2
and R
3
are independently selected from the group consisting of hydrogen, (C
1-8
)alkyl (optionally substituted with one to three halogen substituents), (C
2-6
)alkenyl, (C
3-7
)cycloalkyl, phenyl (wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
3-7
)cycloalkyl, —OCH
2
O—, —O(CH
2
)
2
O— and trifluoromethyl), benzyl (wherein benzyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
1-6
)alkoxy, (C
3-7
)cycloalkyl, —OCH
2
O—, —O(CH
2
)
2
O— and trifluoromethyl), hydroxy(C
1-4
)alkyl, (C
1-6
)alkoxy(C
1-4
)alkyl and trifluoro(C
1-4
)alkoxy; alternatively, R
2
and R
3
may form a single fused moiety selected from the group consisting of 1,4-butylene, 1,5-pentylene, 1,5-(3-oxapentylene) and 1,5-(3-azapentylene); wherein the moiety is optionally substituted with one to four substituents independently selected from the group consisting of (C
1-6
)alkyl, (C
2-6
)alkenyl and (C
3-7
)cycloalkyl;
the moiety —C(═X)Z is substituted on phenyl at the 3 or 4 position; wherein X is selected from the group consisting of S and O; Z is selected from the group consisting of N and O; and, Z is optionally substituted with one to two substituents independently selected from the group consisting of R
2
and R
3
;
with the proviso that:
if Z is O, then Z is optionally substituted with one substituent selected from R
2
;
n is selected from 0 or 1;
Ar is selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl; wherein Ar is optionally substituted with from one to three substituents independently selected from R
4
;
R
4
is independently selected from the group consisting of hydroxy, halogen, (C
1-3
)alkyl, (C
2-3
)alkenyl, (C
1-3
)alkoxy, (C
1-3
)acyl, (C
1-10
)acyloxy, cyano, amino, (C
1-3
)acylamino, (C
1-3
)alkylamino, di(C
1-3
)alkylamino, (C
1-3
)alkylthio, (C
1-3
)alkylsulfonyl, —OCH
2
O—, —O(CH
2
)
2
O—, trifluoromethyl and trifluoromethoxy; and, alternatively, two adjacent R
4
groups may form a single fused moiety, wherein the moiety is selected from the group consisting of —(CH
2
)
3-5
— and —O(CH
2
)
1-3
O—;
and pharmaceutically acceptable diastereomers and salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of a compound of Formula (I) include those compounds wherein, preferably, R
1
is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, 2-ethyl-n-butyl, n-hexyl, cyclopropylmethyl, cyclohexylmethyl, cyclohexyl, allyl, 3,3-dimethylallyl, 2-methylpropenyl, piperonyl, phenethyl, 4-fluorophenethyl, 3,4-dimethoxyphenethyl, diphenylethyl, phenylpropyl, 2-thienylethyl and 2-furanylmethyl. More preferably, R
1
is selected from the group consisting of hydrogen, methyl, n-propyl, allyl, piperonyl, 3,4-dimethoxyphenethyl, phenylpropyl and 2-furanylmethyl. Most preferably, R
1
is selected from the group consisting of hydrogen, allyl and piperonyl.
Embodiments of a compound of Formula (I) also include those compounds wherein, preferably, R
2
and R
3
are independently selected from the group consisting of methyl, ethyl, 2-fluoroethyl, n-propyl, isopropyl, n-butyl, t-butyl, 2-methylallyl, phenyl, 3-fluorophenyl and 4-methylbenzyl; and, alternatively, R
2
and R
3
may form a single fused moiety selected from 1,4-butylene. More preferably, R
2
and R
3
are independently selected from the group consisting of methyl, ethyl, 2-fluoroethyl, n-propyl, n-butyl, 2-methylallyl, phenyl and 3-fluorophenyl. Most preferably, R
2
and R
3
are independently selected from ethyl.
Embodiments of a compound of Formula (I) further include those compounds wherein, preferably, n is 0.
An embodiment of a compound of Formula (I) includes those compounds wherein, preferably, Ar is phenyl.
An embodiment of a compound of Formula (I) also includes those compounds wherein, preferably, R
4
is independently selected from the group consisting of hydroxy, chloro, bromo, fluoro, methyl, ethyl, methoxy, ethoxy, methylamino, N,N-dimethylamino, methylthio, methylsulfonyl, trifluoromethoxy and trifluoromethyl. More preferably, R
4
is independently selected from the group consisting of hydroxy, methoxy and methylthio. Most preferably, R
4
is not present.
Exemplified compounds of the present invention are listed in Table 1
Boyd Robert E.
Carson John R.
Neilson Lou Anne
Dentz Bernard
Harbour John
Ortho-McNeil Pharmaceutical , Inc.
LandOfFree
4-[aryl(8-azabicyclo[3.2.1]octan-3-yl)]a... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 4-[aryl(8-azabicyclo[3.2.1]octan-3-yl)]a..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 4-[aryl(8-azabicyclo[3.2.1]octan-3-yl)]a... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2584386