Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-12-23
2002-08-20
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S329000, C546S224000, C546S208000
Reexamination Certificate
active
06436959
ABSTRACT:
The present invention relates to delta-opioid receptor agonists/antagonists. More particularly, the present invention relates to 4-[aryl(piperidin-4-yl)]aminobenzamides which are delta-opioid receptor agonists useful as analgesics.
BACKGROUND OF THE INVENTION
WO9723466 to Plobeck N. et al., discloses compounds (approximately) of the formula:
which are mu-opioid antagonists.
WO9636620 to Dondio G., discloses compounds (most relevantly) of the formula:
which are delta-opioid agonists/antagonists.
WO9710230 to Dondio G. et al., discloses compounds (most relevantly) of the formula:
which are delta-opioid, kappa-opioid and mu-opioid receptor agonists/antagonists.
WO9315062 to Chang K. et al., discloses compounds (approximately) of the formula:
which are delta-opioid and mu-opioid receptor agonists.
It is an object of the present invention to provide delta-opioid receptor agonists as analgesics.
It is another object of the present invention to provide delta-opioid receptor selective agonists as analgesics having reduced side-effects.
It is another object of the present invention to provide delta-opioid receptor agonists/antagonists as immunosuppressants, antiinflammatory agents, agents for the treatment of mental illness, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases.
It is another object of the present invention to provide delta-opioid receptor selective agonists/antagonists as immunosuppressants, antiinflammatory agents, agents for the treatment of mental illness, 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.
SUMMARY OF THE INVENTION
There are provided by the present invention delta-opioid receptor agonists/antagonists of the general formula:
where
Ar is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 1 to 3 R
7
;
R
1
and R
2
are independently selected from the group consisting of hydrogen, C
1-8
alkyl; phenyl, optionally mono-, di-, or tri-substituted with halo, C
1-6
alkyl, C
1-6
alkoxy or trifluoromethyl; or benzyl, optionally mono-, di-, or tri-substituted with halo, C
1-6
alkyl, C
1-6
alkoxy or trifluoromethyl, or alternatively, R
1
and R
2
are taken together with their N of attachment to form a ring which is selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl and hexamethyleneiminyl, each said ring optionally substituted with 1 to 4 methyl groups;
R
3
, R
4
and R
5
are independently selected from hydrogen and C
1-4
alkyl;
R
6
is selected from the group consisting of hydrogen; C
1-8
alkyl; C
3-6
cycloalkylC
1-3
alkyl, C
3-6
alkenyl; C
1-6
alkoxyC
1-3
alkyl; 4-C
1-4
alkyl-4,5-dihydro-5-oxo-1H-tretrazol-1-ylC
1-4
alkyl; thien-2-ylC
1-4
alkyl; thien-3-ylC
1-4
alkyl; furan-2-ylC
1-4
alkyl; furan-3-ylC
1-4
alkyl; pyrrol-2-ylC
1-4
alkyl; pyrrol-3-ylC
1-4
alkyl; pyridin-2-ylC
1-4
alkyl; pyridin-3-ylC
1-4
alkyl; pyridin-4-ylC
1-4
alkyl; pyrazinylC
1-4
alkyl; pyrimidin-2-ylC
1-4
alkyl; pyrimidin-4-ylC
1-4
alkyl; pyrimidin-5-ylC
1-4
alkyl; thiazol-2-ylC
1-4
alkyl; thiazol-4-ylC
1-4
alkyl; thiazol-5-ylC
1-4
alkyl; oxazol-2-ylC
1-4
alkyl oxazol-4-ylC
1-4
alkyl; oxazol-5-ylC
1-4
alkyl and phenylC
1-4
alkyl, where the foregoing thienyl, furanyl, pyrrolyl, thiazolyl and oxazolyl are optionlly mono-, di-, or tri-substituted with a non-fused R
7
and the foregoing pyridinyl, pyrazinyl, pyrimidinyl and phenyl is optionally mono-, di-, or tri-substituted with R
7
;
R
7
is independently selected from the group consisting of hydroxy, halo, C
1-3
alkyl, C
1-3
alkoxy, C
1-3
acyl, C
1-3
acyloxy, cyano, amino, C
1-3
acylamino, C
1-3
alkylamino, di(C
1-3
alkyl)amino, C
1-3
alkylthio, C
1-3
alkylsulfonyl, trifluoromethyl and trifluoromethoxy, and two R
7
can together form a single fused moiety selected from the group consisting of —(CH
2
)
3-5
— and —O(CH
2
)
1-3
O— attached to adjacent carbon atoms of Ar; and
R
8
is independently selected from the group consisting of halo, C
1-6
alkyl, C
1-6
alkoxy and trifluoromethyl.
As delta-opioid receptor agonists, such compounds are useful as analgesics. Depending on their agonist/antagonist effect, such compounds may also be useful immunosuppressants, antiiinflammantory agents, agents for treatment of mental illness, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases.
DETAILED DESCRIPTION OF THE INVENTION
The core structure of the compounds of the present invention can be made in a two step process. This process must be modified as required by the strategy employed to obtain the various substituents. In a first strategy, the starting materials are substituted as desired with the final substituents and, where the substituents or their protected forms are stable to the reaction conditions, the core structure may be subsequently made by the two step process. In a second strategy, the final core structure is obtained and, where the core structure is stable to the modifying reaction conditions, the substituents are modified as desired. Variations might include modifying the substituents on intermdiates or replacing precursor substituents on the finished core structure.
Scheme A generally describes the manufacture of the compounds of the present invention. The first step of Scheme A is a reductive alkylation of piperidone A1 and amine A2 to produce N-aryl-piperidineamine A3. The reductive alkylation is carried out by combining the ketone A1, amine A2, and an appropriate solvent/reducing agent combination to form a reaction mixture which is cooled or heated as necessary. Suitable solvent/reducing agent combinations include 1,2-dichloroethane or acetonitrile/NaBH(OAc)
3
+acid catalyst; methanol/NaBH
3
CN+acid catalyst; methanol or ethanol or isopropanol/NaBH
4
; or alcoholic solvent/H
2
+noble metal catalyst. The use of the 1,2-dichloroethane or acetonitrile/NaBH(OAc)
3
+acid catalyst combination is further described by Abdel-Magid, A. F., et al., J. Org.Chem., Vol. 61, pp 3849-3862 (1996). In the second step of Scheme A, the N-aryl-piperidineamine A3 is reacted with a bromo, iodo or trifluoromethanesulfonyloxy substituted benzamide A4 in the presence of a palladium catalyst, phosphine ligand and base to give the (N-aryl, N-piperidin-4-yl)aminobenzamide. Preferred palladium catalysts include PdCl
2
+phosphine ligand, tris(dibenzylideneacetone)dipalladium(0) which is Pd
2
(dba)
3
+phosphine ligand, Pd(OAc)
2
+phosphine ligand and Pd(Ph
3
P)
4
(0). Suitable phosphine ligands include BINAP and tri(o-tolyl phosphine). Suitable bases include NaOtBu and Cs
2
CO
3
. The reaction of the second step is an arylation further described by Buchwald, S. L., J. Org. Chem., Vol. 61, p 1133 (1996). The manufacture of the various starting materials for Scheme A is well within the skill of persons versed in this art.
Preferred Ar is phenyl.
Preferred R
1
and R
2
are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, phenyl, p-chlorophenyl, p-fluorophenyl, p-methylphenyl, p-trifluoromethylphenyl, benzyl, p-chlorobenzyl, p-fluorobenzyl, p-methylbenzyl and p-trifluoromethylbenzyl, or alternatively, preferred R
1
and R
2
are taken together with their N of attachment to form a ring which is selected from the group consisting of pyrrolidinyl and piperidinyl.
Preferred R
3
, R
4
and R
5
are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl and t-butyl.
Preferred R
6
are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropylmethyl, ethenyl, allyl, methoxymethyl, benzyl, p-chlorobenzyl, p-fluorobenzyl, p-methylbenzyl, p-trifluoromethylbenzyl, p-aminobenzyl, thien-2-ylCH
2
CH
2
—, thien-3-ylCH
2
CH
2
—, pyridin-3-ylCH
2
CH
2
—, pyridin-4-ylCH
2
CH
2
—, thiazol-2-ylCH
Carmosin Richard J.
Carmosin Susan
Carson John R.
Fitzpatrick Louis J.
Jetter Michele C.
Carmosin Susan
Desai Rita
Harbour John
Ortho-McNeil Pharmaceutical , Inc.
Rotman Alan L.
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