Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-25
2002-11-05
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S199000, C546S201000, C546S118000, C514S322000, C514S323000, C514S309000, C544S264000
Reexamination Certificate
active
06476041
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to novel 1,4 substituted piperidines. In particular, this invention relates to piperidines substituted in the 1- and 4-positions, through a bridge, with i) optionally substituted 2-benzimidazoles, 2-indoles, 2-quinazolines, or 2-imidazopyridines; or ii) phenyl or substituted phenyl that are effective as NOVA NR2B antagonists useful for relieving pain.
Ions such as glutamate play a key role in processes related to chronic pain and pain-associated neurotoxicity—primarily by acting through N-methyl-D-aspartate (“NMDA”) receptors. Thus, inhibition of such action—by employing ion channel antagonists, particularly NMDA antagonists—can be beneficial in the treatment and control of pain.
Known NMDA antagonists include ketamine, dextromophan, and 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (“CPP”). Although these compounds have been reported (J. D. Kristensen, et al.,
Pain
, 51:249-253 (1992); K. Eide, et al.,
Pain
, 61:221-228 (1995); D. J. Knox, et al.,
Anaesth. Intensive Care
23:620-622 (1995); and M. B. Max, et al.,
Clin. Neuropharmacol
. 18:360-368 (1995)) to produce symptomatic relief in a number of neuropathies including postherpetic neuralgia, central pain from spinal cord injury, and phantom limb pain, widespread use of these compounds is precluded by their undesirable side effects. Such side effects at analgesic doses include psychotomimetic effects such as dizziness, headache, hallucinations, dysphoria, and disturbances of cognitive and motor function. Additionally, more severe hallucinations, sedation, and ataxia are produced at doses only marginally higher than analgesic doses. Thus, it would be desirable to provide novel NMDA antagonists that are absent of undesirable side effects or that produce fewer and/or milder side effects.
NMDA receptors are heteromeric assemblies of subunits, of which two major subunit families designated NR1 and NR2 have been cloned. Without being bound by theory, it is generally believed that the various functional NMDA receptors in the mammalian central nervous system (“CNS”) are only formed by combinations of NR1 and NR2 subunits, which respectively express glycine and glutamate recognition sites. The NR2 subunit family is in turn divided into four individual subunit types: NR2A, NR2B, NR2C, and NR2D. I. Ishii, et al.,
J. Biol. Chem
., 268:2836-2843 (1993), A. Wenel, et al.,
Neural Report
, 7:45-48 (1995), and D. J. Laurie et al.,
Mol. Brain Res
., 51:23-32 (1997) describe how the various resulting combinations produce a variety of NMDA receptors differing in physiological and pharmacological properties such as ion gating properties, magnesium sensitivity, pharmacological profile, as well as in anatomical distribution.
For example, while NR1 is found throughout the brain, NR2 subunits are differentially distributed. In particular, it is believed that the distribution map for NR2B lowers the probability of side effects while producing pain relief. For example, S. Boyce, et al.,
Neuropharmacology
, 38:611-623(1999) describes the effect of selective NMDA NR2B antagonists on pain with reduced side-effects. Thus, it would be desirable to provide novel NMDA antagonists that target the NR2B receptor.
Phenol compounds described as NMDA antagonists are described in U.S. Pat. Nos. 5,306,723 and 5,436,255, and in International Patent Publications WO91/17156, WO92/19502, WO93/02052, WO94/29571, WO95/28057, WO96/37226, and EP 04422506. Benzyl piperidine substituted with phenols or imidazoles are described in Z.-L. Zhou, et al.,
J. Medicinal Chemistry
, 42:2993-3000(1999); T. F. Gregory, et al., Poster #94, 218
th
National Meeting American Chemical Society, New Orleans, La., Aug. 22-26, 1999. Other NMDA NR2B selective compounds are described in European Patent Publication EP 787493 and British
J. Pharmacol
., 123:463(1998). However, there continues to be a need for novel NMDA antagonists that target the NR2B receptor.
International Patent Publication WO94/21615 describes benzimidazole-piperidine compounds utilized as dopamine D4 antagonists.
SUMMARY OF THE INVENTION
The present invention relates to novel piperidines substituted in the 1- and 4-positions, through a bridge, with i) optionally substituted 2-benzimidazoles, 2-indoles, 2-quinazolines, or 2-imidazopyridines; or ii) phenyl or substituted phenyl. The present invention also forms pharmaceutical compositions utilizing the compounds. Further, this invention includes novel methods to treat pain by utilizing the compounds.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the compounds of this invention are represented by Formula (I):
or pharmaceutically acceptable salts thereof, wherein
R
1
is i) 2-benzimidazole, 2-imidazopyridine, 2-indole, purine, or 2-quinazoline, each optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylsulfonamide, hydroxy, or carboxy; or ii) phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylsulfonamide, hydroxy, or carboxy;
R
2
is a) 2-benzimidazole, 2-imidazopyridine, 2-indole, purine, or 2-quinazoline, each optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylsulfonamide, hydroxy, or carboxy; or b) phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylsulfonamide, hydroxy, or carboxy;
When R
1
is i, then R
2
is b; when R
1
is ii, then R
2
is a;
When R
1
or R
2
is 2-benzimidazole, respective L
1
or L2 is not C
1
-C
2
alkyl, except when R
1
or R
2
is hydroxy-substituted 2-benzimidazole, respective L
1
or L
2
includes C
1
-C
2
alkyl
L
1
and L
2
are independently C
1
-C
4
alkyl, C
1
-C
4
alkenyl, C
1
-C
4
alkynyl, C
1
-C
4
alkoxy, aminoC
1
-C
4
alkyl, hydroxyC
1
-C
4
alkyl, carbonyl, cycloC
3
-C
6
alkyl or aminocarbonyl; and
optionally substituted at any of the 2, 3, 5, or 6 positions independently with X, wherein X is hydroxy, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, C
1
-C
4
alkyl, ester, carbamate, carbonate, or ether.
In an embodiment of this invention the compound is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R
1
is 2-imidazopyridine, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylsulfonamide, hydroxy, or carboxy;
R
2
is phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylsulfonamide, hydroxy, or carboxy;
L
1
and L
2
are independently C
1
-C
4
alkyl, C
1
-C
4
alkenyl, C
1
-C
4
alkynyl, C
1
-C
4
alkoxy, aminoC
1
-C
4
alkyl, hydroxyC
1
-C
4
alkyl, carbonyl, cycloC
3
-C
6
alkyl or aminocarbonyl; and
optionally substituted at any of the 2, 3, 5, or 6 positions independently with X, wherein X is hydroxy, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, C
1
-C
4
alkyl, ester, carbamate, carbonate, or ether.
In another embodiment of this invention the compound is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R
1
is purine, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylsulfonamide, hydroxy, or carboxy;
R
2
is phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylsulfonamide, hydroxy, or carboxy;
L
1
and L
2
are independently C
1
-C
4
alkyl, C
1
-C
4
alkenyl, C
1
-C
4
alkynyl, C
1
-C
4
alkoxy, aminoC
1
-C
4
alkyl, hydroxyC
1
-C
4
alkyl, carbonyl, cycloC
3
-C
6
alkyl or aminocarb
Claremon David A.
Huscroft Ian
Kulagowski Janusz
Munson Peter M.
Thompson Wayne
Lee Shu M.
Liu Hong
Merck & Co. , Inc.
Rose David L.
Shah Mukund J.
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