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
2002-08-13
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S126000
Reexamination Certificate
active
06432976
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to novel 8-aza-bicyclo[3.2.1]octanes. In particular, this invention relates to novel 3-substituted 8-aza-bicyclo[3.2.1]octanes substituted in the 8-position that are effective as NMDA 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 to produce symptomatic relief in a number of neuropathies including postherpetic neuralgia, central pain from spinal cord injury, and phantom limb pain, (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)) 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 produces 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.,
NeutralReport
, 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.
International Patent Publication WO94/21615 describes benzimidazole-piperidine compounds utilized as dopamine D4 antagonists. 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 piperidines 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., August 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.
SUMMARY OF THE INVENTION
The present invention relates to 3-substituted 8-aza-bicyclo[3.2.1]octanes substituted in the 8-position with benzimidazoles, imidazopyridines, phenols orimidazoles either directly or through a C1-C4alkyl, cycloalkyl, hydroxyalkyl, alkoxy or aminoalkyl chain. The present invention also forms novel pharmaceutical compositions utilizing these novel compounds. Further, this invention includes novel methods to treat pain by utilizing the novel compounds.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the compounds of this invention are 3-substituted 8-aza-bicyclo[3.2.1]octanes (commonly known as “tropanes”) represented by Formula (I):
or pharmaceutically acceptable salts thereof, wherein
R
1
is benzimidazole, imidazole, imidazopyridine, indole, quinazoline, purine, benzoxazolone, or phenol;
R
2
is phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, 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, 4, 6, or 7 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 one embodiment, the compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R
1
is benzimidazole;
R
2
is phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, 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, 4, 6, or 7 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, the compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R
1
is imidazole;
R
2
is phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, 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, 4, 6, or 7 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 yet another embodiment, the compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R
1
is imidazopyridine,
R
2
is phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, 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, 4, 6, or 7 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 still another embodiment, the compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R
1
is purine;
R
2
is phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C
1
-C
4
alkyl, trifluoromethyl, hydroxy, or carboxy;
L
1
and L
2
are independ
Claremon David A.
Munson Peter M.
Phillips Brian
Thompson Wayne
Lee Shu M.
Merck & Co. , Inc.
Morris Patricia L.
Rose David L.
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