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
2001-11-13
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S394000, C514S395000, C546S273400, C548S304700, C548S305100, C548S306400, C548S307400, C548S310100, C548S243000
Reexamination Certificate
active
06316474
ABSTRACT:
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
This invention relates to novel benzimidazole derivatives. In particular, this invention relates to novel benzimidazoles, substituted in the 2-position by substituted benzyl groups or heteroaryl groups, 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. Neurophartnacol.
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 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.,
NeuralReport,
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 distirbution 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.
U.S. Pat. No. 5,714,498 (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, WO94/2957 1, 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., 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.
SUMMARY OF THE INVENTION
The present invention relates to benzimidazoles substituted in the 2-position with substituted benzyl groups. 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 represented by Formula (I):
or pharmaceutically acceptable salts thereof, wherein
R
1
, R
2
, R
4
, and R
5
are independently H, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, cyano, nitro, C
1-7
alkyl, aryl, aminoC
1-4
alkyl, C
1-4
alkyl-carbonylamino, oxo-hydroxy-dibenzopyranyl-carboxyphenyl-thioueido, R
6
SO
2
NH—, R
6
SO
2
N(CH
3
)—, R
6
SO
2
NHCH
2
—, or oxo-hydroxy-dibenzopyranyl-carboxyphenyl-substituted carbonylamino-C
1-4
alkyl-carbonylamino;
R
3
is H, OH, NH
2
, alkylamine, arylamine, or a carbonyl oxygen;
R
6
is C
1-6
alkyl, C
1-6
alkenyl, phenylC
1-3
alkenyl, phenyl, naphthyl, or heterocyclic group, optionally substituted with 1-6 substituents, each substituent independently being halogen, C
1-4
alkyl, C
1-4
alkoxy, haloC
1-4
alkoxy, amino, C
1-4
alkylamino, diC
1-4
alkylamino, C
1-4
alkylcarbonylamino, phthalimidyl, phenylsulfonyl, or oxo-hydroxy-dibenzopyranyl-carboxyphenyl-thioueido;
Y is O, NH, (CH
2
)
n
CO(CH
2
)
n
, (CH
2
)
n
CHR
3
(CH
2
)
n
, n is independently 0, 1, 2, 3, 4, or 5; and
the central ring Ar is substituted with 0-3 nitrogen heteroatoms at any of positions 2, 3, 5, or 6.
As used herein, “alkyl” as well as other groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. “Alkenyl”, “alkynyl” and other like terms include carbon chains containing at least one unsaturated C—C bond.
The term “cycloalkyl” means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene and the like. Similarly, “cycloalkenyl” means carbocycles containing no heteroatoms and at least one non-aromatic C—C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.
Unless otherwise stated, the terms “carbonyl” and “carbonylamino” include short C
1
-C
2
termini. The terms include, for example, —CO—, —CONH—, —CH
2
CO—, —CH
2
CONH—, —C
2
H
4
CO—, —C
2
H
4
CONH—, —COCH
2
—, —CONHCH
2
—, —COC
2
H
4
—, —CONHC
2
H
4
—, —CH
2
COCH
2
—, —CH
2
CONHCH
2
—, —CH
2
COC
2
H
4
—, —CH
2
CONHC
2
H
4
—, —C
2
H
4
COC
2
H
4
—, and —C
2
H
4
CONHC
2
H
4
—.
Unless otherwise stated, the term “C
1-4
alkylamino” includes short C
1
-C
2
termini. The term includes, for example, —CH
2
NH—, —C
2
H
4
NH—, —C
3
H
6
NH—, —C
4
H
8
NH—, —CH
2
NHCH
2
—, —C
2
H
4
NHCH
2
—, —C
3
H
6
NHCH
2
—, —C
4
H
8
NHCH
2
—, —CH
2
NHC
2
H
4
—, —C
2
H
4
NHC
2
H
4
—, —C
3
H
6
NHC
2
H
4
—, and —C
4
H
8
NHC
2
H
4
—. Similarly, unless otherwise stated, the term “diC
1
-C
4
alkylamino” includes short C
1
-C
2
termini.
The term “halogen” includes fluorine, chlorine, bromine and iodine atoms.
The term “aryl” includes, for example, phenyl and naphthyl.
Unless otherwise stated, the term “heterocyclic group” includes, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benz
Claiborne Christopher F.
Claremon David A.
Liverton Nigel J.
McCauley John A.
Theberge Cory R.
Higel Floyd D.
Lee Shu Muk
Merck & Co. , Inc.
Rose David L.
Saeed Kamal
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