Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-25
2002-08-27
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S248000, C514S249000, C514S252020, C544S326000, C544S327000, C544S328000, C544S295000, C544S296000
Reexamination Certificate
active
06440976
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel iminopyrimidine compounds. In particular, this invention relates to novel iminopyrimidine compounds effective as NMDA NR2B antagonists.
2. Related Background
Ions 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. L. 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. S. Boyce, et al.,
Neuropharmacology,
33:1609-1611 (1994) describes the regional distribution of the NMDA receptor contining the NR2B subunit protein in rat lumbar spinal cord. Thus, it would be desirable to provide novel NMDA antagonists that target the NR2B receptor.
SUMMARY OF THE INVENTION
Compounds described by the following chemical structural formula (I):
or a pharmaceutically acceptable salt thereof, wherein
i) Ar is an aromatic group, the aromatic group being phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, quinoxalinyl, furyl, thienyl, pyrrolyl, benzimidazolyl, indolyl, quinolinyl, isoquinolinyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, imidazolyl, benzthienyl, or benzofuryl, the aromatic group optionally substituted by one or two substituents, each substituent independently is halogen, C
1-4
alkyl, or oxyC
1-4
alkyl;
ii) R
1
is a phenyl; or —CH
2
—, —NH—, —NR
4
—, —NR
5
—, or ═N— when optionally connected either via B
1
to R
2
or via B
2
to R
3
;
iii) R
2
is a phenyl group, a C
1-4
alkylphenyl group, or absent, wherein the groups optionally may be substituted by one or two substituents, each substituent is independently halogen, C
1-4
alkyl, or oxyC
1-4
alkyl; R
2
optionally is —CH
2
— or ═CH— connected via B
1
to R
1
;
iv) R
3
is a phenyl group, a C
1-4
alkylphenyl group, or absent, wherein the groups optionally may be substituted by one or two substituents, each substituent is independently halogen, C
1-4
alkyl, or oxyC
1-4
alkyl; R
3
optionally is —CH
2
— or ═CH— connected via B
2
to R
1
;
v) R
4
is a phenyl group, a C
1-4
alkylphenyl group, or absent, wherein the groups optionally may be substituted by one or two substituents, each substituent is independently halogen, C
1-4
alkyl, or oxyC
1-4
alkyl;
vi) R
5
is a phenyl group, a C
1-4
alkylphenyl group, or absent, wherein the groups optionally may be substituted by one or two substituents, each substituent is independently halogen, C
1-4
alkyl, or oxyC
1-4
alkyl;
vii) R
6
is a phenyl group, a C
1-4
alkylphenyl group, or absent;
viii) R
7
is a phenyl group, a C
1-4
alkylphenyl group, or absent;
ix) B
1
is —CH
2
—, ═CH—, —CH
2
CH
2
—, —CH═CH—, or absent; and
x) B
2
is —CH
2
—, ═CH—, —CH
2
CH
2
—, —CH═CH—, or absent;
are useful in the treatment of pain, migraine, depression, anxiety, schizophrenia, Parkinson's disease, stroke, and in the treatment of neuropathies including postherpetic neuralgia, central pain from spinal cord injury, and phantom limb pain.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are described by the following chemical structural formula (I):
or a pharmaceutically acceptable salt thereof, wherein
i) Ar is an aromatic group, the aromatic group being phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, quinoxalinyl, furyl, thienyl, pyrrolyl, benzimidazolyl, indolyl, quinolinyl, isoquinolinyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, imidazolyl, benzthienyl, or benzofuryl, the aromatic group optionally substituted by one or two substituents, each substituent independently is halogen, C
1-4
alkyl, or oxyC
1-4
alkyl;
ii) R
1
is a phenyl; or —CH
2
—, —NH—, —NR
4
—, —NR
5
—, or ═N— when optionally connected either via B
1
to R
2
or via B
2
to R
3
;
iii) R
2
is a phenyl group, a C
1-4
alkylphenyl group, or absent, wherein the groups optionally may be substituted by one or two substituents, each substituent is independently halogen, C
1-4
alkyl, or oxyC
1-4
alkyl; R
2
optionally is —CH
2
— or ═CH— connected via B
1
to R
1
;
iv) R
3
is a phenyl group, a C
1-4
alkylphenyl group, or absent, wherein the groups optionally may be substituted by one or two substituents, each substituent is independently halogen, C
1-4
alkyl, or oxyC
1-4
alkyl; R
3
optionally is —CH
2
— or ═CH— connected via B
2
to R
1
;
v) R
4
is a phenyl group, a C
1-4
alkylphenyl group, or absent, wherein the groups optionally may be substituted by one or two substituents, each substituent is independently halogen, C
1-4
alkyl, or oxyC
1-4
alkyl;
vi) R
5
is a phenyl group, a C
1-4
alkylphenyl group, or absent, wherein the groups optionally may be substituted by one or two substituents, each substituent is independently halogen, C
1-4
alkyl, or oxyC
1-4
alkyl;
vii) R
6
is a phenyl group, a C
1-4
alkylphenyl group, or absent;
viii) R
7
is a phenyl group, a C
1-4
alkylphenyl group, or absent;
ix) B
1
is —CH
2
—, ═CH—, —CH
2
CH
2
—, —CH═CH—, or absent; and
x) B
2
is —CH
2
—, ═CH—, —CH
2
CH
2
—, —CH═CH—, or absent.
In an aspect, the compounds of this invention are described by formula (I), or a pharmaceutically acceptable salt thereof, wherein
Ar is a phenyl ring, optionally substituted by one or two substituents, each substituent independently is halogen, C
1-4
alkyl, or oxyC
1-4
alkyl;
R
1
is a phenyl; or R
1
is —CH
2
—, —NH—, —NR
4
—, —NR
5
—, or ═N— when optionally connected either via B
1
to R
2
or via B
2
to R
3
;
R
2
is a phenyl group, a C
1-4
alkylphenyl group, or absent, wherein the groups optionally may be substi
Claremon David A.
Liverton Nigel J.
McCauley John A.
Theberge Cory R.
Ford John M.
Lee Shu Muk
Merck & Co. , Inc.
Rose David L.
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