Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-29
2003-06-03
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S227800, C514S235500, C514S326000, C514S343000, C514S397000, C514S422000, C514S423000, C544S058200, C544S058500, C544S141000, C544S372000, C546S208000, C546S279100, C548S314700, C548S518000, C548S527000, C548S539000
Reexamination Certificate
active
06573267
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds useful as agents for the treatment of central nervous system disorders. More particularly, this invention relates to aroyl aminoacyl pyrrole compounds useful as agents for the treatment of central nervous system disorders including, but not limited to, epilepsy and neuropathic pain and methods for the treatment thereof.
BACKGROUND OF THE INVENTION
The conditions grouped under the term “central nervous system disorder” constitute an area of continuing medical need. Such conditions include those disorders associated with convulsions, epilepsy, neuroprotective diseases, muscle tension and neuropathic pain.
Epilepsy continues to be an area of development for new drugs and therapies. The structures of newer anticonvulsants has been summarized in Drugs of the Future, 1991, (16) 317-320. However, the impact of such drugs and therapies have yet to be fully evaluated.
Neuropathic pain is defined as pain caused by aberrant somatosensory processing in the peripheral or central nervous system. Chronic or debilitating conditions, such as post-herpetic neuralgia and phantom limb syndrome, are categorized as neuropathic pain.
Central nervous system disorders are widespread and cause pain and suffering. Moreover, current methods of treating such disorders are often inadequate.
Anticonvulsants have been suggested for the treatment of neuropathic pain. Nadin Attal, et al., Effects of Gabapentin on the Different Components of Peripheral and Central Neuropathic Pain Syndromes: A Pilot Study,
Fr. Eur. Neurol.
1998, 40(4), 191-200 describes the anticonvulsant gabapentin having the following formula:
U.S. Pat. No. 5,760,007 describes other anticonvulsants useful in the treatment of neuropathic pain. More particularly, the reference describes the use of the anticonvulsant topiramate in treating neuropathic pain, wherein topiramate has the following general formula:
Also, WO 98/07447 describes compositions combining an anticonvulsant and a non-toxic NMDA (N-methyl-D-aspartate) antagonist for use in neuropathic pain. Anticonvulsants suitable for use in the described combination include lamotrigine, gabapentin, valproic acid, topiramate, famotidine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, clonazepam, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, phenytoin sodium, valproate sodium, clobazam, sulthiame, dilantin, diphenylan and L-5-hydroxytryptophan.
U.S. Pat. No. 5,332,736 to Carmosin, et al, describes other aroyl aminoacyl pyrrole compounds as useful anticonvulsants. The aroyl pyrrole compounds of the present invention, however, have not been previously described as useful agents for the treatment of central nervous system disorders.
Accordingly, it is an object of the present invention to provide aroyl pyrrole compounds useful as agents for the treatment of central nervous system disorders. It is also an object of the present invention to teach a method for the treatment of central nervous system disorders using the aroyl pyrrole compounds of the present invention including, but not limited to, their use as anticonvulsants, antiepileptics, neuroprotective agents, muscle relaxants and agents for the treatment of neuropathic pain.
SUMMARY OF THE INVENTION
The present invention provides aroyl aminoacyl pyrrole compounds as agents for the treatment of central nervous system disorders having Formula (I) and Formula (II):
wherein
A is a substituent selected from the group consisting of aryl and heteroaryl optionally substituted with one to two substituents selected from the group consisting of halogen, C
1-8
alkyl, C
1-8
alkoxy, tri(halogen)C
1-8
alkyl and tri(halogen)C
1-8
alkoxy;
n is an integer from 1 to 5;
R
1
is C
1-8
alkyl optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, C
1-8
alkoxy (optionally substituted with —SC
1-8
alkyl), C
1-8
acyl, carboxy, carbonyl (further substituted with C
1-8
alkyl, C
1-8
alkoxy, amino or —SC
1-8
alkyl), oxy (further substituted with carbonylC
1-8
alkyl, carbonylC
1-8
alkoxy or carbonylamino), amino (optionally further substituted with one or two substituents independently selected from C
1-8
alkyl, C
1-8
acyl, carbonylC
1-8
alkyl, carbonylC
1-8
alkoxy, sulfinylC
1-8
alkyl or sulfonylC
1-8
alkyl), ureido (optionally further substituted with C
1-8
alkyl), thio (optionally further substituted with C
1-8
alkyl or amino), sulfinyl (optionally further substituted with C
1-8
alkyl or amino) and sulfonyl (optionally further substituted with C
1-8
alkyl or amino);
R
2
and R
3
are substituents independently selected from the group consisting of hydrogen and C
1-8
alkyl;
R
4
and R
5
are substituents independently selected from the group consisting of hydrogen, C
1-8
alkyl and arylC
1-8
alkyl; wherein aryl is optionally substituted with one to three substituents selected from the group consisting of C
1-8
alkyl, C
1-8
alkoxy, tri(halo)C
1-8
alkyl and tri(halo)C
1-8
alkoxy;
or, in the alternative, R
4
and R
5
may be fused together with nitrogen to form a heterocyclic ring selected from the group consisting of:
wherein x is an integer from 3 to 7 and Y is selected from the group consisting of N, S, S═O, SO
2
and 0; and
R
6
is a substituent selected from the group consisting of C
1-8
alkyl and hydroxyC
1-8
alkyl;
and pharmaceutically acceptable acid addition salts thereof;
with the proviso that,
in the case of compound wherein:
wherein
n is an integer from 1 to 5; R
1
is selected from the group consisting of hydrogen and C
1-4
alkyl; R
2
and R
3
are selected from the group consisting of hydrogen and C
1-4
alkyl; R
4
and R
5
are independently selected from the group consisting of hydrogen, C
1-4
alkyl, phenylC
1-4
alkyl and substituted phenylC
1-4
alkyl where the substituent is on phenyl and selected from the group consisting of methyl and methoxy; or in the alternative, are fused and together with the nitrogen form a heterocyclic ring selected from the group consisting of: 4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl, 1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-2-yl,
wherein Y is S or O and x is 3 to 7; and, R
6
is selected from the group consisting of methyl and hydroxymethyl; then, A cannot be substituted or unsubstituted phenyl.
The present invention also provides a method for the treatment of central nervous system disorders comprising the step of administering to a mammal suffering from such condition a therapeutically effective amount of an active compound selected from Formula (I) and Formula (II).
DETAILED DESCRIPTION OF THE INVENTION
Relative to the above generic description, certain compounds of Formula (I) and Formula (II) are preferred. Preferred embodiments are those compounds wherein
A is a substituent selected from the group consisting of phenyl, naphthalenyl, furyl, thienyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or quinolinyl optionally mono- or di-substituted with chlorine, methyl, ethyl, methoxy, trifluoromethyl or trifluoromethoxy. More preferably, A is selected from phenyl, naphthalenyl, thienyl or pyridinyl optionally mono- or di-substituted with chlorine, methyl or methoxy.
n is an integer from 1 to 2.
R
1
is C
1-8
alkyl optionally substituted with one to two substituents independently selected from the group consisting of C
1-8
alkoxy and amino; wherein amino is optionally substituted with one to two substituents independently selected from C
1-8
alkyl. More preferably, R
1
is a substituent selected from the group consisting of methyl, ethyl, n-propyl, n-butyl and t-butyl optionally substituted with one to two substituents independently selected from the group consisting of methoxy, ethoxy, propoxy and amino; wherein amino is optionally substituted with one to two su
Carson John R.
Pitis Philip M.
Harbour John W.
Ortho-McNeil Pharmaceutical , Inc.
Raymond Richard L.
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