Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-05
2002-04-09
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S208000
Reexamination Certificate
active
06369228
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds useful in the treatment of neuropathic pain. More particularly, this invention relates to aroyl aminoacyl pyrroles that are useful in the treatment of neuropathic pain.
BACKGROUND OF THE INVENTION
The conditions grouped under the term neuropathic pain constitute an area of continuing medical need.
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. Such conditions are widespread and cause unnecessary pain and suffering. Moreover, current methods of treating neuropathic pain are often inadequate and result in huge medical costs.
Anticonvulsants have been widely 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. Such compounds are believed to act preferentially on lancinating, shooting pain. Gabapentin induced a moderate and statistically significant relief of ongoing spontaneous pain, was particularly effective in reducing paroxysmal pain and was significantly effective on brush-induced and cold allodynia (a painful response to normally innocuous stimuli). In contrast, no effect on detection and pain thresholds to static mechanical and hot stimuli was observed. The study suggests that gabapentin is preferentially antihyperalgesic (mediates exaggerated responses to normally painful stimuli) and/or antiallodynic and similarly effective in pain due to peripheral nerve injuries or central lesions.
Other anticonvulsants have been useful in treating neuropathic pain, Richard P. Shank, et al., Anticonvulsant Derivatives Useful in Treating Neuropathic Pain, U.S. Pat. No. 5,760,007. As disclosed in this reference, studies conducted to evaluate the efficacy of the anticonvulsant topiramate in an animal model of neuropathic pain gave evidence of pharmacological activity in treating neuropathic pain.
Also, therapeutic compositions of anticonvulsants and non-toxic NMDA (N-methyl-D-aspartate) antagonists in neuropathic pain-alleviating amounts have been shown to block a major intracellular consequence of NMDA receptor activation, Frank S. Caruso, et al., Pharmaceutical Compositions Containing Anticonvulsants and NMDA Receptor Antagonists for Treating Neuropathic Pain, WIPO Patent No. 98/07447. This reference teaches the use of these anticonvulsants as suitable for use in this combination: 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.
The aroyl amino acyl pyrrole compounds of the present invention have been previously disclosed and taught as useful anticonvulsants, Richard J. Carmosin, John R. Carson, Philip M. Pitis, Anticonvulsant Aroyl Amino Acyl Pyrroles, U.S. Pat. No. 5,332,736. The compounds of the present invention, however, have not previously been shown as effective for the treatment of neuropathic pain. It is an object of the present invention to teach a method for the treatment of neuropathic pain using the compounds of the present invention.
SUMMARY OF THE INVENTION
Briefly, there is provided by the present invention a method for the treatment of neuropathic pain comprising the step of administering to a mammal suffering from such condition an effective amount, in a pharmaceutically acceptable carrier, of an active compound of the formula:
wherein,
A is simultaneously both
n is an integer from 1 to 5;
R
1
is selected from the group consisting of H and C
1-4
alkyl;
R
2
and R
3
are selected from the group consisting of H and C
1-4
alkyl;
R
4
and R
5
are independently selected from the group consisting of H, C
1-4
alkyl, phenyl C
1-4
alkyl and substituted phenyl C
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 said 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, x is 3 to 7 and R
7
is selected from the group consisting of methyl and hydroxymethyl; and
R
6
is selected from the group consisting of halo, C
1-4
alkyl, C
1-4
alkoxy, hydroxy, nitro, amino, C
1-4
acylamino, cyano, trihaloC
1-4
alkyl, C
1-4
alkylsulfonyl, C
1-4
alkylsulfinyl, and C
1-4
acyl,
including pharmaceutically acceptable acid addition salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention used in the treatment of neuropathic pain may be placed into two categories, those having benzoyl at the 2-position and those having benzoyl at the 4-position. Both categories of compounds may be prepared by variations of what is fundamentally the same reaction scheme.
Scheme 1 exemplifies the preparation of compounds having benzoyl at the 2-position. Referring to Scheme 1, in the first step a simple pyrrole A1 is acylated with an appropriately substituted benzoyl chloride B1 to produce benzoyl pyrrole C1. This acylation may be carried out by simply heating the benzoyl chloride and the pyrrole in an aprotic solvent followed by removing excess benzoyl chloride by reaction with a dibasic amine and extraction with HCl. Typical of the aprotic solvents which may be utilized are aromatic hydrocarbons, such as, benzene, toluene, xylene, chlorobenzene, nitrobenzene, etc.; paraffins, such as, methyl cyclohexane, octane, etc.; halocarbons, such as, methyl chloride, chloroform, tetrachloroethane, etc.; ethers, such as, diethyl ether, diglyme, etc.; ketones, such as, methyl ethyl ketone, cyclohexanone, etc.; esters, such as, ethyl butyrate, etc.; nitroalkanes, such as, nitropropane, etc.; or carbon disulfide. The temperature of the acylation will vary depending upon the desired rate of reaction and the substituents of pyrrole A1. Preferably the acylation is carried out at a temperature of from about 50 to 250° C. A suitable dibasic amine is dimethyl-3-aminopropyl amine. In the case where R
1
is hydrogen the acylation, as described, may not produce desirable yields. In this case, a Vilsmeier type acylation as employed by J. White and G. McGillivrey, J. Org. Chem., Vol. 42, pp 42-48, 1977 might be expeditiously employed. Subsequently, benzoyl pyrrole C1 is acylated at the 4-position in a Friedel-Crafts reaction with acid chloride D1 to produce 2-benzoyl-4-alkanoyl pyrrole E1. The Friedel-Crafts reaction is carried out by refluxing the carboxylic acid chloride D1, in which X is Cl, Br or l, with product C1 in a solvent with a Friedel-Crafts reagent followed by treatment with HCl and evaporation of the solvent. Suitable Friedel-Crafts reagents include aluminum chloride, zinc chloride, BF
3
or TiCl
4
. Suitable solvents include methylene chloride, 1,2-dichloroethane, carbon tetrachloride or chloroform. The temperature of reflux might vary between about 30 and 150° C. In the case where R
6
is amine, it will not survive the Friedel-Crafts reaction in good yield. Thus, it should be protected with well known protecting groups or present as a suitable precursor substituent, such as, nitro which can thereafter be converted to amine. In the third reaction, 2-benzoyl-4-alkanoyl pyrrole E1 is aminated with amine F1 to produce the desired 2-benzoyl-4-aminoalkanoyl pyrrole G1. The amination may be carried out by heating the reactants E1 and F1 neat or in a solvent to a temperature of from about 40 to 120° C. and preferably from about 50 to 90° C. Suitable solvents, where emplo
Carson John R.
Pitis Philip M.
Rogers Kathryn E.
Davis Zinna Northington
Harbour John
Ortho-McNeil Pharmaceutical , Inc.
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