METHOD AND COMPOSITIONS FOR PRODUCING ANALGESIA

Abstract: Compositions and methods for producing analgesia are described. Compounds in accordance with formula (I) are shown to provide analgesia in settings of acute and persistent nociceptive pain and neuropathic pain.

Description: METHOD AND COMPOSITIONS FOR PRODUCING ANALGESIA Field of the Invention The present invention relates to methods and compositions for producing analgesia, particularly in the treatment of acute and persistent nociceptive pain and neuropathic pain. References Dixon, W.J., Ann. Rev. Pharmacol. Toxicol. 20:441-462 (1976). Fernando, C.R. et al., J. Med. Chem. 23:1153-1158 (1980). Glushkov, R.G. etal., SU Patent No. 1,557,964 (7/92); Der ent Abstract No. 93-224958. Jadad, A.R. et al., Lancet 239:1367-1371 (1992). Keenaghan, J.B. et al., J. Pharmacol. Exp. Ther. 180:454 (1972). Kim, S.H. and Chung, J.M., Pain 50:355-363 (1992). McGeer, P.L., in MOLECULAR NEUROBIOLOGY OF THE MAMMALIAN BRAIN. Plenum Press, New York, 1987. Nelson, S.D. et al., J. Pharm. Sci. 66:1180-1190 (1977). Wheeler-Aceto, H. et al., Pain 40:229-238 (1990). Wheeler-Aceto, H. et al, Psychopharmacology 104:35-44 (1991). Wheeler-Aceto, H. et al., Agents Actions 34:264-269 (1991). Yaksh, T.L. and Rudy, T.A., Physiol. Behav. 17:1031-1036 (1976). Yamamoto, T. and Yaksh, T.L., Life Sciences 49:1955-1963 (1991). Yamamoto, T. and Yaksh, T.L., Neuroscience Lett. 135:67-70 (1992). Background of the Invention Chronic or intractable pain, such as may occur in conditions such as bone degenerative diseases and cancer, is a debilitating condition which is treated with a variety of analgesic agents, and often with opioid compounds, such as morphine. Although brain pathways governing the per- ception of pain are still incompletely understood, sensory afferent synaptic connections to the spinal cord, termed "nociceptive pathways," have been documented in some detail (McGeer). Analgesia, or the reduction of pain perception, can be effected by decreasing transmission along such nociceptive pathways. Neuropathic pain is a particular type of pain that has a complex and variable etiology. It is generally a chronic condition attributable to complete or partial transection of a nerve or trauma to a nerve plexus or soft tissue. This condition is characterized by hyperesthesia (enhanced sensitivity to a natural stimulus), hyperalgesia (abnormal sensitivity to pain), allodynia (widespread tenderness, characterized by hypersensitivity to tactile stimuli), and/or spontaneous burning pain. In humans, neuropathic pain tends to be chronic and may be debilitating. Neuropathic pain is generally considered to be non-responsive or only partially responsive to conventional opioid analgesic regiments (Jadad). Opioid compounds may also induce tolerance in patients, requiring increased dosages. At high doses, these compounds produce side effects, such as respiratory depression, which can be life threatening, and may also produce physical dependence in patients. For these reasons, alternate therapies for the management of chronic or neuropathic pain are widely sought. Lidocaine is an well known analgesic compound with sodium channel blocking properties. It operates as a local anesthetic by inhibiting the ionic fluxes needed for conduction of impulses across neuronal membranes. However, because of potentially serious side effects, which can include spinal block, respiratory arrest, and cardiac arrest, minimal dosages are recommended when lidocaine hydrochloride is administered systemically for anesthesia, and it must be adminis¬ tered under careful supervision (Physician's Desk Reference, 1994). Lidocaine also has low aqueous solubility (octanol/water partition coefficient = 43 at pH 7.4). It is therefore desirable to provide analgesic compounds which have low toxicity at effective dosage levels, have improved water solubility, and are effective in treatment of neuropathic pain as well as acute and persistent nociceptive pain. Summary of the Invention The invention includes, in one aspect, a method of treating pain, including acute and persistent nociceptive pain and neuropathic pain. In accordance with the method, a composition is administered to a subject in need of such treatment, comprising a therapeutically effective amount of a compound of formula I: wherein A 1 and A 2 are hydroxyl or hydrogen, with the proviso that at least one of A 1 and A- is hydroxyl; R 1 is a one- or two-carbon linkage between the carbonyl carbon and amine nitrogen of formula I; and R 2 is selected from the group consisting of methyl, ethyl, CH 2 X, and CH 2 CH 2 X, where X is a hydroxyl or amino group, or, R 2 is an alkyl chain linked to R 1 to form a four- to six- membered heterocyclic ring, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. In preferred embodiments, A 1 is hydroxyl and A 2 is hydrogen. Further preferred embodiments are those in which R' is -CH 2 - or -CH 2 CH 2 -, and R 2 is methyl, ethyl, CH 2 X, or CH 2 CH 2 X, where X is a hydroxyl or amino group, and preferably a hydroxyl group. A particularly preferred embodiment employs 2-(ethylamino)-N-(3-hydroxy-2,6-dimethylphenyl) acetamide, also known as 3-hydroxy monoethylglycine xylidide, or 3-hydroxy MEGX. Other preferred compounds administered in accordance with the method include those in which R 1 is a one-carbon linkage as described above, and R 2 is an alkyl chain linked to R 1 to form a four- to six-membered heterocyclic ring, which is preferably a pyrrolidyl ring. In another aspect, the invention provides a pharmaceutical composition for treating pain, comprising a therapeutically effective amount of a compound of formula I, as described above, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. Preferred compositions include the preferred compounds described above. Particularly preferred composi¬ tions include the compounds 2-(emylamino)-N-(3-hydroxy-2,6-dimethylphenyl) acetamide, 2-((2- hydroxyethyl)amino)-N-(3-hydroxy-2,6-dimethylphenyI) acetamide, 2-((2S)-2-pyrrolidyl)-N-(3- hydroxy-2 ,6-dimethylphenyl) acetamide, 2-((2R)-2-pyrroIidyl)-N-(3-hydroxy-2 ,6-dimethylphenyl) acetamide, and 3-(ethylamino)-N-(3-hydroxy-2,6-dimethylphenyl) propanamide. Preferably, the salt is a halide, carboxylate, sulfonate, or sulfate; e.g., chloride, bromide, acetate, oxalate, maleate, fumarate, methanesulfonate, or toluenesulfonate. Most preferably, the counterion is chloride. The invention also provides analgesic compounds having the structure of formula I: wherein A 1 and A 2 are hydroxyl or hydrogen, with the proviso that at least one of A 1 and A 2 is hydroxyl; R 1 is a one- or two-carbon linkage between the carboπyl carbon and amine nitrogen of formula I; and R 2 is selected from the group consisting of methyl, ethyl, CH 2 X, and CH 2 CH 2 X; where X is a hydroxyl or amino group, or, R 2 is linked to R 1 via an alkyl chain to form a four- or five- membered heterocyclic ring, with the proviso that when A 1 or A 2 is hydrogen and R 1 is -CH 2 -, R 2 is not ethyl. Preferred compounds include those in which A 1 is hydroxyl and A 2 is hydrogen, that is, 3- hydroxy substituted compounds. Particularly preferred compounds include 2-(methylamino)-N-(3- hydroxy-2,6-dimethylphenyl) acetamide, 2-((2-hydroxyethyl)amino)-N-(3-hydroxy-2,6-dimethyl- phenyl) acetamide, 2-((2S)-2-pyrrolidyI)-N-(3-hydroxy-2 ) 6-dimethylphenyl) acetamide, 2-((2R)-2- pyrrolidyl)-N-(3-hydroxy-2,6-dimethylphenyl) acetamide, 3-(ethylamino)-N-(3-hydroxy-2,6- dimethylphenyl) propanamide, and 2-(2-(N,N-dimethylamino)ethyl))amino)-N-(3-hydroxy-2,6- dimethylphenyl) acetamide. These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings. Brief Description of the Drawings Figure 1 shows a synthetic scheme for the preparation of 3-hydroxy substituted compounds of the invention; Figure 2 A shows a synthetic scheme for the preparation of 4-hydroxy substituted compounds of the invention; Figure 2B illustrates the preparation of invention compounds having a heterocyclic ring; Figure 3A shows time-effect curves for intrathecally administered SNX-483 (3-hydroxy MEGX) at pH 6.58, showing dose-dependent blockade of acute and persistent nociceptive responses evoked by subsequent subcutaneous injection of 5% formalin into the hindpaw of Sprague-Dawley rats; Figure 3B is a dose-response curve derived from the data in Figure 3A, showing the effects of SNX-483 at pH 6.58 on acute (Phase 1, 0-9 minutes) formalin-induced nociceptive responses in Sprague-Dawley rats; Figure 3C is a dose-response curve derived from the data in Figure 3A, showing the effects of SNX-483 at pH 6.58 on persistent (Phase 2, 10-90 minutes) formalin-induced nociceptive responses in Sprague-Dawley rats; Figure 4 shows the time-effect curve for SNX-483 administered by intrathecal injection after injection of 5% formalin into the hindpaw of Sprague-Dawley rats, showing blockade of persistent (Phase 2) nociceptive responses; Figure 5 shows the time-effect curve for intrathecally administered lidocaine at pH 6.58, showing the effect on formalin-induced paw flinch behavior in adult Sprague-Dawley rats; Figure 6A shows time-effect curves for intrathecally administered SNX-483 (3-hydroxy MEGX) at pH 9.2, showing dose-dependent blockade of acute and persistent nociceptive responses in Sprague-Dawley rats, as in Fig. 3A; Figure 6B illustrates dose-dependent blockade by SNX-483 at pH 9.2 of formalin-induced acute and persistent nociceptive responses in Sprague-Dawley rats; Figure 7 shows time-effect curves for intrathecally administered SNX-507 (4-hydroxy MEGX) at pH 6.58, showing dose-dependent blockade of acute (Phase 1) and persistent (Phase 2) nociceptive responses evoked by subsequent subcutaneous injection of 5% formalin into the hindpaw of Sprague-Dawley rats; Figure 8A shows time-effect and dose response curves showing the inhibition by intrathecally administered SNX-507 of acute nociceptive responses induced by thermal stimulation in rats (hot¬ plate test); Figure 8B shows a comparison of the areas under time-effect curves for SNX-507 and vehicle-treated controls in inhibition by SNX-507 of thermally induced acute nociceptive responses as in Fig. 8A; Figure 9 shows a time-effect curve showing the inhibition by intrathecally administered SNX- 522 (3-hydroxy MMGX) of acute nociceptive responses induced by thermal stimulation in rats; Figure 10 shows time-effect curves showing dose-dependent blockade by intrathecally administered SNX-483 (3-hydroxy MEGX) of mechanical allodynia in Sprague-Dawley rats with a painful peripheral neuropathy produced by unilateral ligation of the L5/L6 spinal nerves distal to the dorsal root ganglia; Figure 11 shows a dose-response curve showing dose-dependent blockade by SNX-483 of mechanical allodynia in Sprague-Dawley rats with an experimentally induced, painful peripheral neuropathy as in Fig. 10; Figures 12A-B show time-effect curves, and the area under the curves, showing dose- dependent blockade by intrathecally administered SNX-507 (4-hydroxy MEGX) of mechanical allodynia in Sprague-Dawley rats with an experimentally induced, painful peripheral neuropathy; Figure 13 shows time-effect curves showing dose-dependent blockade by intrathecally administered SNX-522 (3-hydroxy MMGX) of mechanical allodynia in Sprague-Dawley rats with an experimentally induced, painful peripheral neuropathy; Figures 14-18 show dose-response curves showing blockade of mechanical allodynia in Sprague-Dawley rats with an experimentally induced, painful peripheral neuropathy, by intrathecal Figures 14-18 show dose-response curves showing blockade of mechanical allodynia in Sprague-Dawley rats with an experimentally induced, painful peripheral neuropathy, by intrathecal administration of 0.6 μmol of compounds designated herein as SNX-559, -560, -561, -572, and -579, respectively; and Figure 19 illustrates mechanical allodynia thresholds in rats with an experimentally induced, painful peripheral neuropathy as in Figs. 10-18, after spinal (intrathecal) injections of mexiletine, 3-hydroxy lidocaine, or lidocaine. Detailed Description of the Invention I. Definitions The terms below have the following meanings unless indicated otherwise. A "two-carbon linkage", as used herein, is linked to the carbonyl carbon of formula I via the first carbon atom and to the amine nitrogen of formula I via the second carbon atom; that is, it does not form a branching linkage. A "one- or two-carbon linkage" indicates, respectively, a -CH 2 - group or a -CH 2 CH 2 - or - CH=CH- group, except in cases wherein R 1 and R 2 of formula I form a heterocyclic ring. "Nociceptive pain" is pain resulting from a noxious stimulus, such as mechanical, thermal, or chemical stimulation, to peripheral nerve endings in the skin, underlying tissue, or viscera. Such a stimulus produces an immediate, or "acute", pain response, and may also produce a longer- lasting, or "persistent", response. The latter may result from activation of nerve endings by substances, such as glutamate and tachykinins, released in the acute pain response. Such pain is typically treatable with anti-inflammatory or narcotic analgesics. "Neuropathic pain" is pain resulting from injury to, or chronic changes in, peripheral or central nerve pathways. Such pain can develop and persist, possibly becoming chronic, without an obvious noxious sensory input. Hypersensitivity to normal sensory stimuli (e.g., hyperesthesia or allodynia) may be present. Such pain is rarely relieved by conventional analgesics, and is generally only partially relieved by narcotic analgesics. II. Analgesic Compositions In accordance with the current invention, administration of a composition including a compound having the structure shown in formula I, above, provides analgesia in settings of acute and persistent nociceptive pain and neuropathic pain. In formula I, A 1 and A 2 are hydroxyl or hydrogen, with the proviso that at least one of A 1 and A 2 is hydroxyl, R 1 is a one- or two-carbon linkage between the carbonyl carbon and amine alkyl chain to form a four- to six-membered heterocyclic ring. The compound may also be administered as a pharmaceutically acceptable salt, such as a halide, carboxylate, sulfonate, or sulfate, and is administered in a pharmaceutically acceptable carrier. Preferred compounds include those in which A 1 is hydroxyl and A 2 is hydrogen, that is, 3- hydroxy substituted compounds. Preferred subgroups of formula I also include compounds where R 1 is -CH 2 - or -CH 2 CH 2 -, and R 2 is methyl, ethyl, CH 2 X, and CH 2 CH 2 X, where X is a hydroxyl or amino group. Particularly preferred are compounds where R 2 is methyl, ethyl, or 2- hydroxyethyl. These include the compounds designated herein (see Table I) as SNX-483 (2- (ethylamino)-N-(3-hydroxy-2,6-dimethylphenyl) acetamide), SNX-507 (2-(ethylamino)-N-(4- hydroxy-2,6-dimethylphenyl) acetamide), SNX-522 (2-(methylamino)-N-(3-hydroxy-2,6- dimethylphenyl) acetamide), and SNX-559 (2-(2-hydroxyethyl)amino)-N-(3-hydroxy-2,6- dimethylphenyl) acetamide). Also included in this subgroup are amino-terminated compounds, such as SNX-579 (2-(2-(N,N-dimethylamino)ethyI))amino)-N-(3-hydroxy-2,6-dimethylphenyl) acetamide), and compounds in which R 1 is a two-carbon chain, such as SNX-572 (3-(ethylamino)- N-(3-hydroxy-2,6-dimethylphenyl) propanamide). Table 1 Compound A 1 A 2 R 1 R 2 SNX-483 OH H -CH 2 - -CH1 H 3 SNX-507 H OH -CH 2 - -CH,CH 3 SNX-522 OH H -CH 2 - -CH 3 SNX-559 OH H -CH 2 - -CH 2 CH 2 OH SNX-560 OH H -2-pyrrolidyl (2S) SNX-561 OH H -2-pyrrolidyl (2R) SNX-572 OH H -CH 2 CH 2 - -CH 2 CH 3 SNX-579 OH H -CH 2 - -CH 2 CH 2 N(CH 3 ) 2 In another preferred subgroup, R 1 is a one-carbon linkage between the carbonyl carbon and amine nitrogen of formula I, and R 2 is an alkyl chain linked to R 1 to form a four- to six-membered heterocyclic ring. Particularly preferred are compounds containing a pyrrolidine ring, such as those designated herein as SNX-560 and SNX-561 (the (2S) and (2R) isomers, respectively, of 2- (2-pyrrolidyl)-N-(3-hydroxy-2,6-dimethylphenyl) acetamide). Also contemplated are differently- sized rings such as piperidine and azetidine, and rings containing other heteroatoms, such as morpholine or thiomorpholine. The compounds may also be administered, in accordance with the present method, as their pharmaceutically acceptable salts. The anionic counterion is preferably a halide or a carboxylate-, sulfonate-, or sulfate-containing ion. More preferably, the counterion is chloride, bromide, ace¬ tate, oxalate, maleate, fumarate, methanesulfonate, or toluenesulfonate. Most preferably, the counterion is chloride. In addition to therapeutic methods and compositions, the invention also provides compounds having the structure of formula I, above, where A 1 and A 2 are hydroxyl or hydrogen, with the proviso that at least one of A 1 and A 2 is hydroxyl, R 1 is a one- or two-carbon linkage between the carbonyl carbon and amine nitrogen of formula I, and R 2 is selected from the group consisting of methyl, ethyl, CH 2 X, and CH 2 CH 2 X, where X is a hydroxyl or amino group, or, R 2 is an alkyl chain linked to R 1 to form a four- or five-membered heterocyclic ring; with the proviso that when A 1 or A 2 is hydrogen and R 1 is -CH 2 -, R 2 is not ethyl. Preferred compounds include 3-hydroxy substituted compounds, and particularly those described above and designated as SNX-522, SNX- 559, SNX-560, SNX-561, SNX-572, and SNX-579. These compounds are useful for providing analgesia, as described below. III. Preparation of Analgesic Compounds The compounds of the invention having a 3-hydroxy substituent on the benzene ring may generally be prepared according to methods described in, e.g. , Keenaghan, Nelson, and Glushkov, as shown in Fig. 1. As in standard syntheses of lidocaine, 2,6-xylidine is first acylated with chloroacetyl chloride, or, alternatively, with the reaction product of chloroacetic acid with acetic anhydride (Glushkov), to give 2-chloro-N-(2,6-dimethylphenyl) acetamide. Reaction with an appropriately substituted amine gives a 2-alkylamino-N-(2,6-dimethylphenyl) acetamide (1). Nitra- tion of the benzene ring, followed by diazotization and hydrolysis (Keenaghan) gives the phenol, a 2-alkylamino-N-(3-hydroxy-2,6-dimethylphenyl) acetamide (2). Compounds having 4-hydroxy substitution may be prepared as shown generally in Fig. 2A. The intermediate, 4-hydroxy-2,6-xylidine, or 4-amino-3,5-dimethylphenol (3), can be prepared by known methods. Of the two possible routes shown, one employs nitration of 3,5-dimethylphenol, isolation of the 4-nitro isomer, and reduction to the amine. The alternate route, which follows a method described in Fernando, uses an azo intermediate formed by coupling of 3,5-dimethylphenol with diazotized sulfanilic acid. The azo compound is then reduced to the amine, in a reported overall yield of 89%. Subsequent acylation and alkylation give the substituted acetamide, as described for Fig. 1. The compounds designated herein as SNX-583 (2-ethylamino-N-(3-hydroxy-2,6-dimethyI- phenyl) acetamide, also known as 3-hydroxy monoethyl glycinexylidide, or 3-hydroxy MEGX), SNX-522 (3-hydroxy monomethyl glycinexylidide, or 3-hydroxy MMGX), and SNX-507 are prepared according to the scheme of Fig. 1 or 2A where R is ethyl or methyl, as required. Other compounds of the invention may be prepared by minor variations on the scheme of Figs. 1 and 2 A, according to well known synthetic methods. For example, compounds such as SNX-572, where R 1 is a two-carbon linkage, are prepared by substituting 3-chloropropionyl chloride for chloroacetyl chloride. Compounds with additional reactive groups, such as d e hydroxyl group in SNX-559, may be prepared by employing suitable protecting groups during synthesis. Compounds of the invention where R 1 and R 2 form a ring, such as those designated SNX-560 and SNX-561, may be prepared as shown in Fig. 2B. An appropriate carboxyl-substituted nitrogen heterocycle (in this case, an activated proline) is reacted with 4-amino-3,5- dimethylphenol, shown in Fig. 2, or 3-amino-2,4-dimethyl phenol, which may be prepared from 2,6-xylidine using reactions shown in Fig. 1. IV. Analgesic Activity In accordance with the invention, it has been found that compounds of formula I, above, are effective as analgesic agents. Analgesia in vivo is conveniently measured in one or more of a number of animal models, in which an animal's response to a given pain stimulus is measured. A. Acute and Persistent Nociceptive Pain States 1. Formalin Test One such model, for response to an acute stimulus, is the rat formalin test. This test reflects several levels of processing of nociceptive information in die spinal cord (Wheeler-Aceto). Pro- tracted sensory input generated by the noxious stimulus employed in this test (formalin in the paw) has been shown to induce an acute pain response phase (phase 1) followed by a second, persistent phase (phase 2). This second phase is thought to represent a state of facilitated processing evoked by the afferent input present during phase 1 and to involve release of at least two substances, glutamate and a tachykinin, based on pharmacological evidence (Yamamoto). In the rat formalin test, a standard dose of formalin is injected into the rat paw, and flexions of the paw are quantitated over the following 90 minute period (Example 1). A biphasic response pattern is typically observed, with numerous responses observed during the period 5 min. after injection (Phase 1) and a second phase (Phase 2) which occurs during the period about 10-60 minutes following injection. The mean number of flinches per minute is recorded as a function of time. Quantitation of responses during each phase is made by calculation of area under the curve of flinches/min., as shown in Figs. 3B-3C. Figs. 3A-3C, 4, and 6A-6B, and 7 show results of experiments in which varying doses of 3-hydroxy MEGX, designated SNX-483, and 4-hydroxy MEGX, designated SNX-507, were tested for effects on the formalin response in rats. A 5% formalin solution was injected subcutaneously into the hindpaw of Sprague-Dawley rats. Ten minutes prior to formalin injection, the test compound was administered by bolus injection through an indwelling spinal (intrathecal) catheter terminating at the lumbar enlargement. For the results shown in Figs. 3A-3C, dosing solutions were acidified to pH 6.58 with HC1. Injection volume was 20 μL. Fig. 3 A shows time-effect curves for blockade of acute (Phase 1, 0-9 minutes) and persistent (Phase 2, 10-90 minutes) pain by varying doses of SNX-483 (n = 10 animals/treatment). As can be seen from Fig. 3A, the lowest dose of SNX-483 used (0.07 μmol, closed circles) showed inhibition of both die Phase 1 and Phase 2 responses, with inhibition, relative to the control, lasting up to one hour. Higher doses showed greater and longer-lived (up to 90 minutes or longer) inhibition. Figs. 3B and 3C show dose-response curves generated from these data by plotting the area under the time-effect curve for a given phase against dosage. ED 30 doses (doses which produced approximately 50% inhibition) were determined from the dose-response curves for Phase 1 and Phase 2 responses. For SNX-483, the Phase 1 ED^ was 9.3 μg (42 nmol), and the Phase 2 ED , was 29.9 μg (135 nmol). In the standard rat formalin test, as described above, the test substance is administered prior to formalin injection. As shown in Fig. 4, it has been found that SNX-483 also blocks persistent (Phase 2) nociceptive responses in the rat paw formalin test, compared to controls, when administered intrathecally after formalin injection (n= 10 animals/treatment). This observation indicates that SNX-483 blocks nociceptive behavior produced by pre-existing facilitated states of spinal nociceptive processing. Figs. 5A-5B further illustrate dose-dependent blockade by SNX-483 of formalin-induced acute and persistent nociceptive responses in Sprague-Dawley rats, where dosing solutions of SNX- 483 were adjusted to pH 9.2. Each histogram in Fig. 6B represents the mean (n = 3-4 animals/ group) total number of flinches observed during the indicated phase. Fig. 7 shows the time-effect curve for blockade of acute (Phase 1) and persistent (Phase 2) pain by a 0.6 μmol dose of SNX-507 (n= 10). As can be seen from the figure, this dose of SNX- 507 showed inhibition of the Phase 2 response, with inhibition lasting 90 minutes or longer. These results indicate that the compounds of the invention are effective in relieving both acute and persistent nociceptive pain, and Λat SNX-483 is effective at both physiological (pH=6.58) and basic pH. Furthermore, administration of SNX-483 and SNX-507 at the dosages shown produced no overt changes in behavior. In separate studies, similar tests were carried out using lidocaine (Fig. 5) and 3- hydroxy lidocaine (data not shown). Dosing solutions were acidified to pH 6.58 with HC1; injec¬ tion volume was 20 μL. Results are shown in Fig. 5. As can be seen from the figure, lidocaine had no effect on the formalin-induced nociceptive responses (n= 10). Similar negative results were obtained using a 0.6 μmol dose of 3-hydroxylidocaine. Furthermore, administration of lidocaine in this study produced adverse side effects, in the form of transient hindlimb paresis. 2. Hotplate Test Another model measures the nociceptive response to an acute thermal stimulus. In this test (Example 2 below), animals are placed on a stainless-steel plate kept at a constant temperature of 52 ± 0.5°C, and me time to a hindpaw lick or jump is measured, up to a threshold of 60 seconds. Animals are tested immediately prior to dosing with the test or control substance, and at 30 minute intervals thereafter. Figs. 8A-8B show the effect of intrathecally administration of two levels (0.2 and 0.6 μmol) of SNX-507 (4-hydroxy MEGX) and control vehicle on acute nociceptive response according to the above test protocol. Fig. 9 show the results of similar testing using 0.6 μmol SNX-522 (3- hydroxy MMGX). Data are expressed as mean ± SEM (n = 6-8 animals/treatment). As can be seen from the figures, a low dose (0.2 μmol) of SNX-507 showed a blocking effect, relative to the control, for up to 1.5 hours from dosage. A higher dose (0.6 μmol) showed a stronger and longer-lived (3 hours or longer) blocking effect. A 0.6 μmol dose of SNX-522 showed a significant blocking effect, relative to the control, which was essentially undiminished for 3 hours from dosage, with a possible effect remaining at 8 hours from dosage. These results further demonstrate that the compounds of the invention are effective in relieving acute nociceptive pain. B. Neuropathic Pain States The analgesic potency of the compounds of the invention was also tested in animal models of neuropathic or neurogenic pain. One such model resembles the human condition termed causalgia, or reflex sympathetic dystrophy (RSD), secondary to injury of a peripheral nerve. This condition is characterized by hyperesthesia (enhanced sensitivity to a natural stimulus), hyperalgesia (abnormal sensitivity to pain), allodynia (widespread tenderness, characterized by hypersensitivity to tactile stimuli), and spontaneous burning pain. Experiments carried out in support of the present invention were performed in a rat model of peripheral neuropathy detailed in Example 3. Briefly, in the model used, rats are subjected to a surgical procedure, described by Kim and Chung (1992), designed to reproducibly injure peripheral nerves (spinal nerves L5 and L6). These rats develop a hyperesthetic state, which can be measured using one or more paradigms known in d e art. Here, allodynia was measured by stimulation of neuropathic rat hindlimb using wire hairs having graded degrees of stiffness. Analgesic compounds reverse the heightened sensitivity such animals exhibit to the stimulus. Figs. 10-18 shows results in the allodynia test of animals treated with several compounds of the invention, as described below. Test solutions at pH 6.58 were administered intrathecally as described above. Mechanical allodynia was measured by pressing nylon filaments of varying diameters against the paw. Data are expressed in terms of 50% response threshold, which is the median buckling weight required to evoke paw withdrawal; the lower the stimulus level, the more severe the allodynia. As shown in Fig. 10, treatment of rats (n=6 animals/treatment) with varying doses, from 0.15 to 0.6 μmol, of SNX-483 (3-hydroxy MEGX) resulted in elevation of threshold response. Peak elevation of response due to drug treatment (blockade of allodynia) was observed by 30-60 minutes, and effects of a single bolus injection were long-lived, lasting in excess of 3 hours and possibly up to 20 hours. Dosages of 0.3 μmol (open triangles) and 0.6 μmol (closed triangles) showed significant analgesic effects, as can be seen in Fig. 10, and produced no observable adverse side effects. Fig. 11 shows the dose-response curve derived from the data shown in Fig. 10. Allodynia thresholds measured 30 minutes after injection were plotted against dosage. Each point represents a value for a single animal. As shown in Figs. 12A-B, treatment of rats (n=6 animals/treatment) with 0.6 μmol SNX-507 (4-hydroxy MEGX) also resulted in elevation of threshold response. Peak elevation of response due to drug treatment (blockade of allodynia) was observed by 30 minutes, and effects of a single bolus injection were long-lived, 3 hours or more. Thus, a 0.6 μmol dosage of SNX-507 showed significant analgesic effects, with no observable adverse side effects. Figures 13-18 show the results of the same experiments performed with varying doses of SNX-522 (0.2, 0.6, and 1.8 μmol; n=5 animals/treatment; Fig. 13), and with 0.6 μmol dosages of SNX-559 (n= 17; Fig. 14), SNX-560 (n= 12; Fig. 15), SNX-561 (n= 13; Fig. 16), SNX-572 (n= 12; Fig. 17), and SNX-579 (n= 12; Fig. 18). Blockage of allodynia was demonstrated for all of the above compounds, with particularly significant effects being shown by SNX-559, SNX-560, SNX-561, and SNX-572. In separate studies, similar tests were carried out using lidocaine, 3-hydroxylidocaine and mexiletine. Dosages of 0.6 μmol were used. As shown in Fig. 19 (n=5-6), these dosages of lidocaine and 3-hydroxylidocaine did not block mechanical allodynia, and only a weak response was observed for mexiletine. Furthermore, adverse side effects, in the form of immediate and transient weakness, were observed for rats treated with lidocaine. In contrast, no such effects were noted upon administering the compounds of the invention at dosages up to 2-3 times greater. The above results indicate that the compounds of the invention are capable of reversing the hyperesthetic effects induced by nerve damage, as well as alleviating both acute and persistent nociceptive pain, at dosages which do not produce notable adverse side effects. V. Formulations and Dosages Formulations containing the compounds of the invention may take the form of solid, semi- solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, pills, capsules, powders, sustained-release formulations, solutions, suspensions, emulsions, suppositories, retention enemas, creams, ointments, lotions, aerosols or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, adjuvants, and me like. Preferably, die composition will be about 0.5% to 75% by weight of a compound or compounds of the invention, widi the remainder consisting of suitable pharmaceutical excipients. For oral administration, such excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like. If desired, the composition may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, or buffers. Liquid compositions can be prepared by dissolving or dispersing the compounds (about 0.5 % to about 20%), and optional pharmaceutical adjuvants, in a carrier, such as, for example, aqueous saline, aqueous dextrose, glycerol, or ethanol, to form a solution or suspension. For use in oral liquid preparation, die composition may be prepared as a solution, suspension, emulsion, or syrup, being supplied either in liquid form or a dried form suitable for hydration in water or normal saline. Because the compounds have good aqueous solubility, they may be conveniently administered, in free or salt form, in an aqueous carrier. When the composition is employed in the form of solid preparations for oral administration, the preparations may be tablets, granules, powders, capsules or the like. In a tablet formulation, the composition is typically formulated with additives, e.g. an excipient such as a saccharide or cellulose preparation, a binder such as starch paste or methyl cellulose, a filler, a disintegrator, and other additives typically usually used in the manufacture of medical preparations. An injectable composition for parenteral administration will typically contain a compound of formula I or an acceptable salt in a suitable I.V. (intravenous) solution, such as sterile physio¬ logical salt solution. The composition may also formulated as a suspension in a lipid or phos- pholipid, in a liposomal suspension, or in an aqueous emulsion. Administration in aqueous solution is a preferred route. For some applications, it may be desirable to include in the composition or treatment regimen means for enhancing permeation of the active compound through eningeal membranes which may surround the damaged or target nerve. Means for enhancing trans-meningeal transport of compound are known in the art and may include encapsulating the compound in liposomal mem- branes, addition of a surfactant to the composition, and the like. Alternatively, or in addition, trans-meningeal transport may be facilitated by administering to die subject a hypertonic dosing solution effective to disrupt meningeal barriers, according to methods well known in me art. Methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences (17th Ed., Mack Publishing Co., 1985). Generally, dosages and routes of administration of the compound will be determined ac¬ cording to the site of the pain and the size of the subject, according to standard pharmaceutical practices. The composition may be administered to a subject by various routes, as described in Section VI below. The composition to be administered will contain a quantity of the selected analgesic compound in a pharmaceutically effective amount for producing analgesia in a patient. In treating chronic pain, particularly neuropathic pain, the patient may be given the composition on a periodic basis, at a dosage level sufficient to reduce symptoms and improve patient comfort. The dose administered is dependent on the route of administration, with lower amounts being preferred for parenteral administration, and higher amounts being preferred for oral administration. For parenteral administration, a suitable dose level is about 0.05 to .75 mg/kg patient body weight, and preferably about 0.1 to 0.5 mg/kg. Optimum dosages for a given route can be determined by routine experimentation according to methods known in the art, using, for example, the treatment regimens described in the Examples below. VI. Treatment Methods The compositions of die present invention, useful for treating nociceptive or neuropathic pain, may be administered to a subject in need of such treatment by a variety of known routes, such as oral, perineural or parenteral administration. Parenteral administration includes intravenous, intrathecal, subcutaneous, intraperitoneal, or intramuscular injection. Intrathecal administration allows local administration of compound to those regions of the spinal cord, such as to dorsal horn regions at affected vertebral levels, where polysynaptic relay of pain sensation occurs. This type of local application is described in co-owned U.S. Patent No. 5,587,454. Intrathecal administration, either as a bolus dosage or as a constant infusion, delivers compound directly to the sub-arachnoid space containing cerebral spinal fluid (CSF). While effec¬ tive, this method requires precise technical expertise to ensure delivery to the correct spot. Delivery to spinal cord regions can also be effected by epidural injection to a region of the spinal cord exterior to the arachnoid membrane. As noted above, it may be advantageous to add to the composition means for enhancing permeation of die active compound through meningeal membranes. Such means are known in the art and include liposomal encapsulation, or addition of a surfactant or an ion-pairing agent to the peptide composition. Alternatively, or in addition, increased arachnoid membrane permeation can be effected by administering a hypertonic dosing solution effective to increase permeability of meningeal barriers. Administration by slow infusion is particularly useful when intrathecal or epidural routes are employed. Known in die art are a number of implantable or body-mountable pumps useful in delivering compound at a regulated rate. One such pump, described in U.S. Patent 4,619,652, is a body-mountable pump that can be used to deliver compound at a tonic flow rate or at periodic pulses. An injection site direcdy beneath the pump is provided to deliver compound to the area of need, for example, to die perineural region. Analgesics against neuropathic pain may also be administered perineurally to affected skin regions characterized by proliferation of neurite outgrowth subsequent to nerve damage. Such perineural administration can be by topical means, either directly or wi i the use of a transdermal applicator. Alternatively, perineural administration may be effected by subdermal injection. The resulting blockade of calcium channels reduces the heightened sensation produced by transmission through the neurite proliferation. Perineural delivery may also be effected by forming a cuff around the damaged nerve, preferably of a biodegradable matrix which includes the therapeutic compound. Alternatively or in addition, the therapeutic compound can be placed in close proximity to the damaged nerve by conjugating the compound to or coating the compound on a nerve splint designed for repairing damaged nerves. Examples of such nerve splints are provided by U.S. Patents 4,534,349 and 4,920,962. Perineural delivery may also be effected by incorporating analgesic compounds into suture materials, and using these materials to suture damaged tissues. This method is particularly useful for delivery of compound in areas where it is desirable to provide for inhibition of progression of neuropathy concomitant to tissue damage. U.S. Patent 5,308,889 describes a collagen-based suture material that may be suitable for use for therapeutic delivery of N-type calcium channel blocking compounds. One particularly useful means for delivering compound to perineural sites is transdermal delivery. This form of delivery can be effected according to methods known in the art. Generally, transdermal delivery involves the use of a transdermal "patch" which allows for slow delivery of compound to a selected skin region. Although such patches are generally used to provide systemic delivery of compound, in me context of the present invention, such site-directed delivery can be expected to provide increased concentration of compound in selected regions of neurite proliferation. Examples of transdermal patch delivery systems are provided by U.S. Patent 4,655,766 (fluid-imbibing osmotically driven system), and U.S. Patent 5,004,610 (rate controlled transdermal delivery system). For transdermal delivery, it may be desirable to include permeation enhancing substances, such as fat soluble substances (e.g. , aliphatic carboxylic acids, aliphatic alcohols), or water soluble substances (e.g., alkane polyols such as ethylene glycol, 1,3-propanediol, glycerol, propylene glycol, and the like). In addition, as described in U.S. Patent 5,362,497, a "super water-absorbent resin" may be added to transdermal formulations to further enhance transdermal delivery. Examples of such resins include, but are not limited to, polyacrylates, saponified vinyl acetate- acrylic acid ester copolymers, cross-linked polyvinyl alcohol-maleic anhydride copolymers, saponi- fied polyacrylonitrile graft polymers, starch acrylic acid graft polymers, and the like. Such formulations may be provided as occluded dressings to the region of interest, or may be provided in one or more of the transdermal patch configurations described above. For delayed release, the analgesic compound may be included in a pharmaceutical composition for formulated for slow release, such as in microcapsules formed from biocompatible polymers or in liposomal carrier systems according to metiiods known in the art. VII. Therapeutic Indications The present invention provides methods and compositions for treating both nociceptive and neuropathic pain. Effective therapy for neuropathic pain is widely sought, as previously noted. Neuropamic pain may result from a number of separate etiologies. Generally, such pain may be treated according to any of the methods of described herein. However, in many cases it will be preferable to treat the pain in a manner that addresses its specific source. For example, when the pain is traceable to injury of a particular nerve fiber, it may be appropriate to treat such pain either by perineural application of compound to the affected nerve or by dermal application of compound to the affected region. A discussion of specific formulations and modes of delivery can be found in foregoing Sections V and VI. This section sets forth some exemplary indications for which treatment according to the methods of the present invention may have particular therapeutic utility. The indications described below are by no means exhaustive, but are presented to illustrate some of the various therapeutic situations in which the compounds and method of d e invention can be used in the treatment of acute and persistent nociceptive pain or neuropathic pain. A. Ophthalmic Indications. The eye is a heavily innervated organ. The cornea in particular is heavily innervated with C-fibers, containing an estimated 3-4000 fiber endings per mm 2 compared to an estimated 3-600 fiber endings per mm 2 of skin. Injury of the nerve fibers can lead to neuropathic pain of ophthalmic origin. For treatment with analgesic compounds such as those described herein, topical administration to the eye, or, in more severe cases, suprachoroidal administration, is preferred. Such administration may be conveniently achieved by providing a suprachoroidal implant which includes the active compound. U.S. Patent 5,164,188 describes a biodegradable implant that is suitable for chronic and controlled administration of compound to the suprachoroidal space. Chronic, implanted therapeutics are also indicated after ophthalmic surgery, such as after surgery for detached retina or macular holes, where nerve damage may result. B. Dental Indications. Delivery of analgesic compounds to regions of dental repair, such as endodontic repair concomitant to a root canal procedure, may be desirable as a means of allevi¬ ating neural pain or preventing progression of dental neuropathy. Here, d e therapeutic compound may be included in or added to one or more of me polymer based materials or resins inserted into the root canal after removing the pulp from the region, in accordance with standard techniques known in the art. C. Burn Injury. Burn injuries are characterized by primary hyperalgesia to thermal and mechanical stimuli. This hyperalgesia is a result of nociceptor sensitization in which neurite proliferation occurs in sensory afferent beds. In accordance with die principles discussed above, treatment of burned regions with compositions containing a compound of formula I may provide diminished sensitization and hyperalgesia, as well as reduction of progression of the hyperalgesic response. The therapeutic composition can be applied directly to the affected regions or in a formulation that includes a protective biopolymer matrix, such as an artificial skin matrix. D. Reflex Svmpadietic Dystrophy (RSDL RSD is thought to be due to abnormalities in die peripheral nervous system, and more particularly, to sensitization of cutaneous somatosensory afferents. Sympathetic outflow is thought to activate foci of ectopic neural hyperexcitability. Treatment of this condition and reduction of its progression may be effected by any of the various dermal (topical) or subdermal routes of delivery discussed above. Perineural delivery may also be indicated for this condition. E. Post-Herpetic Neuralgia. Post-herpetic neuralgia is characterized, in its acute phase, by intraneural inflammation which can cause damage to primary afferent axons. This damage may result in abnormal sensitivity to cutaneous stimuli. In general, the mode of treatment of the abnormal sensitivity will depend on the location in the body of the affected nerve(s). Perineural or topical delivery of therapeutic compounds is indicated in this condition. F. Diabetic Neuropad v. Neuropathy of primary afferent axons in long nerves is found in diabetic patients. This results in the dying-back and attempted regeneration of distal tips of primary afferent axons of these nerves. Nociceptor sensitization may ensue. Such sensitization and its progression may be treated according to one or more of the treatment me iods described herein. In particular, perineural or topical application of therapeutic compound will be indicated, in accord with the location of the affected nerve and nerve beds. G. Arthritis. Arthritis is characterized by enhanced sensation of pain via articular afferents. Generally, in treating articular afferents, therapeutic compounds will be administered perineurally, in the vicinity of the affected joint. Example 1 Formalin Test for Analgesia Rats (male Sprague-Dawley, 275-300 g, Harlan Industries, Indianapolis, IN) were implanted with lumbar intrathecal catheters under halothane anesthesia (Yaksh and Rudy, 1976). Catheters (Polyethlyene PE-10) extended from the cisterna to the rostral edge of the lumbar enlargement. Three to five days after implant, animals witiiout motor dysfunction were tested. Drugs tested in this assay were dissolved in sterile saline (0.9% NaCl) and injected in a volume of 10 ul followed by 10 ul sterile saline to clear the catheter. Animals were examined for the effects of drugs given in the formalin test, in which 50 ul of 5% formalin was injected on the plantar surface of the paw of a lightly anesthetized (halothane, 3%) animal. The number of spontaneous flinchings/shakings of the injected paw were counted at intervals after the injection of the formalin. Injection of formalin alone or with vehicle (saline) typically results in a biphasic response pattern of hind paw wididrawals (see, for example, Figs. 3 A and 6A). The area under the curve of flinehes/min was calculated for phase 1 (time = 0-9 min) and phase 2 (10-90 min). These values were plotted against intrathecal log dose (μg) to give the results shown in Figs. 3B and 3C. To produce die data shown in Fig. 4, SNX-483 was administered after formalin injection, radier than prior to formalin injection, as described above. Dosing solutions were at pH 6.58. Animals were also observed for the appearance of general motor dysfunction, as evidenced by inability to ambulate symmetrically and for any other overt signs of unusual activity. Example 2 Hotplate Test for Analgesia Rats (male Sprague-Dawley, 275-300 g, Harlan Industries, Indianapolis, IN) were implanted wi lumbar intrathecal catheters under halodiane anesdiesia (Yaksh and Rudy). Cadieters (Poly¬ ethlyene PE-10) extended from the cisterna to the rostral edge of the lumbar enlargement. Three to five days after implant, animals without motor dysfunction were tested. Drugs tested in this assay were dissolved in sterile saline (0.9% NaCl) and injected in a volume of 10 ul followed by 10 ul sterile saline to clear the catheter. To produce me data shown in Figs. 8 and 9, animals were placed on a stainless-steel plate kept at a constant temperature of 52 ± 0.5 °C, and the time to a hindpaw lick or jump was mea¬ sured. If there was no response within 60 seconds, the trial was terminated, and diis value was noted. Animals were acclimated to the test conditions by conducting two trials at approx. 10 minute intervals prior to initiating die study. Animals were tested immediately prior to dosing with die test or control substance, and at 30 minute intervals thereafter. Example 3 Blockade of Peripheral Neuropathy Male Sprague-Dawley rats (200-350 gm) were prepared widi chronic lumbar intrathecal catheters inserted under halodiane anesthesia (Yaksh and Rudy). Animals were placed in a prone position and die left paraspinal muscles were separated from the spinous processes at the L 4 -S 2 levels, as described by Kim et al. The left L5 and L6 nerve roots were exposed and tightly ligated with 6-0 surgical silk suture. The rats were allowed to recover from anesthesia. Allodynia was typically observed to occur beginning 1-2 days post-surgery and continuing for as long as 45 days. For testing, animals were placed in plastic cubicles with open wire mesh bottoms. Compound dissolved in preservative-free saline solution was administered in a volume of 10 μl through the intrathecal cadieter, followed by 10 μl saline to flush the catheter line. Animals were tested for allodynia at various time points after drug treatment, as described below. To assess the threshold of a non-noxious stimulus required to produce a left hind paw withdrawal (allodynia), Von Frey hairs (ranging from 0.4-15 grams), were systematically applied to the surgically treated hind paw. Failure to evoke a response was cause to test the next stiffer hair. Evocation of a brisk withdrawal response was cause to test the next lower stimulus intensity. This paradigm was repeated according to a statistical method (Dixon) to define die 50% response threshold. Allodynia is evidenced by a threshold generally less than 3 grams (referring to the hair stimulus intensity) exhibited by all surgically treated animals. Data in Figs. 10 and 12-19 are expressed in terms of 50% response threshold, which is the median buckling weight required to evoke paw wididrawal; the lower the stimulus level, the more severe the allodynia. Fig. 11 shows the dose-response curve derived from the data shown in Fig. 10. Allodynia thresholds, measured 30 minutes after injection, were plotted against dosage. Each point represents a value for a single animal. Animals were also observed for the appearance of general motor dysfunction, as evidenced by inability to ambulate symmetrically and for any od er overt signs of unusual activity.

Claims: IT IS CLAIMED: 1. A method of treating pain, comprising administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a compound of formula I: wherein A 1 and A 2 are hydroxyl or hydrogen, with die proviso that at least one of A 1 and A 2 is hydroxyl; R l is a one- or two-carbon linkage between the carbonyl carbon and amine nitrogen of formula I; and R 2 is selected from the group consisting of methyl, ethyl, CH 2 X, and CH 2 CH 2 X, where X is a hydroxyl or amino group, or, R 2 is an alkyl chain linked to R 1 to form a four- to six- membered heterocyclic ring, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. 2. The method of claim 1, wherein A 1 is hydroxyl and A 2 is hydrogen. 3. The method of claim 1 , wherein R' is -CH 2 - or -CH 2 CH 2 -, and R 2 is selected from the group consisting of methyl, ediyl, CH 2 X, and CH 2 CH 2 X, where X is a hydroxyl or amino group. 4. The method of claim 3, wherein R 1 is -CH 2 -, and R 2 is methyl, ethyl, or -CH 2 CH 2 OH. 5. The method of claim 4, wherein R 1 is a one-carbon linkage between the carbonyl carbon and amine nitrogen of formula I, and R 2 is an alkyl chain linked to R 1 to form a four- to six-membered heterocyclic ring. 6. The method of claim 5, wherein said ring is a pyrrolidine ring. 7. The method of claim 1, wherein said compound is 2-(ethylamino)-N-(3-hydroxy-2,6- dimethylphenyl) acetamide. 8. The method of claim 1 , wherein the pain being treated is acute or persistent nociceptive pain, or neuropathic pain. 9. A pharmaceutical composition for treating pain, comprising a therapeutically effective amount of a compound of formula I: wherein A 1 and A 2 are hydroxyl or hydrogen, with the proviso that at least one of A 1 and A 2 is hydroxyl; R 1 is a one- or two-carbon linkage between the carbonyl carbon and amine nitrogen of formula I; and R 2 is selected from the group consisting of methyl, eur/1, CH 2 X, and CH 2 CH 2 X, where X is a hydroxyl or amino group, or, R 2 is an alkyl chain linked to R' to form a four- to six- membered heterocyclic ring, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. 10. The composition of claim 1 , wherein A 1 is hydroxyl and A 2 is hydrogen. 11. The composition of claim 10, wherein said compound is selected from the group consisting of2-(ethylamino)-N-(3-hydroxy-2,6-dimethylphenyl) acetamide, 2-((2-hydroxyethyl)amino)-N-(3- hydroxy-2 , 6-dimethylpheny 1) acetamide , 2-((2S)-2-pyrrolidyl)-N-(3-hydroxy-2 ,6-dimethylpheny 1) acetamide,2-((2R)-2-pyrrolidyl)-N-(3-hydroxy-2,6-dimethylphenyl)acetamide,and3-(ethylamino)- N-(3-hydroxy-2,6-dimethylphenyl) propanamide. 12. The composition of claim 11, wherein said compound is 2-(ethylamino)-N-(3-hydroxy-2,6- dimethylphenyl) acetamide. 13. A compound having the structure of formula I: wherein A 1 and A 2 are hydroxyl or hydrogen, with the proviso that at least one of A 1 and A 2 is hydroxyl; R 1 is a one- or two-carbon linkage between the carbonyl carbon and amine nitrogen of formula I; and RHs selected from die group consisting of methyl, ethyl, CH 2 X, and CH 2 CH 2 X, where X is a hydroxyl or amino group, or, R 2 is an alkyl chain linked to R 1 to form a four- or five- membered heterocyclic ring, with the proviso that when A 1 or A 2 is hydrogen and R 1 is -CH 2 -, R 2 is not ediyl. 14. A compound in accordance with claim 13, wherein A 1 is hydroxyl and A 2 is hydrogen. 15. A compound in accordance with claim 14, said compound being 2-(medιylamino)-N-(3- hydroxy-2 ,6-dimethylphenyl) acetamide. 16. A compound in accordance with claim 14, said compound being 2-((2-hydroxyethyl)amino)- N-(3-hydroxy-2,6-dimethylphenyl) acetamide. 17. A compound in accordance widi claim 14, said compound being 2-((2S)-2-pyrrolidyl)-N-(3- hydroxy-2 ,6-dimethylphenyl) acetamide . 18. A compound in accordance with claim 14, said compound being 2-((2R)-2-pyrrolidyl)-N-(3- hydroxy-2,6-dimethylphenyl) acetamide. 19. A compound in accordance with claim 14, said compound being 3-(ethylamino)-N-(3- hydroxy-2,6-dimethylphenyl) propanamide. 20. A compound in accordance with claim 14, said compound being 2-(2-(N,N-dimethy- lamino)ethyl))amino)-N-(3-hydroxy-2,6-dimethylphenyl) acetamide.

Inventors: ANSTINE D TIMOTHY, BROGLEY LOUIS, FELLMAN JERE, NADASDI LASZLO, URGE LASZLO, WANG YONG XIANG, ANSTINE, D., TIMOTHY, BROGLEY, LOUIS, FELLMAN, JERE, NADASDI, LASZLO, URGE, LASZLO, WANG, YONG, XIANG
Applicants: NEUREX CORP, NEUREX CORPORATION
Application year: 1997
Main classification: C07C237
IPC codes: A61K31, A61P25, C07C237, C07D207