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WO1997033860A1 - Methodes et compositions servant a l'analgesie - Google Patents

Methodes et compositions servant a l'analgesie Download PDF

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Publication number
WO1997033860A1
WO1997033860A1 PCT/US1997/004029 US9704029W WO9733860A1 WO 1997033860 A1 WO1997033860 A1 WO 1997033860A1 US 9704029 W US9704029 W US 9704029W WO 9733860 A1 WO9733860 A1 WO 9733860A1
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WIPO (PCT)
Prior art keywords
compound
hydroxy
hydroxyl
acetamide
dimethylphenyl
Prior art date
Application number
PCT/US1997/004029
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English (en)
Inventor
Yong Xiang Wang
Jere Fellman
Laszlo Nadasdi
D. Timothy Anstine
Louis Brogley
Laszlo Urge
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Neurex Corporation
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Publication date
Application filed by Neurex Corporation filed Critical Neurex Corporation
Priority to AU25298/97A priority Critical patent/AU2529897A/en
Priority to JP53286297A priority patent/JP2001516335A/ja
Priority to EP97916762A priority patent/EP0915834A1/fr
Publication of WO1997033860A1 publication Critical patent/WO1997033860A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated

Definitions

  • the present invention relates to methods and compositions for producing analgesia, particularly in the treatment of acute and persistent nociceptive pain and neuropathic pain.
  • 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.
  • opioid compounds such as morphine.
  • 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.
  • 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.
  • the invention includes, in one aspect, a method of treating pain, including acute and persistent nociceptive pain and neuropathic pain.
  • a composition is administered to a subject in need of such treatment, comprising a therapeutically effective amount of a compound of formula I:
  • 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.
  • a 1 is hydroxyl and A 2 is hydrogen.
  • R' is -CH 2 - or -CH 2 CH 2 -
  • 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.
  • R 1 is a one-carbon linkage as described above
  • 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.
  • 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) prop
  • the salt is a halide, carboxylate, sulfonate, or sulfate; e.g., chloride, bromide, acetate, oxalate, maleate, fumarate, methanesulfonate, or toluenesulfonate.
  • the counterion is chloride.
  • the invention also provides analgesic compounds having the structure of 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 carbo ⁇ yl 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.
  • 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 ⁇ mol of compounds designated herein as SNX-559, -560, -561, -572, and -579, respectively
  • 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.
  • 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.
  • 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.
  • a noxious stimulus such as mechanical, thermal, or chemical stimulation
  • 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.
  • Neuroopathic 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.
  • compositions including a compound having the structure shown in formula I, above, provide analgesia in settings of acute and persistent nociceptive pain and neuropathic pain.
  • 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.
  • 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).
  • 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).
  • R 1 is a one-carbon linkage between the carbonyl carbon and amine nitrogen of formula I
  • 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).
  • SNX-560 and SNX-561 the (2S) and (2R) isomers, respectively, of 2- (2-pyrrolidyl)-N-(3-hydroxy-2,6-dimethylphenyl) acetamide.
  • 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.
  • 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.
  • 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.
  • 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).
  • Fig. 2A Compounds having 4-hydroxy substitution may be prepared as shown generally in Fig. 2A.
  • 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.
  • 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.
  • phase 1 An acute pain response phase
  • phase 2 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).
  • 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
  • 4-hydroxy MEGX designated SNX-507
  • a 5% formalin solution was injected subcutaneously into the hindpaw of Sprague-Dawley rats.
  • the test compound was administered by bolus injection through an indwelling spinal (intrathecal) catheter terminating at the lumbar enlargement.
  • dosing solutions were acidified to pH 6.58 with HC1. Injection volume was 20 ⁇ L.
  • SNX-483 the lowest dose of SNX-483 used (0.07 ⁇ mol, 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.
  • the Phase 1 ED ⁇ was 9.3 ⁇ g (42 nmol)
  • the Phase 2 ED was 29.9 ⁇ g (135 nmol).
  • 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.
  • lidocaine Fig. 5
  • 3- hydroxy lidocaine data not shown.
  • Dosing solutions were acidified to pH 6.58 with HC1; injec ⁇ tion volume was 20 ⁇ L. Results are shown in Fig. 5.
  • Similar negative results were obtained using a 0.6 ⁇ mol dose of 3-hydroxylidocaine.
  • administration of lidocaine in this study produced adverse side effects, in the form of transient hindlimb paresis.
  • Hotplate Test Another model measures the nociceptive response to an acute thermal stimulus.
  • mice 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 ⁇ mol) of SNX-507 (4-hydroxy MEGX) and control vehicle on acute nociceptive response according to the above test protocol.
  • a low dose (0.2 ⁇ mol) of SNX-507 showed a blocking effect, relative to the control, for up to 1.5 hours from dosage.
  • a higher dose (0.6 ⁇ mol) showed a stronger and longer-lived (3 hours or longer) blocking effect.
  • a 0.6 ⁇ mol 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.
  • 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.
  • mice 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.
  • allodynia was measured by stimulation of neuropathic rat hindlimb using wire hairs having graded degrees of stiffness.
  • 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.
  • 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.
  • 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 ⁇ mol dosage of SNX-507 showed significant analgesic effects, with no observable adverse side effects.
  • 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.
  • 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.
  • compositions typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, adjuvants, and me like.
  • 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.
  • excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • 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.
  • a carrier such as, for example, aqueous saline, aqueous dextrose, glycerol, or ethanol
  • 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.
  • the preparations may be tablets, granules, powders, capsules or the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • CSF cerebral spinal fluid
  • Delivery to spinal cord regions can also be effected by epidural injection to a region of the spinal cord exterior to the arachnoid membrane.
  • composition means for enhancing permeation of die active compound through meningeal membranes are known in the art and include liposomal encapsulation, or addition of a surfactant or an ion-pairing agent to the peptide composition.
  • increased arachnoid membrane permeation can be effected by administering a hypertonic dosing solution effective to increase permeability of meningeal barriers.
  • 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.
  • perineural administration can be by topical means, either directly or wi i the use of a transdermal applicator.
  • 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.
  • 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.
  • transdermal delivery This form of delivery can be effected according to methods known in the art.
  • transdermal delivery involves the use of a transdermal "patch" which allows for slow delivery of compound to a selected skin region.
  • 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.
  • 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).
  • 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).
  • fat soluble substances e.g. , aliphatic carboxylic acids, aliphatic alcohols
  • water soluble substances e.g., alkane polyols such as ethylene glycol, 1,3-propanediol, glycerol, propylene glycol, and the like.
  • alkane polyols such as ethylene glycol, 1,3-propanediol, glycerol, propylene glycol, and the like.
  • a "super water-absorbent resin" may be added to transdermal formulations to further enhance transdermal delivery.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • RSDL RSD Reflex Svmpadietic Dystrophy
  • 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.
  • 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.
  • mice 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.
  • mice were placed in plastic cubicles with open wire mesh bottoms. Compound dissolved in preservative-free saline solution was administered in a volume of 10 ⁇ l through the intrathecal cadieter, followed by 10 ⁇ l saline to flush the catheter line. Animals were tested for allodynia at various time points after drug treatment, as described below.
  • 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.

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Compositions et méthodes servant à l'analgésie. Il est démontré que des composés correspondant à la formule (I) assurent une analgésie dans le cas de douleurs nociceptives et neuropathiques aiguës et persistantes.
PCT/US1997/004029 1996-03-15 1997-03-14 Methodes et compositions servant a l'analgesie WO1997033860A1 (fr)

Priority Applications (3)

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AU25298/97A AU2529897A (en) 1996-03-15 1997-03-14 Method and compositions for producing analgesia
JP53286297A JP2001516335A (ja) 1996-03-15 1997-03-14 鎮痛を生じるための方法および組成物
EP97916762A EP0915834A1 (fr) 1996-03-15 1997-03-14 Methodes et compositions servant a l'analgesie

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US1397896P 1996-03-15 1996-03-15
US1825596P 1996-05-24 1996-05-24
US1781096P 1996-05-24 1996-05-24
US2135796P 1996-07-08 1996-07-08
US60/021,357 1996-07-08
US60/013,978 1996-07-08
US60/017,810 1996-07-08
US60/018,255 1996-07-08

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064398A1 (fr) * 1998-06-09 1999-12-16 Nortran Pharmaceuticals, Inc. Composes d'ammonium quaternaire utilises comme agents antitussifs
WO2005084663A1 (fr) * 2004-02-13 2005-09-15 Janssen Pharmaceutica N.V. Analgesiques a base de derives acetanilides hetero-substitues
US7718692B2 (en) 2004-02-13 2010-05-18 Carson John R Hetero-substituted acetanilide derivatives as analgesic agents

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US4532249A (en) * 1981-11-02 1985-07-30 Francois Molnar Derivatives of p-acylaminophenol having a therapeutic action, and compositions having a therapeutic action containing said derivatives as pharmacologically active ingredients
WO1996032100A1 (fr) * 1995-04-14 1996-10-17 The Regents Of The University Of California Compositions et methodes de traitement de la douleur

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US4532249A (en) * 1981-11-02 1985-07-30 Francois Molnar Derivatives of p-acylaminophenol having a therapeutic action, and compositions having a therapeutic action containing said derivatives as pharmacologically active ingredients
WO1996032100A1 (fr) * 1995-04-14 1996-10-17 The Regents Of The University Of California Compositions et methodes de traitement de la douleur

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Y. K. TAM ET AL.: "HPLC of Lidocaine and nine of its metabolites in human plasma and urine", J. CHROMATOGRAPHY, vol. 423, 1987, pages 199 - 206, XP000654707 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064398A1 (fr) * 1998-06-09 1999-12-16 Nortran Pharmaceuticals, Inc. Composes d'ammonium quaternaire utilises comme agents antitussifs
AU761663B2 (en) * 1998-06-09 2003-06-05 Nortran Pharmaceuticals Inc. Quarternary ammonium compounds as anti-tussive agents
US6939889B2 (en) 1998-06-09 2005-09-06 Ucb Farchim Sa Quarternary ammonium compounds
US8357715B2 (en) 2003-01-13 2013-01-22 Janssen Pharmaceutica, Nv Hetero-substituted acetanilide derivatives as analgesic agents
US9018241B2 (en) 2003-01-13 2015-04-28 Janssen Pharmaceutica, Nv Hetero-substituted acetanilide derivatives as analgesic agents
WO2005084663A1 (fr) * 2004-02-13 2005-09-15 Janssen Pharmaceutica N.V. Analgesiques a base de derives acetanilides hetero-substitues
US7718692B2 (en) 2004-02-13 2010-05-18 Carson John R Hetero-substituted acetanilide derivatives as analgesic agents

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CA2248673A1 (fr) 1997-09-18
AU2529897A (en) 1997-10-01
JP2001516335A (ja) 2001-09-25

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