WO1998027984A1

WO1998027984A1 - METHOD OF PRODUCING ANALGESIA BY ADMINISTRATION OF 1,2,3,4-TETRAHYDROBENZO-[b]THIENO[2,3-c]PYRIDINE AND DERIVATIVES

Info

Publication number: WO1998027984A1
Application number: PCT/US1997/023648
Authority: WO
Inventors: Steven S. Bowersox; Tejinder Singh; Yong-Xiang Wang
Original assignee: Neurex Corporation
Priority date: 1996-12-20
Filing date: 1997-12-18
Publication date: 1998-07-02
Also published as: AU5712698A

Abstract

The invention relates to methods of producing analgesia, particularly in the treatment of acute and persistent pain and neuropathic pain. Compositions containing a 1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine compound of formula (I), where X and Y are each independently H, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoro, chloro, or bromo, or a pharmaceutically acceptable salt thereof, are shown to provide analgesia in settings of acute, persistent and neuropathic pain.

Description

METHOD OF PRODUCING ANALGESIA BY ADMINISTRATION OF l,2,3,4-TETRAHYDROBENZO-[blTHIENOr2,3-qPYRIDINE AND DERIVATIVES

Field of the Invention

The present invention relates to methods of producing analgesia, particularly in the treatment of acute and persistent pain and neuropathic pain, by administration of a l,2,3,4-tetrahydrobenzo[b]thieno [2,3-c]-pyridine compound or a pharmaceutically acceptable salt thereof.

References

Bennett, G.J. and Xie, Y.-K, Pain 33:87-107 (1988).

Bennett, J.P. et al., in NEUROTRANSMITTER RECEPTOR BINDING, Raven Press, New York, pp. 61-89 (1983). Bosin, T. et al. , U.S. Patent No. 4,971,974 (1990).

Campaigne, E. et al., J. Heterocyclic Chem. 2:231-235 (1965).

Campaigne, E. et al., J. Heterocyclic Chem. 3:46-50 (1966).

Campaigne, E. et al, J. Med. Chem. U: 1049-1054 (1968).

Campaigne, E. et al, J. Heterocyclic Chem. 16: 1321-1324 (1979). Dixon, Ψ.J. , Ann. Rev. Pharmacol. Toxicol. 20:441-462 (1976).

Jadad, A.R. et al , Lancet 339: 1367-1371 (1992).

Herz, W., J. Am. Chem. Soc. 72:4999 (1950).

Kim, S.H. and Chung, J.M. , Pain 50:355-363 (1992).

Leitch, I.M. et al, J. Pharm. Pharmacol. 46(10):820-5 (1994). Miller, F.P. et al, The Pharmacologist 13:201 (1971).

Nagatani, T. et al, Psychopharmacology (Berlin) 104(4):432-8 (1991).

Pendelton, R.G., EP Patent Appn. No. 0216247 (4/1987).

Suh, U.S. Patent No. 3,516,278 (6/1970).

Suh, U.S. Patent No. 3,636,218 (1/1972). 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. Analgesia, or the reduction of pain perception, can be effected by decreasing transmission along sensory afferent synaptic connections to the spinal cord, termed 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, 1992). 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.

Tricyclic antidepressants (TCAs) are also used for the treatment of painful peripheral neuropathy and central pain states, such as those associated with lesions of the CNS (e.g. spinal injury or ischemic stroke). However, TCAs are not uniformly efficacious and produce dose-limiting sedative and anticholinergic side effects.

For these reasons, alternate therapies for the management of chronic or neuropathic pain are widely sought.

Members of a specific class of benzothiophene derivatives, 1,2,3,4-tetrahydro- benzo[b]thieno[2,3-c]pyridines, have been reported to inhibit antisocial behavior, cause central nervous system depression, and reduce spontaneous motor activity in several mammalian species (Suh 1970, 1972; Miller). They have also been described as appetite suppressants (Bosin). A carboxamide-sub- stituted derivative has been reported to have anxiolytic activity (Nagatani), and tetracyclic derivatives, having an additional ring fused to the pyridyl ring, have been described as anti-adrenergic and anti-5-HT agents (Leitch) and for treatment of colonic spasm and irritable bowel syndrome (Pendelton). However, there has been no disclosure of analgesic activity for this class of compounds. Summary of the Invention

The invention includes, in one aspect, a method of treating pain, including acute, persistent, and neuropathic pain. In accordance with the method, a composition comprising an effective amount of a l,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine compound of formula I:

where X and Y are each independently H, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoro, chloro, or bromo, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier, is administered to a subject in need of such treatment. Preferably, the salt is a halide, carbox- ylate, sulfonate, or sulfate. Most preferably, the salt is a chloride. A particularly preferred composition, the chloride salt in which X = Y = H, is designated herein as SNX-607. Preferred methods are those in which the composition is administered intravenously or orally. The method is useful for the treatment of neuropathic pain as well as acute and persistent nociceptive pain. The method is also useful in producing long term analgesia, having a duration of 8 to 24 hours or longer. Oral administration is the preferred route for producing such long term analgesia. In particular, oral administration is shown to produce analgesic effects having a duration significantly greater than would be predicted from the observed half-life of the composition in systemic circulation when it is administered systemically (e.g., intravenously). In preferred embodiments, such an effect has a duration of 24 to 48 hours or longer.

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 1A shows a synthetic scheme for the preparation of 3-(2-aminoefhyl)benzo-[b]thiophenes, which are intermediates in the preparation of the compounds of the invention;

Figure IB shows a synthetic scheme for the preparation of l,2,3,4-tetrahydro-benzo[b]thieno [2,3-c]pyridine compounds from 3-(2-aminoethyl)benzo-[b]thiophenes; Figures 2A-2B show time-effect curves for intravenously (2A) and orally (2B) administered SNX-607 (1,2,3,4-tetrahydrobenzo [b]thieno[2,3-c]pyridine hydrochloride), showing blockade of acute and persistent nociceptive responses evoked by subsequent subcutaneous injection of 5 % formalin into the hindpaw of Sprague-Dawley rats; Figure 3 shows a time-effect curve showing the inhibition by intravenously administered SNX-

607 of acute nociceptive responses induced by thermal stimulation in rats;

Figure 4 shows a time-effect curve showing the inhibition by intravenously administered SNX- 607 of acute nociceptive responses induced by mechanical stimulation in rats;

Figure 5 shows time-effect curves showing blockade by intravenously administered SNX-607 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;

Figures 6A-6B show time-effect curves showing dose-dependent blockade by orally administered SNX-607 of cold allodynia in Sprague-Dawley rats with a painful peripheral neuropathy, as for Figure 5; and Figures 7A-7B show time-effect curves showing blockade by intravenously (7 A) and orally (7B) administered SNX-607 of cold allodynia in Sprague-Dawley rats with a painful peripheral neuropathy, as for Figures 5 and 6A-6B.

Detailed Description of the Invention I. Definitions

The term "effective amount" refers to that amount of a compound of formula I which effects a measurable analgesic effect when administered. The precise effective amount required will vary with the particular compounds employed, and the species, age and condition of the subject to be treated.

However, the effective amount may be determined by one of ordinary skill in the art with only routine experimentation, following methods known in the art, and disclosed below.

The term "pharmaceutically acceptable carrier" refers to any generally acceptable excipient that is relatively inert, non-toxic, and non-irritating. Suitable formulations and carriers are described in Section IV, below.

II. Preparation of 1,2.3.4-Tetrahvdrobenzorblthieno-pyridine and Derivatives

The pharmaceutical compositions used in the present invention contain, as active ingredients, one or more compounds of formula I, above, where X and Y are each independently hydrogen, hy- droxy, halogen such as bromo, chloro, and fluoro, lower alkyl groups of 1-3 carbon atoms such as methyl, ethyl, and propyl, and lower alkoxy groups such as methoxy, ethoxy, and propoxy. These compounds may be prepared, for example, by the following methods. Starting materials used in the preparation of the above-mentioned compounds may include

3-(2-aminoethyl)benzo-[b]thiophenes 2, as shown in Fig. 1A, in which X and Y are as previously defined. The ethylamines 2 may be prepared from 3-(2-chloroethyl)benzo[b]thiophenes and the corresponding cyano compounds, as shown in the Figure, by any of several conventional methods described in the literature (see e.g. Herz; Campaigne 1965, 1966, 1979).

Representative of the amines 2 which may be used as starting materials to the compounds of the present invention are the following: 3-(2-aminoethyl)benzo[b]thiophene, 4-bromo-3-(2-aminoethyl)benzo[b]thiophene, 5-bromo-3-(2-aminoethyl)benzo[b]thiophene, 6-bromo-3-(2-aminoethyl)benzo]b]thiophene, 7-bromo-3-(2-aminoethyl)benzo[b]thiophene, 4-chloro-3-(2-aminoethyl)benzo[b]thiophene, 5-chloro-3-(2-aminoethyl)benzo[b]thiophene, 6-chloro-3-(2-aminoethyl)benzo [bjthiophene, 7-chloro-3-(2-aminoethyl)benzo[b]thiophene, 4-fluoro-3-(2-aminoethyl)benzo[b]thiophene, 5-fluoro-3-(2-aminoethyl)benzo[b]thiophene, 6-fluoro-3-(2-aminoethyl)benzo[b]thiophene, 7-fluoro-3-(2-aminoethyl)benzo[b]thiophene, 4-hydroxy-3-(2-aminoethyl)benzo[b]thiophene, 5-hydroxy-3-(2-aminoethyl)benzo[b]thiophene, 6-hydroxy-3-(2-aminoethyl)benzo[b]thiophene, 7-hydroxy-3-(2-aminoethyl)benzo[b]thiophene, 4-methoxy-3-(2-aminoethyl)benzo[b]thiophene, 5-methoxy-3-(2-aminoethyl)benzo[b]thiophene, 6-methoxy-3-(2-aminoethyl)benzo[b]thiophene, 7-methoxy-3 -(2-aminoethyl)benzo [b] thiophene , and 5,6-dimethoxy-3-(2-aminoethyl)benzo[b]thiophene. Compounds of the present invention may be prepared from the starting materials 2 by several methods described in the literature (e.g. Campaigne 1979; Suh 1972). One convenient method, illustrated in Fig. IB, involves condensation of 2 with formaldehyde to produce the bis compound, as shown, which can be acid hydrolyzed to the 1 ,2,3,4-tetrahydrobenzo[b]thieno [2,3-c]pyridine derivative 1. Acid-addition salts of the l ,2,3,4-tetrahydrobenzo-[b]thieno[2,3-c]pyridines may be prepared by contacting the free base with a suitable non-toxic acid. Exemplary non-toxic acids include mineral acids such as hydrochloric acid, phosphoric acid, phosphorus acid, and the like, as well as organic acids including, for example, acetic acid, citric acid, maleic acid, tartaric acid, and benzoic acid.

III. Analgesic Activity

In accordance with the invention, it has been found that a representative compound of the invention, l,2,3,4-tetrahydrobenzo-[b]thieno[2,3-c]pyridine hydrochloride (SNX-607), is effective as an analgesic agent for neuropathic as well as nociceptive pain states, as shown in the experiments described below. 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 Models

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 the spinal cord (see Wheeler-Aceto et al. , 1990, 1991). Protracted 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 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 and Yaksh, 1991, 1992). 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 (see Example 1). A biphasic response pattern is typically observed, with numerous responses observed during the period 5 min. after injection (Phase 1), followed by 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. In one experiment, intravenous administration of SNX-607 was tested for its effect on the formalin response in rats. A 10 mg/kg dose of SNX-607 was administered intravenously to Sprague- Dawley rats, followed ten minutes later by subcutaneous injection of a 5% formalin solution into the hindpaw.

Fig. 2A shows time-effect curves for blockade of acute (Phase 1, 0-9 minutes) and persistent (Phase 2, 10-90 minutes) pain by intravenous SNX-607. As can be seen from the Figure, the compound showed significant inhibition of both the Phase 1 and Phase 2 responses, with inhibition lasting over one hour.

Doses of SNX-607 producing 50% reductions (ED₅₀) and 75 % reductions (ED₇₅) in acute (Phase I) and persistent (Phase II) responses were also determined. For Phase I, ED₅₀ and ED₇₅ were 0.6 mg/kg and 1.4 mg/kg, respectively. For Phase II, ED₅₀ and ED₇₅ were 2.8 mg/kg and 4.9 mg/kg, respectively.

Figure 2B shows the results of the same test protocol using a 60 mg/kg dose of SNX-607, administered orally, rather than intravenously, with the additional difference that the compound was administered one hour prior to formalin injection, rather than 10 minutes prior, as above. Even with the significantly longer lead time before onset of the test, the analgesic effect of the orally administered drug lasted longer than that of the intravenously administered drug.

Another in vivo analgesia model, the hotplate test, measures the nociceptive response to an acute thermal stimulus. In this test (see Example 2 below), animals are 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 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.

Fig. 3 shows the effect of intravenous administration of SNX-607 and control vehicle on acute nociceptive response, according to the above test protocol. Data are expressed as mean ± SEM. As can be seen from the figure, a 10 mg/kg dose of SNX-607 showed a significant blocking effect which was essentially undiminished at 1 hour from dosage, with a reduced effect remaining at 8 hours from dosage.

A third model, the paw pressure test, measures nociceptive response to an acute mechanical stimulus. In this test (see Example 3 below), a stylus (1 mm diameter) is pressed to the hindpaw of a test animal, and increasing pressure is applied until a withdrawal response is elicited (Randall-Selitto method). Withdrawal pressure is measured in grams, with a cutoff of 750 grams.

As can be seen from Figure 4, a 10 mg/kg dose of SNX-607 again showed a significant blocking effect, relative to the control, which persisted for 1-2 hours from dosage.

These results show that SNX-607 is effective in relieving nociceptive pain, both acute and persistent, produced by a variety of stimuli. B. Neuropathic Pain Models

The analgesic potency of SNX-607 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. In accordance with the invention, a representative compound of formula I, SNX-607, is effective in providing relief of neuropathic pain, as described below.

Experiments were carried out in a rat model of peripheral neuropathy detailed in Examples 4-5. Rats were first 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 the art. Allodynia was first measured by stimulation of the neuropathic rat hindlimb using wire hairs having graded degrees of stiffness (Example 4). Analgesic compounds reverse the heightened sensitivity such animals exhibit to the stimulus.

Figs. 5 and 6A-6B show results in the allodynia test of animals treated with SNX-607. For the results shown in Fig. 5, a 10 mg/kg dose was administered intravenously. 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. 5, treatment of rats with SNX-607 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 injection lasted 1-2 hours.

To obtain the results shown in Fig. 6A-6B, varying doses (20 mg/kg and 60 mg/kg) of SNX- 607 were administered orally, rather than intravenously. The higher dose showed an initial effect comparable to that of the intravenous injection (Fig. 5), while the lower dose showed a response that was lower but still clearly superior to the control. Significantly, the effect was unexpectedly long-lived for both doses, having diminished only slightly after 4 hours, and still showing significant activity after 24 hours (data not shown). This is especially clear from Figure 6B, where the analgesic effect remained at near-maximum for 8 hours, and a significant effect was still observed after 48 hours. This effect is discussed further below. (Note that icons used in Figs. 6A-6B and Figs. 7A-7B for test compound and control are reversed.)

Cold allodynia was also assessed (see Example 5) in rats with an induced peripheral neuropathy, as described above, by placing a 7-10 μl drop of acetone on the heel of the foot ipsilateral to the nerve injury and noting the occurrence of a paw flick. The response rate, shown in Figs. 7A-7B, was the percentage of trials that elicited such a response. As Fig. 7A shows, intravenous administration of 10 mg/kg produced a complete suppression of response lasting for 1-2 hours, with partial suppression lasting up to about 8 hours. Again, as shown in Fig. 7B, oral administration (60 mg/kg) produced a very long-lasting effect, remaining at near-maximum for 4 hours and persisting for 48 hours or more.

These results indicate that SNX-607 is capable of reversing the hyperesthetic effects induced by nerve damage, as well as alleviating both acute and persistent nociceptive pain. Both intravenous and oral administration were effective, with the latter showing a surprisingly long-lasting analgesic effect.

C. Long Term Analgesia

As noted above, oral administration of SNX-607 produced a surprisingly long-lived analgesic effect. Intravenous administration of SNX-607 in a neuropathic pain model, as shown in Fig. 5, produced an analgesic effect which had largely diminished after two hours post-injection, giving a functional half-life in circulation of about one hour for this dosage, i.e. , 10 mg/kg. The six fold greater dosage used in oral administration, using the same model and protocol, would be predicted to have a functional half-life roughly six times as long, once the drug enters the bloodstream, i.e., to show a half- maximum value at roughly six hours, or slightly longer. As the data in Fig. 6A and especially Fig. 6B shows, the persistence of the analgesic effect of orally administered SNX-607 was significantly greater than such a prediction. The analgesic effect of the 60 mg/kg dosage was still near its maximum value after 4 hours, and significant activity was observed after 24 hours (data not shown). An increase in persistence of analgesia via oral administration, as compared to i.v. administration, was also observed in the formalin test, as discussed above.

Based on these observations, one may hypothesize that the compound of the invention undergoes a transformation in the gut to a species which has a longer lasting analgesic effect. Such an effect could result from longer persistence of the species in circulation, a different mechanism of action in producing the analgesic effect, or a combination of both.

IV. Formulation. Dosage and Administration The composition may be administered to a subject by a variety of known routes, e.g. orally, perineurally or parenterally, that is, by intravenous, intrathecal, subcutaneous, intraperitoneal, or intramuscular injection. As noted above, oral and i.v. administration are convenient and effective routes and are preferred for general application. For delayed release, the analgesic compound may be included in a pharmaceutical composition formulated for slow release, such as in microcapsules formed from biocompatible polymers or in liposomal carrier systems according to methods known in the art.

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, capsules, powders, sustained- release formulations, solutions, suspensions, emulsions, suppositories, 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 the like. Preferably, the composition will be about 0.5% to 75 % by weight of a compound or compounds of the invention, with the remainder consisting of suitable pharmaceutical excipients.

As the compositions of the invention are well suited to oral administration, preferred carriers will include those which facilitate formulation in tablet or capsule form. 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. Other suitable excipients include pharmaceutical grades of mannitol, lactose, albumin, polyethylene glycol, magnesium stearate, talcum, 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, the 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.

An injectable composition for parenteral administration will typically contain the l,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine compound, or an acceptable salt thereof, in a suitable IV solution, such as sterile physiological salt solution. The composition may also formulated as a suspension in a lipid or phospholipid, in a liposomal suspension, or in an aqueous emulsion.

For some applications, it may be desirable to include in the composition or treatment regimen means for enhancing permeation of the active compound through meningeal 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 membranes, addition of a surfactant to the composition, and the like. Alternatively, or in addition, trans-meningeal transport may be facilitated by administering to the subject a hypertonic dosing solution effective to disrupt meningeal barriers, according to methods well known in the 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 Pub. Co., 1985).

The composition to be administered will contain a quantity of the selected compound in a pharmaceutically effective amount for effecting analgesia in a subject. Generally, dosages and routes of administration of the compound will be determined according to the site of the pain and the size of the subject, according to standard pharmaceutical practices. A typical dosage formulation for a human subject would contain 0.1-25 mg/kg of the benzo[b]thieno[2,3-c]pyridine derivative or salt thereof. One or more dosage forms may be administered daily; however, the amount of compound of formula I administered will not normally exceed about 100 mg/kg per day.

V. Therapeutic Indications As stated above, neuropathic pain may result from a number of separate etiologies. For example, injury of the nerve fibers of the eye, a heavily enervated organ, can lead to neuropathic pain of ophthalmic origin. 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 alleviating neural pain or preventing progression of dental neuropathy. Burn injuries are characterized by primary hyperalgesia to thermal and mechanical stimuli, as a result of nociceptor sensitization, and are thus susceptible to treatment with analgesic agents which are effective against neuropathic pain. Other neuropathic indications include reflex sympathetic dystrophy (RSD), post-herpetic neuralgia, diabetic neuropathy, and arthritis.

Generally, such pain may be treated according to any of the methods described herein. The above list of indications is by no means exhaustive, but is presented to illustrate some of the various therapeutic situations in which the compounds of formula I, and SNX-607 in particular, can be used in the treatment of pain, particularly neuropathic pain.

As noted above, the oral administration of the compounds of formula I, in accordance with a preferred embodiment of the method, provides very long lasting analgesic effects, especially in models of neuropathic pain. It is also expected that the compounds would be useful in potentiating the effects of other classes of analgesics, such as opioids or over-the-counter phenolic and salicylate-based analgesics, or that such a combination would achieve a synergistic effect.

While the invention has been described with reference to specific methods and embodiments, it will be appreciated that various modifications may be made without departing from the invention.

EXAMPLES

Example 1: Rat Formalin Test for Analgesia SNX-607 was dissolved in sterile saline (0.9% NaCI) and administered i.v. to male Sprague- Dawley rats (275-300 g, Harlan Industries, Indianapolis, IN), in a volume of 10 ul followed by 10 ul sterile saline, 10 minutes prior to subcutaneous injection of 5 % formalin. The formalin solution (50 μl) was injected on the plantar surface of the paw of a lightly anesthetized (halothane, 3 %) animal. Control rats were similarly injected with 0.9% saline. The number of spontaneous flinchings/shakings of the injected paw were counted at intervals after the injection of the formalin for a 90-minute observation period. Injection of formalin alone or with vehicle (saline) resulted in a biphasic response pattern of hind paw withdrawals, as shown in Fig. 1. Each point in the Figure is the mean ± SEM of the number of flinches in a 1 -minute interval.

A 10 mg/kg dose of SNX-607 was used to produce the data shown in Fig. 1. Doses of SNX- 607 producing 50% reductions (ED₅₀) and 75% reductions (ED₇₅) in acute (Phase I) and persistent (Phase II) responses were also determined, as discussed above.

Example 2: Hotplate Test for Analgesia Male Sprague-Dawley rats were injected with SNX-607 (10 mg/kg) as described for Example 1. Control animals were similarly injected with 0.9% saline. To produce the data shown in Fig. 2, 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 measured. If there was no response within 60 seconds, the trial was terminated, and this value was noted. Animals were acclimated to the test conditions by conducting two trials at approx. 10 minute intervals prior to initiating the study. Animals were tested immediately prior to dosing with the test or control substance, and at 30 minute intervals thereafter. Each point in the Figure is the mean ± SEM for 8 animals.

Example 3: Paw Pressure Test for Analgesia

Male Sprague-Dawley rats were injected with SNX-607, and control rats were similarly injected with 0.9% saline, as described for Examples 1-2. To produce the data shown in Fig. 2, a stylus (1 mm tip diameter) was pressed to the hindpaw, and a constantly increasing pressure was applied until a withdrawal response was elicited (Randall-Selitto method). Withdrawal threshold was measured in grams, with a cutoff of 750 grams. Each point in the Figure is the mean + SEM for 8 animals.

Example 4: Rat Model of Peripheral Neuropathy: Mechanical Allodynia

Male Sprague-Dawley rats (200-350 gm) were prepared with chronic lumbar intrathecal catheters inserted under halothane anesthesia (Yaksh and Rudy). Animals were placed in a prone position and the left paraspinal muscles were separated from the spinous processes at the L₄-S₂ 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.

Compound dissolved in preservative-free saline solution was administered intravenously, to give the results shown in Fig. 5, or orally, to give the results shown in Fig. 6, in the doses described above.

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, 1976) to define the 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. 5-6 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. Each point is the mean ± SEM for 6 animals. Example 5 : Rat Model of Peripheral Neuropathy : Cold Allodynia Male Sprague-Dawley rats (200-350 gm) were prepared with chronic lumbar intrathecal catheters as described for Example 4, above. SNX-670 (10 mg/kg) in saline was administered intravenously. Cold allodynia was assessed by placing a 7-10 μl drop of acetone on the heel of the foot ipsilateral to the nerve injury and noting the occurrence of a paw flick. Each animal was subjected to 5 trials spaced at 5 minute intervals. The response rate, as shown in Fig. 7, was the percentage of trials that elicited a paw flick. Each point is the mean + SEM for 6 animals.

Example 6: Formulations A. A representative capsule formulation is prepared as follows: compound(s) 50.0 mg starch 3.0 mg magnesium stearate 3.0 mg lactose 110.0 mg polyvinylpyrrolidone 3.0 mg

One or more compounds of formula I, starch, magnesium stearate, lactose, and polyvinylpyrrolidone are granulated in methanol, dried, and loaded into capsules. Alternatively, the mixture may be tableted by standard methods.

B. An oral suspension is prepared as follows: compound 60.0 mg fumaric acid 0.5 g

NaCI 2.0 g methyl paraben 0.1 g granulated sugar 25.5 g sorbitol (70% aq) 12.85 g

Veegum K 1.0 g flavorings 0.035 mL colorings 0.5 mg ddiissttiilllleedd water 100.0 mL

The components are mixed and stored in a sealed vessel.

C. A formulation suitable for parenteral administration is prepared as follows:

Compound 40.0 mg

KH₂P0₄ buffer (0.4M) 2.0 mL

KOH (IN) to pH 7.0 distilled water 20.0 mL

The components are mixed and stored under sterile conditions.

Claims

IT IS CLAIMED:

1. A method of treating pain, comprising administering to a subject in need of such treatment a composition comprising an effective amount of a l,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine compound of the formula:

where X and Y are each independently H, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoro, chloro, or bromo, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

2. The method of claim 1, wherein X = Y = H.

3. The method of claim 1, wherein the salt is a halide, carboxylate, sulfonate, or sulfate.

4. The method of claim 3, wherein the salt is a chloride.

5. The method of claim 1, wherein the composition is administered intravenously.

6. The method of claim 1, wherein the composition is administered orally.

7. The method of claim 1, wherein the pain treated is neuropathic pain.

8. The method of claim 1, wherein the pain treated is nociceptive pain.

9. The method of claim 6, wherein said administering produces a long term analgesic effect, having a duration significantly greater than would be predicted from the observed half-life of the composition in systemic circulation when administered systemically.

10. The method of claim 9, wherein said analgesic effect has a duration of 24 hours or longer.

11. The method of claim 10, wherein said analgesic effect has a duration of 48 hours or longer.