WO2006085686A1

WO2006085686A1 - Remedy for neurogenic pain

Info

Publication number: WO2006085686A1
Application number: PCT/JP2006/302778
Authority: WO
Inventors: Tsutomu Tanabe
Original assignee: Japan Science And Technology Agency; Tokyo Medical And Dental University
Priority date: 2005-02-10
Filing date: 2006-02-10
Publication date: 2006-08-17
Also published as: JPWO2006085686A1; JP2007332031A; JP4221383B2

Abstract

It is intended to provide a remedy for neurogenic pain exerting an excellent therapeutic effect on neurogenic pain which is an intractable disease. More specifically speaking, it is intended to provide a remedy for neurogenic pain which contains, as the active ingredient, a PPAR antagonist (in particular, a PPARϜ-selective antagonist such as 2-chloro-5-nitro-N-phenylbenzamide), a medicinal composition for treating neurogenic pain which contains, as the active ingredient, a PPAR antagonist, a method of treating neurogenic pain with the use of a PPAR antagonist and so on.

Description

Specification

Neuropathic pain therapeutics Technical Field

The present invention relates to a therapeutic agent for neuropathic pain having an excellent pain suppressing effect on neuropathic pain, a method for treating neuropathic pain using such a therapeutic agent, and the like. Background art

Neuropathic pain is pain caused by damage or dysfunction of the peripheral nervous system or central nervous system, and is refractory pain for which opioid receptor agonists such as morphine do not sufficiently respond. Examples of diseases associated with neuropathic pain include post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, and post-traumatic or post-traumatic prolonged pain. Can do.

As analgesics that have been used in conventional pharmacotherapy, central opioid receptor agonists such as morphine and nonsteroidal anti-inflammatory drugs (NSAIDs) such as indometacin are known. Yes. However, these analgesics are generally less effective against neuropathic pain, and analgesics (especially narcotic analgesics) that are effective for normal nociceptive pain are known to be particularly ineffective. It has been. Inadequate analgesic effect of narcotic analgesics on neuropathic pain is a major feature of neuropathic pain, and in some cases, this feature is used to diagnose neuropathic pain. .

Various factors are thought to be intricately related to the development of neuropathic pain. To date, neuropathic pain has been treated with neurosurgery such as nerve block, spinal epidural electrostimulation, and intrathecal administration of drugs such as tricyclic antidepressants and baclofen. It has been known. However, these treatments have problems that are not effective enough or have side effects. As an external preparation, capsaicin cream is effective for postherpetic neuralgia and pain syndrome after mastectomy by depleting pain substance substance P released from nerve terminals and reducing pain. There is also a report. However, the problem of burning pain caused by kabusaicin There are problems in terms of usability and safety. Thus, neuropathic pain is an intractable disease, and no effective treatment has yet been established.

Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptor superfamily, forming a heterodimer with retinoid X receptor (RXR) and acting as a transcriptional regulator. So far, specific inhibitors of P PAR include P PAR-alpha and P PAR-gamma antagonists (Special Table 2000- 503643) for the treatment of X syndrome, prophylactic and therapeutic agents for osteoporosis, etc. P PAR module for the purpose (Agonist, Ango gonist, Partial agonist or Partial antagonist) (Special Table 2002-332266), Nuclear Allele Compound (Special Table 2002-539185) Etc. are known. However, these publications do not describe or suggest that PP AR antagonists are effective for neuropathic pain. Disclosure of the invention

As described above, there are currently no known drugs effective for the treatment of neuropathic pain, and development of such drugs is desired. Under such circumstances, an object of the present invention is to provide a novel therapeutic agent for neuropathic pain that exhibits an excellent effect on intractable pain called neuropathic pain.

The present inventors conducted research based on an original idea in order to achieve the above-mentioned problem, and represented 2-chloro-5-nitro-N-phenylpenamide (GW9662) in an intractable neuropathic pain model. As a result, the present inventors have found that the P PARr selective antagonist shows high analgesic effect.

That is, the present invention provides the following therapeutic agent for neuropathic pain, a pharmaceutical composition for treating neuropathic pain, a method for treating neuropathic pain, and the like.

(1) A therapeutic agent for neuropathic pain comprising a peroxisome proliferator-activated receptor (PPAR) antagonist as an active ingredient.

(2) The therapeutic agent for neuropathic pain according to the above (1), wherein the PPAR antagonist is a PPARr selective antagonist.

(3) If the PPAR selective antagonist is 2-cyl! 5-nitro-N-phenylbenzamide (GW9662), 2-chloro-5-nitrone N-4 monopyridinyl Nsamide (T0070907), 2-[(5,5,8,8-tetramethyl-1,5,6,7,8-tetrahydr-2-naphthyl) carbonyl] benzoic acid (LG100641), bisphenol A diglycidyl Ether (BADGE), 4- (5H-2,3- (2,5-Dimethyl-2,5-hexano) 1-Methyl _8-Nitrodibenzo [b, e] [1,4] diazepine 1 1 1 —Y 1) The therapeutic agent for neuropathic pain according to the above (2), which is selected from benzoic acid (HX531), PD068235, and pharmaceutically acceptable salts thereof.

(4) The therapeutic agent for neuropathic pain according to the above (3), wherein the selective PPARr antagonist is selected from 2-chloro mouth-5-nitro-N-phenylbenzamide and pharmaceutically acceptable salts thereof.

(5) Neuropathic pain includes postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, alodynia, post-thoracotomy pain, CRP S, (1) ~ which is one or more symptoms selected from multiple sclerosis pain, AI DS, thalamic pain, paraplegia due to spinal cord disorder, non-sensory pain, and neuropathic pain in phantom limb pain (4) The neuropathic pain therapeutic agent according to any one of (4).

(6) A pharmaceutical composition for treating neuropathic pain comprising a peroxisome proliferator-responsive receptor antagonist and a pharmaceutically acceptable carrier.

(7) A method of treating neuropathic pain by administering an effective amount of a peroxisome proliferator-activated receptor antagonist to a mammal.

(8) Use of a peroxisome proliferator-responsive receptor antagonist for the manufacture of a therapeutic agent for neuropathic pain.

The therapeutic agent for neuropathic pain of the present invention is a neurogenic factor exhibiting symptoms such as postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, and alodynia. Effective in the treatment of sexual pain. Brief Description of Drawings

FIG. 1 is a diagram showing the experimental results of Example 1, and shows changes in the pain threshold for mechanical stimulation when GW 9662 was administered intraperitoneally to hypersensitive rats.

FIG. 2 is a diagram showing the experimental results of Example 2, in which GW96 It is the figure which showed the change of the pain threshold with respect to a heat stimulus by administering 62 intraperitoneally. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

Peroxisome proliferator-activated receptor (PPAR) is one of the nuclear receptor superfamily and is known to be involved in lipid storage and catabolism. PPAR also has three subtypes, β, Ύ, which bind to fatty acids and their metabolites and regulate the expression of genes involved in the transport, metabolism, and buffering of ligands in the cell. Is becoming clearer. Among them, PPARr is considered to be one of the most important factors governing gene expression and differentiation of adipocytes. In addition to the ability to produce adipocytes, PPARr is also involved in the central gene expression of glucose and lipid metabolism. Already used as an effective treatment for diabetes or in the treatment of atherosclerosis and cancer, PPAR 7 is the most studied subtype. It has also been shown that drugs that moderately reduce PPARr activity have anti-obesity and anti-diabetic effects.

In such applications, 2-chloro-5-nitro 1-N-phenylpenamide (GW9662) is known as a PPARr selective antagonist. Surprisingly, the present inventor has proposed a PPARr selective antagonist. This is the first time that GW9662 alone has a therapeutic effect on neuropathic pain. To date, there have been no reports on the pain-suppressing effects of PPAR antagonists in neuropathic pain models, and this fact proves the originality of the present invention.

The present invention has been made based on such findings, and is a neuropathic pain therapeutic agent, a PPAR antagonist, and a pharmaceutically acceptable agent that contain a peroxisome proliferator-activated receptor (PPAR) antagonist as an active ingredient. A pharmaceutical composition for treating neuropathic pain containing a carrier and a method for treating neuropathic pain using a PPAR antagonist are provided.

There are three types of subtypes of PPARs (Hiichi, 13—, Ύ-), and the “PPARa selective antagonists” in this document are selective antagonists to PPARa. That is, for PPAR and P PAR / 3, 006302778

Five

Means a substance having stronger antagonism against The antagonistic action against PPARa can be confirmed by a known method, for example, the method described in J. Biol. Cem., Vol. 277, Issue 22, 19649-19657, May 31, 2002.

As used herein, the term “treatment” generally means amelioration of symptoms in humans and non-human mammals. The term “improvement” refers to, for example, the case where the degree of the disease is reduced or not worsened, as compared to the case where the therapeutic agent of the present invention is not administered, and also includes the meaning of prevention. In addition, the term “pharmaceutical composition” includes active ingredients useful in the present invention (eg, 2-clo-5-nitro-1 N-phenylpenamide) and additives such as carriers used in the preparation of pharmaceuticals. Means a composition.

The P PAR antagonist preferably used in the present invention is a subtype selective antagonist, and the P PAR selective antagonist used preferably includes, for example, 2-chloro-5-nitro-N-phenylbenzamide ( GW9662), 2-black mouth 1 5-nitro 1 N-.4 1 pyridinyl penzamide (T0070907), PD068235, 2 — [(5, 5, 8, 8—tetramethyl 1, 5, 6, 7, 8— Tetrahydro-2-naphthyl) carbonyl] benzoic acid (LG100641), bisphenol A diglycidyl ether (BADGE), 4- (5H-2, 3— (2,5-dimethyl-2,5-hexano) 1 5— And methyl-8-nitrodibenzo [b, e] [1,4] diazepine-1 1-y 1) benzoic acid (HX531) and pharmaceutically acceptable salts thereof. P PAR antagonists described above are all well known, for example, Merck Index ^{(The Merck Index, 13 th Edition} (2001), various documents, pharmacological reference books ^{(e.g., The pharmacological basis of therapeutics 9 lh} Edition, McGraw Hill), etc. The most preferred PPAR-selective antagonist among the above-mentioned compounds is 2-cloguchi-5-nitro-1 N-phenylpenamide, and SI GMA-RB I catalog (Cell Synaring'Neuroscience Research page416-420 (2004-2005)) etc.

In the present specification, the term “containing a PPAR antagonist as an active ingredient” refers to a compound known as a PPAR antagonist and a pharmaceutically acceptable form of this compound (for example, a salt, ester, Amides, hydrated or solvated forms, racemic mixed Product, optically pure form, prodrug, etc.).

Therefore, the compound as an active ingredient used in the present invention may be a free form or a pharmaceutically acceptable salt. Such “salts” include acid salts and base salts. Examples of acid salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, and citrate. Salt, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, dalconate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzenesulfone Acid salt, p-toluenesulfonic acid salt, 1,1′-methylene-bis- (2-hydroxy-1-3-naphthoic acid) salt, and the like. Examples of the basic salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as strong salt and magnesium salt, water-soluble amine addition salts such as ammonium salt and N-methyl darcamamine salt, Examples include lower alcohol salts, salts derived from other bases of pharmaceutically acceptable organic amines.

The therapeutic agent and composition for neuropathic pain of the present invention are effective for the treatment of neuropathic pain. Examples of such neuropathic pain include, for example, postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, alodynia, postthoracotomy pain , CRPS, pain due to multiple sclerosis, AIDS, thalamic pain, paraplegic pain due to spinal cord disorder, non-sensory pain, neuropathic pain in phantom limb pain, etc. The therapeutic agent for neuropathic pain of the present invention is particularly effective for the treatment of hyperalgesia and alodinia.

The administration form of the therapeutic agent for neuropathic pain of the present invention is not particularly limited, and can be administered orally or parenterally. The PPAR antagonist, which is an active ingredient of the therapeutic agent for neuropathic pain of the present invention, may be formulated alone, but in the form of a formulation by adding a pharmaceutically acceptable carrier or a pharmaceutical additive thereto. It can also be provided. In this case, the PPAR antagonist that is the active ingredient of the present invention can be contained in an amount of 0.1 to 99.9% by weight, for example.

Examples of pharmaceutically acceptable carriers or additives include excipients, disintegrants, Disintegration aids, binders, lubricants, coating agents, dyes, diluents, solubilizers, solubilizers, tonicity agents, PH adjusters, stabilizers, etc. can be used.

Examples of preparations suitable for oral administration include powders, tablets, capsules, fine granules, granules, solutions or syrups. For oral administration, various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate, dalysin, starch, preferably corn, potato or starch , And various disintegrants such as alginic acid and certain kainate double salts, and granulating binders such as polyvinylpyrrolidone, sucrose, gelatin, gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very effective for tablet formation. The same kind of solid composition can also be used by filling gelatin capsules. Suitable substances in this connection include lactose or lactose as well as high molecular weight polyethylene glycols. If you want an aqueous suspension and Z or elixir for oral administration, use the active ingredient in combination with various sweeteners or flavors, colorants or dyes, and if necessary, emulsifiers and suspending agents. It can be used with water, ethanol, propylene glycol, glycerin, etc., and diluents that combine them.

Examples of preparations suitable for parenteral administration include injections and suppositories. In the case of parenteral administration, the active ingredient of the present invention can be dissolved in either sesame oil or peanut oil, or a solution dissolved in an aqueous propylene glycol solution can be used. The aqueous solution should be buffered as needed (preferably pH 8 or more) and the liquid diluent is made isotonic. Such aqueous solutions are suitable for intravenous injection and oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. All of these solutions can be easily prepared by standard pharmaceutical techniques well known to those skilled in the art to produce aseptic conditions. Furthermore, the active ingredient of the present invention can be administered locally such as on the skin. In this case, topical administration in the form of creams, jellies, pastes, ointments is desirable according to standard pharmaceutical practice.

The dosage of the therapeutic agent for neuropathic pain of the present invention is not particularly limited, and is suitable according to various conditions such as the type of pain, the age and symptoms of the patient, the administration route, the purpose of treatment, and the presence or absence of a concomitant drug. It is possible to select the right dose. The dose (as the amount of the active ingredient) of the therapeutic agent for neuropathic pain of the present invention is, for example, about 500 to 25000 mg per day, preferably 900 to 9000 mg for an adult (for example, body weight 60 kg). When administered as an injection, the dose is, for example, about 100 to 5000 mg, preferably 180 to 1800 mg per day for adults (for example, body weight 6 O kg). These daily doses may be administered in multiple doses (eg, 2 to 4 times). Example

Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited to these examples.

(Experimental materials used and general experimental methods)

(1) Model animals

As a test animal, a hypersensitivity model prepared by completely ligating the L5 / L6 spinal nerve to 6-week-old male rats (weight: 172.5 to 207.9 g) was used.

(2) Grouping

The mechanical stimulation test was measured using the Dynamic Planter Aesthesiometer (37 shelves, Ugobasil), and the thermal stimulation test was performed using the plantar thermal stimulation device (Planter test 7370, Ugobasil) to measure the pain threshold of the model animal. The groups were divided so that the pain threshold measured before administration on each experimental day was uniform. For mechanical stimulation, animals with a model animal foot pain threshold of 8. Og or more were excluded from the study, and for heat stimulation, animals with a model foot pain threshold of 10 seconds or more were excluded from the study.

(3) Preparation of test substance

For the test substance, the raw powder was pulverized using an agate mortar and pestle, and 0.5wA ^ carboxymethylcellulose sodium (CMC-Na) as a medium was gradually added to obtain a uniform suspension. Dosage concentration adjustment (0.06, 0.6 and 6. Omg / ml solution) was performed using a graduated cylinder or volumetric flask, and all adjustments were made at the time of use.

(4) Administration method The test substance is intended to confirm the direct action on the spinal cord, but it has been confirmed that it passes through the brain barrier. It was administered intraperitoneally at a volume of 5 ml / kg using a syringe and a needle. Example 1

(Mechanical stimulation method)

A group of 5 male rats (309.7-431.5 g) of hypersensitivity pain group. 2 —Black mouth — 5—Nitroen N—Phenilpenamide (GW9662) Maximum pressure: 15.0 g before administration, 30 minutes, 60 minutes and 90 minutes after administration, time to reach maximum pressure: 20 seconds The pain threshold of the left footpad was measured using the stimulator. The results are shown in Fig. 1. In the figure, “* *” indicates that Dunne tt's multiple test method has a dominant difference at P 0.01, and “*” indicates that Dunne tt's multiple test method has a dominant difference at K0. 05 ( The same applies below). As shown in Fig. 1, the maximum pain threshold after administration was 5.4 g in the control group to which physiological saline was administered, whereas (a) 0.3 mg / kg was administered to the group to which GW9662 was administered. In this case, the maximum threshold after administration is 6.3 g, (b) when 3 mg / kg is administered, the maximum threshold after administration is 9.0 g, and (c) when 30 mg / kg is administered, the maximum threshold after administration is 9 . Showed 3g. Thus, administration of GW9662 significantly increased the pain threshold at 3 mg and 30 mg, confirming analgesic effects in neuropathic pain. Example 2

(Thermal stimulation method)

Male rats (35 1. 8 to 463.0 g) of a hypersensitivity model were used in groups of 5 animals. The pain threshold of the left footpad was measured using a plantar thermal stimulation device set to thermal stimulation intensity 35 before GW9662 administration and at 30, 60 and 90 minutes after administration. The result is shown in Fig.2.

As shown in Fig. 2, the maximum pain threshold after administration was 7.3 seconds in the control group administered with physiological saline, whereas (a) 0.3 mg / kg was administered in the group administered GW9662. In the case of administration, the maximum threshold after administration is 7.9 seconds; (b) In the case of 3 mg / kg administration, the maximum threshold after administration is 8.7 seconds; (c) In the case of 30 mg / kg administration, the maximum after administration The threshold was 9.1 seconds. Thus, administration of GW9662 significantly increased the pain threshold at 30 mg. The analgesic effect in the cause pain was confirmed.

(Discussion)

From the above examples, it was revealed that PPAR antagonists are effective for the treatment of neuropathic pain. Industrial applicability

As described above, the therapeutic agent for neuropathic pain containing the PPAR antagonist of the present invention has the effect of improving the symptoms of neuropathic pain due to various causes, so it is effective in treating neuropathic pain. Can be used.

Claims

The scope of the claims

1. A therapeutic agent for neuropathic pain comprising a peroxisome proliferator-activated receptor (PPAR) antagonist as an active ingredient.

2. The therapeutic agent for neuropathic pain according to claim 1, wherein the P PAR antagonist is a P PARα selective antagonist.

3. The PPARr selective antagonist is 2-chloro-5-dihydro N-phenylbenzamide, 2_black mouth _5-nitro 1-N-4 monopyridinylbenzamide,

2-[(5, 5, 8, 8—tetramethyl-5, 6, 7, 8—tetrahydro-2-naphthyl) carbonyl] benzoic acid, bisphenol A diglycidyl ether, 4_ (5H— 2, 3- (2, 5-dimethyl-2,5-hexano) 1 5 1-methyl 1 8-ditrodibenzo [b, e] [l, 4] diazepine 1 1 1- y]) Benzoic acid, PD068235 and their pharmaceutically acceptable The therapeutic agent for neuropathic pain according to claim 2, wherein the therapeutic agent is selected from possible salts.

4. The therapeutic agent for neuropathic pain according to claim 2, wherein the PPARa selective antagonist is selected from 2-chloro-5_nitro-N-phenylpenamide and pharmaceutically acceptable salts thereof.

5. Neuropathic pain is postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, alodynia, post-thoracotomy pain, CRP S, multiple 5. The symptom according to claim 1, wherein the symptom is one or more symptoms selected from pain caused by sclerosis, AI DS, thalamic pain, paraplegia due to spinal cord disorder, non-sensory pain, and neuropathic pain in phantom limb pain The therapeutic agent for neuropathic pain according to any one of the above.

6. A pharmaceutical composition for the treatment of neuropathic pain comprising a peroxisome proliferator-responsive receptor antagonist and a pharmaceutically acceptable carrier.

7. A method of treating neuropathic pain by administering an effective amount of a peroxisome growth factor responsive receptor antagonist to a mammal.

8. Use of a peroxisome proliferator-activated receptor antagonist for the manufacture of a therapeutic agent for neuropathic pain. '