WO2006115304A1 - Agent for treating neuropathic pain - Google Patents

Abstract

It is intended to provide an agent for treating neuropathic pain which has an excellent therapeutic effect on neuropathic pain, which is an intractable disease. More particularly, it is intended to provide an agent for treating neuropathic pain containing a medicament having a glucocorticoid receptor-specific antagonism (particularly dexamethasone 21-mesylate) as an active ingredient, a pharmaceutical composition for treating neuropathic pain, a method of treating neuropathic pain using such a compound and the like.

Description

 Specification

 A therapeutic agent for neuropathic pain.

Technical field

 The present invention relates to a therapeutic agent for neuropathic pain having an excellent action for suppressing 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 to which opioid receptor agonists such as morphine do not sufficiently respond. Examples of the disease accompanied by neuropathic pain include post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, prolonged pain after surgery and post-traumatic pain, and other diseases exhibiting symptoms of Alodynia.

 As analgesics that have been used in conventional pharmacotherapy, there are known central opioid receptor agonists such as morphine and non-steroidal anti-inflammatory agents (NSAIDS) such as indomethacin. However, these analgesics are generally less effective against neuropathic pain, and analgesics (especially narcotic analgesics) that are effective for normal nociceptive pain may be less effective. Are known. Inadequate analgesic effect of narcotic analgesics on neuropathic pain is a major feature of neuropathic pain. 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. So far, neuropathic pain has been treated by nerve block, neurosurgical treatment such as spinal epidural electrical stimulation, lumbar intrathecal administration of drugs such as tricyclic antidepressants and baclofen. Are known. However, these treatments have the problem that they are not fully effective and have side effects. In addition, as an external preparation, force psaicin 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 burning pain caused by kabusaicin There are problems in terms of usability and safety, such as accompanying problems. Thus, neuropathic pain is an intractable disease, and no effective treatment has yet been established. On the other hand, darcocorticoids are considered to be the most important function of corticosteroids (sterolide hormones), and their pharmacological actions include immunosuppression in addition to their effects on sugar, protein, and lipid metabolism. Drugs with darcocorticoid activity that are effective, anti-inflammatory, antiallergic, antishock, etc. are clinically important drugs. In contrast, drugs with anti-darcocorticoid activity have been studied as therapeutic agents for hyperadrenocorticism, and their usefulness has not been studied. A progesterone receptor antagonist, Mif Priston (RU-486: Roussel Uclaf, Paris (US Pat. No. 4,386,085: Patent Document 1)) has been used as an anti-progestagen to end early pregnancy. ing. Recently, Mif Pristone has been reported to be effective in neuropathic pain in experiments using model mice (J. Neurosci. 24: 8595-8605 (2004), J. Neurosci. 25: 488-495 (2005 ): Non-patent document 1). Disclosure of the invention

 As described above, various studies on therapeutic agents for neuropathic pain have been conducted, but at present there are no known drugs effective for neuropathic pain. 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 such as neurogenic ¾: pain.

 The present inventors have conducted research based on an original idea to achieve the above-mentioned problem, and found that a compound having anti-darcocorticoid activity exhibits a high analgesic effect in an intractable neuropathic pain model. The present invention has been completed.

 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 darcocorticoid receptor-specific antagonist as an active ingredient.

(2) The darcocorticoid receptor-specific antagonist is 1,4 one predanagen — 9 α-funoleolone 1 6 α-methinole 1 l 'j3, 1 7, 2 1-triol 1, The therapeutic agent for neuropathic pain according to the above (1), which is 2O-dione 2 1-methanesulfonate (dexamethasone 2 1-mesylate).

 (3) Neuropathic pain is postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, alodynia, postthoracotomy pain, CRPS, multiple (1) or (2) above, which is one or more symptoms selected from pain due to sclerosis, AIDS, thalamic pain, paraplegia due to spinal cord disorder, non-sensory pain, and neuropathic pain in phantom limb pain The therapeutic agent for neuropathic pain as described.

 (4) A pharmaceutical composition for treating neuropathic pain, comprising a darcocorticoid receptor-specific antagonist and a pharmaceutically acceptable carrier. ..

 (5) A method of treating neuropathic pain by administering an effective amount of a darcocorticoid receptor-specific antagonist to a mammal.

 (6) Use of a darcocorticoid receptor-specific 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. It is effective in the treatment of sexual pain. Brief Description of Drawings

 Fig. 1 shows the experimental results of Example 1, in which dexamethasone 21-mesylate was administered intraperitoneally to rats that had undergone neuropathic pain due to nerve injury, and the change in pain threshold for mechanical stimulation was shown. It is a figure.

 FIG. 2 is a diagram showing the experimental results of Example 2, in which dexamethasone 21-mesylate was intraperitoneally administered to rats that had undergone neuropathic pain due to nerve injury, and changes in pain threshold for thermal stimulation were observed. FIG.

 FIG. 3 is a diagram showing the experimental results of Comparative Example 1, which showed changes in the pain threshold for mechanical stimulation after intraperitoneal administration of mifibriston to rats that had caused neuropathic pain due to nerve damage. FIG.

FIG. 4 is a diagram showing the experimental results of Comparative Example 2, in which mifibriston was administered intraperitoneally to rats that developed neuropathic pain due to nerve injury, and It is the figure which showed the change of a pain threshold. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail.

 The present invention relates to a therapeutic agent for neuropathic pain comprising a darcocorticoid receptor-specific antagonist as an active ingredient, a darcocorticoid receptor-specific antagonist and a pharmaceutically acceptable carrier. And a method for treating neuropathic pain using a darcocorticoid receptor-specific antagonist.

 Recently, it was reported that mifepristone, which has both anti-darcocorticoid activity and anti-progesterone activity in a neuropathic pain model, has an analgesic effect on neuropathic pain in an experiment using neuropathic pain model mice. (J. Neurosci. 24: 8595-8605 (2004), J. Neurosci. 25: 488-495 (2005)). However, it was unclear as to whether the analgesic action was based on anti-darcocorticoid activity or anti-progesterone activity. The present inventor has found for the first time that anti-darcocorticoid action has an analgesic effect on neuropathic pain by using a glucocorticoid receptor-specific antagonist.

 Anti-darcocorticoid activity can be confirmed by a known method, for example, the method described in J. Steroid Biochemistry and Molecular Biology, Volume 92, Issue 5, ■ December 2004, Pages 345-356.

 As used herein, the term “treatment” generally means ameliorating the symptoms of humans and non-human mammals. In addition, the term “improvement” means, for example, a case where the degree of the disease is reduced or aggravated as compared with the case where the therapeutic agent of the present invention is not administered, and also includes the meaning of prevention. Furthermore, the term “pharmaceutical composition” means a composition containing an active ingredient useful in the present invention (dexamethasone 21-mesylate, etc.) and an additive such as a carrier used in the preparation of a medicament.

Has antagonism specific to darcocorticoid receptor used in the present invention The compound is not particularly limited, but preferably dexamethasone 2 1-mesylate (1, 4 1 predanagen 9 c 1 fluoro 1 6 α-methino U ^ — 1 1 j3, 1 7, 21—trio 1 20 dione 21-methanesulfonate) and pharmaceutically acceptable salts thereof. All of these are known, and among them, a particularly preferred compound having anti-darcocorticoid activity is dexamethasone 21-mesylate. Dexamethasone 21-mesylate is known, and references such as Proc. Natl. Acd. Sci. USA 100: 7953 (2003) can be referred to. Dexamethasone 21-mesylate can be obtained from, for example, Stellaroid (New Port RI, USA), and its chemical structure, physicochemical properties, etc. can be confirmed on the company's website. can force (http:... // ww steraloids com / products / P / P518 html) 0 in the present specification, the term "Darko glucocorticoid receptor-specific antagonist", Dar here Norre Chico I de receptor A compound known as a compound having a specific antagonistic action on the body and a pharmaceutically acceptable form of this compound (eg, its salt, ester, amide, hydrated or solvated form, racemic mixture, optically In 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, acidic phosphate, acetate, lactate, and kenate. , Acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, dulconate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzenesulfone Acid salt, p-toluenesulfonate, 1,1′-methylene monobis (2-hydroxy-1-naphthoic acid) salt, and the like. Examples of the base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, water-soluble amine addition salts such as ammonium salt and N-methyl darcamamine salt, Examples include lucanolamine salts and salts derived from other pharmaceutically acceptable bases of 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, oral dinia, thoracotomy These include post-pain, CRPS, pain due to multiple sclerosis, AIDS, thalamic pain, paraplegia due to spinal cord injury, sensory pain, neuropathic pain in phantom limb pain, and so on. The therapeutic agent for neuropathic pain of the present invention is particularly effective for the treatment of hyperalgesia and alodynia.

 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 darcocorticoid receptor-specific antagonist, which is an active ingredient of the therapeutic agent for neuropathic pain of the present invention, may be formulated alone, but it is formulated with a pharmaceutically acceptable carrier or formulation additive. It can also be provided in the form of a preparation. In this case, the darcocorticoid receptor-specific antagonist as the active ingredient of the present invention can be contained, for example, in an amount of 0.1 to 99.9% by weight.

 Examples of pharmaceutically acceptable carriers or additives include excipients, disintegrants, disintegration aids, binders, lubricants, coating agents, dyes, diluents, solubilizers, solubilizers, isotonicity. An agent, pH adjuster, stabilizer and the like 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 guanate, calcium carbonate, dipotassium phosphate, glycine, starch, preferably corn, starch or tapio-powered 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. A solid composition of the same kind can also be used in a gelatin capsule. Suitable substances in this connection include lactose or lactose, as well as high molecular weight polyethylene dallicol. If you want to use aqueous suspensions and Z or elixirs for oral administration, use the active ingredient in various sweeteners. In addition to flavoring, coloring, or dye, use with emulsifier and Z or suspending agent if necessary, and use with water, ethanol, propylene glycol, glycerin, etc., and diluents that combine them. be able to.

 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 dallicol solution can be used. The aqueous solution should be buffered as appropriate (preferably pH 8 or higher), and the liquid diluent must first be 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 readily 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 or ointments is desirable according to standard pharmaceutical practice.

 The dose of the therapeutic agent for neuropathic pain of the present invention is not particularly limited, and it is appropriately administered depending on 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 amount. The dosage of the therapeutic agent for neuropathic pain of the present invention is, for example, about 500 to 25000 mg, preferably 900 to 9000 mg per day for an adult (for example, body weight 6 O kg). When administered as an injection, the dosage is, for example, about 100 to .5000 mg, preferably 180 to 1800 mg per day for an adult (for example, body weight 6 O kg). These daily doses may be administered in two to four divided doses. Example

 EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not limited to these Examples at all.

 (Experimental materials used and general experimental methods)

 (1) Model animals

As an experimental animal, a neuropathic pain model prepared by completely ligating the L5 / L6 spinal nerve to a 6-week-old male rat was used. . (2) Grouping

The mechanical stimulation test was measured using the Dynamic Planter Aesthesiometer (37400, Ugobasil), and the thermal stimulation test was measured using the plantar thermal stimulation device (Planter test 7370, Ugobasil) to measure the pain threshold of the model animal's foot. were grouped with each experimental day clinical package Ver _s ion5.0 before as measured pain threshold is ^ one prior to the administration of (SAS Institute Japan). For mechanical stimulation, animals with a model foot pain threshold of 8.0 g or more were excluded from the study, and for thermal 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, after crushing the bulk powder using an agate mortar and pestle, gradually add 0.5w / v% sodium carboxymethylcellulose (CMC—Na) as a medium to obtain a uniform suspension. did. The concentration of the dosing solution was adjusted using a measuring cylinder or a measuring flask, and all adjustments were made before 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 to

 (Dexamethasone 21—Mesylate / Mechanical stimulation method)

Using male rats (311.7-409.9g) of neuropathic pain model in one group, the maximum pressure was 15.0g before dexamethasone 21-mesylate administration, 30 minutes, 60 minutes and 90 minutes after administration, The pain threshold of the left footpad was measured using a stimulator that set the time to reach maximum pressure to 20 seconds. The results are shown in Fig. 1. In the figure, “* *” indicates that Dunnett's multiple test method has a P difference of 0.01, and “*” indicates Dunnett's multiple test method has a P difference of 0.05 (the same applies hereinafter). As shown in Figure 1, the control group administered with 0.5 w / v% sodium carboxymethylcellulose (CMCNa) aqueous solution showed a maximum pain threshold of 5.5 g after administration, whereas dexamethasone 21-mesylate was administered. In the administered group: (a) 0.In the case of 3 mg / kg administration, the maximum threshold after administration is 6.3 g, (b) In the case of 3 mg / kg administration, the maximum threshold after administration is 8.7 g, (c) In the case of 30 mg / kg administration The later maximum threshold was 10.0 g. Thus, administration of dexamethasone 21-mesilei® significantly increased the pain threshold, confirming the analgesic effect in neuropathic pain. In the above-mentioned neuropathic pain model, allodynia that feels tactile stimulation that is not usually felt as pain occurs and the pain threshold decreases significantly, but the intraperitoneal administration of dexamethasone 21-mesylate does not exceed the pain threshold. It was confirmed that it increased in a dependent manner and improved the alodiure. Example 2

 (Dexamethasone 21 _ Mesylate · Thermal stimulation method)

 Male rats of neuropathic pain model (276. 6-446. 7g) were used in a group of 5 rats. Heat stimulation intensity was 35 minutes before administration of dexamethasone 21-mesylate, 30 minutes, 60 minutes and 90 minutes after administration. The pain threshold of the left footpad was measured using the plantar heat stimulator set to. The result is shown in Fig.2.

 As shown in Figure 2, 0.5w / vy. In the control group administered sodium carboxymethylcellulose (CMC-Na) aqueous solution, the maximum pain threshold after administration was 7.7 seconds, whereas in the group administered dexamethasone 21-mesylate, (a) 0 In the case of 3 mg / kg administration, the maximum threshold after administration is 7.3 seconds, (b) In the case of 3 mg / kg administration, the maximum threshold after administration is 9.9 seconds, (c) In the case of 30 mg / kg administration The maximum threshold after administration was 10.7 seconds.

 As a result, as in Example 1, administration of dexamethasone 21-mesylate significantly increased the pain threshold, confirming the analgesic effect in neuropathic pain. Comparative Example 1

 (Mif Everyston study · Mechanical stimulation method)

Five male rats (262.5-25-15.2 g) of neuropathic pain model were used in one group. Maximum pressure: 15.0 g, time to reach maximum pressure: 20 seconds before and after 30 min, 60 min and 90 min after administration The threshold was measured. The results are shown in Fig. 3. In the figure, “* *” indicates that there is a significant difference at P 0.01 by Dunnett's multiple test method, and “*” indicates that there is a significant difference at 0.05 by Dunnett's multiple test method (the same applies hereinafter). .

 As shown in Figure 3, 0.5w / vy. In the control group to which sodium carboxymethylcellulose sodium (CM C-Na) was administered, the maximum pain threshold after administration was 5.2 g, whereas in the group to which mif ヱ pristone was administered (a) 0.3 mg / kg The maximum threshold after administration is 6.0 g, (b) In the case of 3rag / kg administration, the maximum threshold after administration is 9.3 g, (c) In the case of 30 mg / kg administration, the maximum threshold after administration is 10.3 g. It was. Thus, the administration of mif ヱ pristone significantly increased the pain threshold at 3 mg and 30 mg, confirming the analgesic effect in neuropathic pain. Comparative Example 2

 (Mif Everyton study · Thermal stimulation method)

 Five male rats (284.2-380.9 g) of neuropathic pain model were used in one group. The pain threshold of the left footpad was measured using a plantar thermal stimulator set at 35, 60, and 90 minutes before and after administration of mifeverstone. The results are shown in Fig. 4.

 As shown in Figure 4, in the control group administered with 0.5 w / v% sodium carboxymethylcellulose (CM C-Na) aqueous solution: the maximum pain threshold after administration was 7.0 seconds, whereas the group administered mifbriston (A) In the case of 0.3 mg / kg administration, the maximum threshold after administration is 7.5 seconds, (b) In the case of 3 mg / kg administration, the maximum threshold after administration is 10.6 seconds, (c) In the case of 30 rag / kg administration The maximum threshold after administration was 11.6 seconds. Thus, administration of mifepristone significantly increased the pain threshold at 3 mg and 30 mg, confirming the analgesic effect in neuropathic pain.

 (Discussion)

The above examples revealed that a therapeutic agent for neuropathic pain containing a compound having a darcocorticoid receptor-specific antagonist as an active ingredient is effective for the treatment of neuropathic pain. Industrial available 'Ιί

As described above, the therapeutic agent for neuropathic pain containing the darcocorticoid receptor-specific antagonist of the present invention has the action of improving the symptoms of neuropathic pain caused by various causes. It can be effectively used for the treatment of sexual pain.

Claims

The scope of the claims 1. A therapeutic agent for neuropathic pain comprising a darcocorticoid receptor-specific antagonist as an active ingredient.  2. The darcocorticoid receptor-specific antagonist is 1,4-one predanagen — 9 α-funoleolone 16 α-methinore 1 1, 17 7, 2 1—triolone 1,3 2 0—dione 2 1—methane The therapeutic agent for neuropathic pain according to claim 1, which is sulfonate. - 3. Neuropathic pain includes postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, alodynia, post-thoracotomy pain, CRPS, multiple sclerosis 3. The symptom pain, AIDS, thalamic pain, spinal cord disorder, paraplegia, non-sensory pain, and neuropathic pain in phantom limb pain. For treating neuropathic pain.  4. A pharmaceutical composition for treating neuropathic pain comprising a darcocorticoid receptor-specific antagonist and a pharmaceutically acceptable carrier.  5. A method of treating neuropathic pain by administering an effective amount of a darcocorticoid receptor-specific antagonist to a mammal.  6. Use of a darcocorticoid receptor-specific antagonist for the manufacture of a therapeutic agent for neuropathic pain.