JP4222614B2 - Neuropathic pain treatment - Google Patents

Description

  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.

  Neuropathic pain is pain caused by damage or dysfunction of the peripheral nervous system or central nervous system, and is intractable pain that does not sufficiently respond even to opioid drugs such as morphine. Examples of the disease accompanied by neuropathic pain include diseases that exhibit hyperalgesia and allodynia such as postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, prolonged pain after surgery or trauma.

  As analgesics that have been used in conventional pharmacotherapy, central opioid analgesics represented by morphine, nonsteroidal anti-inflammatory drugs (NSAIDs) represented by indomethacin, and the like are known. 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. ing. Inadequate analgesic effect of narcotic analgesics on neuropathic pain is a major feature of neuropathic pain. In some cases, neuropathic pain is diagnosed using this feature.

  Various factors are thought to be intricately related to the development of neuropathic pain. So far, neuropathic pain has been treated by nerve block, neurosurgery such as spinal epidural electrical stimulation, tricyclic antidepressants, intrathecal administration of drugs such as baclofen, etc. Are known. However, these treatment methods have problems that a sufficient effect cannot be obtained and there are side effects. In addition, as a topical agent, capsaicin cream has been reported to be effective in postherpetic neuralgia and pain syndrome after mastectomy by depleting pain substance substance P released from nerve terminals and reducing pain. is there. However, there are problems in terms of usefulness and safety, such as the problem of burning pain caused by capsaicin. Thus, neuropathic pain is an intractable disease, and an effective treatment method has not yet been established.

These monoaminergic neurotransmitters, such as catecholamine (generic name for dopamine, norepinephrine, and epinephrine), serotonin, and histamine, are considered to be strongly related to pain, and many reports have been published so far. .
Histamine has a function as a neurotransmitter and neuromodulator, has been shown to work in the central nervous system and peripheral nervous system, and is involved in the regulation of blood pressure and pain.
Serotonin has more than 90% of the body's serotonin in the gastrointestinal mucosa and forms the serotonin nervous system in the gastrointestinal tract and the intestinal nervous system around the blood vessels, but the nervous system is also found in the raphe nucleus of the brainstem. The brain's serotonin nervous system serves as a neurotransmitter related to mood, sleep, appetite, body temperature, pain, blood pressure and vomiting.

And catecholamines produced in the tyrosine->dopa->dopamine->norepinephrine-> epinephrine pathway also play various roles in physiological responses. Dopamine is a precursor of norepinephrine, but its action as a neurotransmitter dilates the blood vessels of the kidneys, causes relaxation of the intestinal smooth muscle, and also affects blood pressure via the epinephrine receptor. Yes. Epinephrine is related to metabolic systems such as blood pressure, smooth muscle, and pancreas, and norepinephrine is also referred to as an alarm system in the brain. When this becomes abnormal, various stress-related disorders occur.
Thus, since these physiologically active amines express physiological actions via various receptor subtypes, for example, drugs (agonists) that specifically act on certain receptor subtypes, Drugs that specifically antagonize the action (antagonists) or drugs that block the action (blockers) were expected to have an effect on neuropathic pain.

  For example, antidepressants are already used primarily as an analgesic aid in the treatment of chronic pain. However, most of the tricyclic and tetracyclic antidepressants referred to as the first and second generations have an inhibitory effect on the reuptake of both serotonin and norepinephrine, but are non-selective and anticholine. It has been found to have many side effects such as dry mouth due to action, constipation, dysuria, drowsiness due to blurred vision or antihistamine action, or orthostatic hypotension due to anti-adrenergic α1 action. There is also a method for treating chronic pain using SSRI (selective serotonin reuptake inhibitor), which is said to be a third-generation antidepressant (Patent Document 1), but in general, sleepiness, nausea, dry mouth, constipation May cause psychotic symptoms such as hypertension, hallucinations, delusions, sometimes hypersensitivity, hematopoietic disorders, liver disorders, and other antipsychotics in combination with strong muscle tonicity, difficulty swallowing, tachycardia, fever, or tranquilizers When used in combination with this drug, there is a risk of side effects called serotonin syndrome due to abnormally increased serotonin activity in the brain, such as ventricular arrhythmia and other cardiovascular side effects. And The fourth-generation SNRI (serotonin / norepinephrine reuptake inhibitor), which is said to have the least side effects, generally has sleepiness, nausea, dry mouth, constipation, etc. Has the side effects of being prone to convulsions, leukopenia and glaucoma. As with SSRI, there are many interactions with concomitant drugs, so handling with sufficient care is necessary.

In addition, there are some known methods for reducing or improving pain by using a compound that acts on a monoaminergic neurotransmitter (Japanese Patent Publication No. 2004-513916 (Patent Document 1); Japanese Patent Publication No. 9-511739). Publication (Patent Document 2); JP-T 2002-523366 (Patent Document 3); JP-T 2002-537245 (Patent Document 4); JP-T 2000-507544 (Patent Document 5)).
For example, Japanese Patent Publication No. 9-511739 and Japanese Patent Publication No. 2002-537245 disclose serotonin (5-HT3) receptor antagonists for non-inflammatory local diseases, fibromyalgia (fibromyalgia) and the like. It is described to use. JP-T-2002-523366 (Patent Document 3) describes the use of dopamine reuptake inhibitors for various functional disorders including pain.
JP-T-2000-507544 (Patent Document 5) describes a combination of an atypical antipsychotic drug (clozapine, risperidone, quetiapine, perospirone, olanzapine, etc.) and a drug used for pain. Furthermore, JP-T-2002-503224 (Patent Document 6) describes serotonin reuptake inhibitors, combined serotonin-norepinephrine reuptake inhibitors, serotonin receptor agonists and antagonists as synergistic analgesics. .

On the other hand, phenylethanolamine N-methyltransferase (PNMT) is an enzyme that catalyzes the biosynthesis of epinephrine from norepinephrine, which is the last step in the catecholaminergic system, and plays an important role in blood pressure regulation and neuroendocrine function. Yes.
However, to date, what has been shown that PNMT inhibitors, typified by (±) -2,3-dichloro-α-methylbenzylamine (DCMB), are effective against refractory neuropathic pain. Neither listed nor suggested.
Special Table 2004-513916 Japanese National Patent Publication No. 9-511739 Special Table 2002-523366 Special Table 2002-537245 Special Table 2000-507544 Special Table 2002-503224

  As described above, there are currently no known drugs effective for the treatment of neuropathic pain, and the development of such drugs is desired. In such a situation, 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 have conducted research based on an original idea to achieve the above-mentioned problems. As a result, in a refractory neuropathic pain model, a PNMT (phenylethanolamine N-methyltransferase) inhibitor typified by DCMB Was found to show a high analgesic effect, and the present invention was completed.
That is, the present invention provides the following therapeutic agents for neuropathic pain, pharmaceutical compositions for treating neuropathic pain, methods for treating neuropathic pain, and the like.

(1) A therapeutic agent for neuropathic pain comprising a phenylethanolamine N-methyltransferase (PNMT) inhibitor as an active ingredient.
(2) The PNMT inhibitor is
(±) -2,3-dichloro-α-methylbenzylamine ((±) -2,3-dichloro-alpha-methylbenzylamine: DCMB);
8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine);
7,8-dichloro-1,2,3,4-tetrahydroisoquinoline;
2-cyclooctyl-2-hydroxyethylamine;
(±) -7-Aminosulfonyl-3-fluoromethyl-1,2,3,4-tetrahydroisoquinoline ((±) -7-Aminosulfonyl-3-fluoromethyl-1,2,3,4-tetrahydroisoquinoline);
(±) -3-Fluoromethyl-7- (N-2,2,2-trifluoroethylaminosulfonyl) -1,2,3,4-tetrahydroisoquinoline ((±) -3-Fluoromethyl-7- (N -2,2,2-trifluoroethylaminosulfonyl) -1,2,3,4-tetrahydroisoquinoline);
(±) -3-Fluoromethyl 1-7- (N-3,3,3-trifluoropropylaminosulfonyl) -1,2,3,4-tetrahydroisoquinoline)
((±) -3-Fluoromethyl-7- (N-3,3,3-trifluoropropylaminosulfonyl) -1,2,3,4-tetrahydroisoquinoline); and the above selected from pharmaceutically acceptable salts thereof ( 1) The neuropathic pain therapeutic agent according to 1).
(3) The neurogenicity according to the above (2), wherein the PNMT inhibitor is selected from (±) -2,3-dichloro-α-methylbenzylamine (DCMB) and pharmaceutically acceptable salts thereof. Pain treatment agent.

(4) Neuropathic pain is postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, allodynia, post-thoracotomy pain, CRPS, multiple The above (1) to (3), which are one or more symptoms selected from pain due to sclerosis, AIDS, thalamic pain, paraplegic pain 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.
(5) A pharmaceutical composition for treating neuropathic pain comprising a phenylethanolamine N-methyltransferase (PNMT) inhibitor and a pharmaceutically acceptable carrier.
(6) A method of treating neuropathic pain by administering an effective amount of a phenylethanolamine N-methyltransferase (PNMT) inhibitor to a mammal.
(7) Use of a phenylethanolamine N-methyltransferase (PNMT) inhibitor for the manufacture of a therapeutic agent for neuropathic pain.

  The therapeutic agent for neuropathic pain of the present invention containing a PNMT inhibitor as an active ingredient includes postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, etc. It is effective in the treatment of neuropathic pain with the symptoms of

Hereinafter, the present invention will be described in detail.
The present invention relates to a therapeutic agent for neuropathic pain containing a PNMT (phenylethanolamine N-methyltransferase) inhibitor as an active ingredient, a PNMT inhibitor, and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating neuropathic pain using a PNMT inhibitor is provided. DCMB ((±) -2,3-dichloro-α-methylbenzylamine) is well known as a specific inhibitor of PNMT, but surprisingly, the present inventor has identified DCMB as this PNMT inhibitor. For the first time was found to have a therapeutic effect on neuropathic pain alone. In particular, it has been known that alleviation and improvement of pain with compounds acting on certain monoaminergic neurotransmissions (serotonin (5-HT3) receptor antagonists, dopamine reuptake inhibitors), but PNMT inhibitors A DCMB was not thought to have any analgesic action. Therefore, there is no report which examined the pain suppression effect by DCMB until now in the neuropathic pain model. Such a fact is proof of the originality of the present invention.

In the present specification, a “phenylethanolamine N-methyltransferase (PNMT) inhibitor” is a compound that inhibits the action of an enzyme that catalyzes the biosynthesis of epinephrine from norepinephrine, which is the final step in the catecholaminergic system. Means. The epinephrine biosynthesis inhibitory action can be confirmed by a known method, for example, the method described in Endocrinology Vol. 141, No. 3 1142-1150 (2000).
The term “treatment” as used herein generally means ameliorating the symptoms of humans and non-human mammals. 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. Further, the term “pharmaceutical composition” means a composition containing an active ingredient useful in the present invention (such as DCMB) and an additive such as a carrier used in the preparation of a medicament.

As a PNMT (phenylethanolamine N-methyltransferase) inhibitor preferably used in the present invention, for example,
(±) -2,3-dichloro-α-methylbenzylamine (DCMB: this hydrochloride is LY-78335);
8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (LY-134046);
7,8-dichloro-1,2,3,4-tetrahydroisoquinoline (SKF 64139);
2-cyclooctyl-2-hydroxyethylamine (preferably its hydrochloride salt (UK-1187A));
(±) -7-aminosulfonyl-3-fluoromethyl-1,2,3,4-tetrahydroisoquinoline;
(±) -3-fluoromethyl-7- (N-2,2,2-trifluoroethylaminosulfonyl) -1,2,3,4-tetrahydroisoquinoline (preferably its hydrochloride salt);
(±) -3-Fluoromethyll-7- (N-3,3,3-trifluoropropylaminosulfonyl) -1,2,3,4-tetrahydroisoquinoline (preferably its hydrochloride) and their pharmaceuticals Examples of acceptable salts. Among these PNMT inhibitors, DCMB is particularly preferable.
The above-mentioned PNMT inhibitors are known, and are described in Merck Index (The Merck Index, 13 ^th Edition (2001), various literatures, pharmacological reference books (for example, The pharmacological basis of therapeutics 9 ^th Edition, McGraw Hill), etc. In particular, DCMB is commercially available, and can be obtained from, for example, Sigma-Aldrich, and DCMB can be confirmed on the company's website for its physicochemical properties and related main literature.

  In the present specification, the term “containing a phenylethanolamine N-methyltransferase (PNMT) inhibitor as an active ingredient” means a compound known as a PNMT inhibitor and a pharmaceutically acceptable form of the compound. (E.g., its salts, esters, amides, hydrated or solvated forms, racemic mixtures, optically pure forms, prodrugs, etc.) are used to encompass all uses.

  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 the acid salt include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, acetate, lactate, citrate, Acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate , P-toluenesulfonate, 1,1′-methylene-bis- (2-hydroxy-3-naphthoic acid) salt, and the like. Examples of the base salt include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, water-soluble amine addition salts such as ammonium salts and N-methylglucamine salts, and lower alkanols. Mention may be made of ammonium 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, allodynia, 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, and the like. In addition, fibromial gear (fibromyalgia), which has much in common with postherpetic neuralgia in the pathological state, can be expected to have a therapeutic effect.

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

  Examples of pharmaceutically acceptable carriers or additives include excipients, disintegrants, disintegration aids, binders, lubricants, coating agents, dyes, diluents, solubilizers, solubilizers, isotonic agents. Agents, pH adjusters, stabilizers and the like can be used.

  Examples of preparations suitable for oral administration include powders, tablets, capsules, fine granules, granules, liquids or syrups. For oral administration, various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate, glycine are added to starch, preferably corn, potato or tapioca starch, and alginic acid and certain species. It can be used with various disintegrants such as silicate 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. When an aqueous suspension and / or elixir is desired for oral administration, the active ingredient is used in combination with various sweeteners, flavors, colorants or dyes, and if necessary, an emulsifier and / or suspending agent is also used. And can be used with water, ethanol, propylene glycol, glycerin, and the like, and diluents that combine them.

  Examples of preparations suitable for parenteral administration include injections and suppositories. In the case of parenteral administration, a solution in which the active ingredient of the present invention is dissolved in either sesame oil or peanut oil or dissolved in an aqueous propylene glycol solution can be used. The aqueous solution should be appropriately buffered as necessary (preferably pH 8 or more), 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 these solutions can be prepared aseptically by standard pharmaceutical techniques well known to those skilled in the art. Furthermore, the active ingredient of the present invention can also 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 dose of the therapeutic agent for neuropathic pain of the present invention is not particularly limited, and is appropriately administered 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 amount. The dose of the therapeutic agent for neuropathic pain of the present invention is, for example, about 100 to 25000 mg, preferably 150 to 9000 mg per day for an adult (for example, body weight 60 kg). The dose when administered as an injection is, for example, about 100 to 5000 mg, preferably 180 to 1800 mg per day for an adult (for example, body weight 60 kg). These daily doses may be administered in two to four divided doses.

EXAMPLES 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 animal As an experimental animal, a pain hypersensitivity model prepared by completely ligating the L5 / L6 spinal nerve to a 6-week-old male rat (weight: 196.2 to 221.9 g) was used.
(2) Grouping Use the Dynamic Planter Aesthesiometer (37400, Ugo Basil) for the mechanical stimulation test, and the plantar pain stimulation threshold (Planter test 7370, Ugo Basil) for the thermal stimulation test. Each was measured and divided into groups using Preclinical Package Version 5.0 (SAS Institute Japan) so that the pain threshold measured before administration on each experimental day was uniform. For mechanical stimulation, animals with a model animal's foot pain threshold of 8.0 g or more were excluded from the test, and for thermal stimulation, animals with a model foot pain threshold of 10 seconds or more were excluded from the test.

(3) Preparation of test substance A necessary amount of the test substance was weighed and dissolved in a physiological saline solution as a medium to prepare a 3 mg / ml solution having the highest concentration. Each concentration of the administration solution was prepared by diluting the preparation solution of each maximum dose with a medium, and was prepared at the time of use.
(4) Administration method The test substance is intended to confirm the direct action on the spinal cord, but since it has been confirmed that it passes through the brain barrier, it was administered intraperitoneally as a simple administration method. Administration was carried out intraperitoneally at a volume of 10 ml / kg using a syringe barrel and a needle.

(Mechanical stimulation method)
A group of 5 male rats (344.2-436.9g) of hypersensitivity pain group. Maximum pressure: 15.0 g before 20 minutes, 40 minutes and 60 minutes after administration of DCMB ((±) -2,3-dichloro-α-methylbenzylamine), time to reach maximum pressure: 20 seconds The pain threshold of the left footpad was measured using the stimulator. The result is shown in FIG. In the figure, “**” indicates that there is a dominant difference at P <0.01 by Dunnett's multiple test method, and “*” indicates that there is a dominant difference at P <0.05 by Dunnett's multiple test method (the same applies hereinafter).
As shown in FIG. 1, in the control group to which physiological saline was administered, the maximum pain threshold after administration showed 5.7 g, whereas in the group to which DCMB was administered (a) in the case of 0.3 mg / kg administration, When the maximum threshold after administration was 6.3 g, (b) 3 mg / kg administration, the maximum threshold after administration was 8.9 g, and (c) 30 mg / kg administration, the maximum threshold after administration was 12.0 g. Thus, administration of DCMB significantly increased the pain threshold at 3 mg / kg and 30 mg / kg, confirming the analgesic effect in neuropathic pain.

(Thermal stimulation method)
A group of 5 male rats (367.4 to 485.4 g) of hypersensitivity pain group. The pain threshold of the left footpad was measured using a plantar thermal stimulator set to a thermal stimulation intensity of 35 before administration of DCMB and at 20, 40 and 60 minutes after administration. The result is shown in FIG.
As shown in FIG. 2, in the control group to which physiological saline was administered, the maximum pain threshold after administration was 7.5 seconds, whereas in the group to which DCMB was administered, (a) 0.3 mg / kg was administered. The maximum threshold after administration was 7.9 seconds, (b) In the case of 3 mg / kg administration, the maximum threshold after administration was 9.4 seconds, (c) In the case of 30 mg / kg administration, the maximum threshold after administration was 11.4 seconds . Thus, administration of DCMB significantly increased the pain threshold at the dose of 10 mg / kg, confirming the analgesic effect in neuropathic pain.

  As described above, since the therapeutic agent for neuropathic pain containing a PNMT inhibitor such as DCMB of the present invention has an action of improving the symptoms of neuropathic pain due to various causes, the treatment of neuropathic pain Can be used effectively.

FIG. 1 is a diagram showing the experimental results of Example 1, and shows changes in pain threshold to mechanical stimulation when DCMB was intraperitoneally administered to hypersensitive rats. FIG. 2 is a diagram showing the experimental results of Example 2, in which DCMB was intraperitoneally administered to pain-sensitive rats and the change in pain threshold with respect to thermal stimulation was shown.

Claims (4)

A therapeutic agent for neuropathic pain comprising (±) -2,3-dichloro-α-methylbenzylamine (DCMB) or a pharmaceutically acceptable salt thereof as an active ingredient. The active ingredient, (±) -2,3- therapeutic agent for neuropathic pain of claim 1 dichlorophen -α- methylbenzylamine. Neuropathic pain is due to postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, allodynia, post-thoracotomy pain, CRPS, multiple sclerosis The neuropathy according to claim 1 or 2 , wherein the neuropathy is one or more symptoms selected from pain, AIDS, thalamic pain, paraplegia due to spinal cord disorder, non-sensory pain, and neuropathic pain in phantom limb pain. Pain treatment agent. Pharmaceutical composition for treating neuropathic pain comprising (±) -2,3-dichloro-α-methylbenzylamine (DCMB) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier .

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