JP4227121B2 - 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 refractory pain to which opioid receptor agonists such as morphine do not sufficiently respond. 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 drug therapy, central opioid receptor agonists typified by morphine, nonsteroidal anti-inflammatory drugs (NSAIDs) typified 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.

On the other hand, casein kinase is a kind of protein kinase that phosphorylates serine / threonine. Casein kinase 1 (CKI, CK1, or CK-1) and casein kinase 2 (CKII, CK2, or CK-2) are two types. Exists. Both are named because they phosphorylate casein in an in vitro experiment, but they are structurally distinct proteins that do not phosphorylate milk proteins in the mammary gland in vivo. Casein kinase 1 has seven types of isotypes, showing a wide range of localization in the cell membrane, cytoplasm, and nucleus, and regulating various biological functions such as DNA repair, circadian rhythm regulation, nerve firing and development, etc. It is becoming clear that it plays an important role.
So far, casein kinase has been reported in several literatures. For example, JP 2003-156489 (Patent Document 1) lists casein kinase 2β subunit as a target molecule for identification and use of molecules associated with pain. In Japanese translation of PCT 2004-536957 (Patent Document 2), “pain” is mentioned as a part of “disorders related to CK1” in a method for screening a drug for treating a disease or disorder caused by abnormal regulation of CK1. Yes. Furthermore, in Special Table 2004-538323 (Patent Document 3), “Migraine” and “Pain” are recognized as one of “CK1-related disorders”, and in Special Table 2004-537962 (Patent Document 4) Casein kinase 1a is expressed as a pain regulator.
However, the “pain” described in Patent Documents 1 to 4 is normal pain, and there is no description regarding neuropathic pain which is “pain” having a mechanism completely different from these.
Special Table 2003-156489 Special Table 2004-536957 Publication Special Table 2004-538323 Publication Special table 2004-537962 gazette

  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 problem. As a result, the present inventors have found that a casein kinase 1 inhibitor exhibits a high analgesic effect in an intractable neuropathic pain model. 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 casein kinase 1 inhibitor as an active ingredient.
(2) The casein kinase 1 inhibitor is N- (2-aminoethyl) -5-chloro-isoquinoline-8-sulfonamide (CKI-7), 1- (5-chloro-8-isoquinolinesulfonyl) -piperazine ( CKI-8) 1,3-dihydro-3- (2,4,6-trimethoxyphenylmethylene) -2H-indol-2-one (IC261) and their pharmaceutically acceptable salts, The therapeutic agent for neuropathic pain according to (1) above.
(3) The neurogenicity according to (2) above, wherein the casein kinase 1 inhibitor is N- (2-aminoethyl) -5-chloro-isoquinoline-8-sulfonamide or a pharmaceutically acceptable salt 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 casein kinase 1 inhibitor and a pharmaceutically acceptable carrier.
(6) A method of treating neuropathic pain by administering an effective amount of a casein kinase 1 inhibitor to a mammal.
(7) Use of a casein kinase 1 inhibitor for the manufacture of a therapeutic agent for neuropathic pain.

  The therapeutic agent for neuropathic pain of the present invention is post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, allodynia, and other neuropathic pain It is effective for the treatment.

Hereinafter, the present invention will be described in detail.
The present invention relates to a therapeutic agent for neuropathic pain comprising a casein kinase 1 inhibitor as an active ingredient, a pharmaceutical composition for the treatment of neuropathic pain comprising a casein kinase 1 inhibitor and a pharmaceutically acceptable carrier, Methods of treating neuropathic pain using casein kinase 1 inhibitors are provided. It has been known that casein kinase 1 is involved in circadian rhythm regulation, nerve firing, development, normal “pain”, etc. Surprisingly, the present inventor has shown that casein kinase 1 inhibitor It has been found for the first time that it has a therapeutic effect on neuropathic pain that is completely different from normal pain.

Casein kinase is a kind of protein kinase that phosphorylates serine / threonine, and two types of casein kinase 1 (CKI, CK1, or CK-1) and casein kinase 2 (CKII, CK2, or CK-2). It has been known. Both of them are named because they phosphorylate casein in an in vitro experiment, but they are structurally completely different proteins (Reference: Trends in Pharmacol. Sci. 23: 337-343 (2002)). In the present invention, casein kinase 1 inhibitor is used as an active ingredient. In the present specification, the “casein kinase 1 inhibitor” means a substance having a selective inhibitory action against casein kinase 1, and has a stronger inhibitory activity (for example, compared to actions on other protein kinases (for example, 50% inhibitory concentration (IC ₅₀ value) is 1/2 or less, more preferably 1/10 or less).
The casein kinase 1 inhibitory activity used in the present invention is a known method, for example, J. Biol. Chem. 264: 4924-4927 (1989).
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. Furthermore, the term “pharmaceutical composition” means a composition containing an active ingredient (such as CKI-7) useful in the present invention and an additive such as a carrier used in the preparation of a medicament.

  Examples of the casein kinase 1 inhibitor used in the present invention include N- (2-aminoethyl) -5-chloro-isoquinoline-8-sulfonamide (CKI-7), 1- (5-chloro-8-isoquinoline). Sulfonyl) -piperazine (CKI-8), 1,3-dihydro-3- (2,4,6-trimethoxyphenylmethylene) -2H-indol-2-one (IC261) and pharmaceutically acceptable salts thereof Is mentioned.

  A particularly preferred casein kinase 1 inhibitor used in the present invention is N- (2-aminoethyl) -5-chloro-isoquinoline-8-sulfonamide (CKI-7) or a pharmaceutically acceptable salt thereof. CKI-7 is a compound developed by De Western Therapeutics Laboratories. All of the above compounds are known. Biol. Chem. 264: 4924-4927 (1989) and the like, the chemical structure, physicochemical properties, and related main literatures are described.

  In the present specification, the term “containing a casein kinase 1 inhibitor as an active ingredient” refers to a compound known as a casein kinase 1 inhibitor and a pharmaceutically acceptable form of this compound (for example, a salt thereof, Ester, amide, hydrated or solvated form, racemic mixture, optically pure form, 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 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 disorder, non-sensory pain, neuropathic pain in phantom limb pain, and the like. The therapeutic agent for neuropathic pain of the present invention is particularly effective for the treatment of hyperalgesia and allodynia.

  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. The casein kinase 1 inhibitor, which is an active ingredient of the therapeutic agent for neuropathic pain of the present invention, may be incorporated alone, but a pharmaceutically acceptable carrier or a pharmaceutical additive is blended with the casein kinase 1 inhibitor. It can also be provided in the form. In this case, the casein kinase 1 inhibitor, which is the 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 (active ingredient amount) of the therapeutic agent for neuropathic pain of the present invention is not particularly limited, and may vary depending on various conditions such as pain type, patient age and symptoms, administration route, purpose of treatment, presence or absence of concomitant drugs. It is possible to select an appropriate dose accordingly. The dose of the therapeutic agent for neuropathic pain of the present invention is, for example, about 50 to 8000 mg, preferably 100 to 2000 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: 191.3 to 239.3 g) was used.
(2) Grouping Use the Dynamic Planter Aesthesiometer (37400, Ugo Basil) for the mechanical stimulation test, and the plantar pain stimulation device (Planter test 7370, Ugo Basil) for the thermal stimulation test. Each was measured and divided into groups 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 the test substance For the test substance, after crushing the raw powder using an agate mortar and pestle, gradually add 0.5w / v% sodium carboxymethylcellulose (CMC-Na) as a medium to make it uniform Suspension. The concentration adjustment of the administration solution (0.06, 0.6 and 6.0 mg / ml solutions) was carried out using a graduated cylinder or volumetric 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 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 5 ml / kg using a syringe barrel and a needle.

(Mechanical stimulation method)
Use male rats (290.1-348.2g) of hypersensitivity model in 1 group. The pain threshold of the left footpad was measured using a stimulator set at a maximum pressure of 15.0 g and a time to reach the maximum pressure of 20 seconds before and 30 minutes, 60 minutes and 90 minutes after administration. 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 administered with physiological saline, the maximum pain threshold after administration was 5.4 g, whereas in the group administered with CKI-7, (a) 0.3 mg / kg was administered. In this case, the maximum threshold after administration is 6.3 g, (b) 3 mg / kg administration, the maximum threshold after administration is 9.9 g, (c) 30 mg / kg administration, the maximum threshold after administration is 12.8 g It was. Thus, administration of CKI-7 significantly increased the pain threshold with administration of 3 mg and 30 mg, confirming the analgesic effect in neuropathic pain.

(Thermal stimulation method)
A group of 5 male rats (330.3-406.1g) of hypersensitivity pain group. The pain threshold of the left footpad was measured using a plantar thermal stimulator set at a thermal stimulation intensity of 35 before administration of CKI-7 and at 30, 60 and 90 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 7.0 seconds, whereas in the group to which CKI-7 was administered, (a) 0.3 mg / kg was administered. In this case, the maximum threshold after administration is 8.4 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 threshold after administration is 11.3 seconds. Indicated. As described above, administration of CKI-7 significantly increased the pain threshold at any of 0.3, 3 mg / kg and 30 mg / kg, confirming the analgesic effect in neuropathic pain.
(Discussion)
The above examples demonstrated that casein kinase 1 inhibitors are effective in treating neuropathic pain.

As described above, the therapeutic agent for neuropathic pain containing the casein kinase 1 inhibitor of the present invention has the effect of improving the symptoms of neuropathic pain due to various causes, and thus is used for the treatment of neuropathic pain. It can be used effectively.

FIG. 1 is a diagram showing the experimental results of Example 1, and shows changes in the pain threshold to mechanical stimulation when CKI-7 was intraperitoneally administered to rats with hypersensitivity. FIG. 2 is a diagram showing the experimental results of Example 2, and shows changes in the pain threshold to heat stimulation when CKI-7 was intraperitoneally administered to rats with hypersensitivity.

Claims (3)

A therapeutic agent for neuropathic pain comprising N- (2-aminoethyl) -5-chloro-isoquinoline-8-sulfonamide or a pharmaceutically acceptable salt thereof as an active ingredient.   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 4. The method according to claim 1, wherein the symptom 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. For treating neuropathic pain. Pharmaceutical composition for the treatment of neuropathic pain comprising N- (2-aminoethyl) -5-chloro-isoquinoline-8-sulfonamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier object.