WO2006085686A1 - Médicament contre la douleur neurogène - Google Patents

Médicament contre la douleur neurogène Download PDF

Info

Publication number
WO2006085686A1
WO2006085686A1 PCT/JP2006/302778 JP2006302778W WO2006085686A1 WO 2006085686 A1 WO2006085686 A1 WO 2006085686A1 JP 2006302778 W JP2006302778 W JP 2006302778W WO 2006085686 A1 WO2006085686 A1 WO 2006085686A1
Authority
WO
WIPO (PCT)
Prior art keywords
pain
neuropathic pain
therapeutic agent
antagonist
pharmaceutically acceptable
Prior art date
Application number
PCT/JP2006/302778
Other languages
English (en)
Japanese (ja)
Inventor
Tsutomu Tanabe
Original Assignee
Japan Science And Technology Agency
Tokyo Medical And Dental University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Japan Science And Technology Agency, Tokyo Medical And Dental University filed Critical Japan Science And Technology Agency
Priority to JP2007502683A priority Critical patent/JPWO2006085686A1/ja
Publication of WO2006085686A1 publication Critical patent/WO2006085686A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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 for which opioid receptor agonists such as morphine do not sufficiently respond.
  • diseases associated with neuropathic pain include post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, and post-traumatic or post-traumatic prolonged pain. Can do.
  • central opioid receptor agonists such as morphine and nonsteroidal anti-inflammatory drugs (NSAIDs) such as indometacin are known.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • 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. .
  • 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.
  • 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.
  • 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 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
  • 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.
  • 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.
  • a therapeutic agent for neuropathic pain comprising a peroxisome proliferator-activated receptor (PPAR) antagonist as an active ingredient.
  • PPAR peroxisome proliferator-activated receptor
  • 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.
  • 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).
  • a pharmaceutical composition for treating neuropathic pain comprising a peroxisome proliferator-responsive receptor antagonist and a pharmaceutically acceptable carrier.
  • a method of treating neuropathic pain by administering an effective amount of a peroxisome proliferator-activated receptor antagonist to a mammal.
  • 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.
  • 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.
  • Peroxisome proliferator-activated receptor is one of the nuclear receptor superfamily and is known to be involved in lipid storage and catabolism. PPAR also has three subtypes, ⁇ , ⁇ , 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.
  • GW9662 2-chloro-5-nitro 1-N-phenylpenamide
  • 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.
  • PPARa selective antagonists there are three types of subtypes of PPARs (Hiichi, 13—, ⁇ -), and the “PPARa selective antagonists” in this document are selective antagonists to PPARa. That is, for PPAR and P PAR / 3, 006302778
  • 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.
  • 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.
  • 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.
  • GW9662 2-chloro-5-nitro-N-phenylbenzamide
  • T0070907 2-black mouth
  • 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.
  • 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.).
  • 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.
  • 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.
  • 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.
  • 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.
  • preparations suitable for oral administration include powders, tablets, capsules, fine granules, granules, solutions or syrups.
  • various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate, dalysin, starch, preferably corn, potato or starch ,
  • various disintegrants such as alginic acid and certain kainate double salts, and granulating binders such as polyvinylpyrrolidone, sucrose, gelatin, gum arabic.
  • 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.
  • preparations suitable for parenteral administration include injections and suppositories.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the maximum threshold after administration is 6.3 g
  • administration of GW9662 significantly increased the pain threshold at 3 mg and 30 mg, confirming analgesic effects in neuropathic pain.
  • 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Virology (AREA)
  • AIDS & HIV (AREA)
  • Surgery (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un médicament contre la douleur neurogène, une maladie réfractaire, dont l'effet thérapeutique est excellent. Plus spécifiquement, la présente invention concerne un médicament contre la douleur neurogène qui contient, au titre de principe actif, un antagoniste de PPAR (en particulier, un antagoniste sélectif de PPARϜ tel que le 2-chloro-5-nitro-N-phénylbenzamide), une préparation thérapeutique pour le traitement de la douleur neurogène qui contient, au titre de principe actif, un antagoniste de PPAR, une méthode de traitement de la douleur neurogène par le biais d'un antagoniste de PPAR, etc.
PCT/JP2006/302778 2005-02-10 2006-02-10 Médicament contre la douleur neurogène WO2006085686A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2007502683A JPWO2006085686A1 (ja) 2005-02-10 2006-02-10 神経因性疼痛治療剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005033900A JP4221383B2 (ja) 2005-02-10 2005-02-10 神経因性疼痛治療剤
JP2005-033900 2005-02-10

Publications (1)

Publication Number Publication Date
WO2006085686A1 true WO2006085686A1 (fr) 2006-08-17

Family

ID=36793240

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2006/302778 WO2006085686A1 (fr) 2005-02-10 2006-02-10 Médicament contre la douleur neurogène

Country Status (2)

Country Link
JP (2) JP4221383B2 (fr)
WO (1) WO2006085686A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011014600A1 (fr) 2009-07-30 2011-02-03 Aestus Therapeutics, Inc. Procédés de traitement d’une douleur neuropathique avec des agonistes de ppargamma dérivés de benzimidazole

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002332266A (ja) * 2000-04-28 2002-11-22 Sankyo Co Ltd ＰＰＡＲ−γモジュレータ
JP2004537525A (ja) * 2001-06-11 2004-12-16 メルク　エンド　カムパニー　インコーポレーテッド ＰＰＡＲδアゴニストの投与による炎症性疾患の治療法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002332266A (ja) * 2000-04-28 2002-11-22 Sankyo Co Ltd ＰＰＡＲ−γモジュレータ
JP2004537525A (ja) * 2001-06-11 2004-12-16 メルク　エンド　カムパニー　インコーポレーテッド ＰＰＡＲδアゴニストの投与による炎症性疾患の治療法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BENANI A. ET AL.: "Activation of peroxisome proliferator-activated receptor alpha in rat spinal cord after peripheral noxious stimulation", NEUROSCIENCE LETTERS, vol. 369, no. 1, 7 October 2004 (2004-10-07), pages 59 - 63, XP004565974 *
BURSTEIN S. ET AL.: "PPAR-gamma: A nuclear receptor with affinity for cannabinoids", LIFE SCIENCES, vol. 77, no. 14, 19 August 2005 (2005-08-19), pages 1674 - 1684, XP004997100 *
SEARGENT J.M. ET AL.: "GW9662, a potent antagonist of PPARgamma, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARgamma agonist rosiglitazone, independently of PPARgamma activation", BRITISH JOURNAL OF PHARMACOLOGY, vol. 143, no. 8, December 2004 (2004-12-01), pages 933 - 937, XP002992757 *
ZHAO Y. ET AL.: "Angiotensin II induces peroxisome proliferator-activated receptor gamma in PC12W cells via angiotensin type 2 receptor activation", JOURNAL OF NEUROCHEMISTRY, vol. 94, no. 5, September 2005 (2005-09-01), pages 1395 - 1401, XP002999642 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011014600A1 (fr) 2009-07-30 2011-02-03 Aestus Therapeutics, Inc. Procédés de traitement d’une douleur neuropathique avec des agonistes de ppargamma dérivés de benzimidazole

Also Published As

Publication number Publication date
JP2007332031A (ja) 2007-12-27
JP4221383B2 (ja) 2009-02-12
JPWO2006085686A1 (ja) 2008-06-26

Similar Documents

Publication Publication Date Title
JP3221611B2 (ja) 物質乱用障害の治療用医薬組成物
JP2010265316A (ja) 痛みを緩和するための新規な方法および組成物
WO2013029762A1 (fr) Dérivés de morphinane destinés au traitement du diabète et de troubles associés
WO2008057930A2 (fr) Méthodes destinées à traiter la douleur neuropathique à l'aide d'agonistes des récepteurs de l'acide rétinoïque
TW201136916A (en) New uses
JP2010280585A (ja) Ｒｘｒ作動性物質を有効成分とする鎮痛剤
CA3133589A1 (fr) Methode de traitement de l'hypertension arterielle pulmonaire et hypertension arterielle pulmonaire associee et posologie quotidienne
JPWO2008020651A1 (ja) Ｐ２ｘ４受容体アンタゴニスト
JP2006131545A (ja) 神経因性疼痛治療剤
US6537991B1 (en) Method of treating a peripheral neuropathic pain
CA2852142A1 (fr) Posologie pour un modulateur ou un agoniste du recepteur s1p
WO2006085686A1 (fr) Médicament contre la douleur neurogène
AU2021349680B2 (en) Use of sphingosine-1-phosphate receptor agonist
WO2005102331A1 (fr) Agent thérapeutique pour ostéoporose
JP4587961B2 (ja) 神経因性疼痛治療剤
JP4428481B2 (ja) 神経因性疼痛治療剤
JP4104986B2 (ja) 前立腺肥大症に伴う膀胱刺激症状治療剤
JP4362457B2 (ja) 神経因性疼痛治療剤
JP4222614B2 (ja) 神経因性疼痛治療剤
WO2007026928A1 (fr) Agent therapeutique pour une douleur neuropathique
JP4227121B2 (ja) 神経因性疼痛治療剤
WO2007043365A1 (fr) Agent thérapeutique contre la douleur neurogène
WO2006115304A1 (fr) Agent servant à traiter la douleur neuropathique
WO2022051503A1 (fr) Procédés d'administration d'inhibiteurs de glutaminase
WO2003097023A1 (fr) Utilisation du transmetteur de l'inhibiteur de l'acide $g(g)-aminobutyrique (gaba) dans la preparation d'analgesiques

Legal Events

Date Code Title Description
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2007502683

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06713919

Country of ref document: EP

Kind code of ref document: A1