WO2022114122A1 - 神経障害性疼痛を緩和させるための医薬 - Google Patents

神経障害性疼痛を緩和させるための医薬 Download PDF

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WO2022114122A1
WO2022114122A1 PCT/JP2021/043375 JP2021043375W WO2022114122A1 WO 2022114122 A1 WO2022114122 A1 WO 2022114122A1 JP 2021043375 W JP2021043375 W JP 2021043375W WO 2022114122 A1 WO2022114122 A1 WO 2022114122A1
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receptor
hydroxymethyl
tetrahydroquinoline
carboxamide
fluoro
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French (fr)
Japanese (ja)
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陽介 今井
光 山本
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Asahi Kasei Pharma Corp
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Asahi Kasei Pharma Corp
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Priority to EP21898094.4A priority Critical patent/EP4272758A4/en
Priority to AU2021389409A priority patent/AU2021389409A1/en
Priority to CA3198258A priority patent/CA3198258A1/en
Priority to MX2023006289A priority patent/MX2023006289A/es
Priority to KR1020237017766A priority patent/KR20230096055A/ko
Priority to US18/254,270 priority patent/US20240009180A1/en
Priority to IL302972A priority patent/IL302972A/en
Priority to CN202180080359.2A priority patent/CN116782901A/zh
Priority to JP2022565447A priority patent/JPWO2022114122A1/ja
Publication of WO2022114122A1 publication Critical patent/WO2022114122A1/ja
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants

Definitions

  • the present invention relates to a drug or the like for alleviating neuropathic pain.
  • neuropathic pain There are various methods for classifying pain, one of which is the classification based on the cause, and it is divided into nociceptive pain, neuropathic pain, and psychogenic pain. Other categories include, for example, chronic pain and acute pain. Neuropathic pain is a general term for pain caused by neuropathy.
  • Neuropathic pain is generally defined as "pain caused by lesions or disorders of the somatic sensory nervous system” and lesions or disorders are present in any of the nociceptive signaling pathways from the peripheral nerves to the cerebral. It is known that it occurs when the disease occurs (Non-Patent Document 1).
  • Neuropathic pain is broadly divided into peripheral neuropathic pain and central neuropathic pain depending on the site of nerve injury, and the causes are nutritional metabolic, traumatic, ischemic, addictive, hereditary, and infectious diseases. , Compression / strangulation, immunity, neoplastic, degenerative diseases, etc. are known.
  • Neuropathic pain includes Post-Tracic Neuralgia (PHN), Post-traumatic Peripheral Neuropathic Pain, Diabetic Neuropathic Pain (Diabetic Neuro) Trigeminal Neuropathic Pain (TGN), post-spine injury pain (Neuropathic Pain After Spinal Code Industry), chemotherapy-induced peripheral neuropathic pain (Chemotherapy-Induced Nipla) It is known (Non-Pain Document 1).
  • Diabetic Peripheral Neuropathy is a general term for various peripheral neuropathy found in diabetic patients, and is a peripheral neuropathy caused by insufficient insulin action or chronic hyperglycemic state. Diabetic peripheral neuropathy is thought to develop as two major factors, peripheral nerve metabolism disorder and angiopathy caused by hyperglycemia. Hypotheses such as the theory of neuroischemia due to abnormalities and microangiopathy have been proposed (Non-Patent Document 2).
  • Non-Patent Document 3 Pregabalin and gabapentin are known as drugs for neuropathic pain. By binding to the voltage-gated calcium channel ⁇ 2 ⁇ subunit, they cause a decrease in central sensitivity and nociceptive transmission (Non-Patent Document 3).
  • TCA tricyclic antidepressants
  • serotonin-norepinephrine reptake Inhibitors such as duloxetine and venlafaxine may also be drug therapy options for neuropathic pain.
  • Non-Patent Document 3 capsaicin and opioids such as tramadol and tapentadol are also known to be useful in neuropathic pain.
  • ATP receptors are roughly classified into ion channel-embedded receptors (P2X) and G protein-coupled receptors (P2Y), and there are 7 subtypes (P2X1 to P2X7) and 8 subtypes (P2Y1, P2Y2, respectively).
  • P2Y4, P2Y6, P2Y11 to P2Y14) have been reported (Non-Patent Document 4).
  • the P2X7 receptor is expressed in microglia and the like present in the dorsal horn of the spinal cord, and its involvement with neuropathic pain has been reported. For example, in a nerve ligation model test on P2X7 receptor-deficient mice, it has been reported that neuropathic hypersensitivity to mechanical and thermal stimuli completely disappeared (Non-Patent Document 5).
  • Non-Patent Document 6 Specific reported examples of P2X7 receptor antagonists are as follows ((1) to (4) below).
  • Non-Patent Document 8 It has been reported that a P2X7 receptor antagonist, which is A43879 hydrochloride, suppressed the development of hypersensitivity to mechanical stimuli.
  • Patent Document 1 a pharmaceutical composition having a P2X7 receptor inhibitory action and useful for treating pain and the like
  • Patent Document 2 a novel compound having a P2X7 receptor inhibitory action
  • Patent Document 3 a heterocyclic P2X7 antagonist
  • Patent Document 4 P2X7 receptor antagonists and agonists
  • Patent Document 5 the use of tetrahydroquinoline derivatives in the treatment of various disorders mediated by P2X7 receptors
  • mutation of the human P2X7 receptor gene encoding the P2X7 receptor changes the function and expression of the P2X7 receptor such as receptor transport, ATP binding, channel function and pore structure, resulting in functional attenuation. It has been reported that it leads to a type (Loss-Of-Faction; LOF type) and a hyperactive type (Gain-Of-Function; GOF type) phenotype, and mutations in the P2X7 receptor gene make it pain-sensitive in humans. It has also been pointed out that it may be involved (Non-Patent Document 11).
  • SNP Single nucleotide Polymorphism
  • Non-Patent Document 13 Polymorphism can occur when the 489th "C” of the P2X7 receptor gene is mutated to "T” (Non-Patent Document 14). It has been reported that the Minor Allele Frequency (MAF) value is "0.439" (Non-Patent Document 15).
  • Non-Patent Document 13 Polymorphism can occur when the 853rd "G” of the P2X7 receptor gene is mutated to "A” (Non-Patent Document 14). It has been reported that the Minor Allele Frequency (MAF) value is "0.255" (Non-Patent Document 15).
  • Non-Patent Document 13 Polymorphism can occur when the 1068th "G” of the P2X7 receptor gene is mutated to "A” (Non-Patent Document 14). It has been reported that the Minor Allele Frequency (MAF) value is "0.400" (Non-Patent Document 15).
  • Non-Patent Document 13 Polymorphism can occur when the 1513th "A” of the P2X7 receptor gene is mutated to "C” (Non-Patent Document 14). It has been reported that the Minor Allele Frequency (MAF) value is "0.175" (Non-Patent Document 15).
  • H155Y and A348T both hyperactive single nucleotide polymorphisms correlates with strong pain in diabetic peripheral neuropathy pain (DPNP) in female patients.
  • DPNP diabetic peripheral neuropathy pain
  • An object of the present invention is to provide a medicine or the like for alleviating neuropathic pain.
  • One aspect of the pharmaceutical of the present invention is a compound [having a P2X7 receptor inhibitory action (antagonist)] that attenuates the function of the P2X7 receptor (human P2X7 receptor) [P2X7 receptor inhibitory (antagonist) compound, P2X7 receptor.
  • a drug for alleviating (improving, treating) diabetic peripheral neuropathic pain (DPNP), etc., which contains a body-inhibiting (antagonist) agent, P2X7 receptor-inhibiting (antagonist) agent] as an active ingredient. It is characterized by being.
  • Another aspect of the pharmaceutical of the present invention is characterized by being a pharmaceutical for alleviating neuropathic pain, which is administered to a patient with enhanced P2X7 receptor function.
  • the present invention relates to the following inventions and the like.
  • DPNP human diabetic peripheral neuropathy pain
  • PSP human postoperative pain
  • a drug for alleviating (or treating) at least one type of neuropathic pain particularly, human diabetic peripheral neuropathy pain.
  • DPNP human diabetic peripheral neuropathy pain
  • a drug for alleviating (or treating) human diabetic peripheral neuropathy pain (DPNP) containing a compound that attenuates the function of the P2X7 receptor as an active ingredient is a drug for alleviating (or treating) human postoperative pain (Post Surgical Pain; PSP), which comprises a compound that attenuates the function of the P2X7 receptor as an active ingredient.
  • the compound that attenuates the function of the P2X7 receptor is at least one selected from the compounds described in Patent Document 5 (Japanese Patent Laid-Open No. 2020-514371), for example, any of the following compounds and salts thereof.
  • the compound that attenuates the function of the P2X7 receptor is (5S, 8S) -N- (2-chloro-4,6-difluorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl). ) -5,6,7,8-Tetrahydroquinoline-5-carboxamide (Compound 2) or a salt thereof, according to any one of the above [1] to [3].
  • the compound that attenuates the function of the P2X7 receptor is (5S, 8S) -N- (2,4-dichloro-6- (hydroxymethyl) benzyl) -5-fluoro-8-hydroxy-8-.
  • the compound that attenuates the function of the P2X7 receptor is (5S, 8S) -N- ((3,5-dichloropyridin-2-yl) methyl) -5-fluoro-8-hydroxy-8-. (Hydroxymethyl) -5,6,7,8-tetrahydroquinoline-5-carboxamide (Compound 5) or a salt thereof, which is the pharmaceutical according to any one of the above [1] to [3].
  • the compound that attenuates the function of the P2X7 receptor is (5S, 8S) -N-((R) -1- (2,4-dichlorophenyl) ethyl) -5-fluoro-8-hydroxy-8.
  • the compound that attenuates the function of the P2X7 receptor is (5S, 8S) -N- (2-chloro-3,4-difluorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl). ) -5,6,7,8-Tetrahydroquinoline-5-carboxamide (Compound 8) or a salt thereof, according to any one of the above [1] to [3].
  • the compound that attenuates the function of the P2X7 receptor is (5S, 8S) -N- (2,4-dichloro-3-fluorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl).
  • a compound that attenuates the function of the P2X7 receptor is used in humans [or patients, diabetic peripheral neuropathic Pain; DPNP and postoperatively. Administered to humans (or patients) with at least one neuropathic pain selected from Post Surgical Pain (PSP) (particularly human diabetic peripheral neuropathy pain)] and diabetic peripheral neuropathy.
  • PSP Post Surgical Pain
  • a method for alleviating or treating at least one neuropathic pain (particularly, human diabetic peripheral neuropathy pain) selected from pain (Diabetic Peripheral Neuropathic Pain; DPNP) and postoperative pain (Post Surgical Pain; PSP). ..
  • a compound that attenuates the function of the P2X7 receptor [or a drug containing the compound (as an active ingredient)] is used in humans [or patients, diabetic peripheral neuropathy pain (DPNP)).
  • a compound [or a drug containing the compound (as an active ingredient)] that attenuates the function of the P2X7 receptor is administered to a human [or a patient, a human (or a patient) with postoperative pain (PSP)). Patient)] to relieve or treat postoperative pain (Post Surgical Pain; PSP).
  • the compound that attenuates the function of the P2X7 receptor is at least one selected from the compounds described in Patent Document 5 (Japanese Patent Laid-Open No. 2020-514371), for example, any of the following compounds and salts thereof.
  • Patent Document 5 Japanese Patent Laid-Open No. 2020-514371
  • a drug for relieving human neuropathic pain which is administered to P2X7 receptor-enhanced patients.
  • a compound for relieving human neuropathic pain is a compound (pharmaceutical) that attenuates the function of the P2X7 receptor and a compound for relieving neuropathic pain of a different type from the compound (pharmaceutical) (medicine).
  • a drug for relieving human neuropathic pain is administered to P2X7 receptor-enhanced patients to relieve or relieve human neuropathic pain. How to treat.
  • a compound for relieving human neuropathic pain is a compound (pharmaceutical) that attenuates the function of the P2X7 receptor and a compound for relieving neuropathic pain of a different type from the compound (pharmaceutical) (medicine).
  • a drug for alleviating human neuropathic pain a method for alleviating or treating human neuropathic pain, and the like are provided.
  • FIG. 1 is a diagram for explaining the classification (type) of pain scores in Example 5.
  • One aspect of the medicine of the present invention is a medicine for alleviating diabetic peripheral neuropathy pain (DPNP) or the like, which contains a compound that attenuates the function of P2X7 receptor as an active ingredient. ..
  • DPNP diabetic peripheral neuropathy pain
  • One aspect of the therapeutic method of the present invention is characterized in that a compound that attenuates the function of the P2X7 receptor is administered to a diabetic peripheral neuropathy pain (Diabetic Peripheral Neuropathic Pain; DPNP) patient or the like. It is a treatment method for disability pain and the like.
  • DPNP diabetic peripheral neuropathy pain
  • One aspect of the alleviation method of the present invention is characterized by administering a compound that attenuates the function of the P2X7 receptor to a diabetic peripheral neuropathy pain (DPNP) patient or the like. It is a method for alleviating disability pain.
  • One aspect of the invention provides the use of a compound that attenuates the function of the P2X7 receptor for the manufacture of a pharmaceutical for treating neuropathic pain in a patient.
  • One aspect of the invention provides the use of a compound that attenuates the function of the P2X7 receptor for the manufacture of a pharmaceutical for treating diabetic peripheral neuropathy pain in a patient.
  • One aspect of the invention provides the use of a compound that attenuates the function of the P2X7 receptor for the manufacture of a pharmaceutical for treating postoperative pain in a patient.
  • One aspect of the invention is the use of a compound that attenuates the function of the P2X7 receptor for the manufacture of a pharmaceutical for treating diabetic peripheral neuropathy pain in a patient, wherein the patient has P2X7 receptor function.
  • Provided for use which is an enhanced patient or a P2X7 receptor function unchanged patient.
  • One aspect of the invention is the use of a compound that attenuates the function of the P2X7 receptor for the manufacture of a pharmaceutical for treating diabetic peripheral neuropathy pain in a patient, wherein the patient has P2X7 receptor function.
  • Provide use which is an hyperactive patient.
  • One aspect of the invention is the use of a compound that attenuates the function of the P2X7 receptor for the manufacture of a pharmaceutical for treating postoperative pain in a patient, wherein the patient is a P2X7 receptor hyperactive patient or P2X7 receptor function unchanged patient, provides use.
  • One aspect of the invention is the use of a compound that attenuates the function of the P2X7 receptor for the manufacture of a pharmaceutical for treating postoperative pain in a patient, wherein the patient is a P2X7 receptor hyperactive patient. There is, offer use.
  • One aspect of the invention is the use of a compound that attenuates the function of the P2X7 receptor for the manufacture of a pharmaceutical for treating diabetic peripheral neuropathy pain in a patient, wherein the patient has P2X7 receptor function.
  • the compound that is an enhanced patient and attenuates the function of the P2X7 receptor is (5S, 8S) -N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl). 5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof, which is a pharmaceutically acceptable salt thereof, is provided for use.
  • the P2X7 receptor belongs to the P2X ion channel type receptor family activated by extracellular nucleotides (eg, adenosine triphosphate; ATP), and high concentrations of extracellular nucleotides (specifically) are involved in the activation thereof. Is not particularly limited as long as it is a non-selective cation channel that requires (about 0.1 to 1 mM) (Patent Documents 5 and 4).
  • the origin of the P2X7 receptor according to the present invention is also not particularly limited, and may be, for example, a mouse or a human, but a human-derived P2X7 receptor is preferably used.
  • a human-derived P2X7 receptor for example, GenBank accession number Y09561 can be mentioned.
  • the P2X7 receptor according to the present invention the P2X7 receptor described in SEQ ID NO: 2 in the sequence listing can be mentioned, and as the gene encoding the P2X7 receptor according to the present invention, the SEQ ID NO: in the sequence listing can be mentioned.
  • the P2X7 receptor gene described in 1 can be preferably exemplified.
  • Non-Patent Documents 13 to 16 Many single nucleotide polymorphisms have been observed in the P2X7 receptor gene encoding the P2X7 receptor (Non-Patent Documents 13 to 16). Not only the wild-type P2X7 receptor gene but also the P2X7 receptor encoded by the mutant P2X7 receptor gene observed in nature is included in the P2X7 receptor according to the present invention.
  • the tissue or cell in which the P2X7 receptor according to the present invention is expressed in a living body is not particularly limited.
  • glial cells such as microglia and astrosites. It may be present in (Patent Document 5, Non-Patent Document 11).
  • pain follows a route from nociceptors (primary neurons of nerve cells) ⁇ dorsal horn of spinal cord (secondary neurons) ⁇ thorax (tertiary neurons) ⁇ cerebral cortex. Therefore, the P2X7 receptor according to the present invention is used.
  • the central nervous system or central nervous system, eg, brain, spinal cord
  • P2X7 receptors in glial cells located in or near the posterior horn of the spinal cord are present in the central nervous system (or central nervous system, eg, brain, spinal cord) (eg, P2X7 receptors in glial cells located in or near the posterior horn of the spinal cord).
  • the P2X7 receptor is expressed in microglia and the like present in the dorsal horn of the spinal cord, and its involvement with neuropathic pain has been reported.
  • neuropathic hypersensitivity to mechanical and thermal stimuli completely disappeared.
  • the P2X7 receptor can be a target for pain (Non-Patent Document 6).
  • the compound that attenuates the function of the P2X7 receptor may be, in particular, [or reachable] to the central nervous system (or the central nervous system, for example, the brain, spinal cord).
  • a diabetic peripheral neuropathy pain (DPNP) patient a patient having a Gin-Of-Faction (GOF type) P2X7 receptor gene haplotype on both chromosomes.
  • GPF type Gin-Of-Faction
  • LOF type function-degraded type
  • LOF-type diabetic peripheral neuropathy pain patients patients with receptor gene haplotype on one or both chromosomes (however, if only one chromosome shows LOF-type haplotype, the other chromosome is standard haplotype; hereinafter, LOF-type dibetic type diabetic
  • peripheral neuropathy pain sometimes referred to as LOF-type diabetic peripheral neuropathy pain patients
  • LOF-type diabetic peripheral neuropathy pain patients It was found that the pain in GOF type diabetic peripheral neuropathy pain was significantly reduced as compared with the pain in patients with GOF type diabetic peripheral neuropathy pain (Example 5). The present inventors strongly suggest that this result alleviates the pain by pharmacologically attenuating the function of the P2X7 receptor expressed in patients with diabetic peripheral neuropathy pain. do.
  • the active ingredient in the present invention is a compound that "attenuates the function of the P2X7 receptor", and is not particularly limited as long as its application can alleviate neuropathic pain.
  • the P2X7 receptor is activated by a sustained high concentration of ATP extracellularly, and has a non-selective pore structure that promotes the influx of substances of about 900 Da and cations such as sodium ion, calcium ion, and potassium ion. It is known to be formed (Non-Patent Document 12). Therefore, suppressing or preventing such activation by ATP and subsequent non-selective pore structure formation is also considered as one aspect of "attenuating the function of the P2X7 receptor".
  • the P2X7 receptor is expressed on the surface of many cell types, particularly on the surface of cell types known to be involved in inflammatory processes and immune processes (Patent Document 5).
  • P2X7 receptor is activated by extracellular ATP, IL-1 ⁇ and IL-18 are released, giant cells are formed, degranulation and L-selectin are shed (Patent Document 5). ), Suppressing or preventing at least a part of these series of reactions is also considered as one aspect of "attenuating the function of the P2X7 receptor".
  • the compound acting as an antagonist on the P2X7 receptor can suppress or prevent the activation of the P2X7 receptor by high concentration ATP and the subsequent cascade reaction, and is therefore suitable as a compound that attenuates the function of the P2X7 receptor. It can be used (Non-Patent Documents 7 to 10, Patent Documents 1 to 5).
  • the compound that attenuates the function of the P2X7 receptor may be a selective [selective P2X7 receptor inhibitor (antagonist) agent, selective P2X7 receptor inhibitor (antagonist) agent) for the P2X7 receptor.
  • the molecular species of the "compound that attenuates the function of the P2X7 receptor” is not particularly limited, and small molecule compounds, peptides, antibodies, and the like can be exemplified.
  • the P2X7 receptor is preferably a compound having high tissue infiltration.
  • the "compound that attenuates the function of the P2X7 receptor” establishes the blood-brain barrier, which is a barrier for further transition from circulating blood to the central nervous system. It is preferably a passing compound.
  • a low molecular weight compound can be exemplified as a molecular species of a compound that attenuates the function of the P2X7 receptor present in the peripheral nervous system and the central nervous system.
  • a small molecule compound having a molecular weight of about 800 or less can be exemplified, and the upper limit is preferably 600 or less, 500 or less, 450 or less, and the lower limit is not particularly limited, but 10 or more, 50 or more, 100 or more. It can be exemplified. Most preferably, a small molecule compound having a molecular weight of about 100 to 450 can be mentioned.
  • Non-Patent Document 21 a compound having a molecular weight of 450 or less is expected to passively permeate at the blood-brain barrier.
  • cLogP octanol / common logarithmic value of water distribution count
  • Non-Patent Document 7 a low molecular weight compound that attenuates the function of the P2X7 receptor
  • Non-Patent Document 7 a pyroglutamic acid amide derivative
  • II a compound represented by the following formula (I)
  • Non-Patent Document 9 N- (1- ⁇ [(cyanoimino) (5-quinolinylamino) methyl] amino ⁇ -2,2-dimethylcomppyl) -2- (3,4-dimetoxyphenyl) acetamide
  • P2X7 receptor antagonistic low molecular weight compounds such as the compound represented by the following formula (II) (JNJ 47965567; Non-Patent Document 10) can be preferably exemplified.
  • the compound described in Patent Document 5 is more preferably exemplified as a compound that attenuates the function of the P2X7 receptor because it has a P2X7 receptor inhibitory activity in vitro.
  • the following compounds or salts thereof are exemplified.
  • the salt of the compound is preferably a pharmaceutically acceptable salt. It will be appreciated that the salts of the compounds of the invention are pharmaceutically acceptable for use as pharmaceuticals. Suitable pharmaceutically acceptable salts will be apparent to those of skill in the art, for example, J. Mol. Pharm.
  • an acid addition salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or succinic acid, maleic acid.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or succinic acid, maleic acid.
  • acid addition salts formed with organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid. Will be done.
  • compound 7 or compound 10 is a low-molecular-weight compound that exhibits sufficient transferability to blood as well as to the brain and spinal cord (Example 1). , 7). Therefore, the compound 7 or the compound 10, the compounds similar to these compounds and their salts (for example, the compounds described in Patent Document 5 such as the above compounds 1 to 6, 8, 9 and salts thereof) are human.
  • the present inventors consider that the compound can sufficiently exhibit exposure to immune cells (eg, macrophages) and central nervous system tissues / cells (eg, microglia, astrosites) present in blood.
  • immune cells eg, macrophages
  • central nervous system tissues / cells eg, microglia, astrosites
  • compound 7 or compound 10 or a salt thereof can be most preferably exemplified as a compound that attenuates the function of the P2X7 receptor.
  • compound 7 can be most preferably exemplified as a compound that attenuates the function of the P2X7 receptor.
  • compound 10 can be most preferably exemplified as a compound that attenuates the function of the P2X7 receptor.
  • Whether or not a compound attenuates the function of the P2X7 receptor can be confirmed by using a conventional in vitro test method.
  • the function of the P2X7 receptor can be measured by measuring the intracellular Ca 2+ concentration change using a Ca 2+ sensitive fluorescent indicator, and the same compound can be used.
  • a Ca 2+ sensitive fluorescent indicator for example, Fluo4 or Fura2 can be preferably exemplified.
  • an assay system in which the nucleic acid fluorescent staining reagent YO-PRO-1 is incorporated into cells stably expressing the P2X7 receptor can be used together or instead.
  • the means for activating the P2X7 receptor in the same cell is not particularly limited, and for example, BzATP stimulation can be preferably exemplified.
  • Neuropathic pain is generally defined as "pain caused by lesions or disorders of the somatosensory nervous system” and lesions or disorders are present in any of the nociceptive signaling pathways from the peripheral nerves to the cerebral. It is known that it occurs when the disease occurs (Non-Patent Document 1).
  • nociceptive pain is generally defined as "pain caused by excitement of nociceptors due to substantial or potential damage to living tissues other than nervous tissue" (Non-Patent Document 1).
  • Painful diseases are broadly divided into nociceptive pain and neuropathic pain, but both conditions are different because inflammation in the nerve tissue may excite nociceptors and cause pain. It is a concept that can be mixed (Non-Pain Document 1).
  • postoperative pain Post Surgical Pain; PSP
  • PSP Post Surgical Pain
  • neuropathic pain is understood as pain that combines neuropathic and nociceptive elements, and such mixed pain (Mixed Pain).
  • Mened Pain Is also included in the neuropathic pain according to the present invention.
  • Neuropathic pain is broadly divided into peripheral neuropathic pain and central neuropathic pain depending on the site of nerve injury, and the causes are nutritional metabolic, traumatic, ischemic, addictive, hereditary, and infectious diseases. , Compression / strangulation, immunity, neoplasticity, degenerative disease and the like are known, but the neuropathic pain according to the present invention is not particularly limited in its cause, regardless of whether it is peripheral or central. Peripheral neuropathic pain is exemplified as a preferable example of neuropathic pain.
  • the neuropathic pain according to the present invention includes post-herpes zoster neuropathic pain (Phosthepetic Neuropathic Pain), traumatic posterior peripheral neuropathic pain (Post-traumatic Peripheral Neuropathic Pain), and diabetic peripheral neuropathic pain (Diabetic Neuropathic Pain).
  • DPNP post-herpes zoster neuropathic pain
  • TGN Trigeminal Neuropathic Pain
  • TGN Post-spinal injury pain
  • Chemotherapy-induced peripheral neuropathic pain Chemotherapy-induced peripheral neuropathic pain (Chemotherapy-Indupia) Yes)
  • postoperative pain Post Surgical Pain; PSP
  • a preferred example of neuropathic pain is DPNP or PSP.
  • Shingles is a viral disease that generally develops mainly in adults, and when the body's immunity weakens for some reason, the varicella-zoster (HZ) virus lurking in the ganglia is activated.
  • HZ varicella-zoster
  • the main symptoms of shingles are pain and rash. Pain is found along the nerve run caused by the HZ virus and is described as intolerable pain, tingling pain, burning pain, needle stinging pain, tightening pain, etc. Often. Pain may continue for months to years or more after the eruption disappears, and this neuralgia is thought to be the result of severe nerve damage and degeneration by the HZ virus, postherpetic neuralgia (PHN). ).
  • Non-Pain Document 1 A method for evaluating and diagnosing according to the same diagnostic algorithm has been proposed regardless of the lesion or disease that causes neuropathic pain, and is widely used as the current international standard for diagnosing neuropathic pain (non-patent literature). 1).
  • Tests for assessing neurological lesions or disorders that explain neuropathic pain include imaging tests (MRI, CT), neurophysiological tests (neuropathic tests, trigeminal nerve reflexes, laser-induced potentials (LEPs), etc.). There are corneal confocal microscope (CCM), skin biopsy, etc. (Non-Patent Document 1).
  • neuropathic pain presents characteristic pain different from nociceptive pain.
  • Spontaneous pain (persistent or intermittent) or stimulus-induced pain (allodynia, hyperalgesia) is located in the area corresponding to the damaged nerve-dominated area, and various sensations caused by nerve damage. It is characteristic that it is complicated by the abnormality of (Non-Patent Document 1).
  • Non-Patent Document 1 Various screening tools (ID Pain, NPQ, pain DETECT, LANSS, DN4) are known as an aid to diagnosis (Non-Patent Document 1).
  • the method for evaluating the intensity of neuropathic pain is not particularly limited, and for example, VAS (Visual Analog Scale) and NRS (Numeric Racing Scale) can be preferably exemplified (Non-Patent Documents 18 to 19).
  • NRS divides pain into 11 stages from 0 to 10, 0 is no pain at all, 10 is the worst pain that can be considered, and VAS asks the score of pain.
  • the evaluation may be based on the subjectivity of such a patient, or may be, for example, a method using a device for quantifying or analyzing perception or pain sensation (eg, Pain Vision PS-2100; manufactured by Nipro) (non-patent).
  • Patent Document 19 ).
  • VAS and NRS are preferably used in patients with cognitive decline with an MMSE of about 18 or more, and NRS is preferably used in patients with moderate cognitive decline with an MMSE of 10 to 17 points (cancer pain). 2010 version of the guidelines for drug therapy in 2. Comprehensive evaluation of pain).
  • Diabetic Peripheral Neuropathy is a general term for various peripheral neuropathy found in diabetic patients, and is a peripheral neuropathy caused by insufficient insulin action or chronic hyperglycemic state. Diabetic peripheral neuropathy is thought to develop as two major factors, peripheral nerve metabolism disorder and angiopathy caused by hyperglycemia, and intraneuronal sorbitol accumulation, protein glycation, free radicals, and neuronutrient factors due to increased polyol metabolism Hypotheses such as the theory of neuroischemia due to abnormalities and microangiopathy have been proposed (Non-Patent Document 2).
  • DPN diabetic peripheral neuropathy
  • the disease types are classified into four types: “hyperglycemic neuropathy”, “symmetric polyneuropathy”, “local and multifocal neuropathy”, and “mixed type” (Non-Patent Document 17).
  • Hyperglycemic neuropathy refers to a condition mainly characterized by a feeling of needle stick in the foot, which is seen in patients with persistent hyperglycemic conditions. Since this numbness or pain is relieved by improving the glycemic control, hyperglycemic neuropathy is considered to be a physiological or functional symptom against the background of changes in channel function due to hyperglycemia. Therefore, it may be more appropriate to call hyperglycemic neuropathy a hyperglycemic painful state rather than a true peripheral neuropathy. On the other hand, it is recommended that peripheral neuropathy in the original sense accompanied by destruction of peripheral nerve fibers be roughly classified into two types, symmetry disorder and asymmetry disorder (Non-Patent Document 17).
  • the diabetic peripheral neuropathy according to the present invention is a hyperglycemic nerve. It is a concept that comprehensively includes obstacles.
  • symmetry polyneuropathy The type of symmetry disorder is collectively called symmetry polyneuropathy, where unpleasant sensory symptoms and foot lesion formation not only impair daily life (Quality Of Life; QOL), but also autonomic nerve function in severe cases. Since the prognosis of life is shortened due to cardiovascular events due to insufficiency, symmetric polyneuropathy is the most important target in the study of diabetic peripheral neuropathy (Non-Patent Document 17). Symmetric polyneuropathy forms the center of diabetic peripheral neuropathy according to the present invention.
  • Arodinia hypersensitivity, burning pain, bean-like pain, numbness-like pain, etc. are often observed throughout neuropathic pain, and in diabetic peripheral neuropathic pain, Pain that is tingling, pain that is pierced by a spear, and pain that is twitching are often observed as characteristic pain.
  • alleviation of neuropathic pain means that at least one of the intensity, frequency, pain duration, and property of neuropathic pain is alleviated, decreased, shortened, ameliorated, ameliorated, disappeared, and the like.
  • Inclusively means changing to the state of.
  • the intensity of the neuropathic pain that occurred before taking or administering the drug of the present invention is alleviated by taking the medicine of the present invention or administering the active ingredient of the present invention
  • the neuropathic pain is alleviated. It is understood that there is.
  • the reduction in the intensity of neuropathic pain can be determined, for example, based on the difference in NRS scores before and after taking the drug.
  • the strength of neuropathic pain is strong because the guidelines of the European Association for the Study of Neurology (EFNS) and the IASP Neuropathic Pain Subcommittee (NeuPSIG) prioritize reduction of pain intensity rather than multifaceted evaluation of pain.
  • the alleviation or disappearance of swelling can be preferably exemplified as the alleviation of neuropathic pain of the present invention.
  • neuropathic pain is "allodynia”, “hyperalgesia”, “pain pierced by a spear”.
  • neuropathic pain is alleviated when the nature of the neuropathic pain remains "allodynia” and “hyperalgesia” after taking the medicine of the present invention.
  • the neuropathic pain is understood to be relaxed.
  • treatment of neuropathic pain can be meant (with relief) of neuropathic pain relief, for example, nighttime sleep that is not disturbed by pain by relief of neuropathic pain. It may mean that the pain at rest, the pain at the time of body movement, etc. are eliminated.
  • NNT a numerical value indicating how many patients need to be administered a drug to obtain one patient with 50% reduction in pain
  • This index can also be used.
  • peripheral neuropathic pain it has been reported to be approximately 3.1 for tricyclic antidepressants and 4.7 for calcium channel ⁇ 2 ⁇ subunit binding drugs (Patent Document 6).
  • the above-mentioned idea of alleviating neuropathic pain can be applied to alleviation of diabetic neuropathic pain.
  • diabetic neuropathy pain is pain associated with symmetric polyneuropathy, but in pain associated with symmetric polyneuropathy, sensory neuropathy and autonomic neuropathy are generally clinically dominant. Often leads to clinical symptoms of motor neuropathy late. In general, positive symptoms (dust, tingling, bilibili, burning pain) are observed in the early stage of the disease, and negative symptoms often occur as the disease progresses.
  • the positive symptom can be preferably exemplified as the pain.
  • Mutations in the human P2X7 receptor gene encoding the P2X7 receptor can alter the function and expression of the P2X7 receptor, such as receptor transport, ATP binding, channel function and pore structure, resulting in function. It has been reported to induce attenuated (Loss-Of-Function; LOF) and hyperactive (Gain-Of-Function; GOF) phenotypes, and mutations in the P2X7 receptor gene have been reported to lead to pain sensitivity in humans. It has also been pointed out that it may be involved in (Non-Patent Document 11). Specifically, many single nucleotide polymorphisms (SINGLE Nucleotide Polymorphism; SNP) have been reported for the P2X7 receptor gene (Non-Patent Documents 13 to 16).
  • SNP single nucleotide polymorphisms
  • the patient according to the present invention is not particularly limited as long as it is a patient having a symptom of neuropathic pain (neuropathic pain patient), but shows a P2X7 receptor-enhanced type, a functionally unchanged type, or a functionally attenuated type.
  • a neuropathic pain patient can be mentioned, and a neuropathic pain patient exhibiting a P2X7 receptor-enhanced type or a P2X7 receptor function-invariant type, particularly a neuropathic pain patient exhibiting a P2X7 receptor-enhanced type, can be more preferably exemplified as an administration target.
  • the single nucleotide polymorphism of the P2X7 receptor gene according to the present invention is not particularly limited, and examples thereof include 11 types of single nucleotide polymorphisms described in Non-Patent Document 15.
  • Table 1 shows four typical single nucleotide polymorphisms that are associated with missense mutations and have been suggested to be associated with pain as a phenotype.
  • the P2X7 receptor-enhanced diprotype is a P2X7 receptor in which both of the two P2X7 receptor genes (alleles) colocated to each of the homologous chromosomes derived from a certain patient have a hyperfunctional mutation. It is a body gene (P2X7 receptor-enhanced haplotype), and as a result, it means a state in which the function of the mutated P2X7 receptor is enhanced.
  • a P2X7 receptor-enhanced (GOF-type) patient is a patient who exhibits a diprotype (a combination of haplotypes) that has an enhanced-function mutation in the locus of the P2X7 receptor gene, and as a result, the mutation occurs.
  • the patient can be regarded as a P2X7 receptor-enhanced patient (GOF type patient). More specifically, if both of the two P2X7 receptor genes (alleles) lodged on each of the patient-derived homologous chromosomes show the P2X7 receptor GOF-type haplotype shown below, the patient is a GOF-type patient. Can be called.
  • the GOF-type haplotype has, for example, 160% or more, more preferably 170% or more, still more preferably 180% or more, and particularly preferably 190, as a function of the P2X7 receptor measured by an in vitro assay (Yo-Pro-1 test method).
  • haplotype % Or more, most preferably 200% or more (degree of variation with respect to the function of the wild-type haplotype) is exemplified as a haplotype.
  • the P2X7 receptor gene located on one of the homologous chromosomes is shown in Table 3 No.
  • the P2X7 receptor gene, which is a haplotype of 1 and is located on the other chromosome, is No. 3 in Table 3.
  • the haplotype of 3 it can be determined that the patient is a P2X7 receptor-enhanced patient.
  • the P2X7 receptor function-attenuating diprotype is a P2X7 receptor function-attenuating mutation in 1) of two P2X7 receptor genes (alleles) colocated to each of the homologous chromosomes derived from a certain patient.
  • the resulting P2X7 receptor gene (P2X7 receptor function attenuated haplotype) or 2) the P2X7 receptor gene (P2X7 receptor function attenuated haplotype) in which one of them has a P2X7 receptor function attenuated mutation.
  • P2X7 receptor function-invariant gene P2X7 receptor standard haplotype
  • P2X7 receptor encoded by the P2X7 receptor gene that causes the P2X7 receptor function-attenuating mutation It means that the function of is weakened.
  • a P2X7 receptor function-attenuated (LOF type) patient is 1) a diprotype (a combination of haplotypes) in which a function-attenuating mutation is occurring at the locus of the P2X7 receptor gene, or 2) one chromosome.
  • the function of the P2X7 receptor in a patient who exhibits a haplotype with a function-attenuating mutation at the locus of the P2X7 receptor gene and the other chromosome shows a P2X7 receptor standard haplotype. If the patient is in a diminished state, the patient can be regarded as a P2X7 receptor-degraded patient (LOF-type patient).
  • both of the two P2X7 receptor genes (alleles) lodged on each of the patient-derived homologous chromosomes exhibit the P2X7 receptor LOF-type haplotype shown below, or 2). If one exhibits a LOF-type haplotype and the other exhibits a standard-type haplotype, the patient can be referred to as a LOF-type patient.
  • the LOF haplotype has, for example, 80% or less, more preferably 70% or less, still more preferably 60% or less, and particularly preferably 50, as a function of the P2X7 receptor measured by an in vitro assay (Yo-Pro-1 test method).
  • haplotype % Or less, most preferably 40% or less (degree of variation with respect to the function of the wild-type haplotype) is exemplified as a haplotype.
  • the haplotype (No. 13-16) shown in Table 3 showing a P2X7 receptor function of 40% or less is exemplified as a LOF type haplotype.
  • the standard haplotype has, for example, an upper limit of 200% or less, more preferably 190% or less, still more preferably 180% or less, particularly preferably 180% or less, as a function of the P2X7 receptor in an in vitro assay (Yo-Pro-1 test method).
  • the most preferable is 80% or more, 90% or more, or 100% or more.
  • the haplotype (No. 7-12) shown in Table 3, which shows that the function of the P2X7 receptor is more than 40% and less than 120% is exemplified as a standard haplotype.
  • the P2X7 receptor gene located on one of the homologous chromosomes is shown in Table 3 No.
  • Table 3 No. 1 shows the P2X7 receptor gene, which is a haplotype of 15 and is located on the other chromosome. If there are 16 haplotypes, it can be determined to be a P2X7 receptor function-degraded patient.
  • the P2X7 receptor function unchanged type (standard type) patient is a patient other than the P2X7 receptor function-enhanced type (GOF type) patient and the P2X7 receptor function-decreased type (LOF type) patient.
  • GAF type P2X7 receptor function-enhanced type
  • LEF type P2X7 receptor function-decreased type
  • a patient in which both of the two P2X7 receptor genes (alleles) located on each homologous chromosome derived from a patient are wild-type P2X7 receptor genes is typical of P2X7 receptor function-invariant patients. This is an example.
  • the function of the P2X7 receptor is measured by measuring the intracellular Ca 2+ concentration change when stimulated with BzATP using a Ca 2+ sensitive fluorescent indicator.
  • Patent Document 5 an assay system in which the nucleic acid fluorescent staining reagent YO-PRO-1 is incorporated into cells in which the P2X7 receptor is stably expressed can be used together with or instead.
  • the function of the P2X7 receptor is 200% or more.
  • Nos. 1 to 4 show functions within 20% above and below, centering on the functions of P2X7 receptor-enhanced haplotype (GOF type haplotype) and wild-type haplotype.
  • 7 to 12 are standard haplotypes, and P2X7 receptor function is less than 40% NO. 13 to 16 were defined as functionally attenuated haplotypes (LOF type haplotypes).
  • the subject of administration of the drug according to the present invention is not particularly limited as long as it is a diabetic peripheral neuropathy patient or the like, and for example, "hyperglycemic neuropathy”, “symmetric polyneuropathy”, “local and multifocal” according to the Thomas classification. It may be a person suffering from any of "neuropathy” and "mixed type”.
  • the background of the patient such as age, gender, height, weight, comorbidities, and underlying diseases is not particularly limited.
  • the administration target of the drug according to the present invention may be a diabetic peripheral neuropathy patient showing a P2X7 receptor function-enhanced type, a function-invariant type or a function-degraded type, and the administration target may be a P2X7 receptor function-enhanced type.
  • a diabetic peripheral neuropathy patient showing a P2X7 receptor function unchanged type, particularly a P2X7 receptor function-enhanced type, and the like can be preferably exemplified.
  • the administration route of the drug of the present invention is not particularly limited, and may be oral administration or parenteral administration.
  • the parenteral administration includes rectal administration, transdermal administration, subcutaneous administration, intradermal administration, and intramuscular administration.
  • Eye instillation administration, nasal instillation administration, intravenous administration, intramuscular administration and the like can be exemplified.
  • the dose and frequency of administration of the drug of the present invention can be determined by a doctor or the like.
  • the dose and frequency of administration can be appropriately adjusted depending on the active ingredient, the condition of the disease, the progress of the disorder, the age, body weight, underlying disease, etiology of the patient, and the like.
  • the pharmaceutical product of the present invention when used [for example, when the compound described in Patent Document 5 such as compound 7 or a salt thereof is used as a compound (active ingredient) that attenuates the function of the P2X7 receptor to obtain a pharmaceutical product. ],
  • the active ingredient in a dose range of about 0.05 mg to about 3000 mg, about 1 mg to about 1000 mg, or about 10 mg to about 500 mg once a day or at least once a day, for example twice a day, 3 Dosages and usages to be administered once or four times can be preferably mentioned.
  • the drug of the present invention When the drug of the present invention is administered to a patient, it is confirmed by, for example, genotyping whether or not the patient exhibits a P2X7 receptor function-enhanced type or a P2X7 receptor function-decreased type. May be good.
  • genotyping is known as a method for detecting genotype differences (allele combinations, etc.) by identifying the DNA sequence of an individual by DNA sequencing or the like and comparing it with the DNA sequence of another individual. It is possible to carry out by a conventional method (Non-Patent Document 15).
  • a sample derived from the patient eg, peripheral venous blood
  • a sample for genotyping may be prepared by extracting and amplifying DNA from the collected sample by a conventional method.
  • a sample prepared on a chip on which a known DNA fragment is immobilized can be donated and genotyped by hybridization of the DNA in the sample with the known DNA fragment.
  • a sample derived from the patient eg, peripheral venous blood
  • DNA is extracted from the collected sample by a conventional method, a sample containing the extracted DNA, a set of PCR primers, and a sample.
  • TaqMan® probes corresponding to single-nucleotide mutations in DNA including complementary sequences of the mutated DNA, etc.
  • performing PCR single nucleotide polymorphisms related to the probes can be detected. can.
  • Examples of the single nucleotide mutation of the DNA include rS208294 (H155Y), rS7958311 (R270H), rS17181119 (A348T), and rS3751143 (E496A).
  • rS208294 H155Y
  • rS7958311 R270H
  • rS17181119 A348T
  • rS3751143 E496A
  • No. 1 in Table 3 is used as a single-base mutation of the DNA (0 to 4 single-base mutations in the P2X7 gene).
  • No. 1 in Table 3 is used as a single-base mutation of the DNA (0 to 4 single-base mutations in the P2X7 gene).
  • the single nucleotide mutations described in 1 to 16 can be preferably exemplified.
  • tricyclic antidepressants are the first-line drugs.
  • TCA serotonin noradrenaline reuptake inhibitor
  • SNRI serotonin noradrenaline reuptake inhibitor
  • calcium channel ⁇ 2 ⁇ subunit binding drug local anesthetic (lidocaine external drug)
  • opioid analgesic as second-line drug
  • SSRI serotonin reuptake inhibitor
  • anti-arrhythmic drug and capsaicin
  • a pain-therapeutic compound different from the active ingredient of the present invention (a compound for relieving neuropathic pain different from the compound which attenuates the function of the P2X7 receptor exemplified in Embodiment 2 described later). Etc.) can be used together.
  • the compound that can be used in combination is not particularly limited, but the following compounds can be preferably exemplified.
  • TCA Tricyclic antidepressant
  • Non-Patent Document 1 Vaccinia virus inoculated rabbit inflamed skin extract
  • a medicine containing at least one of these compounds may be administered together with the medicine of the present invention or at intervals, and a combination drug containing at least one of these compounds and the active ingredient of the present invention may be taken. ..
  • the usage of these compounds can follow the conventional method (Non-Patent Document 1).
  • Another aspect of the pharmaceutical of the present invention is a pharmaceutical for alleviating neuropathic pain, which is administered to a patient with enhanced P2X7 receptor function.
  • One aspect of the therapeutic method of the present invention is a method for relieving neuropathic pain, which comprises administering a compound for relieving neuropathic pain to a patient having enhanced P2X7 receptor function. be.
  • One aspect of the therapeutic method of the present invention is a method for treating neuropathic pain, which comprises administering a compound for alleviating neuropathic pain to a patient having enhanced P2X7 receptor function. be.
  • Active ingredient compound for relieving neuropathic pain
  • the active ingredient in the present invention may be a compound of the present invention that "attenuates the function of the P2X7 receptor" (such as the compound exemplified in the above aspect 1), and alleviates a type of neuropathic pain different from the compound. It may be a compound for making it (Non-Patent Document 1, Non-Patent Document 3, Patent Document 6).
  • a compound that combines a compound that "attenuates the function of the P2X7 receptor" and a compound for relieving a different type of neuropathic pain may be referred to as a compound for relieving neuropathic pain. ..
  • a tricyclic antidepressant TCA
  • SNRI serotonin / noradrenaline reuptake inhibitor
  • calcium channel ⁇ 2 ⁇ examples thereof include a subunit binding drug, a local anesthetic (lidocaine external drug), an opioid analgesic, a selective serotonin reuptake inhibitor (SSRI), an anti-arrhythmic drug, capsaicin and the like (Non-Patent Document 6).
  • the following compounds can be exemplified.
  • the “neuropathic pain” in aspect 1 is applied to the “neuropathic pain” in the present invention.
  • “alleviation of neuropathic pain” in the present invention "alleviation of neuropathic pain” in aspect 1 is applied.
  • neuropathic pain is roughly classified into peripheral neuropathic pain and central neuropathic pain depending on the site of nerve injury.
  • Peripheral neuropathic pain can be exemplified as the neuropathic pain in the present invention, and peripheral neuropathic pain can be alleviated as the alleviation of neuropathic pain in the present invention.
  • the neuropathic pain according to the present invention includes post-herpes zoster neuropathic pain (Phosthepetic Neuropathic Pain; PHN), traumatic peripheral neuropathic pain (Post-traumatic Peripheral Neuropathic Pain), and diabetic peripheral neuropathic pain (Diabetic).
  • DPNP post-herpes zoster neuropathic pain
  • TGN Trigeminal Neuropathic Pain
  • TGN Post-Spine Injury Pain
  • Chemotherapy-induced Peripheral Neuropathic Pain Chemotherapy-induced Peripheral Neuropathic Pain (Chemotherapy-Indupia) Yes)
  • postoperative pain Post Surgical Pain; PSP
  • the "treatment of neuropathic pain” in aspect 1 is applied to the “treatment of neuropathic pain” in the present invention.
  • neuropathic pain is roughly classified into peripheral neuropathic pain and central neuropathic pain depending on the site of nerve injury.
  • the treatment of peripheral neuropathic pain can be mentioned.
  • the patient is a neuropathic pain patient and the function of the P2X7 receptor is enhanced.
  • the "P2X7 receptor-enhanced neuropathic pain patient (GOF-type patient)" in aspect 1 can be applied to the "Patient with enhanced P2X7 receptor function”.
  • a patient of the present invention specifically, a patient showing a diprotype (a combination of haplotypes) in which a hyperfunctional mutation is generated in the locus of the P2X7 receptor gene, and as a result, the P2X7 receptor in which the mutation is generated. Patients who are in a state of enhanced function can be mentioned.
  • the hyperfunctional mutation for example, NO. P2X7 receptor-enhanced mutations (GOF-type haplotypes) according to 1 to 4 can be preferably mentioned.
  • Whether or not the patient to be administered is a patient with enhanced P2X7 receptor function can be determined by, for example, performing genotyping using a sample derived from the patient to determine the genotype of the P2X7 receptor gene (two alleles). After identification, in cells in which the P2X7 receptor gene was stably expressed, the function of the P2X7 receptor was measured by measuring the change in intracellular Ca 2 concentration when stimulated with BzATP using a Ca 2+ sensitive fluorescent indicator. It is possible to make a judgment by measuring. Alternatively, an assay system in which the nucleic acid fluorescent staining reagent YO-PRO-1 is incorporated into cells stably expressing the P2X7 receptor can be used together with or instead.
  • Administration method (administration route, administration frequency, dose, combination, etc. )
  • administration method administration route, administration frequency, dose, etc.
  • administration method combination in the first aspect
  • the “compound that attenuates the function of the P2X7 receptor” (active ingredient) in aspect 1 may be applied in place of the compound of the present invention (that is, a compound for alleviating neuropathic pain).
  • the "medicine” in aspect 1 can be applied to the medicine in the present invention.
  • Test method A methylcellulose suspension containing a P2X7 receptor antagonist compound (Compound 7 or Compound 10) was prepared for rats (strain: Crl: CD (SD), male, 7 weeks old, with diet). After oral administration, blood was collected from rats 15, 30 minutes, 1, 2, 4, 8 and 24 hours after the administration, and the concentration of the compound contained in the collected blood was measured. The dose of the compound per dose was 30 mg / kg, and the concentration of the compound in the suspension was 3 mg / mL. Administration was performed once daily for 4 consecutive days.
  • This orally administered compound showed sufficient transferability to the central nervous system.
  • Example 2 Effect confirmation test for pain in rat chronic stenosis injury model (CCI or Bennett model)
  • CCI chronic stenosis injury model
  • Bennett model the effect of Compound 7 on hyperalgesia caused by mechanical stimulation occurring in CCI model rats was investigated.
  • Compound 7 was orally administered to rats as a test drug, and the following tests were performed.
  • the experimental animals were composed of four groups: a solvent administration group, compound 7 2, 10 or 50 mg / kg administration group (compound 7 administration group).
  • Compound 7 was orally administered to the compound 7-administered group 12 days after CCI surgery and 3 hours before the measurement test.
  • the solvent of compound 7 was similarly administered to the solvent administration group.
  • Randall-Selitto test For the above rats, Randall LO. Et al., Arch. Int. Pharmacodyn. The. 1957. It was measured according to the foot pressure pain method (Randall-Selitto test) described in 111,409-419. That is, the pressure on the right hind limb and foot was gradually pressurized by the pressure-stimulating analgesic effect device, and the pressure when a screaming reaction or an escape reaction was shown was set as the pain threshold. The baseline threshold was measured prior to CCI surgery and then the pain threshold was measured 12 days after surgery. After confirming that the pain threshold was sufficiently lowered, a measurement test was performed.
  • the pain threshold (Threshold) was significantly lower than that before the CCI operation.
  • the decrease in the threshold value observed in CCI surgery was significantly increased in all the administration groups. From the above results, it was confirmed that there is an example in which Compound 7 has a therapeutic effect on the mechanical hyperalgesia that occurs in CCI model rats.
  • Example 3 Effect confirmation test for pain of rat spinal nerve ligation model (SNL or Chung model)
  • SNL or Chung model In order to confirm the effect of compound 7 on neuropathic pain, compound 7 investigated for the effect of compound 7 on allodynia caused by mechanical stimulation occurring in SNL model rats was orally administered to rats as a test drug, and the following tests were conducted. gone.
  • the experimental animals were composed of 6 groups: a sham operation group, a solvent administration group, and a compound 7 administration group of 0.4, 2, 10, or 50 mg / kg (compound 7 administration group).
  • compound 7 administration group compound 7 was orally administered once a day for 7 days from the 15th day after SNL surgery.
  • the solvent of compound 7 was similarly administered to the sham surgery group and the solvent administration group.
  • the pain threshold (Threshold) was significantly decreased as compared with the sham surgery group, whereas in the 50 mg / kg administration group of compound 7, the decrease in the threshold observed in SNL surgery was significantly increased. From the above results, it was confirmed that there is an example in which Compound 7 has a therapeutic effect on the pain caused in SNL model rats.
  • Human embryonic Kidney Cells 293; HEK293) was cultured in a 10 cm dish (plate) by a conventional method so as to be 3e + 6 cells / dish.
  • Each plasmid incorporating each of the 16 types of human P2X7 receptor gene mutants (Nos. 1 to 16 in the table below) prepared in advance by a conventional method was transfected into HEK293 24 hours after the start of culture, and 96.
  • the well plates were cultured in a conventional manner for an additional 24 hours to 5e + 4cells / well.
  • the cell culture solution was washed with a buffer solution, and an appropriate amount of a 2 ⁇ M concentration coloring dye (Yo-Pro-1) solution or a calcium 5 and probenecid (anion transporter inhibitor) solution was added. Incubation for 10 or 60 minutes was performed and assayed.
  • a 2 ⁇ M concentration coloring dye Yo-Pro-1 solution or a calcium 5 and probenecid (anion transporter inhibitor) solution was added. Incubation for 10 or 60 minutes was performed and assayed.
  • the Yo-Pro-1 / Calcium 5 uptake assay was performed using a FLIPRTETRA® cell-based screening system (manufactured by Molecular Devices).
  • the assay conditions are as follows. ⁇ Experimental Setup Parameter -Excitation Wavelength (nm): 470-495 -Emission Wavelength (nm): 515-575 ⁇ Camera Gain: 100 -Exposure Time (s): 0.4 -Excitation Industry (%): 80
  • the calcium 5 uptake assay was measured for 6.7 minutes after the addition of BzATP-PBS solution.
  • As the assay buffer an HBSS buffer containing 1.8 mM CaCl 2 , 1 mM MgCl 2 , and 20 mM HEPES was used.
  • the values of wild-type haplotype P2X7 receptors stimulated with BzATP 300 ⁇ M were measured on each measuring plate as a reference. With that value as 100%, the function of each combination of P2X7 receptors was evaluated.
  • NO. Nos. 1 to 4 show functions within 20% above and below, centering on the functions of P2X7 receptor-enhanced haplotype (GOF type haplotype) and wild-type haplotype. 7 to 12 are standard haplotypes, and P2X7 receptor function is less than 40% NO. 13 to 16 were designated as functionally attenuated haplotypes (LOF type haplotypes).
  • this result shows that when rs208294 (C>T; hyperactive mutation) and rs1718119 (G>A; hyperfunctional mutation) are compared, rs1718119 (G> A) is a mutation that induces hyperactivity more strongly.
  • the evaluation item was set as a pain score expressed by NRS (Numeric Racing Scale; 11-step category variable of 0 to 10) or VAS (continuous variable of 0 to 10), and neuropathic pain.
  • NRS Numeric Racing Scale; 11-step category variable of 0 to 10
  • VAS continuous variable of 0 to 10
  • neuropathic pain a pain score expressed by NRS (Numeric Racing Scale; 11-step category variable of 0 to 10) or VAS (continuous variable of 0 to 10), and neuropathic pain.
  • Three cohorts according to the cause were set up with the criteria, and each cohort was further divided into two groups according to the type of P2X7 receptor gene monobase mutation derived from the patient. Each group was designated as a P2X7 receptor function-enhanced group (GOF type group) and a P2X7 receptor function-decreased group (LOF type group).
  • Tables 10-12 show patient selection and exclusion criteria for each of the three cohorts.
  • some of the extracted patient's medical information background information, clinical information, etc.
  • genetic information SNPs information for identifying the GOF type group or LOF type group on each of the two chromosomes. Obtained from Biobank.
  • the pain scores extracted according to the above table were analyzed, and the average pain score for each patient was calculated. As a result of extraction according to the above table, patients without a pain score to be analyzed were excluded from the analysis.
  • the pain scores extracted according to Table 13 were classified into three types, “non-therapeutic phase”, “therapeutic effect variable phase”, and “therapeutic effect stable phase” from the viewpoint of therapeutic effect and therapeutic effect variability (Fig. 1). ..
  • Pain score that can be regarded as observed during the non-treatment period (A type pain score) 2) A pain score that can be regarded as observed during the treatment period, and is a pain score observed during the therapeutic effect fluctuation period (B-1 type pain score). 3) A pain score that can be regarded as observed during the therapeutic period, and is a pain score observed during the stable therapeutic effect period (B-2 type pain score).
  • the purpose of this example is to evaluate the effect of a single-base mutation on the human P2X7 receptor gene on neuropathic pain, the extracted A-type pain score, B-1 type pain score, and B-2 type pain score Of the three types, the pain score that can be considered to have been observed in the non-treatment period, that is, only the A type pain score, is evaluated from the viewpoint of eliminating the effects of other neuropathic pain treatment drugs as much as possible. (Evaluation I).
  • evaluation II includes patients in the treatment stage for neuropathy pain treatment (B-2 type pain score), but the number of patients using neuropathy pain treatment is mostly between the GOF type group and the LOF type group.
  • the number of patients who met the selection criteria of each cohort extracted from the above database was as follows.
  • the A-type pain scores of patients who met the selection criteria of each extracted cohort were as follows.
  • each difference (mean value of A-type pain in the GOF type group-average value of A-type pain in the LOF type group) is each cohort or 3 It is believed to indicate how neuropathic pain formed in one cohort is affected by the administration of compounds that attenuate human P2X7 receptor function.
  • a type and B-2 type pain scores of patients who met the selection criteria of each extracted cohort were as follows.
  • the purpose of this example is to evaluate the effect of a single nucleotide mutation in the human P2X7 receptor gene on the effect of a therapeutic drug for neuropathic pain.
  • the B-1 type pain score is a pain score that can be regarded as observed during the treatment period. Since it is the pain score observed during the treatment effect fluctuation period, the difference between the B-2 type pain score and the A type pain score observed during the non-treatment period (B) for the purpose of eliminating the variability of the treatment effect.
  • -2 type pain score-A type pain score was evaluated.
  • the evaluation value is negative, it can be considered that the pain score is weakened, that is, the pain is improved.
  • DPNP diabetic neuropathy pain
  • neuropathic pain remedies used during the treatment period for all 2 cohorts of patients are listed below. These are tricyclic antidepressants (TCA), serotonin noradrenaline reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), calcium channel ⁇ 2 ⁇ subunit binding agents, local anesthetics, opioid analgesics. , Sodium channel inhibitors, NMDA-type glutamate receptor inhibitors, etc.
  • TCA tricyclic antidepressants
  • SNRIs serotonin noradrenaline reuptake inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • calcium channel ⁇ 2 ⁇ subunit binding agents local anesthetics
  • opioid analgesics opioid analgesics.
  • Sodium channel inhibitors NMDA-type glutamate receptor inhibitors, etc.
  • the above-mentioned neuropathy pain treatment drug is particularly effective. It is not limited, and it can be considered that it is not particularly
  • Example 7 Human central transfer confirmation test of P2X7 receptor antagonist compound
  • the pharmaceutical agent of the present invention can be used for alleviating neuropathic pain and the like.
  • the present invention is extremely useful in the pharmaceutical industry.

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014192698A1 (ja) 2013-05-27 2014-12-04 国立大学法人岡山大学 疼痛治療薬
JP2018162269A (ja) 2012-06-01 2018-10-18 アブリンクス エン．ヴェー． Ｐ２ｘ７受容体アンタゴニスト及びアゴニスト
JP2019182865A (ja) 2018-04-16 2019-10-24 塩野義製薬株式会社 二環性含窒素複素環誘導体を含有する医薬組成物
JP2019182806A (ja) 2018-04-16 2019-10-24 塩野義製薬株式会社 二環性複素環誘導体およびそれらを含有する医薬組成物
JP2020514371A (ja) 2017-03-13 2020-05-21 ラクオリア創薬株式会社 Ｐ２ｘ７受容体拮抗薬としてのテトラヒドロキノリン誘導体
JP2020518555A (ja) 2017-05-03 2020-06-25 エーエックスエックスエーエム ソシエタ ペル アツィオーニ 複素環ｐ２ｘ７アンタゴニスト

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018162269A (ja) 2012-06-01 2018-10-18 アブリンクス エン．ヴェー． Ｐ２ｘ７受容体アンタゴニスト及びアゴニスト
WO2014192698A1 (ja) 2013-05-27 2014-12-04 国立大学法人岡山大学 疼痛治療薬
JP2020514371A (ja) 2017-03-13 2020-05-21 ラクオリア創薬株式会社 Ｐ２ｘ７受容体拮抗薬としてのテトラヒドロキノリン誘導体
JP2020518555A (ja) 2017-05-03 2020-06-25 エーエックスエックスエーエム ソシエタ ペル アツィオーニ 複素環ｐ２ｘ７アンタゴニスト
JP2019182865A (ja) 2018-04-16 2019-10-24 塩野義製薬株式会社 二環性含窒素複素環誘導体を含有する医薬組成物
JP2019182806A (ja) 2018-04-16 2019-10-24 塩野義製薬株式会社 二環性複素環誘導体およびそれらを含有する医薬組成物

Non-Patent Citations (34)

* Cited by examiner, † Cited by third party
Title
"Guidelines for the Pharmacologic Management of Neuropathic Pain", 30 July 2016
"Japanese book", 2013, NAKAYAMA SHOTEN CO., LTD, article "Diabetic neuropathy -From basic to clinical", pages: 2 - 4
"Pharmaceutical Safety and Environmental Health Bureau", 2020, MINISTRY OF HEALTH, LABOR AND WELFARE, article "Guidelines for clinical assessment of neuropathic pain therapeutic agents (draft"
"Treatments for neuropathic pain", CLINICAL PHARMACIST, vol. 9, no. 12, 2017
BENNETT ET AL., PAIN, vol. 33, 1988, pages 87 - 107
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 20, 2010, pages 5080 - 5084
BR J PHARMACOL, vol. 170, 2013, pages 624 - 640
CHUNG ET AL., PAIN, vol. 50, 1992, pages 355 - 363
CLINICAL NEUROLOGY, vol. 49, no. 4, 2009, pages 149 - 157
FRONTIERS IN PHARMACOLOGY, vol. 9, no. 52, 2018, pages 1 - 31
J. PHARM. SCI, vol. 66, 1977, pages 1 - 19
KAMBUR O.; CAJANUS K.; KAUNISTO M.; WINSVOLD BENDIK; STUBHAUG AUDUN; ZWART JOHN A.; NIELSEN CHRISTOPHER S.; KALSO E.: "Genetic variation inP2RX7and pain", SCANDINAVIAN JOURNAL OF PAIN, ELSEVIER, AMSTERDAM, NL, vol. 12, 1 January 1900 (1900-01-01), AMSTERDAM, NL , pages 127, XP029632654, ISSN: 1877-8860, DOI: 10.1016/j.sjpain.2016.05.030 *
KIMIKO KOBAYASHI; EMIKO TAKAHASHI; YASUKO MIYAGAWA; HIROKI YAMANAKA; KOICHI NOGUCHI;: "Induction of the P2X7 receptor in spinal microglia in a neuropathic pain model", NEUROSCIENCE LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 504, no. 1, 30 August 2011 (2011-08-30), AMSTERDAM, NL , pages 57 - 61, XP028306292, ISSN: 0304-3940, DOI: 10.1016/j.neulet.2011.08.058 *
LANCET NEUROL., vol. 14, no. 2, February 2015 (2015-02-01), pages 162 - 73
MAGDALENA LANG;ROI TREISTER;MAX KLEIN;ANNE LOUISE OAKLANDER: "Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex for treating facial neuropathic pain ? preliminary results of a randomized, sham-controlled, cross-over study", MOLECULAR PAIN, BIOMED CENTRAL, LONDON, GB, vol. 10, no. Suppl 1, 15 December 2014 (2014-12-15), GB , pages P6, XP021205150, ISSN: 1744-8069, DOI: 10.1186/1744-8069-10-S1-P6 *
MOLECULAR PAIN, no. 10:37, 2014, pages 1 - 11
NAT MED, vol. 18, 2013, pages 595 - 599
NEUROSCIENCE LETTERS, vol. 504, 2011, pages 57 - 61
OLEG KAMBUR, MARI A. KAUNISTO, BENDIK S. WINSVOLD, TOM WILSGAARD, AUDUN STUBHAUG, JOHN A. ZWART, EIJA KALSO, CHRISTOPHER S. NIELSE: "Genetic variation in P2RX7 and pain tolerance :", PAIN, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL, vol. 159, no. 6, 1 June 2018 (2018-06-01), NL , pages 1064 - 1073, XP055729108, ISSN: 0304-3959, DOI: 10.1097/j.pain.0000000000001188 *
PAIN, vol. 114, no. 3, 2005, pages 386 - 396
PAIN, vol. 152, no. 8, 2011, pages 1766 - 1776
PAIN, vol. 159, 2018, pages 1064 - 1073
PHARMACIA, vol. 48, no. 8, 2012, pages 761 - 766
PRISCA HONORE, DIANA DONNELLY-ROBERTS, MARIAN T. NAMOVIC, GIN HSIEH, CHANG Z. ZHU, JOE P. MIKUSA, GRICELDA HERNANDEZ, CHENGMIN ZHO: "A-740003 [N-(1-{[(Cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a Novel and Selective P2X7 Receptor Antagonist, Dose-Dependently Reduces Neuropathic Pain in the Rat", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 319, no. 3, 1 December 2006 (2006-12-01), US , pages 1376 - 1385, XP009536893, ISSN: 0022-3565, DOI: 10.1124/jpet.106.111559 *
PURINERGIC SIGNAL, vol. 5, no. 2, 2009, pages 257 - 262
RANDALL LO ET AL., ARCH. INT. PHARMACODYN. THER., vol. 111, 1957, pages 409 - 419
See also references of EP4272758A4
THE FASEB JOURNAL, vol. 24, 2010, pages 2916 - 2927
THE JOURNAL OF BIOCHEMISTRY, vol. 81, no. 10, 2009, pages 884 - 890
THE JOURNAL OF JAPAN SOCIETY FOR CLINICAL ANESTHESIA, vol. 29, no. 1, 2009, pages 35 - 42
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 319, 2006, pages 1376 - 1385
XU, LAN: "The Mechanisms Underlying the Involvement of Spinal P2X7 Receptor in Painful Diabetic Neuropathy.", DIABETES, AMERICAN DIABETES ASSOCIATION, US, vol. 66, no. 1 suppl, 1 June 2017 (2017-06-01), US , pages A149 - A150, XP055934719, ISSN: 0012-1797, DOI: 10.2337/db17-381-663 *
YING YAN-LU, WEI XU-HONG, XU XUE-BING, SHE SHOU-ZHANG, ZHOU LI-JUN, LV JING, LI DAI, ZHENG BIN, LIU XIAN-GUO: "Over-expression of P2X7 receptors in spinal glial cells contributes to the development of chronic postsurgical pain induced by skin/muscle incision and retraction (SMIR) in rats", EXPERIMENTAL NEUROLOGY, ELSEVIER, AMSTERDAM, NL, vol. 261, 1 November 2014 (2014-11-01), AMSTERDAM, NL , pages 836 - 843, XP055934723, ISSN: 0014-4886, DOI: 10.1016/j.expneurol.2014.09.007 *
ZHANG WEN-JUN; ZHU ZHENG-MING; LIU ZENG-XU: "The role and pharmacological properties of the P2X7 receptor in neuropathic pain", BRAIN RESEARCH BULLETIN, ELSEVIER SCIENCE LTD, OXFORD., GB, vol. 155, 25 November 2019 (2019-11-25), GB , pages 19 - 28, XP085989604, ISSN: 0361-9230, DOI: 10.1016/j.brainresbull.2019.11.006 *

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