WO2010029995A1 - Agent thérapeutique contre la douleur - Google Patents

Agent thérapeutique contre la douleur Download PDF

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WO2010029995A1
WO2010029995A1 PCT/JP2009/065911 JP2009065911W WO2010029995A1 WO 2010029995 A1 WO2010029995 A1 WO 2010029995A1 JP 2009065911 W JP2009065911 W JP 2009065911W WO 2010029995 A1 WO2010029995 A1 WO 2010029995A1
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pain
substituted
unsubstituted
therapeutic agent
preventive
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PCT/JP2009/065911
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Japanese (ja)
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由充 加藤
陽三 小島
史郎 白倉
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協和発酵キリン株式会社
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    • C07D215/38—Nitrogen atoms

Definitions

  • the present invention is associated with inflammatory pain, postoperative pain, diabetic neuropathic pain, HIV-related pain, cancer pain, and cancer chemotherapy containing a pentadienamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to a preventive and / or therapeutic agent for pain (pain) selected from pain.
  • pain is nociceptive pain caused by persistent stimulation of nociceptors by endogenous pain substances, etc., and neuropathic pain caused by abnormalities in the function of nerve fibers involved in nerve transmission , And psychogenic pain.
  • Inflammatory pain included in nociceptive pain is pain associated with inflammation caused by osteoarthritis, rheumatoid arthritis, cancer, surgery, trauma, etc.
  • pain-causing substances bradykinin, serotonin in peripheral damaged tissues
  • the production of pain-inducing substances prostaglandins, inflammatory cytokines, etc.
  • Non-steroidal anti-inflammatory analgesics and opioid analgesics are used to treat inflammatory pain.
  • conventional NSAIDs have side effects such as gastrointestinal disorders (digestive ulcers, bleeding), renal dysfunction, and decreased platelet aggregation function, so their use may be limited in pain management of inflammatory pain.
  • opioid analgesics have side effects such as constipation, nausea, vomiting, drowsiness, respiratory depression, etc. If the dose is reduced to avoid such risks, the pain may not be relieved appropriately. Therefore, development of a therapeutic agent for inflammatory pain having a strong analgesic action and few side effects is desired.
  • TRPV1 Transient Receptor Potential Vanilloid 1 receptor antagonist capsazepine and N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl ) Tetrahydropyrazine-1 (2H) -carboxamide (BCTC), 1-isoquinolin-5-yl-3- (4-trifluoromethylbenzyl) urea (A-425619), N- (4- [6- (4- Trifluoromethylphenyl) pyrimidin-4-yloxy] benzothiazol-2-yl) acetamide (AMG517) is known to be effective in animal models of inflammatory pain [The Journal of Pharmacology The Journal of Pharmacologic and Experimental Therapeutics, 2003, 304, p.56; 2003, 306, p.387; 2005, 314 , P. 410; ibid, 2007, 323, p. 128].
  • Postoperative pain is one of the biggest acute pains experienced by patients, but recently, postoperative pain is not just a pain that is considered as an acute pain, but also a concept of prolonged postoperative pain As refractory chronic pain, it has been elucidated that it can be a cause of pain afterwards.
  • Specific examples of postoperative pain include chest thoracotomy, pain after laparotomy, pain after mastectomy, pain after orthopedic surgery, pain after tooth extraction, and the like.
  • local anesthetics using nerve blocks, NSAIDs, opioid analgesics and the like are used for pharmacological treatment of postoperative pain.
  • NSAIDs and opioid analgesics are known for the above-mentioned side effects, and due to these side effects, doses cannot be increased, and there are cases where sufficient analgesic effects for treatment cannot be obtained. Therefore, development of a postoperative pain therapeutic agent having a strong analgesic action and few side effects is desired.
  • TRPV1 receptor antagonist A-425619 and (E) -N- (7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)- 3- (2- (Piperidin-1-yl) -6- (trifluoromethyl) pyridin-3-yl) acrylamide (AMG0347) is known to be effective in animal models of postoperative pain [The ⁇ The Journal of Pharmacology and Experimental Therapeutics, 2005, Vol.314, p.410; Anesthesiology, 2008, 108 Volume, p.1100].
  • Cancer pain is a symptom that appears as cancer progresses, and 30 to 50% of all cancer patients experience 75 to 95% of patients with metastatic or advanced cancer.
  • causes of the pain include inflammation around the cancer, nerve compression caused by the cancer, bone metastasis, and the like. Pain causes discomfort and dysfunction and significantly reduces the patient's quality of life (QOL).
  • QOL quality of life
  • TRPV1 receptor antagonist 4- (3-trifluoromethylpyridin-2-yl) piperazine-1-carboxylic acid (5-trifluoromethylpyridine-2- Il) amide (JNJ-17203212) and capsazepine are known to be effective in animal models of cancer pain [The Journal of Neuroscience, 2005, Volume 25 , P. 3126; Neuroscience Letter, 2006, volume 393, p. 70].
  • Neuropathic pain includes post-herpetic neuralgia, diabetic neuropathic pain, HIV-related pain, trigeminal neuralgia, fibromyalgia, etc., as well as pain associated with cancer chemotherapy.
  • chemotherapy may be used for the purpose of treating, prolonging life, relieving symptoms, and improving quality of life (QOL).
  • Vinca alkaloid preparations such as vincristine used in chemotherapy, taxane preparations such as paclitaxel, platinum complex preparations such as cisplatin, as side effects, damage the axon function of nerve cells, pain and numbness, sensory disturbances, etc. May cause peripheral neuropathy.
  • Diabetic neuropathic pain is intractable pain that develops with diabetic neuropathy. Diabetic neuropathy is the most frequently developed peripheral neuropathy and is said to occur in about 30% of diabetic patients [Journal of Neurology, Volume 243. , P.431 (1996)]. The onset mechanism of diabetic neuropathic pain is unclear, but the functional and plasticity of the peripheral and central nervous systems is affected by neuronal axonal atrophy and demyelination, ion channel abnormalities, polyol metabolic pathway abnormalities, etc. It is believed to be caused as a result of changes [Diabetologia, Vol. 43, p.957 (2000); Diabetes Metab. Res. Rev.], Volume 19, p.S9 (2003)].
  • Treatment includes gabapentin, pregabalin, duloxetine, capuisaicin ointment, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin / noradrenaline reuptake inhibitors, antiepileptic drugs, anticonvulsants, antiarrhythmic drugs, etc.
  • TRPV1-selective receptor antagonists Although there has been no report on the analgesic action of TRPV1-selective receptor antagonists using diabetic neuropathic pain model animals, it is known that anti-TRPV1 serum is effective in diabetic neuropathic pain model animals [European Journal of Pharmacology, 2001, Vol. 422, p. 83]. In addition, it has been revealed that the function of TRPV1 receptor is enhanced in dorsal root ganglia of diabetic animals, indicating that TRPV1 receptor may be involved in diabetic pain [Journal ⁇ Of Biological Chemistry (Journal of biological chemistry), 2005, Vol.280, p.618].
  • HIV-related pain is one of the most frequent symptoms of neuropathy in HIV infection and AIDS and is seen in more than 1/3 of patients with neuropathy [CNS Drugs, 2005 , Volume 19, p.325].
  • the mechanism of HIV-related pain is not well understood, but recent research suggests that the action of the envelope glycoprotein gp120 present on the surface of HIV virus on nerves or glial cells is involved in the development of pain.
  • TRPV1 receptor antagonist containing a compound used in the present invention as an active ingredient is known (see Patent Document 1).
  • the object of the present invention is to provide inflammatory pain, postoperative pain, diabetic neuropathic pain, HIV-related pain, cancer pain, and cancer chemistry containing, for example, a pentadienamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a preventive and / or therapeutic agent for pain selected from pain associated with therapy.
  • the present invention relates to the following (1) to (48).
  • R 1 represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group
  • R 2 represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted alicyclic heterocyclic group.
  • R 3 represents a hydrogen atom, or together with R 4 and an adjacent nitrogen atom, forms a substituted or unsubstituted heterocyclic group
  • R 4 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted alicyclic heterocyclic group.
  • R 5 , R 6 and R 7 are the same or different and each represents a hydrogen atom or methyl), or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a prophylactic and / or therapeutic agent for pain selected from diabetic neuropathic pain, HIV-related pain, cancer pain, and pain associated with cancer chemotherapy.
  • R 3 and R 4 together with the adjacent nitrogen atom form a substituted or unsubstituted thiomorpholino.
  • R 3 and R 4 together with the adjacent nitrogen atom form a substituted or unsubstituted piperidino or substituted or unsubstituted piperazinyl, and / or the prevention of pain according to (1) or (2) Therapeutic agent.
  • R 4 is substituted or unsubstituted aryl.
  • a method for preventing and / or treating pain selected from HIV-related pain, cancer pain, and pain associated with cancer chemotherapy.
  • the method for preventing and / or treating pain according to (28), wherein the pain is postoperative pain.
  • the method for preventing and / or treating pain according to (28), wherein the pain is cancer pain.
  • the method for preventing and / or treating pain according to (28), wherein the pain is pain associated with cancer chemotherapy.
  • the method for preventing and / or treating pain according to (28), wherein the pain is diabetic neuropathic pain.
  • the method for preventing and / or treating pain according to (28), wherein the pain is HIV-related pain.
  • a prophylactic and / or therapeutic agent for pain selected from inflammatory pain, postoperative pain, diabetic neuropathic pain, HIV-related pain, cancer pain, and pain associated with cancer chemotherapy ( Use of the compound according to any one of 1) to (21) or a pharmaceutically acceptable salt thereof.
  • the use according to (35), wherein the pain is inflammatory pain.
  • the use according to (35), wherein the pain is postoperative pain.
  • the use according to (35), wherein the pain is cancer pain.
  • the use according to (35), wherein the pain is pain associated with cancer chemotherapy.
  • the use according to (35), wherein the pain is diabetic neuropathic pain. (41) The use according to (35), wherein the pain is HIV-related pain.
  • (42) For use in the prevention and / or treatment of pain selected from inflammatory pain, postoperative pain, diabetic neuropathic pain, HIV-related pain, cancer pain, and pain associated with cancer chemotherapy (1) ) To (21) or a pharmaceutically acceptable salt thereof. (43) The agent according to (42), wherein the pain is inflammatory pain. (44) The agent according to (42), wherein the pain is postoperative pain. (45) The agent according to (42), wherein the pain is cancer pain. (46) The agent according to (42), wherein the pain is pain associated with cancer chemotherapy. (47) The agent according to (42), wherein the pain is diabetic neuropathic pain. (48) The agent according to (42), wherein the pain is HIV-related pain.
  • a pentadienamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • An agent for preventing and / or treating pain selected from accompanying pain is provided.
  • FIG. 1 shows the improvement rate (%) of hyperalgesia 3% after administration of a test compound in the compound 332 administration group in a rat CFA (rat complete Freundo adjuvant) -induced inflammatory pain model.
  • FIG. 2 shows the improvement rate (%) of hyperalgesia in the rat CFA-induced inflammatory pain model in the compound 257 administration group 4 hours after administration of the test compound.
  • each group of formula (I) examples include linear or branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Examples include butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • cycloalkyl examples include cycloalkyl having 3 to 10 carbon atoms, and more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, noradamantyl, adamantyl, bicyclo [2.2. 1) heptyl, bicyclo [2.2.2] octyl, bicyclo [3.3.0] octyl, bicyclo [3.3.1] nonyl and the like.
  • cycloalkenyl examples include cycloalkenyl having 3 to 10 carbon atoms, and more specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like.
  • aryl examples include aryl having 6 to 14 carbon atoms, and more specifically include phenyl, naphthyl, indenyl, anthryl and the like.
  • Aryl is, for example, aryl condensed with a cyclohexyl group, such as 1,2,3,4-tetrahydronaphthalene, or 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquino.
  • Ril dihydroquinoxalinyl, tetrahydroquinoxalinyl, dihydrobenzofuranyl, chromanyl, isochromanyl, benzoxazinyl, dihydrobenzoxazinyl, cihydrobenzodioxinyl, 1,3-benzodioxolyl, etc.
  • An aryl fused with an alicyclic heterocyclic group may be used.
  • aromatic heterocyclic group for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring are condensed.
  • Examples of the alicyclic heterocyclic group include a 5-membered or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and a 3- to 8-membered ring. And a condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, pyrrolidinyl, pyrrolidonyl, etc.
  • the heterocyclic group formed together with the adjacent nitrogen atom includes an aromatic heterocyclic group formed together with the adjacent nitrogen atom or an alicyclic ring formed together with the adjacent nitrogen atom. And a formula heterocyclic group.
  • the aromatic heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one nitrogen atom (the monocyclic aromatic group).
  • a heterocyclic group may contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic condensed 3- to 8-membered ring and containing at least one nitrogen atom
  • Aromatic heterocyclic group (the condensed aromatic heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom) and the like, more specifically pyrrolyl, imidazolyl, indolyl, Indazolyl, carbazolyl, pyrazolyl and the like can be mentioned.
  • Examples of the alicyclic heterocyclic group formed together with the adjacent nitrogen atom include a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one nitrogen atom (the monocyclic An alicyclic heterocyclic group may contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic fused 3-8 membered ring and contains at least one nitrogen atom
  • a condensed alicyclic heterocyclic group (the condensed alicyclic heterocyclic group may contain other nitrogen, oxygen or sulfur atoms), and more specifically pyrrolidinyl.
  • the substituents in the substituted alicyclic heterocyclic group formed together with the adjacent nitrogen atom are the same or different, for example, 1 to 3 substituents, more specifically halogen, hydroxy, Amino, hydroxyimino, amidino, hydroxyamidino, nitro, mercapto, cyano, carboxy, methylenedioxy, ethylenedioxy, carbamoyl, sulfamoyl, sulfamoyloxy, lower alkenyl, cycloalkenyl, lower alkynyl, lower alkoxycarbonyl, mono or Di-lower alkylcarbamoyl, lower alkyl Rufinyl, lower alkyls
  • Substituted, unsubstituted lower alkanoylamino may be the same or different, for example, more specifically 1 to 3 substituents.
  • substituted or unsubstituted lower alkylsulfonyl substituted or unsubstituted lower alkylsulfonyl are the same or different, for example, having 1 to 3 substituents, more specifically, Halogen, hydroxy, cyano and the like
  • substituted or unsubstituted lower alkoxy substituted or unsubstituted lower alkoxy [substituents in the substituted lower alkoxy are the same or different, for example, having 1 to 3 substituents, more specifically halogen, amino Mono or di (lower alkyl) amino, hydroxy, cyano, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, cycloalkyl, lower
  • Substituted or unsubstituted lower alkanoyl substituted or different and include, for example, 1 to 3 substituents, more specifically halogen, etc.
  • substituted or non-substituted Substituted aryl substituted or non-substituted Substituted aryl
  • substituted or non-substituted A substituted aralkyl the substituents in the substituted aralkyl are the same or different,
  • the number of substituents is 1 to 3, more specifically, halogen, hydroxy, lower alkoxy and the like, and substituted or unsubstituted aromatic heterocyclic groups (substituents in the substituted aromatic heterocyclic groups are the same) Or differently, for example, having 1 to 3 substituents, more specifically,
  • a substituted aryl, a substituted aromatic heterocyclic group, a substituted alicyclic heterocyclic group, a substituted aromatic heterocyclic group formed together with an adjacent nitrogen atom, and an adjacent nitrogen atom are formed.
  • the substituent in the substituted alicyclic heterocyclic group is a substituted or unsubstituted lower alkyl (the substituents in the substituted lower alkyl are the same or different, for example, 1 to 3 substituents, more specifically halogen Amino, hydroxy, hydroxyimino, cyano, mono- or di-lower alkylamino, aromatic heterocyclic group, alicyclic heterocyclic group, and the like.
  • the substituent in the substituted alicyclic heterocyclic group formed together with the substituted lower alkyl, the substituted alicyclic heterocyclic group and the adjacent nitrogen atom may be oxo.
  • the substituent in the case where the substituted aryl is an aryl condensed with a substituted alicyclic heterocyclic group includes oxo.
  • an alicyclic heterocyclic group, an aromatic heterocyclic group, an aromatic heterocyclic group formed together with an adjacent nitrogen atom, and a substituted alicyclic heterocyclic formed together with an adjacent nitrogen atom When the ring group has a nitrogen atom and / or a sulfur atom in the ring, the nitrogen atom and / or the sulfur atom may be oxidized.
  • lower alkyl, cycloalkyl, cycloalkenyl, aryl, aromatic heterocyclic group and alicyclic heterocyclic group have the same meanings as described above.
  • the halogen include fluorine, chlorine, bromine, and iodine atoms.
  • the lower alkyl-substituted alicyclic heterocyclic group and the lower alkyl moiety of lower alkylthio have the same meaning as the lower alkyl.
  • the two lower alkyl moieties in di-lower alkylamino and di-lower alkylcarbamoyl may be the same or different.
  • the cycloalkylene moiety in the lower alkyl-substituted cycloalkyl has the same meaning as that obtained by removing one hydrogen atom from the cycloalkyl.
  • the cycloalkyl moiety in cycloalkyloxy has the same meaning as the above cycloalkyl.
  • alkylene part in aralkyl, aralkyloxy, alicyclic heterocyclic alkyloxy and hydroxyalkyl has the same meaning as that obtained by removing one hydrogen atom from the lower alkyl.
  • lower alkenyl include linear or branched alkenyl having 3 to 10 carbon atoms, and more specifically, allyl, 2-butenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, Examples include 6-heptenyl, 6-octenyl, 2,6-octadienyl, 9-decenyl and the like.
  • lower alkynyl examples include linear or branched alkynyl having 3 to 6 carbon atoms, and more specifically, propargyl, 3-butynyl, 3-hexynyl, 4-methyl-2-pentynyl and the like. Can be mentioned.
  • Examples of the lower alkanoyl part of lower alkanoyl and lower alkanoylamino include linear or branched alkanoyl having 1 to 8 carbon atoms, and more specifically formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl. , Isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like.
  • the aryl part of aralkyl, aryloxy, aralkyloxy and aroyl has the same meaning as the above aryl.
  • the alicyclic heterocyclic group part in alicyclic heterocyclic oxy and alicyclic heterocyclic alkyloxy is synonymous with the said alicyclic heterocyclic group.
  • the alicyclic heterocyclic group moiety in the lower alkyl-substituted alicyclic heterocyclic group has the same meaning as that obtained by removing one hydrogen atom from the alicyclic heterocyclic group.
  • aromatic heterocyclic group moiety in the aromatic heterocyclic aminosulfonyl has the same meaning as the aromatic heterocyclic group.
  • compound (I) or a pharmaceutically acceptable salt thereof can be used as the preventive and / or therapeutic agent for pain of the present invention.
  • R 5 , R 6 and R 7 are each hydrogen.
  • Compound (I) which is an atom or a pharmaceutically acceptable salt thereof, (ii) Compound (I) wherein R 1 and R 2 are substituted or unsubstituted aryl, or a pharmaceutically acceptable salt thereof (iii) ) Compound (I), wherein R 3 is a hydrogen atom and R 4 is substituted or unsubstituted tetrahydroquinolyl, or a pharmaceutically acceptable salt thereof can be used. More preferably, the compound of the aspect which combined two or three said (i), (ii) and (iii) can be used. More preferably, a compound selected from compounds 188, 191, 229, 240, 257, 270, 310, 314 and 332 can be used.
  • Examples of the pharmaceutically acceptable salt of compound (I) include pharmaceutically acceptable metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, acid addition salts, and the like.
  • Examples of the pharmaceutically acceptable metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt, and the like.
  • Examples of ammonium salts include ammonium and tetramethylammonium salts
  • pharmaceutically acceptable organic amine addition salts include addition salts such as morpholine and piperidine, which are pharmaceutically acceptable.
  • Examples of amino acid addition salts include addition salts of amino acids such as lysine, glycine, and phenylalanine.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloride, sulfate, and phosphate, Examples thereof include organic acid salts such as acetate, maleate, fumarate, tartrate and citrate.
  • Compound (I) and a pharmaceutically acceptable salt thereof in the present invention may exist in the form of an adduct with water or various solvents, and these adducts are also used for the prevention of pain and / or the present invention. Can be used for therapeutic agents.
  • the compound (I) may be purified as it is when it is obtained in the form of a salt. It may be isolated or purified by dissolving or suspending in an appropriate solvent and adding an acid or base to form a salt.
  • Some compounds (I) in the present invention may have various stereoisomers, positional isomers, tautomers, enantiomers and the like. All the possible isomers and mixtures thereof can be used for the preventive and / or therapeutic agent for pain of the present invention, and the mixing ratio may be any ratio. Next, the manufacturing method of the compound used by this invention is demonstrated. Compound (I) or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in WO2008 / 007780. Specific examples of the compounds used in the present invention are shown in Tables 1 to 6, but the compounds used for the preventive and / or therapeutic agents for pain of the present invention are not limited thereto.
  • Intermediates and target compounds in the above production method are isolated and purified by subjecting them to separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. Can do.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • Compound (I) or a pharmaceutically acceptable salt thereof can be used for the prevention and / or treatment of inflammatory pain, and preferably can be used for the prevention and / or treatment of chronic inflammatory pain, More preferably, it can be used for the prevention and / or treatment of pain associated with arthritis such as osteoarthritis and rheumatoid arthritis.
  • postoperative pain include chest thoracotomy, pain after laparotomy, pain after mastectomy, pain after orthopedic surgery, pain after tooth extraction, and the like.
  • Compound (I) or a pharmaceutically acceptable salt thereof can be used for the prevention and / or treatment of postoperative pain.
  • Cancer pain is a symptom that appears as cancer progresses, and the causes of the pain are known to be inflammation around the cancer, nerve compression due to cancer, bone metastasis, and the like.
  • Cancer pain includes, for example, pain associated with various cancers such as breast cancer, prostate cancer, ovarian cancer, uterine cancer, lung cancer, bone cancer, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colon cancer, skin cancer, and tongue cancer. Is mentioned.
  • Compound (I) or a pharmaceutically acceptable salt thereof can be used for the prevention and / or treatment of cancer pain, and preferably used for the prevention and / or treatment of cancer pain associated with bone metastasis. Can do.
  • Neuropathic pain includes postherpetic neuralgia, diabetic neuropathic pain, HIV-related pain, trigeminal neuralgia, pain associated with cancer chemotherapy, fibromyalgia and the like.
  • vinca alkaloid preparations such as vincristine used in chemotherapy, taxane preparations such as paclitaxel, and platinum complex preparations such as cisplatin, as side effects, damage the axon function of nerve cells, causing pain and numbness.
  • peripheral neuropathy such as sensory disorder
  • pain associated with these neuropathies is classified as pain associated with cancer chemotherapy.
  • Compound (I) or a pharmaceutically acceptable salt thereof can be used for the prevention and / or treatment of neuropathic pain, and preferably used for the prevention and / or treatment of pain associated with cancer chemotherapy. Can do.
  • Test Example 1 Analgesic effect in rat model of complete Freund's adjuvant (CFA) -induced inflammatory pain Crl: CD (SD) rats (male, 5 weeks old, Charles River, Japan) Freund's adjuvant (CFA) (DIFCO Laboratories) 100 ⁇ L was subcutaneously administered to induce inflammatory pain.
  • Compound 332 was evaluated 24 hours after CFA administration, and compound 257 was evaluated 7 days after CFA administration.
  • Hot / Cold® Plate® 35100® manufactured by Ugo® Basile
  • Rats were placed on a hot plate maintained at a temperature of 48 ° C., and the time (latency) until a pain reaction such as licking, biting, or shaking of the treated side was measured.
  • the rats were left in the laboratory for about 1 hour, and the latency before drug administration was measured.
  • the latency of normal rats was about 30 seconds, but the latency of CFA-induced inflammatory pain rats with CFA was about 15 seconds, confirming a reduction in latency that was recognized as hyperalgesia.
  • the test compound was administered to this CFA-induced inflammatory pain model according to the following procedure, the latency was measured, and the improvement rate was calculated from the following formula.
  • Compound 332 was suspended in 0.5% methylcellulose (0.5% MC) aqueous solution at concentrations of 0.6 and 2 mg / mL, and doses of 3 and 10 mg / kg were orally administered.
  • Compound 257 was suspended in 0.5% aqueous MC solution at concentrations of 2 and 6 mg / mL, and doses of 10 and 30 mg / kg were orally administered.
  • 0.5% MC aqueous solution was orally administered to a CFA-induced inflammatory pain model. The test was conducted with 8 animals in each group. For Compound 332, the improvement rate 3 hours after its administration was calculated, and for Compound 257, the improvement rate 4 hours after its administration was calculated.
  • Crl CD (SD) rats (male, 5 weeks old, Charles River Japan, Inc.) were anesthetized with pentobarbital (50 mg / kg, intraperitoneal administration) and the sole of the left hind limb was disinfected with popidone iodine. Thereafter, the skin and fascia were incised approximately 1 cm from a position 0.5 mm from the heel. Thereafter, the plantar muscle was lifted with tweezers, and an incision was made about 1 cm. After compression and hemostasis with absorbent cotton, the skin was sutured with two nylon sutures. For evaluation of pain, a plantar test apparatus (manufactured by Ugo Basile) was used.
  • the rat was placed in an acrylic cage (width 390 mm ⁇ depth 210 mm ⁇ height 145 mm, rat 4-chamber cage, manufactured by Ugo Basile) for about 20 minutes to get used to the surrounding environment. Thereafter, radiant heat was applied to the left hind limb incision of the rat, and the time (latency) until an escape reaction (lifting the foot) before drug administration was measured was measured.
  • the latency of normal rats was about 17-19 seconds, but the postoperative pain model rats had a latency of about 7-9 seconds on the surgical foot, confirming a shortened latency that was recognized as hyperalgesia. .
  • test compound was administered to the postoperative pain model according to the following procedure, the latency was measured 3 hours after administration, and the improvement rate was calculated in the same manner as in Test Example 1.
  • Compound 332 was suspended in an aqueous 0.5% methylcellulose (0.5% MC) solution at a concentration of 2 mg / mL, and a dose of 10 mg / kg was orally administered.
  • Compound 257 was suspended in 0.5% MC aqueous solution at a concentration of 6 mg / mL, and was orally administered at a dose of 30 mg / kg.
  • a solvent administration group a group in which 0.5 mL MC aqueous solution was orally administered to a postoperative pain model was provided. The test was conducted with 8 animals in each group.
  • the improvement rate of the compound 332 administration group was 63.0 ⁇ 11.4%, which was significantly higher than the improvement rate of the solvent administration group ( ⁇ 5.9 ⁇ 8.0%). That is, it has been clarified that Compound 332 exhibits a pain suppressing effect in an animal model of postoperative pain.
  • the improvement rate of the compound 257 administration group was 81.7 ⁇ 21.2%, which was significantly higher than the improvement rate of the solvent administration group (3.9 ⁇ 20.4%). That is, it has been clarified that Compound 257 exhibits a pain suppressing effect in an animal model of postoperative pain.
  • Test Example 3 Analgesic effect in mouse cancer pain model A report by Honore et al. [Neuroscience, 2000, Vol. 98, p.585] was used to prepare a cancer pain model.
  • C3H / He mice male, 4 weeks old, Nippon Charles River
  • pentobarbital 50-60 mg / kg, intraperitoneal administration
  • the skin of the left knee joint was about 5
  • An incision was made, and a 26-gauge injection needle was inserted into the bone marrow cavity from the distal end of the femur to open a hole for cell implantation.
  • 10 ⁇ L of a cell solution containing 2.5 ⁇ 10 4 tumor cells (NCTC 2472 osteolytic sarcoma cell, purchased from American Type Culture Collection) was injected into the bone marrow cavity. Thereafter, the skin was sutured. Pain assessment was performed 2-3 weeks after the creation of the cancer pain model.
  • the time for guarding behavior was measured according to the report of Honore et al. That is, the mouse was allowed to walk freely on the observation wire mesh, and the time during which the left hind limb was raised (guarding behavior) out of the observation time of 2 minutes was measured and used as an index of pain behavior. Normal animals did not show guarding behavior, but a guarding behavior of about 10 seconds was observed in the cancer pain model.
  • the test compound was administered to the above cancer pain model animal according to the following procedure, and the guarding time in the observation period of 2 minutes was measured 3 hours later.
  • Compound 332 was suspended in an aqueous 0.5% methylcellulose (0.5% MC) solution at a concentration of 2 mg / mL, and a dose of 10 mg / kg was orally administered.
  • Compound 257 was suspended in 0.5% MC aqueous solution at a concentration of 6 mg / mL, and a dose of 30 mg / kg was orally administered.
  • a solvent administration group a group in which 0.5 mL MC aqueous solution was orally administered to cancer pain mice was provided. Using 10 animals in each group, the average value of guarding action time ⁇ standard error was obtained.
  • the guarding action time per observation time of 2 minutes was 9.3 ⁇ 1.0 seconds in the solvent administration group and 5.7 ⁇ 1.0 seconds in the compound 332 administration group. Compared to the solvent-administered group, the guarding action time was significantly shortened in the compound 332-administered group. That is, Compound 332 showed a pain suppressing effect in an animal model of cancer pain.
  • the guarding behavior time per observation time of 2 minutes was 11.0 ⁇ 1.1 seconds in the solvent administration group and 5.1 ⁇ 0.7 seconds in the compound 257 administration group. Compared to the solvent-administered group, the guarding action time was significantly shortened in the compound 257-administered group. That is, Compound 257 showed a pain suppressing effect in an animal model of cancer pain.
  • Compound (I) or a pharmaceutically acceptable salt thereof suppresses pain behavior in a cancer pain model. Therefore, Compound (I) or a pharmaceutically acceptable salt thereof is effective for the prevention and / or treatment of cancer pain. That is, compound (I) or a pharmaceutically acceptable salt thereof is, for example, breast cancer, prostate cancer, ovarian cancer, uterine cancer, lung cancer, bone cancer, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colon cancer, skin It became clear that it is useful for the treatment and prevention of pain associated with various cancers such as cancer and tongue cancer.
  • Test Example 4 Paclitaxel with reference to the report of the analgesic effect of Flatters et al.
  • the pain was evaluated according to the report of Flatters et al. Place the rat in a transparent acrylic cage (390 mm wide x 210 mm deep x 145 mm high, 4 rat cage, manufactured by Ugo Basile) with a metal mesh on the bottom, and leave the surrounding environment for about 20 minutes. After habituation, the von Frey filament (von Frey filament (trade name: touch test ⁇ sensory evaluator, manufactured by Muromachi Kikai Co., Ltd.)) with a bending pressure of 10 g is vertically placed in the middle of the sole of the hind limb until the filament bends 5 Pressed for 2 seconds and observed for escape behavior (withdrawal of foot).
  • von Frey filament Japanese Frey filament (trade name: touch test ⁇ sensory evaluator, manufactured by Muromachi Kikai Co., Ltd.)
  • a bending pressure of 10 g is vertically placed in the middle of the sole of the hind limb until the filament bends 5 Pressed for 2 seconds and observed for escape behavior (
  • Compound 332 or compound 257 was administered to the above-mentioned paclitaxel-induced painful neuropathy model animal by the following procedure, and the response rate of escape behavior was measured 3 hours after administration of compound 332 and 1 hour after administration of compound 257. .
  • Compound 332 was suspended in an aqueous solution of 0.5% methylcellulose (0.5% MC) at a concentration of 2 mg / mL, and a dose of 10 mg / kg was orally administered.
  • Compound 257 was suspended in a 0.5% aqueous MC solution at a concentration of 6 mg / mL, and a dose of 30 mg / kg was orally administered.
  • a solvent administration group a group in which 0.5% MC aqueous solution was orally administered to a paclitaxel-induced painful neuropathy model was provided. The test was conducted with 8 animals in each group.
  • the response rate of escape behavior 3 hours after administration was 72.5 ⁇ 5.3% in the solvent administration group and 42.5 ⁇ 3.7% in the Compound 332 administration group.
  • the compound 332 administration group showed a marked decrease in the response rate of escape behavior. That is, Compound 332 showed a pain-suppressing effect in an animal model of paclitaxel-induced neuropathic pain.
  • the response rate of the escape behavior 1 hour after administration was 67.5 ⁇ 5.6% in the solvent administration group and 45.0 ⁇ 8.2% in the Compound 257 administration group.
  • the compound 257-administered group showed a marked decrease in the response rate of escape behavior. That is, Compound 257 showed a pain-suppressing effect in an animal model of paclitaxel-induced neuropathic pain.
  • Test Example 5 An analgesic effect experiment in a rat streptozotocin-induced diabetic pain model was performed by the method of Calcutt et al. [British Journal of Pharmacology, 1997, Vol. 122, p.1478]. According to the same procedure. Streptozotocin (60 mg / kg) was intraperitoneally administered to male SD rats to develop diabetes.
  • the rat is placed in a cage made of metal mesh on the bottom and made of acrylic (width 390 mm ⁇ depth 210 mm ⁇ height 145 mm, rat quadruple cage, Ugo Basile, Comerio, VA, Italy)
  • the pain threshold was measured after acclimatization to the surrounding environment for 20 minutes.
  • von Frey filament trade name: touch test sensory evaluator, model number: model 58011, manufactured by Muromachi Kikai Co., Ltd.
  • Pain threshold is based on Dixon's up-down method [Annual Review of Pharmacology and Toxicology, 1980, Volume 20, p.411] Calculated.
  • diabetic rats having a pain threshold of less than 4 g were used.
  • Compound 332 was suspended in an aqueous solution of 0.5% methylcellulose (0.5% MC) at a concentration of 2 mg / mL, and a dose of 10 mg / kg was orally administered.
  • Compound 257 was suspended in 0.5% aqueous MC solution at a concentration of 6 mg / mL and orally administered at a dose of 30 mg / kg.
  • 0.5% MC aqueous solution was orally administered at 5 mL / kg.
  • the solvent administration group and drug administration group were 6 cases, and the normal animal group was 10 cases.
  • the pain threshold for normal rats was around 10 g.
  • the pain threshold was measured 3 hours after administration of the test compound (Compound 332 or Compound 257) and the solvent, and the improvement rate was calculated from the following formula.
  • the improvement rate of the compound 332 administration group was 74.0 ⁇ 22.6%, which was significantly higher than the improvement rate of the solvent administration group ( ⁇ 5.8 ⁇ 5.5%). That is, Compound 332 showed a pain suppressing effect in an animal model of diabetic pain.
  • the improvement rate of the compound 257 administration group was 75.7 ⁇ 22.4%, which was significantly higher than the improvement rate of the solvent administration group ( ⁇ 0.2 ⁇ 3.1%). That is, Compound 257 showed a pain suppressing effect in an animal model of diabetic pain.
  • Test Example 6 Analgesic inhibitory effect in mouse gp120-induced pain model (HIV-related pain model) A ddY male mouse is placed in a cage made of a metal mesh on the bottom and made of acrylic (width 390 mm x depth 210 mm x height 145 mm, 8-mouse cage, Ugo Basile, Comerio, VA, Italy), 120 The pain threshold was measured after acclimatization to the surrounding environment for a minute.
  • von Frey filament (trade name: touch test sensory evaluator, model number: model 58011, manufactured by Muromachi Kikai Co., Ltd.) was used. Pain threshold is based on Dixon's up-down method [Annual Review of Pharmacology and Toxicology, 1980, Volume 20, p.411] Calculated. Evaluate mice whose pain threshold is less than 0.5 g after 1 hour administration of 5 ⁇ L of gp120 solution (2 pg / ⁇ L, dissolved in phosphate buffer) into the medullary canal of mice with a pain threshold of 0.9 g or more Used for. Compound 332 was administered 1.5 hours after administration of the gp120 solution, and the pain threshold was measured 1 hour later.
  • Compound 332 was suspended in an aqueous 0.5% methylcellulose (0.5% MC) solution at a concentration of 1 mg / mL, and a dose of 10 mg / kg was orally administered.
  • the solvent administration group was orally administered with a 0.5% MC aqueous solution at 10 mL / kg.
  • the test was conducted in 7 cases in each group.
  • the improvement rate of the compound 332 administration group was 51.3 ⁇ 12.9%, which was significantly higher than the improvement rate of the solvent administration group (4.0 ⁇ 2.5%). That is, Compound 332 showed a pain suppressing effect in an HIV-related pain animal model.
  • Step 2 (2E, 4Z) -N-[(3R) -3-Hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolyl] -5- (4-isopropoxyphenyl) -5
  • 5- [4- (Trifluoromethyl) phenyl] -2,4-pentadienoic acid (6.00 g, 16.0 mmol) is dissolved in dimethylformamide (DMF, 120 mL), and compound a (3.21 g, 18.0 mmol), 1 -Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) hydrochloride (6.14 g, 32.0
  • Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
  • the pharmaceutical preparation according to the present invention can contain Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment.
  • These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmaceutically acceptable carriers (eg, diluents, solvents, excipients, etc.). It is formulated by any method.
  • the administration route it is desirable to use one that is most effective in the treatment, and can be oral or parenteral, such as intravenous.
  • the dosage form include tablets and injections.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution, or a mixed solution of a saline solution and a glucose solution.
  • the dose and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc.
  • the dose is 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult, once to several times a day.
  • parenteral administration such as intravenous administration
  • 0.001 to 1000 mg preferably 0.01 to 100 mg per adult is usually administered once to several times a day.
  • the dose and the number of doses vary depending on the various conditions described above.
  • Formulation Example 1 Tablet A tablet having the following composition is prepared by a conventional method. 40 g of Compound 257, 286.8 g of lactose and 60 g of potato starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. The obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this, 1.2 g of magnesium stearate is added and mixed, and tableting is performed with a tableting machine having a 8 mm diameter punch to obtain tablets (containing 20 mg of active ingredient per tablet).
  • Formula Compound 257 20 mg Lactose 143.4 mg
  • Formulation Example 2 Tablets As in Example 1, tablets are prepared with the following formulation.
  • Formula Compound 332 20 mg Lactose 143.4 mg
  • Potato starch 30 mg Hydroxypropylcellulose 6 mg
  • Magnesium stearate 0.6 mg 200 mg
  • Formulation example 3 Injection The injection which consists of the following compositions is prepared by a conventional method. 1 mg of Compound 257 is added to and mixed with distilled water for injection, and further, hydrochloric acid and aqueous sodium hydroxide solution are added to adjust the pH to 7. Then, the total volume is made up to 1000 mL with distilled water for injection. The obtained mixed solution is aseptically filled into glass vials by 2 mL to obtain an injection (containing 2 ⁇ g of active ingredient per vial).
  • Formulation Compound 257 2 ⁇ g Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount distilled water for injection appropriate amount 2.00 mL
  • Formulation Example 4 Injection An injection is prepared according to the following formulation in the same manner as in Example 3.
  • Formula Compound 332 2 ⁇ g Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount distilled water for injection appropriate amount 2.00 mL
  • a pentadienamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a prophylactic and / or therapeutic agent for pain selected from accompanying pain can be provided.

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Abstract

La présente invention concerne un agent prophylactique et/ou thérapeutique contre la douleur choisie parmi une douleur induite par une inflammation, une douleur post-opératoire, une douleur neurogène du diabète, une douleur associée au VIH, une douleur cancéreuse et une douleur neurogène associée à une chimiothérapie cancéreuse. Ledit agent comprend un dérivé de pentadiénamide représenté par la formule générale (I) [dans laquelle R1 représente un groupe aryle substitué ou non substitué ou un groupe hétérocyclique aromatique substitué ou non substitué ; R2 représente un groupe aryle substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou analogue ; R3 représente un atome d’hydrogène ou analogue ; R4 représente un groupe alkyle inférieur substitué ou non substitué, un groupe aryle substitué ou non substitué ou un groupe hétérocyclique alicyclique substitué, ou non substitué ou analogue ; et R5, R6 et R7 représentent indépendamment un atome d’hydrogène ou analogue] ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif ; et d’autres.
PCT/JP2009/065911 2008-09-11 2009-09-11 Agent thérapeutique contre la douleur WO2010029995A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014111592A (ja) * 2012-11-08 2014-06-19 Kao Corp 体感温度低減用外用剤
JPWO2013022080A1 (ja) * 2011-08-10 2015-03-05 国立大学法人富山大学 動物を用いた痺れ又は自発痛の評価方法

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JPH05230069A (ja) * 1992-02-20 1993-09-07 Yamanouchi Pharmaceut Co Ltd 新規なピロロチアゾ−ル誘導体
WO2005044786A1 (fr) * 2003-11-08 2005-05-19 Bayer Healthcare Ag Derives bicycliques d'amide, de carbamate ou d'uree tel que recepteur modulateurs vanilloïde
WO2008007780A1 (fr) * 2006-07-13 2008-01-17 Kyowa Hakko Kirin Co., Ltd. Dérivé du pentadiènamide
WO2008096755A1 (fr) * 2007-02-07 2008-08-14 Nippon Suisan Kaisha, Ltd. Inhibiteur du récepteur vanilloïde (vr1) et son utilisation
JP2008533177A (ja) * 2005-03-24 2008-08-21 ノボジェン リサーチ ピーティーワイ リミテッド 抗炎症治療法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05230069A (ja) * 1992-02-20 1993-09-07 Yamanouchi Pharmaceut Co Ltd 新規なピロロチアゾ−ル誘導体
WO2005044786A1 (fr) * 2003-11-08 2005-05-19 Bayer Healthcare Ag Derives bicycliques d'amide, de carbamate ou d'uree tel que recepteur modulateurs vanilloïde
JP2008533177A (ja) * 2005-03-24 2008-08-21 ノボジェン リサーチ ピーティーワイ リミテッド 抗炎症治療法
WO2008007780A1 (fr) * 2006-07-13 2008-01-17 Kyowa Hakko Kirin Co., Ltd. Dérivé du pentadiènamide
WO2008096755A1 (fr) * 2007-02-07 2008-08-14 Nippon Suisan Kaisha, Ltd. Inhibiteur du récepteur vanilloïde (vr1) et son utilisation

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WALKER, KATHARINE M ET AL.: "The VR1 antagonist Capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 304, no. 1, 2003, pages 56 - 62 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2013022080A1 (ja) * 2011-08-10 2015-03-05 国立大学法人富山大学 動物を用いた痺れ又は自発痛の評価方法
JP2014111592A (ja) * 2012-11-08 2014-06-19 Kao Corp 体感温度低減用外用剤

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