WO2018117166A1 - Dérivé de thiazole ou son sel pharmacologiquement acceptable - Google Patents

Dérivé de thiazole ou son sel pharmacologiquement acceptable Download PDF

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WO2018117166A1
WO2018117166A1 PCT/JP2017/045770 JP2017045770W WO2018117166A1 WO 2018117166 A1 WO2018117166 A1 WO 2018117166A1 JP 2017045770 W JP2017045770 W JP 2017045770W WO 2018117166 A1 WO2018117166 A1 WO 2018117166A1
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alkyl
added
mixture
hydroxy
hydrogen atom
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PCT/JP2017/045770
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Japanese (ja)
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文也 棚田
秀明 平澤
陽輔 務台
喜朗 木島
小林　淳一
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キッセイ薬品工業株式会社
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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
    • A61K31/44—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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a thiazole derivative useful as a pharmaceutical product, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
  • TRP channels are non-selective cation channels that are activated by various stimuli such as temperature and chemicals.
  • TRPM1, TRPM2, TRPM3, TRPM4a, TRPM4b, TRPM5, TRPM6, TRPM7, and TRPM8 are known in the TRPM family (see, for example, Non-Patent Document 1).
  • TRPM8 is the 8th channel of the TRPM family cloned in 2002 (see, for example, Non-Patent Document 2) and is also known as CMR1 (cold and menthol sensitive receptor-1).
  • TRPM8 is expressed in primary afferent nerve (A ⁇ fiber and C fiber) and trigeminal nerve, taste papillae, vascular endothelium, aorta, pulmonary artery, prostate, male genital organ (see Non-Patent Document 3, for example), human bladder It is also expressed in nerve fibers that control the epithelium (for example, see Non-Patent Document 4), prostate cancer (for example, see Non-Patent Document 5), oral squamous cell carcinoma (for example, see Non-Patent Document 6), etc. It has been reported.
  • TRPM8 knockout mice lack of cold perception, lack of hypersensitivity to cold stimulation after neuropathy or inflammation, etc.
  • Non-Patent Document 3 In nervous system diseases, expression of TRPM8 is increased in sciatic nerve disorder model rats, and it has been reported that it is involved in cold hyperalgesia (see, for example, Non-Patent Document 7). It has also been shown that TRPM8 expression is increased in rats and mice due to peripheral neuropathy caused by oxaliplatin, and that TRPM8 is involved in cold hyperalgesia due to oxaliplatin (for example, Non-patent Document 8 and 9).
  • TRPM8 is also involved in peripheral neuropathic pain caused by oxaliplatin in humans, as in rodents, because patients taking oxaliplatin have increased responsiveness to menthol compared to healthy individuals (For example, refer nonpatent literature 10).
  • urinary system diseases it has been reported that TRPM8 is involved in frequent urination symptoms caused by low temperature in rats (see, for example, Non-Patent Document 11).
  • TRPM8 is expressed in nerves that doubly control skin and bladder in rats, and is considered to be involved in the feeling of urination urgency caused by low temperature (for example, see Non-Patent Document 12).
  • TRPM8 may play an important role in urine storage in the bladder afferent. Therefore, by inhibiting TRPM8, treatment or prevention of diseases or symptoms resulting from TRPM8 activation is expected.
  • An object of the present invention is to provide a novel thiazole derivative, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
  • the present inventors diligently studied to find a novel thiazole derivative. As a result, the present inventors have found that the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof has a potent TRPM8 inhibitory action, and has made the present invention.
  • Ring A is a group selected from the group consisting of the following (a) to (d): ((**) represents the bonding position with the benzene ring, and (***) represents the bonding position with the ring B);
  • R 1 is a hydrogen atom, hydroxy, amino, C 1-6 alkyl or hydroxy C 1-6 alkyl;
  • Ring B is C 6-10 aryl or heterocycle;
  • R 2a and R 2b each independently represent a hydrogen atom, a halogen atom, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, haloC 1-6 alkyl or haloC 1-6 alkoxy;
  • R 3 is a hydrogen atom, a halogen atom, C 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkyl;
  • R 4a is a hydrogen atom or CR 8 R
  • Ring A is a group represented by the following formula: ((**), (***) and R 1 have the same meanings as [1] above); Or a pharmacologically acceptable salt thereof.
  • Ring B is C 6-10 aryl;
  • R 2a and R 2b are each independently a hydrogen atom, a halogen atom, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy or hydroxy C 1-6 alkyl;
  • R 3 is a hydrogen atom or a halogen atom;
  • R 4b is a hydrogen atom;
  • Ring C is C 6-10 aryl or a group selected from: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
  • R 6 is a hydrogen atom, a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, hydroxy C 1-6 alkyl or hydroxy C 1-6
  • Ring B is phenyl; A compound or a pharmaceutically acceptable salt thereof, wherein n is 1.
  • R 5 is a hydrogen atom
  • R 7a is a hydrogen atom, hydroxy, C 1-6 alkyl or C 1-6 alkoxy
  • R 4a is CR 8 R 9 R 10 (R 8 , R 9 and R 10 have the same meanings as defined in [3] above); Or a pharmacologically acceptable salt thereof.
  • Ring A is a group represented by the following formula: ((**), (***) and R 1 have the same meanings as [1] above); Or a pharmaceutically acceptable salt thereof.
  • R 1 is a hydrogen atom, hydroxy or amino
  • Ring C is a group selected from the group consisting of: pyridyl, pyrimidyl, pyrazolyl and triazolyl; A compound or a pharmaceutically acceptable salt thereof, wherein R 6 is a hydrogen atom, hydroxy or halogen atom.
  • R 2c and R 2d are each independently a hydrogen atom, a halogen atom or C 1-6 alkoxy (however, they are not simultaneously a hydrogen atom);
  • Ring C ′ is a group selected from C 6-10 aryl or the group consisting of: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
  • R 3a is a hydrogen atom, a halogen atom, C 1-6 alkyl or C 1-6 alkoxy;
  • R 4c is a group represented by the following formula:
  • R 6a is a hydrogen atom or a halogen atom;
  • R 7c is a hydrogen atom, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
  • R 9a and R 10a are each independently a hydrogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl or a fluorine atom] or a
  • R 3a is a hydrogen atom or a halogen atom
  • R 4c is a group represented by the following formula: (Wherein R 9a and R 10a have the same meanings as [9] above); Or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of [1] to [10] above or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.
  • means for solving the above problems are the following [13] and [14].
  • a disease caused by hyperexcitation or disorder of afferent nerves comprising administering an effective amount of the compound according to any one of [1] to [10] above or a pharmacologically acceptable salt thereof, How to treat or prevent symptoms.
  • the compound according to any one of [1] to [10] above or a drug thereof for producing a pharmaceutical composition for treating or preventing a disease or symptom caused by hyperexcitability or disorder of afferent nerves The use of a physically acceptable salt.
  • the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof is, for example, an Icilin-induced wet-dog shake inhibitory action confirmation test according to the method described in International Publication No. 2009/012430. Showed a strong inhibitory action. Therefore, the compound represented by the formula (I) of the present invention, or a pharmacologically acceptable salt thereof, is useful as a therapeutic or prophylactic agent for a disease or symptom caused by hyperexcitation or disorder of afferent nerve. .
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably it is a fluorine atom or a chlorine atom.
  • C 1-6 alkyl means an optionally branched alkyl having 1 to 6 carbon atoms.
  • C 1-6 alkoxy means an optionally branched alkoxy having 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
  • Halo C 1-6 alkyl means the above C 1-6 alkyl substituted with 1 to 5 of the same or different halogen atoms.
  • Halo C 1-6 alkoxy means the above C 1-6 alkoxy substituted with 1 to 5 of the same or different halogen atoms.
  • “Hydroxy C 1-6 alkyl” means the above C 1-6 alkyl substituted with 1 to 5 hydroxy. Preferably, it is monohydroxy C 1-6 alkyl or dihydroxy C 1-6 alkyl. For example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 1,3-dihydroxy And propyl.
  • “Hydroxy C 1-6 alkoxy” means the above C 1-6 alkoxy substituted with 1 to 5 hydroxy. Examples include hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxypropan-2-yloxy, 2-hydroxyethoxy, 2-hydroxy-2-methylpropoxy, 3-hydroxypropoxy and the like.
  • C 1-6 alkoxy C 1-6 alkyl means the above C 1-6 alkyl substituted with the above C 1-6 alkoxy.
  • C 1-6 alkoxy C 1-6 alkoxy means the above C 1-6 alkoxy substituted by the above C 1-6 alkoxy.
  • C 6-10 aryl refers to phenyl or naphthyl.
  • Amino C 1-6 alkyl means the above C 1-6 alkyl substituted with amino.
  • (C 1-6 alkyl) carbonyl means a carbonyl substituted with the above C 1-6 alkyl. Examples thereof include acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexylcarbonyl and the like.
  • Heterocycle refers to a 5- or 6-membered heterocycle containing 1 to 4 heteroatoms selected from sulfur, oxygen, and nitrogen, and includes, for example, furyl, thienyl, pyrrolyl, pyrazolyl, Imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, 1-oxidepyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furazanyl and other aromatic heterocycles, pyrrolinyl, imidazolinyl , Pyrazolinyl, dihydropyranyl, dihydrothiopyranyl, dihydropyridyl, dihydropyrimidinyl and the like, and morpholinyl, thiomorpholinyl
  • heterocycle may be condensed with another cyclic group, for example, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, chromenyl, chromanonyl.
  • the “heterocycle” of ring B is preferably pyridyl, benzo [1,3] dioxolyl or thienyl.
  • the compound represented by the formula (I) of the present invention includes stereoisomers such as optical isomers, geometric isomers and the like.
  • the optical isomer of the compound represented by the formula (I) of the present invention may have any configuration of R configuration or S configuration at each asymmetric carbon atom.
  • any optical isomer is included in the present invention, and a mixture of these optical isomers is also included.
  • a racemate consisting of an equal amount of each optical isomer in a mixture of optically active substances is also included in the scope of the present invention.
  • the compound represented by the formula (I) of the present invention is a racemic solid or crystal
  • a racemic compound, a racemic mixture and a racemic solid solution are also included in the scope of the present invention.
  • the present invention when a geometric isomer exists, the present invention includes any of the geometric isomers. Moreover, in the compound represented by the formula (I) of the present invention, when a tautomer exists, the present invention includes any of the tautomers.
  • the compound represented by the formula (I) of the present invention can be converted into a pharmacologically acceptable salt thereof according to a conventional method as necessary.
  • salts include acid addition salts and salts with bases.
  • Acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, Acid addition with organic acids such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid A salt etc. can be mentioned.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, Acid addition with organic
  • salts with bases include salts with inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts, and salts with organic bases such as piperidine, morpholine, pyrrolidine, arginine and lysine.
  • the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
  • TRPM8 is a cation channel that is expressed in dorsal root ganglia and trigeminal ganglia.
  • a TRPM8 inhibitor decreases the amount of cation inflow into cells via TRPM8 and suppresses an increase in intracellular cation concentration. Based on this action, TRPM8 inhibitors are useful as therapeutic or preventive agents for symptoms such as lower urinary tract symptoms (LUTS), especially overactive bladder (OAB), by suppressing overexcited afferent nerve activity. is there.
  • LUTS lower urinary tract symptoms
  • OAB overactive bladder
  • the TRPM8 inhibitory action can be evaluated by the efficacy of suppressing the wet-dog shake action induced by administration of Icilin, which is a TRPM8 agonist.
  • an effect on overactive bladder can be evaluated by a test for confirming an extension effect on the urination interval of acetic acid-induced detrusor overactive bladder according to the method described in J.Urol., 2001, 166, 1142. .
  • R 2c and R 2d are each independently a hydrogen atom, a halogen atom or C 1-6 alkoxy (however, they are not simultaneously a hydrogen atom);
  • Ring C ′ is a group selected from the group consisting of: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
  • R 3a is a hydrogen atom, a halogen atom, C 1-6 alkyl or C 1-6 alkoxy;
  • R 4c is a group represented by the following formula:
  • R 6a is a hydrogen atom or a halogen atom;
  • R 7c is a hydrogen atom, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
  • R 9a and R 10a are each independently a hydrogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl or a fluorine atom
  • R 2c and R 2d are each independently a hydrogen atom, a halogen atom or C 1-6 alkoxy (however, they are not simultaneously a hydrogen atom);
  • Ring C ′ is a group selected from the group consisting of: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
  • R 3a is a hydrogen atom or a halogen atom;
  • R 4c is a group represented by the following formula:
  • R 6a is a hydrogen atom or a halogen atom;
  • R 7c is a hydrogen atom, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
  • R 9a and R 10a are each independently a hydrogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl or a fluorine atom.
  • the compound represented by formula (I) of the present invention or a pharmacologically acceptable salt thereof is a method detailed below or a modification thereof. It can be produced according to a method, a method described in other literature, or a method analogous thereto.
  • Compound (7) can be produced, for example, by the method shown in Scheme 1 (Scheme 1).
  • ring B, R 2a , R 2b and R 3 are as defined above; G is B (OH) 2 or pinacolatoboryl; Ra is C 1-6 alkyl)
  • Process 1-1 Compound (3) can be produced by reacting compound (1) and compound (2) in a solvent in the presence of a base and a palladium catalyst.
  • the solvent used include N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, ethanol, water And a mixed solvent thereof.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium fluoride, cesium fluoride, triethylamine, pyridine, N, N-diisopropylethylamine, 2,6- Lutidine, 1,8-diazabicyclo [5,4,0] -7-undecene and the like.
  • the palladium catalyst examples include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis (diphenylphosphino) ferrocene palladium (II) dichloride, tetrakis (triphenylphosphine) palladium. (0), bis ⁇ ditert-butyl (4-dimethylaminophenyl) phosphine ⁇ palladium (II) dichloride, and the like.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 7 days, although it varies depending on the raw material used, the solvent, the reaction temperature, and the like.
  • the above reaction can also be performed using a microwave reactor.
  • the pressure range is 1 to 30 bar
  • the output range is 1 to 400 W
  • the reaction temperature is room temperature to 300 ° C.
  • the reaction time although it varies depending on the raw material, solvent, and model to be used.
  • the reaction can be carried out under conditions of 1 minute to 1 day.
  • Compound (1) and compound (2) can be produced according to methods described in the literature or a method analogous thereto, in addition to using commercially available products.
  • Process 1-2 Compound (4) can be produced by reacting compound (3) with a brominating agent in a solvent.
  • a brominating agent examples include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran and the like.
  • the brominating agent examples include N-bromosuccinimide, tribromoisocyanuric acid, bromine and the like.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Process 1-3 Compound (6) can be produced from compound (4) and compound (5) by the same method as in step 1-1.
  • Compound (5) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.
  • Process 1-4 Compound (7) can be produced by hydrolyzing compound (6) in a solvent using a base.
  • the solvent to be used include methanol, ethanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like.
  • the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • this process can also use acid hydrolysis and hydrogenolysis as needed.
  • M.M. Examples include a method described in Wuts, “Greene's Protective Groups in Organic Synthesis”, fifth edition, Wiley-Interscience, 2014.
  • Compound (11) can be produced, for example, by the method shown in Scheme 2 (Scheme 2).
  • Process 2-1 Compound (8) can be produced from compound (1) and compound (5) by the same method as in step 1-1.
  • Process 2-2 Compound (9) can be produced from compound (8) and a brominating agent by the same method as in Step 1-2.
  • Process 2-3 Compound (10) can be produced from compound (9) and compound (2) by the same method as in step 1-1.
  • Process 2-4 Compound (11) can be produced from compound (10) by the same method as in Step 1-4.
  • Compound (19) can be produced, for example, by the method shown in Scheme 3 (Scheme 3).
  • Process 3-1 Compound (13) can be produced from compound (12) and compound (2) by the same method as in step 1-1.
  • Compound (12) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.
  • Deprotection Compound (14) can be produced by deprotecting compound (13) according to a conventional method.
  • Process 3-2 Compound (15) can be produced by reacting compound (14) with a nitrite and a brominating agent in a solvent.
  • a solvent used include acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide and the like.
  • the nitrite ester include amyl nitrite, ethyl nitrite, and isobutyl nitrite.
  • the brominating agent include copper (II) bromide.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Process 3-3 Compound (16) can be produced from compound (15) by the same method as in Step 1-4.
  • Process 3-4 Compound (17) can be produced by reacting compound (16) with a base and an azide reagent in tert-butyl alcohol.
  • the base include triethylamine, N, N-diisopropylethylamine and the like.
  • the azidating reagent include diphenyl phosphoryl azide.
  • the reaction temperature is from room temperature to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Process 3-5 Compound (18) can be produced from compound (17) and compound (5) by the same method as in Step 1-1.
  • Process 3-6 Compound (19) can be produced from compound (18) by the same method as in Step 1-4.
  • Compound (25) can be produced, for example, by the method shown in Scheme 4 (Scheme 4).
  • Process 4-1 Compound (21) can be produced by reacting compound (20) with a brominating agent in the presence of a radical initiator in a solvent.
  • a radical initiator examples include azobisisobutyronitrile, 1,1′-azobis (cyclohexanecarbonitrile), benzoyl peroxide, di-tert-butyl peroxide, and the like.
  • the brominating agent examples include N-bromosuccinimide, tribromoisocyanuric acid, bromine and the like.
  • the reaction temperature is from 0 ° C.
  • reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Compound (20) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.
  • Process 4-2 Compound (23) can be produced by reacting compound (21) with compound (22) in a solvent.
  • the solvent used include N, N-dimethylformamide, ethanol, dichloromethane, toluene, benzene and the like.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Compound (22) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.
  • Process 4-3 Compound (24) can be produced by reacting compound (23) with carbon monoxide in a solvent in the presence of RaOH, a base, and a palladium catalyst.
  • the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like.
  • RaOH include n-propanol and n-butanol.
  • Examples of the base include triethylamine, N, N-diisopropylethylamine and the like.
  • the palladium catalyst examples include palladium acetate, bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0). Etc. If necessary, a ligand such as 1,3-bis (diphenylphosphino) propane, 1,1′-bis (diphenylphosphino) ferrocene, bis (adamantan-1-yl) (butyl) phosphine may be added. It can be performed by adding.
  • the reaction temperature is from room temperature to the solvent reflux temperature, and the reaction time is usually from 2 hours to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Process 4-4 Compound (25) can be produced from compound (24) by the same method as in Step 1-4.
  • the optically active compound (31) can be produced, for example, by the method shown in Scheme 5 (Scheme 5).
  • R 4a , R 4b , R 7a and R 7b are as defined above; ring C1 is C 6-10 aryl or a heterocycle containing no NH; R 6z is hydroxy, hydroxy C 1- 6 alkyl, R 6 excluding amino (R 6 is as defined above); the atom marked with * is a chiral atom)
  • Process 5-1 Compound (28) can be produced by reacting compound (26) with compound (27) in the presence of a Lewis acid in a solvent.
  • a Lewis acid examples include tetraethyl orthotitanate and tetraisopropyl orthotitanate.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Compound (26) and compound (27) can be produced in accordance with methods described in the literature or methods analogous thereto, in addition to using commercially available products.
  • Process 5-2 Compound (30) can be produced by reacting compound (28) with compound (29) in the presence of a base in a solvent.
  • a method for synthesizing an optically active amine using Ellman's imine is well known to those skilled in the art, and can be synthesized, for example, using the method described in Chemical Reviews 2010, 110, 3600-3740.
  • the solvent used include tetrahydrofuran, 1,4-dioxane, toluene and the like.
  • the base include n-butyllithium, lithium diisopropylamide, bis (trifluoromethanesulfonyl) imide lithium and the like.
  • the reaction temperature is ⁇ 78 ° C.
  • reaction time is usually 1 hour to 12 hours, although it varies depending on the raw material used, the solvent, the reaction temperature, and the like.
  • Compound (29) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.
  • Process 5-3 Compound (31) can be produced by using compound (30) in a solvent with an acid.
  • the solvent to be used include tetrahydrofuran, 1,4-dioxane, methanol, ethanol, acetonitrile, water, a mixed solvent thereof and the like.
  • the acid include hydrogen chloride, trifluoroacetic acid, acetic acid, sulfuric acid and the like.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 10 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Compound (31b) can be produced, for example, by the method shown in Scheme 6 (Scheme 6).
  • Process 6-1 Compound (33) can be produced by reacting compound (32) with an organic phosphorus compound and an iodinating agent in a solvent in the presence of a base. Substitution of hydroxy to iodine atoms using such organophosphorus compounds and iodinating agents is well known to those skilled in the art, for example, the method described in Angelwandte Chemie International Edition in England 1975, 14, 801-811 Or it can synthesize
  • the solvent to be used include tetrahydrofuran, acetonitrile, dichloromethane, acetone, N, N-dimethylformamide, N, N-dimethylacetamide and the like.
  • Examples of the base include imidazole and pyridine.
  • Examples of the iodinating agent include iodine and sodium iodide.
  • Examples of the organic phosphorus compound include triphenylphosphine and tri (n-butyl) phosphine.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Compound (32) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.
  • Process 6-2 Compound (31a) can be produced by reacting compound (33) with zinc in a solvent and then reacting with compound (34) in the presence of a palladium catalyst.
  • the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, toluene, acetonitrile, tetrahydrofuran and the like.
  • the palladium catalyst examples include bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0), bis ( Examples thereof include dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II), and the like.
  • the reaction temperature is from 0 ° C.
  • reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Compound (34) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.
  • Deprotection Compound (31b) can be produced by deprotecting compound (31a) according to a conventional method.
  • Compound (31d) can be produced, for example, by the method shown in Scheme 7 (Scheme 7).
  • R 4a , R 4b , R 7a , R 7b , R 6 and Q are as defined above; ring C2 is a heterocycle containing NH; ring C3 is a nitrogen-containing heterocycle; Y is a leaving group such as methanesulfonyloxy, p-toluenesulfonyloxy, iodine atom)
  • Process 7-1 Compound (35) (Y is methanesulfonyloxy, p-toluenesulfonyloxy) can be produced by reacting compound (32) with a sulfonyl halide or sulfonic anhydride in the presence of a base in a solvent.
  • a solvent examples include dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile and the like.
  • the base include pyridine, triethylamine, N, N-diisopropylethylamine and the like.
  • Examples of the sulfonyl halide include p-toluenesulfonyl chloride and methanesulfonyl chloride.
  • Examples of the sulfonic acid anhydride include trifluoromethanesulfonic acid anhydride.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • compound (35) (Y is an iodine atom) can also be produced from compound (32) by the same method as in Step 6-1.
  • Process 7-2 Compound (31c) can be produced by reacting compound (35) with compound (36) in the presence of a base in a solvent. Alternatively, compound (35) can be reacted in the presence of a base in a solvent to produce compound (37), and then reacted with compound (36) to produce compound (31c).
  • the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, toluene, acetonitrile, tetrahydrofuran, N-methylpyrrolidone and the like.
  • Examples of the base include cesium carbonate, potassium carbonate, pyridine, triethylamine, N, N-diisopropylethylamine, tert-butoxypotassium, sodium hydride and the like.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Compound (36) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.
  • Deprotection Compound (31d) can be produced by deprotecting compound (31c) according to a conventional method.
  • Compound (31d) can also be produced, for example, by the method shown in Scheme 8 (Scheme 8).
  • ring C2, ring C3, R 4a , R 4b , R 7a , R 7b and R 6 are as defined above; W is a leaving group such as methanesulfonyloxy, p-toluenesulfonyloxy, etc. )
  • Process 8-1 Compound (39) can be produced by reacting compound (38) with an organic phosphorus compound in a solvent in the presence of an azo reagent.
  • the solvent used include tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene and the like.
  • the organic phosphorus compound include triphenylphosphine and tri (n-butyl) phosphine.
  • the azo reagent include azodicarboxylic acid diisopropyl ester, azodicarboxylic acid diethyl ester, azodicarbonyldipiperazine, and the like.
  • the reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Compound (38) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.
  • Process 8-2 Compound (40) can be produced by reacting compound (39) with compound (36) in a solvent in the presence or absence of a base.
  • a solvent examples include N, N-dimethylformamide, N, N-dimethylacetamide, toluene, acetonitrile, tetrahydrofuran and the like.
  • the base examples include cesium carbonate, potassium carbonate, pyridine, triethylamine, N, N-diisopropylethylamine, tert-butoxypotassium, sodium hydride and the like.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Process 8-3 Compound (41) can be produced from compound (40) by the same method as in Step 7-1.
  • Process 8-4 Compound (42) can be produced by reacting compound (41) with an azide reagent in a solvent.
  • the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene and the like.
  • the azide reagent include sodium azide.
  • the reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Process 8-5 Compound (31d) can be produced by reacting compound (42) with hydrogen in a solvent in the presence of a catalyst.
  • the solvent used include methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid and the like.
  • the catalyst include palladium carbon and platinum carbon.
  • the reaction temperature is from room temperature to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • compound (31d) can be produced by reacting compound (42) in a solvent with an organic phosphorus compound and water. Examples of the solvent used include tetrahydrofuran and 1,4-dioxane.
  • Examples of the organic phosphorus compound include triphenylphosphine and tri (n-butyl) phosphine.
  • the reaction temperature is from room temperature to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • the compound represented by the formula (I) of the present invention can be produced, for example, by the method shown in Scheme 9 (Scheme 9).
  • Process 9-1 The compound represented by formula (I) can be produced by reacting compound (43) with a condensing agent and compound (44) in a solvent in the presence or absence of a base.
  • a solvent used include N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, methanol, water and the like.
  • the base include triethylamine, N, N-diisopropylethylamine, pyridine and the like.
  • condensing agent examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N, N′-carbonyldiimidazole, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride, propylphosphonic anhydride and the like. If necessary, an activator such as 1-hydroxybenzotriazole or 1-hydroxyazabenzotriazole may be added.
  • the reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 5 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Compound (43) and compound (44) may each be a commercially available product, or can be produced according to methods described in the literature or methods analogous thereto.
  • the scheme shown above is an example of a method for producing a compound represented by the formula (I) of the present invention or a production intermediate thereof.
  • the above scheme can be modified in various ways as can be easily understood by those skilled in the art.
  • the protection and deprotection operations can be appropriately combined according to a conventional method.
  • the type of protecting group, protection, and deprotection see, eg, Theodora W. Green & Peter G. M. Edited by Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006 or Peter G. M.
  • the intermediates used to produce the compounds of formula (I) of the present invention, or pharmacologically acceptable salts thereof, are optionally isolated as is well known to those skilled in the art.
  • -It can be isolated and purified by means of purification such as solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography and the like.
  • the pharmaceutical composition containing the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient may be used in various dosage forms depending on the usage.
  • dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.
  • compositions are prepared according to known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents. It can be prepared by appropriately mixing or diluting / dissolving with pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • each active ingredient can be used simultaneously or separately. It can be produced by formulating in the same manner as described above.
  • the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof exhibits a strong inhibitory action based on TRPM8 inhibition in an Icilin-induced wet-dog shake inhibitory action confirmation test. Therefore, a medicament containing the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient has a disease or symptom caused by TRPM8 activation due to TRPM8 inhibitory action. It can be used as a therapeutic or prophylactic agent.
  • Disease or symptom resulting from activation of TRPM8 means a disease or symptom resulting from hyperexcitation or disorder of afferent nerves.
  • Diseases or symptoms resulting from afferent nerve overexcitation or disorder include anxiety, depression, lower urinary tract symptoms (LUTS), pain, circulatory disturbance, itching, numbness, urticaria and the like.
  • the compound represented by the formula (I) of the present invention is a lower urine among diseases or symptoms caused by hyperexcitability or disorder of afferent nerves. It is particularly useful as a therapeutic or prophylactic agent for tract symptoms (LUTS) or pain.
  • LUTS tract symptoms
  • “Lower urinary tract symptoms (LUTS)” refers to symptoms caused by lower urinary tract dysfunction, etc.
  • lower urinary tract dysfunction includes overactive bladder, detrusor overactivity, nocturia, stroma Cystitis such as cystitis, prostatitis such as chronic prostatitis, bladder pain syndrome, hypersensitive bladder syndrome, urinary incontinence, prostatic hypertrophy, urethral stricture and the like.
  • Preferred examples include overactive bladder, detrusor overactivity, interstitial cystitis, and bladder pain syndrome.
  • “Circulating disorders” include cold rhinitis, Raynaud's disease, and the like.
  • “Pain” includes toothache, oxaliplatin-induced peripheral neuropathy, migraine, postoperative pain, cold allodynia, anticancer drug-induced peripheral neuralgia, diabetic peripheral neuropathy. Preferred examples include toothache, oxaliplatin-induced peripheral neuropathy, migraine, postoperative pain, and cold allodynia.
  • the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof can be used in appropriate combination with at least one drug other than the TRPM8 inhibitor.
  • Examples of the drug that can be used in combination with the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof include opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and barbiturates.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • ⁇ -adrenergic drug examples include doxazosin, tamsulosin, silodosin, clonidine, guanfacine, dexmedetomidine, modafinil, tizanidine, moxonidine and the like.
  • musclecarinic receptor antagonist examples include oxybutynin, tolterodine, propiverine, darifenacin, solifenacin, temiverine, ipratropium bromide, trospium, propantheline, temiverine, imidafenacin, fesoterodine and the like.
  • EP1 antagonist examples include GSK-269984A, ONO-8539 and the like.
  • ⁇ 3 adrenergic agonist examples include mirabegron, sorabegron, TRK-380 and the like.
  • blade mucosa protective agent examples include polysulfate pentosan, hyaluronic acid, chondroitin sulfate and the like.
  • the present invention includes the following 1) to 5) ): 1) Simultaneous administration with combination drug, 2) As separate formulations, co-administration by the same route of administration, 3) As separate formulations, co-administration by different routes of administration, Any method of administration, including 4) administration at different times by the same route of administration as separate formulations, and 5) administration at different times by different routes of administration as separate formulations is included. Also, when administered at different times as separate preparations such as 4) or 5), it is administered in combination with the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof.
  • the order of administration with the above-mentioned drugs is not particularly limited.
  • the compound of the present invention is advantageously combined with one or more kinds of the above-mentioned drugs in an appropriate combination, and thus has an advantageous effect on the prevention or treatment of the above diseases.
  • An effect can be obtained.
  • reduce the amount used compared to when administered alone reduce the side effects of drugs other than the combined TRPM8 inhibitor, or avoid the side effects of drugs other than the combined TRPM8 inhibitor Or it can be reduced.
  • composition of the present invention can be administered systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal, etc.).
  • the dose of the compound represented by the formula (I) of the present invention is determined by the age of the patient. It is appropriately determined depending on sex, body weight, disease, degree of treatment, and the like.
  • an adult (with a body weight of 60 kg) can be appropriately administered in one or several divided doses within a range of about 1 to 3000 mg per day.
  • the daily dose as an oral preparation is preferably 10 to 1000 mg, more preferably 20 to 400 mg.
  • parenteral administration it can be appropriately administered in one or several divided doses in the range of about 0.6 to 300 mg per day for an adult.
  • the daily dose as a parenteral preparation is preferably 1 to 100 mg, more preferably 6 to 60 mg.
  • the dose of the compound represented by formula (I), which is an active ingredient of the TRPM8 inhibitor of the present invention, or a pharmacologically acceptable salt thereof depends on the dose of the drug other than the TRPM8 inhibitor. You can lose weight.
  • SiO2 means silica gel column chromatography
  • APS means aminopropyl silica gel column chromatography.
  • Low polarity or LP means a compound that elutes first when a mixture of stereoisomers is separated and purified using normal phase column chromatography.
  • High polarity or HP means a compound that elutes later. .
  • N. D. Means unmeasured.
  • T3P is propylphosphonic anhydride (cyclic trimer), TBS is tert-butyldimethylsilyl, TBDPS is tert-butyldiphenylsilyl, Bn is benzyl, MOM is methoxymethyl, Cbz is benzyloxycarbonyl, Boc is tert-butoxycarbonyl, Bu means n-butyl.
  • microwave irradiation was performed using Biotage Initiator + or Biotage Initiator.
  • Reference Example 1-1-1 3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzoic acid
  • Reference Example 1-6-1 (615 mg), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) (130 mg) and aqueous sodium carbonate (2 mol / L, 1.8 mL) were added at room temperature, The mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation.
  • Reference Examples 1-1-2 to 1-1-29 Reference Examples 1-1-2 to 1-1-29 were synthesized in the same manner as Reference Example 1-1-1 using the corresponding starting materials.
  • Reference Examples 1-2-2 to 1-2-6 Reference Examples 1-2-2 to 1-2-6 were synthesized in the same manner as Reference Example 1-2-1 using the corresponding starting materials.
  • Reference Examples 1-3-2 to 1-3-3 Reference Examples 1-3-2 to 1-3-3 were synthesized in the same manner as Reference Example 1-3-1 using the corresponding starting materials.
  • Reference Example 1-5-2 Reference Example 1-5-2 was synthesized in the same manner as Reference Example 1-5-1 using the corresponding starting materials.
  • Reference Example 1-7-1 3-chloro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzoic acid 2-bromo-3-chlorobenzoic acid methyl ester (325 mg) to bromo (1,3-thiazole -2-yl) zinc tetrahydrofuran solution (0.5 mol / L, 8 mL) and dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) (185 mg) were added at room temperature and the mixture was The mixture was stirred at 120 ° C. for 90 minutes under wave irradiation. The reaction mixture was concentrated under reduced pressure.
  • Reference Examples 1-7-2 to 1-7-4 Reference Examples 1-7-2 to 1-7-4 were synthesized in the same manner as Reference Example 1-7-1 using the corresponding starting materials.
  • Reference Examples 1-11-2 to 1-11-3 Reference Examples 1-11-2 to 1-11-3 were synthesized in the same manner as in Reference Example 1-11-1 using the corresponding starting materials.
  • Table 4 shows a reference example represented by the following formula (B).
  • Wb, Yb and Zb represent a group of the formula (B).
  • Reference Examples 2-1-2 to 2-1-3 Reference Examples 2-1-2 to 2-1-3 were synthesized in the same manner as Reference Example 2-1-1 using the corresponding starting materials.
  • Reference Examples 2-3-2 to 2-3-3 Reference Examples 2-3-2 to 2-3-3 were synthesized in the same manner as Reference Example 2-3-1 using the corresponding starting materials.
  • Reference Examples 2-4-2 to 2-4-3 Reference Examples 2-4-2 to 2-4-3 were synthesized in the same manner as Reference Example 2-4-1 using the corresponding starting materials.
  • N-Butyllithium n-hexane solution (2.6 mol / L, 1.0 mL) was added to a solution of 2-methylpyridine (0.27 g) in tetrahydrofuran (5 mL) at ⁇ 78 ° C., and the mixture was added at the same temperature to 10 ° C. Stir for minutes.
  • To this mixture was added (R) -N-[(1E, 2S) -3- (benzyloxy) -2-methoxypropylidene] -2-methylpropane-2-sulfinamide (0.57 g) in tetrahydrofuran (4 mL). The solution was added dropwise at ⁇ 78 ° C., and the mixture was stirred at the same temperature for 1.5 hours.
  • the reaction mixture was passed through a celite pad and the filtrate was concentrated under reduced pressure. This residue was dissolved in dichloromethane (10 mL), iodobenzene diacetate (2.87 g) and AZADOL (registered trademark) (0.046 g) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A sodium thiosulfate aqueous solution (1 mol / L) and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
  • Reference Example 2-11-2 Reference Example 2-11-2 was synthesized in the same manner as Reference Example 2-11-1 using the corresponding starting materials.
  • Sodium hydride (60% oil dispersion, 0.006 g) was added to a solution of the product (0.093 g) in tetrahydrofuran (1 mL) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. To this mixture was added iodomethane (0.145 g) at room temperature and the mixture was stirred at the same temperature overnight. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
  • Trifluoroacetic acid (1.6 mL) was added to a mixture of the product (6.5 g) in methanol (21 mL) and water (7 mL) at room temperature, and the mixture was stirred at the same temperature for 2 days.
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N-[(2R, 3S) -3,4-dihydroxy-1- (1H-pyrazol-1-yl) butane-2- [Il] carbamic acid tert-butyl ester (5.0 g) was obtained.
  • Reference Examples 2-14-2 to 2-14-3 Reference Examples 2-14-2 to 2-14-3 were synthesized in the same manner as in Reference Example 2-14-1, using the corresponding starting materials.
  • Reference Example 2-15-2 Reference Example 2-15-2 was synthesized in the same manner as in Reference Example 2-15-1, using the corresponding starting materials.
  • Reference Example 2-16-1 (2S, 3R) -3-Amino-2-methoxy-4- (pyrimidin-2-yl) butan-1-ol Reference Example 2-15-1 (1.09 g), zinc (268 mg), N, N— A mixture of dimethylformamide (10 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (296 mg) and bis (triphenylphosphine) palladium (II) dichloride (131 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and passed through a celite pad. The crude product was extracted with ethyl acetate.
  • the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (4S) -4-[(1R) -2- (benzyloxy) -1-fluoroethyl] -2,2- Dimethyl-1,3-dioxolane (0.52 g) was obtained.
  • Triphenylphosphine (67 mg) and azodicarboxylic acid diethyl ester toluene solution (2.2 mol / L, 116 ⁇ L) were added to a solution of the product (50 mg) in toluene (1 mL) at room temperature, and the mixture was stirred at 80 ° C. overnight. After the reaction mixture was cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2R) -2-[(1R) -2- (benzyloxy) -1-fluoroethyl] oxirane (40 mg). Obtained.
  • Reference Examples 2-17-2 to 2-17-3 Reference Examples 2-17-2 to 2-17-3 were synthesized in the same manner as in Reference Example 2-17-1, using the corresponding starting materials.
  • Reference Examples 2-18-2 to 2-18-3 Reference Examples 2-18-2 to 2-18-3 were synthesized in the same manner as in Reference Example 2-18-1, using the corresponding starting materials.
  • Reference Example 2-19-2 Reference Example 2-19-2 was synthesized in the same manner as Reference Example 2-19-1 using the corresponding starting materials.
  • the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane).
  • the crude product was purified by reverse phase preparative liquid chromatography (CapcellPak C18 UG80, elution solvent: acetonitrile / water), and a diastereomeric mixture (0.429 g) as a low polarity product and (R)-as a high polarity product.
  • Reference Example 2-25-1 (R) -N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-methoxy-2- (pyridin-2-yl) ethyl] -2-Methylpropane-2-sulfinamide
  • Reference Example 2-24-1 (0.209 g) in tetrahydrofuran (3 mL) was added to sodium hydride (60% oil dispersion, 0.025 g) and iodine methane (0. 346 g) was added at 0 ° C. and the mixture was stirred at room temperature overnight. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate.
  • Reference Examples 2-27-2 to 2-27-4 Reference Examples 2-27-2 to 2-27-4 were synthesized in the same manner as in Reference Example 2-27-1 using the corresponding starting materials.
  • Example 1-1 2- [5- (2-Hydroxyphenyl) -1,3-thiazol-2-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide Reference Example 1-1-3 (19 mg) in dichloromethane To the suspension (1 mL), 2- (pyridin-2-yl) ethan-1-amine (6 mg), N, N-diisopropylethylamine (23 mg) and T3P® N, N-dimethylformamide solution (1 .6 mol / L, 65 ⁇ L) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture and the crude product was extracted with dichloromethane.
  • Examples 1-2 to 1-8 Examples 1-2 to 1-8 were synthesized in the same manner as in Example 1-1 using the corresponding starting materials.
  • Example 2-1 N-[(2R, 3S) -3,4-dihydroxy-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3 -Thiazol-2-yl] benzamide
  • N-dimethylformamide 1 mL
  • 1-hydroxybenzotriazole monohydrate 19 mg
  • Reference Example 2- 28-1 32 mg
  • triethylamine 51 mg
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 24 mg
  • Examples 2-2 to 2-64 were synthesized in the same manner as in Example 2-1, using the corresponding starting materials.
  • Example 3-1 2- [5- (3,4-Difluorophenyl) -1,3-thiazol-2-yl] -3-fluoro-N-[(2R) -4-hydroxy-3- (hydroxymethyl) -1- ( Pyridin-2-yl) butan-2-yl] benzamide
  • Examples 3-2 to 3-4 Examples 3-2 to 3-4 were synthesized in the same manner as in Example 3-1, using the corresponding starting materials.
  • Example 4-1 2- ⁇ 5- [2- (hydroxymethyl) phenyl] -1,3-thiazol-2-yl ⁇ -N- [2- (pyridin-2-yl) ethyl] benzamide
  • Reference Example 1-9-1 (20 mg ) In tetrahydrofuran (1 mL) was added triethylamine (14 mg) and chloroformic acid isobutyl ester (10 mg) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. To this mixture was added sodium borohydride (4 mg) and methanol (0.1 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes.
  • Example 5-1 2- [4-Amino-5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -3,4-dihydroxy-1- (pyridin-2-yl) ) Butan-2-yl] benzamide hydrochloride
  • Reference Example 1-3-1 (30 mg) in N, N-dimethylformamide (1 mL) suspension, 1-hydroxybenzotriazole monohydrate (12 mg), Reference Example 2-28-1 (19 mg), triethylamine (29 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (15 mg) were added at room temperature and the mixture was stirred at the same temperature overnight.
  • Examples 5-2 to 5-6 were synthesized in the same manner as in Example 5-1, using the corresponding starting materials.
  • Example 6-1 N-[(2R) -1-amino-3-phenylpropan-2-yl] -2- (5-phenyl-1,3-thiazol-2-yl) benzamide
  • Reference Example 1-1-2 48 mg
  • Reference Example 2-1-1 60 mg
  • N, N-diisopropylethylamine 77 mg
  • T3P® ethyl acetate solution 1.7 mol / L, 185 ⁇ L
  • Examples 6-2 to 6-3 Examples 6-2 to 6-3 were synthesized in the same manner as in Example 6-1 using the corresponding starting materials.
  • Example 7-1 2- [5- (3,4-Difluorophenyl) -1,3-thiazol-2-yl] -N-[(2S, 3R) -1,2-dihydroxy-4- (pyridin-2-yl) pentane -3-yl] -3-fluorobenzamide Reference Example 22-1 (79 mg) in 1,4-dioxane (1.5 mL) solution in 1,4-dioxane hydrogen chloride solution (4 mol / L, 1.5 mL) was added at room temperature and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation.
  • Examples 7-2 to 7-8 Examples 7-2 to 7-8 were synthesized in the same manner as in Example 7-1 using the corresponding starting materials.
  • Example 8-1 3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R) -1-hydroxy-3- (2-hydroxyphenyl) propane-2- [Il] benzamide
  • boron tribromide dichloromethane solution (1 mol / L, 1 mL) at ⁇ 78 ° C., and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (38 mg).
  • Example 9-1 3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -4-hydroxy-3-methoxy-1- (1H-pyrazole -1-yl) butan-2-yl] benzamide
  • Reference Example 1-1-1 40 mg
  • 1-hydroxybenzotriazole monohydrate 21 mg
  • Reference Example 2-14-1 54 mg
  • diisopropylethylamine 33 mg
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 27 mg
  • Example 10-1 3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -4-hydroxy-3-methoxy-1- (pyridine-2 -Il) butan-2-yl] benzamide
  • Reference Example 1-1-1 40 mg
  • N, N-dimethylformamide 1 mL
  • Reference Example 2-8-1 36 mg
  • 1-hydroxybenzo Triazole monohydrate 21 mg
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 27 mg
  • triethylamine 51 mg
  • Examples 10-2 to 10-5 Examples 10-2 to 10-5 were synthesized in the same manner as in Example 10-1, using the corresponding starting materials.
  • Example 11-1 N-[(2R) -3,3-difluoro-4-hydroxy-1- (2H-1,2,3-triazol-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-Fluorophenyl) -1,3-thiazol-2-yl] benzamide
  • Reference Example 1-1-1 35 mg
  • Reference Example 2-27-1 30 mg
  • 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride 34 mg
  • N, N-diisopropylethylamine 71 mg
  • Examples 11-2 to 11-4 Examples 11-2 to 11-4 were synthesized in the same manner as in Example 11-1, using the corresponding starting materials.
  • Example 12-1 N-[(2R) -3,3-difluoro-4-hydroxy-1- (1H-pyrazol-1-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzamide
  • Reference Example 1-1-1 51 mg
  • Reference Example 2-18-3 50 mg
  • 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride 49 mg was added at room temperature, and the mixture was stirred at the same temperature for 1 hour.
  • Example 13-1 3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -4-hydroxy-3-methoxy-1- (2H-1 , 2,3-Triazol-2-yl) butan-2-yl] benzamide
  • Reference Example 1-1-1 (30 mg) in N, N-dimethylformamide (1 mL) was added Reference Example 2-14-3.
  • Reference Example 2-14-3 (44 mg) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (29 mg) were added at room temperature and the mixture was stirred at the same temperature for 2 hours. did.
  • Example 14-1 N-[(2R) -1-amino-3- (pyridin-2-yl) propan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazole-2 -Il] benzamide
  • Reference Example 1-1-1 35 mg
  • Reference Example 2-1-3 39 mg
  • 1-hydroxybenzotriazole monohydrate 25 mg
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 32 mg
  • triethylamine 45 mg
  • Example 15-1 N-[(2R, 3S) -3,4-dihydroxy-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5- (2-amino-4-fluorophenyl) -1,3-thiazol-2-yl] benzamide
  • N N-dimethylformamide
  • Example 16-1 2- (4-Amino-5-phenyl-1,3-thiazol-2-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide Reference Example 1-3-3 (6 mg) in dichloromethane ( 1 mL) to a suspension, 2- (pyridin-2-yl) ethan-1-amine (4 mg), N, N-diisopropylethylamine (7 mg) and T3P® ethyl acetate solution (1.7 mol / L, 20 ⁇ L) was added at room temperature and the mixture was stirred at the same temperature for 0.5 h. Water was added to the reaction mixture and the crude product was extracted with dichloromethane.
  • Example 16-2 was synthesized in the same manner as in Example 16-1, using the corresponding starting materials.
  • Example 17-1 3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -1,3,4-trihydroxy-1- (pyridine- 2-yl) butan-2-yl] benzamide
  • 1,4-dioxane hydrogen chloride (4 mol / L, 1 mL) in a solution of Reference Example 22-2 (45 mg) in 1,4-dioxane (1 mL) at room temperature
  • the mixture was stirred at 50 ° C. for 5 hours.
  • the reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation.
  • Example 17-2 was synthesized in the same manner as Example 17-1 using the corresponding starting materials.
  • Example 18-1 N-[(2S, 3S) -3,4-Dihydroxy-1-methoxy-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzamide
  • Reference Example 2-29-1 (162 mg) in 1,4-dioxane (2 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) at room temperature And the mixture was stirred at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation.
  • Example 18-2 was synthesized in the same manner as in Example 18-1, using the corresponding starting material.
  • Example 19-1 N-[(2S, 3S) -3,4-Dihydroxy-1-methoxy-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzamide
  • Reference Example 2-25-1 (175 mg) in 1,4-dioxane (2 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) at room temperature And the mixture was stirred at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation.
  • Example 19-2 was synthesized in the same manner as in Example 19-1, using the corresponding starting material.
  • Example 20-1 3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -1,3,4-trihydroxy-1- (pyridine- 2-yl) butan-2-yl] benzamide
  • 1,4-dioxane hydrogen chloride (4 mol / L, 2 mL) at room temperature was added to a solution of Reference Example 2-4-1 (208 mg) in 1,4-dioxane (2 mL).
  • the mixture was stirred at the same temperature for 18 hours.
  • the reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation.
  • Example 21-1 N-[(2S, 4S) -1,4-dihydroxy-1- (pyridin-2-yl) pentan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3 -Thiazol-2-yl] benzamide
  • 1,4-dioxane hydrogen chloride solution 4 mol / L, 2 mL
  • the reaction mixture was concentrated under reduced pressure.
  • N-Hexane was added to the residue, and the solvent was removed by decantation.
  • Example 21-2 was synthesized in the same manner as in Example 21-1, using the corresponding starting material.
  • Test example 1 Icilin-induced wet-dog shake inhibitory action test
  • Test example 2 A test to confirm the prolongation of acetic acid-induced detrusor overactive bladder urination interval
  • Urethane (Sigma) was dissolved in pure water to 25% w / v and anesthetized by subcutaneous administration to female SD rats at 1.25 g / kg.
  • a catheter was inserted into the rat's bladder and femoral vein, and the bladder catheter was connected to a syringe pump and a pressure transducer. Intravesical pressure was monitored using a pressure transducer, and at the same time, 0.25% acetic acid / saline solution was continuously infused into the bladder at 3.6 ml / hour to induce detrusor overactivity.
  • a solution obtained by dissolving a test compound in a mixed solution of dimethylacetamide and physiological saline (20:80) is administered from an intravenous catheter, and the average value of three intervals of urination immediately before administration is defined as 100%.
  • the average value of the interval was calculated as the urination interval extension rate (Elongation of micturition interval (%)).
  • the doses and results are shown in Table 34.
  • the compound of the present invention exhibited a strong TRPM8 inhibitory action. Furthermore, as shown in Table 34, it was found that the compound of the present invention has a prolonging effect on the micturition interval and is effective in suppressing detrusor overactivity.
  • the compound of the present invention has a potent TRPM8 inhibitory action, it treats or prevents a disease or symptom caused by the activation of TRPM8, particularly lower urinary tract symptom (LUTS), particularly, overactive bladder (OAB). Useful as a therapeutic or prophylactic agent.
  • TRPM8 particularly lower urinary tract symptom
  • OAB overactive bladder

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Abstract

L'objectif de la présente invention est de fournir un nouveau dérivé de thiazole ou un sel pharmacologiquement acceptable de celui-ci ; une composition pharmaceutique contenant le dérivé de thiazole ou un sel pharmacologiquement acceptable de celui-ci ; et une utilisation pharmaceutique de la composition pharmaceutique. La présente invention concerne un composé représenté par la formule (I), qui a une activité inhibitrice de TRPM 8, ou un sel pharmacologiquement acceptable du composé. (Dans la formule, le noyau A représente le thiazole ou similaire ; le noyau B représente un aryle en C6-10 ou similaire ; chacun de R2a et R2b représente indépendamment un atome d'hydrogène ou similaire ; R3 représente un atome d'hydrogène ou similaire ; R4a représente un atome d'hydrogène ou similaire ; R4b représente un atome d'hydrogène ou similaire ; R5 représente un atome d'hydrogène ou similaire ; R6 représente un atome d'hydrogène ou similaire ; R7a représente un atome d'hydrogène ou similaire ; R7b représente un atome d'hydrogène ou similaire ; et n représente 0 ou 1.) La présente invention concerne également un composé représenté par la formule (I) ou un sel pharmacologiquement acceptable du composé qui peut être utilisé en tant qu'agent thérapeutique ou prophylactique pour des maladies ou des états pathologiques associés à l'hyperexcitation ou au trouble des nerfs afférents.
PCT/JP2017/045770 2016-12-21 2017-12-20 Dérivé de thiazole ou son sel pharmacologiquement acceptable WO2018117166A1 (fr)

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Citations (8)

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JP2012518616A (ja) * 2009-02-20 2012-08-16 アボット ゲーエムベーハー ウント カンパニー カーゲー カルボキサミド化合物及びカルパイン阻害剤としてのその使用
EP2606889A1 (fr) * 2011-12-21 2013-06-26 Telik, Inc. Thiazoles substitués en tant qu'inhibiteurs de la kinase VEGFR2
JP2014503486A (ja) * 2010-11-05 2014-02-13 セノミックス インコーポレイテッド Ｔｒｐｍ８の活性調節因子として有用な化合物
JP2014074021A (ja) * 2012-09-14 2014-04-24 Mitsubishi Tanabe Pharma Corp 医薬組成物
JP2015504874A (ja) * 2011-12-19 2015-02-16 ドムペ・ソチエタ・ペル・アツィオーニ Ｔｒｐｍ８拮抗薬
JP2016094407A (ja) * 2014-11-07 2016-05-26 キッセイ薬品工業株式会社 新規なｔｒｐｍ８阻害薬
WO2016208602A1 (fr) * 2015-06-23 2016-12-29 キッセイ薬品工業株式会社 Dérivé de pyrazole, ou son sel pharmaceutiquement acceptable

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Publication number Priority date Publication date Assignee Title
US5342851A (en) * 1992-10-07 1994-08-30 Mcneil-Ppc, Inc. Substituted thiazole derivatives useful as platelet aggregation inhibitors
JP2012518616A (ja) * 2009-02-20 2012-08-16 アボット ゲーエムベーハー ウント カンパニー カーゲー カルボキサミド化合物及びカルパイン阻害剤としてのその使用
JP2014503486A (ja) * 2010-11-05 2014-02-13 セノミックス インコーポレイテッド Ｔｒｐｍ８の活性調節因子として有用な化合物
JP2015504874A (ja) * 2011-12-19 2015-02-16 ドムペ・ソチエタ・ペル・アツィオーニ Ｔｒｐｍ８拮抗薬
EP2606889A1 (fr) * 2011-12-21 2013-06-26 Telik, Inc. Thiazoles substitués en tant qu'inhibiteurs de la kinase VEGFR2
JP2014074021A (ja) * 2012-09-14 2014-04-24 Mitsubishi Tanabe Pharma Corp 医薬組成物
JP2016094407A (ja) * 2014-11-07 2016-05-26 キッセイ薬品工業株式会社 新規なｔｒｐｍ８阻害薬
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