WO2015108136A1 - α-SUBSTITUTED GLYCINAMIDE DERIVATIVE - Google Patents

α-SUBSTITUTED GLYCINAMIDE DERIVATIVE Download PDF

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WO2015108136A1
WO2015108136A1 PCT/JP2015/051031 JP2015051031W WO2015108136A1 WO 2015108136 A1 WO2015108136 A1 WO 2015108136A1 JP 2015051031 W JP2015051031 W JP 2015051031W WO 2015108136 A1 WO2015108136 A1 WO 2015108136A1
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Prior art keywords
alkyl
alkoxy
group
halo
carbamoylphenylmethyl
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PCT/JP2015/051031
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French (fr)
Japanese (ja)
Inventor
秀明 平澤
直裕 川村
小林　淳一
哲治 小澤
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キッセイ薬品工業株式会社
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Priority to JP2015557881A priority Critical patent/JP6692162B2/en
Publication of WO2015108136A1 publication Critical patent/WO2015108136A1/en

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    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—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
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    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to an ⁇ -substituted glycinamide 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).
  • menthol e.g., menthol
  • Non-patent documents 13 and 14 In patients with upper central nervous disease such as cats, stroke, and spinal cord injury, infusion of a small amount of cold water into the bladder induces an unusual micturition reflex, which is enhanced by menthol (e.g., menthol) Non-patent documents 13 and 14). Further, in cats, this micturition reflex is reduced by desensitization of C fibers, and therefore, it is considered that menthol-sensitive C fibers are involved (see, for example, Non-Patent Document 13). In addition, an increase in TRPM8 expression was confirmed in nerve fibers in the subepithelial bladder of patients with idiopathic detrusor overactivity / bladder pain syndrome, and TRPM8 expression was correlated with urination frequency and pain score.
  • TRPM8 expression was confirmed in nerve fibers in the subepithelial bladder of patients with idiopathic detrusor overactivity / bladder pain syndrome, and TRPM8 expression was correlated with
  • TRPM8 may play an important role in urine storage in the bladder afferent. Therefore, by inhibiting TRPM8, treatment or prevention of diseases or symptoms caused by TRPM8 activation is expected.
  • substances that inhibit TRPM8 include N- (3-aminopropyl) -2- ⁇ [(3-methylphenyl) methyl] oxy ⁇ -N- (2-thienylmethyl) benzamide hydrochloride (hereinafter referred to as AMTB). Is also known).
  • AMTB has been reported to reduce the frequency of rhythmic bladder contractions and suppress visceral motor reflexes associated with bladder extension.
  • AMTB has a decrease in mean blood pressure at a high concentration of medicinal dose, and a problem remains.
  • A general formula (A):
  • Patent Document 3 [Wherein R 1 , R 2 , R 3 , R 4 , G and Q 1 are as defined in Patent Document 3. ] (For example, refer patent document 3). However, the compound described in Patent Document 3 is an endothelin converting enzyme inhibitor, whereas the compound of the present invention is different in that it is a TRPM8 inhibitor. Further, Patent Document 4 discloses a compound shown below:
  • An object of the present invention is to provide a novel ⁇ -substituted glycinamide derivative, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
  • the present inventors have intensively studied to find an ⁇ -substituted glycinamide derivative. As a result, it has been found that the compound (I) of the present invention or a pharmacologically acceptable salt thereof has a potent TRPM8 inhibitory action, and has led to the present invention.
  • a 1 represents the following a) to d): a) unsubstituted or 1-2 groups independently selected from the group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy C 6-10 aryl substituted with a group, b) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 5-membered heterocycle substituted with a group, c) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 6-membered heterocycle substituted with a group, and d) a group selected from the group
  • a 2 is less e1) and f1): e1) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3 Phenyl substituted with 1 to 3 groups independently selected from -6 cycloalkoxy, and f1) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo From the group consisting of thienyl substituted with 1 to 3 groups independently selected from C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3-6 cycloalkoxy
  • a 1 is the following a) to d): a) unsubstituted or 1-2 groups independently selected from the group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy C 6-10 aryl substituted with a group, b) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 5-membered heterocycle substituted with a group, c) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 6-membered heterocycle substituted with a group,
  • a 1 is the following a1) to c1) and d): a1) phenyl which is unsubstituted or substituted by 1 to 2 halogen atoms, b1) a 5-membered heterocycle which is unsubstituted or substituted by one C 1-6 alkyl, [1] to [5] or a pharmacologically acceptable salt thereof, which is a group selected from the group consisting of c1) an unsubstituted 6-membered heterocycle and d) C 4-6 cycloalkenyl .
  • a 3 is less i1), j1) and k): i1) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkoxy, amino, Mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carbonyl, (C 1-6 alkyl) carbonylamino, and (C 1-6 alkyl) carboxy C 1 Phenyl substituted with 1-2 groups independently selected from -6 alkyl, j1) Heterocycle which is unsubstituted or substituted by one group selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, cyano, and amino And k) the compound or pharmacologically acceptable salt
  • a 2 is unsubstituted or consists of the following: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C Phenyl substituted with 1 to 3 groups independently selected from 3-6 cycloalkoxy;
  • a 3 is, following i2) and j2): i2) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkoxy, amino, Mono (di)
  • a 1 is unsubstituted phenyl or pyridyl;
  • a 3 is, following i3) and j3): i3) unsubstituted or group consisting of: phenyl substituted by 1-2 groups independently selected from halogen atom, C 1-6 alkyl, amino, and hydroxy, and j3) unsubstituted or from A group selected from the group consisting of a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, and pyridyl substituted with one group selected from amino, [1] to [8 Or a pharmaceutically acceptable salt thereof.
  • a 2 is the following group: ((*) Represents a binding position), [1] to [9] or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of [1] to [12] or a pharmacologically acceptable salt thereof.
  • the pharmaceutical composition according to [13] above which is used for treatment or prevention of a disease or symptom caused by hyperexcitability or disorder of afferent nerves.
  • Due to hyperexcitement or disorder of afferent nerve comprising administering an effective amount of the compound according to any one of [1] to [12] above or a pharmacologically acceptable salt thereof A method of treating or preventing a disease or condition.
  • a 1 represents the following a) to d): a) unsubstituted or 1-2 groups independently selected from the group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy C 6-10 aryl substituted with a group, b) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 5-membered heterocycle substituted with a group, c) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 6-membered heterocycle substituted with a group, and d) a group selected from the group
  • a pharmaceutical composition for treating or preventing stenosis Pain, cold rhinitis, itching, numbness, urticaria, overactive bladder, detrusor overactivity, nocturia, interstitial cystitis, bladder pain syndrome, hypersensitive bladder syndrome, urinary incontinence or urethra.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof has a strong inhibitory action in, for example, an Icilin-induced wet-dog shake inhibitory action confirmation test according to the method described in International Publication No. 2009/012430. showed that. Therefore, the compound (I) of the present invention, or a pharmacologically acceptable salt thereof, is useful as a pharmaceutical composition for treating or preventing a disease or symptom caused by hyperexcitability or disorder of afferent nerve.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. A fluorine atom or a chlorine atom is preferred.
  • C 1-6 alkyl means an optionally branched alkyl having 1 to 6 carbon atoms.
  • C 1-6 alkoxy means an alkoxy having 1 to 6 carbon atoms which may be branched. 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 hydroxy. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1,1-dimethylmethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl and the like.
  • C 6-10 aryl refers to phenyl or naphthyl.
  • “Mono (di) C 1-6 alkylamino” refers to an amino mono- or di-substituted with the above C 1-6 alkyl.
  • the C 1-6 alkyl in the case of di-substitution may be different.
  • C 1-6 alkylsulfonyl means a group represented by (C 1-6 alkyl) —SO 2 —. Examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
  • C 1-6 alkylsulfonylamino means amino substituted with the above C 1-6 alkylsulfonyl.
  • (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.
  • (C 1-6 alkyl) carbonylamino means amino substituted with the above (C 1-6 alkyl) carbonyl.
  • C 1-6 alkoxycarbonyl means a carbonyl substituted with the above C 1-6 alkoxy. Examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • C 1-6 alkoxycarbonyl C 2-6 alkenyl means C 2-6 alkenyl substituted with the above C 1-6 alkoxycarbonyl. Examples thereof include methoxycarbonyl vinyl, ethoxycarbonyl vinyl, methoxycarbonyl allyl, ethoxycarbonyl allyl and the like.
  • C 1-6 alkoxycarbonyl C 1-6 alkoxy means the above C 1-6 alkoxy substituted with the above C 1-6 alkoxycarbonyl.
  • C 1-6 alkoxycarbonylphenyl C 1-6 alkoxy means C 1-6 alkoxy substituted with phenyl substituted with the above C 1-6 alkoxycarbonyl.
  • (C 1-6 alkyl) carboxy means carboxy substituted with the above C 1-6 alkyl. Examples include acetoxy, ethyl carboxy, propyl carboxy, isopropyl carboxy, isobutyl carboxy, butyl carboxy, sec-butyl carboxy, tert-butyl carboxy, pentyl carboxy, hexyl carboxy, and the like.
  • (C 1-6 alkyl) carboxy C 1-6 alkyl means the above C 1-6 alkyl substituted.
  • C 3-6 cycloalkyl means a monocyclic saturated alicyclic hydrocarbon having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 3-6 cycloalkoxy means alkoxy having a monocyclic saturated alicyclic hydrocarbon having 3 to 6 carbon atoms. Examples include cyclopropoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.
  • C 4-6 cycloalkenyl means a monocyclic unsaturated alicyclic hydrocarbon having 4 to 6 carbon atoms and having at least one double bond in the ring.
  • cyclobutenyl, cyclopentenyl, cyclohexenyl and the like can be mentioned.
  • Heterocycle means a 5- or 6-membered heterocycle containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom, and examples thereof include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, Aromatics such as imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, pyranyl, pyridyl, 1-oxidepyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furazanyl Heterocycles, pyrrolinyl, imidazolinyl, pyrazolinyl, dihydropyranyl, dihydrothiopyranyl, dihydropyridyl and other unsaturated
  • heterocycle may be condensed with another cyclic group, for example, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, chromenyl, chromanonyl.
  • the “5-membered heterocycle” of A 1 is preferably furyl, thienyl, thiazolyl, imidazolyl, 1,2,3-thiadiazolyl or oxazolyl.
  • pyridyl is preferable.
  • thienyl is preferable.
  • heterocycle As the “heterocycle” of A 3 , thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrrolidinyl, tetrahydropyranyl, quinolyl, and indolyl are preferable, and pyridyl is more preferable.
  • R 1 and R 2 are simultaneously C 1-6 alkyl, they may be bonded to each other to form a ring” means, for example, the following formula: ((*) Represents a bonding position).
  • C 1-6 alkylene means a divalent branched saturated hydrocarbon chain having 1 to 6 carbon atoms.
  • C 7-10 aralkyloxy means an alkoxy having 1 to 4 carbon atoms substituted with a phenyl group. Examples include benzyloxy, phenethyloxy, 1-phenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy and the like.
  • the compound (I) of the present invention includes stereoisomers such as optical isomers and geometric isomers.
  • the optical isomer of the compound (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 (I) of the present invention is a racemic solid or crystal
  • racemic compounds, racemic mixtures and racemic solid solutions 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. In the compound (I) of the present invention, when a tautomer exists, the present invention includes any of the tautomers.
  • Compound (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 (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, the TRPM8 inhibitor suppresses excessively excited afferent nerve activity, thereby treating or preventing symptoms such as lower urinary tract symptoms (LUTS), particularly overactive bladder (OAB).
  • 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. .
  • a 1 is less a3), b3), c2) and d): a3) unsubstituted or group consisting of: phenyl substituted with 1 to 2 groups independently selected from a halogen atom, C 1-6 alkyl and haloC 1-6 alkyl; b3) an aromatic 5-membered heterocycle which is unsubstituted or substituted with C 1-6 alkyl, c2) a group selected from the group consisting of unsubstituted pyridyl and d) C 4-6 cycloalkenyl;
  • a 2 represents the following e2), f2) and h): e2) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3 Phenyl substituted
  • a 1 is unsubstituted phenyl
  • a 2 is unsubstituted or substituted by 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy Phenyl
  • a 3 is, following i5), j5), and k1): i5) unsubstituted or group consisting of: phenyl substituted with 1 to 2 groups independently selected from halogen atom, amino, hydroxy; j5) Unsubstituted or group consisting of: C 1-6 alkoxy, pyridyl substituted with one group selected from amino, k1) a group selected from the group consisting of C 4-6 cycloalkenyl; L 1 is a single bond; R 1 is C 1-6 alkyl and R 2 is a hydrogen atom; L 2 is a single bond.
  • a 1 is unsubstituted phenyl
  • a 2 is unsubstituted or substituted by 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy Phenyl
  • a 3 is, following i6) and j6): i6) unsubstituted or group consisting of: a halogen atom, phenyl substituted with 1 to 2 groups independently selected from amino; j6) a group selected from the group consisting of unsubstituted pyridyl
  • L 1 is a single bond
  • R 1 is C 1-6 alkyl and R 2 is a hydrogen atom
  • L 2 is a single bond.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof can be produced according to the method described in detail below or a method analogous thereto, the method described in other literature or a method analogous thereto.
  • Compound (I) of the present invention can be produced as compound (Ia) by the method shown in Scheme 1.
  • a 1 , A 2 , A 3 , L 1 , L 2 , R 2 , R 1 are as defined above;
  • R c1 is a C 1-6 alkoxy group, C 7-10 aralkyloxy group or amino
  • R c2 represents a leaving group.
  • Step 1-1 Compound (3) can be produced by reacting compound (1) and compound (2) in a solvent.
  • the solvent include tetrahydrofuran, 1,4-dioxane, dichloromethane, acetic acid, methanol, ethanol, toluene, a mixed solvent thereof and the like.
  • this reaction can be carried out by adding an acid such as p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, titanium tetrachloride, boron trifluoride-diethyl ether complex, if necessary.
  • 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.
  • Step 1-2 Compound (4) can be produced by reacting compound (3) with a reducing agent in a solvent.
  • the solvent include tetrahydrofuran, 1,4-dioxane, dichloromethane, acetic acid, methanol, ethanol, acetonitrile, a mixed solvent thereof and the like.
  • the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane / pyridine complex, borane / diethylamine complex, 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 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • this reaction can be carried out by reacting in a solvent with a catalytic amount of a metal catalyst in a hydrogen atmosphere instead of using the reducing agent.
  • a solvent include tetrahydrofuran, 1,4-dioxane, ethyl acetate, methanol, ethanol, a mixed solvent thereof and the like.
  • the metal catalyst include palladium carbon, platinum oxide, Raney nickel 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. This reaction is carried out at normal pressure (about 1 atm) to 10 atm.
  • Step 1-3 Compound (6) can be produced by reacting compound (4) with compound (5) in the presence of a base in an appropriate solvent.
  • the solvent include dichloromethane, dichloroethane, tetrahydrofuran and the like.
  • the base include triethylamine, N, N-diisopropylethylamine and the like.
  • R C2 include a chlorine atom, a bromine atom, (CH 2 CO) 2 N—O—, p-nitrophenoxy and the like.
  • this reaction can be carried out by adding N, N-dimethyl-4-aminopyridine or the like as necessary.
  • the reaction temperature is from 0 ° C.
  • 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.
  • the compound in which R c1 is an amino group represents the compound (Ia)
  • the compound in which R c1 is a C 1-6 alkoxy group or a C 7-10 aralkyloxy group represents the compound (6a).
  • Step 1-4 When compound (6a) is obtained in step 1-3, compound (7) can be produced by reacting compound (6a) with an aqueous alkali solution in a solvent. Further, when R C1 is a benzyloxy group or the like, it can be reacted in a solvent with a metal catalyst in a hydrogen atmosphere. Such reactions are well known to those skilled in the art, and can be performed, for example, using the method described in Greene & Wuts, “Greene's Protective Groups in Organic Synthesis”, Fourth Edition, Wiley-Interscience, 2006.
  • Step 1-5 Compound (Ia) can be produced by reacting compound (7) with an ammonia equivalent in the presence of a condensing agent in a solvent.
  • a condensing agent examples include dichloromethane, N, N-dimethylformamide, tetrahydrofuran and the like.
  • the condensing agent examples include 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium.
  • Examples include hexafluorophosphate, 3- (diethoxyphosphoryloxy) -1,2,3-benzo [d] triazin-4 (3H) -one, and the like.
  • Examples of the ammonia equivalent include ammonium chloride.
  • This reaction can be carried out by adding a base such as triethylamine or N, N-diisopropylethylamine and an activator such as 1-hydroxybenzotriazole as necessary.
  • 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.
  • a 1 , A 2 , L 1 and R 1 are as defined above;
  • R c1 is a C 1-6 alkoxy group, a C 7-10 aralkyloxy group or an amino group;
  • R c3 is a chlorine atom And represents a leaving group such as a bromine atom, an iodine atom, and a methanesulfonyloxy group.
  • Step 2-1 Compound (4) can be produced by reacting compound (8) with compound (9) in a solvent.
  • the solvent include dichloromethane, N, N-dimethylformamide, tetrahydrofuran, acetonitrile and the like.
  • This reaction can be carried out by adding a base such as triethylamine, N, N-diisopropylethylamine, sodium hydrogen carbonate, potassium hydrogen carbonate, or potassium carbonate, if necessary.
  • 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.
  • R c4 , R c5 are each a C 1-6 alkyl group or R c4 , R c5.
  • n is an integer of 2 to 4
  • R c6 represents a hydrogen atom or a phenyl group.
  • Step 3-1 Compound (14) can be produced by reacting compound (10), compound (11), and compound (12) with compound (13) in a solvent.
  • a reaction is well known to those skilled in the art as a Ugi reaction, and can be performed, for example, using the method described in Domling A., Ugi I. Angewandte Chemie International Edition 2000, 39, 3168-3210.
  • the reaction temperature is ⁇ 78 ° C. to solvent reflux temperature
  • the reaction time is usually 10 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature, and the like.
  • compound (10) can be prepared by adding a base such as triethylamine to the corresponding salt in the reaction system.
  • Step 3-2 Compound (I) can be produced by hydrolyzing compound (14) in a solvent under acidic conditions.
  • the solvent include tetrahydrofuran, 1,4-dioxane and the like.
  • the acid include hydrogen chloride, sulfuric acid, trifluoroacetic acid and the like.
  • the reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 5 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
  • Compound (2), Compound (8), Compound (11) and Compound (12) can be obtained as commercially available reagents, respectively, or can be produced by methods described in the literature or a method analogous thereto.
  • Compound (1) can be obtained as a commercially available reagent, and can be produced, for example, by obtaining the corresponding amino acid using a reaction well known to those skilled in the art as the Strecker reaction, and then amidating or esterifying.
  • Compounds (9) and (10) can be obtained as commercially available reagents and can be produced, for example, using the method described in Jonathan A. Ellman et al., Accounts of Chemical Research 2002, 35, 984-995. .
  • Compound (13) can be obtained as a commercially available reagent, and can also be produced, for example, using the method described in W. Maison et al., Bioorganic Medicinal Chemistry 2000, 8, 1343-1360.
  • a protective group when required depending on the type of functional group, it can be carried out by appropriately combining introduction and removal operations according to a conventional method.
  • introduction and removal of protecting groups for example, Theodra W. Greene & Peter G. M. Green Wuts, ed. be able to.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof, and a production intermediate used for producing the compound, if necessary, are isolated and well-known to those skilled in the art. It can be isolated and purified by purification means such as solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography, and the like.
  • the pharmaceutical composition containing the compound (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.
  • a medicament containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is a pharmaceutical composition for treating or preventing a disease or symptom caused by TRPM8 activation due to TRPM8 inhibitory action. Can be used as a thing.
  • Disease or symptom caused by activation of TRPM8 means a disease or symptom caused by hyperexcitation or disorder of afferent nerve.
  • 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. It is preferably used for the treatment or prevention of lower urinary tract symptoms (LUTS), pain, circulatory disturbance.
  • “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. It is preferably used for the treatment or prevention of overactive bladder, detrusor overactivity, nocturia, cystitis such as interstitial cystitis, bladder pain syndrome, hypersensitive bladder syndrome, urinary incontinence, urethral stricture.
  • “Circulating disorders” include cold rhinitis, Raynaud's disease, etc., and is preferably used for the treatment or prevention of cold rhinitis.
  • the compound (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 (I) of the present invention or a pharmacologically acceptable salt thereof include opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), barbiturate sedatives, and benzodiazepines having sedative action.
  • opioid analgesics nonsteroidal anti-inflammatory drugs (NSAIDs)
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • barbiturate sedatives benzodiazepines having sedative action.
  • H 1 blockers having sedative effects, sedatives, skeletal muscle relaxants, NMDA receptor antagonists, alpha-adrenergic agonists, tricyclic antidepressants, anticonvulsants, tachykinin antagonists (NK antagonists), Muscarinic receptor antagonist, COX-2 selective inhibitor, coal tar analgesic, neuroleptic, TRPV1 agonist, TRPV1 inhibitor, beta blocker, local anesthetic, corticosteroid, 5-HT receptor agonist, 5-HT 2A receptor antagonist, cholinergic analgesic, PDE5 inhibitor, PDE9 inhibitor, ⁇ 2 ⁇ ligand, cannabinoid, metabolizing group Rutamate receptor 1 antagonist (mGluR1 antagonist), metabotropic glutamate receptor 5 antagonist (mGluR5 antagonist), serotonin reuptake inhibitor, noradrenaline reuptake inhibitor, serotonin / noradrenaline reuptake inhibitor, inducible type 1 Nitric oxide synthase inhibitor
  • ⁇ -adrenergic agent examples include doxazosin, tamsulosin, silodosin, clonidine, guanfacine, dexmedetomidine, modafinil, tizanidine, moxonidine and the like.
  • musclecarinic receptor antagonists 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 provides 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.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof and the above-mentioned drug administered in combination The order of administration is not particularly limited.
  • the compound of the present invention is more advantageous than the additive effect in preventing or treating the above diseases by administering it in appropriate combination with one or more kinds of the above drugs.
  • 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 (I) of the present invention which is an active ingredient thereof, or a pharmacologically acceptable salt thereof depends on the age, sex, body weight, disease of the patient. It is appropriately determined depending on the degree of treatment.
  • an adult with a body weight of 60 kg
  • the daily dose as an oral preparation is preferably 10 to 1000 mg, more preferably 60 to 600 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 compound (I), which is an active ingredient of the TRPM8 inhibitor of the present invention, or a pharmacologically acceptable salt thereof can be reduced according to the dose of a drug other than the TRPM8 inhibitor.
  • a low-polar product means a compound that elutes first when a mixture of two diastereomers is separated and purified using normal phase column chromatography
  • a high-polar product means a compound that elutes later.
  • LP represents a low polarity product
  • HP represents a high polarity product
  • M represents a mixture of optical isomers.
  • microwave irradiation was performed using Biotage Initiator.
  • Reference Examples 1-2 to 1-8 Reference Examples 1-2 to 1-8 were synthesized in the same manner as Reference Example 1-1 using the corresponding starting materials.
  • the structural formulas and physical property values of Reference Examples 1-2 to 1-8 are shown in Tables 3 to 4.
  • Reference example 2 3-cyclopropyl-5-fluorobenzaldehyde 3-bromo-5-fluorobenzaldehyde (0.05 g), cyclopropylboronic acid monohydrate (0.041 g), palladium acetate (0.0055 g), tricyclohexylphosphine (0 .0069 g), potassium phosphate (0.183 g), and water (0.1 mL) in toluene (1 mL) were irradiated with microwaves and stirred at 150 ° C. for 10 minutes. Water and ethyl acetate were added to the reaction mixture for liquid separation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Reference Examples 3-2 to 3-3 Reference Examples 3-2 to 3-3 were synthesized in the same manner as Reference Example 3-1, using the corresponding starting materials.
  • the structural formulas and physical property values of Reference Examples 3-2 to 3-3 are shown in Table 4.
  • Reference Example 4-2 Reference Example 4-2 was synthesized in the same manner as in Reference Example 4-1, using the corresponding carbonyl compound.
  • the structural formula and physical property values of Reference Example 4-2 are shown in Table 5.
  • Example 1-1 To a solution of N-[(R) -carbamoylphenylmethyl] -N- (3-methoxybenzyl) -2-thienamide (R) -phenylglycinamide hydrochloride (103 mg) in tetrahydrofuran (1 mL) / methanol (1.5 mL) , Triethylamine (0.13 mL) and 3-methoxybenzaldehyde (0.045 mL) were added at room temperature and the mixture was stirred for 4 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in a tetrahydrofuran (1 mL) / methanol (1.5 mL) mixture.
  • Examples 1-2 to 1-95 were synthesized in the same manner as in Example 1-1 using the corresponding starting materials.
  • the structural formulas and physical property values of Examples 1-2 to 1-95 are shown in Tables 6 to 21.
  • Example 2-1 N-[(R) -carbamoylphenylmethyl] -N- (3-trifluoromethylbenzyl) benzamide (R) -phenylglycinamide hydrochloride (0.05 g), triethylamine (75 ⁇ L), and 3-trifluoromethylbenzaldehyde
  • a mixed solution of (0.049 g) in tetrahydrofuran (1 mL) -methanol (1 mL) was stirred at room temperature for 2 hours. Under an argon atmosphere, 10% palladium carbon (0.015 g) was added to the reaction mixture at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • Examples 2-2 to 2-30 were synthesized in the same manner as in Example 2-1, using the corresponding starting materials.
  • the structural formulas and physical property values of Examples 2-2 to 2-30 are shown in Tables 22 to 27.
  • Example 3-1 N- (carbamoylphenylmethyl) -2-hydroxy-N- (3-methoxybenzyl) benzamide 2- ⁇ N-[(R) -carbamoylphenylmethyl] -N- (3-methoxybenzyl) carbamoyl ⁇ phenyl acetate ( In Example 1-44, 0.060 g), a 2 mol / L ammonia methanol solution (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour.
  • Examples 3-2 to 3-6 were synthesized in the same manner as in Example 3-1, using the corresponding starting materials.
  • the structural formulas and physical property values of Examples 3-2 to 3-6 are shown in Table 28.
  • Example 4-2 Example 4-2 was synthesized in the same manner as in Example 4-1, using the compound obtained in Example 1-47.
  • the structural formula and physical property values of Example 4-2 are shown in Table 29.
  • Example 5-1 2-Amino-N-[(R) -carbamoylphenylmethyl] -N- (3-methoxybenzyl) benzamide (R) -Phenylglycinamide hydrochloride (1.0 g) and triethylamine (1.5 mL) with stirring at room temperature 3-Methoxybenzaldehyde (720 ⁇ L) was added to a tetrahydrofuran (10 mL) mixture, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added methanol (10 mL) and sodium borohydride (1.01 g), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the solvent was distilled off under reduced pressure.
  • Examples 5-2 to 5-3 Example 5-2 to 5-3 were synthesized in the same manner as in Example 5-1, using the corresponding starting materials.
  • the structural formulas and physical property values of Examples 5-2 to 5-3 are shown in Table 30.
  • Example 6-1 N-[(R) -carbamoylphenylmethyl] -2-hydroxy-N- (3-trifluoromethoxybenzyl) benzamide
  • (R)- Phenylglycinamide hydrochloride (0.100 g)
  • triethylamine 0.073 mL
  • Examples 6-2 to 6-11 were synthesized in the same manner as in Example 6-1, using the corresponding starting materials.
  • the structural formulas and physical property values of Examples 6-2 to 6-11 are shown in Tables 31 to 32.
  • Example 7-1 N-[(R) -carbamoylphenylmethyl] -N- (2-fluoro-5-methylbenzyl) -2-hydroxybenzamide (R) -phenylglycinamide hydrochloride (0.10 g) and triethylamine ( To a mixture of 150 ⁇ L) of tetrahydrofuran (2 mL) / methanol (2 mL) was added 2-fluoro-5-methylbenzaldehyde (69 ⁇ L), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 10% palladium on carbon (0.03 g) at room temperature and the mixture was stirred under a hydrogen atmosphere for 4 hours.
  • Examples 7-2 to 7-11 were synthesized in the same manner as in Example 7-1 using the corresponding starting materials.
  • the structural formulas and physical property values of Examples 7-2 to 7-11 are shown in Tables 33 to 34.
  • Example 8-1 2-Amino-N-[(R) -carbamoylphenylmethyl] -N- (3-trifluoromethylbenzyl) benzamide (R) -phenylglycinamide hydrochloride (0.10 g) and triethylamine (150 ⁇ L) with stirring at room temperature 3-trifluoromethylbenzaldehyde (75 ⁇ L) was added to a tetrahydrofuran (2 mL) / methanol (2 mL) mixture, and the mixture was stirred at room temperature for 2 hours. 10% Palladium carbon (0.015 g) was added to the reaction mixture at room temperature, and the mixture was stirred for 2 hours under a hydrogen atmosphere.
  • Examples 8-2 to 8-3 were synthesized in the same manner as in Example 8-1, using the corresponding starting materials.
  • the structural formulas and physical property values of Examples 8-2 to 8-3 are shown in Table 35.
  • Example 9-1 4- ⁇ 4-[(carbamoylphenylmethyl)-(3-methoxybenzyl) carbamoyl] phenoxymethyl ⁇ benzoic acid methyl ester N-[(R) -carbamoylphenylmethyl] -4-hydroxy-N- (3-methoxybenzyl )
  • N-dimethylformamide 1 mL
  • sodium hydride 0.003 g
  • methyl 4-bromomethylbenzoate 0.023 g
  • Example 9-2 Example 9-2 was synthesized in the same manner as in Example 9-1 using the compound obtained in Example 7-11. The structural formula and physical property values of Example 9-2 are shown in Table 36.
  • Example 10-1 (S) -N-[(R) -carbamoylphenylmethyl] -N- (3-trifluoromethylbenzyl) pyrrolidine-2-carboxamide
  • (R) -phenylglycinamide hydrochloride 2.0 g
  • To the reaction mixture was added 10% palladium on carbon (0.1 g) at room temperature, and the mixture was stirred under a hydrogen atmosphere for 4 hours.
  • Example 10-2 Example 10-2 was synthesized in the same manner as in Example 10-1, using the corresponding starting materials. The structural formula and physical property values of Example 10-2 are shown in Table 37.
  • Example 11 N- (carbamoylphenylmethyl) -N- (2-fluoro-5-trifluoromethylbenzyl) -2-hydroxybenzamide (R) -phenylglycinamide hydrochloride (0.25 g) and triethylamine (375 ⁇ L) with stirring at room temperature
  • To the reaction mixture was added 10% palladium carbon (25 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours.
  • Example 12 N-[(R) -carbamoylphenylmethyl] -3-methanesulfonylamino-N- (3-trifluoromethylbenzyl) benzamide Under stirring with ice cooling, 3-amino-N-[(R) -carbamoylphenylmethyl]- Methanesulfonyl chloride (6 ⁇ L) was added to a dichloromethane (1 mL) mixture of N- (3-trifluoromethylbenzyl) benzamide (Example 8-3, 0.027 g) and triethylamine (19 ⁇ L), and the mixture was brought to the same temperature. And stirred for 0.5 hour.
  • Example 13 N- (carbamoylphenylmethyl) -N- (cyclohexylmethyl) benzamide
  • 2-hydroxy-2-phenylacetamide 0.1 g
  • triethylamine 167 ⁇ L
  • dichloromethane 2 mL
  • methanesulfonyl chloride 67 ⁇ L
  • the mixture was stirred at the same temperature for 0.5 hour.
  • C-cyclohexylmethylamine (215 ⁇ L) was added to the reaction mixture, and the mixture was stirred for 12 hours with heating under reflux. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Example 14-1 N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-methoxyphenyl) ethyl] benzamide N-[(S) -carbamoylphenylmethyl] -N-[(R) -1 -(3-Methoxyphenyl) ethyl] benzamide (S) -2- (4-Nitrobenzenesulfonyloxy)-was added to a solution of (R) -1- (3-methoxyphenyl) ethylamine (0.100 g) in dichloromethane (3 mL).
  • Benzoyl chloride (0.099 mL) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 14 hours.
  • N, N-dimethyl-4-aminopyridine (0.0069 g), triethylamine (0.235 mL) and benzoyl chloride (0.099 mL) were added to the mixture at room temperature, and the mixture was stirred at 35 ° C. for 23 hours.
  • Triethylamine (0.235 mL) and benzoyl chloride (0.099 mL) were added to the mixture, and the mixture was heated to reflux for 5 hours. The reaction mixture was evaporated under reduced pressure.
  • Aqueous sodium hydroxide (2 mol / L, 0.72 mL) was added to the mixture at room temperature and the mixture was stirred at 40 ° C. for 2 hours.
  • Hydrochloric acid (2 mol / L, 1.56 mL) was added to the reaction mixture under ice cooling, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Ammonium chloride (0.115 g), N, N-diisopropylethylamine (0.585 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.123 g) were added to the mixture under ice cooling, Stir at room temperature for 1.5 days. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • Example 14-2 was synthesized in the same manner as Example 14-1 using the corresponding starting materials. Table 39 shows the structural formula and physical property values of Example 14-2.
  • Example 15-1 N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-trifluoromethylphenyl) ethyl] benzamide N-[(S) -carbamoylphenylmethyl] -N-[(R) -1- (3-trifluoromethylphenyl) ethyl] benzamide
  • Example 15-2 Examples 15-2 to 15-3 were synthesized in the same manner as in Example 15-1, using the corresponding starting materials.
  • the structural formulas and physical property values of Examples 15-2 to 15-3 are shown in Table 40.
  • Example 16-1 N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] benzamide N-[(S) -carbamoylphenylmethyl] -N-[(R) -1- (3-Chlorophenyl) ethyl] benzamide (R) -1- (3-Chlorophenyl) ethylamine (2.11 g) and potassium bicarbonate (2.04 g) in acetonitrile (30 mL) were mixed with (S)-(4-nitrobenzene.
  • N, N-dimethylformamide 50 mL
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 2.03 g
  • 1-hydroxybenzotriazole monohydrate 1.43 g
  • N, N-diisopropylethylamine 8.38 mL was added to the mixture at room temperature and stirred for 2 days.
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Examples 16-2 to 16-24 were synthesized in the same manner as in Example 16-1, using the corresponding starting materials.
  • the structural formulas and physical property values of Examples 16-2 to 16-24 are shown in Tables 41 to 47.
  • Example 17-1 N-[(R) -carbamoylphenylmethyl] -N-[(R) -1-phenylethyl] -2-thienamide N-[(S) -carbamoylphenylmethyl] -N-[(R) -1-phenyl Ethyl] -2-thienamide (R) -1-phenylethylamine (0.427 g) and potassium bicarbonate (0.709 g) in acetonitrile (10 mL) mixed with (S)-(4-nitrobenzenesulfonyloxy) phenyl acetate methyl The ester (1.24 g) was added at room temperature and the mixture was stirred at 60 ° C. for 3 hours.
  • Example 17-2 was synthesized in the same manner as Example 17-1 using the corresponding starting materials.
  • the structural formula and physical property values of Example 17-2 are shown in Table 48.
  • Example 18 N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] -2-hydroxybenzamide N-[(S) -carbamoylphenylmethyl] -N-[(R ) -1- (3-Chlorophenyl) ethyl] -2-hydroxybenzamide (R) -1- (3-Chlorophenyl) ethylamine (2.38 g), potassium bicarbonate (2.29 g) in acetonitrile (30 mL) (S)-(4-Nitrobenzenesulfonyloxy) phenylacetic acid benzyl ester (6.53 g) was added at room temperature, and the mixture was stirred at 50 ° C.
  • Example 19-2 Using N-[(S) -carbamoylphenylmethyl] -2-nitro-N-[(R) -1-phenylethyl] benzamide obtained in Example 19-1, in the same manner as in Example 19-1.
  • Example 19-2 was synthesized.
  • Table 50 shows the structural formula and physical property values of Example 19-2.
  • Example 20 N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] -2-thienamide N-[(S) -carbamoylphenylmethyl] -N-[(R ) -1- (3-Fluorophenyl) ethyl] -2-thienamide (R) -1- (3-fluorophenyl) ethylamine (0.635 g), potassium bicarbonate (0.916 g) in acetonitrile (12 mL) To (S) -2- (4-nitrobenzenesulfonyloxy) -2-phenylacetic acid benzyl ester (1.95 g) was added at room temperature, and the mixture was stirred at 60 ° C.
  • Example 21 N-[(R) -carbamoylphenylmethyl] -2-methylamino-N-[(R) -1-phenylethyl] benzamide 2-amino-N-[(R) -carbamoylphenylmethyl] -N-[( (R) -1-Phenylethyl] benzamide (Example 19-1, 0.018 g) and benzotriazol-1-ylmethanol (0.008 g) in ethanol (0.4 mL) Stir for hours. The reaction mixture was allowed to cool to room temperature and stirred at room temperature for 1 hour.
  • Tetrahydrofuran (1 mL) and sodium borohydride (0.009 g) were added to the mixture under ice-cooling and stirring, and the mixture was stirred overnight at room temperature.
  • the structural formula and physical property values of the title compound are shown in Table 51.
  • Example 22-1 N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] benzamide N-[(S) -carbamoylphenylmethyl] -N-[(R) -1 -(3-Fluorophenyl) ethyl] benzamide
  • a mixture of (R) -1- (3-fluorophenyl) ethylamine (0.050 g) and benzaldehyde (0.038 g) in methanol (1 mL) was added at an external temperature of 50 ° C. Stir for hours.
  • the reaction mixture was allowed to cool to room temperature, benzoic acid (0.044 g) and 4-phenylcyclohexen-1-yl isocyanide (0.066 g) were added, and the mixture was stirred at an external temperature of 50 ° C. for 20 hr.
  • the reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (2 mL) was added to the resulting residue and dissolved.
  • Water (7 ⁇ L) and 4 mol / L hydrogen chloride 1,4-dioxane solution (0.255 mL) were added to the mixture, and the mixture was stirred at room temperature for 1 hour. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate.
  • Examples 22-2 to 22-88 Examples 22-2 to 22-88 were synthesized in the same manner as in Example 22-1 using the corresponding starting materials.
  • the structural formulas and physical property values of Examples 22-2 to 22-88 are shown in Tables 52 to 71.
  • Example 23-1 N-[(R) -carbamoylphenylmethyl] -N- ⁇ (R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl ⁇ benzamide N-[(S) -carbamoylphenylmethyl] -N - ⁇ (R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl ⁇ benzamide (S) -N- ⁇ (R) -1- [3- (1,1-difluoroethyl) phenyl] To a solution of ethyl ⁇ -tert-butanesulfinamide (0.12 g) in methanol (2 mL) was added 4 mol / L hydrogen chloride 1,4-dioxane solution (145 ⁇ L) at room temperature, and the mixture was stirred at the same temperature for 1 hour.
  • Example 23-2 was synthesized in the same manner as Example 23-1 using the corresponding amine.
  • the structural formula and physical property values of Example 23-2 are shown in Table 72.
  • Example 24 N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -4-hydroxymethylbenzamide 4- ⁇ N-[(R) -carbamoylphenylmethyl ] -N-[(R) -1- (3,5-difluorophenyl) ethyl] carbamoyl ⁇ benzyl acetate (Examples 22-31LP, 0.093 g) in methanol (1 mL) in potassium carbonate (0.41 g ) And stirred at room temperature for 30 minutes.
  • Example 25-1 2-Amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] benzamide
  • a mixture of (R) -1- (3,5-difluorophenyl) ethylamine (0.2 g) and benzaldehyde (0.136 g) in methanol (4 mL) was stirred with heating under reflux for 20 minutes.
  • the reaction mixture was cooled to room temperature, 2-nitrobenzoic acid (0.213 g) and 4-phenylcyclohexen-1-yl isocyanide (0.233 g) were added, and the mixture was stirred overnight with heating under reflux.
  • the reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (8 mL) was added to the resulting residue and dissolved. Water (25 ⁇ L) and 4 mol / L hydrogen chloride 1,4-dioxane solution (0.95 mL) were added to the mixture, and the mixture was stirred at room temperature for 3 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Examples 25-2 to 25-8 Examples 25-2 to 25-8 were synthesized in the same manner as in Example 25-1 using the corresponding starting materials. The structural formulas and physical property values of Examples 25-2 to 25-8 are shown in Tables 73 to 74.
  • Example 26 N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -2-hydroxybenzamide
  • a mixture of (R) -1- (3,5-difluorophenyl) ethylamine (0.2 g) and benzaldehyde (0.136 g) in methanol (4 mL) was stirred with heating under reflux for 20 minutes.
  • the reaction mixture was cooled to room temperature, 2-acetoxybenzoic acid (0.229 g) and 4-phenylcyclohexen-1-yl isocyanide (0.233 g) were added, and the mixture was stirred overnight with heating under reflux.
  • the reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (8 mL) was added to the resulting residue and dissolved. Water (25 ⁇ L) and 4 mol / L hydrogen chloride 1,4-dioxane solution (0.95 mL) were added to the mixture, and the mixture was stirred at room temperature for 3 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Example 27 4-Amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] nicotinamide
  • (R) -1- (3,5-difluorophenyl) ethylamine (0.1 g) and benzaldehyde (0.068 g) in methanol (1 mL) was stirred with heating under reflux for 20 minutes.
  • Trifluoroacetic acid (1 mL) was added to a methylene chloride (1 mL) solution, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. Water and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the crude product was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • 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 intervals was calculated as the urination interval extension rate (Elongation of micturition interval (%)).
  • the dosage and results are shown in Table 76.
  • the compound of the present invention exhibited a strong TRPM8 inhibitory action. Furthermore, as shown in Table 76, it was found that the compound of the present invention has a prolonging effect on the urination interval and is effective in suppressing detrusor overactivity.
  • the compound of the present invention has a potent TRPM8 inhibitory action, it is a pharmaceutical composition for treating or preventing a disease or symptom caused by activation of TRPM8, particularly lower urinary tract symptoms (LUTS), particularly overactive bladder ( It is useful as a pharmaceutical composition for treating or preventing OAB).
  • TRPM8 a disease or symptom caused by activation of TRPM8, particularly lower urinary tract symptoms (LUTS), particularly overactive bladder

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Abstract

The present invention provides: a novel α-substituted glycinamide derivative or a pharmacologically acceptable salt thereof; a pharmaceutical composition containing the compound or the pharmacologically acceptable salt; and a use of the compound or the pharmacologically acceptable salt for medical purposes. The present invention provides: a compound which has a TRPM8-inhibiting activity and is represented by general formula (I) [wherein A1 represents a C6-10 aryl group or the like; A2 represents a C6-10 aryl group or the like; A3 represents a C6-10 aryl group or the like; L1 represents a single bond or the like; R1 represents a C1-6 alkyl group or the like; R2 represents a hydrogen atom or the like; and L2 represents a single bond or the like] or a pharmacologically acceptable salt thereof. The compound (I) according to the present invention can be used in a pharmaceutical composition for treating or preventing diseases or conditions associated with excessive excitation or damage of an afferent nerve.

Description

α－置換グリシンアミド誘導体α-Substituted glycinamide derivatives
　本発明は、医薬品として有用なα－置換グリシンアミド誘導体、またはその薬理学的に許容される塩、それを含有する医薬組成物およびその医薬用途に関する。 The present invention relates to an α-substituted glycinamide derivative useful as a pharmaceutical product, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
　一過性受容体電位（Transient Receptor Potential（TRP））チャネルは、温度や化学物質等の様々な刺激により活性化される非選択的カチオンチャネルであり、TRPM、TRPA、TRPV、TRPC、TRPP、TRPML、TRPNファミリーに分けられる。さらに、TRPMファミリーには、TRPM1、TRPM2、TRPM3、TRPM4a、TRPM4b、TRPM5、TRPM6、TRPM7、TRPM8が知られている（例えば、非特許文献１参照）。
　TRPM8は、2002年にクローニングされたTRPMファミリーの8番目のチャネルであり（例えば、非特許文献２参照）、CMR1(cold and menthol sensitive receptor-1)としても知られ、８℃～２８℃の冷刺激や低温感覚を惹起する化学物質（メントールやIcilin）により活性化される（例えば、非特許文献１及び２参照）。TRPM8は、一次求心性神経（Aδ線維及びC線維）や三叉神経に発現している他、味覚乳頭、血管内皮、大動脈、肺動脈、前立腺、雄性生殖器（例えば、非特許文献３参照）、ヒト膀胱上皮を支配している神経線維（例えば、非特許文献４参照）、前立腺癌（例えば、非特許文献５参照）、口腔扁平上皮癌（例えば、非特許文献６参照）等にも発現していることが報告されている。
　TRPM8ノックアウトマウスにおいては、寒冷知覚の欠如、神経障害または炎症後の冷刺激に対する過敏症の欠如等がみられる（例えば、非特許文献３参照）。
　神経系の疾患においては、坐骨神経障害モデルラットにおいてTRPM8の発現が増加し、低温痛覚過敏に関与していると報告されている（例えば、非特許文献７参照）。また、ラット及びマウスにおいてオキサリプラチンによる末梢神経障害によりTRPM8の発現が増加していること、オキサリプラチンによる低温痛覚過敏にTRPM8が関与していることが示されている（例えば、非特許文献８及び９参照）。またオキサリプラチンを服用している患者が健常人と比較してメントールへの反応性が亢進していることから、ヒトにおいてもげっ歯類と同様にオキサリプラチンによる末梢神経障害性疼痛にTRPM8が関与していると考えられている（例えば、非特許文献１０参照）。
　泌尿器系の疾患については、ラットにおいて低温により惹起される頻尿症状にTRPM8が関与していることが報告されている（例えば、非特許文献１１参照）。またラットにおいて皮膚と膀胱を二重同時支配する神経にTRPM8が発現し、低温により惹起される排尿切迫感に関与していると考えられている（例えば、非特許文献１２参照）。ネコおよび脳卒中、脊髄損傷などの上位中枢神経疾患患者においては、膀胱に少量の冷水を注入することで正常では見られない排尿反射の誘発が認められ、この排尿反射はメントールにより増強される（例えば、非特許文献１３及び１４参照）。また、ネコにおいてはC線維の脱感作によりこの排尿反射が軽減することから、メントール感受性のC線維が関与していると考えられている（例えば、非特許文献１３参照）。
　また、特発性排尿筋過活動・膀胱痛症候群患者の膀胱上皮下の神経線維でTRPM8の発現量の増加が確認されること、TRPM8の発現量と排尿回数・疼痛スコアが相関することが報告されており（例えば、非特許文献１５参照）、TRPM8が膀胱求心路において蓄尿に関わる重要な役割を担っている可能性がある。
　従って、TRPM8を阻害することにより、TRPM8の活性化に起因する疾患または症状の治療若しくは予防が期待される。
　一方、TRPM8を阻害する物質としては、Ｎ－(３－アミノプロピル)－２－｛〔（３－メチルフェニル）メチル〕オキシ｝－Ｎ－（２－チエニルメチル）ベンズアミド塩酸塩(以下、AMTBと称すこともある)が知られている。 Transient Receptor Potential (TRP) channels are non-selective cation channels that are activated by various stimuli such as temperature and chemicals. TRPM, TRPA, TRPV, TRPC, TRPP, TRPML Divided into the TRPN family. Furthermore, 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). It is activated by a chemical substance (menthol or Icilin) that causes stimulation or low-temperature sensation (see, for example, Non-Patent Documents 1 and 2). TRPM8 is expressed in primary afferent nerve (Aδ 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.
In TRPM8 knockout mice, lack of cold perception, lack of hypersensitivity to cold stimulation after neuropathy or inflammation, etc. (see, for example, 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).
Regarding 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). In rats, 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). In patients with upper central nervous disease such as cats, stroke, and spinal cord injury, infusion of a small amount of cold water into the bladder induces an unusual micturition reflex, which is enhanced by menthol (e.g., menthol) Non-patent documents 13 and 14). Further, in cats, this micturition reflex is reduced by desensitization of C fibers, and therefore, it is considered that menthol-sensitive C fibers are involved (see, for example, Non-Patent Document 13).
In addition, an increase in TRPM8 expression was confirmed in nerve fibers in the subepithelial bladder of patients with idiopathic detrusor overactivity / bladder pain syndrome, and TRPM8 expression was correlated with urination frequency and pain score. (See, for example, Non-Patent Document 15) TRPM8 may play an important role in urine storage in the bladder afferent.
Therefore, by inhibiting TRPM8, treatment or prevention of diseases or symptoms caused by TRPM8 activation is expected.
On the other hand, substances that inhibit TRPM8 include N- (3-aminopropyl) -2-{[(3-methylphenyl) methyl] oxy} -N- (2-thienylmethyl) benzamide hydrochloride (hereinafter referred to as AMTB). Is also known).
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
　麻酔下のラットにおいて、AMTBが律動性膀胱収縮の頻度を低下させ、膀胱伸展に伴う内臓運動反射を抑制することが報告されている。しかし、AMTBは高濃度の薬効用量では平均血圧の低下が認められ、課題も残されている。（例えば、非特許文献１６参照）。
　AMTBは、以下の一般式（Ａ）： In anesthetized rats, AMTB has been reported to reduce the frequency of rhythmic bladder contractions and suppress visceral motor reflexes associated with bladder extension. However, AMTB has a decrease in mean blood pressure at a high concentration of medicinal dose, and a problem remains. (For example, refer nonpatent literature 16).
AMTB has the following general formula (A):
Figure JPOXMLDOC01-appb-C000007
 〔式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７およびＡは、特許文献１の定義と同義である。〕で表される化合物の実施例としても開示されている（例えば、特許文献１実施例２４参照）。
　しかし、一般式（Ａ）は、本発明の化合物とは構造が異なっている上に、特許文献１には本発明の化合物に関する記載も示唆もない。
Figure JPOXMLDOC01-appb-C000007
 [Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and A are as defined in Patent Document 1. ] Is also disclosed as an example of the compound represented by the formula (for example, see Patent Document 1 Example 24).
However, the structure of the general formula (A) is different from that of the compound of the present invention, and Patent Document 1 does not describe or suggest the compound of the present invention.
　一方、α－置換グリシンアミド誘導体としては、一般式（Ｂ）： On the other hand, as the α-substituted glycinamide derivative, the general formula (B):
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
〔式中、Ｒ１、Ｒ２、Ｒ３、Ｒ５、ｎ、ｙおよびｚは、特許文献２の定義と同義である。〕で表される化合物が開示されている（例えば、特許文献２参照）。
　しかし、特許文献２記載の化合物はオキシトシン阻害剤であるのに対し、本発明の化合物はTRPM8阻害薬である点において異なっている。
　また、一般式（Ｃ）： [Wherein, R 1 , R 2 , R 3 , R 5 , n, y, and z are as defined in Patent Document 2.] ] (For example, refer patent document 2).
However, the compound described in Patent Document 2 is an oxytocin inhibitor, whereas the compound of the present invention is different in that it is a TRPM8 inhibitor.
Moreover, general formula (C):
Figure JPOXMLDOC01-appb-C000009
 〔式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＧおよびＱ１は、特許文献３の定義と同義である。〕で表される化合物が開示されている（例えば、特許文献３参照）。
　しかし、特許文献３記載の化合物はエンドセリン変換酵素阻害薬であるのに対し、本発明の化合物はTRPM8阻害薬である点において異なっている。
　また、特許文献４に、下記に示す化合物：
Figure JPOXMLDOC01-appb-C000009
 [Wherein R 1 , R 2 , R 3 , R 4 , G and Q 1 are as defined in Patent Document 3. ] (For example, refer patent document 3).
However, the compound described in Patent Document 3 is an endothelin converting enzyme inhibitor, whereas the compound of the present invention is different in that it is a TRPM8 inhibitor.
Further, Patent Document 4 discloses a compound shown below:
Figure JPOXMLDOC01-appb-C000010
 が記載されているが、製造中間体として記載されているのみであり、TRPM8阻害活性についての記載はない。
Figure JPOXMLDOC01-appb-C000010
 However, it is only described as a production intermediate, and there is no description about TRPM8 inhibitory activity.
国際公開２００７／０１７０９３号International Publication No. 2007/017093 国際公開２００４／０２０４１４号International Publication No. 2004/020414 特開２０００／１４３６３６号JP 2000/143636 A 特開２０００／１７８２５５号JP 2000/178255 A
　本発明は、新規なα－置換グリシンアミド誘導体、またはその薬理学的に許容される塩、それを含有する医薬組成物およびその医薬用途を提供することを課題とする。 An object of the present invention is to provide a novel α-substituted glycinamide derivative, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
　本発明者らは、α－置換グリシンアミド誘導体を見出すべく鋭意検討した。その結果、本発明の化合物（Ｉ）またはその薬理学的に許容される塩が強力なTRPM8阻害作用があることを見出し、本発明をなすに至った。 The present inventors have intensively studied to find an α-substituted glycinamide derivative. As a result, it has been found that the compound (I) of the present invention or a pharmacologically acceptable salt thereof has a potent TRPM8 inhibitory action, and has led to the present invention.
　即ち、前記課題を解決する為の手段は下記の通りである。
〔１〕一般式（Ｉ）で表される化合物、またはその薬理学的に許容される塩 That is, the means for solving the above problems are as follows.
[1] A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof
Figure JPOXMLDOC01-appb-C000011
 〔式中、
Ａ１は、以下のａ）～ｄ）：
ａ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
ｂ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される５員ヘテロ環、
ｃ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される６員ヘテロ環、および
ｄ）Ｃ４－６シクロアルケニル
からなる群から選択される基であり；
Ａ２は、以下のｅ）～ｈ）：
ｅ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換されるＣ６－１０アリール、
ｆ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換される５員ヘテロ環、
ｇ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換される６員ヘテロ環、および
ｈ）Ｃ３－６シクロアルキル
からなる群から選択される基であり；
Ａ３は、以下のｉ）～ｋ）：
ｉ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、Ｃ１－６アルコキシカルボニルフェニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
ｊ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるヘテロ環、および
ｋ）Ｃ３－６シクロアルキルまたはＣ４－６シクロアルケニル
からなる群から選択される基であり；
Ｌ１は、単結合またはＣ１－６アルキレンであり；
Ｒ１およびＲ２は、互いに独立して、水素原子、Ｃ１－６アルキルまたはヒドロキシＣ１－６アルキルであり（但し、Ｒ１およびＲ２が同時にＣ１－６アルキルである場合、互いに結合し環を形成していてもよく、Ｒ１およびＲ２が同時に水素原子ではない）； 
Ｌ２は、単結合である。〕。
〔２〕Ｌ１が単結合である、〔１〕記載の化合物またはその薬理学的に許容される塩。
〔３〕Ｒ１がメチルである、〔１〕または〔２〕記載の化合物またはその薬理学的に許容される塩。
〔４〕Ａ２が、以下のｅ1）およびｆ１）：
ｅ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるフェニル、および
ｆ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるチエニル
からなる群から選択される基である、〔１〕～〔３〕記載の化合物またはその薬理学的に許容される塩。
〔５〕
式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000012
 〔式中、
Ａ１が、以下のａ）～ｄ）：
ａ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
ｂ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される５員ヘテロ環、
ｃ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される６員ヘテロ環、および
ｄ）Ｃ４－６シクロアルケニル
からなる群から選択される基であり；
Ａ２が、以下のｅ1）およびｆ１）：
ｅ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるフェニル、および
ｆ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるチエニル
からなる群から選択される基であり；
Ａ３は、以下のｉ）～ｋ）：
ｉ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、Ｃ１－６アルコキシカルボニルフェニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
ｊ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるヘテロ環、および
ｋ）Ｃ３－６シクロアルキルまたはＣ４－６シクロアルケニル
からなる群から選択される基である。〕
で表される、〔４〕記載の化合物またはその薬理学的に許容される塩。
〔６〕Ａ１が、以下のａ１）～ｃ１）およびｄ）：
ａ１）非置換または１～２個のハロゲン原子で置換されるフェニル、
ｂ１）非置換または１個のＣ１－６アルキルで置換される５員ヘテロ環、
ｃ１）非置換の６員ヘテロ環、および
ｄ）Ｃ４－６シクロアルケニル
からなる群から選択される基である、〔１〕～〔５〕記載の化合物またはその薬理学的に許容される塩。
〔７〕Ａ３が、以下のｉ１）、ｊ１）およびｋ）：
ｉ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボニル、（Ｃ１－６アルキル）カルボニルアミノ、および（Ｃ１－６アルキル）カルボキシＣ１－６アルキルから独立して選択される１～２個の基で置換されるフェニル、
ｊ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルコキシ、シアノ、およびアミノから選択される１個の基で置換されるヘテロ環、および
ｋ）Ｃ３－６シクロアルキルまたはＣ４－６シクロアルケニル
からなる群から選択される基である、〔１〕～〔６〕記載の化合物またはその薬理学的に許容される塩。
〔８〕Ａ１が以下のａ２）およびc２）：
ａ２）非置換または１～２個のハロゲン原子で置換されるフェニル、および
ｃ２）非置換のピリジル
からなる群から選択される基であり；
Ａ２が非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるフェニルであり；
Ａ３が、以下のｉ２）およびｊ２）：
ｉ２）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボニル、（Ｃ１－６アルキル）カルボニルアミノ、および（Ｃ１－６アルキル）カルボキシＣ１－６アルキルから独立して選択される１～２個の基で置換されるフェニル、および
ｊ２）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルコキシ、シアノ、およびアミノから選択される１個の基で置換されるピリジル
からなる群から選択される基である、〔１〕～〔７〕記載の化合物またはその薬理学的に許容される塩。
〔９〕Ａ１が非置換のフェニルまたはピリジルであり；
Ａ２が非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、およびシアノから独立して選択される１～３個の基で置換されるフェニルであり；
Ａ３が、以下のｉ３）およびｊ３）：
ｉ３）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、アミノ、およびヒドロキシから独立して選択される１～２個の基で置換されるフェニル、および
ｊ３）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、およびアミノから選択される１個の基で置換されるピリジル
からなる群から選択される基である、〔１〕～〔８〕記載の化合物またはその薬理学的に許容される塩。
〔１０〕Ａ２が以下の基：
Figure JPOXMLDOC01-appb-C000013
 である（（＊）は結合位置を表す。）、〔１〕～〔９〕記載の化合物またはその薬理学的に許容される塩。
〔１１〕下記の群から選択される〔１〕記載の化合物またはその薬理学的に許容される塩：
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－クロロフェニル）エチル]ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－クロロフェニル）エチル］－２－フルオロベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－フルオロ－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－ジフルオロメトキシフェニル）エチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－クロロ－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－フルオロ－Ｎ－［（Ｒ）－１－（３－フルオロフェニル）エチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－３－フルオロ－Ｎ－［（Ｒ）－１－（３－フルオロフェニル）エチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－４－フルオロ－Ｎ－［（Ｒ）－１－（３－フルオロフェニル）エチル］ベンズアミド、
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－フルオロフェニル）エチル]ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－クロロ－５－フルオロフェニル）エチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]シクロヘキセン－１－イルカルボキサミド、
２－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]ニコチンアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－｛（Ｒ）－１－［３－（１，１－ジフルオロエチル）フェニル］エチル｝ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルピリジン－３－イルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]－２－ヒドロキシベンズアミド、
２－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]－２－ヒドロキシベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３，５－ジフルオロフェニル）エチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]－２－メトキシニコチンアミド、
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－メトキシフェニル）エチル]ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(５－クロロ－２－フルオロフェニル)エチル]ベンズアミドおよび
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－クロロ－５－フルオロフェニル）エチル］ベンズアミド。
〔１２〕下記の群から選択される〔１〕記載の化合物またはその薬理学的に許容される塩：
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－メトキシフェニル）エチル]ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(５－クロロ－２－フルオロフェニル)エチル]ベンズアミド、
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－クロロフェニル）エチル]ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－クロロフェニル）エチル］－２－フルオロベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－ジフルオロメトキシフェニル）エチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－クロロ－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－フルオロ－Ｎ－［（Ｒ）－１－（３－フルオロフェニル）エチル］ベンズアミド、
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－フルオロフェニル）エチル]ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３，５－ジフルオロフェニル）エチル］ベンズアミド、
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－クロロ－５－フルオロフェニル）エチル］ベンズアミド、
２－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]ニコチンアミドおよび
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－｛（Ｒ）－１－［３－（１，１－ジフルオロエチル）フェニル］エチル｝ベンズアミド。
Figure JPOXMLDOC01-appb-C000011
 [Where,
A 1 represents the following a) to d):
a) unsubstituted or 1-2 groups independently selected from the group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy C 6-10 aryl substituted with a group,
b) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 5-membered heterocycle substituted with a group,
c) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 6-membered heterocycle substituted with a group, and d) a group selected from the group consisting of C 4-6 cycloalkenyl;
A 2 represents the following e) to h):
e) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl C 6-10 aryl substituted with 1 to 3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl,
f) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl A 5-membered heterocycle substituted with 1 to 3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl,
g) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl A 6-membered heterocycle substituted with 1-3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl, and h) C 3- A group selected from the group consisting of 6 cycloalkyl;
A 3 represents the following i) to k):
i) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, C 1-6 alkoxycarbonylphenyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) carboxy C -6 alkyl and C 1-6 C 6-10 aryl substituted with 1-2 groups independently selected from alkylsulfonyl,
j) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) independent of the carboxy C 1-6 alkyl and C 1-6 alkylsulfonyl Heterocycle substituted with 1-2 groups selected, and k) C 3-6 cycloalkyl, or C 4-6 group selected from the group consisting of cycloalkenyl;
L 1 is a single bond or C 1-6 alkylene;
R 1 and R 2 are independently of each other a hydrogen atom, C 1-6 alkyl or hydroxy C 1-6 alkyl (provided that when R 1 and R 2 are simultaneously C 1-6 alkyl, they are bonded to each other) And may form a ring, and R 1 and R 2 are not hydrogen atoms at the same time);
L 2 is a single bond. ].
[2] The compound according to [1] or a pharmacologically acceptable salt thereof, wherein L 1 is a single bond.
[3] The compound or pharmacologically acceptable salt thereof according to [1] or [2], wherein R 1 is methyl.
[4] A 2 is less e1) and f1):
e1) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3 Phenyl substituted with 1 to 3 groups independently selected from -6 cycloalkoxy, and f1) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo From the group consisting of thienyl substituted with 1 to 3 groups independently selected from C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3-6 cycloalkoxy The compound according to [1] to [3], which is a selected group, or a pharmacologically acceptable salt thereof.
[5]
Formula (II):
Figure JPOXMLDOC01-appb-C000012
 [Where,
A 1 is the following a) to d):
a) unsubstituted or 1-2 groups independently selected from the group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy C 6-10 aryl substituted with a group,
b) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 5-membered heterocycle substituted with a group,
c) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 6-membered heterocycle substituted with a group, and d) a group selected from the group consisting of C 4-6 cycloalkenyl;
A 2 is, following e1) and f1):
e1) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3 Phenyl substituted with 1 to 3 groups independently selected from -6 cycloalkoxy, and f1) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo From the group consisting of thienyl substituted with 1 to 3 groups independently selected from C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3-6 cycloalkoxy A selected group;
A 3 represents the following i) to k):
i) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, C 1-6 alkoxycarbonylphenyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) carboxy C -6 alkyl and C 1-6 C 6-10 aryl substituted with 1-2 groups independently selected from alkylsulfonyl,
j) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) independent of the carboxy C 1-6 alkyl and C 1-6 alkylsulfonyl Heterocycle substituted with 1-2 groups selected, and k) a C 3-6 cycloalkyl or C 4-6 group selected from the group consisting of cycloalkenyl. ]
Or a pharmacologically acceptable salt thereof according to [4].
[6] A 1 is the following a1) to c1) and d):
a1) phenyl which is unsubstituted or substituted by 1 to 2 halogen atoms,
b1) a 5-membered heterocycle which is unsubstituted or substituted by one C 1-6 alkyl,
[1] to [5] or a pharmacologically acceptable salt thereof, which is a group selected from the group consisting of c1) an unsubstituted 6-membered heterocycle and d) C 4-6 cycloalkenyl .
[7] A 3 is less i1), j1) and k):
i1) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkoxy, amino, Mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carbonyl, (C 1-6 alkyl) carbonylamino, and (C 1-6 alkyl) carboxy C 1 Phenyl substituted with 1-2 groups independently selected from -6 alkyl,
j1) Heterocycle which is unsubstituted or substituted by one group selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, cyano, and amino And k) the compound or pharmacologically acceptable salt thereof according to [1] to [6], which is a group selected from the group consisting of C 3-6 cycloalkyl or C 4-6 cycloalkenyl.
[8] a2 of A 1 or less) and c2):
a2) a group selected from the group consisting of unsubstituted or substituted with 1 to 2 halogen atoms, and c2) an unsubstituted pyridyl;
A 2 is unsubstituted or consists of the following: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C Phenyl substituted with 1 to 3 groups independently selected from 3-6 cycloalkoxy;
A 3 is, following i2) and j2):
i2) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkoxy, amino, Mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carbonyl, (C 1-6 alkyl) carbonylamino, and (C 1-6 alkyl) carboxy C 1 Phenyl substituted with 1-2 groups independently selected from -6 alkyl, and j2) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, cyano, and a group selected from the group consisting of pyridyl substituted with one group selected from amino, [1] to [7], wherein Compound or the pharmaceutically acceptable salts thereof.
[9] A 1 is unsubstituted phenyl or pyridyl;
A group in which A 2 is unsubstituted or consists of: 1 to 3 groups independently selected from a halogen atom, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano Substituted phenyl;
A 3 is, following i3) and j3):
i3) unsubstituted or group consisting of: phenyl substituted by 1-2 groups independently selected from halogen atom, C 1-6 alkyl, amino, and hydroxy, and j3) unsubstituted or from A group selected from the group consisting of a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, and pyridyl substituted with one group selected from amino, [1] to [8 Or a pharmaceutically acceptable salt thereof.
[10] A 2 is the following group:
Figure JPOXMLDOC01-appb-C000013
 ((*) Represents a binding position), [1] to [9] or a pharmacologically acceptable salt thereof.
[11] The compound according to [1] or a pharmacologically acceptable salt thereof selected from the following group:
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1-phenylethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] -2-fluorobenzamide,
N-[(R) -carbamoylphenylmethyl] -2-fluoro-N-[(R) -1-phenylethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-difluoromethoxyphenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -2-chloro-N-[(R) -1-phenylethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -2-fluoro-N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -3-fluoro-N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -4-fluoro-N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chloro-5-fluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] cyclohexen-1-ylcarboxamide;
2-amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] nicotinamide,
N-[(R) -carbamoylphenylmethyl] -N-{(R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl} benzamide,
N-[(R) -carbamoylpyridin-3-ylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -2-hydroxybenzamide,
2-amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -2-hydroxybenzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -2-methoxynicotinamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-methoxyphenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (5-chloro-2-fluorophenyl) ethyl] benzamide and N-[(R) -carbamoylphenylmethyl] -N- [ (R) -1- (3-Chloro-5-fluorophenyl) ethyl] benzamide.
[12] The compound of [1] selected from the following group or a pharmacologically acceptable salt thereof:
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-methoxyphenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (5-chloro-2-fluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1-phenylethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] -2-fluorobenzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-difluoromethoxyphenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -2-chloro-N-[(R) -1-phenylethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -2-fluoro-N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] benzamide,
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chloro-5-fluorophenyl) ethyl] benzamide,
2-Amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] nicotinamide and N-[(R) -carbamoylphenylmethyl]- N-{(R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl} benzamide.
〔１３〕前記〔１〕～〔１２〕の何れか一項に記載の化合物またはその薬理学的に許容される塩を含有する医薬組成物。
〔１４〕求心性神経の過剰興奮または障害に起因する疾患または症状の治療若しくは予防用の、前記〔１３〕記載の医薬組成物。
〔１５〕前記〔１〕～〔１２〕の何れか一項に記載の化合物またはその薬理学的に許容される塩を有効量投与することからなる、求心性神経の過剰興奮または障害に起因する疾患または症状の治療若しくは予防方法。
〔１６〕求心性神経の過剰興奮または障害に起因する疾患または症状の治療若しくは予防用の医薬組成物を製造するための、前記〔１〕～〔１２〕の何れか一項に記載の化合物またはその薬理学的に許容される塩の使用。
〔１７〕一般式（Ｉ）で表される化合物、またはその薬理学的に許容される塩 [13] A pharmaceutical composition comprising the compound according to any one of [1] to [12] or a pharmacologically acceptable salt thereof.
[14] The pharmaceutical composition according to [13] above, which is used for treatment or prevention of a disease or symptom caused by hyperexcitability or disorder of afferent nerves.
[15] Due to hyperexcitement or disorder of afferent nerve, comprising administering an effective amount of the compound according to any one of [1] to [12] above or a pharmacologically acceptable salt thereof A method of treating or preventing a disease or condition.
[16] The compound according to any one of [1] to [12] above for producing a pharmaceutical composition for treating or preventing a disease or symptom caused by hyperexcitation or disorder of afferent nerves, Use of its pharmacologically acceptable salt.
[17] A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof
Figure JPOXMLDOC01-appb-C000014
 〔式中、
Ａ１は、以下のａ）～ｄ）：
ａ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
ｂ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される５員ヘテロ環、
ｃ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される６員ヘテロ環、および
ｄ）Ｃ４－６シクロアルケニル
からなる群から選択される基であり；
Ａ２は、以下のｅ）～ｈ）：
ｅ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換されるＣ６－１０アリール、
ｆ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換される５員ヘテロ環、
ｇ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換される６員ヘテロ環、および
ｈ）Ｃ３－６シクロアルキル
からなる群から選択される基であり；
Ａ３は、以下のｉ）～ｋ）：
ｉ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、Ｃ１－６アルコキシカルボニルフェニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル
）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
ｊ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるヘテロ環、および
ｋ）Ｃ３－６シクロアルキルまたはＣ４－６シクロアルケニル
からなる群から選択される基であり；
Ｌ１は、単結合またはＣ１－６アルキレンであり；
Ｒ１およびＲ２は、互いに独立して、水素原子、Ｃ１－６アルキルまたはヒドロキシＣ１－６アルキルであり（但し、Ｒ１およびＲ２が同時にＣ１－６アルキルである場合、互いに結合し環を形成していてもよい）； 
Ｌ２は、単結合、Ｃ１－６アルキレンまたは下記の式：
Figure JPOXMLDOC01-appb-C000015
 である（（＊）は結合位置を表す。）。〕を含有する、痛み、寒冷性鼻炎、かゆみ、しびれ、蕁麻疹、過活動膀胱、排尿筋過活動、夜間頻尿、間質性膀胱炎、膀胱痛症候群、過知覚膀胱症候群、尿失禁または尿道狭窄の治療若しくは予防用医薬組成物。
Figure JPOXMLDOC01-appb-C000014
 [Where,
A 1 represents the following a) to d):
a) unsubstituted or 1-2 groups independently selected from the group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy C 6-10 aryl substituted with a group,
b) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 5-membered heterocycle substituted with a group,
c) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 6-membered heterocycle substituted with a group, and d) a group selected from the group consisting of C 4-6 cycloalkenyl;
A 2 represents the following e) to h):
e) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl C 6-10 aryl substituted with 1 to 3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl,
f) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl A 5-membered heterocycle substituted with 1 to 3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl,
g) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl A 6-membered heterocycle substituted with 1-3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl, and h) C 3- A group selected from the group consisting of 6 cycloalkyl;
A 3 represents the following i) to k):
i) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, C 1-6 alkoxycarbonylphenyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) carboxy C -6 alkyl and C 1-6 C 6-10 aryl substituted with 1-2 groups independently selected from alkylsulfonyl,
j) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) independent of the carboxy C 1-6 alkyl and C 1-6 alkylsulfonyl Heterocycle substituted with 1-2 groups selected, and k) C 3-6 cycloalkyl, or C 4-6 group selected from the group consisting of cycloalkenyl;
L 1 is a single bond or C 1-6 alkylene;
R 1 and R 2 are independently of each other a hydrogen atom, C 1-6 alkyl or hydroxy C 1-6 alkyl (provided that when R 1 and R 2 are simultaneously C 1-6 alkyl, they are bonded to each other) And may form a ring);
L 2 represents a single bond, C 1-6 alkylene or the following formula:
Figure JPOXMLDOC01-appb-C000015
 ((*) Represents a bonding position). ), Pain, cold rhinitis, itching, numbness, urticaria, overactive bladder, detrusor overactivity, nocturia, interstitial cystitis, bladder pain syndrome, hypersensitive bladder syndrome, urinary incontinence or urethra A pharmaceutical composition for treating or preventing stenosis.
本発明の化合物（Ｉ）またはその薬理学的に許容される塩は、例えば、国際公開２００９／０１２４３０号記載の方法に準じた、Ｉｃｉｌｉｎ誘発ｗｅｔ－ｄｏｇ　ｓｈａｋｅ抑制作用確認試験において、強力な抑制作用を示した。よって、本発明の化合物（Ｉ）、またはその薬理学的に許容される塩は、求心性神経の過剰興奮または障害に起因する疾患または症状の治療若しくは予防用医薬組成物として有用である。 The compound (I) of the present invention or a pharmacologically acceptable salt thereof has a strong inhibitory action in, for example, an Icilin-induced wet-dog shake inhibitory action confirmation test according to the method described in International Publication No. 2009/012430. showed that. Therefore, the compound (I) of the present invention, or a pharmacologically acceptable salt thereof, is useful as a pharmaceutical composition for treating or preventing a disease or symptom caused by hyperexcitability or disorder of afferent nerve.
　本明細書における用語について説明する。 The terms used in this specification will be explained.
　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を意味する。フッ素原子または塩素原子が好ましい。 “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. A fluorine atom or a chlorine atom is preferred.
　「Ｃ１－６アルキル」とは、炭素数１～６の分枝していても良いアルキルを意味する。例えば、メチル、エチル、プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ－ペンチル、１－メチルブチル、２－メチルブチル、１，２－ジメチルプロピル、ｎ－ヘキシル、イソヘキシル等が挙げられる。 “C 1-6 alkyl” means an optionally branched alkyl having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl , N-hexyl, isohexyl and the like.
　「Ｃ１－６アルコキシ」とは、炭素数１～６の分枝していても良いアルコキシを意味する。例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等が挙げられる。 “C 1-6 alkoxy” means an alkoxy having 1 to 6 carbon atoms which may be branched. Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
　「ハロＣ１－６アルキル」とは、１～５個の同種または異種のハロゲン原子で置換された上記Ｃ1-6アルキルを意味する。例えば、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、２－クロロエチル、２－フルオロエチル、２，２－ジフルオロエチル、１，１－ジフルオロエチル、１，２－ジフルオロエチル、２，２，２－トリフルオロエチル、１，１，２，２，２－ペンタフルオロエチル、２，２，２－トリクロロエチル、３－フルオロプロピル、２－フルオロプロピル、１－フルオロプロピル、３，３－ジフルオロプロピル、２，２－ジフルオロプロピル、１，１－ジフルオロプロピル、１－フルオロブチル、１－フルオロペンチル、１－フルオロヘキシル等が挙げられる。 “Halo C 1-6 alkyl” means the above C 1-6 alkyl substituted with 1 to 5 of the same or different halogen atoms. For example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2,2-tri Fluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 2-fluoropropyl, 1-fluoropropyl, 3,3-difluoropropyl, 2, Examples include 2-difluoropropyl, 1,1-difluoropropyl, 1-fluorobutyl, 1-fluoropentyl, 1-fluorohexyl and the like.
　「ハロＣ１－６アルコキシ」とは、１～５個の同種または異種のハロゲン原子で置換された上記Ｃ１－６アルコキシを意味する。例えば、モノフルオロメトキシ、ジフルオロメトキシ、トリフルオロメトキシ、２－クロロエトキシ、２－フルオロエトキシ、２，２－ジフルオロエトキシ、１，１－ジフルオロエトキシ、１，２－ジフルオロエトキシ、２，２，２－トリフルオロエトキシ、１，１，２，２，２－ペンタフルオロエトキシ、２，２，２－トリクロロエトキシ、３－フルオロプロポキシ、２－フルオロプロポキシ、１－フルオロプロポキシ、３，３－ジフルオロプロポキシ、２，２－ジフルオロプロポキシ、１，１－ジフルオロプロポキシ、４－フルオロブトキシ、５－フルオロペンチルオキシ、６－フルオロヘキシルオキシ等が挙げられる。 “Halo C 1-6 alkoxy” means the above C 1-6 alkoxy substituted with 1 to 5 of the same or different halogen atoms. For example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy, 2,2,2- Trifluoroethoxy, 1,1,2,2,2-pentafluoroethoxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy, 2-fluoropropoxy, 1-fluoropropoxy, 3,3-difluoropropoxy, 2 , 2-difluoropropoxy, 1,1-difluoropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy, 6-fluorohexyloxy and the like.
　「ヒドロキシＣ１－６アルキル」とは、ヒドロキシで置換された上記Ｃ１－６アルキルを意味する。例えば、ヒドロキシメチル、１－ヒドロキシエチル、１－ヒドロキシ－１，１－ジメチルメチル、２－ヒドロキシエチル、２－ヒドロキシ－２－メチルプロピル、３－ヒドロキシプロピル等が挙げられる。 “Hydroxy C 1-6 alkyl” means the above C 1-6 alkyl substituted with hydroxy. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1,1-dimethylmethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl and the like.
　「Ｃ６－１０アリール」とは、フェニルまたはナフチルをいう。 “C 6-10 aryl” refers to phenyl or naphthyl.
　「モノ（ジ）Ｃ１－６アルキルアミノ」とは、上記Ｃ１－６アルキルでモノまたはジ置換されたアミノをいう。ジ置換の場合のＣ１－６アルキルは異なっていてもよい。 “Mono (di) C 1-6 alkylamino” refers to an amino mono- or di-substituted with the above C 1-6 alkyl. The C 1-6 alkyl in the case of di-substitution may be different.
　「Ｃ１－６アルキルスルホニル」とは、（Ｃ１－６アルキル）－ＳＯ２－で表される基を意味する。例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニル、イソブチルスルホニル、ｓｅｃ－ブチルスルホニル、ペンチルスルホニル、ヘキシルスルホニル等が挙げられる。 “C 1-6 alkylsulfonyl” means a group represented by (C 1-6 alkyl) —SO 2 —. Examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
「Ｃ１－６アルキルスルホニルアミノ」とは、上記Ｃ１－６アルキルスルホニルが置換したアミノを意味する。 “C 1-6 alkylsulfonylamino” means amino substituted with the above C 1-6 alkylsulfonyl.
　「（Ｃ１－６アルキル）カルボニル」とは、上記Ｃ１－６アルキルが置換したカルボニルを意味する。例えば、アセチル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、イソブチルカルボニル、ブチルカルボニル、ｓｅｃ－ブチルカルボニル、ｔｅｒｔ－ブチルカルボニル、ペンチルカルボニル、ヘキシルカルボニル等が挙げられる。 “(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.
「（Ｃ１－６アルキル）カルボニルアミノ」とは、上記（Ｃ１－６アルキル）カルボニルが置換したアミノを意味する。 “(C 1-6 alkyl) carbonylamino” means amino substituted with the above (C 1-6 alkyl) carbonyl.
　「Ｃ１－６アルコキシカルボニル」とは、上記Ｃ１－６アルコキシが置換したカルボニルを意味する。例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、イソブトキシカルボニル、ブトキシカルボニル、ｓｅｃ－ブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、ペンチルオキシカルボニル、ヘキシルオキシカルボニル等が挙げられる。 “C 1-6 alkoxycarbonyl” means a carbonyl substituted with the above C 1-6 alkoxy. Examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
「Ｃ１－６アルコキシカルボニルＣ２－６アルケニル」とは、上記Ｃ１－６アルコキシカルボニルが置換したＣ２－６アルケニルを意味する。例えば、メトキシカルボニルビニル、エトキシカルボニルビニル、メトキシカルボニルアリル、エトキシカルボニルアリル等が挙げられる。
  “C 1-6 alkoxycarbonyl C 2-6 alkenyl” means C 2-6 alkenyl substituted with the above C 1-6 alkoxycarbonyl. Examples thereof include methoxycarbonyl vinyl, ethoxycarbonyl vinyl, methoxycarbonyl allyl, ethoxycarbonyl allyl and the like.
「Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ」とは、上記Ｃ１－６アルコキシカルボニルが置換した上記Ｃ１－６アルコキシを意味する。 “C 1-6 alkoxycarbonyl C 1-6 alkoxy” means the above C 1-6 alkoxy substituted with the above C 1-6 alkoxycarbonyl.
「Ｃ１－６アルコキシカルボニルフェニルＣ１－６アルコキシ」とは、上記Ｃ１－６アルコキシカルボニルが置換したフェニルが置換したＣ１－６アルコキシを意味する。 “C 1-6 alkoxycarbonylphenyl C 1-6 alkoxy” means C 1-6 alkoxy substituted with phenyl substituted with the above C 1-6 alkoxycarbonyl.
「（Ｃ１－６アルキル）カルボキシ」とは、上記Ｃ１－６アルキルが置換したカルボキシを意味する。例えば、アセトキシ、エチルカルボキシ、プロピルカルボキシ、イソプロピルカルボキシ、イソブチルカルボキシ、ブチルカルボキシ、ｓｅｃ－ブチルカルボキシ、ｔｅｒｔ－ブチルカルボキシ、ペンチルカルボキシ、ヘキシルカルボキシ等が挙げられる。 “(C 1-6 alkyl) carboxy” means carboxy substituted with the above C 1-6 alkyl. Examples include acetoxy, ethyl carboxy, propyl carboxy, isopropyl carboxy, isobutyl carboxy, butyl carboxy, sec-butyl carboxy, tert-butyl carboxy, pentyl carboxy, hexyl carboxy, and the like.
「（Ｃ１－６アルキル）カルボキシＣ１－６アルキル」とは、上記（Ｃ１－６アルキル）カルボキシが置換した上記Ｃ１－６アルキルを意味する。 The "(C 1-6 alkyl) carboxy C 1-6 alkyl", the (C 1-6 alkyl) carboxy means the above C 1-6 alkyl substituted.
　「Ｃ３－６シクロアルキル」とは、炭素数３～６個の単環性飽和脂環式炭化水素を意味する。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルが挙げられる。 “C 3-6 cycloalkyl” means a monocyclic saturated alicyclic hydrocarbon having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
　「Ｃ３－６シクロアルコキシ」とは、炭素数３～６個の単環性飽和脂環式炭化水素を有するアルコキシを意味する。例えば、シクロプロポキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシが挙げられる。 “C 3-6 cycloalkoxy” means alkoxy having a monocyclic saturated alicyclic hydrocarbon having 3 to 6 carbon atoms. Examples include cyclopropoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.
「Ｃ４－６シクロアルケニル」とは、環内に少なくとも１個の二重結合を有する、炭素数４～６個の単環性不飽和脂環式炭化水素を意味する。例えば、シクロブテニル、シクロペンテニル、シクロヘキセニル等が挙げられる。
“C 4-6 cycloalkenyl” means a monocyclic unsaturated alicyclic hydrocarbon having 4 to 6 carbon atoms and having at least one double bond in the ring. For example, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like can be mentioned.
　「ヘテロ環」とは、硫黄原子、酸素原子、窒素原子の中から選ばれた１～４個の原子を含む５または６員ヘテロ環を示し、例えば、フリル、チエニル、ピロリル、アゼピニル、ピラゾリル、イミダゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、１，２，３－オキサジアゾリル、トリアゾリル、テトラゾリル、１，２，３－チアジアゾリル、ピラニル、ピリジル、１－オキシドピリジル、ピリダジニル、ピリミジニル、ピラジニル、フラザニル等の芳香族ヘテロ環、ピロリニル、イミダゾリニル、ピラゾリニル、ジヒドロピラニル、ジヒドロチオピラニル、ジヒドロピリジル等の不飽和ヘテロ環、およびモルホニル、チオモルホニル、ピロリジニル、イミダゾリニル、ピラゾリジニル、ピペリジル、ピペラジニル、テトラヒドロフラニル、テトラヒドロピラニル等の飽和ヘテロ環を挙げることができる。
なお、上記「ヘテロ環」は他の環式基と縮環していてもよく、例えば、イソベンゾフラニル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、クロメニル、クロマノニル、キサンテニル、フェノキサチイニル、インドリジニル、イソインドリジニル、インドリル、インダゾリル、プリニル、キノリジニル、イソキノリル、キノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、カルバゾリル、カルボリニル、アクリジニル、イソインドリニル、２，３－ジヒドロベンゾフラニル、イミダゾ[１，２－ａ]ピリジル、イミダゾ[１，２－ａ]ピラジニル、ベンゾ[１，３]ジオキソリル、ベンゾチエニル、５，６，７，８－テトラヒドロイミダゾ[１，２－ａ]ピラジニル等を挙げることができる。 “Heterocycle” means a 5- or 6-membered heterocycle containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom, and examples thereof include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, Aromatics such as imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, pyranyl, pyridyl, 1-oxidepyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furazanyl Heterocycles, pyrrolinyl, imidazolinyl, pyrazolinyl, dihydropyranyl, dihydrothiopyranyl, dihydropyridyl and other unsaturated heterocycles, and morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, piperidyl, piperazinyl, te Rahidorofuraniru, can be mentioned saturated heterocyclic ring such as tetrahydropyranyl.
The “heterocycle” may be condensed with another cyclic group, for example, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, chromenyl, chromanonyl. , Xanthenyl, phenoxathiinyl, indolizinyl, isoindolidinyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl, isoindolinyl, 2,3-dihydrobenzofuranyl Nyl, imidazo [1,2-a] pyridyl, imidazo [1,2-a] pyrazinyl, benzo [1,3] dioxolyl, benzothienyl, 5,6,7,8-tetrahydroimidazo [1,2-a] List pyrazinyl, etc. It can be.
　Ａ１の「５員ヘテロ環」として、フリル、チエニル、チアゾリル、イミダゾリル、１，２，３－チアジアゾリルまたはオキサゾリルが好ましい。
　Ａ１の「６員ヘテロ環」として、ピリジルが好ましい。
　Ａ２の「５員ヘテロ環」として、チエニルが好ましい。　　
　Ａ３の「ヘテロ環」として、チエニル、ピロリル、チアゾリル、ピラゾリル、イミダゾリル、ピリジル、ピラジニル、ピロリジニル、テトラヒドロピラニル、キノリル、インドリル、が好ましく、ピリジルがより好ましい。 The “5-membered heterocycle” of A 1 is preferably furyl, thienyl, thiazolyl, imidazolyl, 1,2,3-thiadiazolyl or oxazolyl.
As the “6-membered heterocycle” for A 1 , pyridyl is preferable.
As the “5-membered heterocycle” for A 2 , thienyl is preferable.
As the “heterocycle” of A 3 , thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrrolidinyl, tetrahydropyranyl, quinolyl, and indolyl are preferable, and pyridyl is more preferable.
「Ｒ１およびＲ２が同時にＣ１－６アルキルである場合、互いに結合し環を形成していてもよく」とは、例えば、下記の式：
が挙げられる（（＊）は結合位置を表す。）。 “When R 1 and R 2 are simultaneously C 1-6 alkyl, they may be bonded to each other to form a ring” means, for example, the following formula:
((*) Represents a bonding position).
「Ｃ１－６アルキレン」とは、炭素数１～６の２価の分枝していても良い飽和炭化水素鎖を意味する。例えば、－ＣＨ２－、－ＣＨ２ＣＨ２－、－ＣＨ（ＣＨ３）－、－（ＣＨ２）３－、－ＣＨ（ＣＨ３）ＣＨ２－、－ＣＨ２ＣＨ（ＣＨ３）－、－ＣＨ（ＣＨ２ＣＨ３）－、－Ｃ（ＣＨ３）２－、－（ＣＨ２）４－、－ＣＨ（ＣＨ３）－（ＣＨ２）２－、－（ＣＨ２）２－ＣＨ（ＣＨ３）－、－ＣＨ（ＣＨ２ＣＨ３）－ＣＨ２－、－Ｃ（ＣＨ３）２ＣＨ２－、－ＣＨ２－Ｃ（ＣＨ３）２－、－ＣＨ（ＣＨ３）－ＣＨ（ＣＨ３）－、－（ＣＨ２）５－、－ＣＨ（ＣＨ３）－（ＣＨ２）３－、－Ｃ（ＣＨ３）２ＣＨ２ＣＨ２－、－（ＣＨ２）６－、－Ｃ（ＣＨ３）２（ＣＨ２）３－等が挙げられる。 “C 1-6 alkylene” means a divalent branched saturated hydrocarbon chain having 1 to 6 carbon atoms. For example, -CH 2 -, - CH 2 CH 2 -, - CH (CH 3) -, - (CH 2) 3 -, - CH (CH 3) CH 2 -, - CH 2 CH (CH 3) -, —CH (CH 2 CH 3 ) —, —C (CH 3 ) 2 —, — (CH 2 ) 4 —, —CH (CH 3 ) — (CH 2 ) 2 —, — (CH 2 ) 2 —CH ( CH 3 ) —, —CH (CH 2 CH 3 ) —CH 2 —, —C (CH 3 ) 2 CH 2 —, —CH 2 —C (CH 3 ) 2 —, —CH (CH 3 ) —CH ( CH 3 ) —, — (CH 2 ) 5 —, —CH (CH 3 ) — (CH 2 ) 3 —, —C (CH 3 ) 2 CH 2 CH 2 —, — (CH 2 ) 6 —, —C (CH 3 ) 2 (CH 2 ) 3 — and the like.
「Ｃ７－１０アラルキルオキシ」とは、フェニル基で置換された炭素数１～４個のアルコキシを意味する。例えば、ベンジルオキシ、フェネチルオキシ、１－フェニルエチルオキシ、３－フェニルプロピルオキシ、４－フェニルブチルオキシ等が挙げられる。 “C 7-10 aralkyloxy” means an alkoxy having 1 to 4 carbon atoms substituted with a phenyl group. Examples include benzyloxy, phenethyloxy, 1-phenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy and the like.
　　以下、本発明をより詳細に説明する。 Hereinafter, the present invention will be described in more detail.
　本発明の化合物（Ｉ）には、光学異性体、幾何異性体等のような立体異性体も含まれる。
　本発明の化合物（Ｉ）の光学異性体は、各不斉炭素原子における立体配置がＲ配置またはＳ配置のいずれの立体配置であってもよい。また、いずれの光学異性体も本発明に含まれ、それらの光学異性体の混合物も含まれる。さらに、光学活性体の混合物において、等量の各光学異性体からなるラセミ体も本発明の範囲に含まれる。本発明の化合物（Ｉ）がラセミ体の固体または結晶である場合、ラセミ化合物、ラセミ混合物およびラセミ固溶体も本発明の範囲に含まれる。
　本発明の化合物（Ｉ）において、幾何異性体が存在する場合、本発明はその幾何異性体のいずれも包含する。
　また、本発明の化合物（Ｉ）において、互変異性体が存在する場合、本発明はその互変異性体のいずれも包含する。 The compound (I) of the present invention includes stereoisomers such as optical isomers and geometric isomers.
The optical isomer of the compound (I) of the present invention may have any configuration of R configuration or S configuration at each asymmetric carbon atom. In addition, any optical isomer is included in the present invention, and a mixture of these optical isomers is also included. Furthermore, 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. When the compound (I) of the present invention is a racemic solid or crystal, racemic compounds, racemic mixtures and racemic solid solutions are also included in the scope of the present invention.
In the compound (I) of the present invention, when a geometric isomer exists, the present invention includes any of the geometric isomers.
In the compound (I) of the present invention, when a tautomer exists, the present invention includes any of the tautomers.
　本発明の化合物（Ｉ）は、必要に応じて常法に従い、その薬理学的に許容される塩とすることができる。このような塩としては、酸付加塩または塩基との塩を挙げることができる。 Compound (I) of the present invention can be converted into a pharmacologically acceptable salt thereof according to a conventional method as necessary. Examples of such salts include acid addition salts and salts with bases.
　酸付加塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の鉱酸との酸付加塩、ギ酸、酢酸、トリフルオロ酢酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、プロピオン酸、クエン酸、コハク酸、酒石酸、フマル酸、酪酸、シュウ酸、マロン酸、マレイン酸、乳酸、リンゴ酸、炭酸、グルタミン酸、アスパラギン酸等の有機酸との酸付加塩等を挙げることができる。 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.
　塩基との塩としては、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等の無機塩基との塩、ピペリジン、モルホリン、ピロリジン、アルギニン、リジン等の有機塩基との塩を挙げることができる。 Examples of 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.
　さらに本発明の化合物（Ｉ）またはその薬理学的に許容される塩には、水和物、エタノール等の医薬品として許容される溶媒との溶媒和物も含まれる。 Furthermore, the compound (I) of the present invention or a pharmacologically acceptable salt thereof includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
　TRPM8は、脊髄後根神経節や三叉神経節に発現が認められるカチオンチャネルである。TRPM8阻害薬は、TRPM8を介した細胞内への陽イオン流入量を減少させ、細胞内陽イオン濃度の上昇を抑制する。この作用に基づき、TRPM8阻害薬は、過剰に興奮した求心性神経活動を抑制することで、下部尿路症状（ＬＵＴＳ）、中でも過活動膀胱（ＯＡＢ）等の症状の治療若しくは予防用医薬組成物として有用である。
　また、TRPM8阻害作用は、TRPM8作動薬であるＩｃｉｌｉｎ投与により誘発されるｗｅｔ－ｄｏｇ　ｓｈａｋｅ作用を抑制する効力によって評価することができる。更に、J.Urol.,2001,166,1142記載の方法に準じた、酢酸誘発排尿筋過活動膀胱の排尿間隔に対する延長作用確認試験により、過活動膀胱（ＯＡＢ）に対する効果を評価することができる。 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, the TRPM8 inhibitor suppresses excessively excited afferent nerve activity, thereby treating or preventing symptoms such as lower urinary tract symptoms (LUTS), particularly overactive bladder (OAB). Useful as.
In addition, 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. Furthermore, an effect on overactive bladder (OAB) 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. .
　本発明の一般式（Ｉ）で表される化合物の別の態様としては、
Ａ１は、以下のａ３）、ｂ３）、ｃ２）およびｄ）：
ａ３）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキルおよびハロＣ１－６アルキルから独立して選択される１～２個の基で置換されるフェニル、
ｂ３）非置換またはＣ１－６アルキルで置換される芳香族５員ヘテロ環、
ｃ２）非置換のピリジルおよび
ｄ）Ｃ４－６シクロアルケニル
からなる群から選択される基であり；
Ａ２は、以下のｅ２）、ｆ２）およびｈ）：
ｅ２）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるフェニル、
ｆ２）非置換または以下からなる群：ハロゲン原子およびＣ１－６アルキルから選択される１個の基で置換されるチエニル、
ｈ）Ｃ３－６シクロアルキル
からなる群から選択される基であり；
Ａ３は、以下のｉ４）、ｊ４）およびｋ）：
ｉ４）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、カルバモイル、（Ｃ１－６アルキル）カルボニル、（Ｃ１－６アルキル）カルボニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるフェニル、
ｊ４）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルコキシ、アミノ、ヒドロキシから選択される１個の基で置換されるヘテロ環、および
ｋ）Ｃ３－６シクロアルキルまたはＣ４－６シクロアルケニル
からなる群から選択される基であり；
Ｌ１は、単結合またはＣ１－６アルキレンであり；
Ｒ１およびＲ２は、互いに独立して、水素原子、Ｃ１－６アルキルまたはヒドロキシＣ１－６アルキルであり（但し、Ｒ１およびＲ２が同時にＣ１－６アルキルである場合、互いに結合し環を形成していてもよく、Ｒ１およびＲ２が同時に水素原子ではない）；
Ｌ２は単結合である。 As another aspect of the compound represented by general formula (I) of this invention,
A 1 is less a3), b3), c2) and d):
a3) unsubstituted or group consisting of: phenyl substituted with 1 to 2 groups independently selected from a halogen atom, C 1-6 alkyl and haloC 1-6 alkyl;
b3) an aromatic 5-membered heterocycle which is unsubstituted or substituted with C 1-6 alkyl,
c2) a group selected from the group consisting of unsubstituted pyridyl and d) C 4-6 cycloalkenyl;
A 2 represents the following e2), f2) and h):
e2) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3 Phenyl substituted with 1 to 3 groups independently selected from -6 cycloalkoxy,
f2) unsubstituted or thienyl substituted with one group selected from the group consisting of: a halogen atom and C 1-6 alkyl;
h) a group selected from the group consisting of C 3-6 cycloalkyl;
A 3, the following i4), j4) and k):
i4) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkoxy, amino, Mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, carbamoyl, (C 1-6 alkyl) carbonyl, (C 1-6 alkyl) carbonylamino, (C 1-6 alkyl) carboxy C Phenyl substituted with 1 to 2 groups independently selected from 1-6 alkyl and C 1-6 alkylsulfonyl,
j4) Heterocycle which is unsubstituted or substituted by one group selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, hydroxy, And k) a group selected from the group consisting of C 3-6 cycloalkyl or C 4-6 cycloalkenyl;
L 1 is a single bond or C 1-6 alkylene;
R 1 and R 2 are independently of each other a hydrogen atom, C 1-6 alkyl or hydroxy C 1-6 alkyl (provided that when R 1 and R 2 are simultaneously C 1-6 alkyl, they are bonded to each other) And may form a ring, and R 1 and R 2 are not hydrogen atoms at the same time);
L 2 is a single bond.
また、本発明の一般式（Ｉ）で表される化合物の別の態様としては、
Ａ１が非置換のフェニルであり；
Ａ２が非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換されるフェニルであり；
Ａ３が、以下のｉ５）、ｊ５）およびｋ１）：
ｉ５）非置換または以下からなる群：ハロゲン原子、アミノ、ヒドロキシから独立して選択される１～２個の基で置換されるフェニル、
ｊ５）非置換または以下からなる群：Ｃ１－６アルコキシ、アミノから選択される１個の基で置換されるピリジル、
ｋ１）Ｃ４－６シクロアルケニル
からなる群から選択される基であり；
Ｌ１は、単結合であり；
Ｒ１はＣ１－６アルキルであり、Ｒ２は水素原子であり；
Ｌ２は、単結合である。 Moreover, as another aspect of the compound represented by general formula (I) of this invention,
A 1 is unsubstituted phenyl;
A 2 is unsubstituted or substituted by 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy Phenyl;
A 3 is, following i5), j5), and k1):
i5) unsubstituted or group consisting of: phenyl substituted with 1 to 2 groups independently selected from halogen atom, amino, hydroxy;
j5) Unsubstituted or group consisting of: C 1-6 alkoxy, pyridyl substituted with one group selected from amino,
k1) a group selected from the group consisting of C 4-6 cycloalkenyl;
L 1 is a single bond;
R 1 is C 1-6 alkyl and R 2 is a hydrogen atom;
L 2 is a single bond.
また、本発明の一般式（Ｉ）で表される化合物の別の態様としては、
Ａ１が非置換のフェニルであり；
Ａ２が非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換されるフェニルであり；
Ａ３が、以下のｉ６）およびｊ６）：
ｉ６）非置換または以下からなる群：ハロゲン原子、アミノから独立して選択される１～２個の基で置換されるフェニル、
ｊ６）非置換のピリジル
からなる群から選択される基であり；
Ｌ１は、単結合であり；
Ｒ１はＣ１－６アルキルであり、Ｒ２は水素原子であり；
Ｌ２は、単結合である。
Moreover, as another aspect of the compound represented by general formula (I) of this invention,
A 1 is unsubstituted phenyl;
A 2 is unsubstituted or substituted by 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy Phenyl;
A 3 is, following i6) and j6):
i6) unsubstituted or group consisting of: a halogen atom, phenyl substituted with 1 to 2 groups independently selected from amino;
j6) a group selected from the group consisting of unsubstituted pyridyl;
L 1 is a single bond;
R 1 is C 1-6 alkyl and R 2 is a hydrogen atom;
L 2 is a single bond.
本発明の化合物（Ｉ）の製造方法 Process for producing compound (I) of the present invention
　本発明の化合物（Ｉ）またはその薬理学的に許容される塩は、以下に詳述する方法もしくはそれに準じた方法、またはその他文献記載の方法もしくはそれらに準じた方法に従って製造することができる。 The compound (I) of the present invention or a pharmacologically acceptable salt thereof can be produced according to the method described in detail below or a method analogous thereto, the method described in other literature or a method analogous thereto.
　本発明の化合物（Ｉ）は、化合物（Ｉａ）として、スキーム１に示す方法により製造することができる。 Compound (I) of the present invention can be produced as compound (Ia) by the method shown in Scheme 1.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
（式中、Ａ１、Ａ２、Ａ３、Ｌ１、Ｌ２、Ｒ２、Ｒ1は前記と同義であり；Ｒｃ１はＣ１－６アルコキシ基、Ｃ７－１０アラルキルオキシ基またはアミノ基であり；Ｒｃ２は脱離基を表す。） Wherein A 1 , A 2 , A 3 , L 1 , L 2 , R 2 , R 1 are as defined above; R c1 is a C 1-6 alkoxy group, C 7-10 aralkyloxy group or amino R c2 represents a leaving group.)
工程１－１
　化合物（１）と化合物（２）とを、溶媒中反応させることにより、化合物（３）を製造することができる。溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、ジクロロメタン、酢酸、メタノール、エタノール、トルエン、それらの混合溶媒などが挙げられる。また、本反応は、必要に応じてｐ－トルエンスルホン酸、メタンスルホン酸、硫酸、塩酸、四塩化チタン、ボロントリフルオリド・ジエチルエーテル錯体などの酸を添加して行うことができる。反応温度は、０℃～溶媒還流温度であり、反応時間は用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分～３日間である。 Step 1-1
Compound (3) can be produced by reacting compound (1) and compound (2) in a solvent. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, dichloromethane, acetic acid, methanol, ethanol, toluene, a mixed solvent thereof and the like. In addition, this reaction can be carried out by adding an acid such as p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, titanium tetrachloride, boron trifluoride-diethyl ether complex, if necessary. 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.
工程１－２
　化合物（３）を溶媒中、還元剤と反応させることにより、化合物（４）を製造することができる。溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、ジクロロメタン、酢酸、メタノール、エタノール、アセトニトリル、それらの混合溶媒などが挙げられる。還元剤としては、例えば水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム、ボラン・ピリジン錯体、ボラン・ジエチルアミン錯体などが挙げられる。反応温度は、０℃～溶媒還流温度であり、反応時間は用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分～１日間である。
　また、本反応は上記還元剤を使用する代わりに、溶媒中、触媒量の金属触媒と水素雰囲気下で反応させることにより行うことができる。溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、酢酸エチル、メタノール、エタノール、それらの混合溶媒などが挙げられる。金属触媒としては、例えば、パラジウム炭素、酸化白金、ラネーニッケルなどが挙げられる。反応温度は、０℃～溶媒還流温度であり、反応時間は用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分～３日間である。本反応は、常圧（約１気圧）～１０気圧で実施される。 Step 1-2
Compound (4) can be produced by reacting compound (3) with a reducing agent in a solvent. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, dichloromethane, acetic acid, methanol, ethanol, acetonitrile, a mixed solvent thereof and the like. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane / pyridine complex, borane / diethylamine complex, 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 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
Further, this reaction can be carried out by reacting in a solvent with a catalytic amount of a metal catalyst in a hydrogen atmosphere instead of using the reducing agent. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, ethyl acetate, methanol, ethanol, a mixed solvent thereof and the like. Examples of the metal catalyst include palladium carbon, platinum oxide, Raney nickel 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. This reaction is carried out at normal pressure (about 1 atm) to 10 atm.
工程１－３
　化合物（４）を適切な溶媒中、塩基の存在下、化合物（５）と反応させることにより、化合物（６）を製造することができる。溶媒としては、例えば、ジクロロメタン、ジクロロエタン、テトラヒドロフランなどが挙げられる。塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンなどが挙げられる。ＲＣ２としては、塩素原子、臭素原子、（ＣＨ２ＣＯ）２Ｎ－Ｏ－、ｐ－ニトロフェノキシ等が挙げられる。また、本反応は、必要に応じてＮ，Ｎ－ジメチル－４－アミノピリジンなどを添加して行うことができる。反応温度は、０℃～溶媒還流温度であり、反応時間は用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分～３日間である。
　なお、化合物（６）において、Ｒｃ１がアミノ基である化合物は化合物（Ｉａ）を示し、Ｒｃ１がＣ１－６アルコキシ基、Ｃ７－１０アラルキルオキシ基である化合物は化合物（６ａ）を示す。 Step 1-3
Compound (6) can be produced by reacting compound (4) with compound (5) in the presence of a base in an appropriate solvent. Examples of the solvent include dichloromethane, dichloroethane, tetrahydrofuran and the like. Examples of the base include triethylamine, N, N-diisopropylethylamine and the like. Examples of R C2 include a chlorine atom, a bromine atom, (CH 2 CO) 2 N—O—, p-nitrophenoxy and the like. In addition, this reaction can be carried out by adding N, N-dimethyl-4-aminopyridine or the like as necessary. 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.
In the compound (6), the compound in which R c1 is an amino group represents the compound (Ia), and the compound in which R c1 is a C 1-6 alkoxy group or a C 7-10 aralkyloxy group represents the compound (6a). Show.
工程１－４
　工程１－３において化合物（６ａ）を得た場合、化合物（６ａ）を溶媒中アルカリ水溶液と反応させることにより、化合物（７）を製造することができる。また、ＲＣ１がベンジルオキシ基などの場合は、溶媒中、金属触媒と水素雰囲気下で反応させることもできる。このような反応は当業者には周知であり、例えば、Greene & Wuts著編「Greene’s Protective Groups in Organic Synthesis」fourth Edition, Wiley-Interscience, 2006年に記載の方法を用いて行うことができる。 Step 1-4
When compound (6a) is obtained in step 1-3, compound (7) can be produced by reacting compound (6a) with an aqueous alkali solution in a solvent. Further, when R C1 is a benzyloxy group or the like, it can be reacted in a solvent with a metal catalyst in a hydrogen atmosphere. Such reactions are well known to those skilled in the art, and can be performed, for example, using the method described in Greene & Wuts, “Greene's Protective Groups in Organic Synthesis”, Fourth Edition, Wiley-Interscience, 2006.
工程１－５
　化合物（７）を溶媒中、縮合剤の存在下、アンモニア等価体と反応させることにより、化合物（Ｉａ）を製造することができる。溶媒としては、例えば、ジクロロメタン、Ｎ，Ｎ－ジメチルホルムアミド、テトラヒドロフランなどが挙げられる。縮合剤としては、１－［３－（ジメチルアミノ）プロピル］－３－エチルカルボジイミド、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロフォスファート、３－（ジエトキシホスホリルオキシ）－１，２，３－ベンゾ［ｄ］トリアジン－４（３Ｈ）－オンなどが挙げられる。アンモニア等価体としては、塩化アンモニウムなどが挙げられる。本反応は、必要に応じてトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンなどの塩基および１－ヒドロキシベンゾトリアゾールなどの活性化剤を添加して行うことができる。反応温度は、０℃～溶媒還流温度であり、反応時間は用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分～１日間である。 Step 1-5
Compound (Ia) can be produced by reacting compound (7) with an ammonia equivalent in the presence of a condensing agent in a solvent. Examples of the solvent include dichloromethane, N, N-dimethylformamide, tetrahydrofuran and the like. Examples of the condensing agent include 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium. Examples include hexafluorophosphate, 3- (diethoxyphosphoryloxy) -1,2,3-benzo [d] triazin-4 (3H) -one, and the like. Examples of the ammonia equivalent include ammonium chloride. This reaction can be carried out by adding a base such as triethylamine or N, N-diisopropylethylamine and an activator such as 1-hydroxybenzotriazole as necessary. 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.
　化合物（４）は、スキーム２に示す方法によって製造することもできる。 Compound (4) can also be produced by the method shown in Scheme 2.
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
（式中、Ａ１、Ａ２、Ｌ１、Ｒ１は前記と同義であり；Ｒｃ１はＣ１－６アルコキシ基、Ｃ７－１０アラルキルオキシ基またはアミノ基であり；Ｒｃ３は塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ基等の脱離基を表す。） Wherein A 1 , A 2 , L 1 and R 1 are as defined above; R c1 is a C 1-6 alkoxy group, a C 7-10 aralkyloxy group or an amino group; R c3 is a chlorine atom And represents a leaving group such as a bromine atom, an iodine atom, and a methanesulfonyloxy group.)
工程２－１
　化合物（８）を溶媒中、化合物（９）と反応させることにより化合物（４）を製造することができる。溶媒としては、例えば、ジクロロメタン、Ｎ，Ｎ－ジメチルホルムアミド、テトラヒドロフラン、アセトニトリルなどが挙げられる。本反応は、必要に応じてトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、炭酸水素ナトリウム、炭酸水素カリウム、炭酸カリウムなどの塩基を添加して行うことができる。反応温度は、０℃～溶媒還流温度であり、反応時間は用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分～３日間である。 Step 2-1
Compound (4) can be produced by reacting compound (8) with compound (9) in a solvent. Examples of the solvent include dichloromethane, N, N-dimethylformamide, tetrahydrofuran, acetonitrile and the like. This reaction can be carried out by adding a base such as triethylamine, N, N-diisopropylethylamine, sodium hydrogen carbonate, potassium hydrogen carbonate, or potassium carbonate, if necessary. 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.
　本発明の化合物（Ｉ）は、スキーム３に示す方法によって得ることもできる。 Compound (I) of the present invention can also be obtained by the method shown in Scheme 3.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
（式中、Ａ１、Ａ２、Ａ３、Ｌ１、Ｌ２、Ｒ１、Ｒ２は前記と同義であり；Ｒｃ４、Ｒｃ５はそれぞれＣ１－６アルキル基またはＲｃ４、Ｒｃ５が結合して－（ＣＨＲｃ6）ｎ－で表される基を形成し；ｎは２～４の整数であり；Ｒｃ6は水素原子またはフェニル基を表す。） (Wherein A 1 , A 2 , A 3 , L 1 , L 2 , R 1 , R 2 are as defined above; R c4 , R c5 are each a C 1-6 alkyl group or R c4 , R c5. Are bonded to form a group represented by- (CHR c6 ) n-; n is an integer of 2 to 4; R c6 represents a hydrogen atom or a phenyl group.)
工程３－１
　化合物（１０）、化合物（１１）、化合物（１２）を溶媒中、化合物（１３）と反応させることにより化合物（１４）を製造することができる。このような反応はＵｇｉ反応として当業者には周知であり、例えば、Domling A., Ugi I. Angewandte Chemie International Edition 2000, 39, 3168-3210に記載の方法を用いて行うことができる。反応温度は、－７８℃～溶媒還流温度であり、反応時間は用いる原料物質、溶媒、反応温度などにより異なるが、通常１０分～１日間である。化合物（１０）は必要に応じて、対応する塩にトリエチルアミンなどの塩基を反応系中で加えて調製することができる。 Step 3-1
Compound (14) can be produced by reacting compound (10), compound (11), and compound (12) with compound (13) in a solvent. Such a reaction is well known to those skilled in the art as a Ugi reaction, and can be performed, for example, using the method described in Domling A., Ugi I. Angewandte Chemie International Edition 2000, 39, 3168-3210. The reaction temperature is −78 ° C. to solvent reflux temperature, and the reaction time is usually 10 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature, and the like. If necessary, compound (10) can be prepared by adding a base such as triethylamine to the corresponding salt in the reaction system.
工程３－２
　化合物（１４）を溶媒中、酸性条件下で加水分解することにより化合物（Ｉ）を製造することができる。溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサンなどが挙げられる。酸としては、塩化水素、硫酸、トリフルオロ酢酸などが挙げられる。反応温度は、０℃～溶媒還流温度であり、反応時間は用いる原料物質、溶媒、反応温度などにより異なるが、通常５分～１日間である。 Step 3-2
Compound (I) can be produced by hydrolyzing compound (14) in a solvent under acidic conditions. Examples of the solvent include tetrahydrofuran, 1,4-dioxane and the like. Examples of the acid include hydrogen chloride, sulfuric acid, trifluoroacetic acid and the like. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 5 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
　化合物（２）、化合物（８）、化合物（１１）および化合物（１２）は、それぞれ、市販の試薬として入手できるほか、文献記載の方法もしくはそれに準じた方法で製造することができる。
　化合物（１）は市販の試薬として入手できるほか、例えば、Ｓｔｒｅｃｋｅｒ反応として当業者に周知の反応を用いて対応するアミノ酸を得たのち、アミド化またはエステル化することにより製造することができる。
　化合物（９）および（１０）は市販の試薬として入手できるほか、例えば、Jonathan A. Ellman et al., Accounts of Chemical Research 2002, 35, 984-995に記載の方法を用いて製造することができる。
　化合物（１３）は市販の試薬として入手できるほか、例えば、W. Maison et al., Bioorganic Medicinal Chemistry 2000, 8, 1343-1360に記載の方法を用いて製造することができる。 Compound (2), Compound (8), Compound (11) and Compound (12) can be obtained as commercially available reagents, respectively, or can be produced by methods described in the literature or a method analogous thereto.
Compound (1) can be obtained as a commercially available reagent, and can be produced, for example, by obtaining the corresponding amino acid using a reaction well known to those skilled in the art as the Strecker reaction, and then amidating or esterifying.
Compounds (9) and (10) can be obtained as commercially available reagents and can be produced, for example, using the method described in Jonathan A. Ellman et al., Accounts of Chemical Research 2002, 35, 984-995. .
Compound (13) can be obtained as a commercially available reagent, and can also be produced, for example, using the method described in W. Maison et al., Bioorganic Medicinal Chemistry 2000, 8, 1343-1360.
　上記に示したスキームは、本発明の化合物（Ｉ）またはその製造中間体を製造する為の方法の例示である。これらは、当業者に容易に理解され得るようなスキームへの様々な改変が可能である。 The scheme shown above is an example of a method for producing the compound (I) of the present invention or a production intermediate thereof. These can be variously modified into schemes that can be easily understood by those skilled in the art.
　また、官能基の種類により保護基が必要な場合は、常法に従って適宜導入および除去の操作を組み合わせて実施することができる。保護基の種類、導入、除去に関しては、例えば、Theodra W. Greene & Peter G. M. Wuts著編,「Greene’s　Protective Groups in Organic Synthesis」, fourth edition, Wiley-Interscience, 2006年の記載を例示することができる。 In addition, when a protective group is required depending on the type of functional group, it can be carried out by appropriately combining introduction and removal operations according to a conventional method. Regarding the types, introduction and removal of protecting groups, for example, Theodra W. Greene & Peter G. M. Green Wuts, ed. be able to.
　本発明の化合物（Ｉ）またはその薬理学的に許容される塩、および当該化合物を製造する為に使用される製造中間体は、必要に応じて、当該分野における当業者にとって周知の単離・精製手段である溶媒抽出、晶析・再結晶、クロマトグラフィー、分取高速液体クロマトグラフィー等により、単離・精製することができる。 The compound (I) of the present invention or a pharmacologically acceptable salt thereof, and a production intermediate used for producing the compound, if necessary, are isolated and well-known to those skilled in the art. It can be isolated and purified by purification means such as solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography, and the like.
　本発明の化合物（Ｉ）またはその薬理学的に許容される塩を有効成分として含有する医薬組成物は、用法に応じ種々の剤形のものが使用される。このような剤形としては、例えば、散剤、顆粒剤、細粒剤、ドライシロップ剤、錠剤、カプセル剤、注射剤、液剤、軟膏剤、坐剤、貼付剤、舌下剤等を挙げることができ、経口または非経口的に投与される。 The pharmaceutical composition containing the compound (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. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.
　これらの医薬組成物は、その剤形に応じて公知の手法により、適切な賦形剤、崩壊剤、結合剤、滑沢剤、希釈剤、緩衝剤、等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、溶解補助剤等の医薬品添加物と適宜混合または希釈・溶解することにより調剤することができる。また、本発明の化合物（Ｉ）またはその薬理学的に許容される塩とTRPM8阻害薬以外の薬剤とを組み合わせて使用する場合は、それぞれの活性成分を同時または別々に、前述と同様に製剤化することにより製造することができる。 These pharmaceutical 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. When the compound (I) of the present invention or a pharmacologically acceptable salt thereof and a drug other than a TRPM8 inhibitor are used in combination, the respective active ingredients are formulated in the same manner as described above. Can be manufactured.
　本発明の化合物（Ｉ）またはその薬理学的に許容される塩は、Ｉｃｉｌｉｎ誘発ｗｅｔ－ｄｏｇ　ｓｈａｋｅ抑制作用確認試験においてTRPM8阻害に基づく強力な抑制作用を示す。したがって、本発明の化合物（Ｉ）またはその薬理学的に許容される塩を有効成分として含有する医薬は、TRPM8阻害作用により、TRPM8の活性化に起因する疾患または症状の治療若しくは予防用医薬組成物として使用することができる。 The compound (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 (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is a pharmaceutical composition for treating or preventing a disease or symptom caused by TRPM8 activation due to TRPM8 inhibitory action. Can be used as a thing.
　「TRPM8の活性化に起因する疾患もしくは症状」は、求心性神経の過剰興奮または障害に起因する疾患または症状を意味する。
　「求心性神経の過剰興奮または障害に起因する疾患または症状」には、不安、鬱病、下部尿路症状（ＬＵＴＳ）、痛み、循環障害、かゆみ、しびれ、蕁麻疹等が含まれる。下部尿路症状（ＬＵＴＳ）、痛み、循環障害の治療若しくは予防のために使用するのが好ましい。　　 “Disease or symptom caused by activation of TRPM8” means a disease or symptom caused by hyperexcitation or disorder of afferent nerve.
“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. It is preferably used for the treatment or prevention of lower urinary tract symptoms (LUTS), pain, circulatory disturbance.
　「下部尿路症状（ＬＵＴＳ）」とは、下部尿路機能障害等によって引き起こされる症状をいい、「下部尿路機能障害」としては、過活動膀胱、排尿筋過活動、夜間頻尿、間質性膀胱炎等の膀胱炎、慢性前立腺炎等の前立腺炎、膀胱痛症候群、過知覚膀胱症候群、尿失禁、前立腺肥大症、尿道狭窄等が挙げられる。
過活動膀胱、排尿筋過活動、夜間頻尿、間質性膀胱炎等の膀胱炎、膀胱痛症候群、過知覚膀胱症候群、尿失禁、尿道狭窄の治療若しくは予防のために使用するのが好ましい。 “Lower urinary tract symptoms (LUTS)” refers to symptoms caused by lower urinary tract dysfunction, etc., and “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.
It is preferably used for the treatment or prevention of overactive bladder, detrusor overactivity, nocturia, cystitis such as interstitial cystitis, bladder pain syndrome, hypersensitive bladder syndrome, urinary incontinence, urethral stricture.
　「循環障害」としては、寒冷性鼻炎、レイノー病等が挙げられ、寒冷性鼻炎の治療若しくは予防のために使用するのが好ましい。 “Circulating disorders” include cold rhinitis, Raynaud's disease, etc., and is preferably used for the treatment or prevention of cold rhinitis.
　本発明の化合物（Ｉ）またはその薬理学的に許容される塩は、TRPM8阻害薬以外の少なくとも１種の薬剤と適宜組み合わせて使用することもできる。 The compound (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.
　本発明の化合物（Ｉ）またはその薬理学的に許容される塩と組み合わせて使用できる薬剤としては、オピオイド鎮痛薬、非ステロイド系抗炎症薬（ＮＳＡＩＤ）、バルビツレート系鎮静薬、鎮静作用を有するベンゾジアゼピン系薬剤、鎮静作用を有するＨ１ブロッカー、鎮静剤、骨格筋弛緩薬、ＮＭＤＡ受容体拮抗薬、αアドレナリン作用薬、三環系抗うつ薬、抗痙攣薬、タキキニン拮抗薬（ＮＫ拮抗薬）、ムスカリン受容体拮抗薬、ＣＯＸ－２選択的阻害薬、コールタール鎮痛薬、神経遮断薬、ＴＲＰＶ１作動薬、ＴＲＰＶ１阻害薬、βブロッカー、局所麻酔薬、コルチコステロイド、５－ＨＴ受容体作動薬、５－ＨＴ２Ａ受容体拮抗薬、コリン作動性鎮痛薬、ＰＤＥ５阻害薬、ＰＤＥ９阻害薬、α２δリガンド、カンナビノイド、代謝型グルタミン酸受容体１拮抗薬（ｍＧｌｕＲ１拮抗薬）、代謝型グルタミン酸受容体５拮抗薬（ｍＧｌｕＲ５拮抗薬）、セロトニン再取り込み阻害薬、ノルアドレナリン再取り込み阻害薬、セロトニン・ノルアドレナリン再取り込み阻害薬、誘導型一酸化窒素合成酵素阻害剤（ｉＮＯＳ阻害剤）、アセチルコリンエステラーゼ阻害薬（ＡＣｈＥ阻害薬）、ＥＰ４拮抗薬、ロイコトリエンＢ４拮抗薬、５－リポキシゲナーゼ阻害剤、ナトリウムチャンネルブロッカー、５－ＨＴ３拮抗薬、化学療法のための薬剤、ＥＰ１拮抗薬、β３アドレナリン作動薬、ＴＲＰＡ１阻害薬、ＴＲＰＶ３阻害薬、ＴＲＰＶ４阻害薬、Ｔ型カルシウムチャネル阻害薬、ＡＳＩＣ阻害薬、Ｐ２Ｘ阻害薬、Ｔｒｋ阻害薬、ＦＡＡＨ阻害薬、ボツリヌス毒素、５α還元酵素阻害剤、抗ＮＧＦ抗体、ＮＧＦ調節薬、IgE産生抑制剤、ヒスタミンH2阻害剤、膀胱粘膜保護剤、ＮＯＳ活性調節剤、膀胱筋弛緩薬、ＧＡＢＡ再取り込み阻害薬、ＧＡＢＡ受容体調節薬、GABA aminotransferase inhibitor等が挙げられる。 Examples of the drug that can be used in combination with the compound (I) of the present invention or a pharmacologically acceptable salt thereof include opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), barbiturate sedatives, and benzodiazepines having sedative action. system drugs, H 1 blockers having sedative effects, sedatives, skeletal muscle relaxants, NMDA receptor antagonists, alpha-adrenergic agonists, tricyclic antidepressants, anticonvulsants, tachykinin antagonists (NK antagonists), Muscarinic receptor antagonist, COX-2 selective inhibitor, coal tar analgesic, neuroleptic, TRPV1 agonist, TRPV1 inhibitor, beta blocker, local anesthetic, corticosteroid, 5-HT receptor agonist, 5-HT 2A receptor antagonist, cholinergic analgesic, PDE5 inhibitor, PDE9 inhibitor, α2δ ligand, cannabinoid, metabolizing group Rutamate receptor 1 antagonist (mGluR1 antagonist), metabotropic glutamate receptor 5 antagonist (mGluR5 antagonist), serotonin reuptake inhibitor, noradrenaline reuptake inhibitor, serotonin / noradrenaline reuptake inhibitor, inducible type 1 Nitric oxide synthase inhibitor (iNOS inhibitor), acetylcholinesterase inhibitor (AChE inhibitor), EP4 antagonist, leukotriene B4 antagonist, 5-lipoxygenase inhibitor, sodium channel blocker, 5-HT3 antagonist, chemotherapy Drug, EP1 antagonist, β3 adrenergic agonist, TRPA1 inhibitor, TRPV3 inhibitor, TRPV4 inhibitor, T-type calcium channel inhibitor, ASIC inhibitor, P2X inhibitor, Trk inhibitor, FAAH inhibitor, botulinum toxin 5α reductase inhibition Agent, anti-NGF antibody, NGF modulator, IgE production inhibitor, histamine H2 inhibitor, bladder mucosa protective agent, NOS activity regulator, bladder muscle relaxant, GABA reuptake inhibitor, GABA receptor modulator, GABA aminotransferase inhibitor Etc.
　また、組み合わせて使用される薬剤を以下の通り具体的に例示するが、本発明の内容はこれらに限定されるものではない。また、具体的な化合物においてはそのフリー体、およびその他の薬理学的に許容される塩を含む。 Moreover, although the chemical | medical agent used in combination is specifically illustrated as follows, the content of this invention is not limited to these. In addition, specific compounds include free forms thereof and other pharmacologically acceptable salts.
　　「αアドレナリン作用薬」としては、ドキサゾシン、タムスロシン、シロドシン、クロニジン、グアンファシン、デクスメデトミジン、モダフィニル、チザニジン、moxonidine等を挙げることができる。 Examples of the “α-adrenergic agent” include doxazosin, tamsulosin, silodosin, clonidine, guanfacine, dexmedetomidine, modafinil, tizanidine, moxonidine and the like.
　「ムスカリン受容体拮抗薬」としては、オキシブチニン、トルテロジン、プロピベリン、ダリフェナシン、ソリフェナシン、テミベリン、イプラトロピウム臭化物、トロスピウム、プロパンテリン、テミベリン、イミダフェナシン、フェソテロジン等を挙げることができる。 Examples of “muscarinic receptor antagonists” include oxybutynin, tolterodine, propiverine, darifenacin, solifenacin, temiverine, ipratropium bromide, trospium, propantheline, temiverine, imidafenacin, fesoterodine and the like.
　「ＥＰ１拮抗薬」としては、ＧＳＫ－２６９９８４Ａ、ＯＮＯ－８５３９等を挙げることができる。 Examples of the “EP1 antagonist” include GSK-269984A, ONO-8539 and the like.
　「β３アドレナリン作動薬」としては、ミラベグロン、ソラベグロン、ＴＲＫ－３８０等を挙げることができる。 Examples of the “β3 adrenergic agonist” include mirabegron, sorabegron, TRK-380 and the like.
　「膀胱粘膜保護剤」としては、ポリ硫酸ペントサン、ヒアルロン酸、硫酸コンドロイチン等を挙げることができる。 Examples of the “bladder mucosa protective agent” include polysulfate pentosan, hyaluronic acid, chondroitin sulfate and the like.
　本発明の化合物（Ｉ）またはその薬理学的に許容される塩と上記薬剤の１種類またはそれ以上とを組み合わせて投与する場合、本発明は、以下の１）～５）：
１）配合剤による同時投与、
２）別個の製剤として、同一投与経路による同時投与、
３）別個の製剤として、異なる投与経路による同時投与、
４）別個の製剤として、同一投与経路による異なる時間での投与、および
５）別個の製剤として、異なる投与経路による異なる時間での投与
の何れの投与方法も含まれる。また、４）または５）のような別個の製剤として異なる時間に投与する場合、本発明の化合物（Ｉ）またはその薬理学的に許容される塩と、組み合わせて投与される上記の薬剤との投与順序については特に制限されない。 When the compound (I) of the present invention or a pharmacologically acceptable salt thereof and one or more of the above drugs are administered in combination, the present invention provides 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. When administered at different times as separate preparations such as 4) or 5), the compound (I) of the present invention or a pharmacologically acceptable salt thereof and the above-mentioned drug administered in combination The order of administration is not particularly limited.
　また、本発明の化合物、またはその薬理学的に許容される塩は、１種類またはそれ以上の上記薬剤と適宜組み合わせて投与することにより、上記疾患の予防若しくは治療上相加効果以上の有利な効果を得ることができる。あるいは、同様に、単独に投与する場合と比較してその使用量を減少させたり、併用するTRPM8阻害薬以外の薬剤の副作用を減少させたり、または併用するTRPM8阻害薬以外の薬剤の副作用を回避もしくは軽減させることができる。  In addition, the compound of the present invention, or a pharmacologically acceptable salt thereof, is more advantageous than the additive effect in preventing or treating the above diseases by administering it in appropriate combination with one or more kinds of the above drugs. An effect can be obtained. Or, similarly, 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.
　本発明の医薬組成物は、全身的または局所的に、経口または非経口（経鼻、経肺、静脈内、直腸内、皮下、筋肉内、経皮等）により、投与することができる。 The pharmaceutical composition of the present invention can be administered systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal, etc.).
　本発明の医薬組成物を実際の治療に用いる場合、その有効成分である本発明の化合物（Ｉ）またはその薬理学的に許容される塩の投与量は、患者の年齢、性別、体重、疾患および治療の程度等により適宜決定される。例えば、経口投与の場合、成人（体重６０ｋｇとする）１日当たり概ね６～３０００ｍｇの範囲で、一回または数回に分けて適宜投与することができる。経口剤としての１日当たりの投与量は、１０～１０００ｍｇが好ましく、６０～６００ｍｇがより好ましい。非経口投与の場合、成人１日当たり概ね０．６～３００ｍｇの範囲で、一回または数回に分けて適宜投与することができる。非経口剤としての１日当たりの投与量は、１～１００ｍｇが好ましく、６～６０ｍｇがより好ましい。また、本発明のTRPM8阻害薬の有効成分である化合物（Ｉ）またはその薬理学的に許容される塩の投与量は、TRPM8阻害薬以外の薬剤の投与量に応じて減量することができる。 When the pharmaceutical composition of the present invention is used for actual treatment, the dose of the compound (I) of the present invention, which is an active ingredient thereof, or a pharmacologically acceptable salt thereof depends on the age, sex, body weight, disease of the patient. It is appropriately determined depending on the degree of treatment. For example, in the case of oral administration, an adult (with a body weight of 60 kg) can be appropriately administered in a single dose or divided into several doses within a range of about 6 to 3000 mg per day. The daily dose as an oral preparation is preferably 10 to 1000 mg, more preferably 60 to 600 mg. In the case of 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. In addition, the dose of compound (I), which is an active ingredient of the TRPM8 inhibitor of the present invention, or a pharmacologically acceptable salt thereof can be reduced according to the dose of a drug other than the TRPM8 inhibitor.
　以下、本発明を実施例、参考例及び試験例にて更に詳細に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples, but the scope of the present invention is not limited thereto.
　各参考例、各実施例、各試験例、各表中で用いている記号のうち、Ｒｅｆ．Ｎｏ．は参考例番号、Ｅｘ．Ｎｏ．は実施例番号、Ｓｔｒｃ．は構造式、Ｐ．Ｄ．は物性値、１Ｈ－ＮＭＲは水素核核磁気共鳴スペクトルを意味し、ＣＤＣｌ３はクロロホルム－ｄ、ＤＭＳＯ－ｄ６はジメチルスルホキシド－ｄ６、ＣＤ３ＯＤはメタノール－ｄを意味する。また、ＭＳは質量分析、ＥＳＩはエレクトロスプレーイオン化を意味する。ＲＴは高速液体カラムクロマトグラフィーの保持時間を意味する。低極性生成物とは、２種類のジアステレオマー混合物を順相カラムクロマトグラフィーを用いて分離精製した場合、先に溶出する化合物をいい、高極性生成物とは、後に溶出する化合物を意味する。実施例番号末尾において、ＬＰは低極性生成物、ＨＰは高極性生成物、Ｍは光学異性体の混合物を示す。 Of the symbols used in each reference example, each example, each test example, and each table, Ref. No. Are reference example numbers, Ex. No. Is an example number, Str. Is the structural formula, P.I. D. Is a physical property value, 1 H-NMR means a hydrogen nuclear magnetic resonance spectrum, CDCl 3 means chloroform-d, DMSO-d 6 means dimethyl sulfoxide-d 6 , and CD 3 OD means methanol-d. MS means mass spectrometry and ESI means electrospray ionization. RT means retention time of high performance liquid column chromatography. A low-polar product means a compound that elutes first when a mixture of two diastereomers is separated and purified using normal phase column chromatography, and a high-polar product means a compound that elutes later. . At the end of the example number, LP represents a low polarity product, HP represents a high polarity product, and M represents a mixture of optical isomers.
　各参考例において、マイクロ波の照射はＢｉｏｔａｇｅ社Ｉｎｉｔｉａｔｏｒを用いた。 In each reference example, microwave irradiation was performed using Biotage Initiator.
　各実施例において、高速液体カラムクロマトグラフィーおよび質量分析は下記の条件で行った。
装置：6520 Accurate-Mass Q-TOF instrument (Agilent)
カラム：Inertsil ODS-4 (GL-science) 2.1 x 50mm ３μｍ
流速：0.75mL/min.
グラジエント：
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
 In each Example, high performance liquid column chromatography and mass spectrometry were performed under the following conditions.
Instrument: 6520 Accurate-Mass Q-TOF instrument (Agilent)
Column: Inertsil ODS-4 (GL-science) 2.1 x 50mm 3μm
Flow rate: 0.75mL / min.
Gradient:
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
参考例１－１
（ＲＳ）－２－フルオロフェニルグリシンアミド塩酸塩
　（ＲＳ）－２－フルオロフェニルグリシン（１．０ｇ）の水（１０ｍＬ）／１，４－ジオキサン（２０ｍＬ）懸濁液に、ジ－ｔｅｒｔ－ブチルジカーボネート（１．４２ｇ）およびトリエチルアミン（１．２ｍＬ）を室温で加え、同温度で１４時間撹拌した。反応混合物に２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１２ｍＬ）および水（１０ｍＬ）を加え、この混合液をジエチルエーテルで２回洗浄した。得られた水層に２ｍｏｌ／Ｌ塩酸（１２ｍＬ）を加え、酢酸エチルで３回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して、（ＲＳ）－Ｎ－ｔｅｒｔ－ブトキシカルボニル－２－フルオロフェニルグリシン（１．５７ｇ）を得た。（ＲＳ）－Ｎ－ｔｅｒｔ－ブトキシカルボニル－２－フルオロフェニルグリシン（０．７０ｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍＬ）溶液に１－ヒドロキシベンズトリアゾール１水和物（０．５９７ｇ）を室温で加えた。その混合物に塩化アンモニウム（０．６９５ｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（３．５０ｍＬ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（０．７４８ｇ）を０℃で加え、室温で４日間撹拌した。反応混合物に１ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して、（ＲＳ）－Ｎ－ｔｅｒｔ－ブトキシカルボニル－２－フルオロフェニルグリシンアミド（０．６７８ｇ）を得た。（ＲＳ）－Ｎ－ｔｅｒｔ－ブトキシカルボニル－２－フルオロフェニルグリシンアミド（０．６７８ｇ）の１，４－ジオキサン（１０ｍＬ）溶液に４ｍｏｌ／Ｌ塩化水素１，４－ジオキサン溶液（１０ｍＬ）を室温で加え、同温度で４時間撹拌した。反応混合物にジエチルエーテルを加え、析出物を粉砕した。得られた固体を濾取し、ジエチルエーテルで洗浄後、減圧乾燥させ、標題化合物（０．４８２ｇ）を得た。構造式および物性値を表３に示した。 Reference Example 1-1
(RS) -2-fluorophenylglycinamide hydrochloride (RS) -2-fluorophenylglycine (1.0 g) in water (10 mL) / 1,4-dioxane (20 mL) suspension in di-tert-butyl Dicarbonate (1.42 g) and triethylamine (1.2 mL) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A 2 mol / L aqueous sodium hydroxide solution (12 mL) and water (10 mL) were added to the reaction mixture, and the mixture was washed twice with diethyl ether. 2 mol / L hydrochloric acid (12 mL) was added to the obtained aqueous layer, and the mixture was extracted 3 times 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 to obtain (RS) -N-tert-butoxycarbonyl-2-fluorophenylglycine (1.57 g). 1-hydroxybenztriazole monohydrate (0.597 g) was added to a solution of (RS) -N-tert-butoxycarbonyl-2-fluorophenylglycine (0.70 g) in N, N-dimethylformamide (10 mL) at room temperature. added. To the mixture was added ammonium chloride (0.695 g), N, N-diisopropylethylamine (3.50 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.748 g) at 0 ° C., Stir at room temperature for 4 days. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain (RS) -N-tert-butoxycarbonyl-2-fluorophenylglycinamide (0.678 g). To a solution of (RS) -N-tert-butoxycarbonyl-2-fluorophenylglycinamide (0.678 g) in 1,4-dioxane (10 mL) was added 4 mol / L hydrogen chloride 1,4-dioxane solution (10 mL) at room temperature. In addition, the mixture was stirred at the same temperature for 4 hours. Diethyl ether was added to the reaction mixture, and the precipitate was pulverized. The obtained solid was collected by filtration, washed with diethyl ether and dried under reduced pressure to give the title compound (0.482 g). The structural formula and physical property values are shown in Table 3.
参考例１－２～１－８
　対応する原料を用い、参考例１－１と同様の方法で参考例１－２～１－８を合成した。参考例１－２～１－８の構造式および物性値を表３～４に示した。 Reference Examples 1-2 to 1-8
Reference Examples 1-2 to 1-8 were synthesized in the same manner as Reference Example 1-1 using the corresponding starting materials. The structural formulas and physical property values of Reference Examples 1-2 to 1-8 are shown in Tables 3 to 4.
参考例２
３－シクロプロピル－５－フルオロベンズアルデヒド
　３－ブロモ－５－フルオロベンズアルデヒド（０．０５ｇ）、シクロプロピルボロン酸一水和物（０．０４１ｇ）、酢酸パラジウム（０．００５５ｇ）、トリシクロヘキシルホスフィン（０．００６９ｇ）、リン酸カリウム（０．１８３ｇ）、水（０．１ｍＬ）のトルエン（１ｍＬ）混合液にマイクロ波を照射し、１５０℃で１０分間撹拌した。反応混合物に水および酢酸エチルを加え分液した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／３０）で精製し、標題化合物（０．０３０ｇ）を得た。構造式および物性値を表４に示した。 Reference example 2
3-cyclopropyl-5-fluorobenzaldehyde 3-bromo-5-fluorobenzaldehyde (0.05 g), cyclopropylboronic acid monohydrate (0.041 g), palladium acetate (0.0055 g), tricyclohexylphosphine (0 .0069 g), potassium phosphate (0.183 g), and water (0.1 mL) in toluene (1 mL) were irradiated with microwaves and stirred at 150 ° C. for 10 minutes. Water and ethyl acetate were added to the reaction mixture for liquid separation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/30) to obtain the title compound (0.030 g). The structural formulas and physical property values are shown in Table 4.
参考例３－１
（Ｒ）－１－(２，３－ジフルオロフェニル)エチルアミン塩酸塩
　２，３－ジフルオロベンズアルデヒド（０．３０ｇ）および(Ｓ)－ｔｅｒｔ－ブチルスルフィンアミド（０．２６８ｇ）のテトラヒドロフラン（１０ｍL）混合液にオルトチタン酸テトラエチル（６１０μＬ）を室温で加え、終夜撹拌した。反応混合物に飽和食塩水を加え、セライトろ過した。このろ液に酢酸エチルを加え、抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下濃縮した。この残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／９－２／８）で精製し、(Ｓ)－Ｎ－(２，３－ジフルオロベンジリデン)－ｔｅｒｔ－ブタンスルフィンアミド（０．４２４ｇ）を得た。(Ｓ)－Ｎ－(２，３－ジフルオロベンジリデン)－ｔｅｒｔ－ブタンスルフィンアミド（０．４２ｇ）のジクロロメタン（５ｍＬ）混合液に、１ｍｏｌ／Ｌ臭化メチルマグネシウムテトラヒドロフラン溶液（２．１５ｍＬ）を－４０℃で滴下し、同温にて1時間撹拌した。反応混合物を０℃まで昇温し、同温にて３時間撹拌した。反応混合物を室温まで昇温し、室温にて１０分間撹拌した。反応混合物に水および飽和塩化アンモニウム水溶液を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下濃縮した。この残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－８／２）で精製し、(Ｓ)－Ｎ－[(Ｒ)－１－(２，３－ジフルオロフェニル)エチル]－ｔｅｒｔ－ブタンスルフィンアミド（０．２５ｇ）を得た。(Ｓ)－Ｎ－[(Ｒ)－１－(２，３－ジフルオロフェニル)エチル]－ｔｅｒｔ－ブタンスルフィンアミド（０．２４ｇ）のメタノール（５ｍL）溶液に４ｍｏｌ／Ｌ塩化水素１，４－ジオキサン溶液（３２０μＬ）を室温で加え，同温にて1時間撹拌した。反応混合物を減圧下濃縮した。この残渣に酢酸エチルを加え、析出物を粉砕してろ取した。得られた固体を減圧下乾燥し、標題化合物（０．１４ｇ）を得た。構造式および物性値を表４に示した。 Reference Example 3-1
(R) -1- (2,3-difluorophenyl) ethylamine hydrochloride A mixture of 2,3-difluorobenzaldehyde (0.30 g) and (S) -tert-butylsulfinamide (0.268 g) in tetrahydrofuran (10 mL) Was added with tetraethyl orthotitanate (610 μL) at room temperature and stirred overnight. Saturated brine was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 9-2 / 8), and (S) —N- (2,3-difluorobenzylidene) -tert-butanesulfinamide was obtained. (0.424 g) was obtained. To a mixed solution of (S) -N- (2,3-difluorobenzylidene) -tert-butanesulfinamide (0.42 g) in dichloromethane (5 mL) was added 1 mol / L methylmagnesium bromide tetrahydrofuran solution (2.15 mL)- The solution was added dropwise at 40 ° C. and stirred at the same temperature for 1 hour. The reaction mixture was warmed to 0 ° C. and stirred at the same temperature for 3 hours. The reaction mixture was warmed to room temperature and stirred at room temperature for 10 minutes. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1-8 / 2) and (S) -N-[(R) -1- (2,3-difluorophenyl). ) Ethyl] -tert-butanesulfinamide (0.25 g) was obtained. (S) —N — [(R) -1- (2,3-difluorophenyl) ethyl] -tert-butanesulfinamide (0.24 g) in a methanol (5 mL) solution of 4 mol / L hydrogen chloride 1,4- A dioxane solution (320 μL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitate was pulverized and collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.14 g). The structural formulas and physical property values are shown in Table 4.
参考例３－２～３－３
　対応する原料を用い、参考例３－１と同様の方法で参考例３－２～３－３を合成した。参考例３－２～３－３の構造式および物性値を表４に示した。 Reference Examples 3-2 to 3-3
Reference Examples 3-2 to 3-3 were synthesized in the same manner as Reference Example 3-1, using the corresponding starting materials. The structural formulas and physical property values of Reference Examples 3-2 to 3-3 are shown in Table 4.
参考例４－１
(Ｓ)－Ｎ－｛(Ｒ)－１－［３－ (１，１－ジフルオロエチル)フェニル］エチル｝－ｔｅｒｔ－ブタンスルフィンアミド
３－(１，１－ジフルオロエチル)ベンズアルデヒド（０．１３ｇ）および(Ｓ)－ｔｅｒｔ－ブチルスルフィンアミド（０．０９３ｇ）のテトラヒドロフラン（４ｍL）混合液にオルトチタン酸テトラエチル（２０５μＬ）を室温で加え、終夜撹拌した。反応混合物に飽和食塩水を加え、セライトろ過した。このろ液に酢酸エチルを加え、抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下濃縮した。この残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／９－２５／７５）で精製し、(Ｓ)－Ｎ－[３－(１，１－ジフルオロエチル)ベンジリデン]－ｔｅｒｔ－ブタンスルフィンアミド（０．１４ｇ）を得た。(Ｓ)－Ｎ－[３－(１，１－ジフルオロエチル)ベンジリデン]－ｔｅｒｔ－ブタンスルフィンアミド（０．１４ｇ）のジクロロメタン（２ｍＬ）混合液に、１．１２ｍｏｌ／Ｌ臭化メチルマグネシウムテトラヒドロフラン溶液（０．６４ｍＬ）を－７８℃で滴下し、同温にて1時間撹拌した。反応混合物を室温まで昇温し、同温にて１時間撹拌した。反応混合物に水および飽和塩化アンモニウム水溶液を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下濃縮した。この残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－８／２）で精製し、標題化合物（０．１２ｇ）を得た。構造式および物性値を表５に示した。 Reference Example 4-1
(S) -N-{(R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl} -tert-butanesulfinamide 3- (1,1-difluoroethyl) benzaldehyde (0.13 g) Then, tetraethyl orthotitanate (205 μL) was added to a tetrahydrofuran (4 mL) mixture of (S) -tert-butylsulfinamide (0.093 g) at room temperature and stirred overnight. Saturated brine was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 9-25 / 75), and (S) -N- [3- (1,1-difluoroethyl) benzylidene]- Tert-butanesulfinamide (0.14 g) was obtained. 1.12 mol / L methylmagnesium bromide tetrahydrofuran solution in a mixture of (S) -N- [3- (1,1-difluoroethyl) benzylidene] -tert-butanesulfinamide (0.14 g) in dichloromethane (2 mL) (0.64 mL) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was warmed to room temperature and stirred at the same temperature for 1 hour. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1-8 / 2) to give the title compound (0.12 g). The structural formulas and physical property values are shown in Table 5.
参考例４－２
　対応するカルボニル化合物を用い、参考例４－１と同様の方法で参考例４－２を合成した。参考例４－２の構造式および物性値を表５に示した。 Reference Example 4-2
Reference Example 4-2 was synthesized in the same manner as in Reference Example 4-1, using the corresponding carbonyl compound. The structural formula and physical property values of Reference Example 4-2 are shown in Table 5.
参考例５
(Ｒ)－１－(３－シクロプロポキシ－５－フルオロフェニル)エチルアミン
　３－シクロプロポキシ－５－フルオロベンズアルデヒド（０．５５ｇ）および(Ｓ)－ｔｅｒｔ－ブチルスルフィンアミド（０．３７ｇ）のテトラヒドロフラン（１０ｍL）混合液にオルトチタン酸テトラエチル（８８０μＬ）を室温で加え、終夜撹拌した。反応混合物に飽和食塩水を加え、セライトろ過した。このろ液に酢酸エチルを加え、抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下濃縮した。この残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／９－２／８）で精製し、(Ｓ)－Ｎ－(３－シクロプロポキシ－５－フルオロベンジリデン)－ｔｅｒｔ－ブタンスルフィンアミド（０．７１６ｇ）を得た。(Ｓ)－Ｎ－(３－シクロプロポキシ－５－フルオロベンジリデン)－ｔｅｒｔ－ブタンスルフィンアミド（０．７１６ｇ）のジクロロメタン（６ｍＬ）混合液に、１ｍｏｌ／Ｌ臭化メチルマグネシウムテトラヒドロフラン溶液（３．２ｍＬ）を－２０℃で滴下し、同温にて０．５時間撹拌した。反応混合物を室温まで昇温し、同温にて２時間撹拌した。反応混合物に水および飽和塩化アンモニウム水溶液を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下濃縮した。この残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝４５／５５－６５／３５）で精製し、(Ｓ)－Ｎ－[(Ｒ)－１－(３－シクロプロポキシ－５－フルオロフェニル)エチル]－ｔｅｒｔ－ブタンスルフィンアミド（０．５３ｇ）を得た。(Ｓ)－Ｎ－[(Ｒ)－１－(３－シクロプロポキシ－５－フルオロフェニル)エチル]－ｔｅｒｔ－ブタンスルフィンアミド（０．５３ｇ）のメタノール（５ｍL）溶液に４ｍｏｌ／Ｌ塩化水素１，４－ジオキサン溶液（６２０μＬ）を室温で加え，同温にて終夜撹拌した。反応混合物を減圧下濃縮した。この残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１０／９０－１００／０）で精製し、標題化合物（０．２９ｇ）を得た。構造式および物性値を表５に示した。 Reference Example 5
(R) -1- (3-Cyclopropoxy-5-fluorophenyl) ethylamine 3-cyclopropoxy-5-fluorobenzaldehyde (0.55 g) and (S) -tert-butylsulfinamide (0.37 g) in tetrahydrofuran ( 10 mL) Tetraethyl orthotitanate (880 μL) was added to the mixture at room temperature and stirred overnight. Saturated brine was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 9-2 / 8), and (S) -N- (3-cyclopropoxy-5-fluorobenzylidene) -tert- Butanesulfinamide (0.716 g) was obtained. To a mixed solution of (S) -N- (3-cyclopropoxy-5-fluorobenzylidene) -tert-butanesulfinamide (0.716 g) in dichloromethane (6 mL) was added a 1 mol / L methylmagnesium bromide tetrahydrofuran solution (3.2 mL). ) Was added dropwise at −20 ° C. and stirred at the same temperature for 0.5 hour. The reaction mixture was warmed to room temperature and stirred at the same temperature for 2 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 45 / 55-65 / 35), and (S) -N-[(R) -1- (3-cyclopropoxy-5 -Fluorophenyl) ethyl] -tert-butanesulfinamide (0.53 g) was obtained. (S) -N-[(R) -1- (3-cyclopropoxy-5-fluorophenyl) ethyl] -tert-butanesulfinamide (0.53 g) in a methanol (5 mL) solution of 4 mol / L hydrogen chloride 1 , 4-Dioxane solution (620 μL) was added at room temperature and stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / n-hexane = 10 / 90-100 / 0) to give the title compound (0.29 g). The structural formulas and physical property values are shown in Table 5.
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
実施例１－１
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－（３－メトキシベンジル）－２－チエナミド
　（Ｒ）－フェニルグリシンアミド塩酸塩（１０３ｍｇ）のテトラヒドロフラン（１ｍＬ）／メタノール（１．５ｍＬ）溶液に、トリエチルアミン（０．１３ｍＬ）および３－メトキシベンズアルデヒド（０．０４５ｍＬ）を室温で加え、その混合物を４時間撹拌した。反応混合物を減圧濃縮して得た残渣を、テトラヒドロフラン（１ｍＬ）／メタノール（１．５ｍＬ）混合液に溶解した。この混合物に水素化ホウ素ナトリウム（１３９ｍｇ）を０℃で加えた。この混合物を０℃で３０分間撹拌後、室温で１４時間撹拌した。反応混合物を減圧濃縮して得た残渣に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－４／１）で精製し、（Ｒ）－２－（３－メトキシベンジルアミノ）－２－フェニルアセトアミド（８５ｍｇ）を得た。（Ｒ）－２－（３－メトキシベンジルアミノ）－２－フェニルアセトアミド（４０ｍｇ）のジクロロメタン（１．２ｍＬ）溶液にトリエチルアミン（０．１ｍＬ）を室温で加えた。この混合液に２－テノイルクロリド（０．０３９ｍＬ）を０℃で加え、室温で１１時間撹拌した。反応混合物にジクロロメタンを加えて希釈し、有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－４／１）で精製し、標題化合物（０．０４５ｇ）を得た。標題化合物の構造式および物性値を表６に示した。 Example 1-1
To a solution of N-[(R) -carbamoylphenylmethyl] -N- (3-methoxybenzyl) -2-thienamide (R) -phenylglycinamide hydrochloride (103 mg) in tetrahydrofuran (1 mL) / methanol (1.5 mL) , Triethylamine (0.13 mL) and 3-methoxybenzaldehyde (0.045 mL) were added at room temperature and the mixture was stirred for 4 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in a tetrahydrofuran (1 mL) / methanol (1.5 mL) mixture. To this mixture was added sodium borohydride (139 mg) at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 1-4 / 1) to give (R) -2- (3-methoxybenzylamino). ) -2-Phenylacetamide (85 mg) was obtained. To a solution of (R) -2- (3-methoxybenzylamino) -2-phenylacetamide (40 mg) in dichloromethane (1.2 mL) was added triethylamine (0.1 mL) at room temperature. To this mixture, 2-thenoyl chloride (0.039 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 11 hours. Dichloromethane was added to the reaction mixture for dilution, and the organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 1-4 / 1) to obtain the title compound (0.045 g). The structural formula and physical property values of the title compound are shown in Table 6.
実施例１－２～１－９５
　対応する原料を用い、実施例１－１と同様の方法で実施例１－２～１－９５を合成した。実施例１－２～１－９５の構造式および物性値を表６～２１に示した。 Examples 1-2 to 1-95
Examples 1-2 to 1-95 were synthesized in the same manner as in Example 1-1 using the corresponding starting materials. The structural formulas and physical property values of Examples 1-2 to 1-95 are shown in Tables 6 to 21.
実施例２－１
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－（３－トリフルオロメチルベンジル）ベンズアミド
　（Ｒ）－フェニルグリシンアミド塩酸塩（０．０５ｇ）、トリエチルアミン（７５μＬ）、および３－トリフルオロメチルベンズアルデヒド（０．０４９ｇ）のテトラヒドロフラン（１ｍＬ）－メタノール（１ｍＬ）混合溶液を室温にて２時間撹拌した。アルゴン雰囲気下、反応混合物に１０％パラジウム炭素（０．０１５ｇ）を室温で加え、この混合物を水素雰囲気下２時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。この残渣に酢酸エチルを加え、不溶物を濾取し、濾液を減圧下濃縮した。この残渣をジクロロメタン（２ｍＬ）に溶解させ、トリエチルアミン（７５μＬ）およびベンゾイルクロリド（３４μＬ）を加え、この混合物を室温にて２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝６／４－１００／０）で精製し、標題化合物（０．０４４ｇ）を得た。標題化合物の構造式および物性値を表２２に示した。 Example 2-1
N-[(R) -carbamoylphenylmethyl] -N- (3-trifluoromethylbenzyl) benzamide (R) -phenylglycinamide hydrochloride (0.05 g), triethylamine (75 μL), and 3-trifluoromethylbenzaldehyde A mixed solution of (0.049 g) in tetrahydrofuran (1 mL) -methanol (1 mL) was stirred at room temperature for 2 hours. Under an argon atmosphere, 10% palladium carbon (0.015 g) was added to the reaction mixture at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, the insoluble material was collected by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 mL), triethylamine (75 μL) and benzoyl chloride (34 μL) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 6 / 4-100 / 0) to obtain the title compound (0.044 g). The structural formula and physical property values of the title compound are shown in Table 22.
実施例２－２～２－３０
　対応する原料を用い、実施例２－１と同様の方法で実施例２－２～２－３０を合成した。実施例２－２～２－３０の構造式および物性値を表２２～２７に示した。 Examples 2-2 to 2-30
Examples 2-2 to 2-30 were synthesized in the same manner as in Example 2-1, using the corresponding starting materials. The structural formulas and physical property values of Examples 2-2 to 2-30 are shown in Tables 22 to 27.
実施例３－１
　Ｎ－(カルバモイルフェニルメチル)－２－ヒドロキシ－Ｎ－(３－メトキシベンジル)ベンズアミド
　２－｛Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－(３－メトキシベンジル)カルバモイル｝フェニルアセタート（実施例１－４４，０．０６０ｇ）に２ｍｏｌ／Ｌアンモニアメタノール溶液（２ｍＬ）を室温で加え、その混合物を同温度で１時間撹拌した。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－１００／０）で精製し、標題化合物（０．０４７ｇ）を得た。標題化合物の構造式および物性値を表２８に示した。 Example 3-1
N- (carbamoylphenylmethyl) -2-hydroxy-N- (3-methoxybenzyl) benzamide 2- {N-[(R) -carbamoylphenylmethyl] -N- (3-methoxybenzyl) carbamoyl} phenyl acetate ( In Example 1-44, 0.060 g), a 2 mol / L ammonia methanol solution (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 1-100 / 0) to obtain the title compound (0.047 g). The structural formula and physical property values of the title compound are shown in Table 28.
実施例３－２～３－６
　対応する原料を用い、実施例３－１と同様の方法で実施例３－２～３－６を合成した。実施例３－２～３－６の構造式および物性値を表２８に示した。 Examples 3-2 to 3-6
Examples 3-2 to 3-6 were synthesized in the same manner as in Example 3-1, using the corresponding starting materials. The structural formulas and physical property values of Examples 3-2 to 3-6 are shown in Table 28.
実施例４－１
Ｎ－(カルバモイルフェニルメチル)－４－ヒドロキシ－Ｎ－(３－メトキシベンジル)ベンズアミド
　４－｛Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－(３－メトキシベンジル)カルバモイル｝フェニルアセタート（実施例１－３４，０．０４２ｇ）のメタノール（１ｍＬ）溶液に、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．１５ｍＬ）を加え、その混合物を室温にて１時間撹拌した。反応混合物を減圧下濃縮した。この残渣をシリカゲルカラムクロマトグラフィー（（溶出溶媒：酢酸エチル／メタノール＝１００／０－９／１）で精製し、標題化合物（０．０３８ｇ）を得た。標題化合物の構造式および物性値を表２９に示した。 Example 4-1
N- (carbamoylphenylmethyl) -4-hydroxy-N- (3-methoxybenzyl) benzamide 4- {N-[(R) -carbamoylphenylmethyl] -N- (3-methoxybenzyl) carbamoyl} phenyl acetate ( A 1 mol / L aqueous sodium hydroxide solution (0.15 mL) was added to a methanol (1 mL) solution of Example 1-34, 0.042 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-9 / 1) to give the title compound (0.038 g). 29.
実施例４－２
　実施例１－４７で得た化合物を用い、実施例４－１と同様の方法で実施例４－２を合成した。実施例４－２の構造式および物性値を表２９に示した。 Example 4-2
Example 4-2 was synthesized in the same manner as in Example 4-1, using the compound obtained in Example 1-47. The structural formula and physical property values of Example 4-2 are shown in Table 29.
実施例５－１
２－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－(３－メトキシベンジル)ベンズアミド
　室温撹拌下、（Ｒ）－フェニルグリシンアミド塩酸塩（１．０ｇ）およびトリエチルアミン（１．５ｍＬ）のテトラヒドロフラン（１０ｍＬ）混合液に３－メトキシベンズアルデヒド（７２０μＬ）を加え、その混合物を室温にて２時間撹拌した。反応混合物にメタノール（１０ｍＬ）および水素化ホウ素ナトリウム（１．０１ｇ）を加え、その混合物を室温にて４時間撹拌した。反応混合物に水を加え、減圧下溶媒を留去した。析出物を濾取し、減圧下乾燥して、(Ｒ)－２－(３－メトキシベンジルアミノ)－２－フェニルアセトアミド（１．２４ｇ）を得た。(Ｒ)－２－(３－メトキシベンジルアミノ)－２－フェニルアセトアミド（０．０４ｇ）およびトリエチルアミン（４１μＬ）のジクロロメタン（１ｍＬ）混合液に２－ニトロベンゾイルクロリド（２２μＬ）を加え、その混合物を室温にて終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝８／２－１００／０）で精製し、Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－(３－メトキシベンジル)－２－ニトロベンズアミド（０．０５７ｇ）を得た。Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－(３－メトキシベンジル)－２－ニトロベンズアミド（０．０４８ｇ）のメタノール（１ｍＬ）／テトラヒドロフラン（１ｍＬ）混合液に１０％パラジウム炭素（０．０１ｇ）を室温で加え、その混合物を水素雰囲気下２時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。この残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝８／２－１００／０）で精製し、標題化合物（０．０２６ｇ）を得た。標題化合物の構造式および物性値を表３０に示した。 Example 5-1
2-Amino-N-[(R) -carbamoylphenylmethyl] -N- (3-methoxybenzyl) benzamide (R) -Phenylglycinamide hydrochloride (1.0 g) and triethylamine (1.5 mL) with stirring at room temperature 3-Methoxybenzaldehyde (720 μL) was added to a tetrahydrofuran (10 mL) mixture, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added methanol (10 mL) and sodium borohydride (1.01 g), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The precipitate was collected by filtration and dried under reduced pressure to obtain (R) -2- (3-methoxybenzylamino) -2-phenylacetamide (1.24 g). 2-Nitrobenzoyl chloride (22 μL) was added to a mixture of (R) -2- (3-methoxybenzylamino) -2-phenylacetamide (0.04 g) and triethylamine (41 μL) in dichloromethane (1 mL), and the mixture was added. Stir at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 8 / 2-100 / 0), and N-[(R) -carbamoylphenylmethyl]- N- (3-methoxybenzyl) -2-nitrobenzamide (0.057 g) was obtained. N-[(R) -carbamoylphenylmethyl] -N- (3-methoxybenzyl) -2-nitrobenzamide (0.048 g) in a methanol (1 mL) / tetrahydrofuran (1 mL) mixture was mixed with 10% palladium carbon (0. 01 g) was added at room temperature and the mixture was stirred under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / n-hexane = 8 / 2-100 / 0) to give the title compound (0.026 g). The structural formula and physical property values of the title compound are shown in Table 30.
実施例５－２～５－３
　対応する原料を用い、実施例５－１と同様の方法で実施例５－２～５－３を合成した。実施例５－２～５－３の構造式および物性値を表３０に示した。 Examples 5-2 to 5-3
Examples 5-2 to 5-3 were synthesized in the same manner as in Example 5-1, using the corresponding starting materials. The structural formulas and physical property values of Examples 5-2 to 5-3 are shown in Table 30.
実施例６－１
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－ヒドロキシ－Ｎ－(３－トリフルオロメトキシベンジル)ベンズアミド
　３－トリフルオロメトキシベンズアルデヒド（０．１０２ｇ）のメタノール（３０ｍＬ）溶液に、（Ｒ）－フェニルグリシンアミド塩酸塩（０．１００ｇ）およびトリエチルアミン（０．０７３ｍＬ）を室温で加え、この混合物を２時間撹拌した。反応混合物に水素化ホウ素ナトリウム（０．２０３ｇ）を０℃で加え、この混合物を室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去し得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－２／１）で精製し、（Ｒ）－２－フェニル－２－（３－トリフルオロメトキシベンジルアミノ）アセトアミド（０．０９０ｇ）を得た。（Ｒ）－２－フェニル－２－（３－トリフルオロメトキシベンジルアミノ）アセトアミド（０．０９０ｇ）とトリエチルアミン（０．０４６ｍＬ）のジクロロメタン（５ｍＬ）混液に、２－アセチルオキシベンゾイルクロリド（０．０６１ｇ）を室温で加え、この混合物を２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－酢酸エチル－酢酸エチル／メタノール＝１０／１）で精製し、標題化合物（０．１１５ｇ）を得た。標題化合物の構造式および物性値を表３１に示した。 Example 6-1
N-[(R) -carbamoylphenylmethyl] -2-hydroxy-N- (3-trifluoromethoxybenzyl) benzamide To a solution of 3-trifluoromethoxybenzaldehyde (0.102 g) in methanol (30 mL), (R)- Phenylglycinamide hydrochloride (0.100 g) and triethylamine (0.073 mL) were added at room temperature and the mixture was stirred for 2 hours. To the reaction mixture was added sodium borohydride (0.203 g) at 0 ° C. and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1-1-2 / 1) to give (R) -2-phenyl-2- (3- Trifluoromethoxybenzylamino) acetamide (0.090 g) was obtained. (R) -2-Phenyl-2- (3-trifluoromethoxybenzylamino) acetamide (0.090 g) and triethylamine (0.046 mL) in dichloromethane (5 mL) were mixed with 2-acetyloxybenzoyl chloride (0.061 g). ) Was added at room temperature and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane = 1 / 1-ethyl acetate-ethyl acetate / methanol = 10/1) to give the title compound (0.115 g) was obtained. The structural formula and physical property values of the title compound are shown in Table 31.
実施例６－２～６－１１
　対応する原料を用い、実施例６－１と同様の方法で実施例６－２～６－１１を合成した。なお、実施例６－２～６－１１の構造式および物性値を表３１～３２に示した。 Examples 6-2 to 6-11
Examples 6-2 to 6-11 were synthesized in the same manner as in Example 6-1, using the corresponding starting materials. The structural formulas and physical property values of Examples 6-2 to 6-11 are shown in Tables 31 to 32.
実施例７－１
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－（２－フルオロ－５－メチルベンジル）－２－ヒドロキシベンズアミド
　室温撹拌下、（Ｒ）－フェニルグリシンアミド塩酸塩（０．１０ｇ）およびトリエチルアミン（１５０μＬ）のテトラヒドロフラン（２ｍＬ）／メタノール（２ｍＬ）混合液に２－フルオロ－５－メチルベンズアルデヒド（６９μＬ）を加え、その混合物を室温にて１時間撹拌した。反応混合物に、１０％パラジウム炭素（０．０３ｇ）を室温で加え、その混合物を水素雰囲気下４時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮して(Ｒ)－２－(２－フルオロ－５－メチルベンジルアミノ)－２－フェニルアセトアミド（０．１３５ｇ）を得た。(Ｒ)－２－(２－フルオロ－５－メチルベンジルアミノ)－２－フェニルアセトアミド（０．０７３ｇ）およびトリエチルアミン（７５μＬ）のジクロロメタン（１ｍＬ）混合液にＯ－アセチルサリチロイルクロリド（０．０５９ｇ）を加え、その混合物を室温にて３時間撹拌した。反応混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／メタノール＝１００／０－７／３）で精製し、標題化合物（０．０４０ｇ）を得た。アセチル基はアミノプロピルシリカゲルにより切断された。標題化合物の構造式および物性値を表３３に示した。 Example 7-1
N-[(R) -carbamoylphenylmethyl] -N- (2-fluoro-5-methylbenzyl) -2-hydroxybenzamide (R) -phenylglycinamide hydrochloride (0.10 g) and triethylamine ( To a mixture of 150 μL) of tetrahydrofuran (2 mL) / methanol (2 mL) was added 2-fluoro-5-methylbenzaldehyde (69 μL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 10% palladium on carbon (0.03 g) at room temperature and the mixture was stirred under a hydrogen atmosphere for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give (R) -2- (2-fluoro-5-methylbenzylamino) -2-phenylacetamide (0.135 g). (R) -2- (2-Fluoro-5-methylbenzylamino) -2-phenylacetamide (0.073 g) and triethylamine (75 μL) in dichloromethane (1 mL) were mixed with O-acetylsalicyloyl chloride (0. 059 g) was added and the mixture was stirred at room temperature for 3 hours. Water 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 and the obtained residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-7 / 3) to obtain the title compound (0.040 g). The acetyl group was cleaved with aminopropyl silica gel. The structural formula and physical property values of the title compound are shown in Table 33.
実施例７－２～７－１１
　対応する原料を用い、実施例７－１と同様の方法で実施例７－２～７－１１を合成した。実施例７－２～７－１１の構造式および物性値を表３３～３４に示した。 Examples 7-2 to 7-11
Examples 7-2 to 7-11 were synthesized in the same manner as in Example 7-1 using the corresponding starting materials. The structural formulas and physical property values of Examples 7-2 to 7-11 are shown in Tables 33 to 34.
実施例８－１
２－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－(３－トリフルオロメチルベンジル)ベンズアミド
　室温撹拌下、（Ｒ）－フェニルグリシンアミド塩酸塩（０．１０ｇ）およびトリエチルアミン（１５０μＬ）のテトラヒドロフラン（２ｍＬ）／メタノール（２ｍＬ）混合液に３－トリフルオロメチルベンズアルデヒド（７５μＬ）を加え、その混合物を室温にて２時間撹拌した。反応混合物に１０％パラジウム炭素（０．０１５ｇ）を室温で加え、水素雰囲気下２時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。この残渣に酢酸エチルを加え、不溶物を濾去し、濾液を減圧下濃縮した。この残渣にジクロロメタン（２ｍＬ）を加え、溶解させた。トリエチルアミン（７５μＬ）および２－ニトロベンゾイルクロリド（７８μＬ）をその溶液に加えた。この混合物を室温で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝６／４－１００／０）で精製し、Ｎ－[(Ｒ)－カルバモイルフェニルメチル]－２－ニトロ－Ｎ－(３－トリフルオロメチルベンジル)ベンズアミド（０．１１ｇ）を得た。Ｎ－［(Ｒ)－カルバモイルフェニルメチル］－２－ニトロ－Ｎ－(３－トリフルオロメチルベンジル)ベンズアミド（０．１０７ｇ）のメタノール（１ｍＬ）およびテトラヒドロフラン（１ｍＬ）混合溶液に１０％パラジウム炭素（０．０１ｇ）を室温で加え、その混合物を水素雰囲気下２時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。この残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝３／７－６／４）で精製し、標題化合物（０．０４１ｇ）を得た。標題化合物の構造式および物性値を表３５に示した。 Example 8-1
2-Amino-N-[(R) -carbamoylphenylmethyl] -N- (3-trifluoromethylbenzyl) benzamide (R) -phenylglycinamide hydrochloride (0.10 g) and triethylamine (150 μL) with stirring at room temperature 3-trifluoromethylbenzaldehyde (75 μL) was added to a tetrahydrofuran (2 mL) / methanol (2 mL) mixture, and the mixture was stirred at room temperature for 2 hours. 10% Palladium carbon (0.015 g) was added to the reaction mixture at room temperature, and the mixture was stirred for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) was added to this residue and dissolved. Triethylamine (75 μL) and 2-nitrobenzoyl chloride (78 μL) were added to the solution. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 6 / 4-100 / 0), and N-[(R) -carbamoylphenylmethyl]- 2-Nitro-N- (3-trifluoromethylbenzyl) benzamide (0.11 g) was obtained. N-[(R) -carbamoylphenylmethyl] -2-nitro-N- (3-trifluoromethylbenzyl) benzamide (0.107 g) in a mixed solution of methanol (1 mL) and tetrahydrofuran (1 mL) with 10% palladium carbon ( 0.01 g) was added at room temperature and the mixture was stirred under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / n-hexane = 3 / 7-6 / 4) to give the title compound (0.041 g). The structural formula and physical property values of the title compound are shown in Table 35.
実施例８－２～８－３
　対応する原料を用い、実施例８－１と同様の方法で実施例８－２～８－３を合成した。実施例８－２～８－３の構造式および物性値を表３５に示した。 Examples 8-2 to 8-3
Examples 8-2 to 8-3 were synthesized in the same manner as in Example 8-1, using the corresponding starting materials. The structural formulas and physical property values of Examples 8-2 to 8-3 are shown in Table 35.
実施例９－１
４－{４－[(カルバモイルフェニルメチル)－(３－メトキシベンジル)カルバモイル]フェノキシメチル}安息香酸メチルエステル
　Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－４－ヒドロキシ－Ｎ－(３－メトキシベンジル)ベンズアミド（実施例４－１，０．０３６ｇ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に、水素化ナトリウム（０．００３ｇ）および４－ブロモメチル安息香酸メチル（０．０２３ｇ）を加え、その混合物を室温にて２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝３／７－１００／０）で精製し、標題化合物（０．０３３ｇ）を得た。標題化合物の構造式および物性値を表３６に示した。 Example 9-1
4- {4-[(carbamoylphenylmethyl)-(3-methoxybenzyl) carbamoyl] phenoxymethyl} benzoic acid methyl ester N-[(R) -carbamoylphenylmethyl] -4-hydroxy-N- (3-methoxybenzyl ) To a solution of benzamide (Examples 4-1 and 0.036 g) in N, N-dimethylformamide (1 mL) was added sodium hydride (0.003 g) and methyl 4-bromomethylbenzoate (0.023 g). The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3 / 7-100 / 0) to obtain the title compound (0.033 g). The structural formula and physical property values of the title compound are shown in Table 36.
実施例９－２
　実施例７－１１で得た化合物を用い、実施例９－１と同様の方法で実施例９－２を合成した。実施例９－２の構造式および物性値を表３６に示した。 Example 9-2
Example 9-2 was synthesized in the same manner as in Example 9-1 using the compound obtained in Example 7-11. The structural formula and physical property values of Example 9-2 are shown in Table 36.
実施例１０－１
(Ｓ)－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－(３－トリフルオロメチルベンジル)ピロリジン－２－カルボキサミド
　室温撹拌下、（Ｒ）－フェニルグリシンアミド塩酸塩（２．０ｇ）およびトリエチルアミン（３．０ｍＬ）のテトラヒドロフラン（１０ｍＬ）／メタノール（１０ｍＬ）混合液に３－トリフルオロメチルベンズアルデヒド（１．５ｍＬ）を加え、その混合物を室温にて１時間撹拌した。反応混合物に１０％パラジウム炭素（０．１ｇ）を室温で加え、その混合物水素雰囲気下４時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。この残渣に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣にジエチルエーテル／ヘキサンを加えた。生じた析出物を粉末状にして濾取した。得られた固体をジエチルエーテルで洗浄し、減圧下乾燥して(Ｒ)－２－フェニル－２－(３－トリフルオロメチルベンジルアミノ)アセトアミド（２．８５ｇ）を得た。氷冷撹拌下、１－[(ベンジルオキシ)カルボニル]－Ｌ－プロリン（０．１２ｇ）およびＮ，Ｎ－ジメチルホルムアミド（１０μＬ）のジクロロメタン（１ｍＬ）溶液に二塩化オキサリル（５０μＬ）を加え、室温にて１時間撹拌した。反応混合物を減圧下濃縮して得た残渣にジクロロメタン（１ｍＬ）を加え、(Ｓ)－２－クロロカルボニルピロリジン－１－カルボン酸ベンジルエステルのジクロロメタン溶液を調製した。室温撹拌下、(Ｒ)－２－フェニル－２－(３－トリフルオロメチルベンジルアミノ)アセトアミド（０．１０ｇ）およびトリエチルアミン（１３６μＬ）のジクロロメタン（１ｍＬ）溶液に、(Ｓ)－２－クロロカルボニルピロリジン－１－カルボン酸ベンジルエステルのジクロロメタン溶液を加え、室温にて２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－８／２）で精製し、(Ｓ)－２－｛Ｎ－[(Ｒ)－カルバモイルフェニルメチル]－Ｎ－(３－トリフルオロメチルベンジル)カルバモイル｝ピロリジン－１－カルボン酸ベンジルエステル（０．０７ｇ）を得た。(Ｓ)－２－｛Ｎ－[(Ｒ)－カルバモイルフェニルメチル]－Ｎ－(３－トリフルオロメチルベンジル)カルバモイル｝ピロリジン－１－カルボン酸ベンジルエステル（０．０６５ｇ）のメタノール（１ｍＬ）およびテトラヒドロフラン（１ｍＬ）混合溶液１０％パラジウム炭素（０．００５ｇ）を室温で加え、水素雰囲気下０．５時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。この残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝８／２－１００／０）で精製し、標題化合物（０．０３９ｇ）を得た。標題化合物の構造式および物性値を表３７に示した。 Example 10-1
(S) -N-[(R) -carbamoylphenylmethyl] -N- (3-trifluoromethylbenzyl) pyrrolidine-2-carboxamide With stirring at room temperature, (R) -phenylglycinamide hydrochloride (2.0 g) and To a mixed solution of triethylamine (3.0 mL) in tetrahydrofuran (10 mL) / methanol (10 mL) was added 3-trifluoromethylbenzaldehyde (1.5 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 10% palladium on carbon (0.1 g) at room temperature, and the mixture was stirred under a hydrogen atmosphere for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Diethyl ether / hexane was added to the residue obtained by evaporating the solvent under reduced pressure. The resulting precipitate was powdered and collected by filtration. The obtained solid was washed with diethyl ether and dried under reduced pressure to obtain (R) -2-phenyl-2- (3-trifluoromethylbenzylamino) acetamide (2.85 g). Under ice-cooling, oxalyl dichloride (50 μL) was added to a solution of 1-[(benzyloxy) carbonyl] -L-proline (0.12 g) and N, N-dimethylformamide (10 μL) in dichloromethane (1 mL) at room temperature. For 1 hour. The reaction mixture was concentrated under reduced pressure and dichloromethane (1 mL) was added to the resulting residue to prepare a dichloromethane solution of (S) -2-chlorocarbonylpyrrolidine-1-carboxylic acid benzyl ester. Under stirring at room temperature, (S) -2-chlorocarbonyl was added to a solution of (R) -2-phenyl-2- (3-trifluoromethylbenzylamino) acetamide (0.10 g) and triethylamine (136 μL) in dichloromethane (1 mL). A dichloromethane solution of pyrrolidine-1-carboxylic acid benzyl ester was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate / n-hexane = 1 / 1-8 / 2), and (S) -2- {N- [ (R) -Carbamoylphenylmethyl] -N- (3-trifluoromethylbenzyl) carbamoyl} pyrrolidine-1-carboxylic acid benzyl ester (0.07 g) was obtained. (S) -2- {N-[(R) -carbamoylphenylmethyl] -N- (3-trifluoromethylbenzyl) carbamoyl} pyrrolidine-1-carboxylic acid benzyl ester (0.065 g) in methanol (1 mL) and Tetrahydrofuran (1 mL) mixed solution 10% palladium carbon (0.005 g) was added at room temperature, and the mixture was stirred for 0.5 hour under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / n-hexane = 8 / 2-100 / 0) to give the title compound (0.039 g). The structural formula and physical property values of the title compound are shown in Table 37.
実施例１０－２
　対応する原料を用い、実施例１０－１と同様の方法で実施例１０－２を合成した。実施例１０－２の構造式および物性値を表３７に示した。 Example 10-2
Example 10-2 was synthesized in the same manner as in Example 10-1, using the corresponding starting materials. The structural formula and physical property values of Example 10-2 are shown in Table 37.
実施例１１
Ｎ－(カルバモイルフェニルメチル)－Ｎ－(２－フルオロ－５－トリフルオロメチルベンジル)－２－ヒドロキシベンズアミド
　室温撹拌下、（Ｒ）－フェニルグリシンアミド塩酸塩（０．２５ｇ）およびトリエチルアミン（３７５μＬ）のテトラヒドロフラン（３ｍＬ）／メタノール（３ｍＬ）混合液に、２－フルオロ－５－トリフルオロメチルベンズアルデヒド（２００μＬ）を加え、その混合物を室温にて１時間撹拌した。反応混合物に１０％パラジウム炭素（２５ｍｇ）を室温で加え、水素雰囲気下２時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。この残渣に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝６／４－１００／０）で精製し、(Ｒ)－２－(２－フルオロ－５－トリフルオロメチルベンジルアミノ)－２－フェニルアセトアミド（０．２３ｇ）を得た。(Ｒ)－２－(２－フルオロ－５－トリフルオロメチルベンジルアミノ)－２－フェニルアセトアミド（０．０５ｇ）およびトリエチルアミン（４４μＬ）のジクロロメタン（１ｍＬ）溶液にＯ－アセチルサリチロイルクロリド（０．０４６ｇ）を加え、室温にて３時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣にメタノール（１ｍＬ）を加え溶解させた。その溶液に１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．２３ｍＬ）を加え、その混合物を室温にて３０分間撹拌した。反応混合物を減圧下濃縮し得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝５４／４６－７５／２５）で精製し、標題化合物（０．０６８ｇ）を得た。標題化合物の構造式および物性値を表３８に示した。 Example 11
N- (carbamoylphenylmethyl) -N- (2-fluoro-5-trifluoromethylbenzyl) -2-hydroxybenzamide (R) -phenylglycinamide hydrochloride (0.25 g) and triethylamine (375 μL) with stirring at room temperature To a mixture of tetrahydrofuran (3 mL) / methanol (3 mL) was added 2-fluoro-5-trifluoromethylbenzaldehyde (200 μL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 10% palladium carbon (25 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 6 / 4-100 / 0) to give (R) -2- (2-fluoro-5 -Trifluoromethylbenzylamino) -2-phenylacetamide (0.23 g) was obtained. To a solution of (R) -2- (2-fluoro-5-trifluoromethylbenzylamino) -2-phenylacetamide (0.05 g) and triethylamine (44 μL) in dichloromethane (1 mL) was added O-acetylsalicyloyl chloride (0 0.046 g) was added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Methanol (1 mL) was added and dissolved in the residue obtained by distilling off the solvent under reduced pressure. A 1 mol / L aqueous sodium hydroxide solution (0.23 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 54 / 46-75 / 25) to give the title compound (0.068 g). The structural formula and physical property values of the title compound are shown in Table 38.
実施例１２
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－３－メタンスルホニルアミノ－Ｎ－(３－トリフルオロメチルベンジル)ベンズアミド
　氷冷撹拌下、３－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－(３－トリフルオロメチルベンジル)ベンズアミド（実施例８－３，０．０２７ｇ）およびトリエチルアミン（１９μＬ）のジクロロメタン（１ｍＬ）混合液に塩化メタンスルホニル（６μＬ）を加え、その混合物を同温度にて０．５時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝６０／４０－１００／０）で精製し、標題化合物（０．０１ｇ）を得た。標題化合物の構造式および物性値を表３８に示した。 Example 12
N-[(R) -carbamoylphenylmethyl] -3-methanesulfonylamino-N- (3-trifluoromethylbenzyl) benzamide Under stirring with ice cooling, 3-amino-N-[(R) -carbamoylphenylmethyl]- Methanesulfonyl chloride (6 μL) was added to a dichloromethane (1 mL) mixture of N- (3-trifluoromethylbenzyl) benzamide (Example 8-3, 0.027 g) and triethylamine (19 μL), and the mixture was brought to the same temperature. And stirred for 0.5 hour. Water was added to the reaction mixture, and the mixture 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 and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 60 / 40-100 / 0) to obtain the title compound (0.01 g). The structural formula and physical property values of the title compound are shown in Table 38.
実施例１３
Ｎ－(カルバモイルフェニルメチル)－Ｎ－（シクロヘキシルメチル）ベンズアミド
　２－ヒドロキシ－２－フェニルアセトアミド（０．１ｇ）およびトリエチルアミン（１６７μＬ）のジクロロメタン（２ｍＬ）混合液に塩化メタンスルホニル（６７μＬ）を加え、その混合物を同温にて０．５時間撹拌した。反応混合物にＣ－シクロヘキシルメチルアミン（２１５μＬ）を加え、加熱還流下12時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝０／１００－６／４）で精製し、２－(シクロヘキシルメチルアミノ)－２－フェニルアセトアミド（０．０６６ｇ）を得た。２－(シクロヘキシルメチルアミノ)－２－フェニルアセトアミド（０．０６ｇ）およびトリエチルアミン（６８μＬ）のジクロロメタン（１ｍＬ）混合液にベンゾイルクロリド（３４μＬ）を加え、その混合物を同温にて３時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝３／７－７／３）で精製し、標題化合物（０．０６４ｇ）を得た。標題化合物の構造式および物性値を表３８に示した。 Example 13
N- (carbamoylphenylmethyl) -N- (cyclohexylmethyl) benzamide To a mixture of 2-hydroxy-2-phenylacetamide (0.1 g) and triethylamine (167 μL) in dichloromethane (2 mL) was added methanesulfonyl chloride (67 μL), The mixture was stirred at the same temperature for 0.5 hour. C-cyclohexylmethylamine (215 μL) was added to the reaction mixture, and the mixture was stirred for 12 hours with heating under reflux. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0 / 100-6 / 4) to give 2- (cyclohexylmethylamino) -2-phenylacetamide. (0.066 g) was obtained. Benzoyl chloride (34 μL) was added to a mixture of 2- (cyclohexylmethylamino) -2-phenylacetamide (0.06 g) and triethylamine (68 μL) in dichloromethane (1 mL), and the mixture was stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 3 / 7-7 / 3) to obtain the title compound (0.064 g). The structural formula and physical property values of the title compound are shown in Table 38.
実施例１４－１
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－メトキシフェニル）エチル]ベンズアミド
Ｎ－[（Ｓ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－メトキシフェニル）エチル]ベンズアミド
　（Ｒ）－１－（３－メトキシフェニル）エチルアミン（０．１００ｇ）のジクロロメタン（３ｍＬ）溶液に、（Ｓ）－２－（４－ニトロベンゼンスルホニルオキシ）－２－フェニル酢酸メチルエステル（０．２３２ｇ）および炭酸カリウム水溶液（３０ｗ／ｖ％，１．５ｍＬ）を室温で加えた。その混合物を同温度で１時間撹拌し、５０℃で１６時間撹拌した。反応混合物をジクロロメタンで希釈し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝５／９５－１０／９０）で精製した。得られた混合物をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝５／９５－１０／９０）で精製し、（Ｒ）－２－［（Ｒ）－１－（３－メトキシフェニル）エチルアミノ］－２－フェニル酢酸メチルエステル（０．０８８ｇ）を得た。（Ｒ）－２－［（Ｒ）－１－（３－メトキシフェニル）エチルアミノ］－２－フェニル酢酸メチルエステル（０．１６８ｇ）のジクロロメタン（４ｍＬ）溶液に、室温でトリエチルアミン（０．２３５ｍＬ）を加えた。その混合物にベンゾイルクロリド（０．０９９ｍＬ）を氷冷下加え、室温で１４時間撹拌した。その混合物にＮ，Ｎ－ジメチル－４－アミノピリジン（０．００６９ｇ）、トリエチルアミン（０．２３５ｍＬ）およびベンゾイルクロリド（０．０９９ｍＬ）を室温で加え、３５℃で２３時間撹拌した。その混合物にトリエチルアミン（０．２３５ｍＬ）およびベンゾイルクロリド（０．０９９ｍＬ）を加え、５時間加熱還流させた。反応混合物を減圧下溶媒留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１５／８５－４０／６０）で精製した。得られた混合物をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１０／９０－３５／６５）で精製し、（Ｒ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－メトキシフェニル）エチル］アミノ｝－２－フェニル酢酸メチルエステルと（Ｓ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－メトキシフェニル）エチル］アミノ｝－２－フェニル酢酸メチルエステルの混合物（０．２０３ｇ）を得た。（Ｒ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－メトキシフェニル）エチル］アミノ｝－２－フェニル酢酸メチルエステルと（Ｓ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－メトキシフェニル）エチル］アミノ｝－２－フェニル酢酸メチルエステルの混合物（０．１９４ｇ）、メタノール（１．４４ｍＬ）およびテトラヒドロフラン（２．２ｍＬ）の混合物に、水酸化ナトリウム水溶液（２ｍｏｌ／Ｌ，０．７２ｍＬ）を室温で加え、その混合物を室温で４時間撹拌した。水酸化ナトリウム水溶液（２ｍｏｌ／Ｌ，０．７２ｍＬ）をこの混合物に室温で加え、その混合物を４０℃で２時間撹拌した。反応混合物に塩酸（２ｍｏｌ／Ｌ，１．５６ｍＬ）を氷冷下で加え、粗生成物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣を、シリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１００／０－８０／２０）で精製し、（Ｒ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－メトキシフェニル）エチル］アミノ｝－２－フェニル酢酸と（Ｓ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－メトキシフェニル）エチル］アミノ｝－２－フェニル酢酸の混合物（０．１７２ｇ）を得た。（Ｒ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－メトキシフェニル）エチル］アミノ｝－２－フェニル酢酸と（Ｓ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－メトキシフェニル）エチル］アミノ｝－２－フェニル酢酸の混合物（０．１６７ｇ）のＮ，Ｎ－ジメチルホルムアミド（２ｍＬ）溶液に１－ヒドロキシベンゾトリアゾール１水和物（０．０９９ｇ）を室温で加えた。その混合物に塩化アンモニウム（０．１１５ｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．５８５ｍＬ）および１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（０．１２３ｇ）を氷冷下加え、室温で１．５日間撹拌した。反応混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液および飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣を、シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝５０／５０－７０／３０－８０／２０）で精製し、低極性生成物のＮ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－メトキシフェニル）エチル]ベンズアミド（実施例１４－１ＬＰ，０．０２４ｇ）および高極性生成物のＮ－[（Ｓ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－メトキシフェニル）エチル]ベンズアミド（実施例１４－１ＨＰ，０．１１５ｇ）を得た。標題化合物の構造式および物性値を表３９に示した。 Example 14-1
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-methoxyphenyl) ethyl] benzamide N-[(S) -carbamoylphenylmethyl] -N-[(R) -1 -(3-Methoxyphenyl) ethyl] benzamide (S) -2- (4-Nitrobenzenesulfonyloxy)-was added to a solution of (R) -1- (3-methoxyphenyl) ethylamine (0.100 g) in dichloromethane (3 mL). 2-Phenylacetic acid methyl ester (0.232 g) and aqueous potassium carbonate (30 w / v%, 1.5 mL) were added at room temperature. The mixture was stirred at the same temperature for 1 hour and stirred at 50 ° C. for 16 hours. The reaction mixture was diluted with dichloromethane and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane = 5 / 95-10 / 90). The obtained mixture was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 5 / 95-10 / 90), and (R) -2-[(R) -1- (3-methoxyphenyl) was obtained. ) Ethylamino] -2-phenylacetic acid methyl ester (0.088 g) was obtained. (R) -2-[(R) -1- (3-methoxyphenyl) ethylamino] -2-phenylacetic acid methyl ester (0.168 g) in dichloromethane (4 mL) at room temperature with triethylamine (0.235 mL) Was added. Benzoyl chloride (0.099 mL) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 14 hours. N, N-dimethyl-4-aminopyridine (0.0069 g), triethylamine (0.235 mL) and benzoyl chloride (0.099 mL) were added to the mixture at room temperature, and the mixture was stirred at 35 ° C. for 23 hours. Triethylamine (0.235 mL) and benzoyl chloride (0.099 mL) were added to the mixture, and the mixture was heated to reflux for 5 hours. The reaction mixture was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 15 / 85-40 / 60). The resulting mixture was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 10 / 90-35 / 65), and (R) -2- {N-benzoyl-N-[(R ) -1- (3-methoxyphenyl) ethyl] amino} -2-phenylacetic acid methyl ester and (S) -2- {N-benzoyl-N-[(R) -1- (3-methoxyphenyl) ethyl] A mixture of amino} -2-phenylacetic acid methyl ester (0.203 g) was obtained. (R) -2- {N-benzoyl-N-[(R) -1- (3-methoxyphenyl) ethyl] amino} -2-phenylacetic acid methyl ester and (S) -2- {N-benzoyl-N To a mixture of [(R) -1- (3-methoxyphenyl) ethyl] amino} -2-phenylacetic acid methyl ester (0.194 g), methanol (1.44 mL) and tetrahydrofuran (2.2 mL), Aqueous sodium hydroxide (2 mol / L, 0.72 mL) was added at room temperature, and the mixture was stirred at room temperature for 4 hours. Aqueous sodium hydroxide (2 mol / L, 0.72 mL) was added to the mixture at room temperature and the mixture was stirred at 40 ° C. for 2 hours. Hydrochloric acid (2 mol / L, 1.56 mL) was added to the reaction mixture under ice cooling, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 100 / 0-80 / 20), and (R) -2- {N-benzoyl-N- [ (R) -1- (3-methoxyphenyl) ethyl] amino} -2-phenylacetic acid and (S) -2- {N-benzoyl-N-[(R) -1- (3-methoxyphenyl) ethyl] A mixture of amino} -2-phenylacetic acid (0.172 g) was obtained. (R) -2- {N-benzoyl-N-[(R) -1- (3-methoxyphenyl) ethyl] amino} -2-phenylacetic acid and (S) -2- {N-benzoyl-N- [ (R) -1- (3-methoxyphenyl) ethyl] amino} -2-phenylacetic acid (0.167 g) in N, N-dimethylformamide (2 mL) solution in 1-hydroxybenzotriazole monohydrate ( 0.099 g) was added at room temperature. Ammonium chloride (0.115 g), N, N-diisopropylethylamine (0.585 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.123 g) were added to the mixture under ice cooling, Stir at room temperature for 1.5 days. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 50 / 50-70 / 30-80 / 20), and the low polarity product N- [(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-methoxyphenyl) ethyl] benzamide (Example 14-1LP, 0.024 g) and the highly polar product N-[(S ) -Carbamoylphenylmethyl] -N-[(R) -1- (3-methoxyphenyl) ethyl] benzamide (Example 14-1 HP, 0.115 g) was obtained. The structural formula and physical property values of the title compound are shown in Table 39.
実施例１４－２
　対応する原料を用い、実施例１４－１と同様の方法で実施例１４－２を合成した。実施例１４－２の構造式および物性値を表３９に示した。 Example 14-2
Example 14-2 was synthesized in the same manner as Example 14-1 using the corresponding starting materials. Table 39 shows the structural formula and physical property values of Example 14-2.
実施例１５－１
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－トリフルオロメチルフェニル）エチル]ベンズアミド
Ｎ－[（Ｓ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－トリフルオロメチルフェニル）エチル]ベンズアミド Example 15-1
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-trifluoromethylphenyl) ethyl] benzamide N-[(S) -carbamoylphenylmethyl] -N-[(R) -1- (3-trifluoromethylphenyl) ethyl] benzamide
　α－ブロモフェニル酢酸メチルエステル（０．３００ｇ）のアセトニトリル（１５ｍＬ）溶液に（Ｒ）－１－（３－トリフルオロメチルフェニル）エチルアミン塩酸塩（０．３２５ｇ）およびトリエチルアミン（０．４４６ｍＬ）を室温で加え、その混合物を終夜加熱還流させた。反応混合物を室温まで冷却し、水および酢酸エチルを加えて分液した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジエチルエーテル／ｎ－ヘキサン＝１／３０－１／１０－酢酸エチル／ｎ－ヘキサン＝１／２０－１／１０）で精製し、（Ｒ）－２－フェニル－２－［（Ｒ）－１－（３－トリフルオロメチルフェニル）エチルアミノ］酢酸メチルエステル（０．１３５ｇ）および（Ｓ）－２－フェニル－２－［（Ｒ）－１－（３－トリフルオロメチルフェニル）エチルアミノ］酢酸メチルエステル（０．１８４ｇ）を得た。（Ｒ）－２－フェニル－２－［（Ｒ）－１－（３－トリフルオロメチルフェニル）エチルアミノ］酢酸メチルエステル（０．１３５ｇ）、トリエチルアミン（０．０６５ｍＬ）のジクロロメタン（１０ｍＬ）混合物に、ベンゾイルクロリド（０．０５１ｍＬ）を室温で加え、その混合物を５日間撹拌した。反応混合物に水および酢酸エチルを加えて分液した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１０－１／５－１／２）で精製し、（Ｒ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－トリフルオロメチル）エチル］アミノ｝－２－フェニル酢酸メチルエステル（０．１０１ｇ）を得た。（Ｒ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－トリフルオロメチル）エチル］アミノ｝－２－フェニル酢酸メチルエステル（０．１０１ｇ）の１，４－ジオキサン（５ｍＬ）溶液に、水酸化ナトリウム水溶液（１ｍｏｌ／Ｌ，１．０３ｍＬ）を室温で加え、その混合物を５０℃で８時間撹拌した。反応混合物に塩酸（１ｍｏｌ／Ｌ，１．０３ｍＬ）を加えた。その混合物に水および酢酸エチルを加え分液した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／メタノール＝１０／１）で精製し、（Ｒ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－トリフルオロメチル）エチル］アミノ｝－２－フェニル酢酸と（Ｓ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－トリフルオロメチル）エチル］アミノ｝－２－フェニル酢酸の混合物（０．０８２ｇ）を得た。（Ｒ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－トリフルオロメチル）エチル］アミノ｝－２－フェニル酢酸と（Ｓ）－２－｛Ｎ－ベンゾイル－Ｎ－［（Ｒ）－１－（３－トリフルオロメチル）エチル］アミノ｝－２－フェニル酢酸の混合物（０．０７７ｇ）のＮ，Ｎ－ジメチルホルムアミド（２ｍＬ）溶液に、塩化アンモニウム（０．０４８ｇ）、１－ヒドロキシベンゾトリアゾール１水和物（０．０２９ｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（０．０４２ｇ）およびトリエチルアミン（０．１４７ｍＬ）を室温で順次加え、その混合物を２日間撹拌した。反応混合物に水および酢酸エチルを加えて分液した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／５－１／２－１／１）で精製し、低極性生成物のＮ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－トリフルオロメチルフェニル）エチル]ベンズアミド（実施例１５－１ＬＰ，０．０１３ｇ）および高極性生成物のＮ－[（Ｓ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－トリフルオロメチルフェニル）エチル]ベンズアミド（実施例１５－１ＨＰ，０．０３２ｇ）を得た。標題化合物の構造式および物性値を表４０に示した。 To a solution of α-bromophenylacetic acid methyl ester (0.300 g) in acetonitrile (15 mL) was added (R) -1- (3-trifluoromethylphenyl) ethylamine hydrochloride (0.325 g) and triethylamine (0.446 mL) at room temperature. And the mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added for liquid separation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (elution solvent: diethyl ether / n-hexane = 1 / 30-1 / 10-ethyl acetate / n-hexane = 1 / 20-1 / 10). Purified and (R) -2-phenyl-2-[(R) -1- (3-trifluoromethylphenyl) ethylamino] acetic acid methyl ester (0.135 g) and (S) -2-phenyl-2- [(R) -1- (3-trifluoromethylphenyl) ethylamino] acetic acid methyl ester (0.184 g) was obtained. To a mixture of (R) -2-phenyl-2-[(R) -1- (3-trifluoromethylphenyl) ethylamino] acetic acid methyl ester (0.135 g), triethylamine (0.065 mL) in dichloromethane (10 mL). Benzoyl chloride (0.051 mL) was added at room temperature and the mixture was stirred for 5 days. Water and ethyl acetate were added to the reaction mixture for liquid separation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 10-1 / 5-1 / 2), and (R) -2- {N -Benzoyl-N-[(R) -1- (3-trifluoromethyl) ethyl] amino} -2-phenylacetic acid methyl ester (0.101 g) was obtained. (R) -2- {N-benzoyl-N-[(R) -1- (3-trifluoromethyl) ethyl] amino} -2-phenylacetic acid methyl ester (0.101 g) 1,4-dioxane ( 5 mL) solution was added aqueous sodium hydroxide (1 mol / L, 1.03 mL) at room temperature and the mixture was stirred at 50 ° C. for 8 hours. Hydrochloric acid (1 mol / L, 1.03 mL) was added to the reaction mixture. Water and ethyl acetate were added to the mixture for liquid separation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 10/1), and (R) -2- {N-benzoyl-N-[(R)- 1- (3-trifluoromethyl) ethyl] amino} -2-phenylacetic acid and (S) -2- {N-benzoyl-N-[(R) -1- (3-trifluoromethyl) ethyl] amino} A mixture of -2-phenylacetic acid (0.082 g) was obtained. (R) -2- {N-benzoyl-N-[(R) -1- (3-trifluoromethyl) ethyl] amino} -2-phenylacetic acid and (S) -2- {N-benzoyl-N- To a solution of [(R) -1- (3-trifluoromethyl) ethyl] amino} -2-phenylacetic acid (0.077 g) in N, N-dimethylformamide (2 mL) was added ammonium chloride (0.048 g). 1-hydroxybenzotriazole monohydrate (0.029 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.042 g) and triethylamine (0.147 mL) were sequentially added at room temperature, The mixture was stirred for 2 days. Water and ethyl acetate were added to the reaction mixture for liquid separation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 5-1 / 2-1 / 1), and N- [ (R) -carbamoylphenylmethyl] -N-[(R) -1- (3-trifluoromethylphenyl) ethyl] benzamide (Example 15-1LP, 0.013 g) and the highly polar product N-[( S) -carbamoylphenylmethyl] -N-[(R) -1- (3-trifluoromethylphenyl) ethyl] benzamide (Example 15-1HP, 0.032 g) was obtained. The structural formula and physical property values of the title compound are shown in Table 40.
実施例１５－２
　対応する原料を用い、実施例１５－１と同様の方法で実施例１５－２～１５－３を合成した。実施例１５－２～１５－３の構造式および物性値を表４０に示した。 Example 15-2
Examples 15-2 to 15-3 were synthesized in the same manner as in Example 15-1, using the corresponding starting materials. The structural formulas and physical property values of Examples 15-2 to 15-3 are shown in Table 40.
実施例１６－１
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－クロロフェニル）エチル]ベンズアミド
Ｎ－[（Ｓ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－クロロフェニル）エチル]ベンズアミド
　（Ｒ）－１－（３－クロロフェニル）エチルアミン（２．１１ｇ）、炭酸水素カリウム（２．０４ｇ）のアセトニトリル（３０ｍＬ）混合液に（Ｓ）－（４－ニトロベンゼンスルホニルオキシ）フェニル酢酸ベンジルエステル（５．８０ｇ）を室温で加え、その混合物を５０℃で４時間撹拌した。反応混合物を室温まで冷却して水を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジエチルエーテル／ｎ－ヘキサン＝１／２０－１／１５）で精製し、（Ｒ）－２－[（Ｒ）－１－（３－クロロフェニル）エチルアミノ]－２－フェニル酢酸ベンジルエステル（３．１３ｇ）を得た。（Ｒ）－２－[（Ｒ）－１－（３－クロロフェニル）エチルアミノ]－２－フェニル酢酸ベンジルエステル（３．１３ｇ）、トリエチルアミン（６．７８ｍＬ）、Ｎ，Ｎ－ジメチル－４－アミノピリジン（０．１０１ｇ）のジクロロメタン混合液にベンゾイルクロリド（２．８７ｍＬ）を室温で加え、その混合物を同温度で５日間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１０－１／５）で精製し、（Ｒ）－２－｛Ｎ－ベンゾイル－Ｎ－[（Ｒ）－１－（３－クロロフェニル）エチル]アミノ｝－２－フェニル酢酸ベンジルエステル（３．４１ｇ）を得た。（Ｒ）－２－｛Ｎ－ベンゾイル－Ｎ－[（Ｒ）－１－（３－クロロフェニル）エチル]アミノ｝－２－フェニル酢酸ベンジルエステル（３．４１ｇ）のテトラヒドロフラン（１５０ｍＬ）溶液に１０％パラジウム炭素（０．３５ｇ）を室温で加え、水素雰囲気下１時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。得られた残渣に塩化アンモニウム（１．８８ｇ）を加えた。この混合物に１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（２．０３ｇ）、１－ヒドロキシベンゾトリアゾール１水和物（１．４３ｇ）とのＮ，Ｎ－ジメチルホルムアミド（５０ｍＬ）混合液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（８．３８ｍＬ）を室温で加え、２日間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／５－１／２－１／１）で精製し、低極性生成物のＮ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－クロロフェニル）エチル]ベンズアミド（実施例１６－１ＬＰ，０．９３ｇ）および高極性生成物のＮ－[（Ｓ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－クロロフェニル）エチル]ベンズアミド（実施例１６－１ＨＰ，１．０５ｇ）を得た。標題化合物の構造式および物性値を表４１に示した。 Example 16-1
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] benzamide N-[(S) -carbamoylphenylmethyl] -N-[(R) -1- (3-Chlorophenyl) ethyl] benzamide (R) -1- (3-Chlorophenyl) ethylamine (2.11 g) and potassium bicarbonate (2.04 g) in acetonitrile (30 mL) were mixed with (S)-(4-nitrobenzene. Sulfonyloxy) phenylacetic acid benzyl ester (5.80 g) was added at room temperature and the mixture was stirred at 50 ° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: diethyl ether / n-hexane = 1 / 20-1 / 15) to obtain (R) -2-[(R) -1 -(3-Chlorophenyl) ethylamino] -2-phenylacetic acid benzyl ester (3.13 g) was obtained. (R) -2-[(R) -1- (3-Chlorophenyl) ethylamino] -2-phenylacetic acid benzyl ester (3.13 g), triethylamine (6.78 mL), N, N-dimethyl-4-amino Benzoyl chloride (2.87 mL) was added to a dichloromethane mixture of pyridine (0.101 g) at room temperature, and the mixture was stirred at the same temperature for 5 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 10-1 / 5), and (R) -2- {N-benzoyl-N -[(R) -1- (3-Chlorophenyl) ethyl] amino} -2-phenylacetic acid benzyl ester (3.41 g) was obtained. 10% of (R) -2- {N-benzoyl-N-[(R) -1- (3-chlorophenyl) ethyl] amino} -2-phenylacetic acid benzyl ester (3.41 g) in tetrahydrofuran (150 mL) Palladium on carbon (0.35 g) was added at room temperature and stirred for 1 hour under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Ammonium chloride (1.88 g) was added to the resulting residue. To this mixture was added N, N-dimethylformamide (50 mL) with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.03 g), 1-hydroxybenzotriazole monohydrate (1.43 g). N, N-diisopropylethylamine (8.38 mL) was added to the mixture at room temperature and stirred for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 5-1 / 2-1 / 1), and N- [ (R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] benzamide (Example 16-1 LP, 0.93 g) and the highly polar product N-[(S)- Carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] benzamide (Example 16-1HP, 1.05 g) was obtained. The structural formula and physical property values of the title compound are shown in Table 41.
実施例１６－２～１６－２４
　対応する原料を用い、実施例１６－１と同様の方法で実施例１６－２～１６－２４を合成した。実施例１６－２～１６－２４の構造式および物性値を表４１～４７に示した。 Examples 16-2 to 16-24
Examples 16-2 to 16-24 were synthesized in the same manner as in Example 16-1, using the corresponding starting materials. The structural formulas and physical property values of Examples 16-2 to 16-24 are shown in Tables 41 to 47.
実施例１７－１
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－フェニルエチル］－２－チエナミド
Ｎ－［（Ｓ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－フェニルエチル］－２－チエナミド
　（Ｒ）－１－フェニルエチルアミン（０．４２７ｇ）、炭酸水素カリウム（０．７０９ｇ）のアセトニトリル（１０ｍＬ）混合液に（Ｓ）－（４－ニトロベンゼンスルホニルオキシ）フェニル酢酸メチルエステル（１．２４ｇ）を室温で加え、その混合物を６０℃で３時間撹拌した。反応混合物を室温まで冷却し、水を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝０／１００－１／９）で精製し、(Ｒ)－２－フェニル－２－［(Ｒ)－１－フェニルエチルアミノ］酢酸メチルエステル（０．６０ｇ）を得た。(Ｒ)－２－フェニル－２－［(Ｒ)－１－フェニルエチルアミノ］酢酸メチルエステル（０．２９ｇ）、トリエチルアミン（１ｍＬ）およびＮ，Ｎ－ジメチル－４－アミノピリジン（０．０２６ｇ）のジクロロメタン（４ｍＬ）混合液にチオフェン－２－カルボニルクロリド（５７０μＬ）を加え、その混合物を室温にて１日間撹拌した。反応混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝０／１００－２／８）で精製し、２－フェニル－２－｛Ｎ－［(Ｒ)－１－フェニルエチル］－Ｎ－(チオフェン－２－カルボニル)アミノ｝酢酸メチルエステル（０．３６ｇ）を得た。２－フェニル－２－｛[(Ｒ)－１－フェニルエチル]－(チオフェン－２－カルボニル)アミノ｝酢酸メチルエステル（０．０８５ｇ）および水酸化トリメチルすず（０．４０５ｇ）の１，２－ジクロロエタン（１ｍＬ）懸濁液をマイクロ波照射下、１６０℃で１時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、粗生成物を酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去した。得られた残渣と塩化アンモニウム（０．０６ｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（０．０６５ｇ）、１－ヒドロキシベンゾトリアゾール１水和物（０．０５１ｇ）とのＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）混合液に、トリエチルアミン（２２０μＬ）を室温で加え、その混合物を１日間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－７５／２５）で精製し、低極性生成物のＮ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－フェニルエチル]－２－チエナミド（０．０１４ｇ）および高極性生成物のＮ－[（Ｓ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－フェニルエチル]－２－チエナミド（０．００９ｇ）を得た。標題化合物の構造式および物性値を表４８に示した。 Example 17-1
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1-phenylethyl] -2-thienamide N-[(S) -carbamoylphenylmethyl] -N-[(R) -1-phenyl Ethyl] -2-thienamide (R) -1-phenylethylamine (0.427 g) and potassium bicarbonate (0.709 g) in acetonitrile (10 mL) mixed with (S)-(4-nitrobenzenesulfonyloxy) phenyl acetate methyl The ester (1.24 g) was added at room temperature and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 0 / 100-1 / 9), and (R) -2-phenyl-2-[( R) -1-Phenylethylamino] acetic acid methyl ester (0.60 g) was obtained. (R) -2-Phenyl-2-[(R) -1-phenylethylamino] acetic acid methyl ester (0.29 g), triethylamine (1 mL) and N, N-dimethyl-4-aminopyridine (0.026 g) To a dichloromethane (4 mL) mixture was added thiophene-2-carbonyl chloride (570 μL) and the mixture was stirred at room temperature for 1 day. Water 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 residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 0 / 100-2 / 8) to give 2-phenyl-2- {N-[(R ) -1-phenylethyl] -N- (thiophen-2-carbonyl) amino} acetic acid methyl ester (0.36 g) was obtained. 2-phenyl-2-{[(R) -1-phenylethyl]-(thiophen-2-carbonyl) amino} acetic acid methyl ester (0.085 g) and trimethyltin hydroxide (0.405 g) 1,2- A suspension of dichloroethane (1 mL) was stirred at 160 ° C. for 1 hour under microwave irradiation. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue, ammonium chloride (0.06 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.065 g), 1-hydroxybenzotriazole monohydrate (0.051 g), Of N, N-dimethylformamide (1 mL) was added triethylamine (220 μL) at room temperature and the mixture was stirred for 1 day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 1-75 / 25), and the low polarity product N-[(R)- Carbamoylphenylmethyl] -N-[(R) -1-phenylethyl] -2-thienamide (0.014 g) and the highly polar product N-[(S) -carbamoylphenylmethyl] -N-[(R) -1-Phenylethyl] -2-thienamide (0.009 g) was obtained. The structural formula and physical property values of the title compound are shown in Table 48.
実施例１７－２
　対応する原料を用い、実施例１７－１と同様の方法で実施例１７－２を合成した。実施例１７－２の構造式および物性値を表４８に示した。 Example 17-2
Example 17-2 was synthesized in the same manner as Example 17-1 using the corresponding starting materials. The structural formula and physical property values of Example 17-2 are shown in Table 48.
実施例１８
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３－クロロフェニル)エチル]－２－ヒドロキシベンズアミド
Ｎ－［（Ｓ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３－クロロフェニル)エチル]－２－ヒドロキシベンズアミド
　（Ｒ）－１－（３－クロロフェニル）エチルアミン（２．３８ｇ）、炭酸水素カリウム（２．２９ｇ）のアセトニトリル（３０ｍＬ）混合液に（Ｓ）－（４－ニトロベンゼンスルホニルオキシ）フェニル酢酸ベンジルエステル（６．５３ｇ）を室温で加え、５０℃で４時間撹拌した。反応液を室温まで冷却し、水を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジエチルエーテル／ｎ－ヘキサン＝１／２０－１／１５）で精製し、（Ｒ）－２－[（Ｒ）－１－（３－クロロフェニル）エチルアミノ]－２－フェニル酢酸ベンジルエステル（３．７２ｇ）を得た。（Ｒ）－２－[（Ｒ）－１－（３－クロロフェニル）エチルアミノ]－２－フェニル酢酸ベンジルエステル（０．１００ｇ）、トリエチルアミン（０．２１５ｍＬ）およびＮ，Ｎ－ジメチル－４－アミノピリジン（０．０１６ｇ）のジクロロメタン（５ｍＬ）混合液に、Ｏ－アセチルサリチロイルクロリド（０．１５７ｇ）を室温で加えた。その混合物を同温度で終夜、４０℃で４日間、室温で２日間撹拌した。反応混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジエチルエーテル／ｎ－ヘキサン＝１／１０－１／５）で精製し、（Ｒ）－２－｛Ｎ－（２－アセトキシベンゾイル）－Ｎ－［（Ｒ）－１－（３－クロロフェニル）エチル］アミノ｝－２－フェニル酢酸ベンジルエステル（０．０４５ｇ）を得た。（Ｒ）－２－｛Ｎ－（２－アセトキシベンゾイル）－Ｎ－［（Ｒ）－１－（３－クロロフェニル）エチル］アミノ｝－２－フェニル酢酸ベンジルエステル（０．０４５ｇ）のテトラヒドロフラン（２０ｍＬ）溶液に１０％パラジウム炭素（０．０３０ｇ）を室温で加え、その混合物を水素雰囲気下で３０分間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮して（Ｒ）－２－｛Ｎ－（２－アセトキシベンゾイル）－Ｎ－［（Ｒ）－１－（３－クロロフェニル）エチル］アミノ｝－２－フェニル酢酸（０．０３４ｇ）を得た。（Ｒ）－２－｛Ｎ－（２－アセトキシベンゾイル）－Ｎ－［（Ｒ）－１－（３－クロロフェニル）エチル］アミノ｝－２－フェニル酢酸（０．０３４ｇ）、塩化アンモニウム（０．０２２ｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（０．０２４ｇ）および１－ヒドロキシベンゾトリアゾール１水和物（０．０１７ｇ）のＮ，Ｎ－ジメチルホルムアミド（３ｍＬ）混合液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．０９９ｍＬ）を室温で加え、その混合物を同温度で２日間撹拌した。反応混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣を分取薄層シリカゲルクロマトグラフィー（展開溶媒：酢酸エチル／ｎ－ヘキサン＝１／１，４回展開）で精製し、低極性生成物のＮ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３－クロロフェニル)エチル]－２－ヒドロキシベンズアミド（実施例１８ＬＰ，０．００２ｇ）および高極性生成物のＮ－［（Ｓ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３－クロロフェニル)エチル]－２－ヒドロキシベンズアミド（実施例１８ＨＰ，０．００５ｇ）を得た。標題化合物の構造式および物性値を表４９に示した。 Example 18
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] -2-hydroxybenzamide N-[(S) -carbamoylphenylmethyl] -N-[(R ) -1- (3-Chlorophenyl) ethyl] -2-hydroxybenzamide (R) -1- (3-Chlorophenyl) ethylamine (2.38 g), potassium bicarbonate (2.29 g) in acetonitrile (30 mL) (S)-(4-Nitrobenzenesulfonyloxy) phenylacetic acid benzyl ester (6.53 g) was added at room temperature, and the mixture was stirred at 50 ° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: diethyl ether / n-hexane = 1 / 20-1 / 15) to obtain (R) -2-[(R) -1 -(3-Chlorophenyl) ethylamino] -2-phenylacetic acid benzyl ester (3.72 g) was obtained. (R) -2-[(R) -1- (3-chlorophenyl) ethylamino] -2-phenylacetic acid benzyl ester (0.100 g), triethylamine (0.215 mL) and N, N-dimethyl-4-amino To a mixture of pyridine (0.016 g) in dichloromethane (5 mL), O-acetylsalicyloyl chloride (0.157 g) was added at room temperature. The mixture was stirred at the same temperature overnight, at 40 ° C. for 4 days and at room temperature for 2 days. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: diethyl ether / n-hexane = 1 / 10-1 / 5), and (R) -2- {N- (2- Acetoxybenzoyl) -N-[(R) -1- (3-chlorophenyl) ethyl] amino} -2-phenylacetic acid benzyl ester (0.045 g) was obtained. (R) -2- {N- (2-acetoxybenzoyl) -N-[(R) -1- (3-chlorophenyl) ethyl] amino} -2-phenylacetic acid benzyl ester (0.045 g) in tetrahydrofuran (20 mL ) 10% palladium on carbon (0.030 g) was added to the solution at room temperature and the mixture was stirred under a hydrogen atmosphere for 30 minutes. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give (R) -2- {N- (2-acetoxybenzoyl) -N-[(R) -1- (3-chlorophenyl) ethyl] amino} -2- Phenylacetic acid (0.034 g) was obtained. (R) -2- {N- (2-acetoxybenzoyl) -N-[(R) -1- (3-chlorophenyl) ethyl] amino} -2-phenylacetic acid (0.034 g), ammonium chloride (0. 022 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.024 g) and 1-hydroxybenzotriazole monohydrate (0.017 g) mixed with N, N-dimethylformamide (3 mL) To the solution was added N, N-diisopropylethylamine (0.099 mL) at room temperature, and the mixture was stirred at the same temperature for 2 days. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin layer silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 1/1, 4 times development), and the N-[(( R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] -2-hydroxybenzamide (Example 18LP, 0.002 g) and the highly polar product N-[(S) -Carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] -2-hydroxybenzamide (Example 18 HP, 0.005 g) was obtained. The structural formula and physical property values of the title compound are shown in Table 49.
実施例１９－１
２－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド
　(Ｒ)－１－フェニルエチルアミン（０．０７１ｇ）、炭酸水素カリウム（０．１１７ｇ）のアセトニトリル（２ｍＬ）混合液に（Ｓ）－２－（４－ニトロベンゼンスルホニルオキシ）－２－フェニル酢酸ベンジルエステル（０．２５ｇ）を室温で加え、その混合物を６０℃で８時間撹拌した。反応混合物を室温まで冷却し、水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝０／１００－１／９）で精製し、(Ｒ)－２－フェニル－２－［(Ｒ)－１－フェニルエチルアミノ］酢酸ベンジルエステル（０．１５７ｇ）を得た。(Ｒ)－２－フェニル－２－［(Ｒ)－１－フェニルエチルアミノ］酢酸ベンジルエステル（０．０８ｇ）、トリエチルアミン（３２５μＬ）およびＮ，Ｎ－ジメチル－４－アミノピリジン（０．００６ｇ）のジクロロメタン（２ｍＬ）混合液に２－ニトロベンゾイルクロリド（１５３μＬ）を加え、その混合物を加熱還流下終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝０／１００－２５／７５）で精製し、２－[Ｎ－(２－ニトロベンゾイル)－Ｎ－［（Ｒ）－１－フェニルエチル］アミノ]－２－フェニル酢酸ベンジルエステル（０．０４５ｇ）を得た。２－[Ｎ－(２－ニトロベンゾイル)－Ｎ－［（Ｒ）－１－フェニルエチル］アミノ]－２－フェニル酢酸ベンジルエステル（０．０４５ｇ）の水（０．５ｍＬ）／テトラヒドロフラン（０．５ｍＬ）混合液に、水酸化リチウム１水和物（０．００８ｇ）を加え、その混合物を室温にて２時間撹拌した。反応混合物を外温４０℃で２時間撹拌した。反応混合物にメタノール（１ｍＬ）および２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（９０μＬ）を加え、その混合物を外温４０℃にて４時間撹拌した。反応混合物に２ｍｏｌ／Ｌ塩酸を加え酸性とした。その混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去した。得られた残渣と塩化アンモニウム（０．０２４ｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（０．０２６ｇ）、１－ヒドロキシベンゾトリアゾール１水和物（０．０２１ｇ）とのＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）混合液に、トリエチルアミン（９０μＬ）を室温で加え、その混合物を２日間撹拌した。反応混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝４／６－１００／０）で精製し、低極性生成物のＮ－［（Ｒ）－カルバモイルフェニルメチル］－２－ニトロ－Ｎ－［(Ｒ)－１－フェニルエチル］ベンズアミド（０．００４ｇ）および高極性生成物のＮ－［（Ｓ）－カルバモイルフェニルメチル］－２－ニトロ－Ｎ－［(Ｒ)－１－フェニルエチル］ベンズアミド（０．０１０ｇ）を得た。Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－ニトロ－Ｎ－［(Ｒ)－１－フェニルエチル］ベンズアミド（４ｍｇ）のテトラヒドロフラン（１ｍＬ）溶液に１０％パラジウム炭素（５ｍｇ）を室温で加え、その混合物を水素雰囲気下１時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。この残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／メタノール＝１００／０－８／２）で精製し、２－アミノ－Ｎ－［(Ｒ)－カルバモイルフェニルメチル］－Ｎ－［(Ｒ)－１－フェニルエチル］ベンズアミド（３．６ｍｇ）を得た。なお、標題化合物の構造式および物性値を表５０に示した。 Example 19-1
2-amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1-phenylethyl] benzamide (R) -1-phenylethylamine (0.071 g), potassium bicarbonate (0.117 g ) In acetonitrile (2 mL) was added (S) -2- (4-nitrobenzenesulfonyloxy) -2-phenylacetic acid benzyl ester (0.25 g) at room temperature, and the mixture was stirred at 60 ° C. for 8 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 0 / 100-1 / 9), and (R) -2-phenyl-2-[( R) -1-Phenylethylamino] acetic acid benzyl ester (0.157 g) was obtained. (R) -2-Phenyl-2-[(R) -1-phenylethylamino] acetic acid benzyl ester (0.08 g), triethylamine (325 μL) and N, N-dimethyl-4-aminopyridine (0.006 g) 2-dichlorobenzoyl chloride (153 μL) was added to a dichloromethane (2 mL) mixture, and the mixture was stirred with heating under reflux overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 0 / 100-25 / 75) to give 2- [N- (2-nitrobenzoyl)- N-[(R) -1-phenylethyl] amino] -2-phenylacetic acid benzyl ester (0.045 g) was obtained. 2- [N- (2-nitrobenzoyl) -N-[(R) -1-phenylethyl] amino] -2-phenylacetic acid benzyl ester (0.045 g) in water (0.5 mL) / tetrahydrofuran (0. 5 mL) Lithium hydroxide monohydrate (0.008 g) was added to the mixture and the mixture was stirred at room temperature for 2 hours. The reaction mixture was stirred at an external temperature of 40 ° C. for 2 hours. Methanol (1 mL) and a 2 mol / L aqueous sodium hydroxide solution (90 μL) were added to the reaction mixture, and the mixture was stirred at an external temperature of 40 ° C. for 4 hours. The reaction mixture was acidified with 2 mol / L hydrochloric acid. Water was added to the 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 removed under reduced pressure. The obtained residue, ammonium chloride (0.024 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.026 g), 1-hydroxybenzotriazole monohydrate (0.021 g), Of N, N-dimethylformamide (1 mL) was added triethylamine (90 μL) at room temperature and the mixture was stirred for 2 days. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 4 / 6-100 / 0), and N-[(R)- Carbamoylphenylmethyl] -2-nitro-N-[(R) -1-phenylethyl] benzamide (0.004 g) and the highly polar product N-[(S) -carbamoylphenylmethyl] -2-nitro-N -[(R) -1-phenylethyl] benzamide (0.010 g) was obtained. To a solution of N-[(R) -carbamoylphenylmethyl] -2-nitro-N-[(R) -1-phenylethyl] benzamide (4 mg) in tetrahydrofuran (1 mL) was added 10% palladium carbon (5 mg) at room temperature. The mixture was stirred under a hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-8 / 2) to give 2-amino-N-[(R) -carbamoylphenylmethyl] -N-[( R) -1-Phenylethyl] benzamide (3.6 mg) was obtained. The structural formula and physical property values of the title compound are shown in Table 50.
実施例１９－２
　実施例１９－１で得たＮ－［（Ｓ）－カルバモイルフェニルメチル］－２－ニトロ－Ｎ－［(Ｒ)－１－フェニルエチル］ベンズアミドを用い、実施例１９－１と同様の方法で実施例１９－２を合成した。実施例１９－２の構造式および物性値を表５０に示した。 Example 19-2
Using N-[(S) -carbamoylphenylmethyl] -2-nitro-N-[(R) -1-phenylethyl] benzamide obtained in Example 19-1, in the same manner as in Example 19-1. Example 19-2 was synthesized. Table 50 shows the structural formula and physical property values of Example 19-2.
実施例２０
Ｎ－［(Ｒ)－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３－フルオロフェニル)エチル]－２－チエナミド
Ｎ－［(Ｓ)－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３－フルオロフェニル)エチル]－２－チエナミド
　(Ｒ)－１－(３－フルオロフェニル)エチルアミン（０．６３５ｇ）、炭酸水素カリウム（０．９１６ｇ）のアセトニトリル（１２ｍＬ）混合液に（Ｓ）－２－（４－ニトロベンゼンスルホニルオキシ）－２－フェニル酢酸ベンジルエステル（１．９５ｇ）を室温で加え、その混合物を６０℃で３時間撹拌した。反応混合物を室温まで冷却し、水を加えた。粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝０／１００－１／９）で精製し、２－[(Ｒ)－１－(３－フルオロフェニル)エチルアミノ]－２－フェニル酢酸ベンジルエステル（１．３１ｇ）を得た。２－[(Ｒ)－１－(３－フルオロフェニル)エチルアミノ]－２－フェニル酢酸ベンジルエステル（０．２０ｇ）、トリエチルアミン（５４０μＬ）およびＮ，Ｎ－ジメチル－４－アミノピリジン（０．０１３ｇ）のジクロロメタン（４ｍＬ）混合液に、塩化チオフェン－２－カルボニル（２９０μＬ）を加え、その混合物を室温にて３日間撹拌した。反応混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝０／１００－２／８）で精製し、２－｛Ｎ－［(Ｒ)－１－(３－フルオロフェニル)エチル］－Ｎ－(チオフェン－２－カルボニル)アミノ｝－２－フェニル酢酸ベンジルエステル（０．１１ｇ）を得た。２－｛Ｎ－［(Ｒ)－１－(３－フルオロフェニル)エチル］－Ｎ－(チオフェン－２－カルボニル)アミノ｝－２－フェニル酢酸ベンジルエステル（０．１１ｇ）のメタノール（２ｍＬ）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（４６０μＬ）を加え、その混合物を外温５０℃にて５時間撹拌した。反応混合物に２ｍｏｌ／Ｌ塩酸を加え酸性とした。その混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去した。得られた残渣と塩化アンモニウム（０．０６２ｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（０．０６７ｇ）、１－ヒドロキシベンゾトリアゾール１水和物（０．０５３ｇ）とのＮ，Ｎ－ジメチルホルムアミド（２ｍＬ）混合液に、トリエチルアミン（２２５μＬ）を室温で加え、その混合物を２日間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－７５／２５）で精製し、低極性生成物のＮ－［(Ｒ)－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３－フルオロフェニル)エチル]－２－チエナミド（実施例２０ＬＰ，０．０１４ｇ）および高極性生成物のＮ－［(Ｓ)－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３－フルオロフェニル)エチル]－２－チエナミド（実施例２０ＨＰ，０．１６ｇ）を得た。標題化合物の構造式および物性値を表５１に示した。 Example 20
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] -2-thienamide N-[(S) -carbamoylphenylmethyl] -N-[(R ) -1- (3-Fluorophenyl) ethyl] -2-thienamide (R) -1- (3-fluorophenyl) ethylamine (0.635 g), potassium bicarbonate (0.916 g) in acetonitrile (12 mL) To (S) -2- (4-nitrobenzenesulfonyloxy) -2-phenylacetic acid benzyl ester (1.95 g) was added at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature and water was added. The crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 0 / 100-1 / 9) to give 2-[(R) -1- (3- Fluorophenyl) ethylamino] -2-phenylacetic acid benzyl ester (1.31 g) was obtained. 2-[(R) -1- (3-Fluorophenyl) ethylamino] -2-phenylacetic acid benzyl ester (0.20 g), triethylamine (540 μL) and N, N-dimethyl-4-aminopyridine (0.013 g) ) In dichloromethane (4 mL) was added thiophene-2-carbonyl chloride (290 μL) and the mixture was stirred at room temperature for 3 days. Water 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 residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 0 / 100-2 / 8) to give 2- {N-[(R) -1- (3-Fluorophenyl) ethyl] -N- (thiophen-2-carbonyl) amino} -2-phenylacetic acid benzyl ester (0.11 g) was obtained. 2- {N-[(R) -1- (3-fluorophenyl) ethyl] -N- (thiophen-2-carbonyl) amino} -2-phenylacetic acid benzyl ester (0.11 g) in methanol (2 mL) 2 mol / L aqueous sodium hydroxide solution (460 μL) was added, and the mixture was stirred at an external temperature of 50 ° C. for 5 hours. The reaction mixture was acidified with 2 mol / L hydrochloric acid. Water was added to the 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 removed under reduced pressure. The obtained residue, ammonium chloride (0.062 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.067 g), 1-hydroxybenzotriazole monohydrate (0.053 g), To a mixture of N, N-dimethylformamide (2 mL) was added triethylamine (225 μL) at room temperature and the mixture was stirred for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 1-75 / 25), and N-[(R)- Carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] -2-thienamide (Example 20LP, 0.014 g) and the highly polar product N-[(S) -carbamoylphenyl Methyl] -N-[(R) -1- (3-fluorophenyl) ethyl] -2-thienamide (Example 20 HP, 0.16 g) was obtained. The structural formula and physical property values of the title compound are shown in Table 51.
実施例２１
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－メチルアミノ－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド
　２－アミノ－Ｎ－［(Ｒ)－カルバモイルフェニルメチル］－Ｎ－［(Ｒ)－１－フェニルエチル］ベンズアミド（実施例１９－１，０．０１８ｇ）およびベンゾトリアゾール－１－イルメタノール（０．００８ｇ）のエタノール（０．４ｍＬ）混合液を、加熱還流下０．５時間撹拌した。反応混合物を室温まで放冷し、室温にて１時間撹拌した。その混合物に氷冷撹拌下、テトラヒドロフラン（１ｍＬ）および水素化ホウ素ナトリウム（０．００９ｇ）を加え、室温にて終夜撹拌した。反応混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝４５／５５－５５／４５）で精製し、標題化合物（０．００８ｇ）を得た。標題化合物の構造式および物性値を表５１に示した。 Example 21
N-[(R) -carbamoylphenylmethyl] -2-methylamino-N-[(R) -1-phenylethyl] benzamide 2-amino-N-[(R) -carbamoylphenylmethyl] -N-[( (R) -1-Phenylethyl] benzamide (Example 19-1, 0.018 g) and benzotriazol-1-ylmethanol (0.008 g) in ethanol (0.4 mL) Stir for hours. The reaction mixture was allowed to cool to room temperature and stirred at room temperature for 1 hour. Tetrahydrofuran (1 mL) and sodium borohydride (0.009 g) were added to the mixture under ice-cooling and stirring, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 45 / 55-55 / 45) to obtain the title compound (0.008 g). The structural formula and physical property values of the title compound are shown in Table 51.
実施例２２－１
Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－フルオロフェニル）エチル]ベンズアミド
Ｎ－[（Ｓ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－フルオロフェニル）エチル]ベンズアミド
　(Ｒ)－１－(３－フルオロフェニル)エチルアミン（０．０５０ｇ）およびベンズアルデヒド（０．０３８ｇ）のメタノール（１ｍＬ）混合液を外温５０℃にて６時間撹拌した。反応混合物を室温まで放冷した後、安息香酸（０．０４４ｇ）および４－フェニルシクロヘキセン－１－イルイソシアニド（０．０６６ｇ）を加え、外温５０℃にて２０時間撹拌した。反応混合物を減圧下濃縮した。得られた残渣にテトラヒドロフラン（２ｍＬ）を加え溶解させた。その混合物に水（７μＬ）および４ｍｏｌ／Ｌ塩化水素１，４－ジオキサン溶液（０．２５５ｍＬ）を加え、室温にて１時間撹拌した。反応混合物に水および飽和炭酸水素ナトリウム水溶液を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／１－７５／２５－１００／０）で精製し、低極性生成物のＮ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－フルオロフェニル）エチル]ベンズアミド（実施例２２－１ＬＰ，０．０４７ｇ）および高極性生成物のＮ－[（Ｓ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－フルオロフェニル）エチル]ベンズアミド（実施例２２－１ＨＰ，０．０６０ｇ）を得た。標題化合物の構造式および物性値を表５２に示した。 Example 22-1
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] benzamide N-[(S) -carbamoylphenylmethyl] -N-[(R) -1 -(3-Fluorophenyl) ethyl] benzamide A mixture of (R) -1- (3-fluorophenyl) ethylamine (0.050 g) and benzaldehyde (0.038 g) in methanol (1 mL) was added at an external temperature of 50 ° C. Stir for hours. The reaction mixture was allowed to cool to room temperature, benzoic acid (0.044 g) and 4-phenylcyclohexen-1-yl isocyanide (0.066 g) were added, and the mixture was stirred at an external temperature of 50 ° C. for 20 hr. The reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (2 mL) was added to the resulting residue and dissolved. Water (7 μL) and 4 mol / L hydrogen chloride 1,4-dioxane solution (0.255 mL) were added to the mixture, and the mixture was stirred at room temperature for 1 hour. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 1-75 / 25-100 / 0), and N- [ (R) -carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] benzamide (Example 22-1LP, 0.047 g) and the highly polar product N-[(S) -Carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] benzamide (Example 22-1HP, 0.060 g) was obtained. The structural formula and physical property values of the title compound are shown in Table 52.
実施例２２－２～２２－８８
　対応する原料を用い、実施例２２－１と同様の方法で実施例２２－２～２２－８８を合成した。実施例２２－２～２２－８８の構造式および物性値を表５２～７１に示した。 Examples 22-2 to 22-88
Examples 22-2 to 22-88 were synthesized in the same manner as in Example 22-1 using the corresponding starting materials. The structural formulas and physical property values of Examples 22-2 to 22-88 are shown in Tables 52 to 71.
実施例２３－１
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－｛（Ｒ）－１－［３－（１，１－ジフルオロエチル）フェニル］エチル｝ベンズアミド
Ｎ－［（Ｓ）－カルバモイルフェニルメチル］－Ｎ－｛（Ｒ）－１－［３－（１，１－ジフルオロエチル）フェニル］エチル｝ベンズアミド
　(Ｓ)－Ｎ－｛(Ｒ)－１－［３－ (１，１－ジフルオロエチル)フェニル］エチル｝－ｔｅｒｔ－ブタンスルフィンアミド（０．１２ｇ）のメタノール（２ｍL）溶液に４ｍｏｌ／Ｌ塩化水素１，４－ジオキサン溶液（１４５μＬ）を室温で加え，同温にて1時間撹拌した。反応混合物を減圧下濃縮した。得られた残渣と炭酸水素カリウム（０．０８３ｇ）のアセトニトリル（２ｍＬ）混合液に（Ｓ）－（４－ニトロベンゼンスルホニルオキシ）フェニル酢酸ベンジルエステル（０．２１３ｇ）を室温で加え、その混合物を６０℃で終夜撹拌した。反応混合物を室温まで冷却して水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジエチルエーテル／ｎ－ヘキサン＝１／２０－１／１５）で精製し、（Ｒ）－２－｛(Ｒ)－１－［３－ (１，１－ジフルオロエチル)フェニル］エチルアミノ｝－２－フェニル酢酸ベンジルエステル（０．０８２ｇ）を得た。（（Ｒ）－２－｛(Ｒ)－１－［３－ (１，１－ジフルオロエチル)フェニル］エチルアミノ｝－２－フェニル酢酸ベンジルエステル（０．０８２ｇ）、トリエチルアミン（２７０μＬ）、Ｎ，Ｎ－ジメチル－４－アミノピリジン（０．００７ｇ）のジクロロメタン（１ｍL）混合液にベンゾイルクロリド（１１３μＬ）を室温で加え、その混合物を加熱還流下で１日間撹拌した。反応混合物を室温まで放冷した後，反応混合物に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝０／１０－２５／７５）で精製し、（Ｒ）－２－（Ｎ－ベンゾイル－Ｎ－｛(Ｒ)－１－［３－ (１，１－ジフルオロエチル)フェニル］エチル｝アミノ）－２－フェニル酢酸ベンジルエステル（０．０８ｇ）を得た。（Ｒ）－２－（Ｎ－ベンゾイル－Ｎ－｛(Ｒ)－１－［３－ (１，１－ジフルオロエチル)フェニル］エチル｝アミノ）－２－フェニル酢酸ベンジルエステル（０．０８ｇ）のテトラヒドロフラン（２ｍＬ）溶液に１０％パラジウム炭素（０．０１ｇ）を室温で加え、水素雰囲気下１時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。得られた残渣と塩化アンモニウム（０．０４２ｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（０．０４５ｇ）、１－ヒドロキシベンゾトリアゾール１水和物（０．０３６ｇ）とのＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）混合液に、トリエチルアミン（１５２μＬ）を室温で加え、終夜撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝２／８－４／６）で精製し、低極性生成物のＮ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－｛(Ｒ)－１－［３－ (１，１－ジフルオロエチル)フェニル］エチル｝ベンズアミド（実施例２３－１ＬＰ，０．０２ｇ）および高極性生成物のＮ－[(Ｓ)－カルバモイルフェニルメチル]－Ｎ－｛(Ｒ)－１－［３－ (１，１－ジフルオロエチル)フェニル］エチル｝ベンズアミド（実施例２３－１ＨＰ，０．０２８ｇ）を得た。標題化合物の構造式および物性値を表７２に示した。 Example 23-1
N-[(R) -carbamoylphenylmethyl] -N-{(R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl} benzamide N-[(S) -carbamoylphenylmethyl] -N -{(R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl} benzamide (S) -N-{(R) -1- [3- (1,1-difluoroethyl) phenyl] To a solution of ethyl} -tert-butanesulfinamide (0.12 g) in methanol (2 mL) was added 4 mol / L hydrogen chloride 1,4-dioxane solution (145 μL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. (S)-(4-Nitrobenzenesulfonyloxy) phenylacetic acid benzyl ester (0.213 g) was added to a mixture of the obtained residue and potassium hydrogen carbonate (0.083 g) in acetonitrile (2 mL) at room temperature, and the mixture was added to 60 mL. Stir overnight at ° C. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: diethyl ether / n-hexane = 1 / 20-1 / 15), and (R) -2-{(R) -1 -[3- (1,1-Difluoroethyl) phenyl] ethylamino} -2-phenylacetic acid benzyl ester (0.082 g) was obtained. ((R) -2-{(R) -1- [3- (1,1-difluoroethyl) phenyl] ethylamino} -2-phenylacetic acid benzyl ester (0.082 g), triethylamine (270 μL), N, Benzoyl chloride (113 μL) was added to a mixture of N-dimethyl-4-aminopyridine (0.007 g) in dichloromethane (1 mL) at room temperature, and the mixture was stirred with heating under reflux for 1 day. After adding water to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Purified by chromatography (elution solvent: ethyl acetate / n-hexane = 0 / 10-25 / 75), and (R) -2- (N-benzoyl-N-{(R) -1- [3- ( , 1-difluoroethyl) phenyl] ethyl} amino) -2-phenylacetic acid benzyl ester (0.08 g) was obtained (R) -2- (N-benzoyl-N-{(R) -1- [3 To a solution of (1,1-difluoroethyl) phenyl] ethyl} amino) -2-phenylacetic acid benzyl ester (0.08 g) in tetrahydrofuran (2 mL) was added 10% palladium carbon (0.01 g) at room temperature, and hydrogen atmosphere The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the resulting residue, ammonium chloride (0.042 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0 0.045 g), N, N-dimethylformamide (1 mL) with 1-hydroxybenzotriazole monohydrate (0.036 g), triethylamine ( The reaction mixture was added with water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue thus obtained was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane = 2 / 8-4 / 6), and the low polarity product N-[(R) -carbamoylphenylmethyl] -N-{(R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl} benzamide (Example 23-1LP, 0.02 g) and the highly polar product N-[(S)- Carbamoylphenylmethyl] -N-{(R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl} benzamide (Example 23-1 HP, 0.028 g) was obtained. The structural formula and physical property values of the title compound are shown in Table 72.
実施例２３－２
　対応するアミンを用い、実施例２３－１と同様の方法で実施例２３－２を合成した。実施例２３－２の構造式および物性値を表７２に示した。 Example 23-2
Example 23-2 was synthesized in the same manner as Example 23-1 using the corresponding amine. The structural formula and physical property values of Example 23-2 are shown in Table 72.
実施例２４
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]－４－ヒドロキシメチルベンズアミド
４－{Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]カルバモイル}ベンジルアセタート（実施例２２－３１ＬＰ，０．０９３ｇ）のメタノール（１ｍＬ）溶液に炭酸カリウム（０．４１ｇ）を加え、室温にて３０分間撹拌した。反応混合物に水を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／メタノール＝１００／０－８０／２０）で精製し、標題化合物（０．０４ｇ）を得た。標題化合物の構造式および物性値を表７２に示した。 Example 24
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -4-hydroxymethylbenzamide 4- {N-[(R) -carbamoylphenylmethyl ] -N-[(R) -1- (3,5-difluorophenyl) ethyl] carbamoyl} benzyl acetate (Examples 22-31LP, 0.093 g) in methanol (1 mL) in potassium carbonate (0.41 g ) And stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.04 g). The structural formula and physical property values of the title compound are shown in Table 72.
実施例２５－１
２－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]ベンズアミド
(Ｒ)－１－(３，５－ジフルオロフェニル)エチルアミン（０．２ｇ）とベンズアルデヒド（０．１３６ｇ）のメタノール（４ｍＬ）混合液を加熱還流下２０分間撹拌した。反応混合物を室温まで冷却した後、２－ニトロ安息香酸（０．２１３ｇ）および４－フェニルシクロヘキセン－１－イルイソシアニド（０．２３３ｇ）を加え、加熱還流下終夜撹拌した。反応混合物を減圧下濃縮した。得られた残渣にテトラヒドロフラン（８ｍＬ）を加え溶解させた。その混合物に水（２５μＬ）および４ｍｏｌ／Ｌ塩化水素１，４－ジオキサン溶液（０．９５ｍＬ）を加え、室温にて３時間撹拌した。反応混合物に水および飽和炭酸水素ナトリウム水溶液を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝５５／４５－７５／２５－１００／０）で精製し、Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]－２－ニトロベンズアミド（０．１８５ｇ）を得た。Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]－２－ニトロベンズアミド（０．１８５ｇ）のテトラヒドロフラン（３ｍＬ）懸濁液に１０％パラジウム炭素（０．０３０ｇ）を室温で加え、水素雰囲気下３時間撹拌した。触媒を濾過で除去し、濾液を減圧濃縮した。この残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：メタノール／酢酸エチル＝０／１００－２／８）で精製し、標題化合物（０．１４３ｇ）を得た。標題化合物の構造式および物性値を表７３に示した。 Example 25-1
2-Amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] benzamide
A mixture of (R) -1- (3,5-difluorophenyl) ethylamine (0.2 g) and benzaldehyde (0.136 g) in methanol (4 mL) was stirred with heating under reflux for 20 minutes. The reaction mixture was cooled to room temperature, 2-nitrobenzoic acid (0.213 g) and 4-phenylcyclohexen-1-yl isocyanide (0.233 g) were added, and the mixture was stirred overnight with heating under reflux. The reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (8 mL) was added to the resulting residue and dissolved. Water (25 μL) and 4 mol / L hydrogen chloride 1,4-dioxane solution (0.95 mL) were added to the mixture, and the mixture was stirred at room temperature for 3 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 55 / 45-75 / 25-100 / 0), and N-[(R) -carbamoyl Phenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -2-nitrobenzamide (0.185 g) was obtained. To a suspension of N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -2-nitrobenzamide (0.185 g) in tetrahydrofuran (3 mL). 10% palladium carbon (0.030 g) was added at room temperature, and the mixture was stirred for 3 hours in a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: methanol / ethyl acetate = 0 / 100-2 / 8) to give the title compound (0.143 g). The structural formula and physical property values of the title compound are shown in Table 73.
実施例２５－２～２５－８
　対応する原料を用い、実施例２５－１と同様の方法で実施例２５－２～２５－８を合成した。実施例２５－２～２５－８の構造式および物性値を表７３～７４に示した。 Examples 25-2 to 25-8
Examples 25-2 to 25-8 were synthesized in the same manner as in Example 25-1 using the corresponding starting materials. The structural formulas and physical property values of Examples 25-2 to 25-8 are shown in Tables 73 to 74.
実施例２６
Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]－２－ヒドロキシベンズアミド
(Ｒ)－１－(３，５－ジフルオロフェニル)エチルアミン（０．２ｇ）およびベンズアルデヒド（０．１３６ｇ）のメタノール（４ｍＬ）混合液を加熱還流下２０分間撹拌した。反応混合物を室温まで冷却した後、２－アセトキシ安息香酸（０．２２９ｇ）および４－フェニルシクロヘキセン－１－イルイソシアニド（０．２３３ｇ）を加え、加熱還流下終夜撹拌した。反応混合物を減圧下濃縮した。得られた残渣にテトラヒドロフラン（８ｍＬ）を加え溶解させた。その混合物に水（２５μＬ）および４ｍｏｌ／Ｌ塩化水素１，４－ジオキサン溶液（０．９５ｍＬ）を加え、室温にて３時間撹拌した。反応混合物に水および飽和炭酸水素ナトリウム水溶液を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：メタノール／酢酸エチル＝０／１００－３５／６５）に通した。得られた混合物をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝５５／４５－７５／２５－１００／０）で精製し、標題化合物（０．０７８ｇ）を得た。標題化合物の構造式および物性値を表７４に示した。 Example 26
N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -2-hydroxybenzamide
A mixture of (R) -1- (3,5-difluorophenyl) ethylamine (0.2 g) and benzaldehyde (0.136 g) in methanol (4 mL) was stirred with heating under reflux for 20 minutes. The reaction mixture was cooled to room temperature, 2-acetoxybenzoic acid (0.229 g) and 4-phenylcyclohexen-1-yl isocyanide (0.233 g) were added, and the mixture was stirred overnight with heating under reflux. The reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (8 mL) was added to the resulting residue and dissolved. Water (25 μL) and 4 mol / L hydrogen chloride 1,4-dioxane solution (0.95 mL) were added to the mixture, and the mixture was stirred at room temperature for 3 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was passed through aminopropyl silica gel column chromatography (elution solvent: methanol / ethyl acetate = 0 / 100-35 / 65). The obtained mixture was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 55 / 45-75 / 25-100 / 0) to give the title compound (0.078 g). The structural formula and physical property values of the title compound are shown in Table 74.
実施例２７
４－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]ニコチンアミド
(Ｒ)－１－(３，５－ジフルオロフェニル)エチルアミン（０．１ｇ）およびベンズアルデヒド（０．０６８ｇ）のメタノール（１ｍＬ）混合液を加熱還流下２０分間撹拌した。反応混合物を室温まで冷却した後、４－ｔｅｒｔ－ブトキシカルボニルアミノニコチン酸（０．１５２ｇ）および４－フェニルシクロヘキセン－１－イルイソシアニド（０．１１６ｇ）を加え、加熱還流下２日間撹拌した。反応混合物を減圧下濃縮した。得られた残渣にテトラヒドロフラン（２ｍＬ）を加え溶解させた。その混合物に水（１４μＬ）および４ｍｏｌ／Ｌ塩化水素１，４－ジオキサン溶液（０．６４ｍＬ）を加え、室温にて１.５時間撹拌した。反応混合物に水および飽和炭酸水素ナトリウム水溶液を加え、粗生成物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝５５／４５－７５／２５－１００／０）で精製し、４－ｔｅｒｔ－ブトキシカルボニルアミノ－{Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]カルバモイル}ニコチンアミド（０．１６７ｇ）を得た。４－ｔｅｒｔ－ブトキシカルボニルアミノ－{Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]カルバモイル}ニコチンアミド（０．１６７ｇ）の塩化メチレン（１ｍＬ）溶液にトリフルオロ酢酸（１ｍＬ）を加え、室温にて４時間撹拌した。反応混合物を減圧下濃縮した。この残渣に水および飽和炭酸水素ナトリウム水溶液を加え、粗生成物を塩化メチレンで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去して得た残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／メタノール＝１００／０－８０／２０）で精製し、標題化合物（０．０４ｇ）を得た。標題化合物の構造式および物性値を表７４に示した。 Example 27
4-Amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] nicotinamide
A mixture of (R) -1- (3,5-difluorophenyl) ethylamine (0.1 g) and benzaldehyde (0.068 g) in methanol (1 mL) was stirred with heating under reflux for 20 minutes. After the reaction mixture was cooled to room temperature, 4-tert-butoxycarbonylaminonicotinic acid (0.152 g) and 4-phenylcyclohexen-1-yl isocyanide (0.116 g) were added, and the mixture was stirred with heating under reflux for 2 days. The reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (2 mL) was added to the resulting residue and dissolved. Water (14 μL) and 4 mol / L hydrogen chloride 1,4-dioxane solution (0.64 mL) were added to the mixture, and the mixture was stirred at room temperature for 1.5 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 55 / 45-75 / 25-100 / 0) to give 4-tert-butoxycarbonylamino- {N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] carbamoyl} nicotinamide (0.167 g) was obtained. Of 4-tert-butoxycarbonylamino- {N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] carbamoyl} nicotinamide (0.167 g) Trifluoroacetic acid (1 mL) was added to a methylene chloride (1 mL) solution, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. Water and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the crude product was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.04 g). The structural formula and physical property values of the title compound are shown in Table 74.
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000093
試験例１
Ｉｃｉｌｉｎ誘発ｗｅｔ－ｄｏｇ　ｓｈａｋｅ抑制作用確認試験 Test example 1
Icilin-induced wet-dog shake inhibitory action test
　試験化合物をジメチルアセトアミド（和光純薬）に溶解し、ジメチルアセトアミドの含量が５％となるよう０．５％メチルセルロース溶液（和光純薬）を添加して溶解液あるいは懸濁液を調製後、雌性ＳＤラットに３または１０ｍｇ／ｋｇ／５ｍＬとなるように経口投与した。１時間後にポリエチレングリコール４００（和光純薬）に溶解したＩｃｉｌｉｎ（１ｍｇ／ｋｇ）を腹腔内投与して、ｗｅｔ－ｄｏｇ　ｓｈａｋｅを惹起した。Ｉｃｉｌｉｎ投与５分後から、５分間のｗｅｔ－ｄｏｇ　ｓｈａｋｅをカウントした。比較試験として、媒体（ジメチルアセトアミド（和光純薬）：０．５％メチルセルロース溶液（和光純薬）＝５：９５の混合液）を同様に投与し、このときのｗｅｔ－ｄｏｇ　ｓｈａｋｅの回数を同様にカウントした。試験化合物のｗｅｔ－ｄｏｇ　ｓｈａｋｅ抑制率として、次式より算出した：［１－（試験化合物投与のｗｅｔ－ｄｏｇ　ｓｈａｋｅのカウント／媒体投与のｗｅｔ－ｄｏｇ　ｓｈａｋｅのカウント）］×１００。結果を表７５に示した。 Dissolve the test compound in dimethylacetamide (Wako Pure Chemical Industries), add 0.5% methylcellulose solution (Wako Pure Chemical Industries) so that the content of dimethylacetamide is 5%, prepare a solution or suspension, SD rats were orally administered at 3 or 10 mg / kg / 5 mL. One hour later, Icilin (1 mg / kg) dissolved in polyethylene glycol 400 (Wako Pure Chemical Industries, Ltd.) was intraperitoneally administered to induce wet-dog shake. From 5 minutes after the administration of Icilin, 5 minutes of wet-dog shake were counted. As a comparative test, a medium (dimethylacetamide (Wako Pure Chemical Industries): 0.5% methylcellulose solution (Wako Pure Chemical Industries) = 5:95 mixed solution) was similarly administered, and the number of wet-dog shakes at this time was the same. Counted. The wet-dog shake inhibition rate of the test compound was calculated from the following formula: [1- (wet-dog shake count for test compound administration / wet-dog shake count for vehicle administration)] × 100. The results are shown in Table 75.
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000094
試験例２
酢酸誘発排尿筋過活動膀胱の排尿間隔に対する延長作用確認試験 Test example 2
A test to confirm the prolongation of acetic acid-induced detrusor overactive bladder urination interval
　ウレタン（シグマ）を２５％ｗ／ｖとなるように純水に溶解し、雌性ＳＤラットに１．２５ｇ／ｋｇとなるよう皮下投与し麻酔した。このラットの膀胱及び大腿静脈にカテーテルを挿入し、膀胱カテーテルをシリンジポンプと圧トランスデューサーに接続した。圧トランスデューサーを用いて膀胱内圧をモニターすると同時に、０．２５％酢酸／生理食塩水溶液を３．６ｍｌ／時で膀胱へ持続注入し、排尿筋過活動を惹起した。静脈カテーテルから試験化合物をジメチルアセトアミドと生理食塩水の混合液（２０：８０）に溶解した溶液を投与し、投与直前の排尿３回の間隔の平均値を１００％としたときの、投与直後３回の間隔の平均値を、排尿間隔延長率（Elongation of micturition interval(%)）として算出した。投与量及び結果を表７６に示した。 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. Immediately after administration, 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 intervals was calculated as the urination interval extension rate (Elongation of micturition interval (%)). The dosage and results are shown in Table 76.
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000095
　表７５に示したように、本発明の化合物は強力なTRPM8阻害作用を示した。更に、表７６に示したように、本発明の化合物は排尿間隔に対する延長作用を有し、排尿筋過活動の抑制に有効であることが判明した。 As shown in Table 75, the compound of the present invention exhibited a strong TRPM8 inhibitory action. Furthermore, as shown in Table 76, it was found that the compound of the present invention has a prolonging effect on the urination interval and is effective in suppressing detrusor overactivity.
　本発明の化合物は、強力なTRPM8阻害作用を有するので、TRPM8の活性化に起因する疾患または症状の治療若しくは予防用医薬組成物、中でも、下部尿路症状（ＬＵＴＳ）、特に、過活動膀胱（ＯＡＢ）の治療若しくは予防用医薬組成物として有用である。 Since the compound of the present invention has a potent TRPM8 inhibitory action, it is a pharmaceutical composition for treating or preventing a disease or symptom caused by activation of TRPM8, particularly lower urinary tract symptoms (LUTS), particularly overactive bladder ( It is useful as a pharmaceutical composition for treating or preventing OAB).

Claims (17)

  1. 一般式（Ｉ）で表される化合物、またはその薬理学的に許容される塩
    Figure JPOXMLDOC01-appb-C000001
     〔式中、
    Ａ１は、以下のａ）～ｄ）：
    ａ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
    ｂ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される５員ヘテロ環、
    ｃ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される６員ヘテロ環、および
    ｄ）Ｃ４－６シクロアルケニル
    からなる群から選択される基であり；
    Ａ２は、以下のｅ）～ｈ）：
    ｅ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換されるＣ６－１０アリール、
    ｆ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換される５員ヘテロ環、
    ｇ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換される６員ヘテロ環、および
    ｈ）Ｃ３－６シクロアルキル
    からなる群から選択される基であり；
    Ａ３は、以下のｉ）～ｋ）：
    ｉ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、Ｃ１－６アルコキシカルボニルフェニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
    ｊ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるヘテロ環、および
    ｋ）Ｃ３－６シクロアルキルまたはＣ４－６シクロアルケニル
    からなる群から選択される基であり；
    Ｌ１は、単結合またはＣ１－６アルキレンであり；
    Ｒ１およびＲ２は、互いに独立して、水素原子、Ｃ１－６アルキルまたはヒドロキシＣ１－６アルキルであり（但し、Ｒ１およびＲ２が同時にＣ１－６アルキルである場合、互いに結合し環を形成していてもよく、Ｒ１およびＲ２が同時に水素原子ではない）； 
    Ｌ２は、単結合である。〕。     Compound represented by general formula (I) or a pharmacologically acceptable salt thereof
    Figure JPOXMLDOC01-appb-C000001
     [Where,
    A 1 represents the following a) to d):
    a) unsubstituted or 1-2 groups independently selected from the group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy C 6-10 aryl substituted with a group,
    b) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 5-membered heterocycle substituted with a group,
    c) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 6-membered heterocycle substituted with a group, and d) a group selected from the group consisting of C 4-6 cycloalkenyl;
    A 2 represents the following e) to h):
    e) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl C 6-10 aryl substituted with 1 to 3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl,
    f) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl A 5-membered heterocycle substituted with 1 to 3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl,
    g) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl A 6-membered heterocycle substituted with 1-3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl, and h) C 3- A group selected from the group consisting of 6 cycloalkyl;
    A 3 represents the following i) to k):
    i) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, C 1-6 alkoxycarbonylphenyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) carboxy C -6 alkyl and C 1-6 C 6-10 aryl substituted with 1-2 groups independently selected from alkylsulfonyl,
    j) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) independent of the carboxy C 1-6 alkyl and C 1-6 alkylsulfonyl Heterocycle substituted with 1-2 groups selected, and k) C 3-6 cycloalkyl, or C 4-6 group selected from the group consisting of cycloalkenyl;
    L 1 is a single bond or C 1-6 alkylene;
    R 1 and R 2 are independently of each other a hydrogen atom, C 1-6 alkyl or hydroxy C 1-6 alkyl (provided that when R 1 and R 2 are simultaneously C 1-6 alkyl, they are bonded to each other) And may form a ring, and R 1 and R 2 are not hydrogen atoms at the same time);
    L 2 is a single bond. ].
  2. Ｌ１が単結合である、請求項１記載の化合物またはその薬理学的に許容される塩。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is a single bond.
  3. Ｒ１がメチルである、請求項２記載の化合物またはその薬理学的に許容される塩。 The compound of Claim 2 whose R < 1 > is methyl, or its pharmacologically acceptable salt.
  4. Ａ２が、以下のｅ1）およびｆ１）：
    ｅ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるフェニル、および
    ｆ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるチエニル
    からなる群から選択される基である請求項３記載の化合物またはその薬理学的に許容される塩。     A 2 is, following e1) and f1):
    e1) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3 Phenyl substituted with 1 to 3 groups independently selected from -6 cycloalkoxy, and f1) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo From the group consisting of thienyl substituted with 1 to 3 groups independently selected from C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3-6 cycloalkoxy The compound or a pharmacologically acceptable salt thereof according to claim 3, which is a selected group.
  5. 式（ＩＩ）：
    Figure JPOXMLDOC01-appb-C000002
     〔式中、
    Ａ１が、以下のａ）～ｄ）：
    ａ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
    ｂ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される５員ヘテロ環、
    ｃ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される６員ヘテロ環、および
    ｄ）Ｃ４－６シクロアルケニル
    からなる群から選択される基であり；
    Ａ２が、以下のｅ1）およびｆ１）：
    ｅ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるフェニル、および
    ｆ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるチエニル
    からなる群から選択される基であり；
    Ａ３は、以下のｉ）～ｋ）：
    ｉ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、Ｃ１－６アルコキシカルボニルフェニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
    ｊ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるヘテロ環、および
    ｋ）Ｃ３－６シクロアルキルまたはＣ４－６シクロアルケニル
    からなる群から選択される基である。〕
    で表される、請求項４記載の化合物またはその薬理学的に許容される塩。     Formula (II):
    Figure JPOXMLDOC01-appb-C000002
     [Where,
    A 1 is the following a) to d):
    a) unsubstituted or 1-2 groups independently selected from the group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy C 6-10 aryl substituted with a group,
    b) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 5-membered heterocycle substituted with a group,
    c) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 6-membered heterocycle substituted with a group, and d) a group selected from the group consisting of C 4-6 cycloalkenyl;
    A 2 is, following e1) and f1):
    e1) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3 Phenyl substituted with 1 to 3 groups independently selected from -6 cycloalkoxy, and f1) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo From the group consisting of thienyl substituted with 1 to 3 groups independently selected from C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C 3-6 cycloalkoxy A selected group;
    A 3 represents the following i) to k):
    i) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, C 1-6 alkoxycarbonylphenyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) carboxy C -6 alkyl and C 1-6 C 6-10 aryl substituted with 1-2 groups independently selected from alkylsulfonyl,
    j) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) independent of the carboxy C 1-6 alkyl and C 1-6 alkylsulfonyl Heterocycle substituted with 1-2 groups selected, and k) a C 3-6 cycloalkyl or C 4-6 group selected from the group consisting of cycloalkenyl. ]
    The compound of Claim 4 represented by these, or its pharmacologically acceptable salt.
  6. Ａ１が、以下のａ１）～ｃ１）およびｄ）：
    ａ１）非置換または１～２個のハロゲン原子で置換されるフェニル、
    ｂ１）非置換または１個のＣ１－６アルキルで置換される５員ヘテロ環、
    ｃ１）非置換の６員ヘテロ環、および
    ｄ）Ｃ４－６シクロアルケニル
    からなる群から選択される基である、請求項５記載の化合物またはその薬理学的に許容される塩。     A 1 is the following a1) to c1) and d):
    a1) phenyl which is unsubstituted or substituted by 1 to 2 halogen atoms,
    b1) a 5-membered heterocycle which is unsubstituted or substituted by one C 1-6 alkyl,
    6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, which is a group selected from the group consisting of c1) an unsubstituted 6-membered heterocycle, and d) C 4-6 cycloalkenyl.
  7. Ａ３が、以下のｉ１）、ｊ１）およびｋ）：
    ｉ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボニル、（Ｃ１－６アルキル）カルボニルアミノ、および（Ｃ１－６アルキル）カルボキシＣ１－６アルキルから独立して選択される１～２個の基で置換されるフェニル、
    ｊ１）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルコキシ、シアノ、およびアミノから選択される１個の基で置換されるヘテロ環、および
    ｋ）Ｃ３－６シクロアルキルまたはＣ４－６シクロアルケニル
    からなる群から選択される基である、請求項６記載の化合物またはその薬理学的に許容される塩。     A 3 is, following i1), j1) and k):
    i1) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkoxy, amino, Mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carbonyl, (C 1-6 alkyl) carbonylamino, and (C 1-6 alkyl) carboxy C 1 Phenyl substituted with 1-2 groups independently selected from -6 alkyl,
    j1) Heterocycle which is unsubstituted or substituted by one group selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, cyano, and amino And k) a compound selected from the group consisting of C 3-6 cycloalkyl or C 4-6 cycloalkenyl, or a pharmaceutically acceptable salt thereof.
  8. Ａ１が以下のａ２）およびc２）：
    ａ２）非置換または１～２個のハロゲン原子で置換されるフェニル、および
    ｃ２）非置換のピリジル
    からなる群から選択される基であり；
    Ａ２が非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルキルおよびＣ３－６シクロアルコキシから独立して選択される１～３個の基で置換されるフェニルであり；
    Ａ３が、以下のｉ２）およびｊ２）：
    ｉ２）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、Ｃ３－６シクロアルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボニル、（Ｃ１－６アルキル）カルボニルアミノ、および（Ｃ１－６アルキル）カルボキシＣ１－６アルキルから独立して選択される１～２個の基で置換されるフェニル、および
    ｊ２）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルコキシ、シアノおよびアミノから選択される１個の基で置換されるピリジル
    からなる群から選択される基である、請求項７記載の化合物またはその薬理学的に許容される塩。     A 1 the following a2) and c2):
    a2) a group selected from the group consisting of unsubstituted or substituted with 1 to 2 halogen atoms, and c2) an unsubstituted pyridyl;
    A 2 is unsubstituted or consists of the following: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkyl and C Phenyl substituted with 1 to 3 groups independently selected from 3-6 cycloalkoxy;
    A 3 is, following i2) and j2):
    i2) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, C 3-6 cycloalkoxy, amino, Mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carbonyl, (C 1-6 alkyl) carbonylamino, and (C 1-6 alkyl) carboxy C 1 Phenyl substituted with 1-2 groups independently selected from -6 alkyl, and j2) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, haloC C1-6 alkoxy, a group selected from the group consisting of pyridyl substituted with one group selected from cyano and amino, 7. a compound according Salts other is a pharmacologically acceptable.
  9. Ａ１が非置換のフェニルまたはピリジルであり；
    Ａ２が非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、およびシアノから独立して選択される１～３個の基で置換されるフェニルであり；
    Ａ３が、以下のｉ３）およびｊ３）：
    ｉ３）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、アミノ、およびヒドロキシから独立して選択される１～２個の基で置換されるフェニル、および
    ｊ３）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、およびアミノから選択される１個の基で置換されるピリジル
    からなる群から選択される基である、請求項８記載の化合物またはその薬理学的に許容される塩。     A 1 is unsubstituted phenyl or pyridyl;
    A group in which A 2 is unsubstituted or consists of: 1 to 3 groups independently selected from a halogen atom, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano Substituted phenyl;
    A 3 is, following i3) and j3):
    i3) unsubstituted or group consisting of: phenyl substituted by 1-2 groups independently selected from halogen atom, C 1-6 alkyl, amino, and hydroxy, and j3) unsubstituted or from 9. The compound of claim 8, which is a group selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, and pyridyl substituted with one group selected from amino Or a pharmacologically acceptable salt thereof.
  10. Ａ２が以下の基：
    Figure JPOXMLDOC01-appb-C000003
     である（（＊）は結合位置を表す。）、請求項９記載の化合物またはその薬理学的に許容される塩。     A 2 is the following groups:
    Figure JPOXMLDOC01-appb-C000003
     ((*) Represents a binding position) or the pharmacologically acceptable salt thereof according to claim 9.
  11. 下記の群から選択される請求項１記載の化合物またはその薬理学的に許容される塩：
    Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－クロロフェニル）エチル]ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－クロロフェニル）エチル］－２－フルオロベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－フルオロ－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－ジフルオロメトキシフェニル）エチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－クロロ－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－フルオロ－Ｎ－［（Ｒ）－１－（３－フルオロフェニル）エチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－３－フルオロ－Ｎ－［（Ｒ）－１－（３－フルオロフェニル）エチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－４－フルオロ－Ｎ－［（Ｒ）－１－（３－フルオロフェニル）エチル］ベンズアミド、
    Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－フルオロフェニル）エチル]ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－クロロ－５－フルオロフェニル）エチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]シクロヘキセン－１－イルカルボキサミド、
    ２－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]ニコチンアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－｛（Ｒ）－１－［３－（１，１－ジフルオロエチル）フェニル］エチル｝ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルピリジン－３－イルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]－２－ヒドロキシベンズアミド、
    ２－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]－２－ヒドロキシベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３，５－ジフルオロフェニル）エチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]－２－メトキシニコチンアミド、
    Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－メトキシフェニル）エチル]ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(５－クロロ－２－フルオロフェニル)エチル]ベンズアミドおよび
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－クロロ－５－フルオロフェニル）エチル］ベンズアミド。     The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following group:
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1-phenylethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] -2-fluorobenzamide,
    N-[(R) -carbamoylphenylmethyl] -2-fluoro-N-[(R) -1-phenylethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-difluoromethoxyphenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -2-chloro-N-[(R) -1-phenylethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -2-fluoro-N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -3-fluoro-N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -4-fluoro-N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chloro-5-fluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] cyclohexen-1-ylcarboxamide;
    2-amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] nicotinamide,
    N-[(R) -carbamoylphenylmethyl] -N-{(R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl} benzamide,
    N-[(R) -carbamoylpyridin-3-ylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -2-hydroxybenzamide,
    2-amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -2-hydroxybenzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] -2-methoxynicotinamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-methoxyphenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (5-chloro-2-fluorophenyl) ethyl] benzamide and N-[(R) -carbamoylphenylmethyl] -N- [ (R) -1- (3-Chloro-5-fluorophenyl) ethyl] benzamide.
  12. 下記の群から選択される請求項１記載の化合物またはその薬理学的に許容される塩：
    Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－メトキシフェニル）エチル]ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(５－クロロ－２－フルオロフェニル)エチル]ベンズアミド、
    Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－クロロフェニル）エチル]ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－クロロフェニル）エチル］－２－フルオロベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－ジフルオロメトキシフェニル）エチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－クロロ－Ｎ－［（Ｒ）－１－フェニルエチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－２－フルオロ－Ｎ－［（Ｒ）－１－（３－フルオロフェニル）エチル］ベンズアミド、
    Ｎ－[（Ｒ）－カルバモイルフェニルメチル]－Ｎ－[（Ｒ）－１－（３－フルオロフェニル）エチル]ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３，５－ジフルオロフェニル）エチル］ベンズアミド、
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－［（Ｒ）－１－（３－クロロ－５－フルオロフェニル）エチル］ベンズアミド、
    ２－アミノ－Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－[(Ｒ)－１－(３，５－ジフルオロフェニル)エチル]ニコチンアミドおよび
    Ｎ－［（Ｒ）－カルバモイルフェニルメチル］－Ｎ－｛（Ｒ）－１－［３－（１，１－ジフルオロエチル）フェニル］エチル｝ベンズアミド。     The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following group:
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-methoxyphenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (5-chloro-2-fluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1-phenylethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chlorophenyl) ethyl] -2-fluorobenzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-difluoromethoxyphenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -2-chloro-N-[(R) -1-phenylethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -2-fluoro-N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-fluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] benzamide,
    N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3-chloro-5-fluorophenyl) ethyl] benzamide,
    2-Amino-N-[(R) -carbamoylphenylmethyl] -N-[(R) -1- (3,5-difluorophenyl) ethyl] nicotinamide and N-[(R) -carbamoylphenylmethyl]- N-{(R) -1- [3- (1,1-difluoroethyl) phenyl] ethyl} benzamide.
  13. 請求項１～１２の何れか一項に記載の化合物またはその薬理学的に許容される塩を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.
  14. 求心性神経の過剰興奮または障害に起因する疾患または症状の治療若しくは予防用の、請求項１３記載の医薬組成物。 14. A pharmaceutical composition according to claim 13 for the treatment or prevention of a disease or condition resulting from hyperexcitement or damage of afferent nerves.
  15. 請求項１～１２の何れか一項に記載の化合物またはその薬理学的に許容される塩を有効量投与することからなる、求心性神経の過剰興奮または障害に起因する疾患または症状の治療若しくは予防方法。 Treatment of a disease or condition caused by hyperexcitability or disorder of afferent nerves, comprising administering an effective amount of the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof, or Prevention method.
  16. 求心性神経の過剰興奮または障害に起因する疾患または症状の治療若しくは予防用の医薬組成物を製造するための、請求項１～１２の何れか一項に記載の化合物またはその薬理学的に許容される塩の使用。 The compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for treating or preventing a disease or symptom caused by hyperexcitation or disorder of afferent nerves. Salt used.
  17. 一般式（Ｉ）で表される化合物、またはその薬理学的に許容される塩
    Figure JPOXMLDOC01-appb-C000004
     〔式中、
    Ａ１は、以下のａ）～ｄ）：
    ａ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
    ｂ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される５員ヘテロ環、
    ｃ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキルおよびハロＣ１－６アルコキシから独立して選択される１～２個の基で置換される６員ヘテロ環、および
    ｄ）Ｃ４－６シクロアルケニル
    からなる群から選択される基であり；
    Ａ２は、以下のｅ）～ｈ）：
    ｅ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換されるＣ６－１０アリール、
    ｆ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換される５員ヘテロ環、
    ｇ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、モノ（ジ）Ｃ１－６アルキルアミノ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシおよびＣ１－６アルコキシカルボニルから独立して選択される１～３個の基で置換される６員ヘテロ環、および
    ｈ）Ｃ３－６シクロアルキル
    からなる群から選択される基であり；
    Ａ３は、以下のｉ）～ｋ）：
    ｉ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、Ｃ１－６アルコキシカルボニルフェニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるＣ６－１０アリール、
    ｊ）非置換または以下からなる群：ハロゲン原子、Ｃ１－６アルキル、Ｃ１－６アルコキシ、ハロＣ１－６アルキル、ハロＣ１－６アルコキシ、シアノ、ニトロ、Ｃ３－６シクロアルキル、Ｃ３－６シクロアルコキシ、フェニル、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ、ヒドロキシＣ１－６アルキル、（Ｃ１－６アルキル）カルボキシ、カルバモイル、（Ｃ１－６アルキル）カルボニル、Ｃ１－６アルコキシカルボニル、Ｃ１－６アルコキシカルボニルＣ２－６アルケニル、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ、（Ｃ１－６アルキル）カルボニルアミノ、Ｃ１－６アルキルスルホニルアミノ、（Ｃ１－６アルキル）カルボキシＣ１－６アルキルおよびＣ１－６アルキルスルホニルから独立して選択される１～２個の基で置換されるヘテロ環、および
    ｋ）Ｃ３－６シクロアルキルまたはＣ４－６シクロアルケニル
    からなる群から選択される基であり；
    Ｌ１は、単結合またはＣ１－６アルキレンであり；
    Ｒ１およびＲ２は、互いに独立して、水素原子、Ｃ１－６アルキルまたはヒドロキシＣ１－６アルキルであり（但し、Ｒ１およびＲ２が同時にＣ１－６アルキルである場合、互いに結合し環を形成していてもよい）； 
    Ｌ２は、単結合、Ｃ１－６アルキレンまたは下記の式：
    Figure JPOXMLDOC01-appb-C000005
     である（（＊）は結合位置を表す。）。〕を含有する、痛み、寒冷性鼻炎、かゆみ、しびれ、蕁麻疹、過活動膀胱、排尿筋過活動、夜間頻尿、間質性膀胱炎、膀胱痛症候群、過知覚膀胱症候群、尿失禁または尿道狭窄の治療若しくは予防用医薬組成物。     Compound represented by general formula (I) or a pharmacologically acceptable salt thereof
    Figure JPOXMLDOC01-appb-C000004
     [Where,
    A 1 represents the following a) to d):
    a) unsubstituted or 1-2 groups independently selected from the group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy C 6-10 aryl substituted with a group,
    b) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 5-membered heterocycle substituted with a group,
    c) Unsubstituted or 1 to 2 groups independently selected from the group consisting of: a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy A 6-membered heterocycle substituted with a group, and d) a group selected from the group consisting of C 4-6 cycloalkenyl;
    A 2 represents the following e) to h):
    e) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl C 6-10 aryl substituted with 1 to 3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl,
    f) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl A 5-membered heterocycle substituted with 1 to 3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl,
    g) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, mono (di) C 1-6 alkyl A 6-membered heterocycle substituted with 1-3 groups independently selected from amino, C 3-6 cycloalkyl, C 3-6 cycloalkoxy and C 1-6 alkoxycarbonyl, and h) C 3- A group selected from the group consisting of 6 cycloalkyl;
    A 3 represents the following i) to k):
    i) unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, C 1-6 alkoxycarbonylphenyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) carboxy C -6 alkyl and C 1-6 C 6-10 aryl substituted with 1-2 groups independently selected from alkylsulfonyl,
    j) Unsubstituted or group consisting of: halogen atom, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, nitro, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, amino, mono (di) C 1-6 alkylamino, hydroxy, hydroxy C 1-6 alkyl, (C 1-6 alkyl) carboxy, carbamoyl, (C 1-6 alkyl) carbonyl C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 2-6 alkenyl, C 1-6 alkoxycarbonyl C 1-6 alkoxy, (C 1-6 alkyl) carbonylamino, C 1-6 alkylsulfonylamino, (C 1-6 alkyl) independent of the carboxy C 1-6 alkyl and C 1-6 alkylsulfonyl Heterocycle substituted with 1-2 groups selected, and k) C 3-6 cycloalkyl, or C 4-6 group selected from the group consisting of cycloalkenyl;
    L 1 is a single bond or C 1-6 alkylene;
    R 1 and R 2 are independently of each other a hydrogen atom, C 1-6 alkyl or hydroxy C 1-6 alkyl (provided that when R 1 and R 2 are simultaneously C 1-6 alkyl, they are bonded to each other) And may form a ring);
    L 2 represents a single bond, C 1-6 alkylene or the following formula:
    Figure JPOXMLDOC01-appb-C000005
     ((*) Represents a bonding position). ), Pain, cold rhinitis, itching, numbness, urticaria, overactive bladder, detrusor overactivity, nocturia, interstitial cystitis, bladder pain syndrome, hypersensitive bladder syndrome, urinary incontinence or urethra A pharmaceutical composition for treating or preventing stenosis.
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