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WO2015108136A1 - Dérivé de glycinamide substitué en alpha - Google Patents

Dérivé de glycinamide substitué en alpha Download PDF

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Publication number
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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English (en)
Japanese (ja)
Inventor
秀明 平澤
直裕 川村
小林　淳一
哲治 小澤
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Kissei Pharmaceutical Co Ltd
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Kissei Pharmaceutical Co Ltd
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Priority to JP2015557881A priority Critical patent/JP6692162B2/ja
Publication of WO2015108136A1 publication Critical patent/WO2015108136A1/fr
Anticipated expiration legal-status Critical
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    • 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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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—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
    • 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
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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

La présente invention concerne un nouveau dérivé de glycinamide substitué en alpha ou l'un de ses sels pharmacologiquement acceptable; une composition pharmaceutique contenant le composé ou le sel pharmacologiquement acceptable; et une utilisation à des fins médicales du composé ou du sel pharmacologiquement acceptable. La présente invention concerne un composé présentant une activité inhibitrice du TRPM8, représenté par la formule générale (I) [dans laquelle A1 représente un groupe aryle C6-10 ou similaire; A2 représente un groupe aryle C6-10 ou similaire; A3 représente un groupe aryle C6-10 ou similaire; L1 représente une liaison simple ou similaire; R1 représente un groupe alkyle C1-6 ou similaire; R2 représente un atome d'hydrogène ou similaire; et L2 représente une liaison simple ou similaire] ou un sel pharmacologiquement acceptable de ce dernier. Selon la présente invention, le composé (I) peut être utilisé dans une composition pharmacologique destinée au traitement ou à la prévention de maladies ou d'états de santé associés à une excitation excessive ou une lésion d'un nerf afférent.
PCT/JP2015/051031 2014-01-17 2015-01-16 Dérivé de glycinamide substitué en alpha Ceased WO2015108136A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
JP2000178255A (ja) * 1998-12-18 2000-06-27 Adir 新規イミダゾリン化合物、その製造方法、及びそれらを含有する医薬組成物
JP2006508055A (ja) * 2002-08-28 2006-03-09 ファイザー・インク オキシトシンインヒビター
WO2012120398A1 (fr) * 2011-03-04 2012-09-13 Pfizer Limited Dérivés de carboxamide substitués par aryle en tant que modulateurs de trpm8
JP2013537887A (ja) * 2010-09-08 2013-10-07 ウニヴェルスィダッド ミゲル エルナンデス デ エルチェ ドライアイの治療用医薬組成物

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US20040213264A1 (en) * 2003-04-25 2004-10-28 Nortel Networks Limited Service class and destination dominance traffic management
WO2007017093A1 (fr) * 2005-08-04 2007-02-15 Bayer Healthcare Ag Derives amides d'acide 2-benzyloxy-benzoique substitue

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JP2000178255A (ja) * 1998-12-18 2000-06-27 Adir 新規イミダゾリン化合物、その製造方法、及びそれらを含有する医薬組成物
JP2006508055A (ja) * 2002-08-28 2006-03-09 ファイザー・インク オキシトシンインヒビター
JP2013537887A (ja) * 2010-09-08 2013-10-07 ウニヴェルスィダッド ミゲル エルナンデス デ エルチェ ドライアイの治療用医薬組成物
WO2012120398A1 (fr) * 2011-03-04 2012-09-13 Pfizer Limited Dérivés de carboxamide substitués par aryle en tant que modulateurs de trpm8

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QI LIN ET AL: "Small Molecule Macroarray Construction via Ugi Four-Component Reactions", ORGANIC LETTERS, vol. 7, no. 20, 2005, pages 4455 - 4458, XP055213473 *

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