WO2022050385A1 - フェノール誘導体 - Google Patents
フェノール誘導体 Download PDFInfo
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- WO2022050385A1 WO2022050385A1 PCT/JP2021/032483 JP2021032483W WO2022050385A1 WO 2022050385 A1 WO2022050385 A1 WO 2022050385A1 JP 2021032483 W JP2021032483 W JP 2021032483W WO 2022050385 A1 WO2022050385 A1 WO 2022050385A1
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- optionally substituted
- pharmaceutically acceptable
- acceptable salt
- compound according
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- 150000002989 phenols Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 226
- 150000003839 salts Chemical class 0.000 claims abstract description 115
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 88
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 80
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 55
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 14
- 125000002723 alicyclic group Chemical group 0.000 claims description 131
- -1 4'-{[2- (3,4-dimethoxyphenyl) ethyl] carbamoyl} [1,1'-biphenyl] -4-yl Chemical group 0.000 claims description 119
- 125000003118 aryl group Chemical group 0.000 claims description 115
- 125000001424 substituent group Chemical group 0.000 claims description 77
- MIARGTDEPIMNPQ-UHFFFAOYSA-N 2-(4-hydroxy-3-methoxyphenyl)acetamide Chemical compound COC1=CC(CC(N)=O)=CC=C1O MIARGTDEPIMNPQ-UHFFFAOYSA-N 0.000 claims description 66
- 208000019505 Deglutition disease Diseases 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
- 101150016206 Trpv1 gene Proteins 0.000 claims description 35
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 34
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 33
- 125000005843 halogen group Chemical group 0.000 claims description 33
- 239000003795 chemical substances by application Substances 0.000 claims description 31
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 29
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 25
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 25
- 125000004104 aryloxy group Chemical group 0.000 claims description 24
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 23
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 18
- 208000035475 disorder Diseases 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
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- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 15
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- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 8
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 230000000069 prophylactic effect Effects 0.000 claims description 8
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- DJKKZDMKDAMKOM-UHFFFAOYSA-N (3-phenylphenyl) 2-methylpropanoate Chemical compound CC(C)C(=O)OC1=CC=CC(C=2C=CC=CC=2)=C1 DJKKZDMKDAMKOM-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
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- 229940127557 pharmaceutical product Drugs 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- ZBONBGOYILUGCL-UHFFFAOYSA-N 2,2-dimethylpropanoate Chemical compound CC(C)([CH2+])C([O-])=O ZBONBGOYILUGCL-UHFFFAOYSA-N 0.000 claims description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 2
- 229940095102 methyl benzoate Drugs 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- PIZOACXKIKXRDJ-UHFFFAOYSA-N phenyl 2-methylpropanoate Chemical compound CC(C)C(=O)OC1=CC=CC=C1 PIZOACXKIKXRDJ-UHFFFAOYSA-N 0.000 claims 1
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 claims 1
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- 238000006243 chemical reaction Methods 0.000 description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- 239000002585 base Substances 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 239000000243 solution Substances 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 40
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- 230000009747 swallowing Effects 0.000 description 34
- 238000012360 testing method Methods 0.000 description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
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- 238000004519 manufacturing process Methods 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 239000000203 mixture Substances 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 230000035484 reaction time Effects 0.000 description 20
- 125000005553 heteroaryloxy group Chemical group 0.000 description 19
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 17
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 17
- 241000700159 Rattus Species 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 230000011514 reflex Effects 0.000 description 17
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 16
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 229910052763 palladium Inorganic materials 0.000 description 15
- 239000002994 raw material Substances 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
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- 125000000217 alkyl group Chemical group 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 14
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 12
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- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 12
- 230000003287 optical effect Effects 0.000 description 12
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000011156 evaluation Methods 0.000 description 11
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 10
- 239000003638 chemical reducing agent Substances 0.000 description 10
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- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
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- 229910052723 transition metal Inorganic materials 0.000 description 10
- 150000003624 transition metals Chemical class 0.000 description 10
- HEGSODWIWXKPQE-UHFFFAOYSA-N 2-(4-hydroxy-3-methoxyphenyl)-N-[3-(4-oxocyclohexyl)phenyl]acetamide Chemical compound COC(C=C(CC(NC1=CC=CC(C(CC2)CCC2=O)=C1)=O)C=C1)=C1O HEGSODWIWXKPQE-UHFFFAOYSA-N 0.000 description 9
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- 0 *c1cccc(*)c1 Chemical compound *c1cccc(*)c1 0.000 description 8
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- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 6
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
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- 101000633069 Homo sapiens Transient receptor potential cation channel subfamily V member 1 Proteins 0.000 description 4
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 3
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Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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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- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- C07D309/02—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
- C07D309/04—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon 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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- C07D333/02—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
- C07D333/24—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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- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to a phenol derivative useful as a medicine and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them as an active ingredient, or a therapeutic agent for dysphagia capable of improving the swallowing reflex.
- the swallowing movement is the pre-stage of recognizing food, the preparatory stage of ingesting food into the oral cavity and chewing, the oral stage of sending food to the pharynx with the tongue, and the pharyngeal stage of inducing the swallowing reflex by the stimulation of food to send food to the esophagus. It consists of five phases of the esophagus, which deliver food from the esophagus to the stomach by masticatory movement. If any of these movements is impaired, smooth swallowing will not occur and dysphagia will occur. Abnormalities and decreased swallowing reflexes in the pharyngeal stage are caused by various drugs, cerebrovascular diseases, neurodegenerative diseases, and aging (Non-Patent Documents 1 and 2).
- dysphagia As a treatment method for dysphagia, swallowing guidance, rehabilitation, and surgical treatment are performed. It is recommended to select a highly viscous diet for delaying the swallowing reflex. Rehabilitation is used as a method in which cold pressure stimulation induces a swallowing reflex, and stretching of swallowing-related organs and training of swallowing patterns are performed. In all cases, the effectiveness of randomized controlled trials has been poorly verified, and further studies are needed on their effectiveness. If the above method does not work, surgery to improve swallowing function is considered, but it should be performed carefully because it is invasive and may not produce the expected effect. Therefore, there is a need for a treatment method that can clearly show its effectiveness for dysphagia.
- Non-Patent Document 3 Angiotensin converting enseme (ACE) inhibitor (Non-Patent Document 3), cilostazol (Non-Patent Document 4), nicergoline (Non-Patent Document 5), Hangekobokuto (Non-Patent Document 5) have been reported to have an improving effect on the swallowing reflex. Document 6) and the like. These tend to induce swallowing reflex by increasing the amount of substance P released in the periphery, and as a result, a preventive effect on pneumonia is expected, but the effectiveness is uncertain. Therefore, it is desired to create a therapeutic drug for dysphagia.
- ACE Angiotensin converting enseme
- TRPV1 agonist for example, the compound described in Patent Document 1-5 is disclosed, but it has also been reported that there is a possibility of side effects such as irritation and hypothermia due to systemic administration (Non-Patent Document). 8, 9). Therefore, it is desired to create a TRPV1 agonist having excellent safety.
- An object of the present disclosure is to provide a compound that improves the swallowing reflex and has high safety, which is useful as a therapeutic agent for dysphagia.
- the compound represented by the following formula (1) has TRPV1 operability, exhibits an improving effect on dysphagia, and also has ante-drug-like properties.
- the disclosure has been completed.
- a phenol derivative represented by the following formula (1) (hereinafter, may be referred to as “the compound of the present disclosure”) is provided.
- R 1 represents a hydrogen atom, a optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkyl carbonyl group or an optionally substituted C 6-10 aryl carbonyl group.
- R 2 represents a methoxy group, a hydroxyl group or a hydrogen atom.
- R 3 is a hydrogen atom, a halogen atom, a optionally substituted C 1-6 alkyl group, an optionally substituted C 1-4 alkoxy group, an optionally substituted C 6-10 aryl group or formyl.
- Represents the group R4 may be substituted C 1-6 alkyl group, optionally substituted C 3-7 alicyclic group, optionally substituted C 2-6 alkenyl group, optionally substituted.
- X represents a optionally substituted C 6-10 aryl group or an optionally substituted 5-10 membered heteroaryl group.
- Y may be substituted C 6-10 aryl group, optionally substituted 5-10 membered heteroaryl group, optionally substituted C 3-7 alicyclic group or substituted.
- Q is a single bond, The compound according to Item 1 or 2 or a pharmaceutically acceptable salt thereof.
- X is a optionally substituted phenyl group or an optionally substituted 6-membered heteroaryl group. The compound according to any one of Items 1 to 3 or a pharmaceutically acceptable salt thereof.
- Y may be substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, optionally substituted C 3-7 alicyclic group or optionally substituted 4 ⁇ 7-membered non-aryl heterocyclic group, The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
- R 1 is a hydrogen atom, a C 1-6 alkyl group (the C 1-6 alkyl group is the same or different 1 to 3 substitutions selected from the group consisting of a hydroxyl group, a carboxyl group and -NR 11 R 12 ).
- R 2 represents a methoxy group, a hydroxyl group or a hydrogen atom.
- R 3 is a hydrogen atom, a halogen atom, a optionally substituted C 1-6 alkyl group, an optionally substituted C 1-4 alkoxy group, an optionally substituted C 6-10 aryl group or formyl.
- R4 may be substituted C 1-6 alkyl group, optionally substituted C 3-7 alicyclic group, optionally substituted C 2-6 alkenyl group, optionally substituted.
- Good C 2-6 alkynyl group optionally substituted C 6-10 aryl group, optionally substituted C 1-6 alkoxy group, optionally substituted C 3-7 alicyclic oxy group, Represents a optionally substituted C 6-10 aryloxy group or an optionally substituted 4- to 7-membered non-aryl heterocyclic group.
- R 4 is a 4- to 7-membered non-aryl heterocyclic group which may be substituted, the carbon atom on the non-aryl hetero ring is bonded to the carbonyl group.
- R 11 is a hydrogen atom, a optionally substituted C 1-3 alkyl group, a formyl group, an optionally substituted C 1-3 alkyl carbonyl group, an optionally substituted C 1-4 alkoxycarbonyl group. Alternatively, it represents a C 6-10 arylcarbonyl group which may be substituted.
- R 12 represents a hydrogen atom or a optionally substituted C 1-3 alkyl group.
- Y may be substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, optionally substituted C 3-7 alicyclic group or optionally substituted 4 Represents a ⁇ 7-membered non-aryl heterocyclic group
- X and Y are bonded by carbon atoms on their respective rings.
- R 3 is a hydrogen atom, The compound according to any one of Items 1 to 6 or a pharmaceutically acceptable salt thereof.
- m is 1 or 2
- m is 1,
- R 1 is a hydrogen atom, The compound according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof.
- R 2 is a methoxy group, The compound according to any one of Items 1 to 10 or a pharmaceutically acceptable salt thereof.
- L 2 is a single bond, The compound according to any one of Items 1 to 12 or a pharmaceutically acceptable salt thereof.
- X is the following formula (A), (In the formula, * represents the bond position with L 1 and ** represents the bond position with Q or Y) a is CR 8 or N, b is CR 9 or N, c is CR 10 or N, R 8 , R 9 and R 10 are independently hydrogen atom, halogen atom, cyano group, C 1-6 alkylsulfonyl group, optionally substituted C 1-6 alkyl group or substituted. Good C 1-6 alkoxy group, The compound according to any one of Items 1 to 13 or a pharmaceutically acceptable salt thereof.
- X is the formula (A), Here, (1) when a is N, b is CR 9 and c is CR 10 , and (2) when b is N, a is CR 8 and c is CR 10 . , (3) When c is N, a is CR 8 and b is CR 9 .
- X is the formula (A), Here, when c is CR 10 , (1) a is N, b is CR 9 , and (2) b is N, a is CR 8 .
- X is the formula (A), Here, c is CH, (1) a is N, b is CH, and (2) b is N, a is CH.
- X is the formula (A), Here, a, b and c are CH.
- Y is a optionally substituted phenyl group, an optionally substituted 6-membered heteroaryl group or an optionally substituted C 3-7 alicyclic group. The compound according to any one of Items 1 to 18 or a pharmaceutically acceptable salt thereof.
- Y is a optionally substituted phenyl group or an optionally substituted cyclohexyl group, The compound according to any one of Items 1 to 19 or a pharmaceutically acceptable salt thereof.
- Y is the following formula (B) or (C).
- * represents the bond position with X or Q, and ** represents the bond position with L 2 or an oxygen atom).
- R4 may be substituted C 1-6 alkyl group, optionally substituted C 3-7 alicyclic group, optionally substituted C 2-6 alkenyl group, optionally substituted.
- R4 is a optionally substituted C 1-6 alkyl group, optionally substituted C 3-7 alicyclic group or optionally substituted C 6-10 aryl group.
- R4 is a C 1-6 alkyl group, a C 3-7 alicyclic group or a C 6-10 aryl group (the C 1-6 alkyl group, a C 3-7 alicyclic group and a C 6-10 aryl group).
- R4 is a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a cyclohexylmethyl group, a phenyl group or a benzyl group (the methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a cyclohexylmethyl group, a phenyl group and a benzyl group. It may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom and a C 1-6 alkyl group).
- R4 is a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a phenyl group (the methyl group, the ethyl group, the isopropyl group, the cyclohexyl group and the phenyl group are composed of a fluorine atom, a chlorine atom and a C 1-6 alkyl group. It may be substituted with the same or different 1 to 3 substituents selected from the group).
- the compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof. Item 2.
- the compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the following compounds: 3- ⁇ 6- [2- (4-Hydroxy-3-methoxyphenyl) acetamide] pyridin-2-yl ⁇ phenyl 2-methylpropanol (Example 1), Sith-4- ⁇ 3- [2- (4-hydroxy-3-methoxyphenyl) acetamide] phenyl ⁇ cyclohexylcyclohexanecarboxylate (Example 2), 3'-[2- (4-Hydroxy-3-methoxyphenyl) acetamide] [1,1'-biphenyl] -4-ylbenzoate (Example 3), 3'-[2- (4-Hydroxy-3-methoxyphenyl) acetamide] [1,1'-biphenyl] -4-yl 2-methylpropanoate (Example 4), Sith-4- ⁇ 3- [2- (4-hydroxy-3-methoxypheny
- Item 28 Item 2.
- the compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the following compounds: 3- ⁇ 6- [2- (4-Hydroxy-3-methoxyphenyl) acetamide] pyridin-2-yl ⁇ phenyl 2-methylpropanol (Example 1), Sith-4- ⁇ 3- [2- (4-hydroxy-3-methoxyphenyl) acetamide] phenyl ⁇ cyclohexylcyclohexanecarboxylate (Example 2), Sith-4- ⁇ 3- [2- (4-hydroxy-3-methoxyphenyl) acetamide] phenyl ⁇ cyclohexyl (3-methylphenyl) acetate (Example 9), Sith-4- ⁇ 3- [2- (4-hydroxy-3-methoxyphenyl) acetamide] phenyl ⁇ cyclohexyl (2-chlorophenyl) acetate (Example 10), Sith-4-
- (Item 29) A pharmaceutical product containing the compound according to any one of Items 1 to 28 or a pharmaceutically acceptable salt thereof as an active ingredient.
- (Item 30) A therapeutic or prophylactic agent for a disorder or disease associated with TRPV1 containing the compound according to any one of Items 1 to 28 or a pharmaceutically acceptable salt thereof as an active ingredient.
- (Item 31) Item 30. The therapeutic or prophylactic agent according to Item 30, wherein the disorder or disease in which TRPV1 is involved is dysphagia.
- (Item 32) A pharmaceutical composition containing the compound according to any one of Items 1 to 28 or a pharmaceutically acceptable salt thereof.
- (Item 33) Item 32. The pharmaceutical composition according to Item 32, for treating or preventing a disorder or disease involving TRPV1.
- TRPV1 is involved, which comprises administering to a patient in need of treatment or prevention an effective therapeutic or prophylactic amount of the compound according to any one of Items 1-28 or a pharmaceutically acceptable salt thereof.
- Item 37 Item 5.
- a pharmaceutical composition comprising a combination of the compound according to any one of Items 1 to 28 or a pharmaceutically acceptable salt thereof and one or a plurality of other drugs.
- Item 39 Item 5.
- a pharmaceutical composition containing.
- the compounds of the present disclosure exhibit TRPV1 operability, they exhibit dysphagia due to various causes such as drug-induced dysphagia, dysphagia caused by neurodegenerative diseases such as Parkinson's disease, cerebrovascular disease, and aging. It is useful as a therapeutic agent for dysphagia that decreases.
- the vertical axis represents the number of swallows (times), and is shown by the average ⁇ standard error.
- the horizontal axis represents the group name (treatment drug).
- the substituent in "may be substituted” is selected from the substituent group ⁇ consisting of the following, and may be substituted with the same or different 1 to 5 substituents.
- the type of the substituent is not particularly limited, but when the atom to which the substituent is bonded is an oxygen atom, a nitrogen atom, or a sulfur atom, the atom to be bonded is limited to the carbon atom among the following substituents.
- R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g , R 13h , R 13i , R 13j and R 13k are independent hydrogen atoms, hydroxyl groups and C 1-6 alkyl groups, respectively.
- R 18a and R 18b are each independently a hydrogen atom or a C 1-6 alkyl group.
- Preferred examples of the substituent in "may be substituted” include the following substituents.
- the substituent group ⁇ is preferably preferred. 1) Halogen atom, 2) Hydroxyl group, 3) Carboxyl group, 4) Cyano group, 5) C 1-6 alkyl group, 6) C 1-6 alkoxy group, 7) C 1-6 alkylthio group, 8) C 1-6 alkylcarbonyl group, (However, each of the substituents in 5) to 8) may be substituted with the same or different 1 to 5 substituents selected from the substituent group ⁇ ).
- R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g , and R 13h are each independently a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, or a C 1-6 alkoxy group.
- R 16d , R 16e , R 16f , R 16g , R 17a and R 17b are each independently a hydrogen atom or a C 1-6 alkyl group (the groups are a hydroxyl group, a cyano group, a C 1-6 alkoxy group and-. It may be substituted with 1 to 3 substituents selected from the group consisting of NR 18a R 18b ).
- R 18a and R 18b are independent hydrogen atoms or C 1-6 alkyl groups, respectively.
- substituents in “may be substituted” include the following substituents.
- the substituent group ⁇ is more preferably 1) Halogen atom, 2) Hydroxyl group, 3) Cyano group, 4) C 1-6 alkyl group, 5) C 1-6 alkoxy group, 6) C 1-6 alkylthio group, 7) C 1-6 alkylcarbonyl group, (However, each of the substituents in 4) to 7) may be substituted with the same or different 1 to 5 substituents selected from the substituent group ⁇ ).
- each of the substituents 4) to 14 may be substituted with the same or different 1 to 5 substituents selected from the C 1-6 alkyl group and the substituent group ⁇ ).
- R 17b are each independently selected from the group consisting of a hydrogen atom or a C 1-6 alkyl group (the group is a hydroxyl group, a cyano group, a C 1-6 alkoxy group and -NR 18a R 18b ). It may be substituted with multiple substituents).
- R 18a and R 18b are independent hydrogen atoms or C 1-6 alkyl groups, respectively.
- C 1-6 means that the number of carbon atoms is 1 to 6.
- C 1-4 means that the number of carbon atoms is 1 to 4.
- Heteroatom means oxygen atom, nitrogen atom, sulfur atom, etc.
- Halogen atom means any atom other than carbon atom and hydrogen atom, and means fluorine atom, chlorine atom, bromine atom and iodine atom. Of these, fluorine atoms and chlorine atoms are preferable.
- the "halogen atom” may be referred to as "halogen”.
- the "C 1-6 alkyl” or “C 1-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
- the C 1-6 alkyl group preferably “C 1-4 alkyl group” is mentioned, and more preferably “C 1-3 alkyl group” is mentioned.
- Specific examples of the “C 1-3 alkyl group” include methyl, ethyl, propyl, 1-methylethyl and the like.
- Specific examples of the “C 1-4 alkyl group” include, for example, butyl, 1,1-dimethylethyl, 1-methylpropyl, and 2 in addition to those mentioned as specific examples of the "C 1-3 alkyl group”. -Methylpropyl and the like.
- C 1-6 alkyl group examples include, for example, pentyl, 1,1-dimethylpropyl, and 1,2-dimethylpropyl in addition to those mentioned as specific examples of the "C 1-4 alkyl group”. , 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.
- a “C 2-6 alkenyl” or “C 2-6 alkenyl group” is a linear or branched carbon atom containing 2 or more carbon-carbon double bonds. It means the unsaturated hydrocarbon group of 6.
- the "C 2-6 alkenyl group” is preferably "C 2-4 alkenyl group”.
- Specific examples of the "C 2-6 alkenyl group” include, but are not limited to, a vinyl group, a 1-propyrenyl group, a 2-propyrenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, and the like. Examples thereof include a 2-methyl-1-propyrenyl group and a 2-methyl-2-propyrenyl group.
- C 2-6 alkynyl or “C 2-6 alkynyl group” is a straight or branched chain with 2 to 6 carbon atoms having one or more carbon-carbon triple bonds. It means a saturated aliphatic hydrocarbon group.
- the "C 2-6 alkynyl group” is preferably "C 2-4 alkynyl group”.
- C 2-6 alkynyl group are not limited to these, but for example, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 1-methyl-2-propynyl group, 3 -Butynyl group, 1-pentynyl group, 1-hexynyl group and the like can be mentioned.
- the "C 3-10 alicyclic group” means a monocyclic or bicyclic monovalent non-aromatic hydrocarbon ring group having 3 to 10 carbon atoms and having a partially unsaturated bond. , Those having a partially crosslinked structure, those partially spirosized and those having one or more carbonyl structures are also included.
- the "alicyclic group” includes a cycloalkyl group, a cycloalkenyl group and a cycloalkynyl group. Examples of the “C 3-10 alicyclic group” are preferably "C 3-7 alicyclic group” and more preferably "C 5-6 alicyclic group”.
- C 5-6 alicyclic group examples include cyclopentyl, cyclohexyl and the like.
- Specific examples of the "C 3-7 alicyclic group” include, for example, cyclopropyl, cyclobutyl, cycloheptyl and the like in addition to those mentioned as specific examples of the "C 5-6 alicyclic group”.
- Specific examples of the "C 3-10 alicyclic group” include, for example, cyclooctyl, cyclononyl, cyclodecyl, and adamantyl, in addition to those mentioned as specific examples of the "C 3-7 alicyclic group”. ..
- C 3-10 alicyclic group also includes a compound fused with an aromatic ring.
- Specific examples include the groups represented below.
- the "C 6-10 aryl group” means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms.
- the “C 6-10 aryl group” may be condensed at all possible positions with the "alicyclic group” described above or the "non-aryl heterocyclic group” described below.
- Specific examples of the “C 6-10 aryl group” include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like.
- the "C 6-10 aryl group” is preferably a phenyl group.
- Specific examples of the condensed ring structure include groups represented by the following.
- a “5- to 10-membered heteroaryl group” is simply composed of 5 to 10 atoms, including 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms. It means a cyclic or bicyclic aromatic heterocyclic group.
- the "5- to 10-membered heteroaryl group” may be condensed at all possible positions with the "alicyclic group” described above or the "non-aryl heterocyclic group” described below.
- the “5- to 10-membered heteroaryl group” is preferably "6-membered heteroaryl group", "5- or 6-membered heteroaryl group", "6-10-membered heteroaryl group” or "9-membered”.
- a 10-membered heteroaryl group can be mentioned. More preferably, "6-membered heteroaryl group” and “5- or 6-membered heteroaryl group” can be mentioned. Specific examples of the "6-membered heteroaryl group” include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, and a pyridadinyl group.
- the "5- or 6-membered heteroaryl group” include, for example, a frill group, a thienyl group, a pyrrolyl group, a pyrazolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, an isooxazolyl group, a pyridyl group, a pyrazinyl group and a pyrimidinyl group.
- Examples include a group and a pyridadinyl group.
- the "6 to 10-membered heteroaryl group” include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyrariainyl group, a quinoxalyl group, a triazolopyridyl group and the like.
- Specific examples of the "5- to 10-membered heteroaryl group” include the above-mentioned “6- to 10-membered heteroaryl group” and "5- or 6-membered heteroaryl group”.
- 9-membered or 10-membered heteroaryl group include, but are not limited to, those having the structures shown below.
- the "5- or 6-membered heteroaryl group” or “5- to 10-membered heteroaryl group” may be a condensed ring structure with a C 5-10 alicyclic group or a 5- to 10-membered non-aryl heterocycle. May form a condensed ring structure of. Specific examples include the groups represented below.
- a "4 to 10-membered non-arylheterocyclic group” is one or two heteroatoms that are the same or different and are independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, in addition to a carbon atom. Including, a monocyclic or bicyclic non-aromatic heterocycle composed of 4 to 10 atoms, which has a partially unsaturated bond, a partially crosslinked structure, and / or one. Including those that have been partially spirozed. As the "4 to 10-membered non-aryl heterocyclic group", "4 to 7-membered non-aryl heterocyclic group” is preferable.
- the "4 to 7-membered non-aryl heterocyclic group” include an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group and the like. .. Preferred examples include an azetidineyl group, a pyrrolidinyl group, a piperidyl group, a morpholinyl group, and an oxetanyl group.
- the non-aryl heterocycle may form a fused ring with aryl or heteroaryl.
- condensation with a C 6-10 aryl group or a 5- or 6-membered heteroaryl group is also included in the non-aryl heterocycle.
- the non-aryl heterocycle may contain one or more carbonyl groups, thiocarbonyl groups, sulfinyl groups or sulfonyl groups, for example, lactam, thiolactam, lactone, thiolactone, cyclic. Cyclic groups such as imide, cyclic carbamates, and cyclic thiocarbamates are also included in the non-aryl heterocycle.
- the oxygen atom of the carbonyl group, the sulfinyl group and the sulfonyl group and the sulfur atom of the thiocarbonyl are not included in the number of 4 to 10 members (ring size) and the number of heteroatoms constituting the ring. ..
- a "4 to 7-membered non-aryl heterocycle” is preferable.
- Specific examples of the "4 to 7-membered non-arylheterocycle” include azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, tetrahydropyran and the like.
- Specific examples of the "4 to 10-membered non-aryl heterocycle” include, for example, those having the structure shown below in addition to those mentioned as specific examples of the above-mentioned "4 to 7-membered non-aryl heterocycle”. ..
- C 1-6 alkoxy or "C 1-6 alkoxy group” means “C 1-6 alkyloxy", and the "C 1-6 alkyl” moiety is referred to as the above “C 1-6 alkyl”. It is synonymous.
- C 1-6 alkoxy preferably “C 1-4 alkoxy” is mentioned, and more preferably “C 1-3 alkoxy” is mentioned.
- Specific examples of “C 1-3 alkoxy” include methoxy, ethoxy, propoxy, 1-methylethoxy and the like.
- Specific examples of “C 1-4 alkoxy” include, for example, butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, and 2-methyl, in addition to those mentioned as specific examples of "C 1-3 alkyl”.
- C 1-6 alkoxy include, for example, pentyroxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1 in addition to those mentioned as specific examples of "C 1-4 alkyl".
- -Methylbutoxy, 2-methylbutoxy, 4-methylpentyroxy, 3-methylpentyroxy, 2-methylpentyroxy, 1-methylpentyroxy, hexyloxy and the like can be mentioned.
- C 3-7 alicyclic oxy or "C 3-7 alicyclic oxy group” means (C 3-7 alicyclic group) -O- group, and the C 3-7 alicyclic group.
- the formula part is synonymous with the C 3-7 alicyclic group.
- the "C 3-7 alicyclic oxy group” includes a "C 3-7 cycloalkoxy group”.
- the "cycloalkoxy group” means “cycloalkyloxy”, and the "cycloalkyl” moiety is synonymous with the above-mentioned "cycloalkyl”.
- Specific examples of the "C 3-7 alicyclic oxy group” include a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a cyclohexitoxy group and the like.
- the C 6-10 aryl portion of the "C 6-10 aryloxy group” is synonymous with the C 6-10 aryl group described above.
- the "C 6-10 aryloxy group” preferably “C 6 or C 10 aryloxy group” can be mentioned.
- Specific examples of the “C 6-10 aryloxy group” include, but are not limited to, a phenoxy group, a 1-naphthyloxy group, a 2-naphthyloxy group and the like.
- the 5-membered or 6-membered heteroaryl portion of the "5- or 6-membered heteroaryloxy group” is synonymous with the above-mentioned "5-membered heteroaryl group” or "6-membered heteroaryl group”.
- Specific examples of the "5- or 6-membered heteroaryloxy group” are not limited to these, but for example, a pyrazoyloxy group, a triazoyloxy group, a thiazoyloxy group, a thiadiazoyloxy group, and a pyridyloxy group. , Pyridazoyloxy groups and the like.
- the 4- to 10-membered non-aryl heterocyclic moiety of the "4 to 10-membered non-aryl heterocyclic oxy group” is synonymous with the above “4 to 10-membered non-aryl heterocycle".
- the "4 to 10-membered non-aryl heterocyclic oxy group” is preferably "4 to 6-membered non-aryl heterocyclic oxy group”.
- Specific examples of the "4 to 10-membered non-arylheterocyclic oxy group” are not limited to these, but for example, a tetrahydrofuranyloxy group, a tetrahydropyranyloxy group, an azetidinyloxy group, a pyrrolidinyloxy group, and a pi. Examples thereof include a peridinyloxy group.
- the C 1-6 alkyl moiety of the "C 1-6 alkyl thio group” is synonymous with the above C 1-6 alkyl.
- the "C 1-6 alkylthio group” is preferably "C 1-4 alkylthio group", more preferably "C 1-3 alkylthio group”.
- Specific examples of the "C 1-6 alkylthio group” are not limited to these, but for example, a methylthio group, an ethylthio group, a propylthio group, a butylthio group, an isopropylthio group, an isobutylthio group, a tert-butylthio group, and a sec-butylthio group. Examples thereof include a group, an isopentylthio group, a neopentylthio group, a tert-pentylthio group, a 1,2-dimethylpropylthio group and the like.
- C 3-10 alicyclic thio or "C 3-10 alicyclic thio group” means (C 3-10 alicyclic group) -S- group, and the C 3-10 alicyclic group. The portion is synonymous with the above C 3-10 alicyclic group.
- the "C 3-10 alicyclic thio group” is preferably "C 3-6 alicyclic thio group”. Specific examples of the "C 3-6 alicyclic thio group” include, but are not limited to, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group and the like.
- C 6-10 aryl portion of "C 6-10 arylthio" or “C 6-10 arylthio group” is synonymous with the C 6-10 aryl group described above.
- C 6-10 arylthio group preferably, “C 6 or C 10 arylthio group” is mentioned.
- Specific examples of the "C 6-10 aryloxy group” include, but are not limited to, a phenylthio group, a 1-naphthylthio group, a 2-naphthylthio group and the like.
- the 5- or 6-membered heteroaryl portion of the "5- or 6-membered heteroarylthio" or “5- or 6-membered heteroarylthio group” is the above-mentioned "5-membered heteroaryl group” or "6-membered heteroarylthio group". It is synonymous with "heteroaryl group”.
- Specific examples of the "5- or 6-membered heteroarylthio group” are not limited to these, and examples thereof include a pyrazoylthio group, a triazoylthio group, a thiazoylthio group, a thiasiazoylthio group, a pyridylthio group, and a pyridazoylthio group. Can be mentioned.
- the 4- to 10-membered non-aryl heterocyclic moiety of the "4 to 10-membered non-aryl heterocyclic thio" or “4 to 10-membered non-aryl heterocyclic thio group” is the above-mentioned "4 to 10-membered non-aryl heterocycle". It is synonymous with "group”.
- the "4 to 10-membered non-aryl heterocyclic thio group” is preferably "4 to 6-membered non-aryl heterocyclic thio group”.
- Specific examples of the "4 to 10-membered non-aryl heterocyclic thio group” include, but are not limited to, a tetrahydropyranylthio group, a piperidinylthio group and the like.
- the "C 1-6 alkyl carbonyl” or “C 1-6 alkyl carbonyl group” means a carbonyl group substituted with the above “C 1-6 alkyl group”.
- the "C 1-6 alkylcarbonyl group” is preferably a "C 1-4 alkylcarbonyl group” or a " C1-3 alkylcarbonyl group”.
- Specific examples of the “C 1-6 alkylcarbonyl group” include, but are not limited to, an acetyl group, a propionyl group, a butyryl group and the like.
- the “C 1-6 alkoxycarbonyl” or “C 1-6 alkoxycarbonyl group” means a carbonyl group substituted with the above “C 1-6 alkoxy group”.
- the "C 1-6 alkoxycarbonyl group” is preferably a "C 1-4 alkoxycarbonyl group” or a " C1-3 alkoxycarbonyl group”.
- Specific examples of the "C 1-6 alkoxycarbonyl group” include, but are not limited to, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, and the like.
- the "C 3-10 alicyclic carbonyl” or “C 3-10 alicyclic carbonyl group” means a carbonyl group substituted with the above “C 3-10 alicyclic carbonyl".
- the "C 3-10 alicyclic carbonyl group” is preferably "C 3-6 alicyclic carbonyl group”. Specific examples of the “C 3-10 alicyclic carbonyl group” include, but are not limited to, cyclopropylcarbonyl group, cyclopentylcarbonyl group and the like.
- the "C 6-10 aryl carbonyl” or “C 6-10 aryl carbonyl group” means a carbonyl group substituted with the above “C 6-10 aryl group”.
- the "C 6-10 arylcarbonyl group” is preferably “C 6 or C 10 arylcarbonyl group”. Specific examples of the “C 6-10 arylcarbonyl group” include, but are not limited to, a benzoyl group, a 1-naphthylcarbonyl group, a 2-naphthylcarbonyl group and the like.
- the "5- or 6-membered heteroarylcarbonyl” or “5- or 6-membered heteroarylcarbonyl group” means a carbonyl group substituted with the above "5- or 6-membered heteroaryl group”.
- Specific examples of the "5- or 6-membered heteroarylcarbonyl group” are not limited to these, but for example, a pyrazoylcarbonyl group, a triazoylcarbonyl group, a thiazoylcarbonyl group, a thiathiazoylcarbonyl group, a pyridylcarbonyl group, and the like. Examples thereof include a pyridazoylcarbonyl group.
- the "4 to 10-membered non-aryl heterocyclic carbonyl” or “4 to 10-membered non-aryl heterocyclic carbonyl group” means a carbonyl group substituted with the above "4 to 10-membered non-aryl heterocyclic group”. do.
- the "4 to 10-membered non-aryl heterocyclic carbonyl group” is preferably "4 to 6-membered non-aryl heterocyclic carbonyl group".
- the "4 to 10-membered non-aryl heterocyclic carbonyl group” are not limited to these, but for example, an azetidinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidinylcarbonyl group, a morpholinylcarbonyl group and the like. Can be mentioned.
- C 1-6 alkyl sulfonyl group or "C 1-6 alkyl sulfonyl group” means a sulfonyl group substituted with the above "C 1-6 alkyl sulfonyl group”.
- the "C 1-6 alkyl sulfonyl group” is preferably "C 1-4 alkyl sulfonyl group”.
- Specific examples of the "C 1-6 alkyl sulfonyl group” include, but are not limited to, a methyl sulfonyl group, a propionyl sulfonyl group, a butyryl sulfonyl group and the like.
- C 3-10 alicyclic sulfonyl or "C 3-10 alicyclic sulfonyl group” means a sulfonyl group substituted with the above "C 3-10 alicyclic sulfonyl group”.
- the "C 3-10 alicyclic sulfonyl group” is preferably "C 3-6 alicyclic sulfonyl group”.
- C 3-10 alicyclic sulfonyl group include, but are not limited to, cyclopropylsulfonyl group, cyclobutylsulfonyl group, cyclopentylsulfonyl group, cyclohexylsulfonyl group and the like.
- the "C 6-10 aryl sulfonyl group” or “C 6-10 aryl sulfonyl group” means a sulfonyl group substituted with the above “C 6-10 aryl sulfonyl group”.
- the "C 6-10 aryl sulfonyl group” is preferably "C 6 or C 10 aryl sulfonyl group”.
- Specific examples of the "C 6-10 aryl sulfonyl group” include, but are not limited to, a phenylsulfonyl group, a 1-naphthylsulfonyl group, a 2-naphthylsulfonyl group and the like.
- the "5- or 6-membered heteroarylsulfonyl group” or “5- or 6-membered heteroarylsulfonyl group” means a sulfonyl group substituted with the above-mentioned "5- or 6-membered heteroarylsulfonyl group”.
- the "5- or 6-membered heteroarylsulfonyl group” are not limited to these, but for example, a pyrazoylsulfonyl group, a triazoylsulfonyl group, a thiazoylsulfonyl group, a thiathiazoylsulfonyl group, a pyridylsulfonyl group, and the like. Examples thereof include a pyridazoylsulfonyl group.
- the preferred ones of 11 , R 12 , m, n, L 1 , L 2 , Q, X and Y are as follows, but the technical scope of the present disclosure is not limited to the scope of the compounds listed below. do not have.
- R 1 is a hydrogen atom.
- R2 is a methoxy group.
- R 3 is a hydrogen atom.
- R4 include a C 1-6 alkyl group, a C 3-7 alicyclic group or a C 6-10 aryl group (the C 1-6 alkyl group, C 3-7 alicyclic group and C 6 ).
- the -10 aryl group is a fluorine atom, a chlorine atom, a C 1-6 alkyl group, a C 3-7 alicyclic group, a C 6-10 aryl group, a 5- or 6-membered heteroaryl group, and a 4- to 10-membered heteroaryl group. It may be substituted with the same or different 1 to 3 substituents selected from the group consisting of non-aryl heterocyclic groups).
- R4 is a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a cyclohexylmethyl group, a phenyl group or a benzyl group (the methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a cyclohexylmethyl group, a phenyl group).
- the benzyl group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom and a C 1-6 alkyl group).
- a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group or a phenyl group are a fluorine atom, a chlorine atom and a C 1- ). It may be substituted with the same or different 1 to 3 substituents selected from the group consisting of 6 alkyl groups).
- R 5 , R 6 and R 7 include a hydrogen atom, a C 3-6 alicyclic group or a C 1-6 alkyl group (the C 3-6 alicyclic group and a C 1-6 alkyl group). , Halogen atom, hydroxyl group, C 1-6 alkoxy group, C 3-10 alicyclic group, C 6-10 aryl group and 4-6 member non-aryl heterocyclic group selected from the same or different group. It may be substituted with 1 to 3 substituents).
- R 8 , R 9 and R 10 include a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl sulfonyl group, a C 1-6 alkyl group or a C 1-6 alkoxy group.
- R 11 include a hydrogen atom, a C 1-3 alkyl group, a formyl group, a C 1-3 alkyl carbonyl group, a C 1-4 alkoxycarbonyl group or a C 6-10 aryl carbonyl group (the C 1-3 ).
- the alkyl group, C 1-3 alkylcarbonyl group, C1-4 alkoxycarbonyl group and C6-10arylcarbonyl group are halogen atoms, hydroxyl groups, cyano groups, C 1-6 alkyl groups and C 1-6 alkylsulfonyl groups.
- R 12 is a hydrogen atom or a C 1-3 alkyl group (the C 1-3 alkyl group is a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkyl sulfonyl group, C 1-6 alkoxy group, C 3-7 alicyclic group, C 3-10 alicyclic oxy group, C 6-10 aryl group, 4-10 member non-aryl heterocyclic group, 4-10 member non 1 to 3 identical or different substitutions selected from the group consisting of an aryl heterocyclic oxy group, a C 6-10 aryloxy group, a 5- or 6-membered heteroaryl and a 5- or 6-membered heteroaryloxy group. It may be substituted with a group).
- a preferred embodiment of m is 1 or 2.
- n 0, 1, 2 or 3.
- n 0, 1 or 2.
- n 0 or 1.
- -C ( O) -CH 2-
- -C ( O) -NH-CH 2-
- -NH-C ( O) -CH 2 -CH 2-
- -C ( O) -NH-CH 2 -CH 2-
- a preferred embodiment of L 2 is a single bond.
- a preferred embodiment of Q is a single bond.
- a preferred embodiment of X is a C 6-10 aryl group or a 5-10 membered heteroaryl group (the C 6-10 aryl group and the 5-10 membered heteroaryl group are a halogen atom, a hydroxyl group, a cyano group, C.
- a phenyl group or a 6-membered heteroaryl group (the phenyl group and the 6-membered heteroaryl group are a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkyl).
- Sulfonyl group C 1-6 alkoxy group, C 3-7 alicyclic group, C 3-10 alicyclic oxy group, C 6-10 aryl group, 4-10 member non-aryl heterocyclic group, 4-10
- X include the following formulas (A1), (A2) and (A3).
- * represents the bond position with L 1 and ** represents the bond position with Q or Y
- Preferred embodiments of Y include a C 6-10 aryl group, a 5-10 membered heteroaryl group or a C 3-7 alicyclic group (the C 6-10 aryl group, a 5-10 membered heteroaryl group and C).
- the 3-7 alicyclic group is a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkyl sulfonyl group, a C 1-6 alkoxy group, a C 3-7 alicyclic group, and C 3 -10 alicyclic oxy group, C 6-10 aryl group, 4-10 member non-aryl heterocyclic group, 4-10 member non-aryl heterocyclic oxy group, C 6-10 aryloxy group, 5 member or 6 It may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a membered heteroaryl group and a 5- or 6-membered heteroaryloxy group).
- a more preferred embodiment of Y is a phenyl group or a cyclohexyl group (the phenyl group and the cyclohexyl group are a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkyl sulfonyl group, and a C 1-6 alkoxy.
- Y include the following formulas (B) and (C). (In the formula, * represents the bond position with X or Q, and ** represents the bond position with L 2 or an oxygen atom).
- One embodiment of the compound represented by the formula (1) includes the following (A).
- R 1 is a hydrogen atom
- R 2 is a methoxy group and R 3 is a hydrogen atom
- R4 is a C 1-6 alkyl group, a C 3-7 alicyclic group or a C 6-10 aryl group (the C 1-6 alkyl group, a C 3-7 alicyclic group and a C 6-10 aryl group).
- Q is a single bond
- X is a C 6-10 aryl group or a 5-10 membered heteroaryl group (the C 6-10 aryl group and the 5-10 membered heteroaryl group are a halogen atom, a hydroxyl group, a cyano group, and a C 1-6 alkyl.
- Y is a C 6-10 aryl group, a 5- to 10-membered heteroaryl group or a C 3-7 alicyclic group (the C 6-10 aryl group, a 6-membered heteroaryl group and a C 3-7 alicyclic group).
- the groups are halogen atom, hydroxyl group, cyano group, C 1-6 alkyl group, C 1-6 alkyl sulfonyl group, C 1-6 alkoxy group, C 3-7 alicyclic group, C 3-10 alicyclic oxy.
- One embodiment of the compound represented by the formula (1) includes the following (B).
- R 1 is a hydrogen atom
- R 2 is a methoxy group and R 3 is a hydrogen atom
- R4 is a C 1-6 alkyl group, a C 3-7 alicyclic group or a C 6-10 aryl group (the C 1-6 alkyl group, a C 3-7 alicyclic group and a C 6-10 aryl group).
- m is 1 or 2
- n is 0, 1
- L 2 is a single bond
- Q is a single bond
- X is a C 6-10 aryl group or a 5-10 membered heteroaryl group (the C 6-10 aryl group and the 5-10 membered heteroaryl group are a halogen atom, a hydroxyl group, a cyano group, and a C 1-6 alkyl.
- Y is a C 6-10 aryl group, a 5-10 membered heteroaryl group or a C 3-7 alicyclic group (the C 6-10 aryl group, a 5-10 member heteroaryl group and a C 3-7 fat).
- the cyclic group is a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkyl sulfonyl group, a C 1-6 alkoxy group, a C 3-7 alicyclic group, and a C 3-10 alicyclic group.
- One embodiment of the compound represented by the formula (1) includes the following (C).
- (C) R 1 is a hydrogen atom, R 2 is a methoxy group and R 3 is a hydrogen atom, R4 is a C 1-6 alkyl group, a C 3-7 alicyclic group or a C 6-10 aryl group (the C 1-6 alkyl group, a C 3-7 alicyclic group and a C 6-10 aryl group).
- m is 1, n is 0, 1, 2 or 3
- L 2 is a single bond
- Q is a single bond
- X is a phenyl group or a 6-membered heteroaryl group (the phenyl group and the 6-membered heteroaryl group are a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkyl sulfonyl group, C 1 ).
- Y is a phenyl group or a cyclohexyl group (the phenyl group and the cyclohexyl group are a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkyl sulfonyl group, a C 1-6 alkoxy group, and a C 3- 7 alicyclic group, C 3-10 alicyclic oxy group, C 6-10 aryl group, 4-10 member non-aryl heterocyclic group, 4-10 member non-aryl heterocyclic oxy group, C 6-10 It may be substituted with the same or different 1-3 substituents selected from the group consisting of aryloxy groups, 5- or 6-membered heteroaryl groups and 5- or 6-membered heteroaryloxy groups).
- X and Y are bonded by carbon atoms on their respective rings.
- a compound or a pharmaceutically acceptable salt thereof are bonded by carbon atoms on their respective rings.
- One embodiment of the compound represented by the formula (1) includes the following (D).
- R 1 is a hydrogen atom
- R 2 is a methoxy group and R 3 is a hydrogen atom
- R4 is a C 1-6 alkyl group, a C 3-7 alicyclic group or a C 6-10 aryl group (the C 1-6 alkyl group, a C 3-7 alicyclic group and a C 6-10 aryl group).
- Y is a phenyl group or a cyclohexyl group (the phenyl group and the cyclohexyl group are a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkyl sulfonyl group, a C 1-6 alkoxy group, and a C 3- 7 alicyclic group, C 3-10 alicyclic oxy group, C 6-10 aryl group, 4-10 member non-aryl heterocyclic group, 4-10 member non-aryl heterocyclic oxy group, C 6-10 It may be substituted with the same or different 1-3 substituents selected from the group consisting of aryloxy groups, 5- or 6-membered heteroaryl groups and 5- or 6-membered heteroaryloxy groups).
- X and Y are bonded by carbon atoms on their respective rings.
- a compound or a pharmaceutically acceptable salt thereof are bonded by carbon atoms on their respective rings.
- One embodiment of the compound represented by the formula (1) includes the following (E).
- R 1 is a hydrogen atom
- R 2 is a methoxy group and R 3 is a hydrogen atom
- R4 is a C 1-6 alkyl group, a C 3-7 alicyclic group or a C 6-10 aryl group (the C 1-6 alkyl group, a C 3-7 alicyclic group and a C 6-10 aryl group).
- One embodiment of the compound represented by the formula (1) includes the following (F).
- R 1 is a hydrogen atom
- R 2 is a methoxy group and R 3 is a hydrogen atom
- R4 is a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a cyclohexylmethyl group, a phenyl group or a benzyl group (the methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a cyclohexylmethyl group, a phenyl group and a benzyl group.
- One embodiment of the compound represented by the formula (1) includes the following (G).
- R 1 is a hydrogen atom
- R 2 is a methoxy group and R 3 is a hydrogen atom
- R4 is a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a phenyl group (the methyl group, the ethyl group, the isopropyl group, the cyclohexyl group and the phenyl group are composed of a fluorine atom, a chlorine atom and a C 1-6 alkyl group. It may be substituted with the same or different 1 to 3 substituents selected from the group).
- Examples of the "pharmaceutically acceptable salt” include acid-added salts and base-added salts.
- an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, or citrate, oxalate, phthalate, etc.
- organic acid salts such as salts and camphor sulfonates.
- Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt and aluminum salt, or trimethylamine, triethylamine, pyridine, picolin, 2,6-lutidine, ethanolamine and diethanolamine. , Triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylamine and other organic base salts.
- examples of the "pharmaceutically acceptable salt” include amino acid salts with basic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid or acidic amino acids.
- Suitable salts of raw material compounds and intermediates and acceptable salts as raw materials for pharmaceuticals are conventional non-toxic salts, such as organic acid salts (eg, acetates, trifluoroacetates, maleates, fumaric acids). Salts, citrates, tartrates, methanesulfonates, benzenesulfonates, formates or p-toluenesulfonates, etc.) and inorganic acid salts (eg, hydrochlorides, hydrobromide, hydroiodide, etc.) , Sulfates, nitrates or phosphates, etc.), salts with amino acids (eg, arginine, aspartic acid or glutamate, etc.), alkali metal salts (eg, sodium or potassium salts, etc.) and alkaline earth metals.
- organic acid salts eg, acetates, trifluoroacetates, maleates, fumaric acids.
- Metal salts such as salts (eg calcium salt or magnesium salt), ammonium salts, or organic base salts (eg trimethylamine salt, triethylamine salt, pyridine salt, picolin salt, dicyclohexylamine salt or N, N'-dibenzylethylenediamine salt, etc. ) Etc., etc., can be appropriately selected by those skilled in the art.
- the compound of the present invention when it is desired to obtain a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it may be purified as it is, and if it is obtained in the form of a free form, it may be dissolved in a suitable organic solvent. Alternatively, it may be suspended and an acid or a base may be added to form a salt by a usual method.
- the deuterium converter obtained by converting any one or more of the compounds represented by the formula (1) into 2H (D) is also included in the compound represented by the formula (1).
- the present invention includes a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof. Further, since the compound of the present invention may exist in the form of a hydrate and / or a solvate with various solvents (such as a solvate of ethanol), these hydrates and / or solvates are also present. Included in the compounds of the invention. Further, the present invention includes all tautomers of compound (1) of the present invention, any stereoisomers present, and crystalline forms of any aspect, as well as mixtures thereof.
- the compounds (1) of the present invention are optical isomers based on optically active centers, atropisomers based on axial or planar chirality caused by the constraint of intramolecular rotation, other steric isomers, and mutual mutations. All possible isomers and mixtures thereof, including these, are included within the scope of the invention, although some sexes, geometric isomers and the like may exist.
- the optical isomer and the atrop isomer can be obtained as a racemate, or as an optically active substance when a starting material or an intermediate for optical activity is used.
- the corresponding raw material, intermediate or final racemate is physically separated by a known separation method such as a method using an optically active column or a fractional crystallization method. It can be divided into their optical racemics either or chemically.
- a known separation method such as a method using an optically active column or a fractional crystallization method.
- the diastereomer method two types of diastereomers are formed from a racemate by a reaction using an optically active dividing agent. Since these different diastereomers generally have different physical properties, they can be divided by a known method such as fractional crystallization.
- the compound of the present disclosure is not limited to these, but can be produced, for example, by the production method described below. These production methods can be appropriately improved based on the knowledge of those who are proficient in synthetic organic chemistry. In the following production method, the compounds used as raw materials may use salts thereof as long as they do not interfere with the reaction.
- the target compound can be obtained by protecting other than the reaction point as necessary and deprotecting after the reaction is completed or after a series of reactions are carried out.
- Protecting groups used in these processes are described in the literature (T. W. Greene and P. G. M. Wuts, “Protective Group in Organic Synthesis”, 3rd Ed ., John Wiley and Sons, Inc., New York (1999)). Ordinary protecting groups can be used.
- the protecting group can be introduced and removed by a method commonly used in synthetic organic chemistry (for example, the method described in the above document) or a method similar thereto.
- the starting materials and intermediates in the following production methods can be purchased as commercial products, or can be obtained by synthesizing them from a known document or a known compound according to a known method.
- salts of these starting materials and intermediates may be used as long as they do not interfere with the reaction.
- the intermediate and the target compound in the following production method can also be converted into another compound contained in the present disclosure by appropriately converting their functional groups.
- the conversion of functional groups at that time is described in the methods commonly used in synthetic organic chemistry (eg, R. C. Larock, “Comprehensive Organic Transformations”, 2nd Ed ., John Wiley and Sons, Inc., New York (1999)). It can be done by the method described above) or a method similar thereto.
- the inert solvent in the following production method is a solvent that does not react with the raw materials, reagents, bases, acids, catalysts, ligands, etc. used in the reaction (hereinafter, may be referred to as "raw materials used in the reaction"). means. Further, even when the solvent used in each step reacts with the raw material or the like used in the reaction, it can be used as an inert solvent as long as the target reaction proceeds and the target compound is obtained.
- the compound of the present disclosure represented by the formula (1) can be produced, for example, by the following production methods 1 to 5.
- the compound represented by the formula [A1] can be produced, for example, by the following production method.
- Step 1-1 Condensation reaction
- Compound a5 is produced by reacting compound a1 with compound a2 in the presence or absence of various condensing agents and / or bases in a suitable solvent.
- various condensing agents used in a conventional method can be used, but preferably propiophosphonic acid anhydride or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (hydrochloride) is used.
- Including The base is appropriately selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine is mentioned.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes tetrahydrofuran, dimethylformamide or chloroform.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 1-2 Condensation reaction
- Compound a5 is produced by reacting compound a3 with compound a4 in the presence or absence of various condensing agents and / or bases in a suitable solvent.
- various condensing agents used in a conventional method can be used, but preferably propiophosphonic acid anhydride or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (hydrochloride) is used.
- Including The base is appropriately selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine is mentioned.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes tetrahydrofuran, dimethylformamide or chloroform.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 1-3 Coupling reaction
- Compound a8 is produced by coupling compound a6 to compound a6 or a7 in the presence of a catalyst and a base.
- the catalyst include those supported on a carrier such as a transition metal such as palladium, a salt thereof, a complex thereof, and a polymer.
- the base is appropriately selected from the bases exemplified below, and preferred examples include sodium carbonate, potassium carbonate and the like.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes a mixed solvent of 1,2-dimethoxyethane and water.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 20 ° C to 150 ° C.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 1-4 Condensation reaction
- Compound a12 is produced by reacting compound a8 with compound a9, a10 or a11 in the presence or absence of various condensing agents and / or bases in a suitable solvent.
- the condensing agent various condensing agents used in a conventional method can be used, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride) is preferable.
- the base is appropriately selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine is mentioned.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes tetrahydrofuran, dimethylformamide or chloroform.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 1-5 Debenzylation reaction
- Compound A1 is produced by reducing compound a12 in the presence of a catalyst.
- a catalyst formic acid salts such as hydrogen and ammonium formic acid, and hydrazine can be used.
- the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt or platinum, a salt thereof, a complex thereof, or a polymer.
- the solvent is appropriately selected from the solvents exemplified below, and preferably ethyl acetate, ethanol or methanol.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Compound a1 can be produced by using a commercially available compound or by using a known method, for example, the method described in ACS Chem Neurosci. 2018, 9, 587-602 and the like.
- Compound a3 can be produced by using a commercially available compound or by using a known method, for example, the method described in Nature Communi. 2018, 9, 4123, etc.
- the compound represented by the formula [A2] can be produced, for example, by the following production method.
- Step 2-1 Debenzylation reaction
- Compound a13 is produced by reducing compound a8 in the presence of a catalyst.
- a catalyst formic acid salts such as hydrogen and ammonium formic acid, and hydrazine can be used.
- the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt or platinum, a salt thereof, a complex thereof, or a polymer.
- the solvent is appropriately selected from the solvents exemplified below, and preferably ethyl acetate, ethanol or methanol.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 2-2 Condensation reaction
- Compound a14 is produced by reacting compound a13 with compound a9, a10 or a11 in the presence or absence of various condensing agents and / or bases in a suitable solvent.
- various condensing agents used in a conventional method can be used, but preferably propiophosphonic acid anhydride or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (hydrochloride) is used.
- Including The base is appropriately selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine is mentioned.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes tetrahydrofuran, dimethylformamide or chloroform.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 2-3 Deacyl reaction
- Compound A2 is produced by reacting compound a14 with various bases in a suitable solvent.
- the base is appropriately selected from the bases exemplified below, and preferably ammonia is mentioned.
- the solvent is appropriately selected from the solvents exemplified below, and preferably 2-propanol or tetrahydrofuran.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Manufacturing method 3 The compound represented by the formula [a13] can be produced, for example, by the following production method.
- Y 1 is a C 3-10 alicyclic group having an unsaturated bond
- Y 2 is a C 3-10 alicyclic group
- -C ( O) -NH-
- R2 , R3 and X are synonymous with item 1, and a15, a16 and a17 represent compounds in which the carbonyl group on Y1 is acetal - protected.
- Step 3-1 Coupling reaction
- Compound a17 is produced by coupling compound a15 with compound a15 or a16 in the presence of a catalyst and a base.
- the catalyst include those supported on a carrier such as a transition metal such as palladium, a salt thereof, a complex thereof, and a polymer.
- the base is appropriately selected from the bases exemplified below, and preferred examples include sodium carbonate, potassium carbonate and the like.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes a mixed solvent of 1,2-dimethoxyethane and water.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 20 ° C to 150 ° C.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 3-2 Deacetal reaction
- Compound a18 is produced by reacting compound a17 with various acids in a suitable solvent.
- the acid include hydrochloric acid, trifluoroacetic acid, acetic acid, sulfuric acid and the like.
- the solvent is appropriately selected from the solvents exemplified below, and preferably contains tetrahydrofuran or acetone.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 3-3 Debenzylation reaction
- Compound a19 is produced by reducing compound a18 in the presence of a catalyst.
- a catalyst formic acid salts such as hydrogen and ammonium formic acid, and hydrazine can be used.
- the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt or platinum, a salt thereof, a complex thereof, or a polymer.
- the solvent is appropriately selected from the solvents exemplified below, and preferably ethyl acetate, ethanol or methanol.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 3-4 Reduction reaction
- Compound a13 is produced by reducing compound a19 with a reducing agent in the presence of a catalyst and / or a base. Further, the reaction can be carried out using only a reducing agent.
- a reducing agent for example, salts of formic acid such as hydrogen and sodium formic acid, hydrazine, sodium borohydride, trisec-butylboronized lithium hydride and the like can be used.
- the catalyst include those supported on a carrier such as a transition metal such as ruthenium, palladium, nickel, rhodium, cobalt, platinum, a salt thereof, a complex thereof, and a polymer.
- the base is appropriately selected from the bases exemplified below, and preferred examples thereof include potassium tert-butoxide, potassium hydroxide, and triethylamine.
- the solvent is appropriately selected from the solvents exemplified below, and preferably examples thereof include tetrahydrofuran, 2-propanol, ethanol, methanol and dimethylformamide.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually ⁇ 80 ° C. to 200 ° C., preferably ⁇ 80 ° C. to 100 ° C. More preferably, it is 0 ° C to 100 ° C.
- the compound represented by the formula [A3] can be produced, for example, by the following production method.
- Step 4-1 Condensation reaction
- Compound a22 is produced by reacting compound a20 with compound a2 in the presence or absence of various condensing agents and / or bases in a suitable solvent.
- various condensing agents used in a conventional method can be used, but preferably propiophosphonic acid anhydride or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (hydrochloride) is used. Including).
- the base is appropriately selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine is mentioned.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes tetrahydrofuran, dimethylformamide or chloroform.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 4-2 Condensation reaction
- Compound a22 is produced by reacting compound a21 with compound a4 in the presence or absence of various condensing agents and / or bases in a suitable solvent.
- various condensing agents used in a conventional method can be used, but preferably propiophosphonic acid anhydride or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (hydrochloride) is used. Including).
- the base is appropriately selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine is mentioned.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes tetrahydrofuran, dimethylformamide or chloroform.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 4-3 Coupling reaction
- Compound a23 is produced by coupling compound a6 or a7 in the presence of a catalyst and a base to compound a22.
- the catalyst include those supported on a carrier such as a transition metal such as palladium, a salt thereof, a complex thereof, and a polymer.
- the base is appropriately selected from the bases exemplified below, and preferred examples include sodium carbonate, potassium carbonate and the like.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes a mixed solvent of 1,2-dimethoxyethane and water.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 20 ° C to 150 ° C.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 4-4 Condensation reaction
- Compound A3 is produced by reacting compound a23 with compound a9, a10 or a11 in the presence or absence of various condensing agents and / or bases in a suitable solvent.
- the condensing agent various condensing agents used in a conventional method can be used, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride) is preferable.
- the base is appropriately selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine is mentioned.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes tetrahydrofuran, dimethylformamide or chloroform.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- the compound a20 can be produced by using a commercially available compound or by a known method, for example, the method described in ACS Chem Neurosci. 2018, 9, 587-602 and the like.
- Compound a21 can be produced by using a commercially available compound or by using a known method, for example, the method described in Nature Commun. 2018, 9, 4123 and the like. Manufacturing method 5
- the compound represented by the formula [a23] can be produced, for example, by the following production method.
- Y 1 is a C 3-10 alicyclic group having an unsaturated bond
- Y 2 is a C 3-10 alicyclic group
- -C ( O) -NH-
- R1 , R2 , R3 and X are synonymous with item 1
- a15, a16 and a24 are compounds in which the carbonyl group on Y1 is acetal - protected. show.
- Step 5-1 Coupling reaction
- Compound a24 is produced by coupling compound a22 with compound a15 or a16 in the presence of a catalyst and a base.
- the catalyst include those supported on a carrier such as a transition metal such as palladium, a salt thereof, a complex thereof, and a polymer.
- the base is appropriately selected from the bases exemplified below, and preferred examples include sodium carbonate, potassium carbonate and the like.
- the solvent is appropriately selected from the solvents exemplified below, and preferably includes a mixed solvent of 1,2-dimethoxyethane and water.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 20 ° C to 150 ° C.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 5-2 Deacetal reaction
- Compound a25 is produced by reacting compound a24 with various acids in a suitable solvent.
- the acid include hydrochloric acid, trifluoroacetic acid, acetic acid, sulfuric acid and the like.
- the solvent is appropriately selected from the solvents exemplified below, and preferably contains tetrahydrofuran or acetone.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 5-3 Hydrogenation reaction
- Compound a26 is produced by reducing compound a25 in the presence of a catalyst.
- a catalyst formic acid salts such as hydrogen and ammonium formic acid, and hydrazine can be used.
- the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt or platinum, a salt thereof, a complex thereof, or a polymer.
- the solvent is appropriately selected from the solvents exemplified below, and preferably ethyl acetate, ethanol or methanol.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
- Step 5-4 Reduction reaction
- Compound a23 is produced by reducing compound a26 with a reducing agent in the presence of a catalyst and / or a base. Further, the reaction can be carried out using only a reducing agent.
- a reducing agent for example, salts of formic acid such as hydrogen and sodium formic acid, hydrazine, sodium borohydride, trisec-butylboronized lithium hydride and the like can be used.
- the catalyst include those supported on a carrier such as a transition metal such as ruthenium, palladium, nickel, rhodium, cobalt, platinum, a salt thereof, a complex thereof, and a polymer.
- the base is appropriately selected from the bases exemplified below, and preferred examples thereof include potassium tert-butoxide, potassium hydroxide, and triethylamine.
- the solvent is appropriately selected from the solvents exemplified below, and preferably examples thereof include tetrahydrofuran, 2-propanol, ethanol, methanol and dimethylformamide.
- the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually ⁇ 80 ° C. to 200 ° C., preferably ⁇ 80 ° C. to 100 ° C. More preferably, it is 0 ° C to 100 ° C.
- the base used in each step of each of the above production methods should be selected in a timely manner depending on the reaction, the type of the raw material compound, etc.
- Alkali carbonates such as sodium, potassium carbonate, cesium carbonate, potassium fluoride, metal fluorides such as cesium fluoride, sodium hydride, metal hydrides such as potassium hydride, sodium hydroxide, potassium hydroxide
- Alkali metal hydroxides such as, sodium methoxydo, alkali metal alkoxides such as sodium tert-butoxide, organic metal bases such as butyllithium, lithium diisopropylamide, lithium (bistrimethylsilyl) amide, triethylamine, diisopropylethylamine.
- the solvent used in each step of each of the above production methods should be selected in a timely manner depending on the reaction, the type of raw material compound, etc., for example, alcohols such as methanol, ethanol, 2-propanol, acetone, and methyl ketone.
- Ketones such as methylene chloride, halogenated hydrocarbons such as chloroform, ethers such as tetrahydrofuran (THF), dioxane, aromatic hydrocarbons such as toluene, benzene, xylene, hexane, heptane.
- Hydrocarbons esters such as ethyl acetate, propyl acetate, amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide (DMSO)
- amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone
- sulfoxides such as dimethyl sulfoxide (DMSO)
- nitriles such as acetonitrile
- organic bases may be used as a solvent.
- the compound of the present disclosure represented by the formula (1) or an intermediate thereof can be separated and purified by a method known to those skilled in the art. For example, extraction, partitioning, reprecipitation, column chromatography (eg, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography), recrystallization and the like can be mentioned.
- column chromatography eg, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography
- recrystallized solvent examples include an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, an aromatic hydrocarbon solvent such as benzene or toluene, and acetone.
- a ketone solvent such as, a halogen solvent such as dichloromethane or chloroform, a hydrocarbon solvent such as hexane, an aproton solvent such as dimethylformamide or acetonitrile, water, or a mixed solvent thereof can be used.
- the method described in Volume 1 of the Experimental Chemistry Course (edited by the Chemical Society of Japan, Maruzen) can be used.
- the molecular structure of the compound of the present disclosure is determined by a spectroscopic method such as a nuclear magnetic resonance method, an infrared absorption method, a circular dichroism spectral analysis method, etc., with reference to the structure derived from each raw material compound. And it can be easily done by mass spectrometry.
- a spectroscopic method such as a nuclear magnetic resonance method, an infrared absorption method, a circular dichroism spectral analysis method, etc.
- the intermediate or final product in the above-mentioned production method appropriately converts its functional group, and in particular, extends various side chains from an amino group, a hydroxyl group, a carbonyl group, a halogen atom, etc., and the same. It is also possible to lead to another compound contained in the present disclosure by performing the following protection and deprotection as necessary. Functional group conversion and side chain extension can be performed by common methods commonly used (see, eg, Comprehensive Organic Transformations, R.C. Larock, John Wiley & Sons Inc. (1999), etc.).
- Examples of the protecting group of the amino group include an alkylcarbonyl group (for example, an acetyl group and a propionyl group), a formyl group, a phenylcarbonyl group and an alkyloxycarbonyl group (for example, a methoxycarbonyl group, an ethoxycarbonyl group and a tert-butoxycarbonyl group). ), A phenyloxycarbonyl group, an arylalkyloxycarbonyl group (for example, a benzyloxycarbonyl group), a trityl group, a phthaloyl group, a tosyl group, and a benzyl group.
- an alkylcarbonyl group for example, an acetyl group and a propionyl group
- a formyl group for example, a phenylcarbonyl group and an alkyloxycarbonyl group (for example, a methoxycarbonyl group, an e
- Examples of the protecting group of the carboxyl group include an alkyl group (for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and a tert-butyl group), a phenyl group, a benzyl group, a trityl group and a silyl group (for example).
- alkyl group for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and a tert-butyl group
- a phenyl group for example, a benzyl group, a trityl group and a silyl group (for example).
- a trimethylsilyl group, tert-butyldimethylsilyl group is used.
- Examples of the protective group of the hydroxy group include a methyl group, a tert-butyl group, an allyl group, a substituted methyl group (for example, a methoxymethyl group and a methoxyethoxymethyl group), an ethoxyethyl group, a tetrahydropyranyl group and a tetrahydrofla.
- Nyl group trityl group, arylalkyl group (eg, benzyl group), alkylcarbonyl group (eg, acetyl group, propionyl group), formyl group, benzoyl group, arylalkyloxycarbonyl group (eg, benzyloxycarbonyl group), silyl A group (eg, trimethylsilyl group, tert-butyldimethylsilyl group) is used.
- arylalkyl group eg, benzyl group
- alkylcarbonyl group eg, acetyl group, propionyl group
- formyl group benzoyl group, arylalkyloxycarbonyl group (eg, benzyloxycarbonyl group), silyl A group (eg, trimethylsilyl group, tert-butyldimethylsilyl group) is used.
- the protection of the carbonyl group can be performed by converting the carbonyl group into an acetal ketal (dimethyl ketal, diethyl ketal, etc.) or a cyclic ketal (1,3-dioxolane, 1,3-dioxane, etc.).
- the compound of the present disclosure represented by the formula (1) or a pharmaceutically acceptable salt thereof may be asymmetric or may have a substituent having an asymmetric carbon, and such compounds are present. There are optical isomers.
- the compounds of the present disclosure also include mixtures and isolated compounds of each of these isomers and can be prepared according to conventional methods.
- Examples of the manufacturing method include a method using a raw material having an asymmetric point, or a method of introducing an asymmetry in an intermediate stage.
- optical isomers can be obtained by using an optically active raw material or by performing optical resolution or the like at an appropriate stage in the manufacturing process.
- an optical division method for example, when the compound represented by the formula (1) or an intermediate thereof has a basic functional group, an alcohol system such as methanol, ethanol, 2-propanol or the like is used in an inert solvent.
- Solvent ether solvent such as diethyl ether, ester solvent such as ethyl acetate, hydrocarbon solvent such as toluene, aproton solvent such as acetonitrile, or a mixed solvent of two or more selected from the above solvents), optical Active acids (eg, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartrate acid, diisopropyridene tartrate acid such as o-diisopropyridene tartrate acid, dicarboxylic acid such as malic acid, sulfonic acid such as camphorsulfonic acid, bromocamparsulfonic acid and the like. ) Is used to form a salt.
- monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartrate acid, diisopropyridene tartrate acid such as o-diisopropyridene tartrate acid, dicar
- an optically active amine for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, etc.
- Optical resolution can also be performed by forming a salt using an organic amine such as strikinone).
- the temperature at which the salt is formed is selected from the range from ⁇ 50 ° C. to the boiling point of the solvent, preferably from 0 ° C. to the boiling point, and more preferably from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature to near the boiling point of the solvent. When the precipitated salt is collected by filtration, it can be cooled if necessary to improve the yield.
- the amount of the optically active acid or amine used is preferably in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent with respect to the substrate.
- an inert solvent eg, alcohol solvent such as methanol, ethanol, 2-propanol; ether solvent such as diethyl ether; ester solvent such as ethyl acetate; hydrocarbon solvent such as toluene; acetonitrile. It can also be recrystallized from an aproton solvent such as; or a mixed solvent of two or more selected from the above solvents) to obtain a highly pure optically active salt. Further, if necessary, the optically resolved salt can be treated with an acid or a base by a usual method to obtain a free form.
- an inert solvent eg, alcohol solvent such as methanol, ethanol, 2-propanol
- ether solvent such as diethyl ether
- ester solvent such as ethyl acetate
- hydrocarbon solvent such as toluene
- acetonitrile e.g, acetonitrile
- the "disorder or disease involving TRPV1" is a disorder or disease caused by an increase in the activity of nerve cells expressing TRPV1, for example, dysphagia, pain, skin disease, respiratory disease, gastrointestinal disease, etc.
- Examples include urinary disorders, diabetes and obesity.
- pain include neuropathic pain, postherpetic neuralgia, and pain due to knee osteoarthritis.
- Examples of skin diseases include psoriasis, atopic dermatitis, primary hyperhidrosis, and alopecia.
- Respiratory diseases include cough and asthma.
- gastrointestinal diseases include acute gastritis, acute gastric mucosal lesions, and fecal incontinence.
- urinary diseases include cystitis and overactive bladder.
- the "disorder or disease involving TRPV1" is preferably dysphagia.
- the present disclosure provides a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient for treating or preventing dysphagia.
- Dysphagia refers to a condition in which it becomes difficult to chew or swallow food or drink due to illness or aging. Specific examples include dysphagia, dysphagia, dysphagia, odynophagia, aphagia, and cricopharyngeal muscle dysfunction. It also includes cerebrovascular diseases such as cerebral infarction and cerebral bleeding, neurodegenerative diseases such as Parkinson's disease and ALS, and dysphagia due to dementia such as Alzheimer's type. In addition, it also includes situations in which swallowing function is impaired by therapeutic agents such as analgesics, antipsychotics, antihistamines, and anticholinergic agents.
- dysphagia The effect of the compound of the present disclosure on dysphagia can be evaluated using the dysphagia model animal's dysphagia as an index. Similar to dysphagia in humans, it has been reported that dysphagia occurs in old animals, cerebral infarction model animals, Parkinson's disease model animals, etc., and these models can be used for evaluation. (Dysphagia (2014) 29: 61-67, Dysphagia. 2015 Jun; 30 (3): 328-42, Dysphagia. 2013 Mar; 28 (1): 95-104).
- prevention is an act of administering the active ingredient of the present disclosure to a healthy person who has not developed a disease or exhibits mild symptoms, and for example, to prevent the onset of a disease. Is the purpose.
- Treatment is the act of administering the active ingredient of the present disclosure to a person (patient) who has been diagnosed as having a disease by a doctor.
- the administration route of the compound of the present disclosure may be oral administration, parenteral administration or rectal administration, and the daily dose thereof varies depending on the type of compound, administration method, patient's symptom / age and the like.
- oral administration usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per 1 kg body weight of a human or a mammal can be administered in one to several divided doses.
- parenteral administration such as intravenous injection, for example, about 0.01 mg to 300 mg, more preferably about 0.01 mg to 100 mg per 1 kg body weight of a human or a mammal can be administered.
- the compound of the present disclosure can be formulated and administered directly or by using an appropriate dosage form by oral administration or parenteral administration.
- the dosage form include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices.
- the pharmaceutical product is produced by a known method using a pharmaceutically acceptable additive.
- Additives include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. , Perfume and the like can be used.
- lactose mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, stearate.
- examples thereof include magnesium acid, stearyl sodium fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.
- the compounds of the present disclosure can be used in combination with drugs that may improve swallowing function, and can be administered to treat or prevent dysphagia.
- a drug that can be used in combination with the compound of the present invention is abbreviated as another drug.
- the administration period of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration target at the same time or at different times. Further, it may be a mixture of the compound of the present invention and a combination drug.
- the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
- the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present invention.
- a drug concomitant drug
- it can be used in combination with a drug (concomitant drug) such as an antiemetic agent, a sleep-inducing agent, and an anticonvulsant.
- pin means pinacol.
- s is a single line
- d is a double line
- dd is a double line
- t is a triple line
- q is a quadruple line
- m is a multiple line
- br is a wide range
- brs Means a wide single line and J means a coupling constant.
- N, N-diisopropylethylamine (5.) in a 1,2-dimethoxyethane solution (30 ml) of 4-benzyloxy-3-methoxyphenylacetic acid (4.0 g) and 6-bromopyridine-2-amine (2.8 g). 1 ml) and a 50% propylphosphonic acid anhydride / ethyl acetate solution (10.5 ml) were added, and the mixture was stirred at room temperature for 1.5 hours. After adding water to the reaction solution, the mixture was extracted with ethyl acetate.
- Example 1 and Reference Example 3 3- ⁇ 6- [2- (4-Hydroxy-3-methoxyphenyl) acetamide] pyridin-2-yl ⁇ phenyl 2-methylpropanol
- Example 1 (352 mg) was obtained by recrystallizing the obtained solid from 2-propanol.
- Reference example 11 4- [2- (3- ⁇ (cis) -4-[(cyclohexanecarbonyl) oxy] cyclohexyl ⁇ anilino) -2-oxoethyl] -2-methoxyphenyl cyclohexanecarboxylate
- Reference example 12 3'-Hydroxy-N-[(4-Hydroxy-3-methoxyphenyl) methyl] [1,1'-biphenyl] -3-carboxamide
- Example 2 (469 mg).
- Examples 3 to 48 The compounds shown in Table 2 were obtained by the same method as in Examples 1, 2 and 49 using the corresponding raw material compounds.
- Test Examples The following shows the pharmacological test results of the representative compound of the present invention and describes the pharmacological action of the compound, but the present invention is not limited to these test examples.
- Test Example 1 Evaluation of operability using human TRPV1 transient expression cells (1) Preparation of human TRPV1 transient expression cells Human TRPV1 transient expression cells were prepared and used for culturing. Specifically, HEK293 cells (cat # CCL-82.2, ATCC) were used as host cells. Human TRPV1 and apoequolin were transiently expressed by introduction of a mammalian cell-expressed pcDNA3.1 vector (cat # v790-20, Invitrogen) into which the TRPV1 gene (GenBank NP_542435.2) was inserted.
- Dulvecco's Modified Eagle's Medium (DMEM) medium (cat # 11550-043, Thermo Fisher Scientific) containing 10% deactivated fetal bovine serum (cat # 10270-106, Thermo Fisher Scientific) was used as the medium.
- Culture was performed in a culture dish (cat # 3020-100, Iwaki). During culture, cells are collected by PBS treatment containing 10% 2.5 g / 1-trypsin / 1 mol / L EDTA solution, phenol red (cat # 32777-44, Nacalai Tesque) every 2-3 days, and subcultured. Was done.
- test compound a dimethylsulfoxide solution having a concentration 1000 times the final concentration was prepared, and this solution was used as Hanks / 20 mmol / L HEPES / 0.1% BSA (cat # 01281-84, Nacalai Tesque). The concentration was adjusted to 10 times the final concentration.
- TRPV1 operability FDSS7000 (Hamamatsu Photonics) was used to detect the luminescence signal stimulated by TRPV1 agonist.
- the test compound was added to the plate to which the cells and luminescent substrate were added.
- the emission signal (center wavelength: 465 nm) after the addition of the test compound was measured to calculate Rlu (Max-Min).
- Data on TRPV1 agonistic activity of representative compounds are shown in Tables 3 and 4.
- the compound of the present invention had TRPV1 operability in the TRPV1 operability evaluation test.
- Examples 1, 2, 9, 10, 15, 17, 19, 24, 26 and 46 showed stronger TRPV1 activating activity.
- Test Example 2 Evaluation of swallowing improving effect in rat haloperidol-induced dysphagia model This test is a test to evaluate the swallowing disorder improving effect of a drug. Since haloperidol causes a decrease in dysphagia due to inhibition of dopamine D2 receptor, it is not only a model of drug-induced dysphagia caused by antipsychotics, but also a model of dysphagia against the background of neurodegenerative diseases such as Parkinson's disease. It is also used as a model for other dysphagia with reduced swallowing reflex. Haloperidol was administered to Crl: CD (SD) male rats (8 rats in a group, 8 weeks old, body weight 280 to 310 g: at the time of arrival).
- CD CD
- Test Example 3 Evaluation of taste aversion by drinking water This test is a test to evaluate the taste aversion of a drug.
- Crl CD (SD) rats (8 in a group, 8 weeks old at the time of arrival) were tested by adding a test substance solution to a water bottle during breeding in a home cage. Two water bottles were prepared per cage, each of which was filled with a vehicle (sterile water containing 0.05% ethanol) and a test substance solution and bred overnight, and the amount of drinking water during that period was measured. The ratio of drinking the test substance was calculated from the total amount of water consumed by the two water bottles, and the taste aversion was evaluated. It can be evaluated that the larger the ratio of drinking the test substance, the smaller the taste aversion and the less irritation caused by the test substance. The results are shown in Table 5.
- Test Example 4 S9 Metabolism Stability Evaluation Test A compound was added to a reaction solution obtained by diluting the liver S9 fraction with a phosphate buffer, and incubation was started at 37 ° C. (final compound concentration 10 nM, final volume 300 ⁇ L). After incubation for 15 minutes, the reaction was stopped by adding the reaction solution to acetonitrile, and centrifugation was performed. After filtering the supernatant, the amount of the compound was measured using LC / MS / MS. From the obtained amount of the compound, the residual rate 15 minutes after the start of the reaction with respect to the amount of the compound before the start of the reaction (0 minutes) was calculated. The results are shown in Table 6.
- Test Example 5 Evaluation of swallowing-enhancing effect in normal rats This test is a test to evaluate the swallowing-enhancing effect of a drug. It has been reported that the number of swallows is suppressed when the swallowing reflex is induced in normal rats using water containing NaCl, and the enhancement of swallowing function was evaluated using a solvent containing NaCl.
- Crl CD (SD) male rat (7 to 8 animals in a group, 8 to 9 weeks old, weight 280 to 310 g: at the time of arrival) After anesthesia was introduced, the animal's submandibular gland was shaved with a hair clipper and kept warm at 37 ° C. The limbs were held in the supine position so that they would not move.
- a rat sonde was inserted into the animal's mouth and the tip of the sonde was fastened to the pharynx.
- the test substance administration solution was administered at 12 ml / h for 10 seconds using an infusion pump, and the swallowing motion was measured for 30 seconds from the start of administration.
- As the vehicle a physiological saline solution containing 1% ethanol and 0.1% Tween 80 was used.
- the results are shown in Table 7.
- the number of swallows was significantly increased in capsaicin, Example 12, Example 2, and Example 49 as compared with the solvent-administered group (Dunnett's test: * is P ⁇ 0.05, ** is P ⁇ 0. 01 and *** indicate P ⁇ 0.001, respectively).
- Test Example 6 Evaluation of Desensitization of Swallowing-Promoting Action in Normal Rats TRPV1 agonists are known to induce desensitization of TRPV1 by high-dose and repeated action. Using the same method as in Test Example 5, the effect of inducing drug desensitization on the swallowing function of normal rats was investigated.
- Crl CD (SD) male rat (7 to 8 animals in a group, 8 to 9 weeks old, weight 280 to 310 g: at the time of arrival) After anesthesia was introduced, the animal's submandibular gland was shaved with a hair clipper and kept warm at 37 ° C. The limbs were held in the supine position so that they would not move.
- a rat sonde was inserted into the animal's mouth and the tip of the sonde was fastened to the pharynx.
- the test substance administration solution was administered at 12 ml / h for 10 seconds using an infusion pump, and the swallowing motion was measured for 30 seconds from the start of administration. Then, about 5 minutes later, the same test was carried out, and the evaluation was repeated 5 times in total.
- As the vehicle a physiological saline solution containing 1% ethanol and 0.1% Tween 80 was used. The results are shown in Table 8. With capsaicin, the number of swallows was significantly reduced at the 4th and 5th doses compared to the 1st dose (Dunnett's test: ** indicates P ⁇ 0.01). On the other hand, no significant difference was found in Example 49.
- Example 7 Evaluation of Eye Irritation Test in Normal Rats It has been reported that a TRPV1 agonist is irritating and that administration of a TRPV1 agonist solution to an eye induces wiping behavior. The irritation of the compound was investigated using normal rats. Crl: CD (SD) male rats (5 animals in a group, 8 weeks old, body weight 271-320 g) were retained under anesthesia, and 10 ⁇ L was added dropwise to the right eye using a micropipette. Immediately returned to the observation cage and the wiping behavior was observed for 1 minute. Table 9 shows the number of wiping actions. Capsaicin significantly increased wiping behavior at concentrations above 30 ⁇ M (Dunnett's test: * indicates P ⁇ 0.05, ** indicates P ⁇ 0.01, respectively). On the other hand, no significant difference was observed between Example 12, Example 2, Example 1, and Example 49.
- the compound of the present invention is a potent TRPV1 agonist and exhibits an improving effect on the swallowing reflex in the haloperidol-induced dysphagia animal model used as a dysphagia model. Since the decreased swallowing reflex is improved by antagonizing the dopamine D2 receptor, drug-induced dysphagia due to administration of antipsychotic drugs, neurodegenerative diseases such as Parkinson's disease, and swallowing reflex are decreased. It is useful as a therapeutic agent for dysphagia due to cerebrovascular disease and aging.
- the compounds of the present disclosure exhibit TRPV1 operability, they exhibit dysphagia due to various causes such as drug-induced dysphagia, dysphagia caused by neurodegenerative diseases such as Parkinson's disease, cerebrovascular disease, and aging. It is useful as a therapeutic agent for dysphagia that decreases.
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Abstract
Description
式(1):
R1は、水素原子、置換されていてもよいC1-6アルキル基、置換されていてもよいC1-6アルキルカルボニル基又は置換されていてもよいC6-10アリールカルボニル基を表し、
R2は、メトキシ基、水酸基又は水素原子を表し、
R3は、水素原子、ハロゲン原子、置換されていてもよいC1-6アルキル基、置換されていてもよいC1-4アルコキシ基、置換されていてもよいC6-10アリール基又はホルミル基を表し、
R4は、置換されていてもよいC1-6アルキル基、置換されていてもよいC3-7脂環式基、置換されていてもよいC2-6アルケニル基、置換されていてもよいC2-6アルキニル基、置換されていてもよいC6-10アリール基、置換されていてもよいC1-6アルコキシ基、置換されていてもよいC3-7脂環式オキシ基、置換されていてもよいC6-10アリールオキシ基又は置換されていてもよい4~7員の非アリールヘテロ環基を表し、
mは、0、1又は2を表し、
nは、0、1、2又は3を表し、
L1は、-NH-C(=O)-、-C(=O)-NH-、-O-C(=O)-、-C(=O)-O-、-NH-C(=S)-、-C(=S)-NH-、-NH-C(=O)-CH2-、-C(=O)-NH-CH2-、-NH-C(=O)-CH2-CH2-、-C(=O)-NH-CH2-CH2-、-SO2-NH-、-NH-SO2-、-NH-C(=O)-O-又は-O-C(=O)-NH-を表し、
Qは、単結合、-O-、-S-、-SO2-、-NR5-又は-CR6R7-を表し、
L2は、単結合又は置換されていてもよいC1-6アルキル基を表し、
Xは、置換されていてもよいC6-10アリール基又は置換されていてもよい5~10員のヘテロアリール基を表し、
Yは、置換されていてもよいC6-10アリール基、置換されていてもよい5~10員のヘテロアリール基、置換されていてもよいC3-7脂環式基又は置換されていてもよい4~7員の非アリールヘテロ環基を表し、
R5、R6及びR7は、各々独立して、水素原子、置換されていてもよいC3-6脂環式基又は置換されていてもよいC1-6アルキル基を表す]
で表される化合物又はその製薬学的に許容される塩。
(項2)
L1が、-NH-C(=O)-、-C(=O)-NH-、-NH-C(=S)-、-C(=S)-NH-、-NH-C(=O)-CH2-、-C(=O)-NH-CH2-、-NH-C(=O)-CH2-CH2-、-C(=O)-NH-CH2-CH2-、-SO2-NH-、-NH-SO2-、-NH-C(=O)-O-又は-O-C(=O)-NH-である、
項1に記載される化合物又はその製薬学的に許容される塩。
(項3)
Qが、単結合である、
項1又は2に記載される化合物又はその製薬学的に許容される塩。
(項4)
Xが、置換されていてもよいフェニル基又は置換されていてもよい6員のヘテロアリール基である、
項1~3のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項5)
Yが、置換されていてもよいフェニル基、置換されていてもよい5員若しくは6員のヘテロアリール基、置換されていてもよいC3-7脂環式基又は置換されていてもよい4~7員の非アリールヘテロ環基である、
項1~4のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項6)
式(2):
R1は、水素原子、C1-6アルキル基(該C1-6アルキル基は、水酸基、カルボキシル基及び-NR11R12からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)、置換されていてもよいC1-6アルキルカルボニル基又は置換されていてもよいC6-10アリールカルボニル基を表し、
R2は、メトキシ基、水酸基又は水素原子を表し、
R3は、水素原子、ハロゲン原子、置換されていてもよいC1-6アルキル基、置換されていてもよいC1-4アルコキシ基、置換されていてもよいC6-10アリール基又はホルミル基を表し、
R4は、置換されていてもよいC1-6アルキル基、置換されていてもよいC3-7脂環式基、置換されていてもよいC2-6アルケニル基、置換されていてもよいC2-6アルキニル基、置換されていてもよいC6-10アリール基、置換されていてもよいC1-6アルコキシ基、置換されていてもよいC3-7脂環式オキシ基、置換されていてもよいC6-10アリールオキシ基又は置換されていてもよい4~7員の非アリールヘテロ環基を表し、
ここにおいて、R4が置換されていてもよい4~7員の非アリールヘテロ環基である場合、該非アリールヘテロ環上の炭素原子がカルボニル基と結合しており、
R11は、水素原子、置換されていてもよいC1-3アルキル基、ホルミル基、置換されていてもよいC1-3アルキルカルボニル基、置換されていてもよいC1-4アルコキシカルボニル基又は置換されていてもよいC6-10アリールカルボニル基を表し、
R12は、水素原子又は置換されていてもよいC1-3アルキル基を表し、
mは、0、1又は2を表し、
nは、0、1、2又は3を表し、
L1は、-NH-C(=O)-、-C(=O)-NH-、-NH-C(=S)-、-C(=S)-NH-、-NH-C(=O)-CH2-、-C(=O)-NH-CH2-、-NH-C(=O)-CH2-CH2-、-C(=O)-NH-CH2-CH2-、-SO2-NH-、-NH-SO2-、-NH-C(=O)-O-又は-O-C(=O)-NH-を表し、
L2は、単結合又は置換されていてもよいC1-6アルキル基を表し、
Xは、置換されていてもよいフェニル基又は置換されていてもよい6員のヘテロアリール基を表し、
Yは、置換されていてもよいフェニル基、置換されていてもよい5員若しくは6員のヘテロアリール基、置換されていてもよいC3-7脂環式基又は置換されていてもよい4~7員の非アリールヘテロ環基を表し、
ここにおいて、XとYは、それぞれの環上の炭素原子で結合しており、
ただし、
1)式(W-1):
R1aが、水素原子又はアセチル基であり、
L1aが、-C(=O)-NH-又は-SO2-NH-である}で表される化合物、
2)式(W-2):
R1bが、メチル基又は-CD3であり、
R2bが、下記式(W-2A)、(W-2B)、(W-2C)、(W-2D)、又は(W-2R)であり、
R3bが、下記式(W-2E)、(W-2F)、(W-2G)、(W-2H)、(W-2I)、(W-2J)、(W-2K)、(W-2L)、(W-2M)、(W-2N)、(W-2O)、(W-2P)又は(W-2Q)であり、
Xbが、CH又はNであり、
Ybが、CH又はNであり、
Zbが、-CH2-又は-CHD-である}で表される化合物、
3)4’-{[2-(3,4-ジメトキシフェニル)エチル]カルバモイル}[1,1’-ビフェニル]-4-イル アセテート、
4)2’-(2-{[2-(3,4-ジメトキシフェニル)エチル]アミノ}-2-オキソエチル)-4,4’,5,5’-テトラメトキシ[1,1’-ビフェニル]-2-イル アセテート、
5)(2’-{[2-(3,4-ジメトキシフェニル)エチル]カルバモイル}-4,4’,5,5’-テトラメトキシ[1,1’-ビフェニル]-2-イル)メチル ベンゾエート、
6)6-[4-メトキシ-2-(2-{4-[2-(ピぺリジン-1-イル)エトキシ]フェニル}アセトアミド)フェニル]-5,6,7,8-テトラヒドロナフタレン-2-イル 2,2-ジメチルプロパノエート、
7)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル アセテート、
8)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル ベンゾエート、
9)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル 4-クロロベンゾエート、
10)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル 2-クロロベンゾエート、
11)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル 3-ニトロベンゾエート、及び
12)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル 2,4-ジクロロベンゾエートを除く]
で表される項1に記載される化合物又はその製薬学的に許容される塩。
(項7)
R3が、水素原子である、
項1~6のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項8)
mが、1又は2である、
項1~7のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項9)
mが、1である、
項1~8のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項10)
R1が、水素原子である、
項1~9のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項11)
R2が、メトキシ基である、
項1~10のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項12)
L1が、-NH-C(=O)-又は-C(=O)-NH-である、
項1~11のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項13)
L2が、単結合である、
項1~12のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項14)
Xが、下記式(A)であり、
aが、CR8又はNであり、
bが、CR9又はNであり、
cが、CR10又はNであり、
R8、R9及びR10が、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C1-6アルキルスルホニル基、置換されていてもよいC1-6アルキル基又は置換されていてもよいC1-6アルコキシ基である、
項1~13のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項15)
Xが、式(A)であり、
ここにおいて、(1)aがNの場合、bがCR9であり、かつcがCR10であり、(2)bがNの場合、aがCR8であり、かつcがCR10であり、(3)cがNの場合、aがCR8であり、かつbがCR9である、
項1~14のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項16)
Xが、式(A)であり、
ここにおいて、cがCR10であり、(1)aがNの場合、bがCR9であり、(2)bがNの場合、aがCR8である、
項1~14のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項17)
Xが、式(A)であり、
ここにおいて、cがCHであり、(1)aがNの場合、bがCHであり、(2)bがNの場合、aがCHである、
項1~14のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項18)
Xが、式(A)であり、
ここにおいて、a、b及びcがCHである、
項1~14のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項19)
Yが、置換されていてもよいフェニル基、置換されていてもよい6員のヘテロアリール基又は置換されていてもよいC3-7脂環式基である、
項1~18のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項20)
Yが、置換されていてもよいフェニル基又は置換されていてもよいシクロヘキシル基である、
項1~19のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項21)
Yが、下記式(B)又は(C)である、
項1~20のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項22)
R4が、置換されていてもよいC1-6アルキル基、置換されていてもよいC3-7脂環式基、置換されていてもよいC2-6アルケニル基、置換されていてもよいC2-6アルキニル基又は置換されていてもよいC6-10アリール基である、
項1~21のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項23)
R4が、置換されていてもよいC1-6アルキル基、置換されていてもよいC3-7脂環式基又は置換されていてもよいC6-10アリール基である、
項1~22のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項24)
R4が、C1-6アルキル基、C3-7脂環式基又はC6-10アリール基(該C1-6アルキル基、C3-7脂環式基及びC6-10アリール基は、フッ素原子、塩素原子、C1-6アルキル基、C3-7脂環式基、C6-10アリール基、5員若しくは6員のヘテロアリール基及び4~10員の非アリールヘテロ環基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)である、
項1~23のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項25)
R4が、メチル基、エチル基、イソプロピル基、シクロヘキシル基、シクロヘキシルメチル基、フェニル基又はベンジル基(該メチル基、エチル基、イソプロピル基、シクロヘキシル基、シクロヘキシルメチル基、フェニル基及びベンジル基は、フッ素原子、塩素原子及びC1-6アルキル基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)である、
項1~24のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項26)
R4が、メチル基、エチル基、イソプロピル基、シクロヘキシル基、フェニル基(該メチル基、エチル基、イソプロピル基、シクロヘキシル基及びフェニル基は、フッ素原子、塩素原子及びC1-6アルキル基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)である、
項1~25のいずれか一項に記載される化合物又はその製薬学的に許容される塩。
(項27)
以下の化合物から選択される、項1に記載の化合物又はその製薬学的に許容される塩:
3-{6-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル 2-メチルプロパノエート(実施例1)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル シクロヘキサンカルボキシレート(実施例2)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-4-イル ベンゾエート(実施例3)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-4-イル 2-メチルプロパノエート(実施例4)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル シクロヘキシルアセテート(実施例5)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル フェノキシアセテート(実施例6)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(3,5-ジフルオロフェニル)アセテート(実施例7)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(4-フルオロフェニル)アセテート(実施例8)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(3-メチルフェニル)アセテート(実施例9)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(2-クロロフェニル)アセテート(実施例10)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(オキサ-4-イル)アセテート(実施例11)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル アセテート(実施例12)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(チオフェン-2-イル)アセテート(実施例13)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(4-クロロフェニル)アセテート(実施例14)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(2-フルオロフェニル)アセテート(実施例15)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル プロパノエート(実施例16)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル 2-メチルプロパノエート(実施例17)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル フェニルアセテート(実施例18)、
2’-フルオロ-5’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル 2-メチルプロパノエート(実施例19)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]-4’-メトキシ[1,1’-ビフェニル]-3-イル 2-メチルプロパノエート(実施例20)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]-2’-メトキシ[1,1’-ビフェニル]-3-イル 2-メチルプロパノエート(実施例21)、
4’-フルオロ-3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル 2-メチルプロパノエート(実施例22)、
2’-フルオロ-3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル 2-メチルプロパノエート(実施例23)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル 2-メチルプロパノエート(実施例24)、
3-{2-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-4-イル}フェニル 2-メチルプロパノエート(実施例25)、
3-{4-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル 2-メチルプロパノエート(実施例26)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル(4-メチルフェニル)アセテート(実施例27)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル(2-フルオロフェニル)アセテート(実施例28)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル(オキサ-4-イル)アセテート(実施例29)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル シクロヘキシルアセテート(実施例30)、
3-{4-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル シクロヘキシルアセテート(実施例31)、
3-{6-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル シクロヘキシルアセテート(実施例32)、
3-{4-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル シクロヘキサンカルボキシレート 塩酸塩(実施例33)、
3-{6-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル シクロヘキサンカルボキシレート(実施例34)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル フェニルアセテート(実施例35)、
トランス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル フェニルアセテート(実施例36)、
トランス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル シクロヘキサンカルボキシレート(実施例37)、
トランス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル アセテート(実施例38)、
4-(2-{3-[(シス)-4-(アセチルオキシ)シクロヘキシル]アニリノ}-2-オキソエチル)-2-メトキシフェニル アセテート(実施例39)、
4-(2-{3-[(トランス)-4-(アセチルオキシ)シクロヘキシル]アニリノ}-2-オキソエチル)-2-メトキシフェニル アセテート(実施例40)、
シス-4-{4-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}シクロヘキシル アセテート(実施例41)、
シス-4-(3-{[(4-ヒドロキシ-3-メトキシフェニル)メチル]カルバモイル}フェニル)シクロヘキシル アセテート(実施例42)、
4-[2-({2-[(シス)-4-(アセチルオキシ)シクロヘキシル]ピリジン-4-イル}アミノ)-2-オキソエチル]-2-メトキシフェニル アセテート(実施例43)、
3’-{[(4-ヒドロキシ-3-メトキシフェニル)メチル]カルバモイル}[1,1’-ビフェニル]-3-イル 2-メチルプロパノエート(実施例44)、
3’-{[(4-ヒドロキシ-3-メトキシフェニル)メチル]カルバモイル}[1,1’-ビフェニル]-3-イル シクロヘキシルアセテート(実施例45)、
3-(4-{[(4-ヒドロキシ-3-メトキシフェニル)メチル]カルバモイル}ピリジン-2-イル)フェニル 2-メチルプロパノエート(実施例46)、
3-(6-{[(4-ヒドロキシ-3-メトキシフェニル)メチル]カルバモイル}ピリジン-2-イル)フェニル 2-メチルプロパノエート(実施例47)、
トランス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル 2-メチルプロパノエート(実施例48)及び
3-{4-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル 2-メチルプロパノエート 塩酸塩(実施例49)。
(項28)
以下の化合物から選択される、項1に記載の化合物又はその製薬学的に許容される塩:
3-{6-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル 2-メチルプロパノエート(実施例1)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル シクロヘキサンカルボキシレート(実施例2)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(3-メチルフェニル)アセテート(実施例9)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(2-クロロフェニル)アセテート(実施例10)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル アセテート(実施例12)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(2-フルオロフェニル)アセテート(実施例15)、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル 2-メチルプロパノエート(実施例17)、
2’-フルオロ-5’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル 2-メチルプロパノエート(実施例19)、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル 2-メチルプロパノエート(実施例24)、
3-{4-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル 2-メチルプロパノエート(実施例26)、
3-(4-{[(4-ヒドロキシ-3-メトキシフェニル)メチル]カルバモイル}ピリジン-2-イル)フェニル 2-メチルプロパノエート(実施例46)及び
3-{4-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル 2-メチルプロパノエート 塩酸塩(実施例49)。
(項29)
項1~28のいずれか一項に記載の化合物又はその製薬学的に許容される塩を有効成分として含有する医薬。
(項30)
項1~28のいずれか一項に記載の化合物又はその製薬学的に許容される塩を有効成分として含有するTRPV1が関与する障害又は疾患の治療薬又は予防薬。
(項31)
TRPV1が関与する障害又は疾患が、嚥下障害である、項30に記載の治療薬又は予防薬。
(項32)
項1~28のいずれか一項に記載の化合物又はその製薬学的に許容される塩を含有する医薬組成物。
(項33)
TRPV1が関与する障害又は疾患を治療又は予防するための、項32に記載の医薬組成物。
(項34)
嚥下障害を治療又は予防するための、項32に記載の医薬組成物。
(項35)
治療又は予防が必要な患者に、治療又は予防上の有効量の項1~28のいずれか一項に記載の化合物又はその製薬学的に許容される塩を投与することを含む、TRPV1が関与する障害又は疾患を治療又は予防するための方法。
(項36)
TRPV1が関与する障害又は疾患の治療薬又は予防薬を製造するための、項1~28のいずれか一項に記載の化合物又はその製薬学的に許容される塩の使用。
(項37)
TRPV1が関与する障害又は疾患の治療又は予防に使用するための、項1~28のいずれか一項に記載の化合物又はその製薬学的に許容される塩。
(項38)
項1~28のいずれか一項に記載の化合物又はその製薬学的に許容される塩と、1又は複数の他の薬剤とを組み合わせてなる医薬組成物。
(項39)
1又は複数の他の薬剤と併用して、TRPV1が関与する障害又は疾患を治療又は予防するための、項1~28のいずれか一項に記載の化合物又はその製薬学的に許容される塩を含有する医薬組成物。
置換基群αは、
1)ハロゲン原子、
2)水酸基、
3)カルボキシル基、
4)シアノ基、
5)C1-6アルキル基、
6)C2-6アルケニル基、
7)C2-6アルキニル基、
8)C1-6アルコキシ基、
9)C1-6アルキルチオ基、
10)C1-6アルキルカルボニル基、
11)C1-6アルキルスルホニル基、
(但し、5)から11)の各置換基は、置換基群βから選択される、同一又は異なる1~5個の置換基で置換されていてもよい)
12)C3-10脂環式基、
13)C3-10脂環式オキシ基、
14)C6-10アリールオキシ基、
15)5員若しくは6員のヘテロアリールオキシ基、
16)4~10員の非アリールヘテロ環オキシ基、
17)C3-10脂環式チオ基、
18)C6-10アリールチオ基、
19)5員若しくは6員のヘテロアリールチオ基、
20)4~10員の非アリールヘテロ環チオ基、
21)C6-10アリール基、
22)5員若しくは6員のヘテロアリール基、
23)4~10員の非アリールヘテロ環基、
24)C3-10脂環式カルボニル基、
25)C6-10アリールカルボニル基、
26)5員若しくは6員のヘテロアリールカルボニル基、
27)4~10員の非アリールヘテロ環カルボニル基、
28)C3-10脂環式スルホニル基、
29)C6-10アリールスルホニル基、
30)5員若しくは6員のヘテロアリールスルホニル基、
31)4~10員の非アリールヘテロ環スルホニル基、
(但し12)から31)の各置換基は、C1-6アルキル基及び置換基群βから選択される、同一又は異なる1~5個の置換基で置換されていてもよい)
32)-NR16R17、
33)-SO2-NR10bR11b、
34)-NR10c-C(=O)R11c、
35)-NR10d-C(=O)OR11d、
36)-NR12a-C(=O)NR10eR11e、
37)-NR10f-C(=S)R11f、
38)-NR10g-C(=S)OR11g、
39)-NR12b-C(=S)NR10hR11h、
40)-NR10i-SO2-R11i、
41)-NR12c-SO2-NR10jR11j、
42)-C(=O)OR10k、
43)-C(=O)NR10lR11k、
44)-C(=O)NR10mOR11l、
45)-C(=O)NR12d-NR10nR11m、
46)-C(=S)OR10o、
47)-C(=S)NR10pR11n、
48)-C(=S)NR10qOR11o、
49)-C(=S)NR12e-NR10rR11p、
50)-C(=NR13a)R10s、
51)-C(=NR13b)CHO、
52)-C(=NR13c)NR10tR11q、
53)-C(=NR13d)NR12f-NR10uR11r、
54)-NR17c-C(=NR13k)R17d、
55)-NR12g-C(=NR13e)-NR10vR11s、
56)-NR14-C(=NR13f)NR12h-NR10wR11t、
57)-OC(=O)R10x、
58)-OC(=O)OR10y、
59)-OC(=O)NR10z1R11u、
60)-NR12i-NR10z2R11v、
61)-NR10z3OR11w、
62)-C(=N-OR13a)R10s、
63)-C(=N-OR13b)CHO、
64)-C(=N-OR13c)NR10tR11q、
65)-C(=N-OR13d)NR12f-NR10uR11r、及び
66)-C(=O)H
からなる群であり、
置換基群βは、
1)ハロゲン原子、
2)水酸基、
3)カルボキシル基、
4)シアノ基、
5)C3-10脂環式基、
6)C1-6アルコキシ基、
7)C3-10脂環式オキシ基、
8)C1-6アルキルチオ基、
9)5員若しくは6員のヘテロアリールチオ基、
10)C6-10アリール基、
11)5員若しくは6員のヘテロアリール基、
12)4~10員の非アリールヘテロ環基、
13)C1-6アルキルカルボニル基、
14)C3-10脂環式カルボニル基、
15)C6-10アリールカルボニル基、
16)5員若しくは6員のヘテロアリールカルボニル基、
17)4~10員の非アリールヘテロ環カルボニル基、
18)-NR15aR16a、
19)-SO2-NR15bR16b、
20)-NR15c-C(=O)R16c
21)-NR17a-C(=O)NR15dR16d、
22)-C(=O)NR15eR16e、
23)-C(=NR13g)R15f、
24)-C(=NR13h)NR15gR16f、
25)-NR16g-C(=NR13i)R15h、
26)-NR17b-C(=NR13j)-NR15iR16h、
27)-C(=N-OR13g)R15f、及び
28)-C(=N-OR13h)NR15gR16f
(但し、置換基群βのうち、5)から17)の各置換基は、ハロゲン原子、水酸基、シアノ基、カルボキシル基及び-NR18aR18bからなる群より選択される1~5個の置換基で置換されていてもよい)からなる群であり、
R13a、R13b、R13c、R13d、R13e、R13f、R13g、R13h、R13i、R13j及びR13kは、各々独立して、水素原子、水酸基、C1-6アルキル基又はC1-6アルコキシ基であり、
R10a、R10b、R10c、R10d、R10e、R10f、R10g、R10h、R10i、R10j、R10k、R10l、R10m、R10n、R10o、R10p、R10q、R10r、R10s、R10t、R10u、R10v、R10w、R10x、R10y、R10z1、R10z2、R10z3、R11a、R11b、R11c、R11d、R11e、R11f、R11g、R11h、R11i、R11j、R11k、R11l、R11m、R11n、R11o、R11p、R11q、R11r、11s、R11t、R11u、R11v、R11w、R12a、R12b、R12c、R12d、R12e、R12f、R12g、R12h、R12i、R14、R15a、R15b、R15c、R15d、R15e、R15f、R15g、R15h、R15i、R16a、R16b、R16c、R16d、R16e、R16f、R16g、R16h、R17a、R17b、R17c及びR17dは、各々独立して、水素原子又はC1-6アルキル基(該基は、水酸基、シアノ基、C1-6アルコキシ基及び-NR18aR18bからなる群より選択される1~3個の置換基で置換されていてもよい)であり、
R18a及びR18bは、各々独立して、水素原子又はC1-6アルキル基である。
置換基群αは、好ましくは、
1)ハロゲン原子、
2)水酸基、
3)カルボキシル基、
4)シアノ基、
5)C1-6アルキル基、
6)C1-6アルコキシ基、
7)C1-6アルキルチオ基、
8)C1-6アルキルカルボニル基、
(但し、5)から8)の各置換基は、置換基群βから選択される、同一または異なる1~5個の置換基で置換されていてもよい)
9)C3-10脂環式基、
10)C3-10脂環式オキシ基、
11)C6-10アリールオキシ基、
12)5員若しくは6員のヘテロアリールオキシ基、
13)4~10員の非アリールヘテロ環オキシ基、
14)C3-10脂環式チオ基、
15)C6-10アリールチオ基、
16)5員若しくは6員のヘテロアリールチオ基、
17)4~10員の非アリールヘテロ環チオ基、
18)C6-10アリール基、
19)5員若しくは6員のヘテロアリール基、
20)4~10員の非アリールヘテロ環基、
21)C3-10脂環式カルボニル基、
22)C6-10アリールカルボニル基、
23)5員若しくは6員のヘテロアリールカルボニル基、
24)4~10員の非アリールヘテロ環カルボニル基、
(但し9)から24)の各置換基は、C1-6アルキル基及び置換基群βから選択される、同一又は異なる1~5個の置換基で置換されていてもよい)
25)-NR10aR11a、
26)-SO2-NR10bR11b、
27)-NR10c-C(=O)R11c、
28)-NR12a-C(=O)NR10dR11d、
29)-NR10e-SO2-R11e、
30)-NR12b-SO2-NR10fR11f、
31)-C(=O)NR10gR11g、
32)-C(=NR13a)R10h、
33)-C(=NR13b)NR10iR11h、
34)-NR11f-C(=NR13c)R10g、
35)-NR12c-C(=NR13d)-NR10jR11i、
36)-C(=N-OR13a)R10h、及び
37)-C(=N-OR13b)NR10iR11h
からなる群であり、
置換基群βは、好ましくは、
1)ハロゲン原子、
2)水酸基、
3)シアノ基、
4)C3-10脂環式基、
5)C1-6アルコキシ基、
6)C1-6アルキルチオ基、
7)5員若しくは6員のヘテロアリールチオ基、
8)5員若しくは6員のヘテロアリール基、
9)4~10員の非アリールヘテロ環基、
10)C1-6アルキルカルボニル基、
11)C3-10脂環式カルボニル基、
12)C6-10アリールカルボニル基、
13)5員若しくは6員のヘテロアリールカルボニル基、
14)4~10員の非アリールヘテロ環カルボニル基、
15)-NR15aR16a、
16)-NR15b-C(=O)R16b、
17)-NR17a-C(=O)NR15cR16c、
18)-C(=O)NR15dR16d、
19)-C(=NR13e)R15e、
20)-C(=NR13f)NR15fR16e、
21)-NR16f-C(=NR13g)R15g、
22)-NR17b-C(=NR13h)-NR15hR16g、
23)-C(=N-OR13e)R15e、及び
24)-C(=N-OR13f)NR15fR16e
(但し、置換基群βのうち、4)から14)の各置換基は、ハロゲン原子、水酸基、シアノ基、カルボキシル基及び-NR18aR18bからなる群より選択される1~5個の置換基で置換されていてもよい)からなる群であり、
R13a、R13b、R13c、R13d、R13e、R13f、R13g、R13hは、各々独立して、水素原子、水酸基、C1-6アルキル基又はC1-6アルコキシ基であり、
R10a、R10b、R10c、R10d、R10e、R10f、R10g、R10h、R10i、R10j、R11a、R11b、R11c、R11d、R11e、R11f、R11g、R11h、R11i、R12a、R12b、R12c、R15a、R15b、R15c、R15d、R15e、R15f、R15g、R15h、R16a、R16b、R16c、R16d、R16e、R16f、R16g、R17a及びR17bは、各々独立して、水素原子又はC1-6アルキル基(該基は、水酸基、シアノ基、C1-6アルコキシ基及び-NR18aR18bからなる群より選択される、1~3個の置換基で置換されていてもよい)であり、
R18a、R18bは、各々独立して、水素原子又はC1-6アルキル基である。
置換基群αは、さらに好ましくは、
1)ハロゲン原子、
2)水酸基、
3)シアノ基、
4)C1-6アルキル基、
5)C1-6アルコキシ基、
6)C1-6アルキルチオ基、
7)C1-6アルキルカルボニル基、
(但し、4)から7)の各置換基は、置換基群βから選択される、同一または異なる1~5個の置換基で置換されていてもよい)
8)5員若しくは6員のヘテロアリールオキシ基、
9)4~10員の非アリールヘテロ環オキシ基、
10)5員若しくは6員のヘテロアリールチオ基、
11)4~10員の非アリールヘテロ環チオ基、
12)C6-10アリール基、
13)5員若しくは6員のヘテロアリール基、
14)4~10員の非アリールヘテロ環基、
(但し4)から14)の各置換基は、C1-6アルキル基及び置換基群βから選択される、同一又は異なる1~5個の置換基で置換されていてもよい)
15)-NR10aR11a、
16)-NR11b-C(=O)R10b、
17)-NR12a-C(=O)NR10cR11c、
18)-C(=O)NR10dR11d、
19)-C(=NR13a)R10e、
20)-C(=NR13b)NR10fR11e、
21)-NR11f-C(=NR13c)R10g、
22)-NR12b-C(=NR13d)-NR10hR11g、
23)-C(=N-OR13a)R10e、及び
24)-C(=N-OR13b)NR10fR11e
からなる群であり、
置換基群βは、さらに好ましくは、
1)ハロゲン原子、
2)水酸基、
3)シアノ基、
4)-NR15aR16a、
5)-NR15b-C(=O)R16b、
6)-NR17a-C(=O)NR15cR16c、
7)-C(=O)NR15dR16d、
8)-C(=NR13e)R15e、
9)-C(=NR13f)NR15fR16e、
10)-NR16f-C(=NR13g)R15g、
11)-NR17b-C(=NR13h)-NR15hR16g
12)-C(=N-OR13e)R15e、及び
13)-C(=N-OR13f)NR15fR16e
からなる群であり、
R13a、R13b、R13c、R13d、R13e、R13f、R13g及びR13hは、各々独立して、水素原子、水酸基、C1-6アルキル基又はC1-6アルコキシ基であり、
R10a、R10b、R10c、R10d、R10e、R10f、R10g、R10h、R11a、R11b、R11c、R11d、R11e、R11f、R11g、R12a、R12b、R15a、R15b、R15c、R15d、R15e、R15f、R15g、R15h、R16a、R16b、R16c、R16d、R16e、R16f、R16g、R17a及びR17bは、各々独立して、水素原子又はC1-6アルキル基(該基は、水酸基、シアノ基、C1-6アルコキシ基及び-NR18aR18bからなる群より選択される、1~3個の置換基で置換されていてもよい)であり、
R18a、R18bは、各々独立して、水素原子又はC1-6アルキル基である。
(A)
R1が、水素原子であり、
R2が、メトキシ基であり、
R3が、水素原子であり、
R4が、C1-6アルキル基、C3-7脂環式基又はC6-10アリール基(該C1-6アルキル基、C3-7脂環式基及びC6-10アリール基は、フッ素原子、塩素原子、C1-6アルキル基、C3-7脂環式基、C6-10アリール基、5員若しくは6員のヘテロアリール基及び4~10員の非アリールヘテロ環基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
mが、0、1又は2であり、
nが、0、1、2又は3であり、
L1が、-NH-C(=O)-、-C(=O)-NH-、-NH-C(=S)-、-C(=S)-NH-、-NH-C(=O)-CH2-、-C(=O)-NH-CH2-、-NH-C(=O)-CH2-CH2-、-C(=O)-NH-CH2-CH2-、-NH-C(=O)-O-又は-O-C(=O)-NH-であり、
L2が、単結合又は置換されていてもよいC1-6アルキル基であり、
Qが、単結合であり、
Xが、C6-10アリール基又は5~10員のヘテロアリール基(該C6-10アリール基及び5~10員のヘテロアリール基は、ハロゲン原子、水酸基、シアノ基、C1-6アルキル基、C1-6アルキルスルホニル基、C1-6アルコキシ基、C3-7脂環式基、C3-10脂環式オキシ基、C6-10アリール基、4~10員の非アリールヘテロ環基、4~10員の非アリールヘテロ環オキシ基、C6-10アリールオキシ基、5員若しくは6員のヘテロアリール基及び5員若しくは6員のヘテロアリールオキシ基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
Yが、C6-10アリール基、5~10員のヘテロアリール基又はC3-7脂環式基(該C6-10アリール基、6員のヘテロアリール基及びC3-7脂環式基は、ハロゲン原子、水酸基、シアノ基、C1-6アルキル基、C1-6アルキルスルホニル基、C1-6アルコキシ基、C3-7脂環式基、C3-10脂環式オキシ基、C6-10アリール基、4~10員の非アリールヘテロ環基、4~10員の非アリールヘテロ環オキシ基、C6-10アリールオキシ基、5員若しくは6員のヘテロアリール基及び5員若しくは6員のヘテロアリールオキシ基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
ここにおいて、XとYは、それぞれの環上の炭素原子で結合している、
化合物又はその製薬学的に許容される塩。
(B)
R1が、水素原子であり、
R2が、メトキシ基であり、
R3が、水素原子であり、
R4が、C1-6アルキル基、C3-7脂環式基又はC6-10アリール基(該C1-6アルキル基、C3-7脂環式基及びC6-10アリール基は、フッ素原子、塩素原子、C1-6アルキル基、C3-7脂環式基、C6-10アリール基、5員若しくは6員のヘテロアリール基及び4~10員の非アリールヘテロ環基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
mが、1又は2であり、
nが、0、1、2又は3であり、
L1が、-NH-C(=O)-又は-C(=O)-NH-であり、
L2が、単結合であり、
Qが、単結合であり、
Xが、C6-10アリール基又は5~10員のヘテロアリール基(該C6-10アリール基及び5~10員のヘテロアリール基は、ハロゲン原子、水酸基、シアノ基、C1-6アルキル基、C1-6アルキルスルホニル基、C1-6アルコキシ基、C3-7脂環式基、C3-10脂環式オキシ基、C6-10アリール基、4~10員の非アリールヘテロ環基、4~10員の非アリールヘテロ環オキシ基、C6-10アリールオキシ基、5員若しくは6員のヘテロアリール基及び5員若しくは6員のヘテロアリールオキシ基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
Yが、C6-10アリール基、5~10員のヘテロアリール基又はC3-7脂環式基(該C6-10アリール基、5~10員のヘテロアリール基及びC3-7脂環式基は、ハロゲン原子、水酸基、シアノ基、C1-6アルキル基、C1-6アルキルスルホニル基、C1-6アルコキシ基、C3-7脂環式基、C3-10脂環式オキシ基、C6-10アリール基、4~10員の非アリールヘテロ環基、4~10員の非アリールヘテロ環オキシ基、C6-10アリールオキシ基、5員若しくは6員のヘテロアリール基及び5員若しくは6員のヘテロアリールオキシ基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
ここにおいて、XとYは、それぞれの環上の炭素原子で結合している、
化合物又はその製薬学的に許容される塩。
(C)
R1が、水素原子であり、
R2が、メトキシ基であり、
R3が、水素原子であり、
R4が、C1-6アルキル基、C3-7脂環式基又はC6-10アリール基(該C1-6アルキル基、C3-7脂環式基及びC6-10アリール基は、フッ素原子、塩素原子、C1-6アルキル基、C3-7脂環式基、C6-10アリール基、5員若しくは6員のヘテロアリール基及び4~10員の非アリールヘテロ環基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
mが、1であり、
nが、0、1、2又は3であり、
L1が、-NH-C(=O)-又は-C(=O)-NH-であり、
L2が、単結合であり、
Qが、単結合であり、
Xが、フェニル基又は6員のヘテロアリール基(該フェニル基及び6員のヘテロアリール基は、ハロゲン原子、水酸基、シアノ基、C1-6アルキル基、C1-6アルキルスルホニル基、C1-6アルコキシ基、C3-7脂環式基、C3-10脂環式オキシ基、C6-10アリール基、4~10員の非アリールヘテロ環基、4~10員の非アリールヘテロ環オキシ基、C6-10アリールオキシ基、5員若しくは6員のヘテロアリール基及び5員若しくは6員のヘテロアリールオキシ基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
Yが、フェニル基又はシクロヘキシル基(該フェニル基及びシクロヘキシル基は、ハロゲン原子、水酸基、シアノ基、C1-6アルキル基、C1-6アルキルスルホニル基、C1-6アルコキシ基、C3-7脂環式基、C3-10脂環式オキシ基、C6-10アリール基、4~10員の非アリールヘテロ環基、4~10員の非アリールヘテロ環オキシ基、C6-10アリールオキシ基、5員若しくは6員のヘテロアリール基及び5員若しくは6員のヘテロアリールオキシ基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
ここにおいて、XとYは、それぞれの環上の炭素原子で結合している、
化合物又はその製薬学的に許容される塩。
(D)
R1が、水素原子であり、
R2が、メトキシ基であり、
R3が、水素原子であり、
R4が、C1-6アルキル基、C3-7脂環式基又はC6-10アリール基(該C1-6アルキル基、C3-7脂環式基及びC6-10アリール基は、フッ素原子、塩素原子、C1-6アルキル基、C3-7脂環式基、C6-10アリール基、5員若しくは6員のヘテロアリール基及び4~10員の非アリールヘテロ環基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
mが、1であり、
nが、0、1、2又は3であり、
L1が、-NH-C(=O)-又は-C(=O)-NH-であり、
L2が、単結合であり、
Qが、単結合であり、
Xが、フェニル基又はピリジル基(該フェニル基及びピリジル基は、ハロゲン原子、水酸基、シアノ基、C1-6アルキル基、C1-6アルキルスルホニル基、C1-6アルコキシ基、C3-7脂環式基、C3-10脂環式オキシ基、C6-10アリール基、4~10員の非アリールヘテロ環基、4~10員の非アリールヘテロ環オキシ基、C6-10アリールオキシ基、5員若しくは6員のヘテロアリール基及び5員若しくは6員のヘテロアリールオキシ基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
Yが、フェニル基又はシクロヘキシル基(該フェニル基及びシクロヘキシル基は、ハロゲン原子、水酸基、シアノ基、C1-6アルキル基、C1-6アルキルスルホニル基、C1-6アルコキシ基、C3-7脂環式基、C3-10脂環式オキシ基、C6-10アリール基、4~10員の非アリールヘテロ環基、4~10員の非アリールヘテロ環オキシ基、C6-10アリールオキシ基、5員若しくは6員のヘテロアリール基及び5員若しくは6員のヘテロアリールオキシ基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
ここにおいて、XとYは、それぞれの環上の炭素原子で結合している、
化合物又はその製薬学的に許容される塩。
(E)
R1が、水素原子であり、
R2が、メトキシ基であり、
R3が、水素原子であり、
R4が、C1-6アルキル基、C3-7脂環式基又はC6-10アリール基(該C1-6アルキル基、C3-7脂環式基及びC6-10アリール基は、フッ素原子、塩素原子、C1-6アルキル基、C3-7脂環式基、C6-10アリール基、5員若しくは6員のヘテロアリール基及び4~10員の非アリールヘテロ環基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
mが、1であり、
nが、0、1、2又は3であり、
L1が、-NH-C(=O)-又は-C(=O)-NH-であり、
L2が、単結合であり、
Qが、単結合であり、
Xが、下記式(A)であり、
aが、CR8又はNであり、
bが、CR9又はNであり、
cが、CR10又はNであり、
R8、R9及びR10が、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、C1-6アルキルスルホニル基、C1-6アルキル基又はC1-6アルコキシ基であり、
Yが、下記式(B)又は(C)である、
化合物又はその製薬学的に許容される塩。
(F)
R1が、水素原子であり、
R2が、メトキシ基であり、
R3が、水素原子であり、
R4が、メチル基、エチル基、イソプロピル基、シクロヘキシル基、シクロヘキシルメチル基、フェニル基又はベンジル基(該メチル基、エチル基、イソプロピル基、シクロヘキシル基、シクロヘキシルメチル基、フェニル基及びベンジル基は、フッ素原子、塩素原子及びC1-6アルキル基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)であり、
mが、1であり、
nが、0、1、2又は3であり、
L1が、-NH-C(=O)-又は-C(=O)-NH-であり、
L2が、単結合であり、
Qが、単結合であり、
Xが、下記式(A1)、(A2)又は(A3)であり、
Yが、下記式(B)又は(C)である、
化合物又はその製薬学的に許容される塩。
(G)
R1が、水素原子であり、
R2が、メトキシ基であり、
R3が、水素原子であり、
R4が、メチル基、エチル基、イソプロピル基、シクロヘキシル基、フェニル基(該メチル基、エチル基、イソプロピル基、シクロヘキシル基及びフェニル基は、フッ素原子、塩素原子及びC1-6アルキル基からなる群から選択される同一又は異なる1~3個の置換基で置換されていてもよい)であり、
mが、1であり、
nが、0、1、2又は3であり、
L1が、-NH-C(=O)-,-C(=O)-NH-であり、
L2が、単結合であり、
Qが、単結合であり、
Xが、下記式(A1)、(A2)又は(A3)であり、
Yが、下記式(B)又は(C)である、
化合物又はその製薬学的に許容される塩。
化合物a5は、化合物a1に、種々の縮合剤及び/又は塩基の存在下又は非存在下、適当な溶媒中、化合物a2を反応させることにより製造される。縮合剤としては、常法で使用される種々の縮合剤を使用することができるが、好ましくはプロピオホスホン酸無水物又は1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(塩酸塩を含む)が挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン、ジメチルホルムアミド又はクロロホルムが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a5は、化合物a3に、種々の縮合剤及び/又は塩基の存在下又は非存在下、適当な溶媒中、化合物a4を反応させることにより製造される。縮合剤としては、常法で使用される種々の縮合剤を使用することができるが、好ましくはプロピオホスホン酸無水物又は1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(塩酸塩を含む)が挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン、ジメチルホルムアミド又はクロロホルムが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a8は、化合物a5に触媒及び塩基存在下、化合物a6又はa7とカップリングすることにより製造される。触媒としては、パラジウム等の遷移金属やその塩、その錯体、ポリマー等の担体に担持させたものが挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくは炭酸ナトリウム、炭酸カリウム等が挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくは1,2-ジメトキシエタン及び水の混合溶媒が挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、20℃~150℃である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a12は、化合物a8に、種々の縮合剤及び/又は塩基の存在下又は非存在下、適当な溶媒中、化合物a9、a10又はa11を反応させることにより製造される。縮合剤としては、常法で使用される種々の縮合剤を使用することができるが、好ましくは1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(塩酸塩を含む)が挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン、ジメチルホルムアミド又はクロロホルムが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物A1は、化合物a12を触媒存在下で還元することにより製造される。還元剤としては、例えば水素、蟻酸アンモニウム等の蟻酸の塩、ヒドラジンを用いることができる。触媒としては、パラジウム、ニッケル、ロジウム、コバルト、白金等の遷移金属やその塩、その錯体、ポリマー等の担体に担持させたものが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくは酢酸エチル、エタノール又はメタノールが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a13は、化合物a8を触媒存在下で還元することにより製造される。還元剤としては、例えば水素、蟻酸アンモニウム等の蟻酸の塩、ヒドラジンを用いることができる。触媒としては、パラジウム、ニッケル、ロジウム、コバルト、白金等の遷移金属やその塩、その錯体、ポリマー等の担体に担持させたものが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくは酢酸エチル、エタノール又はメタノールが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a14は、化合物a13に、種々の縮合剤及び/又は塩基の存在下又は非存在下、適当な溶媒中、化合物a9、a10又はa11を反応させることにより製造される。縮合剤としては、常法で使用される種々の縮合剤を使用することができるが、好ましくはプロピオホスホン酸無水物又は1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(塩酸塩を含む)が挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン、ジメチルホルムアミド又はクロロホルムが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物A2は、化合物a14に、適当な溶媒中、種々の塩基を反応させることにより製造される。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくはアンモニアが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくは2-プロパノール又はテトラヒドロフランが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a17は、化合物a5に触媒及び塩基存在下、化合物a15又はa16とカップリングすることにより製造される。触媒としては、パラジウム等の遷移金属やその塩、その錯体、ポリマー等の担体に担持させたものが挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくは炭酸ナトリウム、炭酸カリウム等が挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくは1,2-ジメトキシエタン及び水の混合溶媒が挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、20℃~150℃である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a18は、化合物a17に、適当な溶媒中、種々の酸を反応させることにより製造される。酸としては、塩酸、トリフルオロ酢酸、酢酸、硫酸等が挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン又はアセトンが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a19は、化合物a18を触媒存在下で還元することにより製造される。還元剤としては、例えば水素、蟻酸アンモニウム等の蟻酸の塩、ヒドラジンを用いることができる。触媒としては、パラジウム、ニッケル、ロジウム、コバルト、白金等の遷移金属やその塩、その錯体、ポリマー等の担体に担持させたものが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくは酢酸エチル、エタノール又はメタノールが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a13は、化合物a19を触媒及び/又は塩基存在下で還元剤を用いて還元することにより製造される。また、還元剤のみを用いて、当該反応を行うこともできる。還元剤としては、例えば水素、蟻酸ナトリウム等の蟻酸の塩、ヒドラジン、水素化ホウ素ナトリウム又は水素化トリsec-ブチルホウ素リチウム等を用いることができる。触媒としては、ルテニウム、パラジウム、ニッケル、ロジウム、コバルト、白金等の遷移金属やその塩、その錯体、ポリマー等の担体に担持させたものが挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくはカリウムtert-ブトキシド、水酸化カリウム、トリエチルアミンが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン、2-プロパノール、エタノール、メタノール又はジメチルホルムアミドが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、-80℃~200℃、好ましくは、-80℃~100℃である。より好ましくは、0℃~100℃である。
化合物a22は、化合物a20に、種々の縮合剤及び/又は塩基の存在下又は非存在下、適当な溶媒中、化合物a2を反応させることにより製造される。縮合剤としては、常法で使用される種々の縮合剤を使用することができるが、好ましくはプロピオホスホン酸無水物又は1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(塩酸塩を含む)が挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン、ジメチルホルムアミド又はクロロホルムが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a22は、化合物a21に、種々の縮合剤及び/又は塩基の存在下又は非存在下、適当な溶媒中、化合物a4を反応させることにより製造される。縮合剤としては、常法で使用される種々の縮合剤を使用することができるが、好ましくはプロピオホスホン酸無水物又は1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(塩酸塩を含む)が挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン、ジメチルホルムアミド又はクロロホルムが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a23は、化合物a22に触媒及び塩基存在下、化合物a6又はa7とカップリングすることにより製造される。触媒としては、パラジウム等の遷移金属やその塩、その錯体、ポリマー等の担体に担持させたものが挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくは炭酸ナトリウム、炭酸カリウム等が挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくは1,2-ジメトキシエタン及び水の混合溶媒が挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、20℃~150℃である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物A3は、化合物a23に、種々の縮合剤及び/又は塩基の存在下又は非存在下、適当な溶媒中、化合物a9、a10又はa11を反応させることにより製造される。縮合剤としては、常法で使用される種々の縮合剤を使用することができるが、好ましくは1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(塩酸塩を含む)が挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン、ジメチルホルムアミド又はクロロホルムが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
製造法5
式[a23]で表される化合物は、例えば、下記の製法により製造することができる。
化合物a24は、化合物a22に触媒及び塩基存在下、化合物a15又はa16とカップリングすることにより製造される。触媒としては、パラジウム等の遷移金属やその塩、その錯体、ポリマー等の担体に担持させたものが挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくは炭酸ナトリウム、炭酸カリウム等が挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくは1,2-ジメトキシエタン及び水の混合溶媒が挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、20℃~150℃である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a25は、化合物a24に、適当な溶媒中、種々の酸を反応させることにより製造される。酸としては、塩酸、トリフルオロ酢酸、酢酸、硫酸等が挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン又はアセトンが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a26は、化合物a25を触媒存在下で還元することにより製造される。還元剤としては、例えば水素、蟻酸アンモニウム等の蟻酸の塩、ヒドラジンを用いることができる。触媒としては、パラジウム、ニッケル、ロジウム、コバルト、白金等の遷移金属やその塩、その錯体、ポリマー等の担体に担持させたものが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくは酢酸エチル、エタノール又はメタノールが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、0℃~200℃、好ましくは、0℃~100℃である。
化合物a23は、化合物a26を触媒及び/又は塩基存在下で還元剤を用いて還元することにより製造される。また、還元剤のみを用いて、当該反応を行うこともできる。還元剤としては、例えば水素、蟻酸ナトリウム等の蟻酸の塩、ヒドラジン、水素化ホウ素ナトリウム又は水素化トリsec-ブチルホウ素リチウム等を用いることができる。触媒としては、ルテニウム、パラジウム、ニッケル、ロジウム、コバルト、白金等の遷移金属やその塩、その錯体、ポリマー等の担体に担持させたものが挙げられる。塩基としては、後記に例示される塩基等から適宜選択されるが、好ましくはカリウムtert-ブトキシド、水酸化カリウム、トリエチルアミンが挙げられる。溶媒としては、後記に例示される溶媒等から適宜選択されるが、好ましくはテトラヒドロフラン、2-プロパノール、エタノール、メタノール又はジメチルホルムアミドが挙げられる。反応時間は、通常、5分~72時間であり、好ましくは30分~24時間である。反応温度は、通常、-80℃~200℃、好ましくは、-80℃~100℃である。より好ましくは、0℃~100℃である。
検出機器:ACQUITY(登録商標)SQ detector(Waters社)
HPLC:ACQUITY UPLC(登録商標)SYSTEM
Column:Waters ACQUITY UPLC(登録商標) BEH C18(1.7um, 2.1mm × 30mm)
Solvent:
A液;0.05%ギ酸/H2O、B液;アセトニトリル
Gradient Condition:
0.0-1.3分(linear gradient from B 10% to 95%)
1.3-1.5分(B 10%)
Flow rate:0.8ml/分
UV:220nm and 254nm
カラム温度:40℃
LC-MS,m/z; 427.08 (M+H)+ ESI, Rt; 1.071 (min)
LC-MS,m/z; 441.25 (M+H)+ ESI, Rt; 0.998 (min)
2-[4-(ベンジルオキシ)-3-メトキシフェニル]-N-[6-(3-ヒドロキシフェニル)ピリジン-2-イル]アセトアミド塩酸塩(1.0g)及びトリエチルアミン(0.791ml)のテトラヒドロフラン(23ml)溶液にイソブチリルクロリド(0.263ml)を加え、室温で3時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。硫酸ナトリウムで乾燥、ろ過、減圧濃縮し、参考例3の粗生成物を得た。
LC-MS,m/z; 511.34 (M+H)+ ESI, Rt; 1.234 (min)
3-(6-{2-[4-(ベンジルオキシ)-3-メトキシフェニル]アセトアミド}ピリジン-2-イル)フェニル 2-メチルプロパノエート(1.159g)の酢酸エチル溶液(30ml)にパラジウム-活性炭素(Pd 20%)(1.0g)を加え、水素雰囲気下室温で5時間攪拌した。反応液を窒素置換した後、セライトろ過し、減圧濃縮することで得た残渣に対してヘキサンを加え、粗生成物の固体を得た。得られた固体を2-プロパノールから再結晶することにより実施例1(352mg)を得た。
LC-MS,m/z; 421.2 (M+H)+ ESI, Rt; 0.993 (min)
1H-NMR (400 MHz, CD3OD) δ: 8.07 (1H, d, J = 8.0 Hz), 7.91 (1H, dd, J = 1.4, 7.8 Hz), 7.83-7.79 (2H, m), 7.61 (1H, d, J = 7.2 Hz), 7.48 (1H, t, J = 7.8 Hz), 7.14-7.10 (1H, m), 6.97 (1H, d, J = 2.0 Hz), 6.81 (1H, dd, J = 2.0, 8.4 Hz), 6.76 (1H, d, J = 7.6 Hz), 3.86 (3H, s), 3.67 (2H, s), 2.86 (1H, p, J =6.9 Hz), 1.33 (6H, d, J = 6.8 Hz).
LC-MS,m/z; 426.13 (M+H)+ ESI, Rt; 1.029 (min)
LC-MS,m/z; 440.30 (M+H)+ ESI, Rt; 0.955 (min)
2-(4-(ベンジルオキシ)-3-メトキシフェニル)-N-(3-ブロモフェニル)アセトアミド(500mg)、1,4-ジオキサスピロ[4,5]デカ-7-エン-8-フェニルボロン酸ピナコールエステル(343mg)、炭酸カリウム(486mg)の1,2-ジメトキシエタン(5ml)/水(1ml)溶液にジクロロビス(ジ-tert-ブチル(4-ジメチルアミノフェニル)ホスフィン)パラジウム(II)(42mg)を加え、3時間加熱還流した。反応液を濃縮後、クロロホルムを加え、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た。硫酸ナトリウムで乾燥、ろ過、減圧濃縮し、得られた参考例6の粗生成物(693mg)は次の反応にそのまま用いた。
LC-MS,m/z; 486.37 (M+H)+ ESI, Rt; 1.058 (min)
2-[4-(ベンジルオキシ)-3-メトキシフェニル]-N-[3-(1,4-ジオキサスピロ[4.5]デカ-7-エン-8-イル)フェニル]アセトアミドの粗生成物(693mg)のテトラヒドロフラン(30ml)溶液に、5mol/L塩酸(30ml)を加えて室温で1時間攪拌した。反応液に水を加えた後、酢酸エチルで抽出した。得られた有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過、減圧濃縮した。得られた参考例7の粗生成物(570mg)は次の反応にそのまま用いた。
LC-MS,m/z; 442.31 (M+H)+ ESI, Rt; 0.982 (min)
2-[4-(ベンジルオキシ)-3-メトキシフェニル]-N-(4’-オキソ-2’,3’,4’,5’-テトラヒドロ[1,1’-ビフェニル]-3-イル)アセトアミドの粗生成物(570mg)の酢酸エチル(10ml)溶液にパラジウム-活性炭素(Pd 20%)(250mg)を加え、水素雰囲気下、室温で7時間攪拌した。反応液を窒素置換した後、セライトろ過し、減圧濃縮することで得た残渣に対してジエチルエーテルを加え、析出した固体をろ取することで参考例8(202mg)を得た。
LC-MS,m/z; 354.14 (M+H)+ ESI, Rt; 0.678 (min)
LC-MS,m/z; 356.3 (M+H)+ ESI, Rt; 0.683 (min)
LC-MS,m/z; 356.2 (M+H)+ ESI, Rt; 0.632 (min)
LC-MS,m/z; 576.39 (M+H)+ ESI, Rt; 1.436 (min)
LC-MS,m/z; 350.2 (M+H)+ ESI, Rt; 0.684 (min)
対応する原料化合物を用いて参考例12と同様の方法により、表1に示す化合物を得た。
1H-NMR (400 MHz, CD3OD) δ: 7.45 (1H, t, J = 1.8 Hz), 7.39-7.35 (1H, m), 7.22 (1H, t, J = 7.6 Hz), 6.97 (1H, d, J = 8.0 Hz), 6.94 (1H, d, J = 1.2 Hz), 6.78 (1H, dd, J = 2.0, 6.0 Hz), 6.75 (1H, d, J = 8.0 Hz), 5.04 (1H, s), 3.86 (3H, s), 3.57 (2H, s), 2.63-2.54 (1H, m), 2.42-2.33(1H, m), 2.00-1.89 (4H, m), 1.85-1.63 (9H, m), 1.55-1.43 (2H, m), 1.43-1.25 (3H, m).
LC-MS,m/z; 466.3 (M+H)+ ESI, Rt; 1.134 (min)
1H-NMR (400 MHz, CD3OD) δ: 8.51 (1H, d, J = 6.4 Hz), 8.22 (1H, d, J = 2.0 Hz), 7.86 (1H, d, J = 6.4 Hz), 7.75 (1H, d, J = 8.4 Hz), 7.63-7.58 (2H, m), 7.29 (1H, dd, J = 2.6, 7.8 Hz), 6.94 (1H, d, J = 1.6 Hz), 6.81-6.75 (2H, m), 3.86 (3H, s), 3.70 (2H, s), 2.87 (1H, p, J = 7.0 Hz), 1.33 (6H, d, J = 7.2 Hz).
LC-MS,m/z; 421.3 (M+H)+ ESI, Rt; 0.707 (min)
対応する原料化合物を用いて実施例1、2及び49と同様の方法により、表2に示す化合物を得た。
以下に、本発明の代表的化合物の薬理試験結果を示し、該化合物についての薬理作用を説明するが、本発明はこれらの試験例に限定されるものではない。
(1)ヒトTRPV1一過性発現細胞の作製
ヒトTRPV1一過性発現細胞を作製し、培養に供した。具体的には、宿主細胞としてHEK293細胞(cat#CCL-82.2、ATCC)を用いた。TRPV1遺伝子(GenBank NP_542435.2)を挿入した哺乳類細胞発現pcDNA3.1ベクター(cat#v790-20、Invitrogen)の導入によりヒトTRPV1及びアポエクオリンを一過性に発現させた。
培地には10%非働化ウシ胎児血清(cat#10270-106、Thermo Fisher Scientific)を含むDulbecco’s Modified Eagle’s Medium(DMEM)培地(cat#11550-043、Thermo Fisher Scientific)を用い、組織培養用ディッシュ(cat#3020-100、Iwaki)にて培養を行った。培養中、2-3日毎に10%2.5g/1-トリプシン/1mol/L EDTA溶液、フェノールレッド(cat#32777-44、ナカライテスク)を含むPBS処理にて細胞を回収し、継代培養を行った。
継代から3日後、約80%コンフルエントな状態で10%トリプシン-PBS処理にて細胞を回収し、10%ウシ胎児血清含有DMEM培地にて4000 cells/35μl/wellとなるように懸濁し、384wellプレート(cat#353962、FALCON)に播種した。
播種翌日、Viviren(cat#E6492、Promega)を終濃度4.5μM/HBSS(cat#14065-056、Thermo Fisher Scientific)/90mM HEPES(cat#17514-15、ナカライテスク)/0.1%BSA(cat#01281-84、ナカライテスク)となるように添加し(15μl/well)、遠心後2時間室温、遮光下で静置した。
試験化合物は最終濃度の1000倍濃度のジメチルスルホキシド溶液を作製し、この溶液をHanks/20 mmol/L HEPES/0.1%BSA(cat#01281-84、ナカライテスク)にて最終濃度の10倍濃度に調製した。
TRPV1作動薬刺激による発光シグナルの検出にはFDSS7000(浜松ホトニクス)を用いた。細胞及び発光基質を添加したプレートに試験化合物を添加した。試験化合物添加後の発光シグナル(中心波長:465nm)を測定してRlu(Max-Min)を算出した。代表的化合物のTRPV1作動活性のデータを表3及び4に示す。
本試験は、薬物の嚥下障害改善作用を評価する試験である。ハロペリドールは、ドパミンD2受容体の阻害による嚥下反射の低下を引き起こすことから、抗精神病薬などによる薬剤誘発の嚥下障害のモデルだけでなくパーキンソン病など神経変性疾患を背景とした嚥下障害のモデル、また嚥下反射が低下するその他の嚥下障害のモデルとしても用いられる。Crl:CD(SD)雄性ラット(一群8匹、8週齢、体重280~310g:入荷時)にハロペリドールを投与した。具体的には、23G注射針(テルモ株式会社)を取り付けたポリプロピレン製ディスポーザブル注射筒(テルモ株式会社)を用いて、背部皮下に投与した。投与液量は、投与日に最も近い体重を基に5ml/kgで算出し、投与回数は、1日2回(12±2時間間隔)、7日間、計14回行いモデルを作製した。投与7日の翌日の午前中に嚥下回数を測定した。動物に25g注射針(テルモ株式会社)を取り付けたポリプロピレン製ディスポーザブル注射筒(テルモ株式会社)を用いて、腹腔内に麻酔薬を投与した[投与液量:当日の体重を基に2.3ml/kgで算出。ケタミン(90mg/kg)、キシラジン(10mg/kg)含有]。麻酔導入後、動物の顎下をバリカンで剪毛し、37℃に保温したヒートパッド上で四肢が動かないように仰臥位で保定した。動物の口にラット用ゾンデを1回挿入し、ゾンデの先端を咽頭に留めた。その状態を保ちながら、0.1mlの被験物質投与液を射出した。射出後、嚥下反射によって誘発される1回の嚥下動作を嚥下1回として計測した。1例あたり2回測定し、1回目の測定と2回目の測定の平均値を算出した。なお、ビークルは0.01%エタノールを用いた。結果を図1に示す。
本試験は、薬物の味覚嫌悪性を評価する試験である。Crl:CD(SD)ラット(一群8匹、入荷時8週齢)をホームケージにて飼育中に給水瓶に被験物質溶液を添加することで試験を行った。ケージあたり2本の給水瓶を準備し、それぞれにビークル(0.05%エタノール含有滅菌水)と被験物質溶液を充填して一晩飼育し、その間の飲水量を測定した。2本の給水瓶の合計飲水量から被験物質を飲水した割合を算出し、味覚嫌悪性の評価を行った。被験物質を飲水した割合が大きいほど味覚嫌悪性が小さく、被験物質による刺激性が小さいと評価できる。結果を表5に示す。
肝臓S9画分をリン酸バッファーで希釈した反応溶液中に化合物を添加し、37℃でインキュベーションを開始した(最終化合物濃度10nM、最終容量300μL)。15分間インキュベーションした後、反応液をアセトニトリルに添加することで反応を停止し、遠心分離を行った。上清をフィルター濾過後、LC/MS/MSを用いて化合物量を測定した。得られた化合物量から反応開始前(0分)の化合物量に対する反応を開始してから15分後の残存率を算出した。結果を表6に示す。
本試験は、薬物の嚥下機能亢進作用を評価する試験である。正常ラットにNaClを含む水を用いて嚥下反射を誘発すると、嚥下回数が抑制されることが報告されており、NaClを含む溶媒を用いて嚥下機能の亢進を評価した。Crl:CD(SD)雄性ラット(一群7~8匹、8~9週齢、体重280~310g:入荷時)麻酔導入後、動物の顎下をバリカンで剪毛し、37℃に保温したヒートパッド上で四肢が動かないように仰臥位で保定した。動物の口にラット用ゾンデを挿入し、ゾンデの先端を咽頭に留めた。その状態で、注入ポンプを用いて12ml/hで10秒間被験物質投与液を投与し、投与開始から30秒間の嚥下動作を計測した。なお、ビークルは1%エタノール、0.1%Tween80を含む生理食塩水を用いた。結果を表7に示す。溶媒投与群に比較してカプサイシン、実施例12、実施例2、実施例49では有意に嚥下回数が増加した(ダネットの検定:*は、P<0.05、**は、P<0.01、***は、P<0.001をそれぞれ示す)。
TRPV1作動薬は、高用量また繰り返し作用させることでTRPV1の脱感作を誘発することが知られている。試験例5と同様の方法を用いて、正常ラット嚥下機能に対する薬物の脱感作を誘発する作用を検討した。Crl:CD(SD)雄性ラット(一群7~8匹、8~9週齢、体重280~310g:入荷時)麻酔導入後、動物の顎下をバリカンで剪毛し、37℃に保温したヒートパッド上で四肢が動かないように仰臥位で保定した。動物の口にラット用ゾンデを挿入し、ゾンデの先端を咽頭に留めた。その状態で、注入ポンプを用いて12ml/hで10秒間被験物質投与液を投与し、投与開始から30秒間の嚥下動作を計測した。その後、約5分後に同様の試験を実施し、繰り返し計5回の評価を実施した。なお、ビークルは1%エタノール、0.1%Tween80を含む生理食塩水を用いた。結果を表8に示す。カプサイシンでは、投与1回目に比較して投与4回目と5回目に有意に嚥下回数が減少した(ダネットの検定:**はP<0.01を示す)。一方で、実施例49では有意な差は見られなかった。
TRPV1作動薬は刺激性があり、TRPV1作動薬溶液を眼に投与することで拭い行動を誘発することが報告されている。正常ラットを用いて化合物の刺激性について検討した。Crl:CD(SD)雄性ラット(一群5匹、8週齢、体重271~320g)を無麻酔下で保定し、右眼にマイクロピペットを用いて10μL滴下した。ただちに観察ケージ内に戻し、1分間拭い行動を観察した。拭い行動の回数を表9に示す。カプサイシンでは、30μM以上の濃度で有意に拭い行動が増加した(ダネットの検定:*はP<0.05、**はP<0.01をそれぞれ示す)。一方で、実施例12、実施例2、実施例1、実施例49では有意な差は見られなかった。
Claims (33)
- 式(2):
R1は、水素原子、C1-6アルキル基(該C1-6アルキル基は、水酸基、カルボキシル基及び-NR11R12からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)、置換されていてもよいC1-6アルキルカルボニル基又は置換されていてもよいC6-10アリールカルボニル基を表し、
R2は、メトキシ基、水酸基又は水素原子を表し、
R3は、水素原子、ハロゲン原子、置換されていてもよいC1-6アルキル基、置換されていてもよいC1-4アルコキシ基、置換されていてもよいC6-10アリール基又はホルミル基を表し、
R4は、置換されていてもよいC1-6アルキル基、置換されていてもよいC3-7脂環式基、置換されていてもよいC2-6アルケニル基、置換されていてもよいC2-6アルキニル基、置換されていてもよいC6-10アリール基、置換されていてもよいC1-6アルコキシ基、置換されていてもよいC3-7脂環式オキシ基、置換されていてもよいC6-10アリールオキシ基又は置換されていてもよい4~7員の非アリールヘテロ環基を表し、
ここにおいて、R4が置換されていてもよい4~7員の非アリールヘテロ環基である場合、該非アリールヘテロ環上の炭素原子がカルボニル基と結合しており、
R11は、水素原子、置換されていてもよいC1-3アルキル基、ホルミル基、置換されていてもよいC1-3アルキルカルボニル基、置換されていてもよいC1-4アルコキシカルボニル基又は置換されていてもよいC6-10アリールカルボニル基を表し、
R12は、水素原子又は置換されていてもよいC1-3アルキル基を表し、
mは、0、1又は2を表し、
nは、0、1、2又は3を表し、
L1は、-NH-C(=O)-、-C(=O)-NH-、-NH-C(=S)-、-C(=S)-NH-、-NH-C(=O)-CH2-、-C(=O)-NH-CH2-、-NH-C(=O)-CH2-CH2-、-C(=O)-NH-CH2-CH2-、-SO2-NH-、-NH-SO2-、-NH-C(=O)-O-又は-O-C(=O)-NH-を表し、
L2は、単結合又は置換されていてもよいC1-6アルキル基を表し、
Xは、置換されていてもよいフェニル基又は置換されていてもよい6員のヘテロアリール基を表し、
Yは、置換されていてもよいフェニル基、置換されていてもよい5員若しくは6員のヘテロアリール基、置換されていてもよいC3-7脂環式基又は置換されていてもよい4~7員の非アリールヘテロ環基を表し、
ここにおいて、XとYは、それぞれの環上の炭素原子で結合しており、
ただし、
1)式(W-1):
R1aが、水素原子又はアセチル基であり、
L1aが、-C(=O)-NH-又は-SO2-NH-である}で表される化合物、
2)式(W-2):
R1bが、メチル基又は-CD3であり、
R2bが、下記式(W-2A)、(W-2B)、(W-2C)、(W-2D)、又は(W-2R)であり、
R3bが、下記式(W-2E)、(W-2F)、(W-2G)、(W-2H)、(W-2I)、(W-2J)、(W-2K)、(W-2L)、(W-2M)、(W-2N)、(W-2O)、(W-2P)又は(W-2Q)であり、
Xbが、CH又はNであり、
Ybが、CH又はNであり、
Zbが、-CH2-又は-CHD-である}で表される化合物、
3)4’-{[2-(3,4-ジメトキシフェニル)エチル]カルバモイル}[1,1’-ビフェニル]-4-イル アセテート、
4)2’-(2-{[2-(3,4-ジメトキシフェニル)エチル]アミノ}-2-オキソエチル)-4,4’,5,5’-テトラメトキシ[1,1’-ビフェニル]-2-イル アセテート、
5)(2’-{[2-(3,4-ジメトキシフェニル)エチル]カルバモイル}-4,4’,5,5’-テトラメトキシ[1,1’-ビフェニル]-2-イル)メチル ベンゾエート、
6)6-[4-メトキシ-2-(2-{4-[2-(ピぺリジン-1-イル)エトキシ]フェニル}アセトアミド)フェニル]-5,6,7,8-テトラヒドロナフタレン-2-イル 2,2-ジメチルプロパノエート、
7)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル アセテート、
8)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル ベンゾエート、
9)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル 4-クロロベンゾエート、
10)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル 2-クロロベンゾエート、
11)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル 3-ニトロベンゾエート、及び
12)4’-{[(4-メトキシフェニル)メチル]スルファモイル}[1,1’-ビフェニル]-4-イル 2,4-ジクロロベンゾエートを除く]
で表される化合物又はその製薬学的に許容される塩。 - R3が、水素原子である、
請求項1に記載される化合物又はその製薬学的に許容される塩。 - mが、1又は2である、
請求項1又は2に記載される化合物又はその製薬学的に許容される塩。 - mが、1である、
請求項1又は2に記載される化合物又はその製薬学的に許容される塩。 - R1が、水素原子である、
請求項1~4のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - R2が、メトキシ基である、
請求項1~5のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - L1が、-NH-C(=O)-又は-C(=O)-NH-である、
請求項1~6のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - L2が、単結合である、
請求項1~7のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - Xが、式(A)であり、
ここにおいて、(1)aがNの場合、bがCR9であり、かつcがCR10であり、(2)bがNの場合、aがCR8であり、かつcがCR10であり、(3)cがNの場合、aがCR8であり、かつbがCR9である、
請求項1~9のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - Xが、式(A)であり、
ここにおいて、cがCR10であり、(1)aがNの場合、bがCR9であり、(2)bがNの場合、aがCR8である、
請求項1~9のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - Xが、式(A)であり、
ここにおいて、cがCHであり、(1)aがNの場合、bがCHであり、(2)bがNの場合、aがCHである、
請求項1~9のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - Xが、式(A)であり、
ここにおいて、a、b及びcがCHである、
請求項1~9のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - Yが、置換されていてもよいフェニル基、置換されていてもよい6員のヘテロアリール基又は置換されていてもよいC3-7脂環式基である、
請求項1~13のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - Yが、置換されていてもよいフェニル基又は置換されていてもよいシクロヘキシル基である、
請求項1~14のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - R4が、置換されていてもよいC1-6アルキル基、置換されていてもよいC3-7脂環式基、置換されていてもよいC2-6アルケニル基、置換されていてもよいC2-6アルキニル基又は置換されていてもよいC6-10アリール基である、
請求項1~16のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - R4が、置換されていてもよいC1-6アルキル基、置換されていてもよいC3-7脂環式基又は置換されていてもよいC6-10アリール基である、
請求項1~17のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - R4が、C1-6アルキル基、C3-7脂環式基又はC6-10アリール基(該C1-6アルキル基、C3-7脂環式基及びC6-10アリール基は、フッ素原子、塩素原子、C1-6アルキル基、C3-7脂環式基、C6-10アリール基、5員若しくは6員のヘテロアリール基及び4~10員の非アリールヘテロ環基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)である、
請求項1~18のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - R4が、メチル基、エチル基、イソプロピル基、シクロヘキシル基、シクロヘキシルメチル基、フェニル基又はベンジル基(該メチル基、エチル基、イソプロピル基、シクロヘキシル基、シクロヘキシルメチル基、フェニル基及びベンジル基は、フッ素原子、塩素原子及びC1-6アルキル基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)である、
請求項1~19のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - R4が、メチル基、エチル基、イソプロピル基、シクロヘキシル基、フェニル基(該メチル基、エチル基、イソプロピル基、シクロヘキシル基及びフェニル基は、フッ素原子、塩素原子及びC1-6アルキル基からなる群から選択される、同一又は異なる1~3個の置換基で置換されていてもよい)である、
請求項1~20のいずれか一項に記載される化合物又はその製薬学的に許容される塩。 - 以下の化合物から選択される、請求項1に記載の化合物又はその製薬学的に許容される塩:
3-{6-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル 2-メチルプロパノエート、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル シクロヘキサンカルボキシレート、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(3-メチルフェニル)アセテート、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(2-クロロフェニル)アセテート、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル アセテート、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル(2-フルオロフェニル)アセテート、
シス-4-{3-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]フェニル}シクロヘキシル 2-メチルプロパノエート、
2’-フルオロ-5’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル 2-メチルプロパノエート、
3’-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド][1,1’-ビフェニル]-3-イル 2-メチルプロパノエート、
3-{4-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル 2-メチルプロパノエート
3-(4-{[(4-ヒドロキシ-3-メトキシフェニル)メチル]カルバモイル}ピリジン-2-イル)フェニル 2-メチルプロパノエート、及び
3-{4-[2-(4-ヒドロキシ-3-メトキシフェニル)アセトアミド]ピリジン-2-イル}フェニル 2-メチルプロパノエート 塩酸塩。 - 請求項1~22のいずれか一項に記載の化合物又はその製薬学的に許容される塩を有効成分として含有する医薬。
- 請求項1~22のいずれか一項に記載の化合物又はその製薬学的に許容される塩を有効成分として含有するTRPV1が関与する障害又は疾患の治療薬又は予防薬。
- TRPV1が関与する障害又は疾患が、嚥下障害である、請求項24に記載の治療薬又は予防薬。
- 請求項1~22のいずれか一項に記載の化合物又はその製薬学的に許容される塩を含有する医薬組成物。
- TRPV1が関与する障害又は疾患を治療又は予防するための、請求項26に記載の医薬組成物。
- 嚥下障害を治療又は予防するための、請求項26に記載の医薬組成物。
- 治療又は予防が必要な患者に、治療又は予防上の有効量の請求項1~22のいずれか一項に記載の化合物又はその製薬学的に許容される塩を投与することを含む、TRPV1が関与する障害又は疾患を治療又は予防するための方法。
- TRPV1が関与する障害又は疾患の治療薬又は予防薬を製造するための、請求項1~22のいずれか一項に記載の化合物又はその製薬学的に許容される塩の使用。
- TRPV1が関与する障害又は疾患の治療又は予防に使用するための、請求項1~22のいずれか一項に記載の化合物又はその製薬学的に許容される塩。
- 請求項1~22のいずれか一項に記載の化合物又はその製薬学的に許容される塩と、1又は複数の他の薬剤とを組み合わせてなる医薬組成物。
- 1又は複数の他の薬剤と併用して、TRPV1が関与する障害又は疾患を治療又は予防するための、請求項1~22のいずれか一項に記載の化合物又はその製薬学的に許容される塩を含有する医薬組成物。
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