WO2019156074A1 - アミノアルキル化合物 - Google Patents
アミノアルキル化合物 Download PDFInfo
- Publication number
- WO2019156074A1 WO2019156074A1 PCT/JP2019/004071 JP2019004071W WO2019156074A1 WO 2019156074 A1 WO2019156074 A1 WO 2019156074A1 JP 2019004071 W JP2019004071 W JP 2019004071W WO 2019156074 A1 WO2019156074 A1 WO 2019156074A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- hydrogen atom
- dimethylaminomethyl
- Prior art date
Links
- -1 Aminoalkyl compound Chemical class 0.000 title description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 27
- 208000002193 Pain Diseases 0.000 claims abstract description 18
- 230000002265 prevention Effects 0.000 claims abstract description 5
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 39
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 15
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 208000000094 Chronic Pain Diseases 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- XYTMPKSCEDWOSQ-UHFFFAOYSA-N 3-[3-[(dimethylamino)methyl]-4-fluorooxan-4-yl]phenol Chemical compound CN(C)CC1COCCC1(F)C=1C=C(C=CC=1)O XYTMPKSCEDWOSQ-UHFFFAOYSA-N 0.000 claims description 4
- YXWYFYLNAMMYMC-OCCSQVGLSA-N 3-[(3R,4R)-3-[(dimethylamino)methyl]oxan-4-yl]phenol Chemical compound CN(C)C[C@@H]1COCC[C@H]1C=1C=C(C=CC=1)O YXWYFYLNAMMYMC-OCCSQVGLSA-N 0.000 claims description 3
- 206010058019 Cancer Pain Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 230000000622 irritating effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 239000007788 liquid Substances 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 230000035484 reaction time Effects 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
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- 239000000126 substance Substances 0.000 description 9
- 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 8
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- 229910052783 alkali metal Inorganic materials 0.000 description 7
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- 210000003491 skin Anatomy 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
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- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 5
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 5
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
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- 230000001070 adhesive effect Effects 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
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- JIRYWFYYBBRJAN-ZFWWWQNUSA-N faxeladol Chemical compound CN(C)C[C@@H]1CCCC[C@H]1C1=CC=CC(O)=C1 JIRYWFYYBBRJAN-ZFWWWQNUSA-N 0.000 description 4
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- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- 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
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- 230000037396 body weight Effects 0.000 description 3
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- 238000004587 chromatography analysis Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
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- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 2
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- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
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- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Inorganic materials [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
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- 239000001488 sodium phosphate Substances 0.000 description 1
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- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 description 1
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- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
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- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
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- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
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- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000006097 ultraviolet radiation absorber Substances 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
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- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- 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
- C07D309/06—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- 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
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- the present invention relates to a novel compound used for the treatment and / or prevention of pain with excellent skin permeability and reduced skin irritation, a salt thereof, or a hydrate thereof, and further to a patch containing the compound. .
- a transdermal preparation is a preparation intended to deliver an active ingredient through the skin to the systemic circulation.
- the percutaneous absorption preparations mainly include a method that requires an absorption enhancing technique for changing the barrier function of the stratum corneum and a method that uses a transdermal absorbable compound as a patch.
- Methods that require absorption promotion technology include methods using absorption promoters and methods such as microneedles that destroy the stratum corneum, but these methods are accompanied by skin irritation. Side effects such as these have been reported (Non-patent Documents 2-5).
- the method of preparing a patch that transdermally absorbs a compound with almost no absorption enhancer or the like has been used mainly by changing the route of administration of a drug that is difficult to administer orally. It has been said that it is difficult to find a new compound by such a method in the future, since studies on existing drugs that can be percutaneously absorbed by such a method have been made widely. With a focus on the physical properties necessary for percutaneous absorption, the design of a compound imparted with percutaneous absorbability by newly synthesized development is expected as a new patch.
- Non-Patent Document 6-8 There are several patches currently used in clinical practice for the treatment of cancer pain and non-cancerous chronic pain. Many of such patches have strong side effects, but have side effects such as vomiting, nausea and constipation. In addition, since the skin permeability of the active ingredient is usually low, it is often used as a patch by incorporating a transdermal absorption enhancer, and side effects such as pruritus and erythema are reported at the site of application. (Non-Patent Document 6-8).
- Non-patent Documents 9-11 There is a need for a novel compound suitable for a patch with the same degree of efficacy as an analgesic used as an oral preparation, an injection, and the like, as a medicine that expands the range of options for the treatment and / or prevention of pain.
- the present inventor has found that the compound of the present invention has reduced side effects, strong analgesic action, good pharmacokinetics and solubility, and skin permeability. As a result, the present invention has been completed.
- a compound of formula (I) or a pharmaceutically acceptable salt thereof is as described below.
- R 1 is a hydrogen atom or a methyl group.
- R 2 is a hydrogen atom or a fluorine atom.
- R 3 is a hydrogen atom or a methyl group.
- R 4 is a hydrogen atom or a methyl group.
- R 5 is a hydrogen atom or a methyl group.
- [12] The compound according to any one of [1]-[8] or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of pain.
- [13] [11] The pharmaceutical composition according to [11], wherein the pain is cancer pain and / or non-cancer chronic pain.
- [14] [9] A method for treating and / or preventing pain, comprising administering an effective amount of the pharmaceutical composition according to [10].
- the compound having a specific chemical structure of the present invention or a pharmaceutically acceptable salt thereof has characteristics different from those of existing analgesics from various aspects, and thus is useful as a novel pharmaceutical product. Conceivable.
- the compounds of the present invention and pharmaceutically acceptable salts thereof have analgesic activity, bioavailability, in vitro activity, in vivo activity, rapid onset of drug efficacy, sustained drug efficacy, physical stability, It has excellent properties in terms of drug interaction and toxicity and is useful as a medicine.
- the compound of the present invention and pharmaceutically acceptable salts thereof have excellent solubility in the composition employed in the patch by optimizing the molecular weight, fat solubility, etc. Since it has excellent properties, it is useful because it exhibits excellent effects when used as a patch.
- R 1 is a hydrogen atom or a methyl group.
- R 2 is a hydrogen atom or a fluorine atom.
- R 3 is a hydrogen atom or a methyl group.
- R 4 is a hydrogen atom or a methyl group.
- R 5 is a hydrogen atom or a methyl group.
- a particularly preferred embodiment of the present invention is the compound described in the examples or a pharmaceutically acceptable salt thereof.
- the compounds of the present invention are usually named according to the nomenclature of the International Union of Pure and Applied Chemistry (IUPAC).
- IUPAC International Union of Pure and Applied Chemistry
- the absolute configuration may be indicated by R and S (denoted together with the position number).
- Relative arrangement is indicated by adding an asterisk (R * and S * ) to the arrangement display when the first asymmetric center arrangement is R or S, or prefix (symbol) rel- ( It may be indicated with relative meaning.
- Racemic mixtures usually indicate their absolute configuration without R and S, but use the symbols RS and SR instead of R * and S * or prefix (symbol) rac- ( In some cases, racemic meaning is indicated.
- “Pharmaceutically acceptable salt thereof” refers to a salt that can be used as a medicine.
- the compound of the present invention or a pharmaceutically acceptable salt thereof When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the air or recrystallized, it may absorb water and adsorb water or become a hydrate.
- the present invention also includes such various hydrates, solvates and polymorphic compounds.
- the compound of the present invention may be a geometric isomer such as a cis isomer or a trans isomer, a tautomer, a d isomer, or an l isomer depending on the type or combination of substituents.
- a geometric isomer such as a cis isomer or a trans isomer, a tautomer, a d isomer, or an l isomer depending on the type or combination of substituents.
- There may be various isomers such as optical isomers, etc., but the compound may include all isomers, stereoisomers and any ratio of these isomers and stereoisomer mixtures unless otherwise specified. It is included. A mixture of these isomers can be separated by a known resolution means.
- the compounds of the present invention also include label bodies, that is, compounds in which one or more atoms of the compound are substituted with isotopes (eg, 2H, 3H, 13C, 14C, 35S,
- the compound of the formula (I) of the present invention can be produced according to Method A or Method B described below.
- solvent used in the reaction of each step of the following method A or B is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example.
- Solvent groups include hydrocarbons such as pentane, n-hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N Amides such as methyl-2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, cyclopentyl methyl ether Methanol, ethanol, n-propanol, i-propanol, n-but
- the base used in the reaction of each step of the following method A or B is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal bicarbonates such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates such as cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide and lithium hydroxide; alkali metal phosphates such as sodium phosphate and potassium phosphate; like L-proline sodium and L-proline potassium Alkali metal salts such as sodium fluoride and potassium fluoride Inorganic bases such as potassium metal fluorides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium-t-butoxide, potassium-t-butoxide; sodium tri
- reaction temperature varies depending on the solvent, starting material, reagent, etc.
- reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.
- each target compound is collected from the reaction mixture according to a conventional method.
- the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent.
- the obtained target compound can be used in a conventional manner, for example, recrystallization, reprecipitation, chromatography (for example, silica gel, alumina, magnesium-silica gel-type florisil, SO3H-silica (manufactured by Fuji Silysia))
- a method using a synthetic adsorbent such as distributed column chromatography; a method using ion exchange chromatography; a normal phase / reverse phase column chromatography method (preferably high performance liquid chromatography) using silica gel or alkylated silica gel
- a combination of methods commonly used for separation and purification of organic compounds, such as It can be separated and purified.
- the obtained solid crude product can be purified by washing with a solvent.
- Method A is a method for producing the compound (A8) or (A9) of the present invention.
- L A leaving group usually used in this field, such as a sulfonyloxy group.
- a sulfonyloxy group For example, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like.
- R a1 represents a methyl group
- R a2 represents a methyl group
- R a3 represents a hydrogen atom or a methyl group
- R a4 represents a hydrogen atom or a methyl group
- R a5 represents a hydrogen atom or a methyl group.
- This step is a step of producing compound (A3) by reacting compound (A1) with boric acid compound (A2) in a solvent in the presence of a base.
- the solvent used in this step is preferably an amide or an ether, and more preferably N, N-dimethylformamide or 1,4-dioxane.
- the base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.
- the reaction temperature in this step is usually 50-120 ° C, preferably 80-100 ° C.
- the reaction time in this step is usually 3-72 hours, preferably 12-48 hours. This step can be performed under microwave irradiation.
- the reaction time at that time is usually 10 minutes to 3 hours, preferably 15 to 90 minutes.
- Step A-II This step is a step for producing the compound (A4) by hydrogenating the compound (A3) in the presence of palladium carbon in a solvent.
- the solvent used in this step is preferably an alcohol, and more preferably methanol.
- the reaction temperature in this step is usually 20-50 ° C, preferably 20-30 ° C.
- the reaction time in this step is usually 1-24 hours, preferably 1-6 hours.
- Step A-III is a step for producing compound (A5) by subjecting compound (A4) to an isomerization reaction in a solvent in the presence of a base.
- the solvent used in this step is preferably an alcohol, and more preferably methanol.
- the base used in this step is preferably an alkali metal alkoxide, and more preferably sodium methoxide.
- the reaction temperature in this step is usually 20-100 ° C, preferably 40-70 ° C.
- the reaction time in this step is usually 1-24 hours, preferably 20-24 hours.
- Step A-IV This step is a step for producing the compound (A6) by reacting the compound (A5) with lithium aluminum hydride in a solvent.
- the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
- the reaction temperature in this step is usually 0-60 ° C, preferably 0-20 ° C.
- the reaction time in this step is usually 1-24 hours, preferably 1-2 hours.
- Step AV This step is a step for producing compound (A7) by reacting compound (A6) with, for example, methanesulfonyl chloride in a solvent in the presence of a base.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the base used in this step is preferably a tertiary alkylamine, and more preferably triethylamine.
- the reaction temperature in this step is usually -10-0 ° C, preferably -5-0 ° C.
- the reaction time in this step is usually 1-24 hours, preferably 12-24 hours.
- Step A-VI is a step for producing compound (A8) by reacting compound (A7) with dimethylamine hydrochloride in the presence of a base in a solvent.
- the solvent used in this step is preferably an amide or an ether, and more preferably N, N-dimethylformamide.
- the base used in this step is preferably a tertiary alkylamine, and more preferably triethylamine.
- the reaction temperature in this step is usually 50-120 ° C, preferably 80-100 ° C.
- the reaction time in this step is usually 3-72 hours, preferably 12-48 hours. This step can be performed under microwave irradiation. In this case, the reaction time is usually 10 minutes to 3 hours, preferably 15 minutes to 90 minutes.
- Step A-VII This step is a step for producing the compound (A9) by reacting the compound (A8) with a boron tribromide methylene chloride solution in a solvent.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the reaction temperature in this step is usually -78 ° C-0 ° C, preferably -78 ° C-40 ° C.
- the reaction time in this step is usually 1-24 hours, preferably 12-24 hours.
- Method B is a method for producing the compound (B5) of the present invention.
- R b1 represents a methyl group
- R b3 represents a hydrogen atom or a methyl group
- R b4 represents a hydrogen atom or a methyl group
- R b5 represents a hydrogen atom or a methyl group.
- This step is a step for producing compound (B3) by reacting compound (B1) with magnesium bromide compound (B2) in a solvent.
- the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
- the reaction temperature in this step is usually 0-60 ° C, preferably 0-30 ° C.
- the reaction time in this step is usually 1-24 hours, preferably 2-6 hours.
- Step B-II This step is a step for producing the compound (B4) by reacting the compound (B3) with N, N-diethylaminosulfur trifluoride in a solvent.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the reaction temperature in this step is usually -78-0 ° C, preferably -78--40 ° C.
- the reaction time in this step is usually 1-24 hours, preferably 12-24 hours.
- Step B-III This step is a step for producing a compound (B5) by hydrogenating the compound (B4) in the presence of palladium on carbon in a solvent.
- the solvent used in this step is preferably an alcohol, and more preferably methanol.
- the reaction temperature in this step is usually 20-50 ° C, preferably 20-30 ° C.
- the reaction time in this step is usually 1-24 hours, preferably 1-6 hours.
- the compound (A1) and the compound (B1) are known compounds, or can be easily produced according to a known method or a similar method using a known compound as a starting material.
- the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in various forms. Its administration is oral administration by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as joints, veins, intramusculars, suppositories, eye drops, eye ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
- Solid compositions for oral administration include Tablets, powders, granules and the like are used.
- Such a solid composition contains one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxy, etc. Produced by mixing with propyl cellulose, microcrystalline cellulose, starch, polyvinyl pipridone, and / or magnesium aluminate metasilicate.
- the composition may contain inert additives such as lubricants such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, stabilizers and solubilizers according to conventional methods. Good. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
- Liquid compositions for oral administration are: Contains pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, and contains generally used inert diluents such as purified water or ethanol.
- the liquid composition may contain solubilizers, wetting agents, adjuvants such as suspending agents, sweeteners, flavoring agents, fragrances and preservatives in addition to the inert diluent.
- Injection for parenteral administration Contains sterile aqueous or non-aqueous solutions, suspensions or emulsions.
- aqueous solvent include distilled water for injection or physiological saline.
- non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or bolisolvate 80.
- Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericidal agent or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
- ointments As an external preparation, Includes ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments, patches and the like. These preparations contain generally used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions and the like.
- ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
- a non-aqueous base material can be used as a carrier.
- Specific examples include rubber adhesives, acrylic adhesives, silicone adhesives, and the like.
- the rubber component of the rubber adhesive include natural rubber, polyisoprene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene / butadiene rubber and polyisobutylene.
- the non-aqueous base material can further contain a plasticizer, a tackifier, a permeation accelerator and / or a stabilizer.
- the plasticizer is not particularly limited.
- petroleum oil paraffinic process oil, naphthenic process oil, aromatic process oil, etc.
- squalane squalene
- vegetable oil olive oil, camellia oil, castor oil, Tall oil, peanut oil, etc.
- silicon oil dibasic acid ester (dibutyl phthalate, dioctyl phthalate, etc.)
- liquid rubber polybutene, liquid isoprene rubber, etc.
- liquid fatty acid ester isopropyl myristate, hexyl laurate, diethyl sebacate
- diisopropyl sebacate diethylene glycol, polyethylene glycol, glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, crotamiton and the like.
- the tackifier is not particularly limited.
- rosin derivatives rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, pentaerythritol ester of rosin
- alicyclic saturated hydrocarbon resin Aliphatic hydrocarbon resins, terpene resins, and maleic resin.
- the permeation enhancer is not particularly limited as long as the permeation promoting action in the skin is recognized.
- the fatty acid having 6 to 20 carbon atoms, aliphatic alcohol, fatty acid ester, amide or ether, aromatic Aromatic organic acid, aromatic alcohol, aromatic organic acid ester or ether.
- an antioxidant As the stabilizer, an antioxidant, an ultraviolet absorber or the like can be used.
- Antioxidants include tocopherols and their ester derivatives, ascorbic acid, ascorbic acid stearate, nordihuman logayaretinic acid, dibutylhydroxytoluene (BHT) and butylhydroxyanisole;
- UV absorbers include p -Aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, imidazoline derivatives, pyrimidine derivatives and dioxane derivatives.
- Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods.
- known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
- an appropriate device for inhalation or insufflation can be used.
- a known device or nebulizer such as a metered dose inhalation device
- the compound is administered as a solution or suspension alone or as a powder in a formulated mixture, or in combination with a pharmaceutically acceptable carrier. be able to.
- the dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
- a suitable propellant for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
- the daily dose is about 0.001-100 mg / kg, preferably 0.1-30 mg / kg, more preferably 0.1-10 mg / kg per body weight. Divide into two or more doses.
- the daily dose is suitably about 0.0001-10 mg / kg per body weight, and is administered once or divided into multiple doses per day.
- a transdermal agent about 0.001-100 mg / kg per body weight is administered once a day or divided into multiple times. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
- Combination In this invention, it can use together with the various therapeutic agent or preventive agent of the disease considered to show the effectiveness.
- the combination may be administered simultaneously, separately separately, or at desired time intervals.
- the simultaneous administration preparation may be a compounding agent or may be separately formulated.
- the patch of the present invention was produced from the following components. Active ingredient: 10% by weight of the compound of Example 1 Rubber component of rubber adhesive: Styrene-isoprene-styrene block copolymer 20% Plasticizer: Liquid paraffin 40% by weight Tackifier: Rosin 30% by weight
- Active ingredient 10% by weight of the compound of Example 1
- Rubber component of rubber adhesive Styrene-isoprene-styrene block copolymer 20%
- Plasticizer Liquid paraffin 40% by weight
- Tackifier Rosin 30% by weight
- the above components were melt-kneaded at 150 ° C., the melt-kneaded product was spread on a pet film, and then a polyester cloth was pasted, and then cut into a desired size to obtain a patch.
- silica gel 60F254 manufactured by Merck was used as a TLC plate, a solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method.
- Silica gel for column is Merck silica gel SK-85 (230-400 mesh), Yamazen silica gel (Hi-FlashTM Column, INJECT COLUMNTM), Biotage silica gel (SNAP, SNAP Ultra) or Fuji Silysia Chemical Silica gel (FL100B, Chromatorex-SO3H) manufactured by the company was used.
- Yamazen's automated chromatography device YFLC-5405-FC-GRII, WPrep 2XY
- Biotage's automated chromatography device Isolera, SP-1
- mg milligram
- g gram
- mL milliliter
- MHz megahertz
- Hz hertz
- the nuclear magnetic resonance (hereinafter, 1 H-NMR) spectrum is described with a chemical shift value as a ⁇ value (ppm) using tetramethylsilane as a standard substance.
- CDCl 3 deuterated chloroform
- MeOH-d 4 deuterated methanol
- DMSO-d 6 deuterated dimethyl sulfoxide was used.
- the split pattern is s for single line, d for double line, t for triple line, q for quadruple line, quint for quintet line, sext for hexan line, hept for heptet, m for multiple line, broad for br It showed in.
- MS Mass spectrometry
- Example 1 3-[(3R * , 4R * )-3- (dimethylaminomethyl) tetrahydropyran-4-yl] phenol
- the configuration in the following structural formulas indicates only the relative configuration of substituents.
- the compound of this example is a mixture of two enantiomers.
- the reaction mixture was diluted with ethyl acetate, and the organic layer was washed twice with water and saturated brine, and then dried over anhydrous magnesium sulfate.
- the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (11.8 g) as a yellow oil.
- the reaction mixture was diluted with methylene chloride, and the organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (2.40 g) as a yellow oil.
- Example 2 3-[(4R * , 5R * )-5- (dimethylaminomethyl) -2,2-dimethyltetrahydropyran-4-yl] phenol
- the steric configuration in the following structural formula is only the relative configuration of the substituent.
- the compound of this example is a mixture of two enantiomers.
- Example 4 3-[(3R * , 4R * )-3- (dimethylaminomethyl) tetrahydropyran-4-yl] -2-methylphenol
- the configuration in the following structural formulas indicates only the relative configuration of the substituents.
- the compound of this example is a mixture of two enantiomers.
- the obtained solid was washed with ethanol to obtain a pale yellow solid (1.50 g).
- Aqueous ammonia and methylene chloride were added to the obtained solid to separate it.
- the organic layer was washed with water and then dried over anhydrous magnesium sulfate.
- the organic layer was concentrated under reduced pressure to obtain the title compound (1.50 g) as a white solid.
- reaction mixture was cooled to -5 ° C, water was added, and the mixture was extracted with methylene chloride.
- the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate.
- the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride / methanol) to give the title compound (110 mg) as a colorless oil.
- Test Example 1 (1) Preparation of test substance The compounds described in the examples were used by dissolving or suspending them in isopropyl myristate (IPM) to a concentration of 3.84 mmol / L. The results of the dissolved state in IPM are shown in Table 1.
- IPM isopropyl myristate
- Table 1 The results of the dissolved state in IPM are shown in Table 1.
- (2) Hairless mouse skin permeation test Frozen hairless mouse skin (HR-1 strain, male, 7 weeks old, SLC Japan) was thawed at room temperature, and if there was excess subcutaneous fat, it was excised with scissors. In the horizontal diffusion cell, the temperature of the cell was kept constant by flowing water in a constant temperature circulating water tank (37 ° C.) through the outer jacket of the cell.
- Hairless mouse skin is punched to ⁇ 24mm, sandwiched between horizontal diffusion cells, 0.9mL of receiver liquid (McIlvaine buffer containing 40% polyethylene glycol 400) is added to the dermis side (receiver side), and donor liquid is added to the stratum corneum side (donor side) 0.9 mL of a solution prepared by dissolving or suspending the compound described in the Example so as to have a concentration of 3.84 mmol / L in IPM was added. After application of the donor liquid, 0.45 mL of liquid was collected from the receiver side after an arbitrary time (2, 4, 6, 8, 24 hours after application), and the same amount of new receiver liquid was added. The collected liquid was stored at -80 ° C.
- receiver liquid McIlvaine buffer containing 40% polyethylene glycol 400
- Faxeladol represents 3-[(1R, 2R) -2-[(dimethylamino) methyl] cyclohexyl] phenol).
- Tail Flick test Evaluation of analgesic score in Tail Flick test of mice
- a Tail Flick type analgesic effect measuring device Ugo Brasile
- an adult mouse C57BL / 6JJmsSlc, SLC Japan
- the latency (unit: seconds) of the escape reflex that moves the tail by applying a thermal stimulus to the tail of the animal was measured.
- the maximum irradiation time was 10 seconds.
- the compound described in the Examples was dissolved or suspended in Captisol to prepare as a test substance, which was then subcutaneously administered (10 mL / kg) to an animal at an appropriately selected concentration, and the latency of escape reflex was measured.
- the latency of the escape reflex before administration of the test substance is defined as [measurement value before administration], and the analgesic score (%) is calculated as [([measurement value]-[measurement value before administration]) / (10- [measurement value before administration] )] ⁇ 100.
- the ED50 was determined by calculating the dose at which the analgesic score was 50%. The results of this test are shown in Table 2.
- the compound of the present invention showed excellent skin permeability and strong analgesic action.
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Abstract
Description
経皮吸収型製剤には、角層のバリア機能に変化を加える吸収促進技術を必要とする方法と経皮吸収性を有する化合物を経皮吸収させる貼付剤とする方法が主にある。吸収促進技術を必要とする方法には吸収促進剤を用いる方法やマイクロニードルなど角層の構造破壊による方法があるが、これらの方法は皮膚刺激性が伴うため、適用部位掻痒感や適用部位紅斑などの副作用が報告されている(非特許文献2-5)。
吸収促進剤の配合量が上限を超えると、発赤、浮腫等の要因となる皮膚への刺激性が高くなる傾向にある。吸収促進剤等をほとんど用いずに化合物を経皮吸収させる貼付剤とする方法は、主に経口投与などが困難な薬物を投与経路変更させることで用いられてきた。
このような方法で経皮吸収できる既存薬での検討が長く広くなされてきたため、今後はこのような方法で新たな化合物を見出すのは難しいといわれている。経皮吸収性に必要な物性等に着目した上で、新規に合成展開することによる経皮吸収性を付与した化合物の設計が新たな貼付剤として期待されている。
[1]
式(I)の化合物、又は、その薬学的に許容される塩。
R1は、水素原子、又は、メチル基である。
R2は、水素原子、又は、フッ素原子である。
R3は、水素原子、又は、メチル基である。
R4は、水素原子、又は、メチル基である。
R5は、水素原子、又は、メチル基である。)
[2]
R1が、水素原子である、[1]に記載の化合物、又は、その薬学的に許容される塩。
[3]
R2が、水素原子である、[1]又は[2]に記載の化合物、又は、その薬学的に許容される塩。
[4]
R3が、水素原子である、[1]-[3]のいずれか1項に記載の化合物、又は、その薬学的に許容される塩。
[5]
R4及びR5が、水素原子である、[1]-[4]のいずれか1項に記載の化合物、又は、その薬学的に許容される塩。
[6]
式(I)の化合物が、以下に示される化合物のいずれかである[1]に記載の化合物、又は、その薬学的に許容される塩。
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]フェノール
3-[(4R*,5R*)-5-(ジメチルアミノメチル)-2、2-ジメチルテトラヒドロピラン-4-イル]フェノール
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]-5-メチルフェノール
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]-2-メチルフェノール
3-[3-ジメチルアミノメチル-4-フルオロテトラヒドロピラン-4-イル]-フェノール
[7]
以下に示される化合物、又は、その薬学的に許容される塩。
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]フェノール
[8]
以下に示される化合物、又は、その薬学的に許容される塩。
3-[(3R,4R)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]フェノール
[9]
[1]-[8]のいずれか1項に記載の化合物、又は、その薬学的に許容される塩を有効成分として含有する医薬組成物。
[10]
貼付剤である、[9]に記載の医薬組成物。
[11]
痛みを治療及び/又は予防するための、[9]又は[10]に記載の医薬組成物。
[12]
痛みの治療及び/又は予防における使用のための、[1]-[8]のいずれか1項に記載の化合物、又は、その薬学的に許容される塩。
[13]
痛みが、がん性疼痛及び/又は非がん性慢性疼痛である[11]に記載の医薬組成物。
[14]
[9]又は[10]に記載の医薬組成物の有効量を投与する、痛みの治療及び/又は予防方法。
また、本発明の化合物及びその薬学的に許容される塩は、鎮痛活性、生物学的利用能、in vitro活性、in vivo活性、薬効発現の早さ、薬効の持続性、物理的安定性、薬物相互作用、毒性等の点で優れた性質を有し、医薬として有用である。また、本発明の化合物及びその薬学的に許容される塩は、分子量、脂溶性等を最適化することにより、貼付剤に採用される組成物中における溶解性に優れており、皮膚透過性に優れた性質を有することから貼付剤として用いる場合に優れた効果を発揮することから有用である。
式(I)の化合物、又は、その薬学的に許容される塩。
R1は、水素原子、又は、メチル基である。
R2は、水素原子、又は、フッ素原子である。
R3は、水素原子、又は、メチル基である。
R4は、水素原子、又は、メチル基である。
R5は、水素原子、又は、メチル基である。)
本発明の化合物名において、その化合物の構造中に、不斉中心となる原子を有する場合、その絶対配置をRとS(位置番号と共に記す)によって示す場合がある。
相対配置は、最初に記される不斉中心の配置をR又はSとしたときの配置表示に星印を添える(R*とS*)か、名称の前に接頭辞(記号)rel-(relativeの意)を置いて示す場合がある。
ラセミ混合物は、通常、特に、その絶対配置をRとSを用いずに示すが、R*とS*の代わりに記号RSとSRを用いるか、名称の前に接頭辞(記号)rac-(racemicの意)を置いて示す場合がある。
「その薬学的に許容される塩」とは、医薬として使用することができる塩を示す。
本発明の化合物は、ラベル体、すなわち、化合物の1又は2以上の原子を同位元素(例えば、2H、3H、13C、14C、35S等)で置換した化合物も含まれる。
溶媒群は、ペンタン、n-ヘキサン、オクタン、石油エーテル、リグロイン、シクロヘキサンのような炭化水素類;ホルムアミド、N、N-ジメチルホルムアミド、N、N-ジメチルアセトアミド、N-メチル-2-ピロリドン、N-メチル-2-ピロリジノン、ヘキサメチルリン酸トリアミドのようなアミド類;ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、1、4-ジオキサン、1、2-ジメトキシエタン、ジエチレングリコールジメチルエーテル、シクロペンチルメチルエーテルのようなエーテル類;メタノール、エタノール、n-プロパノール、i-プロパノール、n-ブタノール、2-ブタノール、2-メチル-1-プロパノール、t-ブタノール、イソアミルアルコール、ジエチレングリコール、グリセリン、オクタノール、シクロヘキサノール、メチルセロソルブのようなアルコール類;ジメチルスルホキシドのようなスルホキシド類;スルホランのようなスルホン類;アセトニトリル、プロピオニトリル、ブチロニトリル、イソブチロニトリルのようなニトリル類;蟻酸エチル、酢酸エチル、酢酸プロピル、酢酸ブチル、炭酸ジエチルのようなエステル類;アセトン、メチルエチルケトン、4-メチル-2-ペンタノン、メチルイソブチルケトン、イソホロン、シクロヘキサノンのようなケトン類;ニトロエタン、ニトロベンゼンのようなニトロ化合物類;ジクロロメタン、1、2-ジクロロエタン、クロロベンゼン、ジクロロベンゼン、クロロホルム、四塩化炭素のようなハロゲン化炭化水素類;ベンゼン、トルエン、キシレンのような芳香族炭化水素類;酢酸、蟻酸、プロピオン酸、ブチリル酸、トリフルオロ酢酸のようなカルボン酸類;N-メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、N-メチルピペリジン、ピリジン、2、6-ルチジン、4-ピロリジノピリジン、ピコリン、4-(N、N-ジメチルアミノ)ピリジン、2、6-ジ(t-ブチル)-4-メチルピリジン、キノリン、N、N-ジメチルアニリン、N、N-ジエチルアニリン、1、5-ジアザビシクロ[4.3.0]ノナ-5-エン(DBN)、1、4-ジアザビシクロ[2.2.2]オクタン(DABCO)、1、8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(DBU)、ピペリジンのようなアミン類;水;又は、これらの混合溶媒からなる。
A法は、本発明の化合物(A8)又は(A9)を製造する方法である。
(A法)
L:スルホニルオキシ基等の通常この分野で用いられる脱離基を示す。例えば、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等である。
Ra1は、メチル基を示し、
Ra2は、メチル基を示し、
Ra3は、水素原子、又は、メチル基を示し、
Ra4は、水素原子、又は、メチル基を示し、
Ra5は、水素原子、又は、メチル基を示す。)
本工程は、溶媒中、塩基の存在下、化合物(A1)を、ホウ酸化合物(A2)と反応させることにより、化合物(A3)を製造する工程である。
本工程において使用される溶媒は、好適には、アミド類又はエーテル類であり、より好適には、N、N-ジメチルホルムアミド又は1、4-ジオキサンである。
本工程において使用される塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸カリウムである。
本工程における反応温度は、通常、50-120℃であり、好適には、80-100℃である。
本工程における反応時間は、通常、3-72時間であり、好適には、12-48時間である。
本工程はマイクロウェーブ照射下で行うことができる。その際の反応時間は、通常、10分間-3時間であり、好適には、15-90分間である。
本工程は、溶媒中、パラジウム炭素の存在下、化合物(A3)に、水素添加を行うことにより、化合物(A4)を製造する工程である。
本工程において使用される溶媒は、好適には、アルコール類であり、より好適には、メタノールである。
本工程における反応温度は、通常、20-50℃であり、好適には、20-30℃である。
本工程における反応時間は、通常、1-24時間であり、好適には、1-6時間である。
本工程は、溶媒中、塩基の存在下、化合物(A4)に、異性化反応を行うことにより、化合物(A5)を製造する工程である。
本工程において使用される溶媒は、好適には、アルコール類であり、より好適には、メタノールである。
本工程において使用される塩基は、好適には、アルカリ金属アルコキシド類であり、より好適には、ナトリウムメトキシドである。
本工程における反応温度は、通常、20-100℃であり、好適には、40-70℃である。
本工程における反応時間は、通常、1-24時間であり、好適には、20-24時間である。
本工程は、溶媒中、化合物(A5)を、水素化リチウムアルミニウムと反応させることにより、化合物(A6)を製造する工程である。
本工程において使用される溶媒は、好適には、エーテル類であり、より好適には、テトラヒドロフランである。
本工程における反応温度は、通常、0-60℃であり、好適には、0-20℃である。
本工程における反応時間は、通常、1-24時間であり、好適には、1-2時間である。
本工程は、溶媒中、化合物(A6)を、塩基存在下、例えば、メタンスルホニルクロリドと反応させることにより、化合物(A7)を製造する工程である。
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
本工程において使用される塩基は、好適には、3級アルキルアミンであり、より好適には、トリエチルアミンである。
本工程における反応温度は、通常、-10-0℃であり、好適には、-5-0℃である。
本工程における反応時間は、通常、1-24時間であり、好適には、12-24時間である。
本工程は、溶媒中、塩基の存在下、化合物(A7)と、ジメチルアミン塩酸塩とを反応させることにより、化合物(A8)を製造する工程である。
本工程において使用される溶媒は、好適には、アミド類又はエーテル類であり、より好適には、N、N-ジメチルホルムアミドである。
本工程において使用される塩基は、好適には、3級アルキルアミンであり、より好適には、トリエチルアミンである。
本工程における反応温度は、通常、50-120℃であり、好適には、80-100℃である。
本工程における反応時間は、通常、3-72時間であり、好適には、12-48時間である。
本工程はマイクロウェーブ照射下で行うことができる。その際の反応時間は、通常、10分間-3時間であり、好適には、15分間-90分間である。
本工程は、溶媒中、化合物(A8)を、三臭化ホウ素塩化メチレン溶液と反応させることにより、化合物(A9)を製造する工程である。
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
本工程における反応温度は、通常、-78℃-0℃であり、好適には、-78℃-40℃である。
本工程における反応時間は、通常、1-24時間であり、好適には、12-24時間である。
(B法)
Rb1は、メチル基を示し、
Rb3は、水素原子、又は、メチル基を示し、
Rb4は、水素原子、又は、メチル基を示し、
Rb5は、水素原子、又は、メチル基を示す。)
本工程は、溶媒中、化合物(B1)を、マグネシウムブロミド化合物(B2)と反応させることにより、化合物(B3)を製造する工程である。
本工程において使用される溶媒は、好適には、エーテル類であり、より好適には、テトラヒドロフランである。
本工程における反応温度は、通常、0-60℃であり、好適には、0-30℃である。
本工程における反応時間は、通常、1-24時間であり、好適には、2-6時間である。
本工程は、溶媒中、化合物(B3)を、三フッ化N、N-ジエチルアミノ硫黄と反応させることにより、化合物(B4)を製造する工程である。
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
本工程における反応温度は、通常、-78-0℃であり、好適には、-78--40℃である。
本工程における反応時間は、通常、1-24時間であり、好適には、12-24時間である。
本工程は、溶媒中、パラジウム炭素の存在下、化合物(B4)に、水素添加を行うことにより、化合物(B5)を製造する工程である。
本工程において使用される溶媒は、好適には、アルコール類であり、より好適には、メタノールである。
本工程における反応温度は、通常、20-50℃であり、好適には、20-30℃である。
本工程における反応時間は、通常、1-24時間であり、好適には、1-6時間である。
その投与は錠剤、丸剤、カプセル剤、頼粒剤、散剤、液剤等による経口投与、又は、関節、静脈、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。
経口投与のための固体組成物としては、
錠剤、散剤、顆粒剤等が用いられるが、このような固体組成物は、1種又は2種以上の有効成分を、少なくとも1種の不活性な賦形剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピ口リドン、及び/又はメタケイ酸アルミン酸マグネシウム等と混合して製造される。
その組成物は、常法に従って、不活性な添加剤、例えばステアリン酸マグネシウムのような滑沢剤やカルボキシメチルスターチナトリウム等のような崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は必要により糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してあってもよい。
薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤又はエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水又はエタノールを含む。その液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。
無菌の水性又は非水性の溶液剤、懸濁剤又は乳濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水又は生理食塩水が含まれる。非水性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコール又はオリーブ油のような植物油、エタノールのようなアルコール類、又はボリソルベート80等がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、又は溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通すろ過、殺菌剤の配合又は照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解又は懸濁して使用することもできる。
軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローション剤、点眼剤、眼軟膏、貼付剤等を包含する。これらの製剤では、一般に用いられる軟膏基剤、ローション基剤、水性又は非水性の液剤、懸濁剤、乳剤等を含有する。例えば、軟膏又はローション基剤としては、ポリエチレングリコール、プロピレングリコール、白色ワセリン、サラシミツロウ、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸グリセリン、ステアリルアルコール、セチルアルコール、ラウロマクロゴール、セスキオレイン酸ソルビタン等が挙げられる。
ゴム系粘着剤のゴム成分としては、天然ゴム、ポリイソプレン、スチレン-イソプレン-スチレンブロック共重合体、スチレン-ブタジエン-スチレンブロック共重合体、スチレン・ブタジエンゴムおよびポリイソブチレンが挙げられる。
非水系基材には、さらに可塑剤、粘着付与剤、透過促進剤および/または安定化剤を含有することができる。
可塑剤としては、特に限定されず、例えば、石油系オイル(パラフィン系プロセスオイル、ナフテン系プロセスオイル、芳香族系プロセスオイル等)、スクワラン、スクワレン、植物系オイル(オリーブ油、ツバキ油、ヒマシ油、トール油、ラッカセイ油等)、シリコンオイル、二塩基酸エステル(ジブチルフタレート、ジオクチルフタレート等)、液状ゴム(ポリブテン、液状イソプレンゴム等)、液状脂肪酸エステル(ミリスチン酸イソプロピル、ラウリン酸ヘキシル、セバシン酸ジエチル、セバシン酸ジイソプロピル等)、ジエチレングリコール、ポリエチレングリコール、サリチル酸グリコール、プロピレングリコール、ジプロピレングリコール、トリアセチン、クエン酸トリエチル、クロタミトン等が挙げられる。
透過促進剤としては、皮膚における透過促進作用が認められている化合物であれば特に限定されず、具体的には、炭素数6-20の脂肪酸、脂肪族アルコール、脂肪酸エステル、アミドまたはエーテル、芳香族有機酸、芳香族アルコール、芳香族有機酸エステルまたはエーテル等が挙げられる。
安定化剤としては、抗酸化剤、紫外線吸収剤等を用いることができる。
抗酸化剤としては、トコフェロールおよびこれらのエステル誘導体、アスコルビン酸、アスコルビン酸ステアリン酸エステル、ノルジヒトログアヤレチン酸、ジブチルヒドロキシトルエン(BHT)およびブチルヒドロキシアニソールが挙げられ;紫外線吸収剤としては、p-アミノ安息香酸誘導体、アントラニル酸誘導体、サリチル酸誘導体、クマリン誘導体、アミノ酸系化合物、イミダゾリン誘導体、ピリミジン誘導体およびジオキサン誘導体が挙げられる。
乾燥粉末吸入器等は、単回又は多数回の投与用のものであってもよく、乾燥粉末又は粉末含有カプセルを使用することができる。あるいは、適当な駆出剤、例えば、クロロフルオロアルカン、ヒドロフルオロアルカン又は二酸化炭素等の好適な気体を使用した加圧エアゾールスプレー等の形態であってもよい。
通常経口投与の場合、1日の投与量は、体重当たり約0.001-100mg/kg、好ましくは0.1-30mg/kg、更に好ましくは0.1-10mg/kgが適当であり、これを1回で、あるいは2回以上に分けて投与する。静脈内投与される場合は、1日の投与量は、体重当たり約0.0001-10mg/kgが適当で、1日1回または複数回に分けて投与する。また、経皮剤としては、体重当たり約0.001-100mg/kgを1日1回または複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。
本発明では、その有効性を示すと考えられる疾患の種々の治療剤又は予防剤と併用することができる。当該併用は、同時投与、或いは別個に連続して、若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。
以下の成分より、本発明の貼付剤を製造した。
有効成分:実施例1の化合物 10重量%
ゴム系粘着剤のゴム成分:スチレン-イソプレン-スチレンブロック共重合体 20%
可塑剤:流動パラフィン 40重量%
粘着付与剤:ロジン 30重量%
150℃で上記成分を溶融練合し、その溶解練合物をペットフィルムに展延し、次いでポリエステル布を貼り合せた後、所望の大きさに切断して、貼付剤を得た。
カラム用シリカゲルはメルク社製のシリカゲルSK-85(230~400メッシュ)、山善社製のシリカゲル(Hi-FlashTMColumn、INJECT COLUMNTM)、バイオタージ社製のシリカゲル(SNAP、SNAP Ultra)あるいは富士シリシア化学社製のシリカゲル(FL100B、クロマトレックス-SO3H)を用いた。通常のカラムクロマトグラフィーの他に、山善社の自動クロマトグラフィー装置(YFLC-5405-FC-GRII、WPrep 2XY)、及びバイオタージ社の自動クロマトグラフィー装置(Isolera、SP-1)を適宜使用した。尚、実施例で用いる略号は、次のような意義を有する。
mg:ミリグラム、g:グラム、mL:ミリリットル、MHz:メガヘルツ、Hz:ヘルツ
測定溶媒は、CDCl3:重クロロホルム、MeOH-d4:重メタノールあるいは、DMSO-d6:重ジメチルスルホキシドを用いた。
分裂パターンは一重線をs、二重線をd、三重線をt、四重線をq、五重線をquint、六重線をsext、七重線をhept、多重線をm、ブロードをbrで示した。
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]フェノール
なお、以下の構造式中の立体配置は、置換基の相対配置のみを示すものであって、本実施例の化合物は、2つのエナンチオマーの混合物である。
4-(トリフルオロメチルスルホニルオキシ)-3,6-ジヒドロ-2H-ピラン-5-カルボン酸メチル
4-オキソテトラヒドロピラン-3-カルボン酸メチル(20.0g)を無水テトラヒドロフラン(800mL)に溶解し、水素化ナトリウム(7.5g、60%ミネラルオイル)を氷冷下加え、30分間攪拌した。Comin's試薬(59.5g)を加え、室温で一晩攪拌した。
飽和塩化アンモニウム水溶液を加え、反応混合物を酢酸エチルで希釈し、有機層を水で2回及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥させた。有機層を減圧下で濃縮した後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン)で精製することで、標記化合物(30.0g)を淡黄色油状物として得た。
1H-NMR (300 MHz, CDCl3): δ 4.46 (m, 2H), 3.90 (t, J = 5.7 Hz, 2H), 3.83 (s, 3H), 2.55 (m, 2H).
4-(3-メトキシフェニル)-3,6-ジヒドロ-2H-ピラン-5-カルボン酸メチル
4-(トリフルオロメチルスルホニルオキシ)-3,6-ジヒドロ-2H-ピラン-5-カルボン酸メチル(15.0g)、3-メトキシフェニルホウ酸(15.8g)及び炭酸カリウム(16.4g)をジオキサン(300mL)に懸濁し、窒素置換後、[1、1′-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(3.80g)を加え、加熱還流下一晩攪拌した。
反応液を室温に冷却後、濃縮した。反応混合物を酢酸エチルで希釈し、有機層を水で2回及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥させた。有機層を減圧下で濃縮した後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン)で精製することで、標記化合物(11.8g)を黄色油状物として得た。
1H-NMR (300 MHz, CDCl3): δ 7.28 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.72-6.77 (m, 2H), 4.46 (m, 2H), 3.89 (m, 2H), 3.82(s, 3H), 3.53 (s, 3H), 2.51 (m, 2H).
(3R*,4R*)-4-(3-メトキシフェニル)テトラヒドロピラン-5-カルボン酸メチル
4-(3-メトキシフェニル)-3,6-ジヒドロ-2H-ピラン-5-カルボン酸メチル(11.8g)をエタノール(300mL)と酢酸エチル(60mL)からなる混合溶媒に溶解し、窒素置換後、10%パラジウム炭素(7.0g、wet)を加えた。
水素雰囲気下(50psi)、室温で一晩攪拌した。反応混合物をろ過し減圧下で濃縮した後、標記化合物(10.6g)を淡茶色油状物として得た。
1H-NMR (300 MHz, CDCl3): δ 7.21-7.28 (m, 1H), 6.76-6.89 (m, 3H), 4.18-4.32 (m, 2H), 3.81 (s, 3H), 3.70-3.78 (m, 2H), 3.54 (s, 3H), 3.04-3.10 (m, 1H) , 2.72-2.78 (m, 1H), 2.27 (m, 1H), 1.23-1.28 (m, 1H).
(3S*,4R*)-4-(3-メトキシフェニル)テトラヒドロピラン-5-カルボン酸メチル
(3R*,4R*)-4-(3-メトキシフェニル)テトラヒドロピラン-5-カルボン酸メチル(3.50g)とナトリウムメトキシド(754mg)を無水メタノール(100mL)に溶解し、加熱還流下一晩攪拌した。反応液を室温に冷却後、濃縮した。
飽和塩化アンモニウム水溶液を加え、反応混合物を酢酸エチルで希釈し、有機層を水で2回及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥させた。有機層を減圧下で濃縮し、標記化合物(2.30g)を黄色油状物として得た。
1H-NMR (300 MHz, CDCl3): δ 7.20-7.28 (m, 1H), 6.75-6.83 (m, 3H), 4.17-4.21 (m, 1H), 4.06-4.11 (m, 1H), 3.81 (s, 3H), 3.52-3.61 (m, 2H), 3.49 (s, 3H), 2.92-3.06(m, 2H), 1.77-1.89 (m, 2H).
[(3R*,4R*)-4-(3-メトキシフェニル)テトラヒドロピラン-3-イル]-メタノール
(3S*,4R*)-4-(3-メトキシフェニル)テトラヒドロピラン-5-カルボン酸メチル(2.20g)を無水テトラヒドロフラン(80mL)に溶解し、窒素雰囲気下、水素化リチウムアルミニウム(502mg)を氷冷下少しずつ加えた。反応混合物を室温に昇温し一晩攪拌した。
飽和塩化アンモニウム水溶液を加え、反応混合物を塩化メチレンで抽出した。有機層を減圧下で濃縮した後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン)で精製することで、標記化合物(1.70g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3): δ 7.22-7.28 (m, 1H), 6.79-6.84 (m, 3H), 4.21-4.26 (m, 1H), 4.02-4.10 (m, 1H), 3.82 (s, 3H), 3.27-3.55 (m, 4H), 2.54-2.62 (m, 1H), 2.03-2.10 (m, 1H) , 1.88-1.93 (m, 1H) , 1.72-1.79 (m, 1H).
[(3S*,4R*)-4-(3-メトキシフェニル)テトラヒドロピラン-3-イル]-メタンスルホン酸メチルエステル
[(3R*,4R*)-4-(3-メトキシフェニル)テトラヒドロピラン-3-イル]-メタノール(1.80g)を塩化メチレン(40mL)に溶解し、トリエチルアミン(1.22g)を加えた。氷冷下攪拌下、メタンスルホニルクロリド(2.03g)を滴下した。反応混合物を室温に昇温し2時間攪拌した。
反応混合物を塩化メチレンで希釈し、有機層を飽和塩化アンモニウム水溶液及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥させた。有機層を減圧下で濃縮し、標記化合物(2.40g)を黄色油状物として得た。
1-[(3R*,4R*)-4-(3-メトキシフェニル)テトラヒドロピラン-3-イル]-N,N-ジメチル-メタンアミン
[(3S*,4R*)-4-(3-メトキシフェニル)テトラヒドロピラン-3-イル]-メタンスルホン酸メチルエステル(2.40g)をジメチルホルムアミド(15mL)に溶解し、ジメチルアミン塩酸塩(5.40g)とトリエチルアミン(4.90g)を加えた。
反応混合物を70℃で2日間攪拌した。減圧下で濃縮した後、残渣をシリカゲルカラムクロマトグラフィー(メタノール/塩化メチレン)で精製することで、標記化合物(0.20g)を白色固体として得た。
1H-NMR (300 MHz, CDCl3): δ 7.30 (m, 1H), 6.85 (m, 3H), 4.58 (m, 1H), 4.10 (m, 1H), 3.80 (s, 3H) 3.50 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.50 (s, 6H), 2.45 (m, 2H), 1.75 (m, 2H).
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]フェノール
1-[(3R*,4R*)-4-(3-メトキシフェニル)テトラヒドロピラン-3-イル]-N,N-ジメチル-メタンアミン(2.00g)を塩化メチレン(15mL)に溶解し、-78℃に冷却後、1M三臭化ホウ素塩化メチレン溶液(6.0mL)を窒素雰囲気下、滴下した。反応混合物を-78℃で3時間攪拌後、室温で一晩攪拌した。
メタノール(5mL)を加えた後、飽和炭酸水素ナトリウム水溶液でpH8とし、酢酸エチルで希釈し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥させた。有機層を減圧下で濃縮した後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/メタノール)で精製することで、標記化合物(60mg)を白色固体として得た。
1H-NMR (400 MHz, CDCl3): δ 7.15-7.19 (t, J = 11.6 Hz, 1H), 6.73 (d, J = 11.2 Hz, 1H), 6.67-6.70 (m, 2H), 4.30-4.34 (dd, J = 11.6 Hz, 3.2 Hz, 1H), 4.03-4.07 (dd, J = 11.2 Hz, 3.6 Hz, 1H), 3.45-3.51 (t, J = 11.6 Hz, 1H), 3.14-3.19 (t, J = 11.6 Hz, 1H) , 2.31 (m, 1H), 2.09 (m, 1H), 2.06 (s, 6H), 1.79-1.90 (m, 3H), 1.73 (m, 1H). MS (APCI) m/z: 236(M+H)+。
3-[(4R*,5R*)-5-(ジメチルアミノメチル)-2,2-ジメチルテトラヒドロピラン-4-イル]フェノール
なお、以下の構造式中の立体配置は、置換基の相対配置のみを示すものであって、本実施例の化合物は、2つのエナンチオマーの混合物である。
1H-NMR (400 MHz, CDCl3): δ 7.15 (t, J = 8.0 Hz, 1H), 6.75-6.65 (m, 3H), 4.11 (d, J1 = 12.8 Hz, J2 = 4 Hz, 1H), 3.48 (t, J = 11.6 Hz, 1H), 2.56-2.48 (m, 1H), 2.13-2.00 (m, 8H), 1.94-1.88 (m, 1H), 1.70-1.64 (m, 2H), 1.30 (s, 3H), 1.26 (s, 3H). MS (APCI) m/z: 264(M+H)+.
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]-5-メチルフェノール
なお、以下の構造式中の立体配置は、置換基の相対配置のみを示すものであって、本実施例の化合物は、2つのエナンチオマーの混合物である。
1H-NMR (400 MHz, CD3OD): δ 6.61 (s, 1H), 6.58 (s, 1H), 6.53 (s, 1H), 3.79-3.74 (m, 1H), 3.70-3.65 (m, 1H), 3.59-3.54 (m, 2H), 3.40-3.35 (m, 1H) , 3.32 (m, 4H), 3.26 (s, 3H), 3.23-3.21 (m, 1H), 2.56-2.55 (m, 1H), 2.33-2.30 ( m, 1H), 2.26 ( s, 3H), 2.23-2.20 ( m, 1H). MS (APCI) m/z: 250(M+H)+。
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]-2-メチルフェノール
なお、以下の構造式中の立体配置は、置換基の相対配置のみを示すものであって、本実施例の化合物は、2つのエナンチオマーの混合物である。
1H-NMR (400 MHz, CD3OD): δ 7.00 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 3.91 (dd, J1= 12.8 Hz, J2 = 3.2 Hz, 1H), 3.66-3.64 (m, 1H), 3.60-3.52 (m, 4H), 3.17 (dd, J1 = 11.6 Hz, J2 = 2.4 Hz, 1H), 2.82-2.81 (m, 6H) , 2.57-2.52 (m, 2H), 2.21 (s, 3H), 2.04-1.98 ( m, 1H). MS (APCI) m/z: 250(M+H)+。
3-[3-ジメチルアミノメチル-4-フルオロテトラヒドロピラン-4-イル]-フェノール
3-(ジメチルアミノメチル)テトラヒドロピラン-4-オン
テトラヒドロピラン-4-オン(20g)、パラホルムアルデヒド(7.00g)、ジメチルアミン塩酸塩(17.0g)及び12N塩酸(0.10mL)をジメチルホルムアミド(100mL)に溶解し、40℃で3時間攪拌した。反応混合物を減圧下で濃縮し、残渣にエタノール/酢酸エチル混合溶媒を加え、固体を析出させた後、ろ過して固体を得た。
得られた固体に塩化メチレン(500mL)とアンモニア水を加え、分液した。有機層を飽和食塩水(300mL)で洗浄した後、無水硫酸マグネシウムで乾燥させた。有機層を減圧下で濃縮し、標記化合物(14.0g)を黄色油状物として得た。
1H-NMR (300 MHz, CDCl3): δ 4.17-4.03 (m, 2H), 3.89-3.81 (m, 1H), 3.59-3.53 (m, 1H), 2.76-2.67 (m, 2H), 2.53-2.49 (m, 2H), 2.36-2.28 (m, 1H), 2.19 (s, 6H).
4-(3-ベンジルオキシフェニル)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-オール
マグネシウム片(0.81g)を無水テトラヒドロフラン(20mL)に懸濁させ、窒素雰囲気下ヨードメタン(0.05mL)とm-ブロモフェノールベンジルエステル(9.00g)を加えた。反応混合物を加熱還流下1時間攪拌した。反応混合物を室温に冷却後、氷冷下攪拌し、3-(ジメチルアミノメチル)テトラヒドロピラン-4-オン(4.30g)の無水テトラヒドロフラン溶液(30mL)を滴下後、室温で一晩攪拌した。
氷冷下、飽和塩化アンモニウム水溶液(15mL)を加え、有機層を分離した。水層を塩化メチレンで抽出し、有機層を合わせ、無水硫酸マグネシウムで乾燥させた。有機層を減圧下で濃縮した。得られた残渣に酢酸エチル(100mL)を加え、塩酸ガスと反応させ、塩酸塩として固体を析出させた後、ろ過して固体を得た。
得られた固体をエタノールで洗浄し淡黄色固体(1.50g)を得た。得られた固体にアンモニア水と塩化メチレンを加え、分液した。有機層を水で洗浄した後、無水硫酸マグネシウムで乾燥させた。有機層を減圧下で濃縮し、標記化合物(1.50g)を白色固体として得た。
1H-NMR (400 MHz, CDCl3): δ 7.44 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 6.8 Hz, 2H), 7.33-7.27 (m, 2H), 7.23 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.70 (dd, J = 7.6, 2.4 Hz, 1H), 5.09 (s, 2H), 4.17-4.13 (m, 1H), 4.01 (t, J = 12.0 Hz, 1H), 3.85-3.81 (m, 1H), 3.79-3.75 (m, 1H), 2.43-2.39 (m, 1H), 2.17-1.93 (m, 9H), 1.57 (m, 1H).
1-[4-(3-ベンジルオキシフェニル)-4-フルオロテトラヒドロピラン-3-イル]-N,N-ジメチルアミノメタンアミン
三フッ化N,N-ジエチルアミノ硫黄(163mg)を塩化メチレン(5mL)に溶解し、-40℃に冷却攪拌下、4-(3-ベンジルオキシフェニル)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-オール(300mg)の塩化メチレン溶液(2mL)を滴下した。反応混合物を-40℃で2時間攪拌し、1時間かけて室温に昇温した。
その後、反応混合物を-5℃に冷却し、水を加え塩化メチレンで抽出した。有機層を水と飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥させた。有機層を減圧下で濃縮した後、残渣をシリカゲルカラムクロマトグラフィー(塩化メチレン/メタノール)で精製することで、標記化合物(110mg)を無色油状物として得た。
1H-NMR (400 MHz, CD3OD): δ 7.44-7.42 (m, 2H), 7.38-7.33 (m, 2H), 7.32-7.27 (m, 2H), 7.02-6.99 (m, 1H), 6.97-6.91 (m, 2H), 5.11 (s, 2H), 4.11-4.07 (dd, J = 11.6 Hz, 4.8 Hz, 1H), 3.92-3.85 (m, 1H), 3.83-3.74 (m, 1H), 3.55 (t, J = 11.6 Hz, 1H), 2.44-2.15 (m, 3H), 2.01(s, 6H), 1.89-1.74 (m, 2H).
3-[3-ジメチルアミノメチル-4-フルオロテトラヒドロピラン-4-イル]-フェノール
1-[4-(3-ベンジルオキシフェニル)-4-フルオロテトラヒドロピラン-3-イル]-N,N-ジメチルアミノメタンアミン(110mg)をメタノール(3mL)に溶解し、窒素置換後、10%パラジウム炭素(55mg、wet)を加えた。水素雰囲気下(1atm)、室温で2時間攪拌した。反応混合物をろ過し減圧下で濃縮した後、実施例1(1-h)と同様の条件で精製することで、標記化合物(25mg)を白色固体として得た。
1H-NMR (400 MHz, CD3OD): δ 7.21 (t, J = 8.4 Hz, 1H), 6.88-6.79 (m, 2H), 6.76-6.70 (m, 1H), 4.12 (dd, J = 12.0, 4.8 Hz, 1H), 3.94-3.86 (m, 1H), 3.85-3.75 (m, 1H), 3.57 (t, J= 11.2 Hz, 1H), 2.45-2.11 (m, 3H), 2.05 (s, 6H), 1.93-1.88 (m, 1H), 1.86-1.76 (m, 1H), MS (APCI) m/z: 254(M+H)+.
(1)試験物質の調製
実施例に記載の化合物は、ミリスチン酸イソプロピル(IPM)に3.84mmol/Lの濃度になるように、溶解あるいは縣濁して使用した。IPMへの溶解状態の結果を表1に示す。
(2)へアレスマウス皮膚透過試験
凍結ヘアレスマウス皮膚(HR-1系、雄性、7週齢、日本エスエルシー)は、室温で解凍し、余分な皮下脂肪がある場合は、ハサミで切除した。横型拡散セルは、セルの外部ジャケットに恒温循環水槽(37℃)の水を流すことで、セルの温度を一定に保った。ヘアレスマウス皮膚はφ24mmに打ち抜き、横型拡散セルに挟み、真皮側(レシーバー側)にレシーバー液(40%ポリエチレングリコール400を含んだMcIlvaine buffer)を0.9mL加え、角質層側(ドナー側)にドナー液(実施例に記載の化合物をIPMに3.84mmol/Lの濃度になるように、溶解あるいは縣濁した液)を0.9mL加えた。
ドナー液を適用後、任意の時間(適用後2、4、6、8、24時間)経過後に、それぞれレシーバー側から0.45mLの液体を採取し、それぞれ同量の新しいレシーバー液を追加した。採取した液体は、-80℃で保管した。なお、各群における例数は3例とした。
(3)皮膚透過性試験解析法
皮膚透過性試験で採取した液体中の化合物を定量した。得られた結果は、平均値±S.D.(N=3)で示した。各時点で得られたレシーバー側の液体中の薬物濃度に基づき、累積透過量(mmol/cm2) - 時間(hr)プロファイルをグラフ上にプロットした。
プロファイルより定常時における回帰直線の傾きおよびX軸切片からそれぞれ皮膚透過速度(flux、mmol/cm2/hr)およびLag time(hr)を算出し、皮膚透過性の指標とした。皮膚透過性試験の結果を表1に示した。
Tail Flick式鎮痛効果測定装置(Ugo Brasile)と成体マウス(C57BL/6JJmsSlc、 日本エスエルシー)を評価に用いた。Tail Flick試験では、動物の尾へ熱刺激を与え、尾を動かす逃避反射の潜時(単位:秒)を測定した。火傷を防ぐため、最長照射時間を10秒とした。
実施例に記載の化合物をCaptisolに溶解あるいは懸濁させて試験物質として調整した後、それを適宜選択した濃度で動物に皮下投与(10mL/kg)し、逃避反射の潜時を測定した。試験物質投与前の逃避反射の潜時を[投与前測定値]として、鎮痛スコア(%)を、[([測定値]-[投与前測定値])/(10-[投与前測定値])]×100として算出した。
鎮痛スコアが50%となる用量を算出することでED50を決定した。本試験の結果を表2に示す。
Claims (14)
- R1が、水素原子である、請求項1に記載の化合物、又は、その薬学的に許容される塩。
- R2が、水素原子である、請求項1又は2に記載の化合物、又は、その薬学的に許容される塩。
- R3が、水素原子である、請求項1-3のいずれか1項に記載の化合物、又は、その薬学的に許容される塩。
- R4及びR5が、水素原子である、請求項1-4のいずれか1項に記載の化合物、又は、その薬学的に許容される塩。
- 式(I)の化合物が、以下に示される化合物のいずれかである請求項1に記載の化合物、又は、その薬学的に許容される塩。
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]フェノール
3-[(4R*,5R*)-5-(ジメチルアミノメチル)-2、2-ジメチルテトラヒドロピラン-4-イル]フェノール
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]-5-メチルフェノール
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]-2-メチルフェノール
3-[3-ジメチルアミノメチル-4-フルオロテトラヒドロピラン-4-イル]-フェノール - 以下に示される化合物、又は、その薬学的に許容される塩。
3-[(3R*,4R*)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]フェノール - 以下に示される化合物、又は、その薬学的に許容される塩。
3-[(3R,4R)-3-(ジメチルアミノメチル)テトラヒドロピラン-4-イル]フェノール - 請求項1-8のいずれか1項に記載の化合物、又は、その薬学的に許容される塩を有効成分として含有する医薬組成物。
- 貼付剤である、請求項9に記載の医薬組成物。
- 痛みを治療及び/又は予防するための、請求項9又は10に記載の医薬組成物。
- 痛みの治療及び/又は予防における使用のための、請求項1-8のいずれか1項に記載の化合物、又は、その薬学的に許容される塩。
- 痛みが、がん性疼痛及び/又は非がん性慢性疼痛である請求項11に記載の医薬組成物。
- 請求項9又は10に記載の医薬組成物の有効量を投与する、痛みの治療及び/又は予防方法。
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CN201980011567.XA CN111655675B (zh) | 2018-02-06 | 2019-02-05 | 氨基烷基化合物 |
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WO2021256181A1 (ja) * | 2020-06-19 | 2021-12-23 | 株式会社カネカ | アミノアルキルテトラヒドロピラン誘導体の製造方法 |
WO2022050056A1 (ja) * | 2020-09-03 | 2022-03-10 | 株式会社カネカ | 貼付剤、及びその製造方法 |
WO2023022050A1 (ja) * | 2021-08-17 | 2023-02-23 | 株式会社カネカ | アミノアルキルテトラヒドロピラン誘導体 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0931033A (ja) * | 1995-07-11 | 1997-02-04 | Gruenenthal Gmbh | 医薬有効物質としての6− ジメチルアミノメチル− 1− フエニル− シクロヘキサン化合物 |
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US20090104266A1 (en) | 2005-09-15 | 2009-04-23 | Tobias Jung | 3-(2-dimethylaminomethylcy clohexyl)phenol retard formulation |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Non-Patent Citations (13)
Title |
---|
"Publication Department of Medical Books", 5 April 2018, SHINKO TRADING CO., LTD., article "Health, Labor and Welfare Policy Grants (Research on Chronic Pain),''Research on Constructing a System for the Treatment and Education of Chronic Pain Problems" |
AM J CLIN DERMATOL, vol. 1, 2000, pages 361 - 368 |
BRITISH JOURNAL OF PHARMACOLOGY, vol. 172, 2015, pages 2179 - 2209 |
CLINICAL, COSMETIC AND INVESTIGATIONAL DERMATOLOGY, vol. 10, 2017, pages 289 - 298 |
CONTACT DERMATITIS., vol. 59, no. 6, December 2008 (2008-12-01), pages 366 - 369 |
CURR MED RES OPIN., vol. 22, no. 3, March 2006 (2006-03-01), pages 501 - 509 |
CUTAN OCUL TOXICOL., vol. 29, no. 4, December 2010 (2010-12-01), pages 241 - 246 |
DERMATOL SURG, vol. 0, 2017, pages 1 - 8 |
FRITZ EIDEN ,MICHAEL SCHMIDT: "ZNS active phenylpyrans: 3-(dimethylaminomethyl)-4-(3-methoxyphenyl)tetrahydro-4-pyra nol and -4-thiopyranol", ARCHIV DER PHARMAZIE, vol. 320, 1987, pages 1099 - 1103, XP055718504 * |
GENERAL HOSPITAL PSYCHIATRY, vol. 31, 2009, pages 206 - 219 |
MOLECULES, vol. 23, 2018, pages 681 |
See also references of EP3750883A4 |
THER DELIV., vol. 1, no. 1, July 2010 (2010-07-01), pages 109 - 131 |
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WO2021256181A1 (ja) * | 2020-06-19 | 2021-12-23 | 株式会社カネカ | アミノアルキルテトラヒドロピラン誘導体の製造方法 |
WO2022050056A1 (ja) * | 2020-09-03 | 2022-03-10 | 株式会社カネカ | 貼付剤、及びその製造方法 |
WO2023022050A1 (ja) * | 2021-08-17 | 2023-02-23 | 株式会社カネカ | アミノアルキルテトラヒドロピラン誘導体 |
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CN111655675B (zh) | 2023-09-22 |
US20210040057A1 (en) | 2021-02-11 |
EP3750883A1 (en) | 2020-12-16 |
KR20200118022A (ko) | 2020-10-14 |
EP3750883A4 (en) | 2021-09-22 |
ES2963437T3 (es) | 2024-03-27 |
JPWO2019156074A1 (ja) | 2021-01-14 |
EP3750883B1 (en) | 2023-10-04 |
CN111655675A (zh) | 2020-09-11 |
JP7183196B2 (ja) | 2022-12-05 |
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US11440896B2 (en) | 2022-09-13 |
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