TWI534142B - Azole derivatives - Google Patents
Azole derivatives Download PDFInfo
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- TWI534142B TWI534142B TW101108668A TW101108668A TWI534142B TW I534142 B TWI534142 B TW I534142B TW 101108668 A TW101108668 A TW 101108668A TW 101108668 A TW101108668 A TW 101108668A TW I534142 B TWI534142 B TW I534142B
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- compound
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- methyl
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- hydroxy
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- 150000007980 azole derivatives Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 283
- 150000003839 salts Chemical class 0.000 claims description 39
- 201000004384 Alopecia Diseases 0.000 claims description 30
- 208000024963 hair loss Diseases 0.000 claims description 27
- 230000003676 hair loss Effects 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- 125000003277 amino group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 229940124597 therapeutic agent Drugs 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 230000000069 prophylactic effect Effects 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000005947 C1-C6 alkylsulfonyloxy group Chemical group 0.000 claims description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 3
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 2
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
- 239000002904 solvent Substances 0.000 description 68
- 239000000243 solution Substances 0.000 description 62
- -1 radiation Substances 0.000 description 53
- 230000009977 dual effect Effects 0.000 description 50
- 238000000034 method Methods 0.000 description 46
- 239000011734 sodium Substances 0.000 description 44
- 239000012044 organic layer Substances 0.000 description 38
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000012043 crude product Substances 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- 239000000203 mixture Substances 0.000 description 24
- 230000003779 hair growth Effects 0.000 description 23
- 235000019439 ethyl acetate Nutrition 0.000 description 22
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 210000004209 hair Anatomy 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 17
- 239000012267 brine Substances 0.000 description 16
- 230000012010 growth Effects 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 230000001737 promoting effect Effects 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
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- 235000019198 oils Nutrition 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 11
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 10
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 10
- 102100027913 Peptidyl-prolyl cis-trans isomerase FKBP1A Human genes 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 108050006400 Cyclin Proteins 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 102000009339 Proliferating Cell Nuclear Antigen Human genes 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 8
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 230000007935 neutral effect Effects 0.000 description 8
- 125000004430 oxygen atom Chemical group O* 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
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- 101710111682 Peptidyl-prolyl cis-trans isomerase FKBP1A Proteins 0.000 description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 7
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 7
- 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- GOJHEQCIVYDFGQ-IBGZPJMESA-N 1-[(2s)-2-[5-[(3,4-dimethoxyphenoxy)methyl]-1-methyl-1,2,4-triazol-3-yl]pyrrolidin-1-yl]-2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)ethanone Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=NC([C@H]2N(CCC2)C(=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)=NN1C GOJHEQCIVYDFGQ-IBGZPJMESA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- URNUHNTWOWWNFJ-QFIPXVFZSA-N C1=C(OC)C(OC)=CC=C1OCC1=CC([C@H]2N(CCC2)C(=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)=NN1C Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=CC([C@H]2N(CCC2)C(=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)=NN1C URNUHNTWOWWNFJ-QFIPXVFZSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
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- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
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- BLKNOVDRFRHCTP-SFHVURJKSA-N 1-[(2s)-2-[5-[(3,4-dimethoxyphenoxy)methyl]-1,3,4-thiadiazol-2-yl]pyrrolidin-1-yl]-2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)ethanone Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=NN=C([C@H]2N(CCC2)C(=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)S1 BLKNOVDRFRHCTP-SFHVURJKSA-N 0.000 description 5
- IZQLJVNWGSKPHE-FQEVSTJZSA-N 1-[(2s)-2-[5-[(3,4-dimethoxyphenoxy)methyl]-1,3-oxazol-2-yl]pyrrolidin-1-yl]-2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)ethanone Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=CN=C([C@H]2N(CCC2)C(=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)O1 IZQLJVNWGSKPHE-FQEVSTJZSA-N 0.000 description 5
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- YCJZWBZJSYLMPB-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,5-dimethyl-1-phenylimidazole-4-carboxamide Chemical compound CC=1N(C=2C=CC=CC=2)C(C)=NC=1C(=O)NC1=CC=NC(Cl)=N1 YCJZWBZJSYLMPB-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000004894 pentylamino group Chemical group C(CCCC)N* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 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
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JXIYXIWBJYCVST-QMMMGPOBSA-N tert-butyl (2s)-2-(2,2-dibromoethenyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br JXIYXIWBJYCVST-QMMMGPOBSA-N 0.000 description 1
- JTAJZIACJJWQCT-ZETCQYMHSA-N tert-butyl (2s)-2-(c-chloro-n-hydroxycarbonimidoyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(Cl)=NO JTAJZIACJJWQCT-ZETCQYMHSA-N 0.000 description 1
- YVNILLRYGFOXKG-QMMMGPOBSA-N tert-butyl (2s)-2-(hydroxyiminomethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C=NO YVNILLRYGFOXKG-QMMMGPOBSA-N 0.000 description 1
- IKBKBRZWHMEAMT-AWEZNQCLSA-N tert-butyl (2s)-2-[3-[(3,4-dimethoxyphenoxy)methyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboxylate Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=NOC([C@H]2N(CCC2)C(=O)OC(C)(C)C)=N1 IKBKBRZWHMEAMT-AWEZNQCLSA-N 0.000 description 1
- IIRXYFVBLJHSDC-HNNXBMFYSA-N tert-butyl (2s)-2-[4-(3,4-dimethoxyphenoxy)-3-oxobut-1-ynyl]pyrrolidine-1-carboxylate Chemical compound C1=C(OC)C(OC)=CC=C1OCC(=O)C#C[C@H]1N(C(=O)OC(C)(C)C)CCC1 IIRXYFVBLJHSDC-HNNXBMFYSA-N 0.000 description 1
- UPXSWMWQKSONEV-AWEZNQCLSA-N tert-butyl (2s)-2-[5-[(3,4-dimethoxyphenoxy)methyl]-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=NN=C([C@H]2N(CCC2)C(=O)OC(C)(C)C)O1 UPXSWMWQKSONEV-AWEZNQCLSA-N 0.000 description 1
- FRDXRBOZSRZQCK-AWEZNQCLSA-N tert-butyl (2s)-2-[5-[(3,4-dimethoxyphenoxy)methyl]-1,3,4-thiadiazol-2-yl]pyrrolidine-1-carboxylate Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=NN=C([C@H]2N(CCC2)C(=O)OC(C)(C)C)S1 FRDXRBOZSRZQCK-AWEZNQCLSA-N 0.000 description 1
- JMRHHMLTGUMXIT-INIZCTEOSA-N tert-butyl (2s)-2-[5-[(3,4-dimethoxyphenoxy)methyl]-1,3-oxazol-2-yl]pyrrolidine-1-carboxylate Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=CN=C([C@H]2N(CCC2)C(=O)OC(C)(C)C)O1 JMRHHMLTGUMXIT-INIZCTEOSA-N 0.000 description 1
- AZEIEPKQCNOBBU-INIZCTEOSA-N tert-butyl (2s)-2-[5-[(3,4-dimethoxyphenoxy)methyl]-1,3-thiazol-2-yl]pyrrolidine-1-carboxylate Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=CN=C([C@H]2N(CCC2)C(=O)OC(C)(C)C)S1 AZEIEPKQCNOBBU-INIZCTEOSA-N 0.000 description 1
- MWSMIMGFBWAZKJ-AWEZNQCLSA-N tert-butyl (2s)-2-[5-[(3,4-dimethoxyphenoxy)methyl]-1h-1,2,4-triazol-3-yl]pyrrolidine-1-carboxylate Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=NN=C([C@H]2N(CCC2)C(=O)OC(C)(C)C)N1 MWSMIMGFBWAZKJ-AWEZNQCLSA-N 0.000 description 1
- SEYPDQWLXINNIG-KRWDZBQOSA-N tert-butyl (2s)-2-[5-[(3,4-dimethoxyphenoxy)methyl]-1h-pyrazol-3-yl]pyrrolidine-1-carboxylate Chemical compound C1=C(OC)C(OC)=CC=C1OCC1=CC([C@H]2N(CCC2)C(=O)OC(C)(C)C)=NN1 SEYPDQWLXINNIG-KRWDZBQOSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cosmetics (AREA)
Description
本發明係關於與FKBP12結合之新穎化合物或其醫藥上容許之鹽、以及含有該等作為有效成分之脫毛症的預防或治療劑。
脫毛症中係存在有男性型脫毛症、老人性脫毛症、圓形脫毛症、停經後女性之脫毛症等各種類型。其多數雖無關生死,但因其外觀上的問題而亦多伴隨著精神上的痛苦,而期望脫毛症之優良預防或治療劑。
毛髮係經過成長期、退行期、及休止期之階段而循環再生(毛週期)。此毛週期通常1循環需要2~7年的期間,若有某種異常產生而使此期間縮短時,毛髮會在尚未充分成長時即停止成長。結果,會觀察到伴隨著脫毛數增加之毛髮密度的減少、或每1根毛髮之粗度減少。使該毛週期之節奏崩壞的因子,可列舉睪固酮或二氫睪固酮等之男性荷爾蒙、放射線、抗癌劑等之藥劑、年齡增長、及壓力等。
針對使用了以脫毛症之治療藥創造為目的之多種多樣的化合物進行了探討,例如在複數個的動物模式中報告了於免疫抑制劑FK506(他克莫司,Tacrolimus)觀察到有生髮促進效果(參照專利文獻1及非專利文獻1)。其作用不僅是在認為是自體免疫疾病的圓形脫毛症模式(參照非專利
文獻2及3),在使用正常小鼠或藥劑性脫毛症模式之生髮試驗中亦得到確認(參照非專利文獻4及5)。但是,FK506因為其免疫抑制作用故副作用之危險高,作為脫毛症之治療劑者,期望無免疫抑制作用且更安全的化合物。
近年來,發現了不具有免疫抑制作用,且結合於免疫親和素(immunophilin)FKBP12(FK506所結合之分子量12kDa的蛋白質)之複數個的化合物(參照專利文獻2~10)。並且揭示了其中之一部分的衍生物中,顯示有生髮促進作用(參照專利文獻11及12)。但是,對其他衍生物並無報告有生髮促進作用,對免疫親和素FKBP12之結合活性與生髮促進活性的關聯,不明確之處尚多。且,上述之與FKBP12結合之化合物,並無揭示與本案發明相同之唑構造。
[專利文獻1]日本專利2925285號公報
[專利文獻2]WO1996/040633國際公開公報
[專利文獻3]WO1992/019593國際公開公報
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本發明之課題,係發現與FKBP12結合之新穎化合物或其醫藥上容許之鹽,提供有用於脫毛症之預防或治療之新治療藥。
本發明者等人,發現以下述式(1)表示之化合物或其醫藥上容許之鹽會解決上述課題,完成了本發明。
亦即本發明為(I)一種以式(1)表示之化合物或其醫藥上容許之鹽,
[此處,式(1)中R1表示下式(2)或式(3)之任一者,
環A表示下式(4)之任一者的環,
X表示-(CH2)m-X1-(CH2)n-,X1表示鍵結鍵、-O-、-NRaC(=O)-、-C(=O)NRb-、-NRcS(=O)2-或-S(=O)2NRd-,Ra、Rb、Rc及Rd係相同或相異地分別表示氫原子或C1-6烷基,m及n係相同或相異地分別表示0~3之整數,R2表示芳基、雜芳基(該芳基或雜芳基可經由鹵素原子、C1-6烷基及C1-6烷氧基(該C1-6烷基或C1-6烷氧基可經由鹵素原子及羥基所構成群組中選出之1~3個取代基取代)所構成群組中選出之1~3個取代基取代)、1,3-苯并二氧雜環戊基、吲哚基、嗎啉基、羥基、C1-6烷基(該C1-6烷基可經1~2個羥基取代)、胺基、單-C1-6烷基胺基、二-C1-6烷基胺基、C1-6烷氧基、C1-6烷基磺醯基氧基、吡啶酮基或嘧啶酮基]。
(I’)
如(I)之化合物或其醫藥上容許之鹽,其中R2係表示芳基、雜芳基(該芳基或雜芳基可經由C1-6烷基及C1-6烷氧基(該C1-6烷基或C1-6烷氧基可經由鹵素原子及羥基所構成群組中選出之1~3個取代基取代)所構成群組中選出之1~3個取代基取代)、1,3-苯并二氧雜環戊基、吲哚基、嗎啉基、羥基、C1-6烷基(該C1-6烷基可經1~2個羥基取代)、胺基、單-C1-6烷基胺基、二-C1-6烷基胺基、C1-6烷氧基、或C1-6烷基磺醯基氧基。
(II)如(I)或(I’)之化合物或其醫藥上容許之鹽,其中X為鍵結鍵、-CH2O-、-CH2-、-(CH2)2-、-(CH2)3-、-O-、-CH2-NHC(=O)-、-CH2-NHC(=O)-CH2-或-CH2-NHS(=O)2-。
(III)如(I)或(I’)之化合物或其醫藥上容許之鹽,其中X為-CH2O-或-CH2-。
(IV)如(I)~(III)及(I’)中任一項之化合物或其醫藥上容許之鹽,其中R1為式(2)。
(V)如(I)~(IV)及(I’)中任一項之化合物或其醫藥上容許之鹽,其中環A為下式(5)之任一者之環;
(VI)如(I)~(V)及(I’)中任一項之化合物或其醫藥上容許之鹽,其中R2為苯基、吡啶基、嗒嗪基或嘧啶基(該苯基、吡啶基或嘧啶基可經1~3個鹵素原子或甲氧基取代)、吡啶酮基或嘧啶酮基。
(VII)如(VI)之化合物或其醫藥上容許之鹽,其中R2為苯基或吡啶基(該苯基或吡啶基可經1~3個甲氧基取代)。
(VIII)如(I)之化合物或其醫藥上容許之鹽,其係(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)異噁唑基-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((吡啶-3-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮、(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((3,4,5-三甲氧基苯氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮、(S)-N-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)苄醯胺、
(S)-N-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)苯磺醯胺、(S)-1-(2-(5-((二甲基胺基)甲基)異噁唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-3-(1-((環己基甲基)磺醯基)吡咯啶-2-基)-5-((3,4-二甲氧基苯氧基)甲基)異噁唑、(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-(苯氧基甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-基)乙酮、(S)-N-((5-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)-1,3,4-氧雜二唑-2-基)甲基)苄醯胺、(S)-1-(2-(5-((二甲基胺基)甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮)、(S)-1-(2-(3-((3,4-二甲氧基苯氧基)甲基)-1,2,4-氧雜二唑-5-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1-甲基-1H-吡唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-1-(2-(3-((3,4-二甲氧基苯氧基)甲基)異噁唑-5-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮
、(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1H-吡唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1,3,4-噻二唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-4H-1,2,4-三唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1-甲基-1H-1,2,4-三唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)噁唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)噻唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-(苯氧基甲基)異噁唑-3-基)吡咯啶-1-基)乙酮、(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((嘧啶-5-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮、(S)-1-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)
乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)嘧啶-4(1H)-酮、(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((嘧啶-4-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮、(S)-2,2-二氟-1-(2-(5-((3-氟苯氧基)甲基)異噁唑-3-基)吡咯啶-1-基)-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮、或(S)-1-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)吡啶-4(1H)-酮。
(IX)一種醫藥,其係含有如(I)~(VIII)及(I’)中任一項之化合物或其醫藥上容許之鹽作為有效成分。或
(X)一種脫毛症之預防或治療劑,其係以如(I)~(VIII)及(I’)中任一項之化合物或其醫藥上容許之鹽作為有效成分。
本發明化合物及其醫藥上容許之鹽,係與FKBP12結合,而抑制FKBP12之肽脯胺醯異構酶(旋轉異構酶)活性。又,本發明之化合物及其醫藥上容許之鹽,顯示了展現出優良溶解性且適合使用作為外用劑的樣態。進一步地,本發明之化合物及其醫藥上容許之鹽,係顯示優良的生髮促進作用。
本發明之化合物及其醫藥上容許之鹽,不顯著抑制蛋白質去磷酸酶鈣調磷酸酶(protein phosphatase calcineurin),因此並不具有任何重大的免疫抑制活性。因此,含有本
發明之化合物及其醫藥上容許之鹽的製劑,被期待作為脫毛症之預防或治療劑於安全性方面優良。
本說明書中之用語的定義如以下所述。
「鹵素原子」意指氟原子、氯原子、溴原子、碘原子。
「C1-6烷基」意指直鏈狀或支鏈狀之碳原子數1至6個的烷基,可列舉例如甲基、乙基、丙基、丁基、戊基、己基、異丙基、異丁基、tert-丁基、sec-丁基、異戊基、新戊基、tert-戊基、1,2-二甲基丙基等。
「C1-6烷氧基」意指直鏈狀或支鏈狀之碳原子數1至6個的烷氧基,可列舉例如甲氧基、乙氧基、丙氧基、丁氧基、戊基氧基、己基氧基、異丙氧基、異丁氧基、tert-丁氧基、sec-丁氧基、異戊基氧基、新戊基氧基、tert-戊基氧基、1,2-二甲基丙氧基等。
「芳基」意指以碳原子數6至18個構成之單環至4環式的芳香族碳環式基,可列舉例如苯基、萘基、蒽基、菲基、稠四苯基、芘基等。
「雜芳基」意指單環式或縮合環式芳香族雜環基,可列舉例如吡啶基、嗒嗪基、嘧啶基、吡嗪基、噻吩基、吡咯基、噻唑基、異噻唑基、吡唑基、咪唑基、呋喃基、噁唑基、異噁唑基、噁二唑基、1,3,4-噻二唑基、1,2,3-三唑基、1,2,4-三唑基、四唑基、喹啉基、異喹啉基、萘啶基
、喹唑啉基、苯并呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并異噁唑基、1H-吲唑基、2H-吲唑基、苯并咪唑基、苯并噁二唑基、苯并噻二唑基、吲哚嗪基、苯并呋吖基、噻吩并吡啶基、吡唑并吡啶基、咪唑并吡啶基、咪唑并吡嗪基、吡唑并嘧啶基、三唑并嘧啶基、噻吩并噻吩基、咪唑并噻唑基等。
「單-C1-6烷基胺基」意指經1個上述C1-6烷基取代之胺基,可列舉例如甲基胺基、乙基胺基、丙基胺基、丁基胺基、戊基胺基、己基胺基、異丙基胺基、異丁基胺基、tert-丁基胺基、sec-丁基胺基、異戊基胺基、新戊基胺基、tert-戊基胺基、1,2-二甲基丙基胺基等。
「二-C1-6烷基胺基」意指經各自獨立之2個上述C1-6烷基取代之胺基,可列舉例如二甲基胺基、二乙基胺基、二丙基胺基、二丁基胺基、二戊基胺基、二己基胺基、二異丙基胺基、二異丁基胺基、二-tert-丁基胺基、二-sec-丁基胺基、二-異戊基胺基、二-新戊基胺基、二-tert-戊基胺基、二-1,2-二甲基丙基胺基、乙基甲基胺基、異丙基甲基胺基、異丁基異丙基胺基等。
「C1-6烷基磺醯基氧基」意指經上述C1-6烷基取代之磺醯基氧基,可列舉例如甲基磺醯基氧基、乙烷磺醯基氧基、n-丙基磺醯基氧基、異丙基磺醯基氧基、n-丁基磺醯基氧基、2-甲基-n-丁基磺醯基氧基、tert-丁基磺醯基氧基、n-戊基磺醯基氧基及n-己基磺醯基氧基等。
本發明之化合物中,
較佳X為鍵結鍵、-CH2O-、-CH2-、-(CH2)2-、-(CH2)3-、-O-、-CH2-NHC(=O)-、-CH2-NHC(=O)-CH2-或-CH2-NHS(=O)2-。更佳X為-CH2O-。又更佳R1為式(2),環A表示下式(5)之任一者之環,
R2為苯基或吡啶基(該苯基或吡啶基可經1~3個甲氧基取代)。
「脫毛症」意指毛髮之一部分或全部脫落、消失之狀態,或變細、變短的狀態。脫毛症並無特殊限定,係有男性型脫毛症、脂漏性脫毛症、老人性脫毛症、圓形脫毛症、投予抗癌劑等為原因的藥物脫毛症、瘢痕性脫毛症、生產後引起的產後脫毛症。脫毛症多起因於毛週期的破壞,其觸發之原因為細胞增殖之停止等所造成的成長期之期間縮短。
又「毛週期」意為毛髮之成長循環,係指由下列3期所構成的週期:(1)成長期(毛囊細胞重複分裂,毛髮活潑成長的期間,對頭髮而言係持續2~6年)、(2)退行期(毛髮之成長變弱,毛囊萎縮的期間,對頭髮而言持續1~2週)、及(3)休止期(毛囊完全退縮而休止的期間,對頭髮而
言係持續3~4個月)。通常,80至90百分比之毛髮為處在成長期,低於1%在退行期,剩下者為休止期。脫毛症中毛週期係產生異常,特別是男性型脫毛症中,成長期之期間縮短,毛成長為粗的硬毛前即轉移至退行期/休止期,因此會發生休止期毛比率之增加及由硬毛至細的軟毛之變化。
本發明之「脫毛症之預防或治療劑」,係指具有以下任一項者:(1)由休止期朝向成長期之誘導(生髮誘導)、(2)毛成長之促進、(3)成長期之延長、(4)脫毛之抑制、延遲、或減少;且期望具有複數之作用者。
「醫藥上容許之鹽」,意指藥劑學上可容許之鹽。該等可列舉例如與乙酸、丙酸、丁酸、甲酸、三氟乙酸、馬來酸、酒石酸、檸檬酸、硬脂酸、琥珀酸、乙基琥珀酸、丙二酸、乳糖酸、葡萄糖酸、葡萄醣庚酸、安息香酸、甲烷磺酸、乙烷磺酸、2-羥基乙烷磺酸、苯磺酸、對甲苯磺酸(甲苯磺酸)、月桂基硫酸、蘋果酸、天門冬胺酸、麩胺酸、己二酸、半胱胺酸、N-乙醯基半胱胺酸、鹽酸、氫溴酸、磷酸、硫酸、氫碘酸、菸鹼酸、草酸、苦味酸、硫氰酸、十一酸、丙烯酸聚合物及羧基乙烯聚合物等酸之鹽;鋰鹽、鈉鹽、鉀鹽及鈣鹽等與無機鹼之鹽;嗎啉及哌啶等之有機胺;以及與胺基酸之鹽。
本發明化合物及其醫藥上容許之鹽,亦可作為各種溶劑合物存在。又,由作為醫藥之適用性方面而言,亦可作為水合物。
本發明化合物(1)或醫藥上容許之鹽,可直接、或者與醫藥上容許之載體一起,遵照本身公知之手段來製劑化。醫藥上容許之載體,可列舉作為製劑材料所慣用的各種有機或無機載體物質,例如固體製劑中之賦形劑(例如乳糖、白糖、D-甘露醇、澱粉、玉米澱粉、結晶纖維素、輕質矽酸酐等)、潤滑劑(例如硬脂酸鎂、硬脂酸鈣、滑石、膠質二氧化矽等)、結合劑(例如結晶纖維素、白糖、D-甘露醇、糊精、羥基丙基纖維素、羥基丙基甲基纖維素、聚乙烯吡咯啶酮、澱粉、蔗糖、明膠、甲基纖維素、羧甲基纖維素鈉等)、崩解劑(例如、澱粉、羧甲基纖維素、羧甲基纖維素鈣、交聯羧甲基纖維素鈉、羧甲基澱粉鈉、低取代度羥基丙基纖維素等)、或液狀製劑中之溶劑(例如注射用水、醇、丙二醇、聚乙二醇、麻油、玉米油等)、溶解輔助劑(例如聚乙二醇、丙二醇、D-甘露醇、安息香酸苄酯、乙醇、三胺基甲烷、膽固醇、三乙醇胺、碳酸鈉、檸檬酸鈉等)、懸浮劑(例如硬脂基三乙醇胺、月桂基硫酸鈉、月桂基胺基丙酸、卵磷脂、氯化殺藻胺、苄索氯銨(Benzethonium chloride)、單硬脂酸甘油等界面活性劑;或例如聚乙烯醇、聚乙烯吡咯啶酮、羧甲基纖維素鈉、甲基纖維素、羥基甲基纖維素、羥基丙基纖維素等親水性高分子等)、等張化劑(例如葡萄糖、D-山梨醇、氯化鈉、甘油、D-甘露醇等)、緩衝劑(例如磷酸鹽、乙酸鹽、碳酸鹽、檸檬酸鹽等)、止痛劑(例如苄基醇等)等。又,製劑化時,亦可依照需要,使用防腐劑(例如、對氧基安息香酸酯
類、氯丁醇、苄基醇、苯乙醇、去氫乙酸、山梨酸等)、抗氧化劑(例如、亞硫酸鹽、抗壞血酸等)、著色劑、甘味劑、吸附劑、濕潤劑等。
本發明化合物或醫藥上容許之鹽,可經口或非經口(例如靜脈、局部、直腸投予等)投予。其投予劑型,係為例如錠劑(糖衣錠,含包膜錠)、散劑、顆粒劑、粉劑、錠劑、膠囊劑(含軟膠囊)、液劑、注射劑(例如皮下注射劑、靜脈內注射劑、肌肉內注射劑、腹腔內注射劑等)、外用劑(例如經鼻投予製劑、經皮製劑、軟膏劑、乳劑等)、栓劑(例如、直腸栓劑、陰道栓劑等)、緩釋劑(例如、緩釋性微膠囊等)、丸劑、點滴劑等,均可藉由慣用之製劑技術(例如第15改訂之日本藥典所記載之方法等)來製造。較佳之劑型,就可直接投予至患部的觀點、容易投予之觀點、全身副作用發生之可能性降低之點等而言,可列舉外用劑。又,本發明化合物並無免疫抑制作用,全身副作用之可能性低,因此亦能夠作為經口劑來利用。
如以上方式製造之本發明之脫毛症的預防或治療劑投予量,可依患者體重、年齡、性別等作適宜增減。具體而言,作為外用劑使用的情況時,可使用含有本發明化合物0.0001%~20%之濃度的外用劑,1天1次~數次投予。此時對毛髮之適用量為0.00001~4mg/cm2左右、較佳為0.01~1mg/cm2左右。
又,作為經口劑使用時,成人每1天以本發明化合物1~1000mg/kg,1天1次~數次投予即可。
進一步地,本發明化合物亦可與其他脫毛症預防劑或治療劑之有效成分合併使用。可合併使用之藥劑,雖可列舉敏諾西迪、非那雄胺,但不限定於該等。又,亦可合併使用其他生髮劑/育毛劑、血管擴張劑、抗雄性激素劑、環孢靈素衍生物、抗菌劑、抗發炎劑、甲狀腺荷爾蒙衍生物、前列腺素作用物質或拮抗物質、類視色素、三萜等藥劑。本發明之化合物與其他脫毛症預防劑或治療劑的有效成分,可作為各別製劑來使用、亦可作為1個調配劑來使用。
說明本發明化合物之製造方法,但本發明化合物之製造方法並不限定於該等。本發明化合物之製造所使用的原料化合物,可藉由公知方法或本身公知之方法輕易地製造。以由製造方法A起至E為止,環A之構築作為中心來進行例示、說明。關於有機殘基-R1之加成,於此在最後顯示有導入之方法,但亦可在構築環A之前、或途中之階段進行。又,關於有機殘基-X-R2之加成或轉換,亦可適當地在任何階段進行。各步驟中,具有反應性官能基的情況時,進行適當保護、去保護即可。
以一般式(1)表示之化合物中,環A以下式
表示之化合物(Y1表示氧原子、NMe、NH),係以例如以下方法製造。
以式(a-2)表示之化合物,可藉由使以式(a-1)表示之化合物於通常所進行之醯化反應中與甲氧基甲基胺反應而得。例如,使以式(a-1)表示之化合物之羧酸以氯化亞磺醯基、氯化草醯基等轉換為對應的酸鹵化物;或以氯甲酸乙酯、氯甲酸異丁酯等轉換為對應的混合酸酐,於溶劑中或無溶劑下,依需要在鹼存在下,與甲氧基甲基胺反應以得到。又,使以式(a-1)表示之化合物與甲氧基甲基胺,亦可藉
由使用二環己基碳二醯亞胺、1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺等縮合劑予以反應而得到。溶劑係使用二氯甲烷、氯仿等鹵素系溶劑;四氫呋喃、二噁烷等醚系溶劑;甲苯、二甲苯等芳香族烴系溶劑;N、N-二甲基甲醯胺等非質子性極性溶劑或該等之混合溶劑。鹼係使用吡啶、三乙基胺等有機鹼;或氫氧化鈉、碳酸氫鈉等無機鹼。
以式(a-4)表示之化合物,可藉由使以式(a-3)表示之化合物在溶劑中,與MeLi、n-BuLi、EtMgBr等有機金屬試劑反應而生成之炔化物,與以式(a-2)表示之化合物反應而得到。溶劑係使用四氫呋喃、二噁烷等醚系溶劑;己烷、戊烷等脂肪族烴溶劑或該等之混合溶劑。
以式(a-6)表示之化合物,可藉由使以式(a-4)表示之化合物,與以式(a-5)表示之化合物或其鹽,在溶劑中或無溶劑下,依需要在酸或鹼存在下反應而得到。溶劑係使用甲醇、乙醇等醇類;四氫呋喃、二噁烷等醚系溶劑;N、N-二甲基甲醯胺等非質子性極性溶劑;水或該等之混合溶劑。酸係使用鹽酸、硫酸等無機酸或乙酸、p-甲苯磺酸等有機酸。鹼係使用吡啶、三乙基胺等有機鹼;或AcONa、NaOMe、Na2SO4、K2CO3等無機鹼。
以式(a-7)表示之化合物,可藉由使以式(a-6)表示之化合物之胺基的保護基去保護而得到。就去保護之方法而言,該保護基為t-丁氧基羰基時,係有與三氟乙酸、鹽酸等酸反應的方法,該保護基為苄基氧基羰基時,係有在鈀-碳、氧化鉑等觸媒存在下,進行氫化反應之方法或與HBr-AcOH等之酸反應之方法。使其他保護基去保護的情況時,為了使該保護基去保護,只要係進行通常所進行的方法即可。
以式(a-9)表示之化合物,可藉由使以式(a-8)表示之化合物(L為OH基時)藉由與步驟A-1記載之方法同樣的方法成為酸鹵化物,與以式(a-7)表示之化合物反應、或在縮合劑存在下,藉由與以式(a-7)表示之化合物反應而得到。又,以式(a-9)表示之化合物,亦可藉由使以式(a-8)表示之化合物(L為脫離基時)與以式(a-7)表示之化合物在溶劑中,依需要在鹼存在下反應而得到。
以一般式(1)表示之化合物當中,環A以下式
表示之化合物,係以例如以下的方法製造。
以式(b-2)表示之化合物,可藉由Journal of Medicinal Chemistry 1990年第33卷3190頁所記載之方法或根據其之方法,使以式(b-1)表示之化合物在二氯甲烷、氯仿等鹵素系溶劑中,與CBr4,PPh3反應而得到。
以式(b-3)表示之化合物,可藉由使以式(b-2)表示之化合物在溶劑中與鹼反應而得到。鹼係使用MeLi、n-BuLi、sec-BuLi、LiN(i-Pr)2等。溶劑係使用四氫呋喃、二噁烷等醚系溶劑;己烷、戊烷等脂肪族烴溶劑或該等之混合溶劑。
以式(b-5)表示之化合物,可藉由使以式(b-3)表示之化合物在溶劑中,與MeLi、n-BuLi、EtMgBr等有機金屬試劑反應而生成之炔化物,與以式(b-4)表示之化合物反應而得到。溶劑係使用四氫呋喃、二噁烷等醚系溶劑;己烷、戊烷等脂肪族烴溶劑或該等之混合溶劑。又,以式(b-5)表示之化合物,亦可使藉由步驟B-2所示反應於反應系中生成之以式(b-3)表示之化合物所對應之炔化物、與以式(b-4)表示之化合物反應而得到。
以式(b-6)表示之化合物,可藉由使以式(b-5)表示之化合物在溶劑中或無溶劑下,依需要在酸或鹼存在下與羥基胺或其鹽反應而得到。溶劑係使用甲醇、乙醇等醇類;四氫呋喃、二噁烷等醚系溶劑;N、N-二甲基甲醯胺等非質子性極性溶劑;水或該等之混合溶劑。酸係使用鹽酸、硫酸等無機酸或乙酸、p-甲苯磺酸等有機酸。鹼係使用吡
啶、三乙基胺等有機鹼;或AcONa、NaOMe、Na2SO4、K2CO3等無機鹼。
以式(b-7)表示之化合物,係由以式(b-6)表示之化合物,藉由與步驟A-4同樣之方法而得到。
以式(b-8)表示之化合物,係由以式(b-7)表示之化合物,藉由與步驟A-5同樣之方法而得到。
以一般式(1)表示之化合物當中,環A以下式
表示之化合物(Y2表示氧原子、硫原子),係由例如以下之方法製造。
以式(c-1)表示之化合物,可由以式(a-1)表示之化合物與聯胺,藉由步驟A-1所記載之通常所進行的醯化反應而得到。
以式(c-3)表示之化合物,可由以式(c-1)及式(c-2)表示之化合物,藉由步驟A-1所記載之通常所進行的醯化反應而得到。
以式(c-4)表示之化合物當中,Y2為氧原子之化合物,可使以式(c-3)表示之化合物在溶劑中,藉由使用了伯吉斯試劑(Burgess reagent)、或CBr4、PPh3、咪唑等之脫水環化反應而得到。溶劑係使用二氯甲烷、氯仿等鹵素系溶劑;甲苯、二甲苯等芳香族烴系溶劑。
以式(c-4)表示之化合物當中,Y2為硫原子之化合物,可使以式(c-3)表示之化合物在溶劑中,與勞森試劑(Lawesson’s reagent)等反應而得到。溶劑係使用二氯甲烷、氯仿等鹵素系溶劑;甲苯、二甲苯等芳香族烴系溶劑。
以式(c-5)表示之化合物,係可由以式(c-4)表示之化合物,藉由與步驟A-4同樣的方法得到。
以式(c-6)表示之化合物,係可由以式(c-5)表示之化合物,藉由與步驟A-5同樣的方法得到。
以一般式(1)表示之化合物當中,環A為以下式
表示之化合物(Y3表示氫原子或Me基),係由例如以下之方法製造。
以式(d-2)表示之化合物,可由式(a-1),藉由步驟A-1記載之通常所進行的醯化反應與以式(d-1)表示之聯胺化合物反應、或與以式(d-1)表示之聯胺化合物所對應的保護聯胺體反應,接著再藉由去保護而得到。
以式(d-4)表示之化合物,可由以式(d-2)及式(d-3)表示之氰基化合物,在溶劑中,依需要在酸或鹼存在下加熱
藉以得到。溶劑係使用甲醇、丁醇等醇類;二噁烷、二苯基醚等醚系溶劑。酸係使用乙酸等有機酸。鹼係使用NaOMe、K2CO3等無機鹼。反應溫度係由溶劑回流溫度至220℃,於常壓下、加壓下、微波照射下等來實施。
以式(d-5)表示之化合物,可由以式(d-4)表示之化合物,藉由與步驟A-4同樣的方法得到。
以式(d-6)表示之化合物,可由以式(d-5)表示之化合物,藉由與步驟A-5同樣的方法得到。
以一般式(1)表示之化合物當中,環A以下式
表示之化合物,係由例如以下之方法製造。
以式(e-2)表示之化合物,可由式(a-1),藉由步驟A-1記載之通常所進行的醯化反應,與以式(e-1)表示之化合物反應而得到。
以式(e-3)表示之化合物,可使以式(e-2)表示之化合物在溶劑中,依需要在酸或鹼存在下進行脫水反應而得到。溶劑係使用二噁烷等醚系溶劑;甲苯、二甲苯等芳香族烴系溶劑。酸係使用p-甲苯磺酸等有機酸。鹼係使用吡啶、三乙基胺等有機鹼;n-Bu4NF等銨鹽等。反應溫度為於室溫至溶劑回流溫度來實施。
以式(e-4)表示之化合物,可由以式(e-3)表示之化合物,藉由與步驟A-4同樣的方法而得到。
以式(e-5)表示之化合物,可由以式(e-4)表示之化合物,藉由與步驟A-5同樣的方法而得到。
以一般式(1)表示之化合物當中,環A為以下式
表示之化合物(Y4表示氧原子、硫原子),係由例如以下之方法製造。
(上述式中、R1,R2,X係與前述同義,P為胺基之保護基(例如t-丁氧基羰基、苄基氧基羰基等);Y4表示氧原子或硫原子;L表示羥基或脫離基(例如氯、溴、碘等))。
以式(f-2)表示之化合物,可由式(a-1),藉由步驟A-1記載之通常所進行之醯化反應,與以式(f-1)表示之化合物反應而得到。
以式(f-3)表示之化合物當中,Y4為氧原子之化合物,可使以式(f-2)表示之化合物在溶劑中,藉由使用了伯吉斯試劑、或CBr4、pph3、咪唑等之脫水環化反應而得到。溶劑係使用二氯甲烷、氯仿等鹵素系溶劑;甲苯、二甲苯等芳香族烴系溶劑。
以式(f-3)表示之化合物當中,Y4為硫原子之化合物,可使以式(f-2)表示之化合物在溶劑中,藉由與勞森試劑等反應而得到。溶劑係使用二氯甲烷、氯仿等鹵素系溶劑;甲苯、二甲苯等芳香族烴系溶劑。
以式(f-4)表示之化合物,可由以式(f-3)表示之化合物,藉由與步驟A-4同樣的方法而得到。
以式(f-5)表示之化合物,可由以式(f-4)表示之化合物,藉由與步驟A-5同樣的方法而得到。
接著,藉由實施例及試驗例進一步詳細地說明本發明。本發明化合物並不受下述實施例中記載之化合物所限定。
無特別記載時,矽膠層析法中之載體係使用洞海化學工業股份有限公司製M.S.GEL D-75-60-A、NH型矽膠層析法中之載體係使用富士silysia化學股份有限公司製Chromatorex NH-DM1020、中性矽膠層析法中之載體係使用關東化學股份有限公司製二氧化矽凝膠60N或Biotage公司製KP-Sil 20μm二
氧化矽凝膠。
NMR光譜係表示質子NMR,使用四甲基矽烷作為內部基準,δ值係以ppm表示。
MS係使用LCMS-2010EV(ESI/APCI dual安裝)來測定。逆相分離HPLC係使用GILSON preparative HPLC system。分離所用之管柱、溶劑係如下述。
管柱:Waters,SunFire Prep C18,OBD 5.0μm,30×50mmColumn
溶劑:CH3CN(0.1%CF3COOH),H2O(0.1%CF3COOH)
又,實施例中之縮寫係如以下所示。
AcOEt:乙酸乙酯
APCI:大氣壓化學離子化
Boc:t-丁氧基羰基
Brine:飽和食鹽水
DBU:二氮雜雙環十一烯
DPPA:疊氮磷酸二苯酯
Et3N:三乙基胺
Et2O:二乙基醚
ESI:電噴灑離子化
HOBt:1-羥基苯并三唑
MsCl:氯化甲烷磺醯基
NMP:N-甲基-吡咯啶酮
Pd-C:鈀碳
PPh3:三苯基膦
PTLC:分離薄層層析法
THF:四氫呋喃
WSC:1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺鹽酸鹽
伯吉斯試劑:N-(三乙基銨磺醯基)胺基甲酸甲酯
勞森試劑:2,4-雙(4-甲氧基苯基)-1,3,2,4-二硫雜二磷雜環
丁烷(dithiadiphosphetane)-2,4-二硫化物
s:單重態(singlet)
br.s.:寬單重態(broad singlet)(寬廣的單重態)
d:二重態(doublet)
dd:雙二重態(double doublet)
m:多重態(multiplet)
(S)-5-((3,4-二甲氧基苯氧基)甲基)-3-(吡咯啶-2-基)異噁唑
在氬環境下,1,2-二甲氧基-4-(丙-2-炔-1-基氧基)苯(81.85g)之THF(1000mL)溶液中,於-60℃~-70℃花費55分鐘滴下n-BuLi(147mL、2.76N己烷溶液),於同溫度攪拌30分鐘後,滴下(S)-t-丁基2-(甲氧基(甲基)胺甲醯基)吡咯啶-1-羧酸酯(100.00g)之THF(600mL)溶液,花費2小時昇溫至室溫,於25℃攪拌30分鐘。將反應溶液加入至飽和NH4Cl水溶液(3L)、冰水(2L)、己烷(1L)及AcOEt(1L),分離有機層,以brine(5L)、水(2L)、brine(1L)依次洗淨,將乾燥(MgSO4)、過濾、濃縮而得之褐色油狀物(161.24g)溶解於EtOH(1000mL),添加羥基胺鹽酸鹽(53.79g),加熱回流13小時後,於室溫攪拌13小時。將反應混合物再度加熱回流6小時後,於濃縮而得到之褐色油狀物中添加鹽酸(1000mL、4.0N AcOEt溶液),於室溫攪拌64小時。於反應
混合物中添加水(2L),分離有機層,冰浴下於水層中添加NaOH(230g),以CHCl3(2L)萃取,將使有機層乾燥(Na2SO4)、過濾、濃縮而得到之粗精製物以中性矽膠層析法(MeOH/CHCl3)精製,得到標題化合物(49.98g、褐色油狀物)。
1H NMR(200MHz,CHLOROFORM-d)δ 6.78(d,J=8.8 Hz,1 H),6.57(d,J=3.1 Hz,1 H),6.45(dd,J=3.1,8.8 Hz,1 H),6.31(s,1 H),5.07(s,2 H),4.38-4.24(m,1 H),3.85(s,3 H),3.84(s,3 H),3.22-2.92(m,2 H),2.33-1.72(m,4 H)
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)異噁唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物1)
於2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酸(87.83g)與Et3N(122mL)之THF(2000mL)溶液中,於室溫
添加氯甲酸乙酯(30.8mL),攪拌30分鐘。於反應混合物中將於實施例1-(1)得到之化合物(89.00g)之THF(500mL)溶液於室溫花費1小時滴下後,於室溫攪拌20小時。將反應混合物濃縮,添加AcOEt(2L)與飽和NH4Cl水溶液(2L),將不溶物過濾後,分離有機層,以飽和碳酸氫鈉水(2L)洗淨、乾燥(MgSO4)、過濾、濃縮而得到粗精製物(165.0g)。將以同樣的方法使用2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酸(34.64g)與(S)-5-((3,4-二甲氧基苯氧基)甲基)-3-(吡咯啶-2-基)異噁唑(35.10g)而得到之粗精製物(60.10g)與前述粗精製物合併,以矽膠層析法(AcOEt/己烷)及NH型矽膠層析法(AcOEt/己烷)精製後再結晶(Et2O/戊烷),得到標題化合物(134.30g、無色粉體)。
1H NMR(600MHz,CHLOROFORM-d)δ 6.78(d,J=8.7 Hz,1 H),6.57(d,J=2.8 Hz,1 H),6.44(dd,J=2.8,8.7 Hz,1 H),6.26[6.18](s,1 H),5.43-5.39[5.60-5.55](m,1 H),5.11-5.00(m,2 H),4.23-4.13(m,1 H),3.99-3.71(m,2 H),3.86(s,3 H),3.84(s,3 H),2.34-0.78(m,22 H)
融點99.0-101.0℃
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((吡啶-3-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物40)
(S)-t-丁基2-((羥基亞胺基甲基)吡咯啶-1-羧酸酯
於(S)-t-丁基2-甲醯基吡咯啶-1-羧酸酯(40.94g)之吡啶(411mL)溶液中,於0℃添加羥基胺1鹽酸鹽(28.56g),於室溫攪拌17小時。將反應混合物添加至AcOEt(1.5L)與鹽酸(2L、3.0N)之混合物中。分離有機層,以飽和碳酸氫鈉水(1L)洗淨、乾燥(MgSO4)、過濾、濃縮而得到標題化合物(39.78g、無色固體)。
ESI+237(M+Na)+
(S)-tert-丁基2-(5-((吡啶-3-基氧基)甲基)異噁唑基-3-基)吡咯啶-1-羧酸酯
於實施例2-(1)中得到之化合物(8.57g)之DMF(60mL)溶液中,於0℃每次少量添加NCS(5.341g),於室溫攪拌1小時。將反應混合物冷卻至0℃,添加3-(丙-2-炔-1-基氧基)吡啶(2.663g)之THF(5mL)溶液與Et3N(5.6mL)之THF(15mL)溶液,於室溫攪拌14小時。將反應混合物添加至飽和碳酸氫鈉水(200mL)中,以AcOEt(200mL)萃取。將所得之有機層以brine(200mL)洗淨,將乾燥(MgSO4)、過濾、濃縮而得之粗精製物,以中性矽膠層析法(AcOEt/己烷)精製,而得到標題化合物(3.81g、淡黃色固體)。
1H NMR(200MHz,CHLOROFORM-d)δ 8.42-8.26(m,2 H),7.30-7.20(m,2 H),6.39-6.19(m,1 H),5.18(br s,2 H),5.10-4.86(m,1 H),3.65-3.35(m,2 H),2.44-1.83(m,4 H),1.59-1.14(m,9 H)
(S)-5-((吡啶-3-基氧基)甲基)-3-(吡咯啶-2-基)異噁唑
於實施例2-(2)中得到之化合物(3.81g)的AcOEt(20mL)溶液中添加HCl(40mL、4.0N AcOEt溶液),於室溫攪拌40小時。將反應混合物濃縮,添加飽和碳酸氫鈉水(200mL)及食鹽,以CHCl3(200mL×2)萃取。將所得之有機層乾燥(Na2SO4)、過濾、濃縮而得到標題化合物(2.614g、褐色油狀物)。
1H NMR(200MHz,CHLOROFORM-d)δ 8.42-8.35(m,1 H),8.32-8.25(m,1 H),7.32-7.19(m,2 H),6.35(s,1 H),5.17(s,2 H),4.39-4.26(m,1 H),3.20-2.93(m,2 H),2.30-1.70(m,4 H)
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((吡啶-3-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物40)
於2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酸(3.192g)與Et3N(4.44mL)之THF(100mL)溶液中,於室溫添加氯甲酸乙酯(1.12mL),攪拌1小時。於反應混合物中將於實施例2-(3)中得到之化合物(2.607g)之THF(50mL)溶液於室溫滴下後,於室溫攪拌64小時。於反應混合物中添加飽和碳酸氫鈉水(200mL),將以AcOEt(200mL)萃取之有機層以brine(200mL)洗淨,將乾燥(MgSO4)、過濾、濃縮而得之粗精製物以NH型矽膠層析法(AcOEt/己烷)精製而得之化合物再結晶(Et2O/戊烷),得到標題化合物(2.969g、無色粉體)。
1H NMR(600MHz,CHLOROFORM-d)δ 8.41-8.34(m,1 H),8.32-8.25(m,1 H),7.28-7.20(m,2 H),6.29[6.20](s,1 H),5.41-5.37[5.58-5.55](m,1 H),5.17-5.12(m,2 H),4.20-4.13(m,1 H),3.90-3.70(m,2 H),2.33-0.82(m,22 H)融點102.0-104.0℃
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((3,4,5-三甲氧基苯氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物21)
(S)-t-丁基2-(4-((tert-丁基二苯基矽烷基)氧基)丁-2-炔醯基)吡咯啶-1-羧酸酯
在氬環境下,於t-丁基二苯基(丙-2-炔-1-基氧基)矽
烷(8.576g)之THF(200mL)溶液中,於-78℃花費10分鐘滴下n-BuLi(10.3mL、2.64N己烷溶液),於同溫度攪拌50分鐘後,於(S)-t-丁基2-(甲氧基(甲基)胺甲醯基)吡咯啶-1-羧酸酯(5.01g)之THF(200mL)溶液中,使用套管滴下反應混合物,花費1小時昇溫至室溫。將反應溶液添加至飽和NH4Cl水溶液(500mL),以AcOEt萃取,將使有機層乾燥(MgSO4)、過濾、濃縮而得之粗精製物以中性矽膠層析法(AcOEt/己烷)精製,得到標題化合物(5.36g、無色油狀物)。
ESI/APCI Dual 514(M+Na)+
(S)-5-(((tert-丁基二苯基矽烷基)氧基)甲基)-3-(吡咯啶-2-基)異噁唑
於實施例3-(1)中得到之化合物(492mg)之EtOH(10mL)溶液中,添加羥基胺鹽酸鹽(139mg),加熱回流17小時。於反應混合物中添加飽和碳酸氫鈉水(50ml),將以AcOEt萃取後之有機層乾燥(MgSO4)、過濾、濃縮而得之
粗精製物,以中性矽膠層析法(AcOEt~MeOH/CHCl3)精製,得到標題化合物(163mg、褐色油狀物)。
ESI/APCI Dual 407(M+H)+
(S)-1-(2-(5-(((tert-丁基二苯基矽烷基)氧基)甲基)異噁唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮
使用實施例3-(2)中得到之化合物(150mg)來取代實施例1-(1)中得到之化合物,進行與實施例1-(2)同樣的操作,得到標題化合物(133mg、無色非晶質)。
ESI/APCI Dual 639(M+H)+
實施例3-(4)
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-(羥基甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物18)
於實施例3-(3)中得到之化合物(1.784g)之THF(20mL)溶液中添加n-Bu4NF(3.4mL、1.0M THF溶液),於室溫攪拌20分鐘。於反應混合物中添加飽和NH4Cl水溶液,將以AcOEt萃取後之有機層乾燥(MgSO4)、過濾、濃縮而得之粗精製物以中性矽膠層析法(AcOEt/己烷)精製,得到標題化合物(1.010g、無色固體)。
ESI/APCI Dual 426(M+Na)+
(S)-(3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基甲烷磺酸酯
於實施例3-(4)中得到之化合物(45mg)與Et3N(31μL)之AcOEt(3mL)溶液中,於0℃添加MsCl(13μL),攪拌30分鐘後,添加MsCl(13μL),於0℃攪拌30分鐘後,添加Et3N(31μL),於0℃攪拌2.5小時。將反應混合物添加至水(50mL)中,將以AcOEt(50mL)萃取之有機層乾燥(MgSO4)、過濾、濃縮,而得到標題化合物(58mg、無色油狀物)。
ESI/APCI Dual 501(M+Na)+
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((3,4,5-三甲氧基苯氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物21)
於實施例3-(5)中得到之化合物(20.8mg)與3,4,5-三甲氧基酚(16.0mg)之DMF(1.0mL)溶液中添加K2CO3(24.0mg)
,於室溫攪拌30分鐘後,於50℃攪拌2小時。將反應混合物添加入水(20mL)中,將以AcOEt(20mL×2)萃取之有機層乾燥(MgSO4)、過濾、濃縮而得之粗精製物以PTLC(NH型)精製,而得到標題化合物(20.5mg、無色非晶質)。
1H NMR(600MHz,CHLOROFORM-d)δ 6.30-6.16(m,3 H),5.61-5.35(m,1 H),5.14-5.02(m,2 H),4.25-4.12(m,1 H),3.84(s,6 H),3.80(s,3 H),3.94-3.68(m,2 H),2.36-0.85(m,22 H)ESI/APCI Dual 589(M+Na)+
(S)-N-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)苄醯胺(化合物44)
(S)-1-(2-(5-(疊氮甲基)異噁唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮
於實施例3-(4)中得到之化合物(657mg)之甲苯(20mL)混合物中添加DBU(368μL)與DPPA(530μL),於室溫攪拌20小時。於反應混合物中添加水(50mL),將以AcOEt(50mL)萃取而得到之有機層以brine(50mL)洗淨,將乾燥(MgSO4)、過濾、濃縮得到之粗精製物以中性矽膠層析法(AcOEt/己烷)精製,而得到標題化合物(645mg、無色非晶質)。
ESI/APCI Dual 426(M+H)+
(S)-1-(2-(5-(胺基甲基)異噁唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物42)
於實施例4-(1)中得到之化合物(632mg)之THF(20mL)溶液中添加PPh3(779mg)與水(1.0mL),加熱回流3小時。將反應混合物濃縮,加水(50mL),將以AcOEt(50mL×2)萃取、乾燥(Na2SO4)、過濾、濃縮而得之粗精製物以NH型矽膠層析法(AcOEt/己烷)及中性矽膠層析法(MeOH/CHCl3)精製,而得到標題化合物(463mg、無色非晶質)。
ESI/APCI Dual 400(M+H)+
(S)-N-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)苄醯胺(化合物44)
將實施例4-(2)中得到之化合物(40mg)溶解於CHCl3(3ml),添加氯化苯甲醯基(17μL)及Et3N(43μL),於室溫攪拌19小時。於反應混合物中添加CHCl3(20ml)與5% KHSO4(20ml),分離有機層。將所得之有機層以飽和碳酸氫鈉水(20ml)及brine(20ml)洗淨、乾燥(MgSO4)、過濾、濃縮而得之粗精製物以矽膠層析法(AcOEt/己烷)精製,而得到標題化合物(43mg、無色非晶質)。ESI/APCI Dual 504(M+H)+
(S)-N-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)苯磺醯胺(化合物45)
使用氯化苯磺醯基以取代氯化苯甲醯基,進行與實施
例4-(3)同樣的操作,得到標題化合物。
ESI/APCI Dual 540(M+H)+
(S)-1-(2-(5-((二甲基胺基)甲基)異噁唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物46)
將實施例3-(5)中得到之化合物(160 mg)溶解於MeCN,添加二甲基胺之THF溶液(2M,250μL),於室溫攪拌3小時。於反應混合物中加入AcOEt(50ml)與飽和NaCO3水溶液(50ml),分離有機層。將所得之有機層以brine(50ml)洗淨,將乾燥(MgSO4)、過濾、濃縮而得之粗精製物以矽膠層析法(AcOEt/己烷)精製,得到標題化合物(83mg、無色非晶質)。
ESI+428(M+H)+
(S)-3-(1-((環己基甲基)磺醯基)吡咯啶-2-基)-5-((3,4-二甲氧基苯氧基)甲基)異噁唑(化合物43)
於實施例1-(1)中得到之化合物(913mg)之THF(10mL)溶液中添加Et3N(555μL)與環己基甲烷磺醯基氯化物(393mg)之THF(5.0mL)溶液,於室溫攪拌3.5天。於反應混合物中添加飽和NH4Cl水溶液(50mL),將以AcOEt(50mL×2)萃取而得之有機層以brine(50mL)洗淨,將乾燥(MgSO4)、過濾、濃縮而得之粗精製物以中性矽膠層析法(AcOEt/己烷)及NH型矽膠層析法(AcOEt/己烷)精製,得到標題化合物(202mg、無色非晶質)。
ESI/APCI Dual 465(M+H)+、487(M+Na)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物2)
(S)-t-丁基=2-(2-(2-(3,4-二甲氧基苯氧基)乙醯基)聯胺羰基)吡咯啶-1-羧酸酯
於(S)-t-丁基2-(聯胺羰基)吡咯啶-1-羧酸酯(50.0g)與2-(3,4-二甲氧基苯氧基)乙酸(47.8g)之氯仿(1000ml)溶液中,添加HOBt(35.3g)、WSC鹽酸鹽(50.0g),於室溫攪拌4
小時。於減壓下餾除溶劑後,加水,以乙酸乙酯萃取。將有機層以飽和碳酸氫鈉水、brine依次洗淨,進行MgSO4乾燥後過濾。於減壓下餾除溶劑,得到粗精製之標題化合物(61.0g)。
1H NMR(200 MHz,CHLOROFORM-d)δ ppm 8.79(br.s.,1 H),6.78(d,J=8.79 Hz,1 H),6.58(d,J=2.64 Hz,1 H),6.40(dd,J=8.79,3.08 Hz,1 H),4.57(s,2 H),4.47-4.32(m,1 H),3.87(s,3 H),3.84(s,3 H),3.52-3.32(m,2 H),2.48-2.30(m,1 H),2.03-1.87(m,3 H),1.54-1.43(m,9 H)
(S)-t-丁基2-(5-((3,4-二甲氧基苯氧基)甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-羧酸酯
於實施例8-(1)中得到之化合物(61.0g)之甲苯(700ml)溶液中添加伯吉斯試劑(45.0g),於120℃攪拌4小時。於反應混合物中加水後,將以AcOEt萃取之有機層乾燥(Na2SO4)、過濾,將減壓下餾除溶劑而得之殘渣以矽膠層
析法(AcOEt)精製,得到標題化合物(42.0g)。
1H NMR(600 MHz,CHLOROFORM-d)δ ppm 6.77(d,J=8.71 Hz,1 H),6.62-6.57(m,1 H),6.51(dd,J=8.94,2.98 Hz,1 H),5.21-5.13(m,2 H),5.07-5.01(m,1 H),3.85(s,3 H),3.84(s,3 H),3.66-3.38(m,2 H),2.42-2.22(m,1 H),2.20-2.06(m,2 H),1.99(m,1 H),1.26-1.49(m,9 H)
(S)-2-((3,4-二甲氧基苯氧基)甲基)-5-(吡咯啶-2-基)-1,3,4-氧雜二唑 鹽酸鹽
於實施例8-(2)中得到之化合物(42.0g)之AcOEt(200ml)溶液中,添加4N HCl-AcOEt溶液(200ml),於室溫攪拌4小時。於減壓下餾除溶劑,得到粗精製之標題化合物(35.0g)。
1H NMR(200 MHz,DMSO-d6)δ ppm 6.88(d,J=8.79 Hz,1 H),6.70(d,J=3.08 Hz,1 H),6.64-6.55(m,1 H),5.38(s,2 H),5.13-5.00(m,1 H),3.75(s,3 H),3.70(s,3 H),3.34-
3.23(m,2 H),2.44-1.90(m,4 H)
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物2)
使用實施例8-(3)中得到之化合物(35.0g)以取代實施例1-(1)中得到之化合物,將進行與實施例1-(2)同樣的操作而得到之粗精製物以二氧化矽凝膠管柱層析法(AcOEt/己烷)精製後,以AcOEt-戊烷進行再結晶,得到標題化合物(39.0g)之無色固體。
1H NMR(600 MHz,CHLOROFORM-d)δ ppm 6.80-6.77(m,1 H),6.62-6.60(m,1 H),6.50(dd,J=8.71,2.75 Hz,1 H),5.50-5.46[5.71-5.67](m,1 H),5.21-5.15(m,2 H),4.41-4.34(m,1 H),3.97(s,1 H),3.86(s,3 H),3.84(s,3 H),3.80-3.72(m,1 H),2.37-0.79(m,22 H)
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-(苯氧基甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-基)乙酮(化合物29)
(S)-t-丁基2-(2-(2-((tert-丁基二苯基矽烷基)氧基)乙醯基)聯胺羰基)吡咯啶-1-羧酸酯
將(S)-t-丁基2-(聯胺羰基)吡咯啶-1-羧酸酯(4.791g)
與2-((t-丁基二苯基矽烷基)氧基)乙酸(6.28g)、WSC.HCl(4.371g)及HOBt.H2O(3.081g)之CHCl3(100mL)混合物於室溫攪拌15小時。於反應混合物中添加飽和NH4Cl水溶液(500mL),以AcOEt(500mL)萃取。將有機層以飽和碳酸氫鈉水(500mL)與brine(500mL)依次洗淨,將乾燥(MgSO4)、過濾、濃縮而得之粗精製物以矽膠層析法(AcOEt/己烷)精製,而得到標題化合物(6.42g、無色非晶質)。
ESI/APCI Dual 548(M+Na)+
(S)-t-丁基2-(5-(((tert-丁基二苯基矽烷基)氧基)甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-羧酸酯
於實施例9-(1)中得到之化合物(5.87g)之甲苯(112mL)溶液中,添加伯吉斯試劑(5.322g),加熱回流2.5小時。將使反應混合物濃縮而得之粗精製物以矽膠層析法(AcOEt/己烷)精製而到標題化合物(4.151g、無色非晶質)。
ESI/APCI Dual 508(M+H)+、530(M+Na)+
(S)-2-(((tert-丁基二苯基矽烷基)氧基)甲基)-5-(吡咯啶-2-基)-1,3,4-氧雜二唑
於實施例9-(2)中得到之化合物(3.832g)之THF(3.8mL)溶液中添加H3PO4(6.1mL、85%水溶液),於室溫攪拌1小時。將於反應溶液中添加有THF(50mL)之混合物,加入至NaOH(150mL、1.0N水溶液)與冰(50g),以CHCl3(300mL)萃取。將使有機層乾燥(Na2SO4)、過濾、濃縮而得之粗精製物以NH型矽膠層析法(MeOH/CHCl3)精製,而得到標題化合物(1.261g、無色油狀物)。
ESI/APCI Dual 408(M+H)+
(S)-1-(2-(5-(((tert-丁基二苯基矽烷基)氧基)甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮
使用實施例9-(3)中得到之化合物(1.186g)以取代實施例1-(1)中得到之化合物,進行與實施例1-(2)同樣的操作,得到標題化合物(1.287g、無色非晶質)。
ESI/APCI Dual 640(M+H)+、662(M+Na)+
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-(羥基甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-基)乙酮(化合物22)
使用實施例9-(4)中得到之化合物(1.378g)以取代實施例3-(3)中得到之化合物,進行與實施例3-(4)同樣的操作,得到標題化合物(750mg、無色固體)。
ESI/APCI Dual 402(M+H)+、424(M+Na)+
(S)-(5-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)-1,3,4-氧雜二唑-2-基)甲基甲烷磺酸酯(化合物23)
使用實施例9-(5)中得到之化合物(340mg)以取代實施例3-(4)中得到之化合物,將進行與實施例3-(5)同樣的操作得到之粗精製物再結晶(AcOEt/己烷),得到標題化合物(7349mg、無色粉體)。
ESI/APCI Dual 480(M+H)+、502(M+Na)+
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-(苯氧基甲基)-1,3,4-氧雜二唑-2-基)吡咯啶-1-基)乙酮(化合物29)
於實施例9-(6)中得到之化合物(32.5mg)與酚(13mg)之DMF(1.0mL)溶液中添加K2CO3(37mg),於50℃攪拌3.5小時。將反應混合物加入水(20mL)中,將以AcOEt(20mL×2)萃取之有機層乾燥(MgSO4)、過濾、濃縮而得之粗精製物以矽膠層析法(AcOEt/己烷)精製,得到標題化合物(31.6mg、無色非晶質)。
ESI/APCI Dual 478(M+H)+、500(M+Na)+
(S)-N-((5-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)-1,3,4-氧雜二唑-2-基)甲基)苄醯胺(化合物38)
使用實施例9-(6)中得到之化合物以取代實施例3-(4)中得到之化合物,進行與實施例4同樣的操作,得到標題化合物。
ESI/APCI Dual 505(M+H)+、527(M+Na)+
(S)-1-(2-(5-((二甲基胺基)甲基)-1,3,4-氧雜二唑-2-基)吡咯
啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物39)
使用實施例9-(6)中得到之化合物以取代實施例3-(5)中得到之化合物,進行與實施例6同樣的操作,得到標題化合物。
ESI/APCI Dual 429(M+H)+、451(M+Na)+
(S)-1-(2-(3-((3,4-二甲氧基苯氧基)甲基)-1,2,4-氧雜二唑-5-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物3)
2-(3,4-二甲氧基苯氧基)-N'-羥基乙醯醯亞胺醯胺
於2-(3,4-二甲氧基苯氧基)乙腈(3.8g)之MeOH-H2O(1:1)溶液中添加羥基胺鹽酸鹽後,於100℃攪拌3小時。於減壓下餾除溶劑後,濾取,以水、己烷洗淨。得到粗精製之標題化合物(4.9g)。
ESI/APCI Dual 227(M+H)+、249(M+Na)+
(S)-t-丁基2-(3-((3,4-二甲氧基苯氧基)甲基)-1,2,4-氧雜二唑-5-基)吡咯啶-1-羧酸酯
於實施例12-(1)中得到之化合物(1.0g),(S)-1-(tert-丁氧基羰基)吡咯啶-2-羧酸(1.0g)之CHCl3(20ml)溶液中添加
WSC.HCl(1.0g),於室溫攪拌4小時。加水,以CHCl3萃取。於減壓下餾除溶劑後,溶解於甲苯(20ml),回流2小時。於減壓下餾除溶劑,將殘渣以矽膠層析法(AcOEt/己烷)精製而得到標題化合物(190mg)。
ESI/APCI Dual 424(M+H)+、446(M+Na)+
(S)-1-(2-(3-((3,4-二甲氧基苯氧基)甲基)-1,2,4-氧雜二唑-5-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物3)
使用實施例12-(2)中得到之化合物以取代實施例2-(2)中得到之化合物,進行與實施例2-(3)、實施例2-(4)同樣的操作,得到標題化合物。
ESI/APCI Dual 538(M+H)+、560(M+Na)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1-甲基-1H-吡唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物9)
(S)-t-丁基2-(4-(3,4-二甲氧基苯氧基)丁-2-炔醯基)吡咯啶-1-羧酸酯
於1,2-二甲氧基-4-(丙-2-炔-基氧基)苯(2.118g)之THF(50mL)溶液中,於-78℃滴下n-BuLi(4.0mL、2.64N己烷溶液),將於同溫度攪拌30分鐘後之反應混合物,於-78℃滴下至(S)-t-丁基2-(甲氧基(甲基)胺甲醯基)吡咯啶-1-
羧酸酯(2.578g)之THF(100mL)溶液中,於同溫度攪拌1小時後,花費1小時昇溫至室溫。將反應溶液加入至飽和NH4Cl水溶液(300mL)中,分離有機層,以飽和NH4Cl水溶液(100mL)洗淨,將乾燥(Na2SO4)、過濾、濃縮而得之粗精製物以中性矽膠層析法(AcOEt/己烷)精製,得到標題化合物(2.479g、淡褐色油狀物)。
ESI/APCI Dual 412(M+Na)+
(S)-t-丁基2-(5-((3,4-二甲氧基苯氧基)甲基)-1-甲基-1H-吡唑-3-基)吡咯啶-1-羧酸酯
於實施例31-(1)中得到之化合物(390mg)之EtOH(5.0mL)溶液中添加甲基聯胺(106μL)與乙酸鈉(246mg),加熱回流20小時。將反應混合物濃縮,添加飽和NH4Cl水溶液(50mL),分離有機層,將乾燥(MgSO4)、過濾、濃縮而得之粗精製物以中性矽膠層析法(AcOEt/己烷)精製,得到標題化合物(378mg、淡褐油狀物)。
ESI/APCI Dual 418(M+H)+
(S)-5-((3,4-二甲氧基苯氧基)甲基)-1-甲基-3-(吡咯啶-2-基)-1H-吡唑
於實施例13-(2)中得到之化合物(365mg)之CHCl3(1.0mL)溶液中,於0℃添加TFA(5.0mL),於室溫攪拌2小時。將反應混合物濃縮後,添加飽和碳酸氫鈉水(50mL),將以CHCl3(50mL×2)萃取之有機層乾燥(Na2SO4)、過濾、濃縮而得到標題化合物(283mg、淡褐色油狀物)。
ESI/APCI Dual 318(M+H)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1-甲基-1H-吡唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物9)
使用實施例31-(3)中得到之化合物(274mg)以取代實施例1-(1)中得到之化合物,將進行與實施例1-(2)同樣的操作而得到之粗精製物以矽膠層析法(AcOEt/己烷)精製,得到標題化合物(129mg、無色非晶質)。
ESI/APCI Dual 550(M+H)+、572(M+Na)+
(S)-1-(2-(3-((3,4-二甲氧基苯氧基)甲基)異噁唑-5-基)吡咯
啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物10)
2-(3,4-二甲氧基苯氧基)-N-甲氧基-N-甲基乙醯胺
於2-(3,4-二甲氧基苯氧基)乙酸(4.244g)、N,O-二甲基羥基胺鹽酸鹽(2.341g)、WSC.HCl(4.984g)及HOBt.H2O(3.513g)之CHCl3(100mL)混合物中添加Et3N(3.62mL),於室溫攪拌20小時。將反應混合物濃縮,將添加H2O(400mL)且以AcOEt(500mL)萃取後之有機層以飽和碳酸氫鈉水(400mL)、水(400mL)及brine(400mL)依次洗淨,將乾燥(MgSO4)、過濾、濃縮而得之粗精製物以矽膠層析法(AcOEt)精製,得到標題化合物(4.01g、淡褐色油狀物)。
ESI/APCI Dual 256(M+H)+
(S)-t-丁基2-(4-(3,4-二甲氧基苯氧基)-3-側氧丁-1-炔-1-基)吡咯啶-1-羧酸酯
於(S)-t-丁基2-(2,2-二溴乙烯基)吡咯啶-1-羧酸酯(5.326g)之THF(120mL)溶液中,於-78℃滴下n-BuLi(11.6mL、2.64N己烷溶液),於同溫度攪拌1小時後,滴下實施例14-(1)中得到之化合物(4.00g)之THF(50mL)溶液,花費1小時昇溫至室溫。將反應混合物加入至飽和NH4Cl水溶液(400mL)中,將以AcOEt(400mL×2)萃取之有機層乾燥(MgSO4),將過濾、濃縮而得之粗精製物以中性矽膠層析法(AcOEt/己烷)精製,得到標題化合物(2.934g、淡黃色油狀物)。
ESI/APCI Dual 388(M-H)-
(S)-3-((3,4-二甲氧基苯氧基)甲基)-5-(吡咯啶-2-基)異噁唑
於實施例14-(2)中得到之化合物(390mg)之EtOH(10mL)溶液中添加羥基胺鹽酸鹽(139mg),加熱回流20小時。於將反應混合物濃縮而得之褐色油狀物中添加CHCl3(1.0mL)與TFA(5.0mL),於室溫攪拌21小時。將反應混合物濃縮後,添加飽和碳酸氫鈉水(50mL),將以CHCl3(50mL×2)萃取之有機層乾燥(Na2SO4)、過濾、濃縮,而得到標題化合物(326mg、褐色油狀物)與雜質之混合物。
ESI/APCI Dual 305(M+H)+
使用實施例14-(3)中得到之化合物(321mg)以取代實施例1-(1)中得到之化合物,將進行與實施例1-(2)同樣的操作而得到之粗精製物以中性矽膠層析法(AcOEt/己烷)及NH型矽膠層析法(AcOEt/己烷)精製,得到標題化合物(142mg、黃色非晶質)。
ESI/APCI Dual 537(M+H)+、559(M+Na)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1H-吡唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物11)
(S)-t-丁基2-(5-((3,4-二甲氧基苯氧基)甲基)-1H-吡唑-3-基)吡咯啶-1-羧酸酯
於實施例14-(2)中得到之化合物(395mg)之EtOH(10mL)溶液中添加聯胺水合物(63μL),於室溫攪拌30分鐘。將反應混合物濃縮、加水(50mL),將以AcOEt(50mL)萃取之有機層乾燥(MgSO4)、過濾、濃縮而得到標題化合物(466mg、淡褐色非晶質)。
ESI/APCI Dual 404(M+H)+、426(M+Na)+
(S)-5-((3,4-二甲氧基苯氧基)甲基)-3-(吡咯啶-2-基)-1H-吡唑
使用實施例15-(1)中得到之化合物(460mg)以取代實施例13-(2)中得到之化合物,進行與實施例13-(3)同樣的操作而得到標題化合物(339mg、淡褐色油狀物)。
ESI+ 304(M+H)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1H-吡唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物11)
使用實施例15-(2)中得到之化合物(332mg)以取代實施例1-(1)中得到之化合物,將進行與實施例1-(2)同樣的操作而得之粗精製物以矽膠層析法(AcOEt/己烷)精製,得到標題化合物(463mg、淡桃色非晶質)。
ESI/APCI Dual 536(M+H)+、558(M+Na)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1,3,4-噻二唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物4)
(S)-t-丁基2-(5-((3,4-二甲氧基苯氧基)甲基)-1,3,4-硫雜二唑-2-基)吡咯啶-1-羧酸酯
於實施例8-(1)中得到之化合物(540mg)之甲苯(30ml)溶液中添加勞森試劑(750mg),於90℃攪拌6小時。加水後,以AcOEt萃取。於減壓下餾除溶劑,將殘渣以矽膠層析法(AcOEt/己烷)精製,得到標題化合物(291mg)。
ESI/APCI Dual 422(M+H)+、444(M+Na)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1,3,4-硫雜二唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物4)
使用實施例16-(1)中得到之化合物以取代實施例2-(2)中得到之化合物,進行與實施例2-(3)、實施例2-(4)同樣的操作,得到標題化合物。
ESI/APCI Dual 554(M+H)+、576(M+Na)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-4H-1,2,4-三唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物5)
(S)-t-丁基2-(5-((3,4-二甲氧基苯氧基)甲基)-4H-1,2,4-三唑-3-基)吡咯啶-1-羧酸酯
於2-(3,4-二甲氧基苯氧基)乙腈(1.26g)、(S)-t-丁基2-(聯胺羰基)吡咯啶-1-羧酸酯(500mg)之n-丁醇(10ml)溶液中添加K2CO3(150mg)。於微波照射下、160℃攪拌1小時。於減壓下餾除溶劑後,加水,以乙酸乙酯萃取。於減
壓下餾除溶劑後,將殘渣以矽膠層析法及NH型矽膠層析法精製,得到標題化合物(281mg)。
ESI/APCI Dual 405(M+H)+、427(M+Na)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-4H-1,2,4-三唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物5)
使用實施例17-(1)中得到之化合物以取代實施例2-(2)中得到之化合物,進行與實施例2-(3)、實施例2-(4)同樣的操作,得到標題化合物。
ESI/APCI Dual 537(M+H)+、559(M+Na)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1-甲基-1H-1,2,4-三唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物8)
(S)-t-丁基2-(5-((3,4-二甲氧基苯氧基)甲基)-1-甲基-1H-1,2,4-三唑-3-基)吡咯啶-1-羧酸酯
使用(S)-t-丁基2-(2-甲基聯胺羰基)吡咯啶-1-羧酸酯以取代(S)-2-(聯胺羰基)吡咯啶-1-羧酸酯,進行與實施例17-(1)同樣的操作,得到標題化合物。
ESI/APCI Dual 419(M+H)+、441(M+Na)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)-1-甲基-1H-1,2,4-三唑-3-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物8)
使用實施例18-(1)中得到之化合物以取代實施例2-(2)中得到之化合物,進行與實施例2-(3)、實施例2-(4)同樣的操作,得到標題化合物。
ESI/APCI Dual 551(M+H)+、573(M+Na)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)噁唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物6)
1-(1H-苯并[d][1,2,3]三唑-1-基)-2-(3,4-二甲氧基苯氧基)乙酮
於1H-苯并[d][1,2,3]三唑(11.2g)之CHCl3(120ml)溶液中添加氯化亞磺醯基(1.7ml),於室溫下攪拌30分鐘後,添加2-(3,4-二甲氧基苯氧基)乙酸(5.00g),於室溫下攪拌1.5小時。將析出物以過濾去除,將濾液以2N NaOH水溶液洗淨後,將有機層乾燥(MgSO4)、過濾、濃縮,得到標題化合物(8.06g、無色固體)。
1-(3,4-二甲氧基苯氧基)-3-硝基丙烷-2-酮
於tert-丁氧基鉀(3.38g)之DMSO(60ml)懸濁液中,於10℃添加硝基甲烷(0.836g)之DMSO(5ml)溶液,直接持續攪拌30分鐘。於10℃滴下實施例19-(1)中得到之化合物(4.30g)之DMSO(65ml)懸濁液,直接持續攪拌1小時後,於室溫下攪拌3小時。將反應液注入水(250ml)中,以10%乙酸水使其成為酸性,以AcOEt萃取。將有機層以水洗淨後,將乾燥(MgSO4)、過濾、濃縮而得之粗精製物以矽膠層析法(AcOEt/己烷)精製,進一步進行再結晶(AcOEt/己烷),得到標題化合物(0.808g、淡黃色固體)。
ESI/APCI Dual 254(M-H)-
1-胺基-3-(3,4-二甲氧基苯氧基)丙烷-2-酮 鹽酸鹽
於實施例19-(2)中得到之化合物(0.660g)之MeOH(7ml)溶液中,添加10%Pd-C(0.330g)、1N HCl水溶液(14ml),在氫環境下、室溫攪拌5小時。將不溶物過濾去除後,濃縮濾液,而得到標題化合物(0.715g、茶色非晶質)。
ESI/APCI Dual 226(M+H)+
(S)-tert-丁基2-((3-(3,4-二甲氧基苯氧基)-2-側氧丙基)胺甲醯基)吡咯啶-1-羧酸酯
於(S)-1-(tert-丁氧基羰基)吡咯啶-2-羧酸(0.557g)、及Et3N(0.790ml)之THF(14ml)溶液中,於冰浴下添加氯甲酸乙酯(0.295g),直接持續攪拌30分鐘。將反應液於0℃添加至實施例19-(3)中得到之化合物(0.701g)之THF(7ml)溶液中,於室溫下攪拌17小時。加水,以AcOEt萃取後,將有機層以飽和食鹽水洗淨,將乾燥(MgSO4)、過濾、濃
縮而得之粗精製物以矽膠層析法(AcOEt/己烷)精製,得到標題化合物(0.540g、茶色非晶質)。
ESI/APCI Dual 445(M+Na)+
(S)-t-丁基2-(5-((3,4-二甲氧基苯氧基)甲基)噁唑-2-基)吡咯啶-1-羧酸酯
於實施例19-(4)中得到之化合物(0.250g)之甲苯(10ml)溶液中添加伯吉斯試劑(0.281g),於50℃攪拌1.5小時。回到室溫,將濃縮而得之粗精製物以矽膠層析法(AcOEt/己烷)精製,得到標題化合物(0.156g、無色油狀)。
ESI/APCI Dual 405(M+H)+
(S)-5-((3,4-二甲氧基苯氧基)甲基)-2-(吡咯啶-2-基)噁唑
於實施例19-(5)中得到之化合物(0.146g)之AcOEt(1ml)溶液中添加4N HCl-AcOEt(0.5ml),於室溫下攪拌12小時。添加4N HCl-AcOEt(0.5ml)攪拌3小時後,進一步添加4N HCl-AcOEt(0.5ml),攪拌1小時。添加2N NaOH水溶液,以AcOEt萃取後,將有機層以brine洗淨,乾燥(MgSO4)、過濾、濃縮,得到標題化合物(0.078g、淡黃色固體)。
ESI/APCI Dual 305(M+H)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)噁唑-2-基)吡咯
啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物6)
於2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酸(0.075g)與Et3N(0.038ml)之THF(1ml)溶液中,在冰浴下添加氯甲酸乙酯(0.028g),直接持續攪拌1小時。於反應混合物中,冰浴下添加(S)-5-((3,4-二甲氧基苯氧基)甲基)-2-(吡咯啶-2-基)噁唑(0.075g)之THF(1ml)溶液,於室溫下攪拌15小時。加水,以AcOEt萃取後,將有機層以飽和食鹽水洗淨,將乾燥(MgSO4)、過濾、濃縮而得之粗精製物以矽膠層析法(AcOEt/己烷)精製,得到標題化合物(0.104g、無色非晶質)。
ESI/APCI Dual 537(M+H)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)噻唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物7)
(S)-tert-丁基2-(5-((3,4-二甲氧基苯氧基)甲基)噻唑-2-基)吡咯啶-1-羧酸酯
於實施例19-(4)中得到之化合物(0.287g)之甲苯(5ml)溶液中添加勞森試劑(0.275g),於110℃攪拌1小時。回到室溫,將濃縮而得之粗精製物以矽膠層析法(AcOEt/己烷)精製,得到標題化合物(0.100g、無色非晶質)。
ESI/APCI Dual 421(M+H)+
(S)-5-((3,4-二甲氧基苯氧基)甲基)-2-(吡咯啶-2-基)噻唑
使用實施例20-(2)中得到之化合物以取代實施例19-
(5)中得到之化合物,進行與實施例19-(6)同樣的操作而得到標題化合物(0.063g、無色固體)。
ESI/APCI Dual 321(M+H)+
(S)-1-(2-(5-((3,4-二甲氧基苯氧基)甲基)噻唑-2-基)吡咯啶-1-基)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物7)
使用實施例20-(2)中得到之化合物以取代實施例19-(6)中得到之化合物,進行與實施例19-(7)同樣的操作,得到標題化合物(0.077g、無色非晶質)。
ESI/APCI Dual 575(M+Na)+
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((嗒嗪-4-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物53)
於密封管中,將於化合物18(30mg)、4-溴嗒嗪 氫溴酸鹽(22mg)、Pd(OAc)2(2mg)、Cs2CO3(37mg)、[1,1'-聯萘]-2-基二-tert-丁基膦(3mg)中添加有甲苯(2ml)之混合物,於100℃攪拌4小時。將反應混合物冷卻至室溫後,添加NH二氧化矽凝膠,攪拌一段時間。將二氧化矽凝膠濾除後,以氯仿洗淨,將餾除溶劑而得之殘渣以逆相分離HPLC精製,得到標題化合物(6.0mg、無色油狀物)。
1H NMR(600MHz,CHLOROFORM-d)δ=9.08-8.98(m,2 H),7.02-6.96(m,1 H),6.35[6.26](s,1 H),5.62-5.37(m,1 H),5.22[5.24](s,2 H),4.21-3.71(m,2 H),2.38-0.82(m,22 H)
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((吡嗪-2-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物55)
於化合物18(40mg)之DMF(1.0ml)溶液中,於室溫添加NaH(5.2mg、>55% in minerai oil),攪拌30分鐘後,添加2-溴吡嗪(23.8mg),於室溫攪拌0.5小時。於反應混合物中添加DMSO(1.0ml),將不溶物過濾後,以逆相分離HPLC精製而得到標題化合物(6.7mg、無色油狀物)。
1H NMR(600MHz,CHLOROFORM-d)δ 8.34-8.29(m,1 H),8.24-8.18(m,1 H),8.13-8.08(m,1 H),6.28[6.19](s,1 H),5.60-5.36(m,3 H),4.24-4.13(m,1 H),3.95-3.87(m,1 H),3.82-3.69(m,1 H),2.35-0.76(m,22 H)
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((吡啶-2-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物54)及(S)-1-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)吡啶-2(1H)-酮
於實施例3-(5)中得到之化合物(30mg)與吡啶-2-醇(12mg)之DMF(1.0mL)溶液中添加K2CO3(35mg),於50℃攪拌1小時。於反應混合物中添加DMSO(1.0ml)將不溶物過濾後,以逆相分離HPLC精製而得到化合物54(2.0mg、無色油狀物)與化合物60(16.0mg、無色油狀物)。
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((吡啶-2-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物54)
1H NMR(600MHz,CHLOROFORM-d)δ 8.20-8.12(m,1 H),7.66-7.57(m,1 H),6.97-6.90(m,1 H),6.85-6.78(m,1 H),6.24[6.15](s,1 H),5.59-5.30(m,3 H),4.25-4.14(m,1 H),
4.05-3.92(m,1 H),3.81-3.69(m,1 H),2.33-0.77(m,22 H)(S)-1-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)吡啶-2(1H)-酮(化合物60)
1H NMR(600MHz,CHLOROFORM-d)δ 7.42-7.31(m,2 H),6.59(d,J=9.1 Hz,1 H),6.28-6.11(m,2 H),5.56-5.07(m,3 H),4.23-4.09(m,1 H),3.98-3.83(m,1 H),3.80-3.67(m,1 H),2.35-0.72(m,22 H)
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((吡啶-3-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮鹽酸鹽1水合物(化合物67)
於實施例2中得到之化合物40(2.24g)之AcOEt(50ml)溶液中添加HCl(50ml,4.0N in AcOEt),於室溫攪拌15小時,添加戊烷(140ml)攪拌8天。將使反應混合物濃縮而得之殘渣再結晶(MeOH/Et2O),得到標題化合物(2.23g
、無色粉體)。
1H NMR(600MHz,DMSO-d6)δ=8.65-8.52(m,1 H),8.46-8.36(m,1 H),7.97-7.84(m,1 H),7.75-7.65(m,1 H),6.61[6.63](s,1 H),5.79-3.01(m,7 H),5.42[5.44](s,2 H),2.31-0.66(m,22 H)Anal.calcd for C25H33F2N3O4.HCl.H2O:C,56.44;H,6.82;N,7.90;found C,56.20;H,6.66;N,7.76。
藉由與實施例3同樣的方法,得到以下化合物。(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-(((6-甲氧基吡啶-3-基)氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物41)
1H NMR(600MHz,CHLOROFORM-d)δ 7.91-7.82(m,1 H),7.30-7.21(m,1 H),6.74-6.66(m,1 H),6.39-6.15(m,1 H),5.60-5.33(m,1 H),5.12-5.02(m,2 H),3.89(s,3 H),4.24-3.64(m,3 H),2.35-0.84(m,22 H)
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-(苯氧基甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物52)
1H NMR(600MHz,CHLOROFORM-d)δ 7.37-7.28(m,2 H),7.05-6.92(m,3 H),6.26[6.18](s,1 H),5.44-5.37[5.60-5.54](m,1 H),5.17-5.05(m,2 H),4.41-3.54(m,3 H),2.39-0.68(m,22 H)
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((嘧啶-5-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物59)
1H NMR(600MHz,CHLOROFORM-d)δ 8.93(s,1 H),8.49(s,2 H),6.34[6.25](s,1 H),5.44-5.36[5.61-5.56](m,1 H),5.26-5.17(m,2 H),4.21-4.11(m,1 H),3.89-3.70(m,2 H),2.38-0.77(m,22 H)
(S)-2,2-二氟-1-(2-(5-((3-氟苯氧基)甲基)異噁唑-3-基)吡咯啶-1-基)-2-(1-羥基-3,3,5,5-四甲基環己基)乙酮(化合物64)
1H NMR(600MHz,CHLOROFORM-d)δ 7.30-7.21(m,1 H),6.77-6.65(m,3 H),6.27[6.18](s,1 H),5.44-5.38[5.59-5.55](m,1 H),5.15-5.05(m,2 H),4.23-4.14(m,1 H),3.93-3.87(m,1 H),3.84-3.70(m,1 H),2.35-0.78(m,22 H)(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((p-甲苯甲醯基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物65)
1H NMR(600MHz,CHLOROFORM-d)δ 7.13-7.08(m,2 H),6.87-6.82(m,2 H),6.25[6.17](s,1 H),5.44-5.37[5.58-5.55](m,1 H),5.13-5.04(m,2 H),4.24-4.15(m,1 H),3.98-3.91(m,1 H),3.82-3.69(m,1 H),2.30(s,3 H),2.25-0.86(m,22 H)
藉由與實施例21同樣的方法,得到以下化合物。(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((吡啶-4-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物57)
1H NMR(600MHz,CHLOROFORM-d)δ 8.49(br.s.,2 H),
6.93-6.82(m,2 H),6.30[6.21](s,1 H),5.46-5.35[5.61-5.55](m,1 H),5.21-5.10(m,2 H),4.24-4.08(m,1 H),3.92-3.69(m,2 H),2.40-0.75(m,22 H)
藉由與實施例22同樣的方法,得到以下化合物。(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((嗒嗪-3-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物56)
1H NMR(600MHz,CHLOROFORM-d)δ 8.93-8.86(m,1 H),7.47-7.40(m,1 H),7.10-7.02(m,1 H),6.35[6.25](s,1 H),5.70-5.60(m,2 H),5.44-5.37[5.60-5.56](m,1 H),4.25-4.13(m,1 H),3.99-3.87(m,1 H),3.82-3.69(m,1 H),2.35-0.77(m,22 H)
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((嘧啶-2-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物58)
1H NMR(600MHz,CHLOROFORM-d)δ 8.59-8.52(m,2 H),7.06-6.99(m,1 H),6.30[6.23](s,1 H),5.63-5.35(m,3 H),4.26-4.14(m,1 H),4.02-3.91(m,1 H),3.82-3.68(m,1 H),2.38-0.75(m,22 H)
藉由與實施例23同樣的方法,得到以下化合物。
(S)-1-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)嘧啶-4(1H)-酮(化合物61)
1H NMR(600MHz,CHLOROFORM-d)δ 8.22-8.10(m,1 H),
7.36-7.30(m,1 H),6.33-6.15(m,2 H),5.40-5.30[5.60-5.54](m,1 H),5.02-4.96(m,2 H),4.17-4.06(m,1 H),3.86-3.60(m,2 H),2.36-0.77(m,22 H)
(S)-3-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)嘧啶-4(3H)-酮(化合物62)
1H NMR(600MHz,CHLOROFORM-d)δ 8.26-8.21(m,1 H),7.95-7.87(m,1 H),6.50-6.46(m,1 H),6.28[6.21](s,1 H),5.40-5.31[5.57-5.50](m,1 H),5.21-5.11(m,2 H),4.21-4.08(m,1 H),3.91-3.68(m,2 H),2.31-0.83(m,22 H)
(S)-2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)-1-(2-(5-((嘧啶-4-基氧基)甲基)異噁唑-3-基)吡咯啶-1-基)乙酮(化合物63)
1H NMR(600MHz,CHLOROFORM-d)δ 8.81(s,1 H),8.53-8.46(m,1 H),6.85-6.79(m,1 H),6.29[6.20](s,1 H),5.63-5.34(m,3 H),4.24-4.13(m,1 H),3.97-3.68(m,2 H),2.38-0.77(m,22 H)
(S)-1-((3-(1-(2,2-二氟-2-(1-羥基-3,3,5,5-四甲基環己基)乙醯基)吡咯啶-2-基)異噁唑-5-基)甲基)吡啶-4(1H)-酮(化合物66)
1H NMR(600MHz,CHLOROFORM-d)δ 7.36-7.30(m,2 H),6.44-6.38(m,2 H),6.16[6.08](s,1 H),5.61-5.31(m,1 H),5.06-4.91(m,2 H),4.22-4.07(m,1 H),3.92-3.62(m,2 H),2.38-0.77(m,22 H)
實施例2-(2)中,雖使用系統中生成之下述中間體來進行環化反應,但亦可將下述中間體單離而進行環化反應。
(S)-tert-丁基2-(氯(羥基亞胺基)甲基)吡咯啶-1-羧酸酯
於實施例2-(1)中得到之(S)-t-丁基2-((羥基亞胺基)甲基)吡咯啶-1-羧酸酯(32.0g)之AcOEt(270ml)溶液中添加NMP(43.1ml),於30-40℃,以20-30分鐘之間隔將NCS(21.94g)分成3份加入,於室溫攪拌0.5小時。合計進行4次以同樣量進行的同樣反應。於反應混合物中加水(400ml),分離有機層。合併有機層,以水(1.2L×2)洗淨,將乾燥(MgSO4)、過濾、濃縮而得之粗精製物(淡黃色固體、174g)以AcOEt/己烷(AcOEt/己烷=140ml/840ml)洗淨,乾燥而得到標題化合物(109.3g、無色固體)。
1H NMR(600MHz,DMSO-d6)δ 11.77-11.62(m,1 H),4.55-4.41(m,1 H),3.58-3.20(m,2 H),2.25-1.71(m,4 H),1.39[1.33](s.,9 H)
ESI/APCI Dual 237(M+Na)+
使用與實施例1~24所示之任一方法同樣的方法,得
到表1-1~表1-11所示之化合物。
化合物之旋轉異構酶(肽脯胺醯異構酶)抑制活性,係遵照公知之方法(Harding等人,Nature 341,758-760,1989、Holt等人,J.Am.Chem.Soc.115,9925-9938,1993)來測定。亦即,於塑膠製比色管中,添加35mM HEPES(pH7.8)、12nM人類重組FKBP12(Sigma,F-5398)、0.4mg/mL α-胰凝乳蛋白酶、及溶解於DMSO之各種濃度的測試化合物(DMSO之最終濃度為0.1%)。接著,添加溶解於含500mM之LiCl的三氟乙醇之24mM基質胜肽之琥珀醯基-Ala-Phe-Pro-Phe-對硝基苯胺(para-nitroanilide)使其成為最終濃度48μM,開始反應。反應係在4℃進行,監測伴隨著對硝基苯胺生成物之遊離而於390nm之吸光度變化。算出初速度,將減去酵素非觸媒下之初速度後的值作為旋轉異構酶活性之指標。試驗化合物之旋轉異構酶抑制活性,係
以化合物非存在下之旋轉異構酶活性為對照組的相對值(%)來表示,由化合物之濃度反應曲線算出旋轉異構酶活性被抑制50%之化合物濃度IC50值。
各化合物之IC50值如表1-1~表1-11所示。
於1,3-丁二醇5g中添加水10g,攪拌使成均質後,以總量成為100mL的方式添加乙醇,以調製基劑。將過剩量之試驗化合物裝入試驗管,添加上述調製之基劑,於25℃攪拌7天後,以薄膜過濾器(0.45μm)過濾,所得之濾液以乙腈稀釋,以HPLC測定濃度,作為溶解度。
比較例(WO2008/075735國際公開公報中揭示之1-[2-((2S)-2-[5-[(3,4-二甲氧基苯氧基)甲基]-1,2,4-氧雜二唑-3-基]吡咯啶-1-基)-1,1-二氟-2-側氧乙基]-3,3,5,5-四甲基環己醇)之溶解度為30.8mg/mL、化合物1之溶解度為57.5mg/mL。
將C57BL小鼠(雌、約7週齡)之背部剃毛,於剃毛部位塗佈試驗例2中調製之基劑、或溶解於基劑之5%化合物1溶液(w/v),由剃毛3天後開始1天1次塗布投予每次200μL(各群10隻)。由投予開始日起每2或3日,使用以下之生髮分數基準,對剃毛部之生髮狀態評分。
生髮分數基準
1=無生髮
2=於剃毛部位未達30%有生髮
3=於剃毛部位之30%以上、未達60%有生髮
4=於剃毛部位之60%以上、未達90%有生髮
5=於剃毛部位之90%以上有生髮
如圖1所示,投予了5%化合物1溶液之群,相較於投予基劑之群,由早期開始其生髮分數即有增加。化合物1投予群之生髮分數,由投予第15天以後之試驗期間中,顯示了比基劑投予群之生髮分數更高的值。明顯可知本化合物顯示了優良的生髮促進效果。此生髮促進效果,係除了化合物之旋轉異構酶抑制活性之外,亦藉由優良的安定性、吸收性、組織轉移性等複數之特性的組合而發揮。
於乙醇79mL中,以總量成為100mL的方式加水,以調製基劑。將過剩量之試驗化合物裝入試驗管,添加上述調製之基劑,於5℃攪拌3天後,以薄膜過濾器(0.45μm)過濾,所得之濾液以乙腈稀釋,以HPLC測定濃度,作為溶解度。
化合物40之溶解度為113.2mg/mL。
將C57BL小鼠(雌、約7週齡)之背部剃毛,於剃毛部位塗佈試驗例4中調製之基劑、或溶解於基劑之5%化合物40溶液(w/v),由剃毛3天後開始1天1次塗布投予每次200μL(各群10隻)。由投予開始日起每2或3日,使用試驗例3所記載之生髮分數基準,對剃毛部位之生髮狀態評分。
如圖2所示,投予了化合物40溶液之群,相較於投予基劑之群,由早期開始其生髮分數即有增加。化合物40投予群知生髮分數,由投予第15天以後之試驗期間中,顯示了比基劑投予群之生髮分數更高的值。明顯可知本化合物顯示了優良的生髮促進效果。
化合物40之生髮促進效果,係除了旋轉異構酶抑制活性之外,亦藉由優良的安定性、吸收性、組織轉移性等複數之特性的組合而發揮。
已知於小鼠皮膚中,伴隨著由毛週期之休止期向成長期之轉移及成長期之進行,毛囊內之proliferating cellnuclear antigen(PCNA)陽性細胞會增加(Craven等人、”J.Endocrinol.
”,191,415-425,2006),PCNA量之增加為成長期誘導之標記之一。
以皮膚PCNA量為指標,由以下方法測定化合物之成長期誘導促進效果。
將C57BL小鼠(雌、約7週齡)之背部剃毛,於剃毛部位塗佈基劑(80%乙醇)、及溶解於基劑之化合物40、52、59、61、63、64、或66之各5%化合物溶液(w/v),由剃毛3天後開始1天1次塗布投予兩天,每次200μL(各群5隻)。第2天之投予約4小時後,採取塗布部位之皮膚,在含有50mM Tris-HCl(pH7.6)、150mM NaCl、1% NP-40及蛋白酶抑制劑之緩衝液內均質化。藉由離心分離操作,調製含有PCNA之蛋白質溶液,使用Calbiochem公司之PCNA-ELISA套組來測定溶液中之PCNA量。
如圖3所示,試驗例5中顯示生髮促進效果之投予化合物40之群,相較於投予基劑之群,顯示了較高之皮膚PCNA量的值。明顯可知本化合物於投予開始早期,即顯示優良的成長期誘導促進效果。
投予了化合物52、59、61、63、或64溶液之各群,亦與化合物40投予群同樣地,顯示了皮膚PCNA量之增加。明顯可知該等化合物均顯示成長期誘導促進效果(圖3)。
又,對投予了化合物66之群亦進行同樣試驗後,相
較於投予基劑之群,皮膚PCNA量顯示了約高1.4倍的值。
該等化合物之成長期誘導促進效果,係除了旋轉異構酶抑制活性之外,亦藉由優良的安定性、吸收性、組織轉移性等複數之特性的組合而發揮。
藉由本發明,可提供與FKBP12結合之新穎化合物或其醫藥上容許之鹽,進一步地可提供含有該化合物或其醫藥上容許之鹽之有用於脫毛症預防或治療的新穎治療藥。
圖1顯示小鼠剃毛模式中之化合物1的生髮促進效果。
圖2顯示小鼠剃毛模式中之化合物40的生髮促進效果。
圖3顯示小鼠剃毛模式中之化合物40、52、59、61、63、及64的成長期誘導促進效果。
Claims (9)
- 一種以式(1)表示之化合物或其醫藥上容許之鹽,
- 如申請專利範圍第1項之化合物或其醫藥上容許之鹽,其中X為鍵結鍵、-CH2O-、-CH2-、-(CH2)2-、-(CH2)3-、-O-、-CH2-NHC(=O)-、-CH2-NHC(=O)-CH2-或-CH2-NHS(=O)2-。
- 如申請專利範圍第1項之化合物或其醫藥上容許之鹽,其中X為-CH2O-或-CH2-。
- 如申請專利範圍第1至3項中任一項之化合物或其醫藥上容許之鹽,其中R2為苯基、吡啶基、嗒嗪基或嘧啶基(該苯基、吡啶基或嘧啶基可經1~3個鹵素原子或甲氧基取代)、吡啶酮基或嘧啶酮基。
- 如申請專利範圍第1至3項中任一項之化合物或其醫藥上容許之鹽,其中R2為苯基或吡啶基(該苯基或吡啶基可經1~3個甲氧基取代)。
- 如申請專利範圍第1項之化合物或其醫藥上容許之 鹽,其係以表示。
- 如申請專利範圍第1項之化合物或其醫藥上容許 之鹽,其係以表示。
- 一種醫藥,其係含有如申請專利範圍第1、2、3、6及7項中任一項之化合物或其醫藥上容許之鹽作為有效成分。
- 一種脫毛症之預防或治療劑,其係含有如申請專利範圍第1、2、3、6及7項中任一項之化合物或其醫藥上容許之鹽作為有效成分。
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