JP4616454B2 - 1-Substituted phenyl-1- (1H-imidazol-4-yl) alcohols, their production and use - Google Patents
1-Substituted phenyl-1- (1H-imidazol-4-yl) alcohols, their production and use Download PDFInfo
- Publication number
- JP4616454B2 JP4616454B2 JP2000320485A JP2000320485A JP4616454B2 JP 4616454 B2 JP4616454 B2 JP 4616454B2 JP 2000320485 A JP2000320485 A JP 2000320485A JP 2000320485 A JP2000320485 A JP 2000320485A JP 4616454 B2 JP4616454 B2 JP 4616454B2
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- Japan
- Prior art keywords
- group
- imidazol
- methyl
- biphenyl
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000004519 manufacturing process Methods 0.000 title claims description 64
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 title claims description 12
- 150000001298 alcohols Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 300
- -1 phenyloxycarbonyl Chemical group 0.000 claims description 279
- 125000001424 substituent group Chemical group 0.000 claims description 64
- 239000000203 mixture Substances 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000005843 halogen group Chemical group 0.000 claims description 28
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 125000003277 amino group Chemical group 0.000 claims description 17
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 12
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 11
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000002697 lyase inhibitor Substances 0.000 claims description 8
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- IHOBBYHEOBWAPZ-UHFFFAOYSA-L steroid c Chemical compound [Na+].[Na+].C1CC2CC(OS([O-])(=O)=O)C(OS([O-])(=O)=O)CC2(C)C(CCC23C)C1C3CC(O1)C2C2(C)OC1OC2CC(C(C)C)=C(C)C IHOBBYHEOBWAPZ-UHFFFAOYSA-L 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 229940122014 Lyase inhibitor Drugs 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- DDQPLMGLQXMKLK-UHFFFAOYSA-N n-[3-[4-[1-hydroxy-1-(1h-imidazol-5-yl)-2-methylpropyl]phenyl]phenyl]acetamide Chemical compound C=1C=C(C=2C=C(NC(C)=O)C=CC=2)C=CC=1C(O)(C(C)C)C1=CNC=N1 DDQPLMGLQXMKLK-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- FRDLFNZPCFFPFV-UHFFFAOYSA-N 1-[4-(4-fluorophenyl)phenyl]-1-(1h-imidazol-5-yl)-2-methylpropan-1-ol Chemical compound C=1C=C(C=2C=CC(F)=CC=2)C=CC=1C(O)(C(C)C)C1=CNC=N1 FRDLFNZPCFFPFV-UHFFFAOYSA-N 0.000 claims description 5
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 claims description 5
- 102100024028 Progonadoliberin-1 Human genes 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 4
- IMIWIUDULMYEKK-UHFFFAOYSA-N n-[6-[4-[1-hydroxy-1-(1h-imidazol-5-yl)-2-methylpropyl]phenyl]pyridin-2-yl]acetamide Chemical compound C=1C=C(C=2N=C(NC(C)=O)C=CC=2)C=CC=1C(O)(C(C)C)C1=CNC=N1 IMIWIUDULMYEKK-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 4
- 230000000069 prophylactic effect Effects 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- CFCJVXMNOZCNMK-UHFFFAOYSA-N 3-[4-[1-hydroxy-1-(1h-imidazol-5-yl)-2-methylpropyl]phenyl]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(C=2C=CC(=CC=2)C(O)(C(C)C)C=2N=CNC=2)=C1 CFCJVXMNOZCNMK-UHFFFAOYSA-N 0.000 claims description 3
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 3
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 150000004795 grignard reagents Chemical class 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims 4
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims 3
- 125000005116 aryl carbamoyl group Chemical group 0.000 claims 2
- 125000001589 carboacyl group Chemical group 0.000 claims 2
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 207
- 238000006243 chemical reaction Methods 0.000 description 200
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 192
- 238000005160 1H NMR spectroscopy Methods 0.000 description 190
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 114
- 239000000243 solution Substances 0.000 description 104
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 99
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 92
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 89
- 239000013078 crystal Substances 0.000 description 79
- 239000000843 powder Substances 0.000 description 71
- KEQWGBKMIOLHDS-UHFFFAOYSA-N 3-[4-[1-hydroxy-1-(1h-imidazol-5-yl)-2-methylpropyl]phenyl]-4-methoxy-n-methylbenzamide Chemical compound CNC(=O)C1=CC=C(OC)C(C=2C=CC(=CC=2)C(O)(C(C)C)C=2N=CNC=2)=C1 KEQWGBKMIOLHDS-UHFFFAOYSA-N 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 50
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 44
- 230000002829 reductive effect Effects 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
- 235000002639 sodium chloride Nutrition 0.000 description 36
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 239000003480 eluent Substances 0.000 description 28
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 27
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 26
- 229910000029 sodium carbonate Inorganic materials 0.000 description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
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- QFJCBOFOYAROIC-UHFFFAOYSA-N [4-[1-hydroxy-2-methyl-1-(1-tritylimidazol-4-yl)propyl]phenyl]boronic acid Chemical compound C=1C=C(B(O)O)C=CC=1C(O)(C(C)C)C(N=C1)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 QFJCBOFOYAROIC-UHFFFAOYSA-N 0.000 description 19
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
- ODZAFQPQTIEMNY-UHFFFAOYSA-N 1-(3-bromophenyl)-2-methyl-1-(1-tritylimidazol-4-yl)propan-1-ol Chemical compound C=1C=CC(Br)=CC=1C(O)(C(C)C)C(N=C1)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ODZAFQPQTIEMNY-UHFFFAOYSA-N 0.000 description 12
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- ILFPCMXTASDZKM-UHFFFAOYSA-N sarkomycin Natural products OC(=O)C1CCC(=O)C1=C ILFPCMXTASDZKM-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229950010372 sobuzoxane Drugs 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 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
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 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
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095374 tabloid Drugs 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
- FQZYTYWMLGAPFJ-OQKDUQJOSA-N tamoxifen citrate Chemical compound [H+].[H+].[H+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 FQZYTYWMLGAPFJ-OQKDUQJOSA-N 0.000 description 1
- 229960003454 tamoxifen citrate Drugs 0.000 description 1
- 229960003198 tamsulosin hydrochloride Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 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
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- QNMBSXGYAQZCTN-UHFFFAOYSA-N thiophen-3-ylboronic acid Chemical compound OB(O)C=1C=CSC=1 QNMBSXGYAQZCTN-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960004167 toremifene citrate Drugs 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 125000005389 trialkylsiloxy group Chemical group 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- SANWDQJIWZEKOD-UHFFFAOYSA-N tributyl(furan-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CO1 SANWDQJIWZEKOD-UHFFFAOYSA-N 0.000 description 1
- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
- UKTDFYOZPFNQOQ-UHFFFAOYSA-N tributyl(thiophen-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CS1 UKTDFYOZPFNQOQ-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【0001】
【発明の属する技術分野】
本発明は、医薬とりわけステロイドC17,20リアーゼ阻害作用を有する新規1-置換フェニル−1−(1H−イミダゾール−4−イル)アルコール類およびそれを含んでなる医薬組成物に関する。
【0002】
【従来の技術】
性ホルモンは細胞の分化・増殖を始めとして多彩な生理活性を有している。一方、ある種の疾患ではアンドロゲンやエストロゲンが増悪因子として作用することが明らかになっている。生体内におけるアンドロゲンの生合成においてステロイドC17,20リアーゼがその最終段階に関与していることが知られている。すなわち、ステロイドC17,20リアーゼは、コレステロールから生成する17−ヒドロキシプレグネノロン及び17−ヒドロキシプロゲステロンを基質として、デヒドロエピアンドロステロンおよびアンドロステンジオンを生成する。従って、ステロイドC17,20リアーゼを阻害する薬剤は、アンドロゲンの生成を抑制するとともにアンドロゲンを基質として合成されるエストロゲンの生成を抑制し、アンドロゲンやエストロゲンを憎悪因子とする疾患の予防及び治療薬として有用である。アンドロゲンまたはエストロゲンが憎悪因子となる疾患としては、例えば、前立腺癌、前立腺肥大症、男性化症、多毛症、男性型禿頭症、男児性早熟症、乳癌、子宮癌、卵巣癌、乳腺症、子宮筋腫、子宮内膜症、子宮腺筋症、多曩胞性卵巣症候群などが挙げられる。
すでにステロイドC17,20リアーゼ阻害剤としてステロイドタイプの化合物及び非ステロイドタイプの化合物が知られている。ステロイドタイプの化合物は、例えば、WO 92/15404,WO 93/20097,EP−A 288053,EP−A 413270等に開示されている。非ステロイドタイプの化合物としては、例えば、特開昭64−85975に(1H−イミダゾール−1−イル)メチル置換ベンズイミダゾール誘導体、WO94/27989及びWO96/14090にカルバゾール誘導体、WO95/09157にアゾール誘導体、US5,491,161 に1H−ベンズイミダゾール誘導体、WO99/18075にジヒドロナフタレン誘導体、バイオオーガニック・メディシナル・ケミストリー1999年(7巻)p1913-1924に(1H−イミダゾール−1−イル)メチルビフェニル誘導体が示されている。
【0003】
【発明が解決しようとする課題】
現在まで、医療の場で使用できるステロイドC17,20リアーゼ阻害剤はまだ得られておらず、医薬として有用性の高いステロイドC17,20リアーゼ阻害剤の早期開発が期待されている。
【0004】
【課題を解決するための手段】
本発明者らは、優れたステロイドC17,20リアーゼ阻害剤を見いだすために鋭意研究を重ねた結果、式(I)で示されるベンゼン環とイミダゾール環を連結するメチレン基に低級アルキルまたは環状炭化水素基および水酸基が置換していることに化学構造上の特徴を有する新規な化合物またはその塩を始めて合成し、得られた化合物(I)またはその塩がその特異な化学構造に基づいて予想外にも優れた医薬用途、特に優れたステロイドC17,20リアーゼ阻害活性を有しており、しかも毒性が少なく医薬品として優れた性質を有していることを見出し、これらの知見に基づいて本発明を完成した。
すなわち本発明は、
(1)式:
【化10】
(式中、Rは水素原子または保護基を、R1は低級アルキル基または環状炭化水素基を、R2は置換基を有していてもよい芳香族炭化水素基または置換基を有していてもよい芳香族複素環基を、R3は置換基を有していてもよい炭化水素基、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基またはハロゲン原子を、nは0ないし4の整数を示す。)で表される化合物またはその塩、
(2)Rが1)水素原子、2)ホルミル、3)第1群から選ばれた1ないし3個の基で置換されていてもよいC1-6アルキルカルボニル、4)第1群から選ばれた1ないし3個の基で置換されていてもよいフェニルカルボニル、5)第1群から選ばれた1ないし3個の基で置換されていてもよいC1-6アルキル−オキシカルボニル、6)第1群から選ばれた1ないし3個の基で置換されていてもよいフェニルオキシカルボニル、7)第1群から選ばれた1ないし3個の基で置換されていてもよいC7-10アラルキルオキシ−カルボニル、8)第1群から選ばれた1ないし3個の基で置換されていてもよいトリチル、9)第1群から選ばれた1ないし3個の基で置換されていてもよいフタロイルおよび10)第1群から選ばれた1ないし3個の基で置換されていてもよいN,N−ジメチルアミノメチレンであり、R1がC1-6アルキルまたはC3-6シクロアルキルであり、R2が第2群から選ばれた1ないし4個で置換されていてもよいC6-10アリール基または第2群から選ばれた1ないし4個で置換されていてもよい第3群から選ばれた芳香族複素環基であり、R3が1)C1-4アルキル、2)置換基としてC2-4アルカノイル、カルボキシルまたはC1-4アルコキシ−カルボニルを有するC1-4アルキル、3)水酸基、4)C1-4低級アルコキシ、5)C1-4アルカノイルオキシ、6)カルバモイルオキシ、7)1または2個のC1-4アルキル基で置換されたカルバモイルオキシ、8)チオール基、9)C1-4アルキルチオ基、10)C1-4アルカノイルチオ、11)アミノ基、12)C1-4アルキルアミノ基、13)ジC1-4アルキルアミノ、14)C1-4アルカノイルアミノ、15)ホルミル、16)C2-6アルカノイル、17)C1-4アルキルスルホニル、18)カルバモイル基、19)モノ−またはジ−C1-10アルキルカルバモイル基、20)モノ−またはジ−C6-14アリールカルバモイル、21)モノ−またはジ−C7-16アラルキルカルバモイル基、22)スルファモイル、23)モノ−またはジ−C1-10アルキルスルファモイル基、24)モノ−またはジ−C6-14アリールスルファモイル基、25)モノ−またはジ−C7-16アラルキルスルファモイル基または26)ハロゲン原子である上記(1)記載の化合物
(上記において、
【0005】
第1群は
ハロゲン原子、ホルミル基、C1-6アルキル−カルボニル基およびニトロ基、
第2群は
1) C1-6アルキル基、2) 1ないし5個のハロゲン原子で置換されたC1-4アルキル基、3)1ないし2個のC1-4アルコキシで置換されたC1-4アルキル基、4)水酸基、5)C1-4アルコキシ基、6)C1-4アルカノイルオキシ基、7)カルバモイルオキシ基、8)C1-4アルキル基で置換されたカルバモイルオキシ基、9)アミノ基、10)モノまたはジC1-4アルキルアミノ基、11)C1-4アルカノイルアミノ基、12)ホルミル基、13)C2-6アルカノイル基、14)C1-4アルキルスルホニル基、15)カルバモイル基、16)モノ−またはジ−C1-10アルキルカルバモイル基、17)C3-6シクロアルキルカルバモイル基、18)モノ−またはジ−C6-14アリールカルバモイル基、19)モノ−またはジ−C7-16アラルキルカルバモイル基、20)スルファモイル基、21)モノ−またはジ−C1-10アルキルスルファモイル基、22)モノ−またはジ−C6-14アリールスルファモイル基、23)モノ−またはジ−C7-16アラルキルスルファモイル基および24)ハロゲン原子、25)シアノ基および26)オキソ基、
第3群は
2−チエニル基、3−チエニル基、2−ピリジル基、3−ピリジル基、4−ピリジル基、2−フリル基、3−フリル基、2−キノリル基、4−キノリル基、8−キノリル基、3−イソキノリル基、4−イソキノリル基、ピラジニル基、2−ピリミジニル基、3−ピロリル基、1−イミダゾリル基、2−イミダゾリル基、1−ピラゾリル基、2−チアゾリル基、4−チアゾリル基、5−チアゾリル基、3−イソチアゾリル基、4−イソチアゾリル基、2−オキサゾリル基、4−オキサゾリル基、5−オキサゾリル基、3−イソオキサゾリル基、3−ピリダジニル基、1−インドリル基、1−イソインドリル基、2−イソインドリル基、1−テトラゾリル基、2−テトラゾリル基および5−テトラゾリル基、
をそれぞれ示す。)、
(3)Rが水素原子、R1がC1-6アルキル基またはC3-6シクロアルキル基であり、R2がそれぞれ第4群から選ばれた1ないし4個の基で置換されていてもよいフェニール基、ピリジル基、チエニル基、フリール基またはイソインドリニル基であり、nが0または1であり、R3がC1-4低級アルコキシ基、C1-4アルカノイルオキシ基またはC1-4アルカノイルアミノ基である上記(1)記載の化合物
(上記において、
第4群は
1) C1-6アルキル基、2) 1ないし5個のハロゲン原子で置換されたC1-4アルキル基、3)1ないし2個のC1-4アルコキシで置換されたC1-4アルキル基、4)C1-4アルコキシ基、5)C1-4アルカノイルアミノ基、6)C2-6アルカノイル基、7)モノ−またはジ−C1-10アルキルカルバモイル基、8)C3-6シクロアルキルカルバモイル基、9)モノ−またはジ−C1-10アルキルスルファモイル基、10)ハロゲン原子、11)シアノ基および12)オキソ基
を示す。)、
【0006】
(4)R2が第5群から選ばれた1または2個の基で置換されていてもよいフェニール基、ピリジル基、チエニル基、フリール基またはイソインドリニル基である上記(3)記載の化合物
(上記において、
第5群は
1) C1-4アルカノイルアミノ基、2)C2-6アルカノイル基、3)モノ−C1-10アルキルカルバモイル基、4)モノ−C1-10アルキルスルファモイル基、5)ハロゲン原子および6)オキソ基
を示す。)、
(5)Rが水素原子であり、R1がC1-6アルキル基であり、R2が1)ハロゲンまたはアセチルアミノで置換されたフェニール基または2)ハロゲンまたはアセチルアミノで置換されたピリジル基、であり、nが0である上記(1)記載の化合物、
(6)1-(4’-フルオロ[1,1’-ビフェニル]-4-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノール、(‐)‐N-(6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-2-ピリジル)アセタミド、(‐)-N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミド、4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-N-メチル[1,1'-ビフェニル]-3-カルボキサミド、N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-3-イル]アセタミド、またはその塩である上記(1)記載の化合物、
(7)式:
【化11】
(式中、Rは水素原子または保護基を、R1は低級アルキル基または環状炭化水素基を、R2は置換基を有していてもよい芳香族炭化水素基または置換基を有していてもよい芳香族複素環基を、R3は置換基を有していてもよい炭化水素基、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基またはハロゲン原子を、nは0ないし4の整数を示す。)で表される化合物またはその塩のプロドラッグ、
(8)式:
【化12】
(式中、Rは水素原子または保護基を、R1は低級アルキル基または環状炭化水素基を、R2は置換基を有していてもよい芳香族炭化水素基または置換基を有していてもよい芳香族複素環基を、R3は置換基を有していてもよい炭化水素基、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基またはハロゲン原子を、nは0ないし4の整数を示す。)で表される化合物、その塩またはそのプロドラッグを含有する医薬組成物、
【0007】
(9)ステロイドC17,20リアーゼ阻害剤である上記(8)記載の組成物、
(10)抗腫瘍剤である上記(9)記載の組成物、
(11)乳癌または前立腺癌の予防・治療剤である上記(9)記載の抗腫瘍剤組成物、
(12)式:
【化13】
(式中、Rは水素原子または保護基を、R1は低級アルキル基または環状炭化水素基を、R2は置換基を有していてもよい芳香族炭化水素基または置換基を有していてもよい芳香族複素環基を、R3は置換基を有していてもよい炭化水素基、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基またはハロゲン原子を、nは0ないし4の整数を示す。)で表される化合物もしくはその塩またはそのプロドラッグとLHRH調節薬とを併用することを特徴とするアンドロゲン低下剤、
(13)式:
【化14】
(式中、R1は低級アルキル基または環状炭化水素基を、R2は置換基を有していてもよい芳香族炭化水素基または置換基を有していてもよい芳香族複素環基を、R3は置換基を有していてもよい炭化水素基、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基またはハロゲン原子を、nは0ないし4の整数を示す。)で表される化合物と、式:
【化15】
(式中、Xは脱離基を、Rは水素原子または保護基を示す)で表される化合物とグリニヤール試薬またはアルキルリチウムとの反応生成物とを反応させることを特徴とする式:
【化16】
(式中、各記号は前記と同意義である。)で表される化合物またはその塩の製造法、
(14)哺乳動物に対して、式:
【化17】
(式中、Rは水素原子または保護基を、R1は低級アルキル基または環状炭化水素基を、R2は置換基を有していてもよい芳香族炭化水素基または置換基を有していてもよい芳香族複素環基を、R3は置換基を有していてもよい炭化水素基、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基またはハロゲン原子を、nは0ないし4の整数を示す。)で表される化合物もしくはその塩またはそのプロドラッグの有効量を投与することを特徴とするステロイドC17,20リアーゼ阻害方法、および
【0008】
(15)ステロイドC17,20リアーゼ阻害剤を製造するための式:
【化18】
(式中、Rは水素原子または保護基を、R1は低級アルキル基または環状炭化水素基を、R2は置換基を有していてもよい芳香族炭化水素基または置換基を有していてもよい芳香族複素環基を、R3は置換基を有していてもよい炭化水素基、置換基を有していてもよい水酸基、置換基を有していてもよいチオール基、置換基を有していてもよいアミノ基、アシル基またはハロゲン原子を、nは0ないし4の整数を示す。)で表される化合物もしくはその塩またはそのプロドラッグの使用、
などに関する。
上記式中、R1で示される低級アルキル基としては炭素数1ないし6の直鎖状または分枝状のもの、例えばメチル、エチル、n−プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、n−ペンチル、イソペンチル、ネオペンチル、tert−ペンチル、n−ヘキシル、イソヘキシルなどのC1-6アルキル基などが挙げられる。R1で示される環状炭化水素基としては、たとえばシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルなどのC3-6シクロアルキル基などが挙げられる。R1としては、C1-4アルキル基(例えば、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、sec−ブチル、tert−ブチルなど)などが好ましい。
R2で示される「置換基を有していてもよい芳香族炭化水素基」における「芳香族炭化水素基」としては、例えば6ないし18個の炭素原子から構成される単環式芳香族炭化水素基、縮合多環式芳香族炭化水素基などが挙げられ、具体的には、フェニル、1−ナフチル、2−ナフチル、2−インデニル、2−アンスリルなどのC6-14アリール基が挙げられ、C6-10アリール基(例えば、フェニルなど)などが好ましい。R2で示される「置換基を有していてもよい芳香族複素環基」における「芳香族複素環基」としては、たとえば2−チエニル、3−チエニル、2−ピリジル、3−ピリジル、4−ピリジル、2−フリル、3−フリル、2−キノリル、4−キノリル、8−キノリル、3−イソキノリル、4−イソキノリル、ピラジニル、2−ピリミジニル、3−ピロリル、1−イミダゾリル、2−イミダゾリル、1−ピラゾリル、2−チアゾリル、4−チアゾリル、5−チアゾリル、3−イソチアゾリル、4−イソチアゾリル、2−オキサゾリル、4−オキサゾリル、5−オキサゾリル、3−イソオキサゾリル、3−ピリダジニル、1−インドリル、1−イソインドリル、2−イソインドリル、1−テトラゾリル、2−テトラゾリル、5−テトラゾリルなどが挙げられる。
【0009】
R2で示される「置換基を有していてもよい芳香族炭化水素基」および「置換基を有していてもよい芳香族複素環基」における「置換基」は環上の置換可能な位置に1−4個置換していてもよく、該置換基としては、 低級(C1-6)アルキル基(例、メチル、エチル、n−プロピル、i−プロピル、n−ブチル、i−ブチル、t−ブチル、n−ペンチル、n−ヘキシルなど)、1ないし5個のハロゲン原子(例、フッ素、塩素など)で置換された低級アルキル基(クロロメチル、ブロモメチル、フルオロメチル、トリクロロメチル、1−クロロエチル、2−クロロエチル、1,1−ジクロロエチル、1,2−ジブロモエチル、1,1,2−トリクロロプロピルなど炭素数1−4のもの)、1−2個のC1-4アルコキシで置換されたC1-4アルキル基(例、メトキシメチル、エトキシメチル、1−メトキシエチル、2−メトキシエチル、1−エトキシエチル、2−エトキシエチル、ジメトキシメチルなど)、置換基を有していてもよい水酸基[例、水酸基、低級アルコキシ(例、メトキシ、エトキシ、プロポキシなどのC1-4アルコキシ基)、低級アルカノイルオキシ(例、アセチルオキシ、プロピオニルオキシなどC1-4アルカノイルオキシ)、置換基を有していてもよいカルバモイルオキシ(例、無置換のカルバモイルオキシの他たとえばメチルカルバモイルオキシ、エチルカルバモイルオキシ、ジメチルカルバモイルオキシ、ジエチルカルバモイルオキシ、メチルエチルカルバモイルオキシなど1または2個のC1-4アルキル基で置換されたカルバモイルオキシ)など]、置換基を有していてもよいアミノ基[例、アミノ、低級アルキルアミノ(例、メチルアミノ、エチルアミノ、プロピルアミノなどのC1-4アルキルアミノ基)、ジ低級アルキルアミノ(例、ジメチルアミノ、ジエチルアミノなどのジC1-4アルキルアミノ)、C1-4アルカノイルアミノ(例、アセトアミド、プロピオンアミドなど)など]、アシル基[例、置換基を有していてもよいカルバモイル基(例、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイルなどのモノ−またはジ−C1-10アルキルカルバモイル基、たとえばフェニルカルバモイル、ジフェニルカルバモイルなどのモノ−またはジ−C6-14アリールカルバモイル、たとえばベンジルカルバモイル、ジベンジルカルバモイルなどのモノ−またはジ−C7-16アラルキルカルバモイル基など)、アルカノイル基(例、ホルミル、アセチル、プロピオニルなどのC1-6アルカノイル)、アルキルスルホニル基(例、メチルスルホニル、エチルスルホニルなどのC1-4アルキルスルホニル)、置換基を有していてもよいカルバモイル基(例、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイルなどのモノ−またはジ−C1-10アルキルカルバモイル基、たとえばシクロプロピルカルバモイル、シクロペンチルカルバモイル、シクロヘキシルカルバモイルなどのC3-6シクロアルキルカルバモイル、たとえばフェニルカルバモイル、ジフェニルカルバモイルなどのモノ−またはジ−C6-14アリールカルバモイル、たとえばベンジルカルバモイル、ジベンジルカルバモイルなどのモノ−またはジ−C7-16アラルキルカルバモイル基など)、置換基を有していてもよいスルファモイル(例、メチルスルファモイル、エチルスルファモイル、ジメチルスルファモイル、ジエチルスルファモイルなどのモノ−またはジ−C1-10アルキルスルファモイル基、たとえばフェニルスルファモイル、ジフェニルスルファモイルなどのモノ−またはジ−C6-14アリールスルファモイル基、たとえばベンジルスルファモイル、ジベンジルスルファモイルなどのモノ−またはジ−C7-16アラルキルスルファモイル基など)など]、ハロゲン原子(フッ素、塩素、臭素、ヨウ素)などが挙げられる。
【0010】
R3示される置換基を有していてもよい炭化水素基としては、たとえばメチル、エチル、プロピル等の無置換のC1-4アルキルの他、これらのアルキル基にアセチル、プロピオニルなどのアルカノイル、カルボキシル、C1-4アルコキシ−カルボニル(例、メトキシカルボニル、エトキシカルボニル、ブトキシカルボニルなど)などが置換したものなどが挙げられる。
R3で示される置換基を有していてもよい水酸基としては、無置換の水酸基の他たとえば低級アルコキシ(例、メトキシ、エトキシ、プロポキシなどのC1-4アルコキシ基)、低級アルカノイルオキシ(例、アセチルオキシ、プロピオニルオキシなどC1-4アルカノイルオキシ)、置換基を有していてもよいカルバモイルオキシ(例、無置換のカルバモイルオキシの他たとえばメチルカルバモイルオキシ、エチルカルバモイルオキシ、ジメチルカルバモイルオキシ、ジエチルカルバモイルオキシ、メチルエチルカルバモイルオキシなど1または2個のC1-4アルキル基で置換されたカルバモイルオキシ)などが挙げられる。
R3で示される置換基を有していてもよいチオール基としては無置換のチオール基の他たとえば低級アルキルチオ(例、メチルチオ、エチルチオ、プロピルチオなどのC1-4アルキルチオ基)、低級アルカノイルチオ(例、アセチルチオ、プロピオニルチオなどC1-4アルカノイルチオ)などが挙げられる。
R3で示される置換基を有していてもよいアミノ基としては、無置換のアミノ基の他たとえば低級アルキルアミノ(例、メチルアミノ、エチルアミノ、プロピルアミノなどのC1-4アルキルアミノ基)、ジ低級アルキルアミノ(例、ジメチルアミノ、ジエチルアミノなどのジC1-4アルキルアミノ)、C1-4アルカノイルアミノ(例、アセトアミド、プロピオンアミドなど)などが挙げられる。
R3で示されるアシル基としては、たとえばアルカノイル基(例、ホルミル、アセチル、プロピオニルなどのC1-6アルカノイル)、アルキルスルホニル基(例、メチルスルホニル、エチルスルホニルなどのC1-4アルキルスルホニル)、置換基を有していてもよいカルバモイル基(例、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイルなどのモノ−またはジ−C1-10アルキルカルバモイル基、たとえばフェニルカルバモイル、ジフェニルカルバモイルなどのモノ−またはジ−C6-14アリールカルバモイル、たとえばベンジルカルバモイル、ジベンジルカルバモイルなどのモノ−またはジ−C7-16アラルキルカルバモイル基など)、置換基を有していてもよいスルファモイル(例、メチルスルファモイル、エチルスルファモイル、ジメチルスルファモイル、ジエチルスルファモイルなどのモノ−またはジ−C1-10アルキルスルファモイル基、たとえばフェニルスルファモイル、ジフェニルスルファモイルなどのモノ−またはジ−C6-14アリールスルファモイル基、たとえばベンジルスルファモイル、ジベンジルスルファモイルなどのモノ−またはジ−C7-16アラルキルスルファモイル基など)などが挙げられる。
R3で示されるハロゲン原子としては、フッ素、塩素、臭素、沃素が挙げられる。
【0011】
Rで示される保護基としては、例えば、ホルミル、それぞれ置換基を有していてもよい、C1-6アルキルカルボニル(例えば、アセチル、プロピオニルなど)、フェニルカルボニル、C1-6アルキル−オキシカルボニル(例えば、メトキシカルボニル、エトキシカルボニルなど)、フェニルオキシカルボニル、C7-10アラルキルオキシ−カルボニル(例えば、ベンジルオキシカルボニルなどのフェニル−C1-4アルキルオキシ−カルボニルなど)、トリチル、フタロイルまたはN,N−ジメチルアミノメチレンなどが用いられる。これらの置換基としては、ハロゲン原子(例えば、フッ素、塩素、臭素、ヨウ素など)、ホルミル、C1-6アルキル−カルボニル(例えば、アセチル、プロピオニル、バレリルなど)、ニトロ基などが用いられ、置換基の数は1ないし3個程度である。
Xで示される脱離基としては、ハロゲン原子(塩素原子、臭素原子、ヨウ素原子など)、アルキルまたはアリールスルホニルオキシ基(メタンスルホニルオキシ、エタンスルホニルオキシ、ベンゼンスルホニルオキシ、p−トルエンスルホニルオキシなど)などが挙げられる。
本発明の式(I)で表わされる化合物は、塩を形成していてもよく、該塩としては酸付加塩、例えば無機酸塩(例えば、塩酸塩、硫酸塩、臭化水素酸塩、リン酸塩など)、有機酸塩(例えば、酢酸塩、トリフルオロ酢酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、プロピオン酸塩、クエン酸塩、酒石酸塩、乳酸塩、蓚酸塩、メタンスルホン酸塩、p−トルエンスルホン酸塩など)などが挙げられる。
尚、一般式(I)で表わされる化合物またはその塩は水和物であってもよく、以下、塩、水和物も含め化合物(I)と称する。
化合物(I)のプロドラッグは、生体内において酵素や胃酸等による反応によりステロイドC17,20リアーゼ阻害作用を有する化合物(I)に変換する化合物をいう。
化合物(I)のプロドラッグとしては、化合物(I)のイミダゾール窒素がアシル化またはアルキル化された化合物(例、ジメチルアミノスルホニル化、アセトキシメチル化、(5−メチル−2−オキソ−1,3−ジオキソレン−4−イル)メトキシカルボニルメチル化、ピバロイルオキシメチル化、ベンジルオキシメチル化された化合物など);化合物(I)の水酸基がアシル化、アルキル化、りん酸化、硫酸化、ほう酸化された化合物(例、化合物(I)の水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、スクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物など)等が挙げられる。これらの化合物は自体公知の方法によって製造することができる。
化合物(I)のプロドラッグはそれ自身であっても、薬理学的に許容される塩であってもよい。このような塩としては、化合物(I)のプロドラッグがカルボキシル基等の酸性基を有する場合、無機塩基(例、ナトリウム、カリウム等のアルカリ金属、カルシウム、マグネシウム等のアルカリ土類金属、亜鉛、鉄、銅等の遷移金属等)や有機塩基(例、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ジシクロヘキシルアミン、N,N’−ジベンジルエチレンジアミンなどの有機アミン類、アルギニン、リジン、オルニチンなどの塩基性アミノ酸類等)などとの塩が挙げられる。
【0012】
化合物(I)のプロドラッグがアミノ基等の塩基性基を有する場合、無機酸や有機酸(例、塩酸、硝酸、硫酸、燐酸、炭酸、重炭酸、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、フマール酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸等)、アスパラギン酸、グルタミン酸などの酸性アミノ酸等との塩が挙げられる。
また、化合物(I)のプロドラッグは水和物および非水和物のいずれであってもよい。
化合物(I)は分子内に1ないしそれより多い不斉炭素を有するが、これら不斉炭素に関しR配置、S配置のいずれも本発明に包含される。
本明細書全体において式(I)、(I’)、(II)、(III)、(III’)、(IV)、(IV’)、(V)、(VI)、(VIII)、(VIII’)および(IX)で表される化合物において、塩基性基または酸性基を有する化合物はそれぞれ酸付加塩との塩または塩基との塩を形成しうる。これらの酸付加塩および塩基との塩は前記化合物(I)で述べたものと同様のものが挙げられる。以下それぞれの式で表される化合物はその塩を含めて化合物(式の符号)と略す。たとえば式(II)で表される化合物およびその塩を単に化合物(II)という。
化合物(I)は、例えば以下に示される方法等によって製造される。
原料化合物及び合成中間体は、遊離体のほか化合物(I)と同様の塩として用いてもよく、また反応混合液のまま、あるいは公知の手段に従って単離した後に反応に供してもよい。
【化19】
[式中、Mは金属またはその塩を示し、他の記号は前記と同意義である。]
Mで示される金属としてはリチウムまたはマグネシウムなどが挙げられ、その塩としてはたとえばマグネシウムクロリド、マグネシウムブロミドなどの金属ハライドなどが挙げられる。
[工程AおよびB]
化合物(I)は化合物(II)に有機金属化合物(III’)を反応させることによって得ることができる。すなわち、化合物(III)をアルキルリチウムまたはアルキルマグネシウムハライド等と反応させて有機金属化合物(III’)に変換し、続いて化合物(II)と反応させると化合物(I)を得ることができる。
本反応で用いられるアルキルリチウムとしてはn−ブチルリチウム、s−ブチルリチウム、t−ブチルリチウム等のC1-4アルキルリチウムが挙げられ、その使用量は原料化合物(III)または(IV)1モルに対して1モルから3倍モル量、好ましくは1〜1.5倍モル量である。アルキルリチウムを反応させる場合の反応温度は−100℃から0℃、好ましくは−80℃〜−20℃である。アルキルマグネシウムハライドとしてはエチルマグネシウムブロミド、メチルマグネシウムクロリドなどが挙げられ、その使用量は原料化合物(III)1モルに対して1モルから10倍モル量、好ましくは1モルから4モルである。化合物(III)に対してアルキルマグネシウムハライドを反応させる場合、反応温度は−40℃から20℃、好ましくは−20℃から0℃である。反応時間は5分から20時間程度である。本反応は通常反応に影響のない有機溶媒中で行われる。反応に悪影響のない有機溶媒としては、例えば、ジエチルエーテル、ジオキサン、テトラヒドロフラン(THF)などのエーテル類、ヘキサン、ペンタンなどの飽和炭化水素類、ジクロロメタン、クロロホルムなどのハロゲン化炭化水素類、ベンゼン、トルエンなどの芳香族炭化水素類などが用いられ、これらは一種又は二種以上適宜の割合で混合して用いてもよい。化合物(II)は化合物(III)に対して0.1当量ないし10当量、好ましくは0.2〜2当量である。
【0013】
[工程CおよびD]
化合物(IV)にアルキルリチウムやマグネシウム等の金属を反応させて有機金属化合物(IV’)に変換した後、化合物(V)と反応させることによっても化合物(I)を得ることができる。 本反応で用いられるアルキルリチウムとしてはn−ブチルリチウム、s−ブチルリチウム、t−ブチルリチウム等のC1-4アルキルリチウムが挙げられ、その使用量は原料化合物(III)または(IV)1モルに対して1モルから3倍モル量、好ましくは1〜1.5倍モル量である。アルキルリチウムを反応させる場合の反応温度は−100℃から0℃、好ましくは−80℃〜−20℃である。化合物(IV)に金属マグネシウムを反応させる場合、その使用量は化合物(IV)1モルに対して1モルから3倍モル量、好ましくは1モルから1.5倍モルである。反応温度は−20℃ から100℃、好ましくは10℃から50℃である。反応時間は5分から20時間程度である。本反応は通常反応に影響のない有機溶媒中で行われる。反応に悪影響のない有機溶媒としては、例えば、ジエチルエーテル、ジオキサン、テトラヒドロフラン(THF)などのエーテル類、ヘキサン、ペンタンなどの飽和炭化水素類、ジクロロメタン、クロロホルムなどのハロゲン化炭化水素類、ベンゼン、トルエンなどの芳香族炭化水素類などが用いられ、これらは一種又は二種以上適宜の割合で混合して用いてもよい。化合物 (V) は化合物 (IV) に対して0.1当量ないし10当量、好ましくは0.2〜2当量である。
[工程E]
化合物(VI)と有機金属試薬(VII)を反応させることによっても化合物(I)を得ることができる。
化合物(VII)の使用量は化合物(VI)1モルに対して1モルから10倍モル量、好ましくは1〜5倍モル量である。反応温度は−80℃から60℃、好ましくは−80℃〜50℃である。反応時間は5分から20時間程度である。本反応は通常反応に影響のない有機溶媒中で行われる。反応に悪影響のない有機溶媒としては、例えば、ジエチルエーテル、ジオキサン、テトラヒドロフラン(THF)などのエーテル類、ヘキサン、ペンタンなどの飽和炭化水素類、ジクロロメタン、クロロホルムなどのハロゲン化炭化水素類、ベンゼン、トルエンなどの芳香族炭化水素類などが用いられ、これらは一種又は二種以上適宜の割合で混合して用いてもよい。
[工程F]
化合物(I)のRが保護基である場合、それ自体公知またはそれに準じた方法で保護基を除去し、化合物(I’)を得ることができる。例えば、Rがトリチル基の場合、酸性条件下での処理、または水素化分解によりトリチル基を除去することができる。該酸としては、ぎ酸、酢酸等の有機酸、塩酸等の無機酸などが使用される。反応にはアルコール類、THF等のエーテル類など、反応に不活性な溶媒を用いて行うこともできる。反応温度は通常 0℃〜100℃である。
【化20】
[式中、Yは脱離基(ハロゲン原子、アルキルまたはアリールスルホニルオキシ基等)または脱離基に変換しうる置換基(例、保護された水酸基)、 Zはトリアルキルスズ、ホウ酸等の脱離基を示す。他の記号は前記と同意義である。]
【0014】
[工程GおよびH]
工程GおよびHにおいて、化合物(VIII)にアルキルリチウムまたはマグネシウム等の金属を作用させて有機金属化合物(VIII’)に変換したのち、化合物(V)と反応させることにより化合物(IX)を得ることができる。反応の条件は前述の工程AおよびBと同様である。化合物(VIII)におけるYが脱離基に変換しうる保護された水酸基(例、トリアルキルシリルオキシ基)である場合、化合物(IX)に変換した後、Yを脱離基(例トリフルオロメタンスルホニルオキシ基)に変換するのが好ましい。この変換は常法に従って行うことができる。
[工程I]
化合物(IX)をパラジウム触媒存在下、化合物(X)と反応させると化合物(I)が得られる。本反応で用いるパラジウム触媒としてはテトラキストリフェニルホスフィンパラジウム、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などの0価または二価のパラジウム錯体が用いられる。反応温度は0℃から150℃、好ましくは50℃から120℃である。反応時間は1時間から48時間程度である。本反応は通常反応に影響のない溶媒中で行われる。反応に悪影響のない溶媒としては、例えば、ジメトキシエタン、ジオキサン、テトラヒドロフラン(THF)などのエーテル類、メタノール、エタノールなどのアルコール類、ジクロロメタン、クロロホルムなどのハロゲン化炭化水素類、ベンゼン、トルエンなどの芳香族炭化水素類、水などが用いられ、これらは一種又は二種以上適宜の割合で混合して用いてもよい。化合物(X)がホウ素化合物の場合は反応系内に塩基(炭酸ナトリウム等)を存在させることが好ましい。
[工程J]
化合物(I)のRが保護基である場合、それ自体公知またはそれに準じた方法で保護基を除去し、化合物(I’)を得ることができる。例えば、Rがトリチル基の場合、酸性条件下での処理、または水素化分解によりトリチル基を除去することができる。該酸としては、ぎ酸、酢酸等の有機酸、塩酸等の無機酸などが使用される。反応にはアルコール類、THF等のエーテル類など、反応に不活性な溶媒を用いて行うこともできる。反応温度は通常 0℃〜100℃である。
上記反応によって、目的物が遊離の状態で得られる場合には、常法に従って塩に変換してもよく、また塩として得られる場合には、常法に従って遊離体または他の塩に変換することもできる。かくして得られる化合物(I)および(I’)は、公知の手段例えば転溶、濃縮、溶媒抽出、分溜、結晶化、再結晶、クロマトグラフィーなどにより反応溶液から単離、精製することができる。
また、上記各反応において、反応に供される化合物またはその塩において、反応に関与しないアミノ基、カルボキシル基、ヒドロキシ基に対して、保護基を用いてもよく、保護基の付加、除去は公知の手段により行うことができる。
【0015】
アミノ基の保護基としては、例えば、ホルミル、それぞれ置換基を有していてもよい、C1-6アルキルカルボニル(例えば、アセチル、プロピオニルなど)、フェニルカルボニル、C1-6アルキル−オキシカルボニル(例えば、メトキシカルボニル、エトキシカルボニルなど)、フェニルオキシカルボニル、C7-10アラルキルオキシ−カルボニル(例えば、ベンジルオキシカルボニルなどのフェニル−C1-4アルキルオキシ−カルボニルなど)、トリチル、フタロイルまたはN,N−ジメチルアミノメチレンなどが用いられる。これらの置換基としては、ハロゲン原子(例えば、フッ素、塩素、臭素、ヨウ素など)、ホルミル、C1-6アルキル−カルボニル(例えば、アセチル、プロピオニル、バレリルなど)、ニトロ基などが用いられ、置換基の数は1ないし3個程度である。
カルボキシル基の保護基としては、例えば置換基を有していてもよい、C1-6アルキル(例えば、メチル、エチル、プロピル、イソプロピル、ブチル、tert−ブチルなど)、フェニル、トリチルまたはシリルなどが用いられる。これらの置換基としては、ハロゲン原子(例えば、フッ素、塩素など)、ホルミル、C1-6アルキル−カルボニル(例えば、アセチル、プロピオニル、バレリルなど)、ニトロ基などが用いられ、置換基の数は1ないし3個程度である。
ヒドロキシ基の保護基としては、例えば置換基を有していてもよい、C1-6アルキル(例えば、メチル、エチル、プロピル、イソプロピル、ブチル、tert−ブチルなど)、フェニル、C7-10アラルキル(例えば、ベンジルなどのフェニル−C1-4アルキルなど)、ホルミル、C1-6アルキル−カルボニル(例えば、アセチル、プロピオニルなど)、フェニルオキシカルボニル、ベンゾイル、(C7-10アラルキルオキシ)カルボニル(例えば、ベンジルオキシカルボニルなどのフェニル−C1-4アルキルオキシ−カルボニルなど)、ピラニル、フラニルまたはシリルなどが用いられる。これらの置換基としては、ハロゲン原子(例えば、フッ素、塩素など)、C1-6アルキル(例えば、メチル、エチル、プロピルなど)、フェニル、C7-10アラルキル(例えば、ベンジルなどのフェニル−C1-4アルキルなど)、ニトロ基などが用いられ、置換基の数は1ないし4個程度である。
また、保護基の除去方法としては、それ自体公知またはそれに準じた方法が用いられるが、例えば酸、塩基、還元、紫外光、ヒドラジン、フェニルヒドラジン、N−メチルジチオカルバミン酸ナトリウム、テトラブチルアンモニウムフルオリド、酢酸パラジウムなどで処理する方法が用いられる。
化合物(I)は医薬として優れた作用を有しており、特にステロイドC17,20リアーゼに対し優れた阻害活性を有する。化合物(I)は毒性が低く、副作用も少ないので、哺乳動物(例えば、ヒト、ウシ、ウマ、ブタ、イヌ、ネコ、サル、マウス、ラットなど、特にヒト)に対して、例えば(i)アンドロゲンあるいはエストロゲン低下薬、(ii)アンドロゲンあるいはエストロゲンに関連する疾病、例えば(1)悪性腫瘍(例えば、前立腺癌、乳癌、子宮癌、卵巣癌など)の原発癌、およびこれらの転移、再発、(2)それらの癌に伴う諸症状(例えば、痛み、悪液質など)、(3)前立腺肥大症、男性化症、多毛症、男性型禿頭症、男児性早熟症、子宮内膜症、子宮筋腫、子宮腺筋症、乳腺症、多曩胞性卵巣症候群などのような各種疾病の治療および予防薬として有用である。
【0016】
化合物(I)は、単剤で使用しても優れた効果を示すが、さらに他の医薬製剤および療法と併用することによって、その効果をより一層増強させることができる。併用剤および療法としては、たとえば性ホルモン剤、アルキル化剤、代謝拮抗剤、抗癌性抗生物質、植物アルカロイド、免疫療法剤などが挙げられるが、これらに限定されるものではない。
ホルモン系薬剤として、例えば、ホスフェストロール、ジエチルスチルベストロール、クロロトリアニセリン、酢酸メドロキシプロゲステロン、酢酸メゲストロール、酢酸クロルマジノン、酢酸シプロテロン、ダナゾール、アリルエストレノール、ゲストリノン、メパルトリシン、ラロキシフェン、オルメロキフェン、レボルメロキシフェン、抗エストロゲン剤(例えば、クエン酸タモキシフェン、クエン酸トレミフェンなど)、ピル製剤、メピチオスタン、テストラクトン、アミノグルテチイミド、LH−RHアゴニスト(例えば、酢酸ゴセレリン、ブセレリン、リュープロレリンなど)、LH−RHアンタゴニスト(例えば、ガニレリクス、セトロレリクス、アバレリクスなど)、ドロロキシフェン、エピチオスタノール、スルホン酸エチニルエストラジオール、アロマターゼ阻害薬(例えば、塩酸ファドロゾール、アナストロゾール、レトロゾール、エキセメスタン、ボロゾール、フォルメスタンなど)、抗アンドロゲン薬(例えば、フルタミド、ビカルタミド、ニルタミドなど)、5α−レダクターゼ阻害薬(例えば、フィナステリド、エプリステリドなど)、副腎皮質ホルモン系薬剤(例えば、コルチゾール、デキサメタゾン、プレドニゾロン、ベタメタゾン、トリアムシノロンなど)、アンドロゲン合成阻害薬(例えば、アビラテロンなど)、レチノイドおよびレチノイドの代謝を遅らせる薬剤(例えば、リアロゾールなど)などが挙げられる。
アルキル化剤として、例えば、ナイトロジェンマスタード、塩酸ナイトロジェンマスタード−N−オキシド、クロラムブチル、シクロフォスファミド、イホスファミド、チオテパ、カルボコン、トシル酸インプロスルファン、ブスルファン、塩酸ニムスチン、ミトブロニトール、メルファラン、ダカルバジン、ラニムスチン、リン酸エストラムスチンナトリウム、トリエチレンメラミン、カルムスチン、ロムスチン、ストレプトゾシン、ピポブロマン、エトグルシド、カルボプラチン、シスプラチン、ミボプラチン、ネダプラチン、オキサリプラチン、アルトレタミン、アンバムスチン、塩酸ジブロスピジウム、フォテムスチン、プレドニムスチン、プミテパ、リボムスチン、テモゾロミド、トレオスルファン、トロフォスファミド、ジノスタチンスチマラマー、アドゼレシン、システムスチン、ビゼレシンなどが挙げられる。
【0017】
代謝拮抗剤として、例えば、メルカプトプリン、6−メルカプトプリンリボシド、チオイノシン、メトトレキサート、エノシタビン、シタラビン、シタラビンオクフォスファート、塩酸アンシタビン、5−FU系薬剤(例えば、フルオロウラシル、テガフール、UFT、ドキシフルリジン、カルモフール、ガロシタビン、エミテフールなど)、アミノプテリン、ロイコボリンカルシウム、タブロイド、ブトシン、フォリネイトカルシウム、レボフォリネイトカルシウム、クラドリビン、フルダラビン、ゲムシタビン、ヒドロキシカルバミド、ペントスタチン、ピリトレキシム、イドキシウリジン、ミトグアゾン、チアゾフリンなどが挙げられる。
抗癌性抗生物質として、例えば、アクチノマイシンD、アクチノマイシンC、マイトマイシンC、クロモマイシンA3、塩酸ブレオマイシン、硫酸ブレオマイシン、硫酸ペプロマイシン、塩酸ダウノルビシン、塩酸ドキソルビシン、塩酸アクラルビシン、塩酸ピラルビシン、塩酸エピルビシン、ネオカルチノスタチン、ミスラマイシン、ザルコマイシン、カルチノフィリン、ミトタン、塩酸ゾルビシン、塩酸ミトキサントロン、塩酸イダルビシン、などが挙げられる。
植物アルカロイドとして、例えば、エトポシド、リン酸エトポシド、硫酸ビンブラスチン、硫酸ビンクリスチン、硫酸ビンデシン、テニポシド、パクリタキセル、ビノレルビンなどが挙げられる。
免疫療法剤(BRM)として、例えば、ピシバニール、クレスチン、シゾフィラン、レンチナン、ウベニメクス、インターフェロン、インターロイキン、マクロファージコロニー刺激因子、顆粒球コロニー刺激因子、エリスロポイエチン、リンホトキシン、BCGワクチン、コリネバクテリウムパルブム、レバミゾール、ポリサッカライドK、プロコダゾールなどが挙げられる。
その他、L−アスパラギナーゼ、アセグラトン、塩酸プロカルバジン、プロトポルフィリン・コバルト錯塩、水銀ヘマトポルフィリン・ナトリウム、トポイソメラーゼI阻害薬(例えば、イリノテカン、トポテカンなど)、トポイソメラーゼII阻害薬(例えば、ソブゾキサンなど)、分化誘導剤(例えば、レチノイド、ビタミンD類など)、増殖因子阻害薬(例えば、スラミンなど)、抗体(例えば、ハーセプチンなど)、血管新生阻害薬、α−ブロッカー(例えば、塩酸タムスロシンなど)、チロシンキナーゼ阻害薬なども用いることができる。
また化合物(I)を投与する化学療法とともに、たとえば除睾術を含む手術、温熱療法、放射線療法など化学療法以外の療法を併用することもできる。
特に、本発明の化合物はLHRH調節薬(LHRHモジュレーター)例えばLHRHアゴニスト(例えば、酢酸ゴセレリン、ブセレリン、リュープロレリンなど)あるいはLHRHアンタゴニスト(例えば、ガニレリクス、セトロレリクス、アバレリクスなど)と併用することにより、より効果的に血中のアンドロゲンあるいはエストロゲンを除去することができる。
このように、本発明の化合物はステロイドC17,20リアーゼに対する選択性が高く、CYP3A4等の薬物代謝酵素に影響を与えることなくアンドロゲン濃度を低下させる作用を有する。
【0018】
医薬的に許容される担体としては、製剤素材として慣用の各種有機あるいは無機担体物質が用いられ、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤、増粘剤;液状製剤における溶剤、分散剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤などとして適宜適量配合される。また必要に応じて、常法にしたがって防腐剤、抗酸化剤、着色剤、甘味剤などの添加物を用いることもできる。賦形剤の好適な例としては、例えば乳糖、白糖、D−マンニトール、デンプン、結晶セルロース、軽質無水ケイ酸などが挙げられる。滑沢剤の好適な例としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカなどが挙げられる。結合剤の好適な例としては、例えば結晶セルロース、白糖、D−マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドンなどが挙げられる。崩壊剤の好適な例としては、例えばデンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウムなどが挙げられる。増粘剤の好適な例としては、例えば天然ガム類、セルロース誘導体、アクリル酸重合体などが挙げられる。溶剤の好適な例としては、例えば注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油などが挙げられる。分散剤の好適な例としては、例えば、ツイーン(Tween)80,HCO 60,ポリエチレングリコール、カルボキシメチルセルロース、アルギン酸ナトリウムなどが挙げられる。溶解補助剤の好適な例としては、例えばポリエチレングリコール、プロピレングリコール、D−マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウムなどが挙げられる。懸濁化剤の好適な例としては、例えばステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸クセリセリン、などの界面活性剤;例えばポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロースなどの親水性高分子などが挙げられる。等張化剤の好適な例としては、例えば塩化ナトリウム、グリセリン、D−マンニトールなどが挙げられる。
緩衝剤の好適な例としては、例えばリン酸塩、酢酸塩、炭酸塩、クエン酸塩などの緩衝液などが挙げられる。無痛化剤の好適な例としては、例えばベンジルアルコールなどが挙げられる。防腐剤の好適な例としては、例えばパラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸などが挙げられる。抗酸化剤の好適な例としては、例えば亜硫酸塩、アスコルビン酸などが挙げられる。
本発明の医薬組成物および製剤は、常法に従って製造することができ、製剤中の化合物(I)の含有割合は通常0.1〜100%(w/w)である。具体例を以下に示す。
(1)錠剤、散剤、顆粒剤、カプセル剤:
化合物(I)に、例えば賦形剤、崩壊剤、結合剤または滑沢剤などを添加して圧縮成型し、次いで必要により、味のマスキング、腸溶性あるいは持続性を目的とするコーティングを行うことにより製造することができる。
【0019】
(2)注射剤:
化合物(I)を、例えば分散剤、保存剤、等張化剤などと共に水性注射剤として、あるいはオリーブ油、ゴマ油、綿実油、コーン油等の植物油、プロピレングリコール等に溶解、懸濁あるいは乳化して油性注射剤として成型することにより製造することができる。
(3)座剤:
化合物(I)を油性または水性の固状、半固状あるいは液状の組成物とすることにより製造される。このような組成物に用いる油性基剤としては、例えば、高級脂肪酸のグリセリド(例えば、カカオ脂、ウイテプゾル類など)、中級脂肪酸(例えば、ミグリオール類など)、あるいは植物油(例えば、ゴマ油、大豆油、綿実油など)などが挙げられる。水性ゲル基剤としては、例えば天然ガム類、セルロース誘導体、ビニール重合体、アクリル酸重合体などが挙げられる。
これらの製剤における化合物(I)の配合割合は、製剤の種類により異なるが、通常0.01〜50%配合される。
前記医薬製剤における本発明の化合物の使用量は、選択される化合物、投与対象に選ばれる動物種、その投与回数などにより変化するが、広範囲にわたって有効性を発揮する。例えば、成人の固形腫瘍患者(例えば、前立腺癌患者)に対して、本発明の医薬製剤を経口投与する場合の一日当たりの投与量は、本発明の化合物(I)の有効量として、通常、約0.001ないし約500mg/kg体重、好ましくは、約0.05ないし約40mg/kg体重、さらに好ましくは、約0.1ないし約10mg/kg体重であるが、非経口投与の場合や他の抗癌剤と併用される場合は、一般にこれらの投与量より少ない値になる。しかし、実際に投与される化合物の量は、化合物の選択、各種製剤形態、患者の年齢、体重、性別、疾患の程度、投与経路、その投与を実施する期間および間隔などの状況によって決定されるものであり、医師の判断によって随時変更が可能である。
前記医薬製剤の投与経路は、種々の状況により特に制限されないが、例えば経口あるいは非経口経路で投与することができる。ここで使用される「非経口」には、静脈内、筋肉内、皮下、鼻腔内、皮内、点眼、脳内、直腸内、腟内および腹腔内などへの投与を含む。
前記医薬製剤の投与期間および間隔は、種々の状況に応じて変更されるものであり、医師の判断により随時判断されるものであるが、分割投与、連日投与、間歇投与、短期大量投与、反復投与などの方法がある。例えば、経口投与の場合は、1日1ないし数回(特に1日2ないし3回)に分割して投与することが望ましい。また、徐放性の製剤として投与することや長時間かけて点滴静注することも可能である。
【0020】
【発明の実施の形態】
本発明はさらに下記の実施例、製剤例、試験例で詳しく説明されるが、これらの例は単なる実施であって本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。実施例中の略号は次の意味を有する。
s:シングレット,d:ダブレット,t:トリプレット,q:クワルテット,dd:ダブルダブレット,dt:ダブルトリプレット,m:マルチプレット,br:幅広い,J:カップリング定数,室温:0〜30℃,DMF:ジメチルホルムアミド,THF:テトラヒドロフラン。
【実施例】
参考例1
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸の製造
p−ジブロモベンゼン(66.0 g)のTHF(700 ml)溶液に-78℃でn−ブチルリチウムへキサン溶液(1.6M;180ml)を滴下し、同温度で15分間攪拌した。2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノン(85.0 g)のTHF(250ml)溶液を滴下し、さらに15分攪拌した。本反応液に-78℃でn−ブチルリチウムへキサン溶液(1.6M;270ml)を滴下し、同温度で15分間攪拌した後、ほう酸トリメチル(196 ml)を加えた。反応液を室温で2時間攪拌し、塩化アンモニウム水溶液を加えて室温で12時間攪拌した。有機層を分離し、1N 水酸化ナトリウムと食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を留去し、表題化合物の粗生成物(126 g)をアモルファス粉末として得た。本品は精製することなく反応に用いた。
実施例1
1-(1H-イミダゾール-4-イル)-1-(4’-メトキシ-[1,1’-ビフェニル] -4-イル)-2-メチル-1-プロパノールの製造
(i) 4-ブロモ-4'-メトキシ-1,1'-ビフェニルの製造
アルゴン雰囲気下p−ジブロモベンゼン(9.99 g)および4−メトキシフェニルボロン酸(2.03 g)およびテトラキストリフェニルホスフィンパラジウム(497 mg)をジメトキシエタン(20 ml)に溶解し、2M炭酸ナトリウム水溶液(20 ml)を加えて14時間加熱還流した。反応液を室温まで冷却した後、析出した結晶をろ別した。得られた結晶を酢酸エチルに溶解後、不溶物をろ過し、溶媒を留去した。得られた固体をヘキサンで洗浄して無色固体の表題化合物(2.09 g)を得た。
1H-NMR (CDCl3)δ: 3.84 (3H, s), 6.97 (2H, d, J=8.8 Hz), 7.37-7.56 (6H, m).
IR (KBr) : 1483, 1291, 1258, 1038, 812 cm-1.
(ii) 1-(1H-イミダゾール-4-イル)-1-(4’-メトキシ-[1,1’-ビフェニル] -4-イル)-2-メチル-1-プロパノールの製造
4-ブロモ-4'-メトキシ-1,1'-ビフェニル(1.95 g)をTHF(40 ml)に溶解し-78 ℃に冷却した。 n-ブチルリチウムのヘキサン溶液(1.6 M ; 5.5 ml)を滴下し、-78 ℃で1時間撹拌した後、1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノン(335 mg)のTHF溶液(10 ml)をゆっくり滴下した。-78 ℃から室温まで昇温した後、反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を乾燥後濃縮し、得られた残さを酢酸エチルから再結晶して無色固体の表題化合物 (322 mg)を得た。
1H-NMR (CDCl3+CD3OD)δ: 0.83 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz), 2.52-2.76 (1H, m), 3.85 (3H, s), 6.92-7.02 (3H, m), 7.38-7.62 (7H, m).
IR (KBr) : 3218, 1497, 1252, 1038, 1007, 816 cm-1.
【0021】
実施例2
1-[1,1'-ビフェニル]-4-yl-1-(1H-イミダゾール-4-yl)-2-メチル-1-プロパノールの製造
4-ブロモ-1,1'-ビフェニル(5.17 g)を用いて、実施例1-(ii)と同様の反応を行い、無色固体の表題化合物(1.76 g)を得た。
1H-NMR (CDCl3+CD3OD)δ: 0.83 (3H, d, J=6.8 Hz), 0.99 (3H, d, J=6.8Hz), 2.57-2.74 (1H, m), 6.98 (1H, d, J=1.2 Hz), 7.30-7.47 (3H, m), 7.50-7.65 (7H, m).
IR (KBr) : 3142, 2965, 1487, 826, 762 cm-1.
実施例3
1-(1H-イミダゾール-4-yl)-1-(2'-メトキシ[1,1'-ビフェニル]-4-yl)-2-メチル-1-プロパノールの製造
(i) 4-ブロモ-2'-メトキシ-1,1'-ビフェニルの製造
2-メトキシフェニルボロン酸(3.15 g)を用いて、実施例1-(i)と同様の反応を行い、無色固体の表題化合物(4.77 g)を得た。
1H-NMR (CDCl3)δ: 3.81 (3H, s), 6.92-7.08 (2H, m), 7.21-7.44 (4H, m), 7.45-7.60 (2H, m).
IR (KBr) : 1478, 1256, 1003, 754 cm-1.
(ii) 1-(1H-イミダゾール-4-イル)-1-(2'-メトキシ[1,1'-ビフェニル]-4-イル)-2-メチル-1-プロパノールの製造
4-ブロモ-2'-メトキシ-1,1'-ビフェニル(1.58 g)を用いて、実施例1-(ii)と同様の反応を行い、無色固体の表題化合物(225 mg)を得た。
1H-NMR (CDCl3)δ: 0.85 (3H, d, J=7.0 Hz), 0.98 (3H, d, J=7.0 Hz), 2.52-2.72 (1H, m), 3.79 (3H, s), 6.92-7.06 (3H, m), 7.26-7.36 (2H, m), 7.42-7.62 (5H, m).
IR (KBr) : 3073, 2967, 1487, 1260, 1238, 1005, 752 cm-1.
【0022】
実施例4
1-(4’-フルオロ[1,1’-ビフェニル]-4-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 1-(4-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
p-ジブロモベンゼン (20.0 g)のジエチルエーテル-THF (4 : 1) (210 ml) 溶液に-78 ℃でn-ブチルリチウムのヘキサン溶液 (1.6 M; 34.6 ml)をゆっくりと滴下し、-78 ℃で40 分間、-78〜-30 ℃で15分間攪拌後、2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパン (14.0 g)のTHF (80 ml)溶液をゆっくりと滴下し、-78〜-50 ℃で40分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去後、残渣を酢酸エチル-ヘキサンより再結晶し、表題化合物 (16.2 g)を無色針状結晶として得た。
1H-NMR (CDCl3) δ: 0.71 (3H, d, J = 6.6 Hz), 0.89 (3H, d, J = 6.6 Hz), 2.30-2.44 (1H, m), 3.50 (1H, s), 6.72 (1H, d, J = 1.2 Hz), 7.09-7.16 (6H, m), 7.30-7.38 (14H, m)
IR (KBr): 1489, 1445, 1159, 1009, 909, 812, 747, 735, 702, 660 cm-1
(ii) 1-(4’-フルオロ[1,1’-ビフェニル]-4-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(4-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (3.60 g)、4-フルオロフェニルボロン酸 (1.50 g)、2 M炭酸ナトリウム水溶液 (26.8 ml)のジメトキシエタン (50 ml)懸濁液に、テトラキス(トリフェニルホスフィン)パラジウム (0) (387 mg)を加え、アルゴン雰囲気下、12時間加熱還流した。反応液を酢酸エチル-THF (8 : 3)で抽出し、水、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー (溶出液、ヘキサン : 酢酸エチル = 6 : 1→4 : 1)で精製し、表題化合物 (3.16 g)を無色針状結晶として得た。
1H-NMR (CDCl3) δ: 0.77 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.42-2.49 (1H, m), 3.53 (1H, s), 6.78 (1H, s), 7.06-7.15 (7H, m), 7.33-7.57 (17H, m)
IR (KBr): 1493, 1445, 1223, 1159, 818, 748, 733, 702 cm-1
(iii) 1-(4’-フルオロ[1,1’-ビフェニル]-4-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(4’-フルオロ[1,1’-ビフェニル]-4-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (3.12 g)、ピリジン塩酸塩 (1.11 g)のメタノール溶液 (75 ml)を60 ℃で3.5時間攪拌した。反応液の溶媒を減圧留去後、酢酸エチルで希釈し、飽和重曹水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去後、残渣をカラムクロマトグラフィー (溶出液、ヘキサン : 酢酸エチル = 2 : 1→1 : 5)で精製し、酢酸エチル-ヘキサンより再結晶し、表題化合物 (1.34 g)を無色針状晶として得た。
1H-NMR (CDCl3) δ: 0.85 (3H, d, J = 7.0 Hz), 1.00 (3H, d, J = 7.0 Hz), 2.60-2.74 (1H, m), 3.42 (1H, br s), 7.02-7.16 (3H, m), 7.48-7.66 (7H, m), 9.16 (1H, br s)
IR (KBr): 3241, 1493, 1397, 1242, 1009, 814, 781, 762, 623, 511 cm-1
【0023】
実施例5
1-(4’-クロロ[1,1’-ビフェニル]-4-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 1-(4’-クロロ[1,1’-ビフェニル]-4-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(4-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (3.60 g)、4-クロロフェニルボロン酸 (1.68 g)、2 M炭酸ナトリウム水溶液 (26.8 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (387 mg)を用いて、実施例4-(ii)と同様の反応を行い、表題化合物 (3.04 g)を無色針状結晶として得た。
1H-NMR (CDCl3) δ: 0.76 (3H, d, J = 7.0 Hz), 0.92 (3H, d, J = 7.0 Hz), 2.42-2.49 (1H, m), 3.53 (1H, s), 6.78 (1H, s), 7.13-7.15 (6H, m), 7.32-7.59 (18H, m)
IR (KBr): 1485, 1445, 1094, 1005, 909, 812, 747, 733, 700 cm-1
(ii) 1-(4’-クロロ[1,1’-ビフェニル]-4-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(4’-クロロ[1,1’-ビフェニル]-4-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (3.00 g)、ピリジン塩酸塩 (1.04 g)を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (1.18 g)を無色板状結晶として得た。
1H-NMR (CDCl3) δ: 0.83 (3H, d, J = 7.0 Hz), 0.98 (3H, d, J = 7.0 Hz), 2.58-2.75 (1H, m), 3.38 (1H, br s), 7.00 (1H, s), 7.37 (2H, d, J = 8.4 Hz), 7.48-7.64 (7H, m), 9.24 (1H, br s)
IR (KBr): 3200, 1485, 1364, 1190, 1094, 1028, 1005, 808, 781 cm-1
実施例6
1-[1,1'-ビフェニル]-3-イル-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
3-ブロモ-1,1'-ビフェニル(0.98 g)を用いて、実施例1-(ii)と同様の反応を行い、無色固体の表題化合物(0.25 g)を得た。
1H-NMR (CDCl3+CD3OD)δ: 0.83 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz), 2.55-2.73 (1H, m), 6.97 (1H, d, J=1.0 Hz), 7.28-7.50 (7H, m), 7.54-7.62 (2H, m), 7.72-7.77 (1H, m).
IR (KBr) : 3200, 1005, 799 cm-1.
【0024】
実施例7
1-(1H-イミダゾール-4-イル)-1-(2'-メトキシ[1,1'-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
(i) 3-ブロモ-2'-メトキシ-1,1'-ビフェニルの製造
2-メトキシフェニルボロン酸(2.90 g)を用いて、実施例1-(i)と同様の反応を行い、無色油状の表題化合物(4.38 g)を得た。
1H-NMR (CDCl3)δ: 3.81 (3H, s), 6.97 (1H, d, J=8.2 Hz), 7.02 (1H, dt, J=1.0, 7.4 Hz), 7.21-7.49 (5H, m), 7.68 (1H, t, J=1.8 Hz).
IR (KBr) : 1466, 1254, 1235, 1028 cm-1.
(ii) 1-(1H-イミダゾール-4-イル)-1-(2'-メトキシ[1,1'-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
3-ブロモ-2'-メトキシ-1,1'-ビフェニル(2.10 g)を用いて、実施例1-(ii)と同様の反応を行い、無色固体の表題化合物(0.44 g)を得た。
1H-NMR (CDCl3+CD3OD) δ: 0.85 (3H, d, J=6.8 Hz), 0.99 (3H, d, J=6.8 Hz), 2.40-2.80 (1H, m), 3.77 (3H, s), 6.93-7.07 (3H, m), 7.25-7.49 (6H, m), 7.63 (1H, s).
IR (KBr) : 2961, 1473, 1236, 1024 cm-1.
実施例8
1-(1H-イミダゾール-4-イル)-1-(3'-メトキシ[1,1'-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
(i) 3-ブロモ-3'-メトキシ-1,1'-ビフェニルの製造
3-メトキシフェニルボロン酸(3.04 g)を用いて、実施例1-(i)と同様の反応を行い、無色油状の表題化合物(3.10 g)を得た。
1H-NMR (CDCl3)δ: 3.85 (3H, s), 6.86-6.96 (1H, m), 7.04-7.17 (2H, m), 7.23-7.54 (4H, m), 7.70-7.75 (1H, m).
IR (KBr) : 1591, 1559, 1470, 1213 cm-1.
(ii) 1-(1H-イミダゾール-4-イル)-1-(3'-メトキシ[1,1'-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
3-ブロモ-3'-メトキシ-1,1'-ビフェニル(2.09 g)を用いて、実施例1-(ii)と同様の反応を行い、無色固体の表題化合物(0.24 g)を得た。
1H-NMR (CDCl3)δ: 0.83 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.7 Hz), 2.58-2.78 (1H, m), 3.86 (3H, s), 6.88 (1H, d, J=8.4 Hz), 7.00 (1H, s), 7.08-7.24 (2H, m), 7.24-7.60 (6H, m), 7.79 (1H, s).
IR (KBr) : 3202, 1472, 1044, 1005 cm-1.
【0025】
実施例9
1-(1H-イミダゾール-4-イル)-1-(4'-メトキシ[1,1'-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
(i) 3-ブロモ-4'-メトキシ-1,1'-ビフェニルの製造
4-メトキシフェニルボロン酸(3.08 g)を用いて、実施例1-(i)と同様の反応を行い、無色針状晶の表題化合物(3.84 g)を得た。
1H-NMR (CDCl3)δ: 3.85 (3H, s), 6.92-7.02 (2H, m), 7.22-7.32 (1H, m), 7.38-7.54 (4H, m), 7.69 (1H, t, J=1.9 Hz).
IR (KBr) : 1520, 1474, 1252, 837 cm-1.
(ii) 1-(1H-イミダゾール-4-イル)-1-(4'-メトキシ[1,1'-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
3-ブロモ-4'-メトキシ-1,1'-ビフェニル(2.01 g)を用いて、実施例1-(ii)と同様の反応を行い、無色固体の表題化合物(0.50 g)を得た。
1H-NMR (CDCl3)δ: 0.82 (3H, d, J=6.9 Hz), 0.98 (3H, d, J=6.9 Hz), 2.50-2.74 (1H, m), 3.83 (3H, s), 6.89-6.99 (3H, m), 7.26-7.55 (6H, m), 7.71-7.76 (1H, m).
IR (KBr) : 2969, 1516, 1480, 1248, 1181 cm-1.
実施例10
1-(1H-イミダゾール-4-イル)-1-(4-メトキシ[1,1'-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
(i) 4-メトキシ[1,1'-ビフェニル]-3-カルボアルデヒドの製造
5-ブロモ-o-アニスアルデヒド(8.00 g)を用いて、実施例1-(i)と同様の反応を行い、無色固体の表題化合物(3.75 g)を得た。
1H-NMR (CDCl3)δ: 3.98 (3H, s), 7.08 (1H, d, J=8.8 Hz), 7.28-7.48 (3H, m), 7.49-7.63 (2H, m), 7.80 (1H, dd, J=2.5, 8.8 Hz), 8.08 (1H, d, J=2.5 Hz), 10.52 (1H, s).
IR (KBr) : 1680, 1609, 1483, 1271 cm-1.
(ii) 1H-イミダゾール-4-イル(4-メトキシ[1,1'-ビフェニル]-3-イル)メタノールの製造4-ブロモ-1H-イミダゾール(5.20 g)をTHF(50 ml)に溶解した後、-78℃に冷却し、t-ブチルリチウムのペンタン溶液(1.7 M; 50ml)を加えた。0℃で1.5時間撹拌した後、再び-78℃に冷却し、4-メトキシ[1,1'-ビフェニル]-3-カルボアルデヒド(2.54 g)のTHF溶液(30 ml)を加えた。-78℃から室温まで昇温した後、さらに24時間室温で撹拌した。塩化アンモニウム水溶液を加え、酢酸エチルで抽出した後、有機層を乾燥後濃縮した。残留物をシリカゲルカラムクロマトグラフィー(溶出液、ジクロロメタン:メタノール=15:1)にて精製し、酢酸エチルから再結晶して、無色固体の表題化合物(1.15 g)を得た。
1H-NMR (CDCl3)δ: 3.84 (3H, s), 6.15 (1H, s), 6.70 (1H, s), 6.96 (1H, d, J=8.4 Hz), 7.23-7.44 (3H, m), 7.46-7.57 (4H, m), 7.69 (1H, d, J=2.2 Hz).
IR (KBr) : 3134, 1481, 1242, 1030 cm-1.
【0026】
(iii) (1H-イミダゾール-4-イル)(4-メトキシ[1,1'-ビフェニル]-3-イル)メタノンの製造
1H-イミダゾール-4-イル(4-メトキシ[1,1'-ビフェニル]-3-イル)メタノール(0.94 g)をジクロロメタン(100 ml)に溶解させ、二酸化マンガン(5.52 g)を加えて室温で14時間攪拌した。反応液を濾過後濃縮し、得られた残さに酢酸エチルを加えて結晶化を行い、無色固体の表題化合物(0.84 g)を得た。
1H-NMR (CDCl3+CD3OD)δ: 3.87 (3H, s), 7.11 (1H, d, J=8.4 Hz), 7.28-7.49 (3H, m), 7.51-7.60 (3H, m), 7.67-7.76 (2H, m), 7.83 (1H, m).
IR (KBr) : 3000, 1636, 1483, 1273 cm-1.
(vi) 1-(1H-イミダゾール-4-イル)-1-(4-メトキシ[1,1'-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
1H-イミダゾール-4-イル(4-メトキシ[1,1'-ビフェニル]-3-イル)メタノン(0.62 g)をTHF(15 ml)に溶解させ-40 ℃に冷却した。イソプロピルマグネシウムクロリドのTHF溶液(0.6 M ; 15 ml)をゆっくりと滴下した後、室温まで昇温し1時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、水で希釈した後、酢酸エチルで抽出した。抽出液を乾燥後濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出液、ジクロロメタン:メタノール=40:1)に付して精製し、無色アモルファスの表題化合物(0.16 g)を得た。
1H-NMR (CDCl3)δ: 0.92 (3H, d, J=6.6 Hz), 0.95 (3H, d, J=6.6 Hz), 2.70-2.95 (1H, m), 3.90 (3H, s), 6.97 (1H, d, J=8.6 Hz), 7.06 (1H, s), 7.24-7.56 (7H, m), 7.73 (1H, d, J=1.8 Hz).
IR (KBr) : 2967, 1481, 1242, 1024 cm-1.
実施例11
1-(1H-イミダゾール-4-イル)-1-(6-メトキシ[1,1'-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
(i) 6-メトキシ[1,1'-ビフェニル]-3-カルボアルデヒドの製造
3-ブロモ-p-アニスアルデヒド(7.98 g)を用いて、実施例1-(i)と同様の反応を行い、無色油状の表題化合物(7.78 g)を得た。
1H-NMR (CDCl3)δ: 3.90 (3H, s), 7.09 (1H, d, J=9.2 Hz), 7.30-7.56 (5H, m), 7.85 (1H, s), 7.87 (1H, dd, J=2.2, 7.8 Hz), 9.93 (1H, s).
IR (KBr) : 1694, 1595, 1265, 1175 cm-1.
(ii) (1H-イミダゾール-4-イル)(6-メトキシ[1,1'-ビフェニル]-3-イル)メタノールの製造
6-メトキシ[1,1'-ビフェニル]-3-カルボアルデヒド(3.10 g)を用いて、実施例10-(ii)と同様の反応を行い、無色固体の表題化合物(3.84 g)を得た。
1H-NMR (CDCl3+CD3OD) δ: 3.81 (3H, s), 5.81 (1H, s), 6.73 (1H, s), 6.97 (1H, d, J=8.8 Hz), 7.24-7.46 (5H, m), 7.46-7.58 (2H, m), 7.59 (1H, d, J=1.0 Hz).
IR (KBr) : 2996, 1487, 1175, 1022, 986 cm-1.
【0027】
(iii) (1H-イミダゾール-4-イル)(6-メトキシ[1,1'-ビフェニル]-3-イル)メタノンの製造
(1H-イミダゾール-4-イル)(6-メトキシ[1,1'-ビフェニル]-3-イル)メタノール(3.74 g)を用いて、実施例10-(iii)と同様の反応を行い、無色固体の表題化合物(2.64 g)を得た。
1H-NMR (CDCl3+CD3OD)δ: 3.92 (3H, s), 7.10 (1H, d, J=8.8 Hz), 7.35-7.60 (5H, m), 7.73 (1H, s), 7.83 (1H, s), 7.90-8.10 (2H, brs).
IR (KBr) : 3004, 1644, 1343, 1264 cm-1.
(vi) 1-(1H-イミダゾール-4-イル)-1-(6-メトキシ[1,1'-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
(1H-イミダゾール-4-イル)(6-メトキシ[1,1'-ビフェニル]-3-イル)メタノン(1.10 g)を用いて、実施例10-(iv)と同様の反応を行い、無色固体の表題化合物(0.48 g)を得た。
1H-NMR (CDCl3)δ: 0.84 (3H, d, J=6.8 Hz), 0.96 (3H, d, J=6.8 Hz), 2.45-2.70 (1H, m), 3.77 (3H, s), 6.86-6.96 (2H, m), 7.26-7.56 (8H, m).
IR (KBr) : 2969, 1505, 1487, 1264 cm-1.
実施例12
1-(4'-クロロ[1,1'-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 1-(3-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(1-トリチル-1H-イミダゾール-4-yl)-2-メチル-1-プロパノン(34.90 g)とO-ジブロモベンゼン(50.7 g)を用いて、実施例1-(ii)と同様の反応を行い、無色固体の表題化合物(37.7 g)を得た。
1H-NMR (CDCl3)δ: 0.72 (3H, d, J=6.8 Hz), 0.90 (3H, d, J=6.8 Hz), 2.22-2.44 (1H, m), 6.73 (1H, d, J=1.6 Hz), 7.06-7.19 (7H, m), 7.26-7.39 (11H, m), 7.46 (1H, dt, J=7.8, 1.3 Hz), 7.59 (1H, t, J=1.8 Hz).
IR (KBr) : 1493, 1472, 1445, 702 cm-1.
(ii) 1-(4'-クロロ[1,1'-ビフェニル]-3-イル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造4-クロロフェニルボロン酸(0.49 g)および1-(3-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(1.04 g)を用いて、実施例1-(i)と同様の反応を行い、無色固体の表題化合物(0.77 g)を得た。
1H-NMR (CDCl3)δ: 0.75 (3H, d, J=6.7 Hz), 0.94 (3H, d, J=6.7 Hz), 2.35-2.55 (1H, m), 6.78 (1H, d, J=1.4 Hz), 7.05-7.60 (23H, m), 7.65 (1H, s).
IR (KBr) : 1493, 1476, 1445, 909 cm-1.
【0028】
(iii) 1-(4'-クロロ[1,1'-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(4'-クロロ[1,1'-ビフェニル]-3-イル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(0.71 g)およびピリジン塩酸塩(0.25 g)をメタノール(20 ml)に溶解した後、60℃で2時間撹拌した。反応液に飽和重曹水を加えて濃縮した後、水および酢酸エチルを加えて酢酸エチルで抽出した。有機層を乾燥後濃縮し、得られた残さをシリカゲルカラムクロマトグラフィー(溶出液、ジクロロメタン:メタノール=40:1)にて精製し、ヘキサン-酢酸エチルから再結晶して、無色固体の表題化合物(0.31 g)を得た。
1H-NMR (CDCl3)δ: 0.82 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz), 2.50-2.78 (1H, m), 6.99 (1H, d, J=1.0 Hz), 7.33-7.44 (4H, m), 7.45-7.56 (4H, m), 7.78 (1H, s).
IR (KBr) : 2969, 1476, 1092, 1013 cm-1.
実施例13
1-(4'-フルオロ[1,1'-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 1-(4'-フルオロ[1,1'-ビフェニル]-3-イル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
4-フルオロフェニルボロン酸(0.41g)および1-(3-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(1.01 g)を用いて、実施例1-(i)と同様の反応を行い、淡黄色固体の表題化合物(0.71 g)を得た。
1H-NMR (CDCl3)δ: 0.75 (3H, d, J=6.8 Hz), 0.93 (3H, d, J=6.8 Hz), 2.35-2.52 (1H, m), 6.78 (1H, d, J=1.0 Hz), 7.04-7.18 (8H, m), 7.22-7.38 (12H, m), 7.44-7.55 (3H, m), 7.63 (1H, s).
IR (KBr) : 1512, 1480, 1233, 1159 cm-1.
(ii) 1-(4'-フルオロ[1,1'-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(4'-フルオロ[1,1'-ビフェニル]-3-イル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(0.62 g)を用いて、実施例4-(iii)と同様の反応を行い、無色固体の表題化合物(0.27 g)を得た。
1H-NMR (CDCl3+CD3OD)δ: 0.82 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz), 2.40-2.80 (1H, m), 6.70-7.16 (3H, m), 7.30-7.59 (6H, m), 7.72 (1H, s).
IR (KBr) : 3187, 1514, 1236, 1005, 795 cm-1.
【0029】
実施例14
1-(2',4'-ジクロロ[1,1'-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 1-(2',4'-ジクロロ[1,1'-ビフェニル]-3-イル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
2,4-ジクロロフェニルボロン酸(0.55 g)および1-(3-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(1.00 g)を用いて、実施例1-(i)と同様の反応を行い、アモルファスの表題化合物(0.85 g)を得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J=6.8 Hz), 0.92 (3H, d, J=6.8 Hz), 2.30-2.52 (1H, m), 6.74 (1H, d, J=1.4 Hz), 7.04-7.50 (16H, m), 7.57 (1H, dt, J=7.8, 1.5 Hz).
IR (KBr) : 1493, 1464, 1445, 1165 cm-1.
(ii) 1-(2',4'-ジクロロ[1,1'-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(2',4'-ジクロロ[1,1'-ビフェニル]-3-イル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(0.80 g)を用いて、実施例12-(iii)と同様の反応を行い、アモルファスの表題化合物(0.30 g)を得た。
1H-NMR (CDCl3)δ: 0.81 (3H, d, J=6.7 Hz), 0.97 (3H, d, J=6.7 Hz), 2.45-2.70 (1H, m), 6.94 (1H, s), 7.12-7.60 (8H, m).
IR (KBr) : 2969, 1466, 1103 cm-1.
実施例15
1-[2'-(ジメトキシメチル)[1,1'-ビフェニル]-3-イル]-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 3'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-2-カルボアルデヒドの製造
2-ホルミルフェニルボロン酸(0.50 g)および1-(3-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(1.02 g)を用いて、実施例1-(i)と同様の反応を行い、アモルファスの表題化合物(0.93 g)を得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J=6.7 Hz), 0.93 (3H, d, J=6.7 Hz), 2.30-2.55 (1H, m), 6.73 (1H, d, J=1.4 Hz), 7.05-7.69 (23H, m), 8.03 (1H, dd, J=1.4, 7.8 Hz), 9.92 (1H, d, J=0.8 Hz).
IR (KBr) : 1692, 1597, 1493, 1447 cm-1.
(ii) 1-[2'-(ジメトキシメチル)[1,1'-ビフェニル]-3-イル]-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
3'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-2-カルボアルデヒド(0.89 g)を用いて、実施例12-(iii)と同様の反応を行い、アモルファスの表題化合物(0.28 g)を得た。
1H-NMR (CDCl3)δ: 0.82 (3H, d, J=6.7 Hz), 0.97 (3H, d, J=6.7 Hz), 2.45-2.70 (1H, m), 3.10-3.40 (6H, m), 5.13 (1H, s), 6.93 (1H, m), 7.10-7.75 (9H, m).
IR (KBr) : 2969, 1472, 1092, 1073 cm-1.
【0030】
実施例16
1-[3'-(ジメトキシメチル)[1,1'-ビフェニル]-3-イル]-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 3'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-カルボアルデヒドの製造
3-ホルミルフェニルボロン酸(0.45 g)および1-(3-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(1.05 g)を用いて、実施例1-(i)と同様の反応を行い、アモルファスの表題化合物(0.80 g)を得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J=6.8 Hz), 0.95 (3H, d, J=6.8 Hz), 2.35-2.58 (1H, m), 6.79 (1H, d, J=1.6 Hz), 7.07-7.64 (20H, m), 7.74-7.90 (3H, m), 8.06 (1H, t, J=1.7 Hz), 10.07 (1H, s).
IR (KBr) : 1698, 1445, 1163 cm-1.
(ii) 1-[3'-(ジメトキシメチル)[1,1'-ビフェニル]-3-イル]-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
3'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-カルボアルデヒド(0.70 g)を用いて、実施例12-(iii)と同様の反応を行い、無色固体の表題化合物(0.27 g)を得た。
1H-NMR (CDCl3)δ: 0.83 (3H, d, J=6.7 Hz), 0.99 (3H, d, J=6.7 Hz), 2.50-2.77 (1H, m), 3.37 (6H, m), 5.42 (1H, s), 6.93-7.01 (1H, m), 7.28-7.60 (7H, m), 7.66 (1H, s), 7.81 (1H, d, J=1.6 Hz).
IR (KBr) : 2967, 1198, 1107, 1055 cm-1.
実施例17
1-(1H-イミダゾール-4-イル)-2-メチル-1-(2'-メチル[1,1'-ビフェニル]-3-イル)-1-プロパノールの製造
(i) 2-メチル-1-(2'-メチル[1,1'-ビフェニル]-3-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
o-トリルボロン酸(0.69 g)および1-(3-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(1.01 g)を用いて、実施例1-(i)と同様の反応を行い、アモルファスの表題化合物(0.61 g)を得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J=6.7 Hz), 0.92 (3H, d, J=6.7 Hz), 2.18 (3H, s), 2.30-2.55 (1H, m), 6.73 (1H, d, J=1.4 Hz), 7.05-7.39 (23H, m), 7.54 (1H, dt, J=7.8, 1.2 Hz).
IR (KBr) : 1493, 1474, 1445, 1161 cm-1.
(ii) 1-(1H-イミダゾール-4-イル)-2-メチル-1-(2'-メチル[1,1'-ビフェニル]-3-イル)-1-プロパノールの製造
2-メチル-1-(2'-メチル[1,1'-ビフェニル]-3-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(0.55 g)を用いて、実施例12-(iii)と同様の反応を行い、アモルファスの表題化合物(0.20 g)を得た。
1H-NMR (CDCl3)δ: 0.81 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz), 2.19 (3H, s), 2.48-2.70 (1H, m), 6.85-6.97 (1H, m), 7.10-7.54 (9H, m).
IR (KBr) : 2970, 1474, 909 cm-1.
【0031】
実施例18
1-(1H-イミダゾール-4-イル)-2-メチル-1-(4'-メチル[1,1'-ビフェニル]-3-イル)-1-プロパノールの製造
(i) 2-メチル-1-(4'-メチル[1,1'-ビフェニル]-3-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
p-トリルボロン酸(0.45 g)および1-(3-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(1.03 g)を用いて、実施例1-(i)と同様の反応を行い、無色固体の表題化合物(0.76 g)を得た。
1H-NMR (CDCl3)δ: 0.75 (3H, d, J=6.7 Hz), 0.93 (3H, d, J=6.7 Hz), 2.35-2.55 (1H, m), 2.40 (3H, s), 6.79 (1H, d, J=1.4 Hz), 7.06-7.54 (23H, m), 7.66 (1H, t, J=1.6 Hz).
IR (KBr) : 1493, 1480, 1445, 1163 cm-1.
(ii) 1-(1H-イミダゾール-4-イル)-2-メチル-1-(4'-メチル[1,1'-ビフェニル]-3-イル)-1-プロパノールの製造
2-メチル-1-(4'-メチル[1,1'-ビフェニル]-3-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(0.61 g)を用いて、実施例12-(iii)と同様の反応を行い、無色固体の表題化合物(0.23 g)を得た。
1H-NMR (CDCl3)δ: 0.82 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.7 Hz), 2.38 (3H, s), 2.55-2.75 (1H, m), 6.98 (1H, s), 7.16-7.54 (8H, m), 7.77 (1H, t, J=1.6 Hz).
IR (KBr) : 2969, 1480, 791, 735 cm-1.
実施例19
1-(2’,4’-ジフルオロ[1,1’-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 1-(2’,4’-ジフルオロ[1,1’-ビフェニル]-3-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(3-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (6.00 g)、2,4-ジフルオロフェニルボロン酸 (2.82 g)、2 M炭酸ナトリウム水溶液 (45 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (647 mg)を用いて、実施例4-(ii)と同様の反応を行い、表題化合物 (6.39 g)を黄色アモルファスとして得た。
1H-NMR (CDCl3) δ: 0.76 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.8 Hz), 2.35-2.49 (1H, m), 3.68 (1H, s), 6.76 (1H, d, J = 1.4 Hz), 6.83-6.97 (2H, m), 7.09-7.16 (6H, m), 7.26-7.35 (13H, m), 7.36-7.57 (2H, m)
IR (KBr): 1508, 1480, 1447, 1140, 909, 747, 735, 702 cm-1
(ii) 1-(2’,4’-ジフルオロ[1,1’-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(2’,4’-ジフルオロ[1,1’-ビフェニル]-3-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (6.31 g)、ピリジン塩酸塩 (2.17 g)を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (2.93 g.)を無色針状晶として得た。
1H-NMR (CDCl3) δ: 0.83 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 2.56-2.73 (1H, m), 6.84- 6.98 (3H, m), 7..32-7.52 (5H, m), 7.69 (1H, s)IR (KBr): 3202, 1508, 1478, 1385, 1364, 1142, 1005, 855, 845, 797 cm-1
【0032】
実施例20
1-(3’-フルオロ[1,1’-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 1-(3’-フルオロ[1,1’-ビフェニル]-3-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール
1-(3-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (2.62 g)、3-フルオロフェニルボロン酸 (1.09 g)、2M炭酸ナトリウム水溶液 (19.5 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (281 mg)を用いて、実施例4-(ii)と同様の反応を行い、表題化合物 (2.55 g)を黄色アモルファスとして得た。
1H-NMR (CDCl3) δ: 0.75 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 2.36-2.50 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J = 1.2 Hz), 6.98-7.43 (22H, m), 7.55 (1H, dt, J = 6.6, 2.0 Hz), 7.65 (1H, s)
IR (KBr) cm-1: 1493, 1472, 1445, 1159, 909, 781, 747, 735, 702 cm-1
(ii) 1-(3’-フルオロ[1,1’-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(3’-フルオロ[1,1’-ビフェニル]-3-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (2.55 g)、ピリジン塩酸塩 (906 mg) を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (1.15 g)を無色針状晶として得た。
1H-NMR (CDCl3) δ: 0.83 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J = 7.0 Hz), 2.59-2.72 (1H, m), 3.52 (1H, br s), 7.00- 7.06 (2H, m), 7.30-7.40 (5H, m), 7.55 (2H, br s), 7.81 (1H, br s), 9.28 (1H, br s)
IR (KBr) cm-1: 3179, 1576, 1472, 1362, 1304, 1200, 1005, 777, 693 cm-1
実施例21
1-(1H-イミダゾール-4-イル)-2-メチル-1-[4’-(トリフルオロメチル)[1,1’-ビフェニル]-3-イル]-1-プロパノールの製造
(i) 2-メチル-1-[4’-(トリフルオロメチル)[1,1’-ビフェニル]-3-イル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(3-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (3.01 g) 4-トリフルオロメチルフェニルボロン酸 (1.70 g)、2M炭酸ナトリウム水溶液 (22.4 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (323 mg)を用いて、実施例4-(ii)と同様の反応を行い、表題化合物 (2.58 g)を無色針状結晶として得た。
1H-NMR (CDCl3) δ: 0.76 (3H, d, J = 7.0 Hz), 0.94 (3H, d, J = 7.0 Hz), 2.45-2.50 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J = 1.2 Hz), 7.09-7.14 (6H, m), 7.23-7.40 (12H, m), 7.55-7.69 (6H, m)
IR (KBr): 1447, 1327, 1167, 1125, 1073, 849, 793, 747, 735, 702 cm-1
(ii) 1-(1H-イミダゾール-4-イル)-2-メチル-1-[4’-(トリフルオロメチル)[1,1’-ビフェニル]-3-イル]-1-プロパノールの製造
2-メチル-1-[4’-(トリフルオロメチル)[1,1’-ビフェニル]-3-イル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (2.55 g)、ピリジン塩酸塩 (831 mg) を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (1.31 g)を無色針状結晶として得た。
1H-NMR (CDCl3) δ: 0.83 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.59-2.73 (1H, m), 3.37 (1H, br s), 7.01 (1H, s), 7.35-7.46 (2H, m), 7.55-7.67 (6H, m), 7.84 (1H, s), 9.24 (1H, br s)
IR (KBr): 3252, 1327, 1171, 1119, 1073, 966, 845, 797 cm-1
【0033】
実施例22
1-(1H-イミダゾール-4-イル)-2-メチル-1-[4’-(トリフルオロメトキシ)[1,1’-ビフェニル]-3-イル]-1-プロパノールの製造
(i) 2-メチル-1-[4’-(トリフルオロメトキシ)[1,1’-ビフェニル]-3-イル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(3-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (3.80 g) 4-トリフルオロメトキシフェニルボロン酸 (2.33 g)、2M炭酸ナトリウム水溶液 (28.3 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (408 mg)を用いて、実施例4-(ii)と同様の反応を行い、表題化合物 (3.67 g)を無色針状結晶として得た。
1H-NMR (CDCl3) δ: 0.75 (3H, d, J = 7.0 Hz), 0.94 (3H, d, J = 7.0 Hz), 2.36-2.50 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J = 1.0 Hz), 7.10-7.16 (6H, m), 7.23-7.40 (14H, m), 7.50-7.64 (4H, m)
IR (KBr): 1493, 1481, 1445, 1264, 1225, 1165, 1015, 793, 747, 700 cm-1
(ii) 1-(1H-イミダゾール-4-イル)-2-メチル-1-[4’-(トリフルオロメトキシ)[1,1’-ビフェニル]-3-イル]-1-プロパノールの製造
2-メチル-1-[4’-(トリフルオロメトキシ)[1,1’-ビフェニル]-3-イル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (3.63 g)、ピリジン塩酸塩 (1.22 g)を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (3.76 g)を無色針状結晶として得た。
1H-NMR (CDCl3) δ: 0.82 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 2.57-2.71 (1H, m), 6.98 (1H, d, J = 0.8 Hz), 7.18-7.39 (4H, m), 7.51-7.59 (4H, m), 7.78 (1H, s)
IR (KBr): 1510, 1478, 1271, 1227, 1167, 1105, 855, 829, 791, 708 cm-1
実施例23
1-[4’-フルオロ-3’-(メトキシメチル)[1,1’-ビフェニル]-3-イル]-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 4-ブロモ-1-フルオロ-2-(メトキシメチル)ベンゼンの製造
(5-ブロモ-2-フルオロフェニル)メタノール (5.00 g)のTHF (100 ml)溶液に0 ℃で60 %水素化ナトリウム (1.08 g)を加え、室温で30分撹拌後、よう化メチル (3.80 ml)を加え、1.5時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去後、残渣をカラムクロマトグラフィー (溶出液、ヘキサン→ヘキサン : 酢酸エチル = 50 : 1)で精製し、表題化合物 (4.86 g)を褐色油状物として得た。
1H-NMR (CDCl3) δ: 3.42 (3H, s), 4.92 (2H, s), 6.93 (1H, dd, J = 8.8, 8.8 Hz), 7.34-7.42 (1H, m), 7.56 (1H, dd, J = 2.2, 6.2 Hz)
IR (KBr): 1485, 1456, 1383, 1238, 1177, 1123, 1101, 814, 623 cm-1
【0034】
(ii) 1-[4’-フルオロ-3’-(メトキシメチル)[1,1’-ビフェニル]-3-イル]-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
4-ブロモ-1-フルオロ-2-(メトキシメチル)ベンゼン (4.86 g)のTHF (60 ml)溶液に-78℃でn-ブチルリチウム (1.6M; 15.3 ml)を滴下し、40分攪拌後、トリイソプロポキシボラン (10.2 ml)を滴下し、室温で15時間攪拌した。反応液に0 ℃で2規定塩酸 (20 ml)を加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去し、4-フルオロ-3-(メトキシメチル)フェニルボロン酸の粗生成物 (4.50 g)を黄色油状物として得た。本品 (1.36 g)、1-(3-ブロモフェニル)-(1-トリチル-1-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (1.50 g)、2M炭酸ナトリウム水溶液 (11.2 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (161 mg) を用いて、実施例4-(ii)と同様の反応を行い、表題化合物 (1.36 g)を黄色アモルファスとして得た。
1H-NMR (CDCl3) δ: 0.78 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 6.6 Hz), 2.43-2.50 (1H, m), 3.45 (3H, s), 4.58 (2H, s), 6.80 (1H, d, J = 1.2 Hz), 7.12-7.19 (7H, m), 7.28-7.52 (15H, m), 7.62 (1H, d, J = 2.2, 7.0 Hz), 7.71 (1H, s)
IR (KBr): 1493, 1478, 1445, 1188, 1159, 1121, 1094, 909, 748, 733, 702 cm-1
(iii) 1-[4’-フルオロ-3’-(メトキシメチル)[1,1’-ビフェニル]-3-イル]-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-[4’-フルオロ-3’-(メトキシメチル)[1,1’-ビフェニル]-3-イル]-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (1.35 g)、ピリジン塩酸塩 (469 mg)を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (629 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3) δ: 0.79 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 6.4 Hz), 2.56-2.62 (1H, m), 3.41 (3H, s), 4.54 (2H, s), 6.88 (1H, s), 6.99-7.08 (1H, m), 7.30-7.57 (6H, m), 7.73 (1H, s) IR (KBr): 2971, 1505, 1478, 1385, 1229, 1192, 1123, 1092, 1007, 828, 793 cm-1
実施例24
1-(4’-フルオロ-6-メトキシ[1,1’-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 4’-フルオロ-6-メトキシ[1,1’-ビフェニル]-3-カルボアルデヒドの製造
3-ブロモ-p-アニスアルデヒド (14.0 g)、4-フルオロフェニルボロン酸 (14.6 g)、2M炭酸ナトリウム水溶液 (260 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (3.76 g)を用いて、実施例5-(ii)と同様の反応を行い、表題化合物 (11.9 g)を白色針状結晶として得た。
1H-NMR (CDCl3) δ: 3.91 (3H, s), 7.07-7.16 (3H, m), 7.46-7.53 (2H, m), 7.82-7.90 (2H, m), 9.94 (1H, s)
IR (KBr): 1694, 1599, 1497, 1265, 1225, 1177, 1020, 839, 814 cm-1
【0035】
(ii) 1-(4’-フルオロ-6-メトキシ[1,1’-ビフェニル]-3-イル)-2-メチル-1-プロパノールの製造
4’-フルオロ-6-メトキシ[1,1’-ビフェニル]-3-カルボアルデヒド (5.00 g)のTHF (80 ml)溶液に、0 ℃で臭化イソプロピルマグネシウムのTHF溶液 (0.63; 44.8 ml)を滴下し、1時間45分攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去後、残渣をカラムクロマトグラフィー (溶出液、ヘキサン : 酢酸エチル = 6 : 1→2 : 1)で精製し、表題化合物 (3.82 g)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.81 (3H, d, J = 6.6 Hz), 1.02 (3H, s, J = 6.6 Hz), 1.79 (1H, d, J = 3.2 Hz), 1.88-2.02 (1H, m), 3.81 (3H, s), 4.35 (1H, dd, J = 3.0, 7.0 Hz), 6.92-7.15 (3H, m), 7.24-7.29 (2H, m), 7.44-7.53 (2H, m)
IR (KBr): 1514, 1495, 1464, 1264, 1233, 1159, 1044, 1026, 837, 814 cm-1(iii) 1-(4’-フルオロ-6-メトキシ[1,1’-ビフェニル]-3-イル)-2-メチル-1-プロパノンの製造
1-(4’-フルオロ-6-メトキシ[1,1’-ビフェニル]-3-イル)-2-メチル-1-プロパノール (3.82 g)のジクロロメタン (60 ml)溶液に二酸化マンガン (IV) (12.1 g)を加え、室温で17時間攪拌後、さらに二酸化マンガン (IV) (17.7 g)を加え、室温で1.5時間攪拌後、22時間加熱還流した。反応液をセライト濾過後、溶媒を減圧留去し、表題化合物 (3.73 g)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.6 Hz), 3.55 (1H, m, J = 6.6 Hz), 3.89 (3H, s), 7.00-7.17 (3H, m), 7.44-7.54 (2H, m), 7.92-8.01 (2H, m)
IR (KBr): 1674, 1599, 1514, 1497, 1267, 1208, 1159, 1150, 990, 839 cm-1(iv) 1-(4’-フルオロ-6-メトキシ[1,1’-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノール
4-ヨード-1H-イミダゾール (2.13 g)、テトラメチルエチレンジアミン (1.66 ml)のTHF (50 ml)溶液に氷冷下、臭化エチルマグネシウムのジエチルエーテル溶液 (3M; 14.7 ml)を滴下し、55 ℃に昇温して1時間攪拌後、40 ℃でよう化銅 (I) (178 mg)を加え、40〜45 ℃で5分攪拌した。30 ℃で1-(4’-フルオロ-6-メトキシ[1,1’-ビフェニル]-3-イル)-2-メチル-1-プロパン (3.73 g)のTHF (20 ml)溶液を滴下後、室温で4時間攪拌した。反応液に飽和塩化アンモニウムを加え、酢酸エチルで抽出し、5 %エチレンジアミン水溶液、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去後、残渣をカラムクロマトグラフィー (溶出液、ヘキサン :酢酸エチル = 1 : 2→酢酸エチル)で精製し、表題化合物 (922 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3) δ: 0.84 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 7.0 Hz), 2.54-2.67 (1H, m), 3.78 (3H, s), 6.89-7.11 (4H, m), 7.43-7.54 (5H, m)IR (KBr): 1514, 1493, 1464, 1264, 1227, 1157, 1026, 837, 818 cm-1
【0036】
実施例25
3’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロピル][1,1’-ビフェニル]-4-カルボニトリルの製造
(i) 3’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロピル][1,1’-ビフェニル]-4-カルボニトリルの製造
1-(3-ブロモフェニル)-(1-トリチル-1-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (978 mg)、4-シアノフェニルボロン酸 (535 mg)、2M炭酸ナトリウム水溶液 (7.28 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (105 mg)を用いて、実施例4-(ii)と同様の反応を行い、表題化合物 (622 mg)を無色針状結晶として得た。
1H-NMR (CDCl3) δ: 0.75 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 7.0 Hz), 2.40-2.47 (1H, m), 3.68 (1H, s), 6.78 (1H, d, J = 1.6 Hz), 7.10-7.14 (6H, m), 7.29-7.40 (12H, m), 7.55-7.73 (6H, m)
IR (KBr) : 2965, 2226, 1605, 1491, 1480, 1445, 845, 795, 754, 745, 700 cm-1
(ii) 3’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロピル][1,1’-ビフェニル]-4-カルボニトリルの製造
3’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロピル][1,1’-ビフェニル]-4-カルボニトリル (590 mg)、ピリジン塩酸塩 (111 mg)を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (261 mg)を無色針状結晶として得た。
1H-NMR (CDCl3) δ: 0.82 (3H, d, J = 7.0 Hz), 0.91 (3H, d, J = 6.6 Hz), 2.59-2.73 (1H, m), 6.99 (1H, s), 7.36-7.43 (2H, m), 7.53-7.69 (6H, m), 7.83 (1H, s)
IR (KBr): 2232, 1605, 1478, 1103, 843, 791, 727, 708, 644 cm-1
実施例26
1-(4’-フルオロ[1,1’-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-1-エタノールの製造
(i) 1-(4’-フルオロ[1,1’-ビフェニル]-3-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-1-エタノールの製造
3-ブロモ-4’-フルオロ-1,1’-ビフェニル (1.50 g)のTHF (20 ml)溶液に-78 ℃でn-ブチルリチウムのヘキサン溶液 (1.6 M; 3.73 ml)を滴下し、20分撹拌後、-78 ℃で1-(1-トリチル-1H-イミダゾール-4-イル)-1-エタノン (1.91 g)のTHF (25 ml)溶液を滴下し、-78 ℃で1時間、-35 〜 -10℃で1時間、0 ℃で1時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えて、酢酸エチルで抽出し、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去後、残渣をカラムクロマトグラフィー (溶出液、ヘキサン : 酢酸エチル = 3 : 1→1 : 1)で精製し、酢酸エチル-ヘキサンより再結晶し、表題化合物 (1.57 g)を無色プリズム晶として得た。
1H-NMR (CDCl3) δ: 1.81 (3H, s), 3.44 (1H, s), 6.77 (1H, d, J = 1.4 Hz), 7.06-7.28 (8H, m), 7.30-7.55 (16H, m)
IR (KBr): 1514, 1483, 1441, 1221, 1163, 839, 797, 758, 750, 702 cm-1
【0037】
(ii) 1-(4’-フルオロ[1,1’-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-1-エタノールの製造
1-(4’-フルオロ[1,1’-ビフェニル]-3-イル)-1-(1-トリチル-1H-イミダゾール-4-イル)-1-エタノール (1.51 g)、ピリジン塩酸塩 (599 mg) を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (559 mg.)を無色板状結晶として得た。
1H-NMR (CDCl3+CD3OD) δ: 1.91 (3H, s), 6.89 (1H, s), 7.05-7.14 (2H, m), 7.35-7.42 (3H, m), 7.48-7.55 (3H, m), 7.65 (1H, s)
IR (KBr): 3166, 1514, 1481, 1456, 1231, 1190, 1067, 833, 799, 623 cm-1
実施例27
1-[4’-フルオロ[1,1’-ビフェニル]-3-イル]-1-(1H-イミダゾール-4-イル)-1-プロパノールの製造
3-ブロモ-4’-フルオロ-1,1’-ビフェニル (2.80 g)、 n-ブチルリチウムのヘキサン溶液 (1.6 M; 6.96 ml)、1-(1H-イミダゾール-4-イル)-1-プロパノン (419 mg)を用いて、実施例26-(i)と同様の反応を行い、表題化合物 (796 mg)を無色板状結晶として得た。
1H-NMR (CDCl3+CD3OD) δ: 0.89 (3H, J = 7.2 Hz), 2.14-2.36 (2H, m), 6.90 (1H, s), 7.05-7.14 (2H, m), 7.37-7.56 (6H, m), 7.65 (1H, s)
IR (KBr): 3191, 1512, 1235, 1181, 1096, 963, 934, 835, 799, 619 cm-1
実施例28
1-(1H-イミダゾール-4-イル)-2-メチル-1-[3-(2-チエニル)フェニル]-1-プロパノールの製造
(i) 2-メチル-1-[3-(2-チエニル)フェニル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(3-ブロモフェニル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (1.70 g)、トリ-n-ブチル(2-チエニル)スズ (1.31 ml)のDMF (10 ml)溶液を脱気後、テトラキス(トリフェニルホスフィン)パラジウム (0) (110 mg)を加え、アルゴン雰囲気下、80 ℃で4時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、水で2回、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー (溶出液、ヘキサン : 酢酸エチル = 6 : 1→3 : 1)で精製し、酢酸エチル-ヘキサンから再結晶を行い表題化合物 (1.32 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.75 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.35-2.48 (1H, m), 3.68 (1H, s), 6.79 (1H, d, J = 1.0 Hz), 7.04-7.16 (6H, m), 7.24-7.35 (14H, m), 7.41-7.47 (2H, m), 7.72 (1H, s)
IR (KBr): 1493, 1445, 1165, 1003, 909, 747, 700 cm-1
【0038】
(ii) 1-(1H-イミダゾール-4-イル)-2-メチル-1-[3-(2-チエニル)フェニル]-1-プロパノールの製造
2-メチル-1-[3-(2-チエニル)フェニル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (1.21 g)、ピリジン塩酸塩 (465 mg)を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (585 mg)を無色板状結晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.82 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J = 6.4 Hz), 2.56-2.70 (1H, m), 6.98 (1H, d, J = 1.2 Hz), 7.06 (1H, dd, J = 3.8, 5.2 Hz), 7.24-7.49 (5H, m), 7.51 (1H, d, J = 1.2 Hz), 7.80 (1H, s)
IR (KBr): 3194, 2969, 1385, 1366, 1306, 1007, 822, 787, 693, 635 cm-1
実施例29
1-(1H-イミダゾール-4-イル)-2-メチル-1-[3-(3-チエニル)フェニル]-1-プロパノールの製造
(i) 2-メチル-1-[3-(3-チエニル)フェニル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(3-ブロモフェニル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (1.70 g)、3-チオフェンボロン酸 (607 mg)、2 M炭酸ナトリウム水溶液 (3.16 ml)のトルエン-エタノール (6 : 1) (17.5 ml)懸濁液に、テトラキス(トリフェニルホスフィン)パラジウム (0) (110 mg)を加え、アルゴン雰囲気下、3時間加熱還流した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー (溶出液、ヘキサン : 酢酸エチル = 6 : 1→4 : 1→3 : 1)で精製し、酢酸エチル-ヘキサンから再結晶を行い表題化合物 (1.48 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.75 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.36-2.49 (1H, m), 3.67 (1H, s), 6.78 (1H, d, J = 1.4 Hz), 7.10-7.17 (6H, m), 7.25-7.48 (16H, m), 7.70 (1H, dd, J = 1.8, 1.8 Hz)
IR (KBr): 1493, 1445, 1163, 1003, 909, 775, 747, 733, 702 cm-1
(ii) 1-(1H-イミダゾール-4-イル)-2-メチル-1-[3-(3-チエニル)フェニル]-1-プロパノールの製造
2-メチル-1-[3-(3-チエニル)フェニル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (1.43 g)、ピリジン塩酸塩 (550 mg)を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (585 mg)を無色板状結晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.82 (3H, d, J = 7.0 Hz), 0.98 (3H, d, J = 7.0 Hz), 2.57-2.70 (1H, m), 6.96 (1H, d, J = 1.0 Hz), 7.28-7.48 (7H, m), 7.79 (1H, s)
IR (KBr): 3196, 2969, 1358, 1304, 1007, 801, 787, 774 cm-1
【0039】
実施例30
1-[3-(2-フリル)フェニル]-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 1-[3-(2-フリル)フェニル]-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(3-ブロモフェニル)-1-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (1.70 g)、トリ-n-ブチル(2-フリル)スズ (1.29 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (110 mg) を用いて、実施例28-(i)と同様の反応を行い、表題化合物 (1.62 g)を無色粉末晶として得た。
1H-NMR (CDCl3) δ: 0.75 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.8 Hz), 2.36-2.50 (1H, m), 3.67 (1H, s), 6.46 (1H, dd, J = 1.8, 3.2 Hz), 6.60 (1H, d, J = 3.2 Hz), 6.79 (1H, d, J = 1.4 Hz), 7.10-7.15 (6H, m), 7.28-7.35 (11H, m), 7.41-7.51 (3H, m), 7.79 (1H, dd, J = 1.8, 1.8 Hz)
IR (KBr): 1493, 1472, 1445, 1161, 1013, 910, 791, 733, 702, 660 cm-1
(ii) 1-[3-(2-フリル)フェニル]-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-[3-(2-フリル)フェニル]-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (1.54 g)、ピリジン塩酸塩 (610 mg)を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (597 mg)を無色板状結晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.81 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.57-2.71 (1H, m), 6.46 (1H, dd, J = 1.8, 3.4 Hz), 6.65 (1H, d, J = 1.8 Hz), 6.98 (1H, d, J = 3.4 Hz), 7.27-7.51 (5H, m), 7.85 (1H, s)
IR (KBr): 3200, 2975, 1306, 1188, 1007, 789, 729, 693, 635 cm-1
実施例31
N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
(i) N-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
1-(4-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (1.04 g)、 3-(アセチルアミノ)フェニルボロン酸 (571 mg) およびテトラキス(トリフェニルホスフィン)パラジウム(0) (301 mg) を用いて実施例4-(ii)と同様の反応を行ない、表題化合物(1.10 g)を淡黄色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J=6.6Hz), 0.92 (3H, d, J=6.6Hz), 2.20 (3H, s), 2.38-2.56 (1H, m), 3.55 (1H, s), 6.77 (1H, d, J=1.2Hz), 7.06-7.20 (6H, m), 7.24-7.76 (18H, m).
IR (KBr): 3063, 1674, 1557, 1483, 1445 cm-1.
【0040】
(ii) N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
N-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}アセタミド(978 mg) およびピリジン塩酸塩 (310 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(276 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.82 (3H, d, J=6.8Hz), 0.98 (3H, d, J=6.8Hz), 2.17 (3H, s), 2.51-2.74 (1H, m), 6.96 (1H, d, J=1.0Hz), 7.25-7.39 (3H, m), 7.42-7.56 (5H, m), 7.68 (1H, s).
IR (KBr): 3210, 2971, 1672, 1557, 1483 cm-1.
実施例32
N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-4-イル}アセタミドの製造
(i) N-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-4-イル}アセタミドの製造
1-(4-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (1.00 g) 、4-(アセチルアミノ)フェニルボロン酸 (510 mg) およびテトラキス(トリフェニルホスフィン)パラジウム(0) (200 mg)用いて実施例4-(ii)と同様の反応を行ない、表題化合物(350 mg)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J=6.6Hz), 0.93 (3H, d, J=6.6Hz), 2.20 (3H, s), 2.30-2.56 (1H, m), 3.53 (1H, s), 6.77 (1H, d, J=1.4Hz), 7.08-7.14 (6H, m), 7.27-7.38 (10H, m), 7.43-7.58 (8H, m).
IR (KBr): 2971, 1671, 1535, 1493 cm-1.
(ii) N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-4-イル}アセタミドの製造
N-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-4-イル}アセタミド(601 mg) と ピリジン塩酸塩 (0.17 g)用いて実施例4-(iii)と同様の反応を行ない、表題化合物(73 mg)を無色粉末晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.82 (3H, d, J=6.8Hz), 0.98 (3H, d, J=6.8Hz), 2.17 (3H, s), 2.49-2.70 (1H, m), 6.96 (1H, d, J=0.8Hz), 7.44-7.60 (9H, m).IR (KBr): 3173, 1667, 1534, 1499 cm-1.
【0041】
実施例33
N-{4-フルオロ-4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
(i) N-(5-ブロモ-2-フルオロフェニル)アセタミドの製造
4-ブロモ-1-フルオロ-2-ニトロベンゼン (5.81 g)、 鉄粉(6.20 g) および無水酢酸 (5 ml) を酢酸 (50 ml)中、60 ℃で16時間攪拌した。減圧下で酢酸を留去し、水と酢酸エチルを加えた。有機層を重曹水と食塩水で洗浄した後、硫酸マグネシウムで乾燥し、減圧濃縮した。残留物をへキサン-酢酸エチルから再結晶すると表題化合物(3.56 g)が無色プリズム晶として得られた。
1H-NMR (CDCl3)δ: 2.23 (3H, s), 6.87-7.03 (1H, m), 7.06-7.21 (1H, m), 7.43 (1H, brs), 8.53 (1H, d, J= 6.8 Hz).
IR (KBr): 3262, 1672, 1613, 1535, 1408 cm-1.
(ii) N-{4-フルオロ-4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.50 g)、N-(5-ブロモ-2-フルオロフェニル)アセタミド(1.17 g)およびテトラキス(トリフェニルホスフィン)パラジウム (0) (0.17 g)を用いて実施例4-(ii)と同様の反応を行ない、表題化合物(1.39g)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J= 7.0 Hz), 0.92 (3H, d, J= 7.0 Hz), 2.24 (3H, s), 3.55 (1H, s), 6.77 (1H, d, J= 1.0 Hz), 7.06-7.20 (7H, m), 7.20-7.36 (11H, m), 7.47 (2H, d, J= 8.8 Hz), 7.54 (2H, d, J= 8.8 Hz), 8.55 (1H, d, J= 5.2 Hz).
IR (KBr): 2960, 1680, 1545, 1493 cm-1.
(iii) N-{4-フルオロ-4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
N-{4-フルオロ-4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}アセタミド(1.29 g)とピリジン塩酸塩(297 mg)用いて実施例4-(iii)と同様の反応を行ない、表題化合物(399 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.81 (3H, d, J= 6.8 Hz), 0.97 (3H, d, J= 6.8 Hz), 2.23 (3H, s), 2.50-2.70 (1H, m), 6.95 (1H, s), 7.04-7.26 (2H, m), 7.38-7.60 (5H, m), 8.47 (1H, d, J= 7.8 Hz).
IR (KBr): 2971, 1682, 1669, 1609, 1487 cm-1.
【0042】
実施例34
N-{6-フルオロ-4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
(i) 2-ブロモ-1-フルオロ-4-ニトロベンゼンの製造
2-フルオロ-5-ニトロアニリン(25.90 g)、47%臭化水素水(100ml)、水(200ml)および酢酸(200ml)の混合物に亜硝酸ナトリウム(11.56g)の水溶液(100ml)を滴下し、0℃で1時間攪拌した。本混合物を0℃で、臭化銅(CuBr:27.30 g)を溶解した47%臭化水素水(100ml)溶液に加え、室温で16時間かき混ぜた。反応液を酢酸エチルで抽出し、乾燥(無水硫酸マグネシウム)後、減圧濃縮した。残留物をシリカゲルクロマトグラフィー(溶出液:へキサン)で精製後、ヘキサンから結晶化を行ない、表題化合物(4.01 g)を無色針状晶として得た。
1H-NMR (CDCl3)δ: 7.22-7.35 (1H, m), 8.17-8.29 (1H, m), 8.51 (1H, dd, J= 2.4, 6.0 Hz).
IR (KBr): 1537, 1470, 1348 cm-1.
(ii) N-(3-ブロモ-4-フルオロフェニル)アセタミドの製造
2-ブロモ-1-フルオロ-4-ニトロベンゼン(2.27 g)、鉄粉(2.90 g)および無水酢酸 (2.0 ml)用いて実施例33-(i)と同様の反応を行ない、表題化合物(2.28 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 2.17 (3H, s), 7.06 (1H, t, J= 8.4 Hz), 7.26-7.43 (2H, m), 7.80 (1H, dd, J= 2.6, 5.6 Hz).
IR (KBr): 3306, 1669, 1609, 1549, 1493 cm-1.
(iii) N-{6-フルオロ-4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.19 g)、N-(3-ブロモ-4-フルオロフェニル)アセタミド(990 mg)および テトラキス(トリフェニルホスフィン)パラジウム(0) (0.21 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(870 mg)を淡黄色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J= 6.6 Hz), 0.93 (3H, d, J= 6.6 Hz), 2.11 (3H, s), 2.30-2.58 (1H, m), 3.59 (1H, s), 6.79 (1H, d, J= 1.0 Hz), 6.96-7.20 (7H, m), 7.25-7.70 (15H, m), 7.88 (1H, s).
IR (KBr): 3287, 2969, 1672, 1553, 1489 cm-1.
(iv) N-{6-フルオロ-4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
N-{6-フルオロ-4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}アセタミド(820 mg)とピリジン塩酸塩 (230 mg)用いて実施例4-(iii)と同様の反応を行ない、表題化合物(250 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.82 (3H, d, J= 7.0 Hz), 0.98 (3H, d, J= 7.0 Hz), 2.14 (3H, s), 2.56-2.70 (1H, m), 6.94-7.12 (2H, m), 7.40-7.58 (7H, m).IR (KBr): 3158, 2973, 1667, 1489 cm-1.
【0043】
実施例35
N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-6-メトキシ[1,1'-ビフェニル]-3-イル}アセタミドの製造
(i) N-(3-ブロモ-4-メトキシフェニル)アセタミドの製造
2-ブロモ-4-ニトロアニソール(5.41 g)、鉄粉(6.49 g)および無水酢酸(4.4 ml)を用いて実施例33-(i)と同様の反応を行ない、表題化合物(4.87 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 2.15 (3H, s), 3.87 (3H, s), 6.83 (1H, d, J= 8.8 Hz), 7.32 (1H, brs), 7.43 (1H, dd, J= 2.5, 8.8 Hz), 7.67 (1H, d, J= 2.5 Hz).
IR (KBr): 3173, 1667, 1597, 1495 cm-1.
(ii) N-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-6-メトキシ[1,1'-ビフェニル]-3-イル}アセタミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.21 g) 、N-(3-ブロモ-4-メトキシフェニル)アセタミド(1.05 g) およびテトラキス(トリフェニルホスフィン)パラジウム (0) (0.16 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.14 g)を無色アモルファス粉末として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.77 (3H, d, J= 6.6 Hz), 0.92 (3H, d, J= 6.6 Hz), 2.14 (3H, s), 2.40-2.58 (1H, m), 3.77 (3H, s), 6.79 (1H, d, J= 1.2 Hz), 6.92 (1H, d, J= 8.8 Hz), 7.06-7.20 (6H, m), 7.24-7.62 (16H, m).
IR (KBr): 2971, 1663, 1549, 1493 cm-1.
(iii) N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-6-メトキシ[1,1'-ビフェニル]-3-イル}アセタミドの製造
N-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-6-メトキシ[1,1'-ビフェニル]-3-イル}アセタミド(975 mg)とピリジン塩酸塩 (299 mg)用いて実施例4-(iii)と同様の反応を行ない、表題化合物(290 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.83 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz), 2.11 (3H, s), 2.40-2.70 (1H, m), 3.73 (3H, s), 6.87 (1H, d, J=8.4 Hz), 6.93 (1H, s), 7.24 (2H, s), 7.34 (2H, d, J=8.0 Hz), 7.41 (2H, d, J=8.0 Hz), 7.50 (1H, d, J=8.4 Hz).
IR (KBr): 3183, 2973, 1667, 1495 cm-1.
【0044】
実施例36
N-[4’-[1-ヒドロキシ-1-(-1H-イミダゾール-4-イル)-2-メチルプロピル]-2-メチル[1,1’-ビフェニル]-3-イル]アセタミドの製造
(i) N-[4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-2-メチル[1,1’-ビフェニル]-3-イル]アセタミドの製造
N-(3-ブロモ-2-メチル)アセタミド(1.19 g)、4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸の粗生成物(3.40 g)、2 M炭酸ナトリウム水溶液 (5.20 ml)、テトラキス(トリフェニルホスフィン)パラジウム(0) (301 mg)を用いて、実施例33-(ii)と同様の反応を行い表題化合物 (1.15 g)を無色アモルファスとして得た。
1H-NMR (CDCl3) δ: 0,78 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 2.14 (3H, s), 2.24 (3H, s), 2.41-2.48 (1H, m), 3.61 (1H, s), 6.77 (1H, d, J = 1.4 Hz), 7.00-7.38 (20H, m), 7.50-7.54 (2H, m), 7.22 (2H, d, J = 7.8 Hz).
IR (KBr): 1667, 1535, 1491, 1468, 1445, 910, 733, 702 cm-1.
(ii) N-[4’-[1-ヒドロキシ-1-(-1H-イミダゾール-4-イル)-2-メチルプロピル]-2-メチル[1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-2-メチル[1,1’-ビフェニル]-3-イル]アセタミド(1.10 g)とピリジン塩酸塩(378 mg)を用いて実施例4-(iii)と同様の反応を行い、表題化合物 (605 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.81 (3H, d, J = 7.0 Hz), 0.97 (3H, d, J = 6.6 Hz), 2.05 (3H, s), 2.20 (3H, s), 2.59-2.63 (1H, m), 6.91 (1H, s), 7.03-7.19 (4H, m), 7.41-7.50 (4H, m).
IR (KBr): 1665, 1535, 1468, 1439, 1372, 997, 828, 793 cm-1.
実施例37
N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-5-メチル[1,1’-ビフェニル]-3-イル]アセタミドの製造
(i) N-[4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-5-メチル[1,1’-ビフェニル]-3-イル]アセタミドの製造
N-(3-ブロモ-5-メチルフェニル)アセタミド (612 mg)、4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸の粗生成物 (1.75 g)、2 M炭酸ナトリウム水溶液 (2.68 ml)、テトラキス(トリフェニルホスフィン)パラジウム(0) (310 mg)を用いて実施例33-(ii)と同様の反応を行い、表題化合物 (1.07 g)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.18 (3H, s), 2.39-2.48 (4H, m), 3.56 (1H, s), 6.78 (1H, s), 7.13-7.15 (7H, m), 7.32-7.72 (17H, m).
IR (KBr): 1674, 1615, 1559, 1447, 1121, 747, 725, 700 cm-1.
【0045】
(ii) N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-5-メチル[1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-5-メチル[1,1’-ビフェニル]-3-イル]アセタミド (1.02 g)とピリジン塩酸塩 (350 mg)を用いて実施例4-(iii)と同様の反応を行い、表題化合物 (410 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.83 (3H, d, J = 6.8 Hz), 0.98 (3H, d, J = 7.0 Hz), 2.16 (3H, s), 2.37 (3H, s), 2.60-2.66 (1H, m), 6.96 (1H, s), 7.13 (1H, s), 7.37 (1H, s), 7.46-7.50 (6H, m).
IR (KBr): 1669, 1613, 1599, 1559, 1435, 1372, 822 cm-1.
実施例38
N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-5-(トリフルオロメチル)[1,1’-ビフェニル]-3-イル]アセタミドの製造
(i) N-[4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-5-(トリフルオロメチル)[1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[3-ブロモ-5-(トリフルオロメチル)フェニル]アセタミド (1.00 g)、4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸の粗生成物 (2.50 g)、2 M炭酸ナトリウム水溶液 (3.56 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (221 mg)を用いて実施例33-(ii)と同様の反応を行い、表題化合物 (1.80 g)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 2.42-2.49 (1H, m), 3.54 (1H, s), 6.79 (1H, d, J = 1.2 Hz), 7.10-7.15 (6H, m), 7.32-7.36 (10H, m), 7.45-7.64 (6H, m), 7.77 (1H, s), 7.86 (1H, s).
IR (KBr): 1682, 1456, 1364, 1262, 1167, 1127, 747, 735, 702 cm-1.
(ii) N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-5-(トリフルオロメチル)[1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-5-(トリフルオロメチル)[1,1’-ビフェニル]-3-イル]アセタミド (1.85 g)、ピリジン塩酸塩 (551 mg)を用いて実施例4-(iii)と同様の反応を行い、表題化合物 (591 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.81 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.18 (3H, s), 2.50-2.62 (1H, m), 6.98 (1H, s), 7.44-7.58 (6H, m), 7.85 (2H, s).
IR (KBr): 1678, 1566, 1460, 1366, 1264, 1169, 1127, 824 cm-1.
【0046】
実施例39
N-[4’-[1-ヒドロキシ-(1H-イミダゾール-4-イル)エチル][1,1’-ビフェニル]-3-イル]アセタミドの製造
(i) (4-ブロモフェニル)(1-トリチル-1H-イミダゾール-4-イル)メタノールの製造
p-ジブロモベンゼン(54.7 g)、n-ブチルリチウムのヘキサン溶液 (1.6 M; 94.7 ml)、1-トリチル-1H-イミダゾール-4-カルボアルデヒド (34.2 g)を用いて実施例4-(i)と同様の反応を行い、表題化合物 (27.8 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 3.56 (1H, br s), 5.71 (2H, d, J = 4.4 Hz), 6.58 (1H, s), 7.07-7.13 (7H, m), 7.25-7.44 (12H, m).
IR (KBr): 1493, 1445, 1128, 1011, 909, 747, 733, 702 cm-1.
(ii) (4-ブロモフェニル)(1-トリチル-1H-イミダゾール-4-イル)メタノンの製造(4-ブロモフェニル)(1-トリチル-1H-イミダゾール-4-イル)メタノール (30.0 g)、二酸化マンガン(52.6 g) を用いて実施例24-(iii)と同様の反応を行い、表題化合物 (23.3 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 7.10-7.19 (6H, m), 7.31-7.41 (9H, m), 7.52 (1H, d, J = 1.4 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.77 (1H, d, J = 1.4 Hz), 8.21 (2H, d, J = 8.4 Hz).
IR (KBr): 1644, 1520, 1213, 887, 756, 747, 702 cm-1.
(iii) N-[4’-[(1-トリチル-1H-イミダゾール-4-イル)カルボニル][1,1’-ビフェニル]-3-イル]アセタミドの製造
(4-ブロモフェニル)(1-トリチル-1H-イミダゾール-4-イル)メタノン (12.0 g)、3-アセトアミドベンゼンボロン酸 (5.66 g)、2 M炭酸ナトリウム水溶液 (24.3 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (842 mg)を用いて、実施例29-(i)と同様の反応を行い表題化合物 (10.1 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 2.20 (3H, s), 7.14-7.21 (6H, m), 7.36-7.44 (12H, m), 7.54-7.77 (6H, m), 8.33 (2H, d, J = 8.4 Hz).
IR (KBr): 1671. 1645. 1603. 1553. 1524. 756. 702 cm-1.
(iv) N-[4’-[1-ヒドロキシ-1-(1-トリチル-1H-イミダゾール-4-イル)エチル][1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[(1-トリチル-1H-イミダゾール-4-イル)カルボニル][1,1’-ビフェニル]-3-イル]アセタミド (800 mg)のTHF (14 ml)溶液に0 °CでメチルマグネシウムブロミドのTHF溶液 (1.0 M; 4.38 ml)を滴下し、0 °Cで20分間攪拌した。反応液に飽和塩化アンモニウムを加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣を酢酸エチル-メタノール-ヘキサンより再結晶を行い表題化合物 (823 mg)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 1.81 (3H, s), 2.20 (3H, s), 3.37 (1H, s), 6.79 (1H, d, J = 1.4 Hz), 7.12-7.20 (8H, m), 7.31-7.52 (16H, m), 7.65 (1H, br s).
IR (KBr): 1672, 1553, 1483, 1445, 909, 747, 733, 700 cm-1.
【0047】
(v) N-[4’-[1-ヒドロキシ-(1H-イミダゾール-4-イル)エチル][1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[1-ヒドロキシ-1-(1-トリチル1H-イミダゾール-4-イル)エチル][1,1’-ビフェニル]-3-イル]アセタミド (775 mg)、ピリジン塩酸塩 (286 mg)を用いて、実施例4-(iii)と同様の反応を行い表題化合物 (262 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 1.89 (3H, s), 2.16 (3H, s), 6.89 (1H, s), 7.27-7.52 (8H, m), 7.69 (1H, s).
IR (KBr): 3031, 1672, 1609, 1591, 1559, 1483, 1397, 1312, 791 cm-1.
実施例40
N-[4’-[シクロプロピル(ヒドロキシ)(1H-イミダゾール-4-イル)メチル][1,1’-ビフェニル]-3-イル]アセタミドの製造
(i) N-[4’-[シクロプロピル(ヒドロキシ)(1-トリチル-1H-イミダゾール-4-イル)メチル][1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[(1-トリチル-1H-イミダゾール-4-イル)カルボニル][1,1’-ビフェニル]-3-イル]アセタミド (1.50 g)、シクロプロピルマグネシウムブロミドのTHF溶液 (1.0 M; 9.59 ml)を用いて、実施例39-(iv)と同様の反応を行い表題化合物 (996 mg)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.41-0.49 (4H, m), 1.47-1.55 (1H, m), 2.20 (3H, s), 3.26 (1H, s), 6.82 (1H, d, J = 1.4 Hz), 7.11-7.41 (19H, m), 7.50-7.53 (5H, m), 7.65 (1H, s).
IR (KBr): 1671, 1591, 1559, 1483, 1445, 731, 702 cm-1.
(ii) N-[4’-[シクロプロピル(ヒドロキシ)(1H-イミダゾール-4-イル)メチル][1,1’-ビフェニル]-3-イル]アセタミド
N-[4’-[シクロプロピル(ヒドロキシ)(1-トリチル-1H-イミダゾール-4-イル)メチル][1,1’-ビフェニル]-3-イル]アセタミド (946 mg)、ピリジン塩酸塩 (334 mg)を用いて、実施例4-(iii)と同様の反応を行い表題化合物 (216 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.47-0.60 (4H, m), 1.57-1.64 (1H, m), 2.17 (3H, s), 7.00 (1H, s), 7.36-7.58 (8H, m), 7.71 (1H, s).
IR (KBr): 3148, 1667, 1591, 1555, 1485, 831, 791 cm-1.
実施例41
N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)ブチル][1,1’-ビフェニル]-3-イル]アセタミドの製造
(i) N-[4’-[1-ヒドロキシ-1-(1-トリチル-1H-イミダゾール-4-イル)-3-ブテニル][1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[(1-トリチル-1H-イミダゾール-4-イル)カルボニル][1,1’-ビフェニル]-3-イル]アセタミド (1.00 g)、アリルマグネシウムブロミドのTHF溶液 (1.0 M; 5.48 ml)を用いて、実施例39-(iv)と同様の反応を行い表題化合物 (909 mg,)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 2.19 (3H, s), 2.85 (1H, dd, J = 6.2, 14.0 Hz), 3.01 (1H, dd, J = 7.6, 14.0 Hz), 3.34 (1H, s), 5.04-5.11 (2H, m), 5.62-5.79 (1H, m), 6.78 (1H, d, J = 1.6 Hz), 7.11-7.18 (6H, m), 7.32-7.51 (18H, m), 7.65 (1H, s).
IR (KBr): 1669, 1609, 1593, 1485, 1445, 909, 747, 733, 702 cm-1.
【0048】
(ii) N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)ブチル][1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[1-ヒドロキシ-1-(1-トリチル-1H-イミダゾール-4-イル)-3-ブテニル][1,1’-ビフェニル]-3-イル]アセタミド (829 mg)、10 %パラジウム炭素 (829 mg)、1N塩酸 (1.41 ml)のエタノール (14 ml)懸濁液を水素雰囲気下室温で9.5時間攪拌した。重曹 (130 mg)を加えて撹拌後、反応液をセライト濾過し、濾液を濃縮後、残渣をシリカゲルクロマトグラフィー (溶出液;クロロホルム→クロロホルム : メタノール = 10 : 1→7 : 1→4 : 1)で精製し、表題化合物 (420 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.90 (3H, t, J = 7.0 Hz), 1.22-1.38 (2H, m), 2.16-2.36 (5H, m), 6.89 (1H, s), 7.29-7.56 (8H, m), 7.71 (1H, s).
IR (KBr): 3144, 1659, 1609, 1557, 1485, 1435, 791 cm-1.
実施例42
N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-3-イル]アセタミドの製造
(i) N-[4’-[1-ヒドロキシ-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[(1-トリチル-1H-イミダゾール-4-イル)カルボニル][1,1’-ビフェニル]-3-イル]アセタミド (1.50 g)、エチルマグネシウムブロミドのジエチルエーテル溶液 (3.0 M; 2.74 ml)を用いて、実施例39-(iv)と同様の反応を行い表題化合物 (1.36 g)を淡黄色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.86 (3H, t, J = 7.6 Hz), 2.12-2.20 (5H, m), 3.35 (1H, s), 6.67 (1H, s), 7.13-7.22 (6H, m), 7.26-7.48 (18H, m), 7.66 (1H, s).
IR (KBr): 1674, 1609, 1557, 1485, 1445, 747, 733, 702 cm-1.
(ii) N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[1-ヒドロキシ-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-3-イル]アセタミド (1.31 g)、10 %パラジウム炭素 (1.31 g)、1N塩酸 (2.27 ml)を用いて、実施例41-(ii)と同様の反応を行い表題化合物 (640 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.89 (3H, t, J = 7.6 Hz), 2.17-2.32 (5H, m), 6.91 (1H, s), 7.30-7.53 (8H, m), 7.69 (1H, s).
IR (KBr): 3148, 1667, 1609, 1591, 1557, 1485, 831, 791 cm-1.
【0049】
実施例43
N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}プロパナミドの製造
(i) N-(3-ブロモフェニル)プロパナミドの製造
3-ブロモアニリン (5.10 g)とトリエチルアミン (8.3 ml)のTHF(40ml)溶液に0℃でプロピオニルクロリド(2.8 ml) を滴下し、0℃で2時間かき混ぜた。反応液に水と酢酸エチルを加え、有機層を分離した。水、食塩水で洗浄し、乾燥(硫酸マグネシウム)後、減圧濃縮した。残留物をへキサン-酢酸エチルから再結晶し、表題化合物(5.60 g)を無色針状晶として得た。
1H-NMR (CDCl3)δ: 1.24 (3H, t, J=7.5 Hz), 2.39 (2H, q, J=7.5 Hz), 7.11-7.30 (3H, m), 7.41 (1H, d, J=7.8 Hz), 7.79 (1H, brs).
IR (KBr): 3243, 1661, 1593, 1539 cm-1.
(ii) N-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}プロパナミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.12g)、N-(3-ブロモフェニル)プロパナミド(1.56 g)およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.133 g)用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.26 g)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.6 Hz), 1.25 (3H, t, J=7.5 Hz), 2.30-2.50 (3H, m), 3.55 (1H, s), 6.78 (1H, s), 7.08-7.44 (20H, m), 7.48 (2H, d, J=8.3 Hz), 7.54 (2H, d, J=8.3 Hz), 7.72 (1H, brs).
IR (KBr): 2973, 1669, 1557, 1485 cm-1.
(iii) N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}プロパナミドの製造
N-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}プロパナミド(1.46 g)とピリジン塩酸塩(440 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(280 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.79 (3H, d, J=7.0 Hz), 0.96 (3H, d, J=7.0 Hz), 1.22 (3H, t, J=7.4 Hz), 2.39 (2H, q, J=7.4 Hz), 2.40-2.70 (1H, m), 6.91 (1H, d, J=1.2 Hz), 7.24-7.55 (8H, m), 7.67 (1H, s).
IR (KBr): 3196, 2975, 1669, 1557 cm-1.
【0050】
実施例44
N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-3-メチルブチル][1,1’-ビフェニル]-3-イル]アセタミドの製造
(i) N-[4’-[1-ヒドロキシ-3-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)ブチル][1,1’-ビフェニル]-3-イル]アセタミドノ製造
N-[4’-[(1-トリチル-1H-イミダゾール-4-イル)カルボニル][1,1’-ビフェニル]-3-イル]アセタミド (1.26 g)、イソブチルマグネシウムブロミドのTHF溶液 (1.0 M; 8.05 ml)を用いて、実施例39-(iv)と同様の反応を行い表題化合物 (408 mg)を淡黄色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J = 6.8 Hz), 0.88 (3H, d, J = 6.6 Hz), 1.68-1.74 (1H, m), 2.02 (2H, d, J = 5.2 Hz), 2.20 (3H, s), 3.43 (1H, s), 6.74 (1H, s), 7.12-7.17 (8H, m), 7.32-7.48 (16H, m), 7.65 (1H, s).
IR (KBr): 1672, 1607, 1557, 1485, 1445, 909, 747, 733, 702 cm-1.
(ii) N-[4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-3-メチルブチル][1,1’-ビフェニル]-3-イル]アセタミドの製造
N-[4’-[1-ヒドロキシ-3-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)ブチル][1,1’-ビフェニル]-3-イル]アセタミド (1.31 g)、10 %パラジウム炭素 (386 mg)、1N塩酸 (0.637 ml)を用いて、実施例41-(ii)と同様の反応を行い表題化合物 (141 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.75 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 1.66-1.78 (1H, m), 2.13-2.16 (5H, m), 6.86 (1H, s), 7.30-7.53 (8H, m), 7.68 (1H, s).
IR (KBr): 1669, 1559, 1483, 1435, 1395, 1372, 791 cm-1.
実施例45
3’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
(i) 3-ブロモフェニルカルボキサミドの製造
3-ブロモベンゾイルクロリド (21.75 g)のTHF (20 ml)溶液に0℃で40%メチルアミンメタノール溶液(50ml)を加えて0℃で1時間かき混ぜた後、溶媒を減圧留去した。残留物を酢酸エチルに溶解後、水、食塩水で洗浄し、乾燥(硫酸マグネシウム)後、減圧濃縮した。残留物を酢酸エチル-へキサンから再結晶し表題化合物(18.6 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 2.99 (3H, d, J=5.0Hz), 6.55 (1H, brs), 7.28 (1H, t, J=7.9Hz), 7.56-7.72 (2H, m), 7.91 (1H, t, J=1.8Hz).
IR (KBr): 3304, 1640, 1557 cm-1.
【0051】
(ii) 3’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
3-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (1.01 g)、3-ブロモフェニルカルボキサミド(567 mg)およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.33 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(435 mg)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J=6.6Hz), 0.94 (3H, d, J=6.6Hz), 2.36-2.58 (1H, m), 3.03 (3H, d, J=4.6Hz), 3.66 (1H, s), 6.23 (1H, brs), 6.78 (1H, d, J=1.2Hz), 7.06-7.17 (6H, m), 7.23-7.54 (14H, m), 7.62-7.80 (3H, m), 7.88-7.93 (1H, m).
IR (KBr): 3378, 2969, 1644, 1549, 1447 cm-1.
(iii) 3’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
3’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミド(576 mg)とピリジン 塩酸塩 (0.22 g)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(55 mg)を無色粉末晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.81 (3H, d, J=6.6Hz), 0.97 (3H, d, J=6.6Hz), 2.60-2.84 (1H, m), 3.02 (3H, s), 7.00 (1H, d, J=1.0Hz), 7.30-7.55 (5H, m), 7.67-7.90 (3H, m), 8.01 (1H, t, J=1.5Hz).
IR (KBr): 2967, 2872, 1644, 1541 cm-1.
実施例46
4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-N-メチル[1,1'-ビフェニル]-3-カルボキサミドの製造
(i) 4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-N-メチル[1,1'-ビフェニル]-3-カルボキサミド.
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.44 g)、3-ブロモ-N-メチルベンズアミド (1.10 g)およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.21 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.00 g)を淡黄色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J= 6.7 Hz), 0.93 (3H, d, J= 6.7 Hz), 2.30-2.54 (1H, m), 3.02 (3H, d, J= 4.8 Hz), 3.58 (1H, s), 6.33 (1H, brs), 6.78 (1H, d, J= 1.4 Hz), 7.04-7.20 (6H, m), 7.22-7.38 (9H, m), 7.39-7.76 (8H, m), 7.98 (1H, t, J= 1.4 Hz).
IR (KBr): 3295, 2969, 1644, 1549, 1121 cm-1.
(ii) 4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-N-メチル[1,1'-ビフェニル]-3-カルボキサミドの製造
4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-N-メチル[1,1'-ビフェニル]-3-カルボキサミド(850 mg)とピリジン塩酸塩(270 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(210 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.81 (3H, d, J= 6.9 Hz), 0.98 (3H, d, J= 6.9 Hz), 2.40-2.80 (1H, m), 3.00 (3H, s), 6.96 (1H, s), 7.30 (1H, d, J= 1.4 Hz), 7.38-7.60 (5H, m), 7.60-7.74 (2H, m), 7.93 (1H, s).
IR (KBr): 3277, 2969, 1645, 1547 cm-1.
【0052】
実施例47
N-エチル-4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-カルボキサミドの製造
(i) 3-ブロモ-N-エチルベンズアミドの製造
水酸化ナトリウム (3.80 g)のメタノール(50 ml)-水(15 ml)溶液に0℃でエチルアミン塩酸塩(7.80 g)を少量ずつ加えて5分間かき混ぜ、3-ブロモベンゾイルクロリド(5.53 g)を滴下して、室温で1時間かき混ぜた。減圧下、メタノールを留去し、残留物に酢酸エチルを加えて分液した。有機層を水、食塩水で洗浄し、乾燥(硫酸マグネシウム)後、減圧濃縮した。残留物をへキサン-酢酸エチルから再結晶し表題化合物(5.47 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 1.26 (3H, t, J= 7.1 Hz), 3.40-3.59 (2H, m), 6.11 (1H, brs), 7.30 (1H, t, J= 8.2 Hz), 7.57-7.72 (2H, m), 7.90 (1H, t, J= 1.4 Hz).
IR (KBr): 3308, 1638, 1541 cm-1.
(ii) N-エチル-4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-カルボキサミド.
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (7.40 g, 14.7 mmol)、3-ブロモ-N-エチルベンズアミド(2.20 g)およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.441 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(2.56 g)を黄色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J= 6.8 Hz), 0.93 (3H, d, J= 6.8 Hz), 1.27 (3H, t, J= 7.2 Hz), 2.36-2.54 (1H, m), 3.42-3.61 (3H, m), 6.15 (1H, brs), 6.78 (1H, d, J= 1.6 Hz), 7.06-7.18 (6H, m), 7.27-7.38 (9H, m), 7.40-7.75 (8H, m), 7.97 (1H, t, J= 1.6 Hz).
IR (KBr): 3295, 2971, 1644, 1537 cm-1.
(iii) N-エチル-4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-カルボキサミドの製造
N-エチル-4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-カルボキサミド(4.00 g)とピリジン塩酸塩(1.14 g)用いて実施例4-(iii)と同様の反応を行ない、表題化合物(664 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.79 (3H, d, J= 6.7 Hz), 0.96 (3H, d, J= 6.7 Hz), 1.23 (3H, t, J= 7.1 Hz), 2.48-2.70 (1H, m), 3.36-3.56 (2H, m), 6.92 (1H, d, J= 1.2 Hz), 7.09 (1H, t, J= 5.5 Hz), 7.35-7.56 (6H, m), 7.58-7.72 (2H, m), 7.92 (1H, t, J= 1.6 Hz).
IR (KBr): 2973, 1644, 1537 cm-1.
【0053】
実施例48
4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-N-イソプロピル[1,1'-ビフェニル]-3-カルボキサミドの製造
(i) 3-ブロモ-N-イソプロピルベンズアミドの製造
3-ブロモベンゾイルクロリド (5.70 g)とイソプロピルアミン(4.10 g)を用いて実施例45-(i)と同様の反応を行ない、表題化合物(5.75 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 1.26 (6H, d, J= 6.6 Hz), 4.18-4.40 (1H, m), 5.97 (1H, brs), 7.23-7.34 (1H, m), 7.55-7.71 (2H, m), 7.84-7.90 (1H, m).
IR (KBr): 3241, 2973, 1634, 1545 cm-1.
(ii) 4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-N-イソプロピル[1,1'-ビフェニル]-3-カルボキサミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.40 g)、3-ブロモ-N-イソプロピルベンズアミド(1.70 g)およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.220 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.88 g)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J= 6.4 Hz), 0.93 (3H, d, J= 6.4 Hz), 1.28 (6H, d, J= 6.6 Hz), 2.36-2.58 (1H, m), 3.56 (1H, s), 4.20-4.44 (1H, m), 5.95 (1H, d, J= 7.0 Hz), 6.78 (1H, d, J= 1.4 Hz), 7.06-7.20 (6H, m), 7.26-7.38 (10H, m), 7.42-7.74 (7H, m), 7.95 (1H, t, J= 1.6 Hz).
IR (KBr): 2971, 1636, 1537 cm-1.
(iii) 4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-N-イソプロピル[1,1'-ビフェニル]-3-カルボキサミドの製造
4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-N-イソプロピル[1,1'-ビフェニル]-3-カルボキサミド(1.67 g) と ピリジン塩酸塩(490 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(480 mg)を無色粉末晶として得た。
1H-NMR (DMSO-d6)δ: 0.60-1.00 (6H, m), 1.19 (6H, d, J= 6.6 Hz), 2.54-2.78 (1H, m), 4.00-4.26 (1H, m), 7.42-7.68 (4H, m), 7.68-7.88 (4H, m), 8.08 (1H, s), 8.24-8.40 (1H, m), 11.80 (1H, brs).
IR (KBr): 3243, 2975, 1628, 1547 cm-1.
【0054】
実施例49
N-シクロプロピル-4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-カルボキサミドの製造
(i) 3-ブロモ-N-シクロプロピルベンズアミドの製造
3-ブロモベンゾイルクロリド(5.50 g)とシクロプロピルアミン(4.30 g)を用いて実施例45-(i)と同様の反応を行ない、表題化合物(5.20 g)を無色針状晶として得た。
1H-NMR (CDCl3)δ: 0.56-0.68 (2H, m), 0.82-0.96 (2H, m), 2.80-2.98 (1H, m), 6.20 (1H, brs), 7.30 (1H, t, J= 8.0 Hz), 7.58-7.70 (2H, m), 7.87 (1H, t, J= 1.9 Hz).
IR (KBr): 3283, 1638, 1563, 1537 cm-1.
(ii) N-シクロプロピル-4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-カルボキサミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.40 g)、3-ブロモ-N-シクロプロピルベンズアミド(1.53 gおよびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.290 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.84 g)を淡黄色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.58-0.74 (2H, m), 0.76 (3H, d, J= 6.8 Hz), 0.83-0.98 (5H, m), 2.35-2.60 (1H, m), 2.81-3.01 (1H, m), 3.56 (1H, s), 6.31 (1H, brs), 6.78 (1H, d, J= 1.4 Hz), 7.04-7.18 (6H, m), 7.26-7.38 (9H, m), 7.39-7.74 (8H, m), 7.93 (1H, t, J= 1.8 Hz).
IR (KBr): 3270, 2969, 1644, 1532 cm-1.
(iii) N-シクロプロピル-4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-カルボキサミドの製造
N-シクロプロピル-4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-カルボキサミド(2.13 g)とピリジン塩酸塩 (650 mg)用いて実施例4-(iii)と同様の反応を行ない、表題化合物(375 mg)を無色粉末晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.56-0.90 (7H, m), 0.96 (3H, d, J= 6.6 Hz), 2.44-2.70 (1H, m), 2.78-2.96 (1H, m), 6.92 (1H, s), 7.00 (1H, brs), 7.31-7.57 (6H, m), 7.58-7.74 (2H, m), 7.89 (1H, s).
IR (KBr): 3183, 2969, 1645, 1532 cm-1.
【0055】
実施例50
4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-6-メトキシ-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
(i) 4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-6-メトキシ-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
3-ブロモ-4-メトキシ-N-メチルベンズアミド (934 mg)、4-[1-ヒドロキシ-2-メチル-1-(1トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸の粗生成物 (2.50 g) 、2 M炭酸ナトリウム水溶液 (3.83 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (221 mg)を用いて、実施例33-(ii)と同様の反応を行い表題化合物 (1.45 g)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.78 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 7.0 Hz), 2.42-2.49 (1H, m), 3.00 (3H, d, J = 4.8 Hz), 3.56 (3H, s), 3.85 (3H, s), 6.10 (1H, br s), 6.78 (1H, d, J = 1.0 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.13-7.16 (5H, m), 7.32-7.80 (15H, m).
IR (KBr): 1645, 1491, 1464, 1258, 1182, 747, 733, 702 cm-1.
(ii) 4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-6-メトキシ-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-6-メトキシ-N-メチル[1,1’-ビフェニル]-3-カルボキサミド (1.40 g)、ピリジン塩酸塩 (468 mg)を用いて、実施例4-(iii)と同様の反応を行い表題化合物 (576 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.85 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 7.0 Hz), 2.58-2.71 (1H, m), 2.96 (3H, d, J = 4.4 Hz), 3.83 (3H, s), 6.96-7.00 (3H, m), 7.41-7.54 (5H, m), 7.68 (1H, d, J = 2.6 Hz), 7.77 (1H, dd, J = 2.6, 8.4 Hz).
IR (KBr): 1626, 1603, 1556, 1493, 1262, 1020, 829, 631 cm-1.
実施例51
6-フルオロ-4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
(i) 6-フルオロ-4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
3-ブロモ-4-フルオロ-N-メチルベンズアミド (889 mg)、4-[1-ヒドロキシ-2-メチル-1-(1トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸の粗生成物 (2.50 g)、2 M炭酸ナトリウム水溶液 (3.83 ml)、テトラキス(トリフェニルホスフィン)パラジウム(0) (221 mg)を用いて、実施例33-(ii)と同様の反応を行い表題化合物 (1.69 g)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 7.0 Hz), 2.42-2.49 (1H, m), 3.02 (3H, d, J = 4.8 Hz), 3.58 (1H, s), 6.13 (1H, br s), 6.78 (1H, d, J = 1.4 Hz), 7.11-7.23 (7H, m), 7.31-7.35 (9H, m), 7.46-7.72 (7H, m), 7.85 (1H, dd, J = 2.4, 7.2 Hz).
IR (KBr): 1647, 1487, 1447, 909, 747, 733, 702 cm-1.
【0056】
(ii) 6-フルオロ-4’-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
6-フルオロ-4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミド (1.64 g)、ピリジン塩酸塩 (559 mg)を用いて、実施例4-(iii)と同様の反応を行い、表題化合物 (535 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.83 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J = 6.0 Hz), 2.67 (1H, br s), 2.97 (3H, s), 6.98 (1H, s), 7.17 (1H, dd, J = 8.8, 8.8 Hz), 7.51-7.57 (5H, m), 7.70-7.73 (1H, m), 7.87 (1H, dd, J = 2.6, 7.2 Hz).
IR (KBr): 1645, 1559, 1539, 1487, 1325, 1252, 829 cm-1.
実施例52
[4’-[1-ヒドロキシ-(1H-イミダゾール-4-イル)エチル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミド
(i) N-メチル-[4’-[(1-トリチル-1H-イミダゾール-4-イル)カルボニル][1,1’-ビフェニル]-3-カルボキサミドの製造
3-ブロモ-N-メチルベンズアミド (16.0 g)のTHF (180 ml)溶液に-78 °Cでn-ブチルリチウムのヘキサン溶液 (1.6 M; 103 ml)をゆっくりと滴下し、-78 °Cで20分間撹拌後、-78 °Cでトリメトキシボラン(50.2 ml)を滴下し、-78 °Cで30分間、さらに室温で17時間撹拌した。反応液に2N塩酸 (82.0 ml)を加え、1時間撹拌後、酢酸エチルで抽出し、飽和食塩水で洗浄後、乾燥した。溶媒を減圧留去して3-[(メチルアミノ)カルボニル]フェニルボロン酸の粗生成物 (22.5 g)を淡黄色油状物として得た。本品 (19.2 g)、(4-ブロモフェニル)(1-トリチル-1H-イミダゾール-4-イル)メタノン (10.0 g)、2 M炭酸ナトリウム水溶液 (81.2 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (1.17 g)を用いて、実施例29-(i)と同様の反応を行い表題化合物 (6.89 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 3.05 (3H, d, J = 4.6 Hz), 6.22 (1H, br s), 7.14-7.22 (6H, m), 7.36-7.55 (10H, m), 7.62-7.78 (6H, m), 8.03 (1H, s), 8.37 (2H, d, J = 8.8 Hz).
IR (KBr): 1644, 1526, 1186, 1119, 891, 725, 702 cm-1.
(ii) [4’-[1-ヒドロキシ-(1-トリチル-1H-イミダゾール-4-イル)エチル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
N-メチル-[4’-[(1-トリチル-1H-イミダゾール-4-イル)カルボニル][1,1’-ビフェニル]-3-カルボキサミド (700 mg)、メチルマグネシウムブロミドのTHF溶液 (1.0 M; 3.83 ml)を用いて、実施例39-(iv)と同様の反応を行い表題化合物 (557 mg)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 1.81 (3H, s), 3.04 (3H, d, J = 5.2 Hz), 3.36 (1H, s), 6.17 (1H, br s), 6.79 (1H, d, J = 1.4 Hz), 7.13-7.18 (6H, m), 7.33-7.51 (15H, m), 7.66-7.71 (2H, m). 7.95 (1H, dd, J = 1.8, 1.8 Hz).
IR (KBr): 1644, 1547, 1445, 1159, 910, 735, 702 cm-1.
【0057】
(iii) [4’-[1-ヒドロキシ-(1H-イミダゾール-4-イル)エチル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
[4’-[1-ヒドロキシ-(1-トリチル-1H-イミダゾール-4-イル)エチル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミド (527 mg)、10 %パラジウム炭素 (527 mg)、1N塩酸 (0.935 ml)を用いて、実施例41-(ii)と同様の反応を行い表題化合物 (144 mg)を無色粉末晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 1.93 (3H, s), 3.00 (3H, s), 6.88 (1H, s), 7.44-7.74 (8H, m). 7.99 (1H, s).
IR (KBr): 3279, 1636, 1603, 1582, 1551, 737, 629 cm-1.
実施例53
[4’-[1-ヒドロキシ-(1H-イミダゾール-4-イル)プロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
(i) [4’-[1-ヒドロキシ-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
N-メチル-[4’-[(1-トリチル-1H-イミダゾール-4-イル)カルボニル][1,1’-ビフェニル]-3-カルボキサミド (1.50 g)、エチルマグネシウムブロミドのジエチルエーテル溶液 (3.0 M; 2.74 ml)を用いて、実施例39-(iv)と同様の反応を行い表題化合物 (1.34 g)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.86 (3H, t, J = 7.2 Hz), 2.01-2.24 (2H, m), 3.04 (3H, d, J = 2.3 Hz), 3.39 (1H, s), 6.24 (1H, br s), 6.78 (1H, d, J = 0.7 Hz), 7.13-7.19 (6H, m), 7.31-7.55 (15H, m), 7.67-7.78 (2H, m), 7.94-7.96 (1H, m).
IR (KBr): 1644, 1582, 1541, 1493, 1447, 909, 733, 700 cm-1.
(ii) [4’-[1-ヒドロキシ-(1H-イミダゾール-4-イル)プロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
[4’-[1-ヒドロキシ-(1-トリチル-1H-イミダゾール-4-イル)プロピル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミド (1.29 g)、10 %パラジウム炭素 (1.29 g)、1N塩酸 (2.23 ml)を用いて実施例41-(ii)と同様の反応を行い表題化合物 (540 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.90 (3H, t, J = 7.6 Hz), 2.22-2.33 (2H, m), 3.00 (3H, s), 6.93 (1H, s), 7.43-7.71 (8H, m), 8.00 (1H, s).
IR (KBr): 3189, 1634, 1603, 1582, 1557, 835, 812, 627 cm-1.
実施例54
[4’-[1-ヒドロキシ-(1H-イミダゾール-4-イル)ブチル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
(i) [4’-[1-ヒドロキシ-(1-トリチル-1H-イミダゾール-4-イル)-3-ブテニル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
N-メチル-[4’-[(1-トリチル-1H-イミダゾール-4-イル)カルボニル][1,1’-ビフェニル]-3-カルボキサミド (800 mg)、アリルマグネシウムブロミドのTHF溶液 (1.0 M; 6.57 ml)を用いて、実施例39-(iv)と同様の反応を行い表題化合物 (770 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 2.80-3.05 (5H, m), 3.36 (1H, s), 5.04-5.12 (2H, m), 5.66-5.82 (1H, m), 6.23 (1H, br s), 6.79 (1H, d, J = 1.4 Hz), 7.12-7.19 (6H, m), 7.32-7.54 (15H, m), 7.63-7.78 (2H, m), 7.95-7.96 (1H, m).
IR (KBr): 1644, 1541, 1445, 909, 747, 733, 702 cm-1.
【0058】
(ii) [4’-[1-ヒドロキシ-(1H-イミダゾール-4-イル)ブチル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミドの製造
[4’-[1-ヒドロキシ-(1-トリチル-1H-イミダゾール-4-イル)-3-ブテニル]-N-メチル[1,1’-ビフェニル]-3-カルボキサミド (690 mg)、10 %パラジウム炭素 (690 mg)、1N塩酸 (1.17 ml)を用いて、実施例41-(ii)と同様の反応を行い表題化合物 (269 mg)を無色アモルファスとして得た。
表題化合物 (420 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.91 (3H, t, J = 7.2 Hz), 1.21-1.43 (2H, m), 2.09-2.19 (2H, m), 3.00 (3H, s), 6.91 (1H, s), 7.38-7.58 (6H, m), 7.70-7.74 (2H, m), 7.98 (1H, s).
IR (KBr): 3212, 1636, 1582, 1557, 831, 812, 737 cm-1.
実施例55
2-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}-N-メチルアセタミドの製造
(i) 2-(3-ブロモフェニル)-N-メチルアセタミドの製造
3-ブロモフェニル酢酸(3.02 g)、メチルアミンTHF溶液(2.0 M; 8.5 ml)、 1−[3−(ジメチルアミノ)プロピル]−3−エチルカルボジイミド塩酸塩(3.20 g)、1-ヒドロキシベンゾトリアゾール (2.60 g) およびトリエチルアミン(2.3 ml)の混合物をDMF(30 ml)中、室温で24時間かき混ぜた。反応液を酢酸エチルで希釈し、水、1N水酸化ナトリウム水溶液、1N塩酸、重曹水、食塩水で順次洗浄し、乾燥(硫酸マグネシウム)後、減圧濃縮した。残留物をシリカゲルクロマトグラフィー(溶出液;酢酸エチル)に付して精製し、へキサン-酢酸エチルから再結晶すると表題化合物(1.30 g)が無色プリズム晶として得られた。
1H-NMR (CDCl3)δ: 2.70 (3H, d, J= 4.8 Hz), 3.45 (2H, s), 5.34 (1H, brs), 7.04-7.20 (2H, m), 7.28-7.39 (2H, m).
IR (KBr): 3285, 1651, 1568 cm-1.
(ii) 2-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}-N-メチルアセタミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸(3.47 g)、2-(3-ブロモフェニル)-N-メチルアセタミド(0.93 g) および テトラキス(トリフェニルホスフィン)パラジウム(0) (0.21 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(580 mg)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J= 6.6 Hz), 0.93 (3H, d, J= 6.6 Hz), 2.36-2.54 (1H, m), 2.76 (3H, d, J= 4.6 Hz), 3.55 (1H, s), 3.64 (2H, s), 5.41 (1H, brs), 6.78 (1H, d, J= 1.4 Hz), 7.08-7.24 (7H, m), 7.28-7.62 (17H, m).
IR (KBr): 3303, 2969, 1651, 1481, 1445 cm-1.
(iii) 2-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}-N-メチルアセタミドの製造
2-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}-N-メチルアセタミド(1.09 g)とピリジン塩酸塩 (309 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(260 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.80 (3H, d, J= 6.8 Hz), 0.96 (3H, d, J= 6.8 Hz), 2.44-2.66 (1H, m), 2.71 (3H, d, J= 4.8 Hz), 3.56 (2H, s), 5.88 (1H, brs), 6.89 (1H, s), 7.16 (1H, d, J= 7.8 Hz), 7.27-7.49 (6H, m), 7.53 (2H, d, J= 8.4 Hz).
IR (KBr): 3071, 2969, 1651 cm-1.
【0059】
実施例56
N-({4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}メチル)アセタミドの製造
(i) N-(3-ブロモベンジル)アセタミドの製造
3-ブロモベンジルアミン塩酸塩(5.20 g)のピリジン(30 ml)溶液に0℃で無水酢酸(3.2 ml) を加えて室温で24時間かき混ぜた。反応液に水と酢酸エチルを加えて分液し、有機層を1N塩酸、重曹水と食塩水で洗浄し、乾燥(硫酸ンマグネシウム)後、減圧濃縮した。残留物をへキサン-酢酸エチルから再結晶すると表題化合物(4.00 g)が無色針状晶として得られた。
1H-NMR (CDCl3)δ: 2.02 (3H, d, J= 1.4 Hz), 4.38 (2H, d, J= 6.0 Hz), 6.04 (1H, brs), 7.10-7.26 (2H, m), 7.30-7.48 (2H, m).
IR (KBr): 3283, 1636, 1549 cm-1.
(ii) N-({4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}メチル)アセタミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.30 g)、N-(3-ブロモベンジル)アセタミド(1.05 g) およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.18 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.24 g)を淡黄色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J= 6.7 Hz), 0.92 (3H, d, J= 6.7 Hz), 2.04 (3H, s), 2.36-2.54 (1H, m), 3.55 (1H, s), 4.49 (2H, d, J= 5.8 Hz), 5.80 (1H, brs), 6.78 (1H, d, J= 1.4 Hz), 7.06-7.24 (7H, m), 7.26-7.60 (17H, m).
IR (KBr): 3293, 2967, 1659, 1445 cm-1.
(iii) N-({4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}メチル)アセタミドの製造
N-({4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}メチル)アセタミド(1.05 g)とピリジン塩酸塩(278 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(490 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.82 (3H, d, J= 6.8 Hz), 0.98 (3H, d, J= 6.8 Hz), 2.02 (3H, s), 2.53-2.70 (1H, m), 4.46 (2H, d, J= 5.6 Hz), 5.94 (1H, brs), 6.96 (1H, d, J= 1.0 Hz), 7.19-7.26 (1H, m), 7.37 (1H, t, J= 7.7 Hz), 7.42-7.53 (5H, m), 7.58 (2H, d, J= 8.4 Hz).
IR (KBr): 3264, 1651, 1559 cm-1.
【0060】
実施例57
1-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}エタノンの製造
(i) 1-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}エタノンの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (6.22 g) and 3’-ブロモアセトフェノン(2.30 g) および テトラキス(トリフェニルホスフィン)パラジウム(0) (0.210 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.50 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J= 7.0 Hz), 0.93 (3H, d, J= 7.0 Hz), 2.38-2.58 (1H, m), 2.66 (3H, s), 3.55 (1H, s), 6.78 (1H, d, J= 1.4 Hz), 7.07-7.20 (6H, m), 7.28-7.40 (9H, m), 7.46-7.71 (6H, m), 7.74-7.84 (1H, m), 7.87-7.95 (1H, m), 8.17 (1H, t, J= 1.7 Hz).
IR (KBr): 2967, 1688, 1236 cm-1.
(ii) 1-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}エタノンの製造
1-{4'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}エタノン(3.30 g)とピリジン塩酸塩(870 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(910 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.83 (3H, d, J= 6.6 Hz), 0.99 (3H, d, J= 6.6 Hz), 2.50-2.80 (4H, m), 6.99 (1H, s), 7.44-7.69 (6H, m), 7.76 (1H, d, J= 8.0 Hz), 7.90 (1H, d, J= 8.0 Hz), 8.15 (1H, s).
IR (KBr): 2971, 1682, 1238 cm-1.
実施例58
(−)-1-(4'-フルオロ[1,1'-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
実施例13で得られた1-(4'-フルオロ[1,1'-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールを光学活性カラム (Chiralpak AD)を用いる液体クロマトグラフィー(溶出液;へキサン:エタノール=9:1)に付し、第一溶出の対掌体として(−)-1-(4'-フルオロ[1,1'-ビフェニル]-3-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールを得た。
光学純度; 99 %ee (Chiralpak AD)
[α]D 20 −47.1 °(C=0.31, メタノール)
【0061】
実施例59
4-フルオロ-4’-[1-ヒドロキシ-1-(-1H-イミダゾール-4-イル)-2-メチルプロピル][1,1’-ビフェニル]-3-カルボキサミドの製造
(i) 4-フルオロ-4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-3-カルボキサミドの製造
5-ブロモ-2-フルオロベンゾニトリル (1.04 g)、4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸の粗生成物 (3.40 g)、2 M炭酸ナトリウム水溶液 (5.20 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (211 mg)を用いて、実施例33-(ii)と同様の反応を行い表題化合物 (1.25 g)を無色針状結晶として得た。
1H-NMR (CDCl3)δ: 0,75 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.41-2.48 (1H, m), 3.54 (1H, s), 6.78 (1H, d, J = 1.0 Hz), 7.12-7.15 (4H, m), 7.22-7.35 (13H, m), 7.42 (2H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.74-7.81 (2H, m).
IR (KBr): 2236, 1493, 1447, 910, 818, 747, 735, 702 cm-1.
(ii) 4-フルオロ-4’-[1-ヒドロキシ-1-(-1H-イミダゾール-4-イル)-2-メチルプロピル][1,1’-ビフェニル]-3-カルボキサミド
4-フルオロ-4’-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-3-カルボキサミド (1.20 g)、ピリジン塩酸塩 (432 mg)を用いて、実施例4-(iii)と同様の反応を行い表題化合物 (577 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.82 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 6.6 Hz), 2.57-2.67 (1H, m), 6.98 (1H, s), 7.29 (1H, d, J = 6.6 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.56-7.63 (3H, m), 7.76-7.79 (2H, m).
IR (KBr): 3133, 2973, 2236, 1493, 1273, 1244, 1119, 1015, 818 cm-1.
実施例60
(−)-N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
実施例31で得られたN-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドを光学活性カラム (Chiralpak AD)を用いる液体クロマトグラフィー(溶出液;へキサン:エタノール=9:1)に付し、第一溶出の対掌体として(−)-N-{4'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドを得た。
光学純度; 99.9 %ee (Chiralpak AD)
[α]D 20 −17.3 °(C=1.0 , メタノール)
【0062】
実施例61
1-(3’,4’-ジメトキシ[1,1’-ビフェニル]-4-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 1-(3’,4’-ジメトキシ[1,1’-ビフェニル]-4-イル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(4-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (1.50 g)、3,4-ジメトキシフェニルボロン酸 (762 mg)、2 M炭酸ナトリウム水溶液 (2.79 ml)、 テトラキス(トリフェニルホスフィン)パラジウム(0) (96.7 mg)を用いて、実施例29-(i)と同様の反応を行い表題化合物 (1.42 g)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.40-2.53 (1H, m), 3.51 (1H, s), 3.92 (3H, s), 3.95 (3H, s), 6.78 (1H, d, J = 1.0 Hz), 6.93 (1H, d, J = 8.2 Hz), 7.11-7.16 (8H, m), 7.31-7.35 (10H, m), 7.46 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz).
IR (KBr): 1470, 1445, 1250, 1217, 1173, 747, 731, 702 cm-1.
(ii) 1-(3’,4’-ジメトキシ[1,1’-ビフェニル]-4-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(3’,4’-ジメトキシ[1,1’-ビフェニル]-4-イル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (1.37 g)、ピリジン塩酸塩 (479 mg) を用いて、実施例4-(iii)と同様の反応を行い表題化合物(660 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.83 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.57-2.67 (1H, m), 3.91 (3H, s), 3.93 (3H, s), 6.90-6.98 (2H, m), 7.10-7.15 (2H, m), 7.47-7.63 (5H, m).
IR (KBr): 1526, 1505, 1464, 1219, 1171, 1142, 1026, 829, 806 cm-1.
実施例62
1-(3’-メトキシ[1,1’-ビフェニル]-4-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
(i) 1-(3’-メトキシ[1,1’-ビフェニル]-4-イル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(4-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (1.50 g)、3-メトキシフェニルボロン酸 (635 mg)、2 M炭酸ナトリウム水溶液 (2.79 ml)、テトラキス(トリフェニルホスフィン)パラジウム (0) (96.7 mg)を用いて、実施例29-(i)と同様の反応を行い表題化合物 (1.01 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 7.0 Hz), 2.39-2.49 (1H, m), 3.54 (1H, s), 3.86 (3H, s), 6.77 (1H, d, J = 1.4 Hz), 6.87 (1H, dd, J = 2.4, 7.2Hz), 7.11-7.19 (8H, m), 7.30-7.38 (10H, m), 7.47-7.66 (5H, m).
IR (KBr): 1599, 1480, 1447, 1213, 1167, 909, 822, 747, 733, 702 cm-1.
【0063】
(ii) 1-(3’-メトキシ[1,1’-ビフェニル]-4-イル)-1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパノールの製造
1-(3’-メトキシ[1,1’-ビフェニル]-4-イル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (960 mg)、ピリジン塩酸塩 (354 mg)を用いて、実施例4-(iii)と同様の反応を行い表題化合物 (483 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.82 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 2.59-2.69 (1H, m), 3.85 (3H, s), 6.86-6.96 (2H, m), 7.11-7.18 (2H, m), 7.29-7.65 (6H, m).
IR (KBr): 1481, 1296, 1219, 1171, 1032, 1015, 826, 775, 696 cm-1.
実施例63
1-(1H-イミダゾール-4-イル)-2-メチル-1-[3-(4-ピリジル)フェニル]-1-プロパノールの製造
(i) 2-メチル-1-[3-(4-ピリジル)フェニル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(3-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (1.20 g)、4-ピリジルボロン酸 (754 mg)、2 M炭酸ナトリウム水溶液 (2.23 ml)、テトラキス(トリフェニルホスフィン)パラジウム(0) (155 mg)を用いて、実施例29-(i)と同様の反応を行い表題化合物 (1.13 g)を淡黄色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.75 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6 Hz), 2.05-2.50 (1H, m), 3.72 (1H, s), 7.86 (1H, d, J = 0.6 Hz), 7.10-7.15 (7H, m), 7.27-7.47 (12H, m), 7.51-7.75 (3H, m), 8.62-8.65 (2H, m).
IR (KBr): 1597, 1445, 909, 791, 747, 735, 702, 660 cm-1.
(ii) 1-(1H-イミダゾール-4-イル)-2-メチル-1-[3-(4-ピリジル)フェニル]-1-プロパノールの製造
2-メチル-1-[3-(4-ピリジル)フェニル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (1.08 g)、ピリジン塩酸塩 (419 mg)を用いて、実施例4-(iii)と同様の反応を行い表題化合物 (477 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.82 (3H, d, J = 7.0 Hz), 1.00 (3H, d, J = 7.0 Hz), 2.59-2.72 (1H, m), 7.00 (1H, s), 7.36-7.62 (6H, m), 7.89 (1H, s), 8.57-8.60 (2H, m).
IR (KBr): 3073, 2969, 1599, 1476, 1005, 909, 831, 789, 733, 619 cm-1.
【0064】
実施例64
1-(1H-イミダゾール-4-イル)-2-メチル-1-[3-(3-ピリジル)フェニル]-1-プロパノールの製造
(i) 2-メチル-1-[3-(3-ピリジル)フェニル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(3-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (1.01 g)、ジエチル(3-ピリジル)ボラン(0.497 g)およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.170 g)を用いて実施例4-(ii)と同様の反応を行ない、表題化合物(0.657 g)を淡黄色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J=6.7 Hz), 0.94 (3H, d, J=6.7 Hz), 2.30-2.55 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J=1.4 Hz), 7.05-7.46 (19H, m), 7.50-7.62 (1H, m), 7.69 (1H, s), 7.82 (1H, dt, J=8.0, 2.0Hz), 8.59 (1H, dd, J=2.0, 4.8 Hz), 8.80 (1H, d, J=2.2 Hz).
IR (KBr): 1491, 1470, 1445, 912 cm-1.
(ii) 1-(1H-イミダゾール-4-イル)-2-メチル-1-[3-(3-ピリジル)フェニル]-1-プロパノールの製造
2-メチル-1-[3-(3-ピリジル)フェニル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(0.57 g)とピリジン塩酸塩(208 mg)用いて実施例4-(iii)と同様の反応を行ない、表題化合物(288 mg)を無色粉末晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.82 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz), 2.55-2.76 (1H, m), 6.99 (1H, d, J=1.3 Hz), 7.34-7.47 (3H, m), 7.52 (1H, d, J=1.3 Hz), 7.50-7.59 (1H, m), 7.77 (1H, s), 7.88-7.98 (1H, m), 8.50 (1H, dd, J=2.2, 5.0 Hz), 8.75 (1H, dd, J=0.8, 2.2 Hz).
IR (KBr): 2971, 1470, 1022, 970 cm-1.
実施例65
1-(1H-イミダゾール-4-イル)-2-メチル-1-[3-(2-ピリジル)フェニル]-1-プロパノールの製造
(i) 2-メチル-1-[3-(2-ピリジル)フェニル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
1-(3-ブロモフェニル)-(1-トリチル-1H-イミダゾール-4-イル)-2-メチル-1-プロパノール (1.15 g)、トリ-n-ブチル(2-ピリジル)すず (1.01 g)のDMF (10 ml)溶液を脱気後、テトラキス(トリフェニルホスフィン)パラジウム(0) (73.1 mg)を加え、アルゴン雰囲気下、80 °Cで5時間攪拌後、よう化銅(I) (20.1 mg)、テトラキス(トリフェニルホスフィン)パラジウム(0) (48.7 mg)を加え、100 °Cで18時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、5%エチレンジアミン水溶液、水(2回)、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィー (溶出液;ヘキサン : 酢酸エチル = 3 : 1→2 : 1)で精製し、酢酸エチル-ヘキサンから再結晶を行い表題化合物 (577 mg, 51 %)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.45-2.52 (1H, m), 3.68 (1H, s), 6.86 (1H, d, J = 1.6 Hz), 7.10-7.43 (18H, m), 7.58-7.86 (4H, m), 8.09-8.10 (1H, m), 8.66-8.69 (1H, m).
IR (KBr): 1586, 1493, 1472, 1445, 909, 774, 747, 733, 702 cm-1.
【0065】
(ii) 1-(1H-イミダゾール-4-イル)-2-メチル-1-[3-(2-ピリジル)フェニル]-1-プロパノールの製造
2-メチル-1-[3-(2-ピリジル)フェニル]-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (527 mg)、ピリジン塩酸塩 (205 mg)を用いて、実施例4-(iii)と同様の反応を行い表題化合物 (197 mg)を無色板状結晶として得た。
1H-NMR (CDCl3)δ: 0.80 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 6.6 Hz), 2.58-2.71 (1H, m), 6.89 (1H, s), 7.17-7.24 (1H, m), 7.35-7.43 (2H, m), 7.59 (1H, d, J = 7.8 Hz), 7.67-7.79 (3H, m), 8.16 (1H, s), 8.62 (1H, d, J = 4.8 Hz).
IR (KBr): 3187, 1584, 1460, 1362, 1304, 1007, 799, 768 cm-1.
実施例66
N-{3'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
(i) N-{3'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
1-(3-ブロモフェニル)-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (1.02 g)、3-アセタミドベンゼンボロン酸 (0.531 g)および テトラキス(トリフェニルホスフィン)パラジウム(0) (0.170 g)を用いて実施例4-(ii)と同様の反応を行ない、表題化合物(0.980 g)を淡黄色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.75 (3H, d, J=6.8 Hz), 0.93 (3H, d, J=6.8 Hz), 2.16 (3H, s), 2.35-2.58 (1H, m), 3.68 (1H, brs), 6.80 (1H, d, J=1.4 Hz), 7.04-7.18 (6H, m), 7.20-7.42 (13H, m), 7.44-7.56 (3H, m), 7.62-7.74 (2H, m).
IR (KBr): 3289, 1669, 1557, 1493 cm-1.
(ii) N-{3'-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1'-ビフェニル]-3-イル}アセタミドの製造
N-{3'-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1'-ビフェニル]-3-イル}アセタミド(0.781 g)とピリジン塩酸塩(290 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(315 mg)を無色粉末晶として得た。
1H-NMR (DMSO-d6)δ: 0.69 (3H, d, J=6.6 Hz), 0.82 (3H, d, J=6.6 Hz), 2.07 (3H, s), 2.57-2.78 (1H, m), 5.12 (1H, brs), 6.96 (1H, s), 7.21-7.43 (4H, m), 7.50-7.66 (3H, m), 7.80 (1H, s), 7.88 (1H, s).
IR (KBr): 3295, 1667, 1557, 789 cm-1.
【0066】
実施例67
5-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-N-メチルニコチンアミドの製造
(i) 5-ブロモ-N-メチルニコチンアミドの製造
5-ブロモニコチン酸 (5.01g)、メチルアミンTHF溶液(2.0 M ; 30 ml)、1−[3−(ジメチルアミノ)プロピル]−3−エチルカルボジイミド塩酸塩(5.79 g)および 1-ヒドロキシベンゾトリアゾール (4.72 g)を用いて実施例55-(i)と同様の反応を行ない、表題化合物(2.30 g)を無色プリズム晶として得た。
1H-NMR (CDCl3)δ: 3.04 (3H, d, J=4.8 Hz), 6.45 (1H, brs), 8.27 (1H, t, J=2.1 Hz), 8.78 (1H, d, J=2.1 Hz), 8.86 (1H, d, J=2.1 Hz).
IR (KBr): 3297, 3025, 1645, 1416 cm-1.
(ii) 5-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-N-メチルニコチンアミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.0 g)、5-ブロモ-N-メチルニコチンアミド(1.01 g)およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.177 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.26 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.76 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6 Hz), 2.36-2.60 (1H, m), 3.07 (3H, d, J=5.2 Hz), 3.59 (1H, s), 6.30 (1H, brs), 6.78 (1H, d, J=1.4 Hz), 7.06-7.20 (6H, m), 7.26-7.38 (10H, m), 7.52 (2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.4 Hz), 8.29 (1H, t, J=2.2 Hz), 8.88 (1H, d, J=2.2 Hz), 8.94 (1H, d, J=2.2 Hz).
IR (KBr): 3227, 2969, 1651 cm-1.
(iii) 5-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-N-メチルニコチンアミドの製造
5-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-N-メチルニコチンアミド(1.44 g)とピリジン塩酸塩(466 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(360 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.80 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz), 2.40-2.80 (1H, m), 3.02 (3H, s), 6.98 (1H, d, J=1.0 Hz), 7.45 (2H, d, J=8.4 Hz), 7.48 (1H, d, J=1.0 Hz), 7.59 (2H, d, J=8.4 Hz), 8.28 (1H, t, J=2.1 Hz), 8.78 (1H, d, J=2.1 Hz), 8.84 (1H, d, J=2.1 Hz).
IR (KBr): 3200, 2971, 1651, 1557 cm-1.
【0067】
実施例68
N-(6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-2-ピリジル)アセタミドの製造
(i) N-(6-ブロモ-2-ピリジル)アセタミドの製造
2-アミノ-6-ブロモピリジン(2.97 g)と無水酢酸 (2.9 ml)を用いて実施例56-(i)と同様の反応を行ない、表題化合物(2.30 g)を無色鱗片状晶として得た。
1H-NMR (CDCl3)δ: 2.20 (3H, s), 7.21 (1H, d, J=8.0 Hz), 7.56 (1H, t, J=8.0 Hz), 8.05 (1H, brs), 8.15 (1H, d, J=8.0 Hz).
IR (KBr): 3231, 1661, 1574, 1439, 1391 cm-1.
(ii) N-(6-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-2-ピリジル)アセタミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.01 g)、N-(6-ブロモ-2-ピリジル)アセタミド(1.05 g)およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.138 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(0.720 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.74 (3H, d, J=6.8 Hz), 0.92 (3H, d, J=6.8 Hz), 2.20 (3H, s), 2.34-2.58 (1H, m), 3.60 (1H, s), 6.77 (1H, d, J=1.4 Hz), 7.06-7.20 (6H, m), 7.28-7.42 (10H, m), 7.44 (1H, dd, J=0.8, 7.9 Hz), 7.59 (2H, d, J=8.4 Hz), 7.75 (1H, t, J=7.9 Hz), 7.83 (2H, d, J=8.4 Hz), 8.05-8.16 (2H, m).
IR (KBr): 2969, 1732, 1690, 1447 cm-1.
(iii) N-(6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-2-ピリジル)アセタミドの製造
N-(6-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-2-ピリジル)アセタミド(1.48 g) と ピリジン塩酸塩(520 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(520 mg)を無色粉末晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.81 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.7 Hz), 2.22 (3H, s), 2.52-2.74 (1H, m), 6.97 (1H, d, J=1.0 Hz), 7.44 (1H, d, J=7.8 Hz), 7.52 (1H, d, J=1.0 Hz), 7.59 (2H, d, J=8.4 Hz), 7.76 (1H, t, J=7.8 Hz), 7.83 (2H, d, J=8.4 Hz), 8.09 (1H, d, J=7.8 Hz).
IR (KBr): 3177, 2967, 1651, 1559, 1451 cm-1.
実施例69
6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-N-メチル-2-ピリジンカルボキサミドの製造
(i) 6-ブロモ-N-メチル-2-ピリジンカルボキサミドの製造
6-ブロモピコリン酸(3.00 g)、メチルアミンTHF溶液 (2.0 M; 18 ml)、1−[3−(ジメチルアミノ)プロピル]−3−エチルカルボジイミド塩酸塩(3.41 g)および1-ヒドロキシベンゾトリアゾール (2.99 g)を用いて実施例55-(i)と同様の反応を行ない、表題化合物(2.60 g)を淡褐色油状物として得た。
1H-NMR (CDCl3)δ: 3.04 (3H, d, J=5.2 Hz), 7.60 (1H, dd, J=1.0, 7.6 Hz), 7.72 (1H, t, J=7.6 Hz), 8.16 (1H, dd, J=1.0, 7.6 Hz).
IR (neat): 3391, 1682, 1669, 1557, 1539 cm-1.
【0068】
(ii) 6-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-N-メチル-2-ピリジンカルボキサミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (2.97 g)、6-ブロモ-N-メチル-2-ピリジンカルボキサミド(1.30 g) およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.110 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.11 g)を無色粉末晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.76 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz), 2.44-2.64 (1H, m), 3.04-3.10 (3H, m), 6.83 (1H, d, J=1.2 Hz), 7.08-7.20 (6H, m), 7.30-7.40 (10H, m), 7.63 (2H, d, J=8.4 Hz), 7.82-7.98 (4H, m), 8.06-8.14 (1H, m), 8.33 (1H, brs).
IR (KBr): 3387, 2967, 1672, 1449 cm-1.
(iii) 6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-N-メチル-2-ピリジンカルボキサミドの製造
6-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-N-メチル-2-ピリジンカルボキサミド(1.44 g)とピリジン塩酸塩(550 mg) を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(255 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.81 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz), 2.48-2.70 (1H, m), 3.02 (3H, d, J=5.2 Hz), 6.98 (1H, s), 7.48 (1H, s), 7.64 (2H, d, J=8.4 Hz), 7.70-7.83 (2H, m), 7.88 (2H, d, J=8.4 Hz), 8.04 (1H, d, J=7.0 Hz), 8.16-8.30 (1H, m).
IR (KBr): 2969, 1667, 1537, 1449 cm-1.
実施例70
N-(2-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-4-ピリジル)アセタミドの製造
(i) 1-[4-(4-アミノ-2-ピリジル)フェニル]-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (5.78 g)、4-アミノ-2-クロロピリジン (1.00 g)、臭化ナトリウム(810 mg)およびテトラキス(トリフェニルホスフィン)パラジウム(0)(0.190 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(2.30 g)を黄色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.74 (3H, d, J=6.5 Hz), 0.91 (3H, d, J=6.5 Hz), 2.36-2.56 (1H, m), 3.61 (1H, s), 4.17 (2H, s), 6.46 (1H, dd, J=2.2, 5.6 Hz), 6.77 (1H, s), 6.93 (1H, d, J=2.2 Hz), 7.06-7.19 (6H, m), 7,27-7,39 (10H, m), 7.56 (2H, d, J=8.2 Hz), 7.82 (2H, d, J=8.2 Hz), 8.29 (1H, d, J=5.6 Hz).
IR (KBr): 3335, 3210, 1599, 1445 cm-1.
【0069】
(ii) N-(2-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-4-ピリジル)アセタミドの製造
1-[4-(4-アミノ-2-ピリジル)フェニル]-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール(1.40 g)、 無水酢酸(0.46 ml)、トリエチルアミン(0.71 ml) およびp-ジメチルアミノピリジン(20 mg)の混合物をTHF (20 ml)中、60℃で16時間かき混ぜた。溶媒を留去し、残留物に酢酸エチルと水を加えて分液した。有機層を重曹水と食塩水で洗浄し、乾燥(硫酸マグネシウム)後、減圧濃縮した。残留物をアセトニトリル(10 ml)-水(10ml)の混液に溶解し、臭化テトラブチルアンモニウム(13 mg)を加えて室温で10時間攪拌した。有機層を分離し、水層を酢酸エチルで抽出した。有機層を合わせて乾燥(硫酸マグネシウム)し、減圧下濃縮した。残留物をシリカゲルクロマトグラフィー(溶出液;へキサン:酢酸エチル=2:1 )に付して精製し、酢酸エチルから再結晶すると表題化合物(630 mg)が無色粉末晶として得られた。
1H-NMR (CDCl3+CD3OD)δ: 0.74 (3H, d, J=6.8 Hz), 0.92 (3H, d, J=6.8 Hz), 2.19 (3H, s), 2.42-2.62 (1H, m), 6.82 (1H, d, J=1.0 Hz), 7.06-7.20 (6H, m), 7.26-7.42 (10H, m), 7.50-7.62 (3H, m), 7.77-7.88 (3H, m), 8.46 (1H, d, J=5.6 Hz).
IR (KBr): 3264, 2973, 1707, 1588 cm-1.
(iii) N-(2-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-4-ピリジル)アセタミドの製造
N-(2-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-4-ピリジル)アセタミド(0.590 g)とピリジン塩酸塩(190 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(150 mg)を無色粉末晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.81 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz), 2.19 (3H, s), 2.50-2.78 (1H, m), 6.98 (1H, m), 7.50-7.66 (4H, m), 7.74-7.86 (2H, m), 7.92 (1H, s), 8.43 (1H, dd, J=2.6, 7.4 Hz).
IR (KBr): 3094, 1703, 1599, 1522 cm-1.
実施例71
N-エチル-6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-2-ピリジンカルボキサミドの製造
(i) 6-ブロモ-N-エチル-2-ピリジンカルボキサミドの製造
6-ブロモピコリン酸 (3.06 g)、エチルアミン塩酸塩 (2.49 g) 、トリエチルアミン(6 ml)、1−[3−(ジメチルアミノ)プロピル]−3−エチルカルボジイミド塩酸塩(3.61 g)および1-ヒドロキシベンゾトリアゾール (2.66 g)を用いて実施例55-(i)と同様の反応を行ない、表題化合物(3.20 g)を無色油状物として得た。
1H-NMR (CDCl3)δ: 1.28 (3H, t, J=7.3 Hz), 3.40-3.64 (2H, m), 7.60 (1H, d, J=7.9 Hz), 7.72 (1H, t, J=7.9 Hz), 7.82 (1H, brs), 8.16 (1H, d, J=7.9 Hz).
IR (KBr): 2975, 1669, 1557, 1532, 1427 cm-1.
【0070】
(ii) N-エチル-6-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-2-ピリジンカルボキサミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.10 g)、6-ブロモ-N-エチル-2-ピリジンカルボキサミド(1.20 g)およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.170 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.89 g)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J=7.0 Hz), 0.93 (3H, d, J=7.0 Hz), 1.31 (3H, t, J=7.3 Hz), 2.40-2.60 (1H, m), 3.44-3.64 (2H, m), 3.54 (1H, s), 6.79 (1H, d, J=1.6 Hz), 7.08-7.19 (6H, m), 7.28-7.39 (10H, m), 7.66 (2H, d, J=8.8 Hz), 7.79-7.96 (4H, m), 8.13 (1H, dd, J=1.4, 7.4 Hz).
IR (KBr): 1671, 1524, 1449 cm-1.
(iii) N-エチル-6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-2-ピリジンカルボキサミドの製造
N-エチル-6-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-2-ピリジンカルボキサミド(1.82 g)とピリジン塩酸塩(570 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(560 mg)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.84 (3H, d, J= 6.6 Hz), 1.00 (3H, d, J= 6.6 Hz), 1.29 (3H, t, J= 7.3 Hz), 2.56-2.78 (1H, m), 3.44-3.64 (2H, m), 7.01 (1H, d, J= 1.2 Hz), 7.55 (1H, d, J= 1.2 Hz), 7.69 (2H, d, J= 8.6 Hz), 7.77-7.88 (2H, m), 7.93 (2H, d, J= 8.6 Hz), 8.10 (1H, dd, J=1.4, 7.0 Hz), 8.18 (1H, brs).
IR (KBr): 3441, 3395, 2975, 1676, 1530, 1449 cm-1.
実施例72
6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-N-イソプロピル-2-ピリジンカルボキサミドの製造
(i) 6-ブロモ-N-イソプロピル-2-ピリジンカルボキサミドの製造
6-ブロモピコリン酸(3.04 g)、イソプロピルアミン(5 ml)、1−[3−(ジメチルアミノ)プロピル]−3−エチルカルボジイミド塩酸塩(3.44 g) および1-ヒドロキシベンゾトリアゾール (2.70 g)を用いて実施例55-(i)と同様の反応を行ない、表題化合物(3.10 g)を無色油状物として得た。
1H-NMR (CDCl3)δ: 1.29 (6H, d, J=6.6 Hz), 4.10-4.40 (1H, m), 7.60 (1H, dd, J=1.2, 7.8 Hz), 7.71 (1H, t, J=7.8 Hz), 8.16 (1H, dd, J=1.2, 7.8 Hz).IR (KBr): 2973, 1674, 1557, 1520 cm-1.
【0071】
(ii) 6-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-N-イソプロピル-2-ピリジンカルボキサミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (3.10 g)、6-ブロモ-N-イソプロピル-2-ピリジンカルボキサミド(1.13 g) およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.160 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(1.67 g)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.78 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz), 1.32 (6H, d, J=6.6 Hz), 2.40-2.58 (1H, m), 3.56 (1H, s), 4,20-4.42 (1H, m), 6.80 (1H, s), 7.00-7.20 (6H, m), 7.21-7.46 (10H, m), 7.66 (2H, d, J=8.5 Hz), 7.79-7.86 (1H, m), 7.92 (2H, d, J=8.5 Hz), 8.04 (1H, d, J=7.4 Hz), 8.14 (1H, dd, J=1.0, 6.2 Hz).
IR (KBr): 3382, 2969, 1667, 1524, 1447 cm-1.
(iii) 6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-N-イソプロピル-2-ピリジンカルボキサミドの製造
6-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-N-イソプロピル-2-ピリジンカルボキサミド(1.60 g)とピリジン塩酸塩(770 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(350 mg)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 0.80 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz), 1.25 (6H, d, J=6.6 Hz), 2.44-2.70 (2H, m), 6.93 (1H, d, J=0.9 Hz), 7.41 (1H, d, J=7.8 Hz), 7.46 (1H, d, J=0.9 Hz), 7.60 (2H, d, J=8.4 Hz), 7.73 (1H, t, J=7.8 Hz), 7.84 (2H, d, J=8.4 Hz), 8.15 (1H, d, J=7.8 Hz), 8.15 (1H, brs).
IR (KBr): 2973, 1672, 1518,1447 cm-1.
実施例73
2-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-N-メチルイソニコチンアミドの製造
(i) 2-ブロモ-N-メチルイソニコチンアミドの製造
2-ブロモイソニコチン酸 (2.69 g)、メチルアミンTHF溶液 (2.0 M; 15 ml)、1−[3−(ジメチルアミノ)プロピル]−3−エチルカルボジイミド塩酸塩(3.20 g)および 1-ヒドロキシベンゾトリアゾール (2.59 g)用いて実施例55-(i)と同様の反応を行ない、表題化合物(361mg)を無色粉末晶として得た。
1H-NMR (CDCl3)δ: 3.04 (3H, d, J=4.6 Hz), 7.55 (1H, dd, J=1.4, 5.1 Hz), 7.79-7.82 (1H, m), 8.49 (1H, d, J=5.1 Hz).
IR (KBr): 3291, 1644, 1557, 1537 cm-1.
【0072】
(ii) 2-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-N-メチルイソニコチンアミドの製造
4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸 (1.30 g)、2-ブロモ-N-メチルイソニコチンアミド(310 mg)およびテトラキス(トリフェニルホスフィン)パラジウム(0) (0.110 g)を用いて実施例33-(ii)と同様の反応を行ない、表題化合物(480 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3)δ: 0.74 (3H, d, J= 6.6 Hz), 0.92 (3H, d, J= 6.6 Hz), 2.36-2.54 (1H, m), 3.06 (3H, d, J= 4.8 Hz), 3.61 (1H, s), 6.36 (1H, brs), 6,78 (1H, d, J= 1.4 Hz), 7.06-7.18 (6H, m), 7.28-7.38 (10H, m), 7.45 (1H, dd, J= 1.4, 5.2 Hz), 7.61 (2H, d, J= 8.4 Hz), 7.93 (2H, d, J= 8.4 Hz), 8.05-8.20 (1H, m), 8.75 (1H, dd, J= 0.6, 5.2 Hz).
IR (KBr): 3304, 1651, 1549 cm-1.
(iii) 2-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-N-メチルイソニコチンアミドの製造
2-{4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル}-N-メチルイソニコチンアミド(0.450 g)とピリジン塩酸塩(230 mg)を用いて実施例4-(iii)と同様の反応を行ない、表題化合物(110 mg)を無色アモルファス粉末として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.79 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz), 2.52-2.76 (1H, m), 3.02 (3H, s), 6.95 (1H, d, J=1.0 Hz), 7.44-7.60 (4H, m), 7.81 (2H, d, J=8.4 Hz), 7.97 (1H, s), 8.67 (1H, d, J=5.2 Hz).
IR (KBr): 3175, 2973, 1651, 1549 cm-1.
実施例74
N-[4’-フルオロ-5-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1’-ビフェニル]-2-イル]アセタミドの製造
(i) 4’-フルオロ[1,1’-ビフェニル]-2-イル メチル エーテルの製造
2-ブロモアニソール (8.91 g)、4-フルオロフェニルボロン酸 (10.0 g)、2M炭酸ナトリウム水溶液 (47.6 ml)、テトラキス(トリフェニルホスフィン)パラジウム(0) (2.20 g)を用いて、実施例4-(ii)と同様の反応を行い表題化合物 (8.14 g,)を無色針状結晶として得た。
1H-NMR (CDCl3)δ: 3.81 (3H, s), 6.96-7.13 (4H, m), 7.27-7.37 (2H, m), 7.45-7.33 (2H, m).
IR (KBr): 1514, 1487, 1260, 1236, 1223, 1159, 1028, 835, 754 cm-1.
【0073】
(ii) 5-ブロモ-4’-フルオロ[1,1’-ビフェニル]-2-オールの製造
4’-フルオロ[1,1’-ビフェニル]-2-イル メチル エーテル (107 g)、臭化水素酸ピリジニウムペルブロミド (34.0 g)、水-酢酸-ジエチルエーテル混液(1 : 4 : 5,500 ml)の混合物を室温で18時間攪拌した。反応液にハイポ水を加え、濃縮して生じた結晶を濾過し、5-ブロモ-4’-フルオロ[1,1’-ビフェニル]-2-イルメチルエーテルの粗生成物 (15.2 g)を黄色固体として得た。本品 (14.1 g)のジクロロメタン (150 ml)溶液に-78 °Cで三臭化ほう素 (5.69 ml)のジクロロメタン (40 ml)溶液を滴下し、室温で18時間攪拌した。反応液を氷に注ぎ、有機層を分離後、重曹水で中和し、食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィー (溶出液;ヘキサン→ヘキサン : 酢酸エチル = 5 : 1)で精製し、表題化合物 (13.2 g)を無色油状物として得た。
1H-NMR (CDCl3)δ: 5.11 (1H, s), 6.83-6.86 (1H, m), 7.13-7.24 (2H, m), 7.32-7.46 (4H, m).
IR (KBr): 1514, 1487, 1480, 1260, 1229, 1159, 839, 812 cm-1.
(iii) 4’-フルオロ-5-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-2-オールの製造
5-ブロモ-4’-フルオロ[1,1’-ビフェニル]-2-オール (13.2 g)、イミダゾール (5.04 g)のDMF (60 ml)溶液に0 °Cでt-ブチルジメチルシリルクロリド(7.82 g)を加え、室温で21時間攪拌した。反応液に水を加えて、酢酸エチルで抽出し、水で2回、食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して、3-ブロモ-6-[[tert-ブチル(ジメチル)シリル]オキシ]-4’-フルオロ-1,1’-ビフェニルの粗生成物 (18.1 g)を黄色油状物として得た。本品 (18.1 g)、n-ブチルリチウムのヘキサン溶液 (1.6 M; 31.3 ml)、2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパン (12.0 g)を用いて、実施例4-(i)と同様の反応を行い、1-[4’-フルオロ-6-[[tert-ブチル(ジメチル)シリル]オキシ][1,1’-ビフェニル]-3-イル]-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの粗生成物 (18.2 g)を無色アモルファスとして得た。本品 (18.2 g)のTHF (100 ml)溶液に0 °Cでテトラブチルアンモニウムブロミドの THF溶液 (1.0 M; 27.7 ml)溶液を滴下し、室温で15時間攪拌した。反応液に水と酢酸エチルを加えて濃縮した。残留物に酢酸エチル、ジイソプロピルエーテルを加えて析出した結晶をろ取し、ジイソプロピルエーテルで洗浄後、減圧下乾燥して、表題化合物 (11.2 g)を無色粉末として得た。
1H-NMR (DMSO-d6)δ: 0.65 (3H, d, J = 6.6 Hz), 0.73 (3H, d, J = 6.6 Hz), 2.44-2.51 (1H, m), 4.92 (1H, s), 6.78-6.83 (2H, m), 7.04-7.08 (7H, m), 7.16-7.55 (15H, m), 9.37 (1H, s).
IR (KBr): 1501, 1271, 1223, 1184, 1157, 1001, 835, 756, 748, 702 cm-1.
【0074】
(iv) 4’-フルオロ-5-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-2-イル トリフルオロメタンスルホネートの製造
4’-フルオロ-5-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-2-オール (1.10 g)のピリジン(7 ml)溶液に0 °Cでトリフルオロメタンスルホン酸無水物 (0.423 ml)を滴下し、0 °Cで20分間、室温で40分間攪拌した。反応液を減圧濃縮後、酢酸エチルで希釈し、5%クエン酸水溶液で3回、水、飽和重曹水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィー (溶出液;ヘキサン : 酢酸エチル = 5 : 1)で精製し、表題化合物 (1.06 g)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.73 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.35-2.42 (1H, m), 3.74 (1H, s), 6.74 (1H, d, J = 1.6 Hz), 7.08-7.17 (7H, m), 7.24-7.40 (14H, m), 7.52-7.61 (2H, m).
IR (KBr): 1481, 1424, 1248, 1217, 1161, 1140, 885, 837, 747, 702 cm-1.
(v) 1-[6-[(ジフェニルメチレン)アミノ]-4’-フルオロ[1,1’-ビフェニル]-3-イル]-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
4’-フルオロ-5-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-2-イル トリフルオロメタンスルホネート (1.06 g)、ベンゾフェノンイミン (0.305 ml)、炭酸セシウム (1.23 g)のトルエン (15 ml)溶液に、(RS)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (56.4 mg)、トリ(ジベンジリデンアセトン)ジパラジウム(0) (27.7 mg)を加え、80-90 °Cで26時間攪拌した。さらに(RS)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル (112 mg)、トリ(ジベンジリデンアセトン)パラジウム(0) (55.4 mg)を加え、80-90 °Cで16.5時間、105 °Cで3.5時間攪拌した。反応液をセライト濾過し、濾液を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。
溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィー (溶出液;ヘキサン :酢酸エチル = 5 : 1→1 : 1)で精製し、表題化合物 (115 mg)を黄色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.69 (3H, d, J = 6.6 Hz), 0.88 (3H, d, J = 7.0 Hz), 2.28-2.35 (1H, m), 3.60 (1H, s), 6.60-6.66 (3H, m), 6.82-7.44 (29H, m), 7.60-7.64 (2H, m).
IR (KBr): 1599, 1510, 1491, 1480, 1447, 1223, 1157, 909, 837, 747, 735, 700 cm-1.
【0075】
(vi) N-[4’-フルオロ-5-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-2-イル]アセタミドの製造
1-[6-[(ジフェニルメチレン)アミノ]-4’-フルオロ[1,1’-ビフェニル]-3-イル]-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (110 mg)のTHF-メタノール (1 : 1) (6 ml)溶液に室温で無水酢酸ナトリウム (29.6 mg)、塩化ヒドロキシアンモニウム (18.7 mg)を加え、22時間攪拌した。本応液を濃縮後、酢酸エチルに希釈し、0.5N水酸化ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、1-[6-アミノ-4’-フルオロ[1,1’-ビフェニル]-3-イル]-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの粗生成物 (118 mg)を黄色油状物として得た。本品 (116 mg)、ピリジン (29.6 ml)のTHF (2 ml)溶液に0 °Cで無水酢酸 (28.3 ml)を滴下し、室温で16時間攪拌した。反応液に飽和重曹水を加えて、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィー (溶出液;ヘキサン : 酢酸エチル = 3 : 1→3 : 2)で精製し、表題化合物 (79.6 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.75 (3H, d, J = 6.6 Hz), 0.91 (3H, d, J = 6.6 Hz), 2.02 (3H, s), 2.30-2.41 (1H, m), 3.64 (1H, s), 6.73 (1H, d, J = 1.6 Hz), 6.96 (1H, br s), 7.09-7.19 (8H, m), 7.29-7.39 (14H, m), 8.09 (1H, d, J = 8.8 Hz).
IR (KBr): 1669, 1514, 1493, 1472, 1447, 1225, 1159, 747, 733, 702 cm-1.
(vii) N-[4’-フルオロ-5-[1-ヒドロキシ-1-(1H-イミダゾール-4-イミダゾール)-2-メチルプロピル][1,1’-ビフェニル]-2-イル]アセタミドの製造
N-[4’-フルオロ-5-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル][1,1’-ビフェニル]-2-イル]アセタミド (78.2 mg)、ピリジン塩酸塩 (26.7 mg)を用いて実施例4-(iii)と同様の反応を行い表題化合物 (25.0 mg)を無色針状晶として得た。
1H-NMR (CDCl3)δ: 0.83 (3H, d, J = 6.8 Hz), 0.95 (3H, d, J = 6.6 Hz), 2.02 (3H, s), 2.52-2.66 (1H, m), 6.95 (1H, br s) 7.10-7.19 (1H, m), 7.29-7.36 (3H, m), 7.47-7.52 (3H, m), 8.11 (1H, d, J = 8.8 Hz).
IR (KBr): 3169, 2973, 1665, 1514, 1491, 1304, 1225, 839, 820 cm-1.
実施例75
4’-フルオロ-5-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1’-ビフェニル]-2-イル アセテートの製造
(i) ベンジル 5-ブロモ-4’-フルオロ[1,1’-ビフェニル]-2-イル エーテルの製造
5-ブロモ-4’-フルオロ[1,1’-ビフェニル]-2-オール (7.00g)、炭酸カリウム (3.80 g)、ベンジルブロミド (3.27 ml)のDMF (10 ml)溶液を60 °Cで5時間攪拌した。反応液を水で希釈後、酢酸エチルで抽出し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィー (溶出液;ヘキサン→ヘキサン : 酢酸エチル = 10 : 1)で精製し、表題化合物 (8.31 g)を茶色油状物として得た。
1H-NMR (CD3OD)δ: 5.05 (2H, s), 6.89 (1H, d, J = 8.8 Hz), 7.04-7.14 (2H, m), 7.25-7.55 (9H, m).
IR (KBr): 1512, 1483, 1454, 1265, 1227, 1159, 1024, 837, 737 cm-1.
【0076】
(ii) 1-[6-ベンジロキシ-4’-フルオロ[1,1’-ビフェニル]-3-イル]-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノールの製造
ベンジル 5-ブロモ-4’-フルオロ[1,1’-ビフェニル]-2-イル エーテル (3.86 g)、n-ブチルリチウムのヘキサン溶液 (1.6 M; 7.29 ml)、1-(1H-イミダゾール-4-イル)-2-メチル-1-プロパン (597 mg)を用いて、実施例4-(i)と同様の反応を行い、表題化合物 (672 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3)δ: 0.84 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 6.6 Hz), 2.53-2.67 (1H, m), 5.05 (2H, s), 6.94-7.10 (4H, m), 7.30-7.33 (5H, m), 7.43-7.56 (5H, m).
IR (KBr): 1514, 1491, 1265, 1225, 1157, 1017, 837, 735 cm-1.
(iii) 4’-フルオロ-5-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1’-ビフェニル]-2-オールの製造
1-[6-ベンジロキシ-4’-フルオロ[1,1’-ビフェニル]-3-イル]-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)-1-プロパノール (647 mg)、10 %パラジウム炭素 (647 mg)のメタノール (15 ml)懸濁液を水素雰囲気下、室温で4時間攪拌後した。反応液をセライト濾過し、濾液を濃縮後、残渣をシリカゲルクロマトグラフィー (溶出液;酢酸エチル→酢酸エチル : メタノール = 20 : 1)で精製し、酢酸エチル-ヘキサンから再結晶を行い表題化合物 (396 mg)を無色粉末晶として得た。
1H-NMR (CDCl3+CD3OD)δ: 0.83 (3H, d, J = 7.0 Hz), 0.95 (3H, d, J = 7.0 Hz), 2.52-2.65 (1H, m), 6.65 (1H, d, J = 8.4 Hz), 6.94 (1H, d, J = 1.2 Hz), 7.04-7.14 (2H, m), 7.26 (1H, d, J = 2.2, 8.4 Hz), 7.34 (1H, d, J = 2.2 Hz), 7.47-7.54 (3H, m).
IR (KBr): 1514, 1493, 1229, 1213, 1007, 841, 814, 627, 606 cm-1.
(iv) 4’-フルオロ-5-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1’-ビフェニル]-2-イル アセテートの製造
4’-フルオロ-5-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル][1,1’-ビフェニル]-2-オール (390 mg)のピリジン (4 ml)溶液に室温で無水酢酸 (0.135 ml)を滴下し、4時間攪拌後、さらに無水酢酸 (22.5 ml)を加え、15時間攪拌した。反応液をトルエンと共沸させて濃縮後、酢酸エチルで希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣 (414 mg)のピリジン (4 ml)溶液に室温で無水酢酸 (0.209 ml)を滴下し、15時間攪拌した。反応液をトルエンと共沸させて濃縮後、残渣のメタノール (15 ml)溶液に室温で0.1N p-トルエンスルホン酸水溶液 (7.5 ml)を加え、1時間攪拌した。反応液を濃縮後、酢酸エチルで希釈し、飽和重曹水で中和後、酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をカラムクロマトグラフィー (溶出液;酢酸エチル→酢酸エチル:メタノール = 20 : 1)で精製し、表題化合物 (337 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.83 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 6.6 Hz), 2.08 (3H, s), 2.57-2.65 (1H, m), 6.96 (1H, d, J = 1.0 Hz), 7.03-7.11 (3H, m), 7.32-7.39 (2H, m), 7.50-7.59 (3H, m).
IR (KBr): 1748, 1516, 1487, 1372, 1223, 1196, 1161, 839 cm-1.
【0077】
実施例76
5-[4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル]-N-メチル-2-チオフェンカルボキサミドの製造
(i) 5-[4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル]-N-メチル-2-チオフェンカルボキサミドの製造
5-ブロモ-N-メチル-2-チオフェンカルボキサミド (1.01 g)、4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸の粗生成物 (3.00 g) 、2 M炭酸ナトリウム水溶液 (4.59 ml)、テトラキス(トリフェニルホスフィン)パラジウム(0) (265 mg)を用いて、実施例33-(ii) と同様の反応を行い、表題化合物 (1.44 g)を無色粉末晶として得た
1H-NMR (CDCl3)δ: 0.75 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 7.0 Hz), 2.43-2.47 (1H, m), 3.01 (3H, d, J = 4.8 Hz), 3.53 (1H, s), 5.93 (1H, br s), 6.76 (1H, d, J = 1.4 Hz), 7.10-7.15 (7H, m), 7.24-7.53 (15H, m).
IR (KBr): 1626, 1553, 1493, 1449, 810, 747, 733, 702 cm-1.
(ii) 5-[4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル]-N-メチル-2-チオフェンカルボキサミドの製造
5-[4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル]-N-メチル-2-チオフェンカルボキサミド (1.39 g)、ピリジン塩酸塩 (484 mg)を用いて、実施例4-(iii)と同様の反応を行い表題化合物 (769 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.82 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 7.0 Hz), 2.59-2.66 (1H, m), 2.97 (3H, s), 6.96 (1H, d, J = 0.8 Hz), 7.22 (1H, d, J = 4.0 Hz), 7.47 (1H, d, J = 4.0 Hz), 7.54-7.56 (5H, m).
IR (KBr): 3079, 1626, 1557, 1528, 1451, 1410, 1314, 812 cm-1.
実施例77
5-[4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル]-N-メチル-2-チオフェンスルホンアミドの製造
(i) 5-[4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル]-N-メチル-2-チオフェンスルホンアミドの製造
5-ブロモ-N-メチル-2-チオフェンスルホンアミド (1.18 g)、4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸の粗生成物 (3.00 g) 、2 M炭酸ナトリウム水溶液 (4.59 ml)、テトラキス(トリフェニルホスフィン)パラジウム(0) (265 mg)を用いて、実施例33-(ii)と同様の反応を行い表題化合物 (1.67 g)を無色針状結晶として得た。
1H-NMR (CDCl3)δ: 0.74 (3H, d, J = 7.0 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.40-2.47 (1H, m), 2.78 (3H, d, J = 5.6 Hz), 3.54 (1H, s), 4.44 (1H, q J = 5.6 Hz), 6.76 (1H, d, J = 1.2 Hz), 7.10-7.15 (6H, m), 7.22-7.35 (11H, m), 7.48-7.58 (5H, m).
IR (KBr): 1445, 1335, 1159, 808, 747, 733, 702, 594 cm-1.
【0078】
(ii) 5-[4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル]-N-メチル-2-チオフェンスルホンアミドの製造
5-[4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニル]-N-メチル-2-チオフェンスルホンアミド (1.62 g)、ピリジン塩酸塩 (532 mg)を用いて、実施例4-(iii)と同様の反応を行い表題化合物 (884 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.80 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 6.6 Hz), 2.56-2.72 (4H, m), 6.97 (1H, s), 7.21 (1H, d, J = 4.0 Hz), 7.30 (1H, s), 7.48-7.58 (5H, m).
IR (KBr): 1435, 1327, 1157, 1134, 1090, 1015, 806, 594 cm-1.
実施例78
4-[4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル]]-1-イソインドリノンの製造
(i) メチル 3-ブロモ-2-メチルベンゾアートの製造
3-ブロモ-2-メチル安息香酸 (9.95 g)、濃硫酸 (0.2 ml)のメタノール (50 ml)溶液を室温で69時間撹拌後、96時間加熱還流した。反応液を1規定水酸化ナトリウム水溶液で中和後、濃縮した。残渣を酢酸エチルで希釈し、1規定水酸化ナトリウム水溶液で3回、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して表題化合物 (10.2 g)を無色油状物として得た。
1H-NMR (CDCl3)δ: 2.65 (3H, s), 3.93 (3H, s), 7.12 (1H, dd, J = 8.0, 8.0 Hz), 7.69-7.77 (2H, m).
IR (KBr): 1728, 1435, 1285, 1256, 1215, 1098, 754 cm-1.
(ii) メチル 3-ブロモ-2-(ブロモメチル)ベンゾアートの製造
メチル 3-ブロモ-2-メチルベンゾエート (1.00g)、N-ブロモコハク酸イミド (855 mg)、2,2’-アゾビス(イソブチロニトリル) (71.8 mg)の四塩化炭素 (50 ml)溶液を8時間加熱還流した。反応液を濃縮後、残渣を酢酸エチルで希釈し、飽和重曹水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をカラムクロマトグラフィー (溶出液;ヘキサン:酢酸エチル = 20:1)で精製し、表題化合物 (1.29 g)を無色油状物として得た。
1H-NMR (CDCl3)δ: 3.96 (3H, s), 5.14 (2H, s), 7.23 (1H, dd, J = 6.8, 6.8 Hz), 7.77 (1H, dd, J = 1.2, 6.8 Hz), 7.89 (1H, dd, J = 1.2, 6.8 Hz).
IR (KBr): 1725, 1435, 1291, 1264, 1223, 1115, 760 cm-1.
(iii) 4-ブロモ-1-イソインドリノンの製造
メチル 3-ブロモ-2-(ブロモメチル)ベンゾアート (1.28 g)を11%アンモニアメタノール溶液-THF混液 (3:2,25 ml) に溶解し室温で16時間撹拌した。反応液を濃縮後、残渣を飽和食塩水で洗浄後、酢酸エチル-ヘキサンより再結晶を行い表題化合物 (671 mg, 76 %)を無色針状結晶として得た。
1H-NMR (CDCl3)δ: 4.42 (2H, s), 7.42 (1H, dd, J = 7.8, 7.8 Hz), 7.48 (1H, br s), 7.73 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz).
IR (KBr): 3167, 1728, 1684, 1667, 1470, 1462, 1107, 745 cm-1.
【0079】
(iv) 4-[4-[1-ヒドロキシ-2-メチル1-(1-トリチル-1H-イミダゾール-4-イル)-プロピル]フェニル]]-1-イソインドリノンの製造
4-ブロモ-1-イソインドリノン (620 mg)、4-[1-ヒドロキシ-2-メチル-1-(1-トリチル-1H-イミダゾール-4-イル)プロピル]フェニルボロン酸の粗生成物 (2.06 g)、2 M炭酸ナトリウム水溶液 (2.92 ml)、テトラキス(トリフェニルホスフィン)パラジウム(0) (169 mg)を用いて、実施例33-(ii)と同様の反応を行い表題化合物 (1.07 g)を無色針状結晶として得た。
1H-NMR (CDCl3)δ: 0.77 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 2.42-2.49 (1H, m), 3.60 (1H, s), 4.51 (2H, s), 6.38 (1H, br s), 6.79 (1H, d, J = 1.0 Hz), 7.11-7.16 (6H, m), 7.32-7.39 (12H, m), 7.55-7.62 (4H, m), 7.85 (1H, dd, J = 2.2, 6.2 Hz).
IR (KBr): 1694, 1491, 1478, 1445, 812, 756, 702 cm-1.
(v) 4-[4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル]]-1-イソインドリノンの製造
4-[4-[1-ヒドロキシ-2-メチル1-(1-トリチル-1H-イミダゾール-4-イル)-プロピル]フェニル]]-1-イソインドリノン(1.02 g)の90 %ぎ酸-THF(1:1,8 ml)溶液を1.5時間加熱還流した。反応液を濃縮後、残渣をTHF-酢酸エチル混液(1 : 1)で希釈し、飽和重曹水-飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をカラムクロマトグラフィー (溶出液;ジクロロメタン→ジクロロメタン : メタノール = 20 : 1→7 : 1)で精製し、表題化合物 (503 mg)を無色アモルファスとして得た。
1H-NMR (CDCl3+CD3OD)δ: 0.83 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.58-2.72 (1H, m), 4.46 (2H, s), 7.01 (1H, d, J = 1.2 Hz), 7.37 (2H, d, J = 8.4 Hz), 7.50-7.57 (3H, m), 7.62 (2H, d, J = 8.6 Hz), 7.84 (1H, dd, J = 2.2, 6.2 Hz).
IR (KBr): 1682, 1480, 1456, 862, 812, 756, 741 cm-1.
実施例79
(−)‐N-(6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-2-ピリジル)アセタミドの製造
実施例68で得られたN-(6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-2-ピリジル)アセタミドを光学活性カラム (Chiralpak AD)を用いる液体クロマトグラフィー(溶出液;へキサン:エタノール=9:1)に付し、第一溶出の対掌体として(−)‐N-(6-{4-[1-ヒドロキシ-1-(1H-イミダゾール-4-イル)-2-メチルプロピル]フェニル}-2-ピリジル)アセタミドを得た。
光学純度; >99.9 %ee (Chiralpak AD)
[α]D 20 −11.8 °(C=1.02 , メタノール)
【0080】
上記(1)、(2)及び(3)の全量と5mgの(4)を混和した後、顆粒化し、これに残りの(4)を5mg加えて、全体をゼラチンカプセルに封入した。
上記(1)、(2)及び(3)の全量と20mgの(4)及び2.5mgの(5)を混和した後、顆粒化し、この顆粒に残りの(4)を10mgおよび(5)を2.5mg加えて加圧成型し、錠剤とした。
試験例1
ラットステロイドC17,20リアーゼ阻害活性の測定
ザ・プロステート(The Prostate),Vol. 26, 140-150(1995)に準じて行った。
13週齢雄性SDラットより精巣を摘出し、精巣をホモゲナイズした後、遠心分離によりミクロゾームを調製した。最終濃度10nMの[1.2−3H]−17α−ヒドロキシプロゲステロン、NADPH溶液、および試験化合物を pH7.4の100mMリン酸緩衝液10μl に溶かし、7μg/10μl のミクロゾームタンパク質を加えて、37℃で7分インキュベートした。酢酸エチル40μl を加えて遠心し、上清中の基質および生成物(アンドロステンジオンおよびテストステロン)をシリカゲル薄層クロマトグラフィー(TLC)で分離した。スポットの検出および定量をBAS 2000バイオイメージアナライザーで行った。試験化合物を加えていない時(対照)の生成物の量を100%として、対照に対し生成物の量を50%抑制させるのに必要な化合物濃度(IC50値)を算出した。これらを〔表1〕に示す。
【0081】
【表1】
試験例2
ラット生体内でのテストステロン合成阻害活性の測定
9週齢の雄のSD(Sprague Dawley)ラットに試験化合物(50mg/kg)を経口投与した。化合物投与から2時間後に採血を行い、得られた血清中のテストステロン濃度を放射免疫測定法で測定した。対照群のテストステロン濃度に対する試験薬物投与群のテストステロン濃度の割合(T/C, %)を算出し、テストステロン合成阻害活性を求めた。
【表2】
【0082】
【発明の効果】
本発明の化合物又はその塩はステロイドC17,20リアーゼ阻害活性を有し哺乳動物に対して、例えば性ステロイドおよびそれらの代謝物で影響を受ける悪性腫瘍の原発癌、およびこれらの転移、再発、それらの癌に伴う諸症状、前立腺肥大症、男性化症、多毛症、男性型禿頭症、男児性早熟症、子宮内膜症、子宮筋腫、乳腺症、多曩胞性卵巣症候群などのような各種疾病の治療および予防に有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceuticals, especially steroid C17,20The present invention relates to novel 1-substituted phenyl-1- (1H-imidazol-4-yl) alcohols having a lyase inhibitory action and pharmaceutical compositions comprising the same.
[0002]
[Prior art]
Sex hormones have various physiological activities including cell differentiation and proliferation. On the other hand, it has been clarified that androgen and estrogen act as exacerbation factors in certain diseases. Steroid C in androgen biosynthesis in vivo17,20It is known that lyase is involved in its final stage. That is, steroid C17,20The lyase produces dehydroepiandrosterone and androstenedione using 17-hydroxypregnenolone and 17-hydroxyprogesterone produced from cholesterol as substrates. Therefore, steroid C17,20A drug that inhibits lyase suppresses the production of androgen and suppresses the production of estrogen synthesized using androgen as a substrate, and is useful as a prophylactic and therapeutic drug for diseases in which androgen or estrogen is an exacerbation factor. Examples of diseases in which androgen or estrogen are exacerbated include prostate cancer, benign prostatic hyperplasia, masculinosis, hirsutism, androgenetic baldness, male prematurity, breast cancer, uterine cancer, ovarian cancer, mastopathy, uterus Examples include myoma, endometriosis, adenomyosis, polycystic ovary syndrome.
Already steroid C17,20Steroid type compounds and non-steroid type compounds are known as lyase inhibitors. Steroid type compounds are disclosed in, for example, WO 92/15404, WO 93/20097, EP-A 288053, EP-A 41270, and the like. Examples of non-steroid type compounds include (1H-imidazol-1-yl) methyl-substituted benzimidazole derivatives in JP-A No. 64-85975, carbazole derivatives in WO94 / 27989 and WO96 / 14090, azole derivatives in WO95 / 09157, US Pat. No. 5,491,161 shows 1H-benzimidazole derivatives, WO99 / 18075 shows dihydronaphthalene derivatives, Bioorganic Medicinal Chemistry 1999 (7) p1913-1924 shows (1H-imidazol-1-yl) methylbiphenyl derivatives Has been.
[0003]
[Problems to be solved by the invention]
To date, steroid C can be used in medical settings17,20A lyase inhibitor has not yet been obtained, and steroid C is highly useful as a medicine.17,20Early development of lyase inhibitors is expected.
[0004]
[Means for Solving the Problems]
The inventors have identified excellent steroid C17,20As a result of extensive research to find a lyase inhibitor, the chemical structure is that a lower alkyl or cyclic hydrocarbon group and a hydroxyl group are substituted on the methylene group connecting the benzene ring and the imidazole ring represented by the formula (I). A novel compound having the above characteristics or a salt thereof is synthesized for the first time, and the resulting compound (I) or a salt thereof is unexpectedly excellent in pharmaceutical use based on its unique chemical structure, particularly excellent steroid C17, It has been found that it has 20 lyase inhibitory activity, has low toxicity and has excellent properties as a pharmaceutical, and the present invention has been completed based on these findings.
That is, the present invention
(1) Formula:
Embedded image
(Wherein R represents a hydrogen atom or a protecting group, R1Is a lower alkyl group or a cyclic hydrocarbon group, R2Represents an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, RThreeIs a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent, a thiol group which may have a substituent, an amino group which may have a substituent, an acyl A group or a halogen atom, n represents an integer of 0 to 4; Or a salt thereof,
(2) R may be substituted with 1 to 3 groups selected from 1) hydrogen atom, 2) formyl, 3) group 11-6Alkylcarbonyl, 4) phenylcarbonyl optionally substituted with 1 to 3 groups selected from the first group, 5) optionally substituted with 1 to 3 groups selected from the first group C1-6Alkyl-oxycarbonyl, 6) phenyloxycarbonyl optionally substituted with 1 to 3 groups selected from the first group, 7) substituted with 1 to 3 groups selected from the first group C7-10Aralkyloxy-carbonyl, 8) trityl optionally substituted with 1 to 3 groups selected from the first group, 9) optionally substituted with 1 to 3 groups selected from the first group Good phthaloyl and 10) N, N-dimethylaminomethylene optionally substituted with 1 to 3 groups selected from the first group, R1Is C1-6Alkyl or C3-6Cycloalkyl and R2May be substituted with 1 to 4 groups selected from the second group6-10An aryl group or an aromatic heterocyclic group selected from the third group optionally substituted with 1 to 4 selected from the second group, and RThree1) C1-4Alkyl, 2) C as substituent2-4Alkanoyl, carboxyl or C1-4C with alkoxy-carbonyl1-4Alkyl, 3) hydroxyl group, 4) C1-4Lower alkoxy, 5) C1-4Alkanoyloxy, 6) carbamoyloxy, 7) 1 or 2 C1-4Carbamoyloxy substituted with an alkyl group, 8) thiol group, 9) C1-4Alkylthio group, 10) C1-4Alkanoylthio, 11) amino group, 12) C1-4Alkylamino group, 13) di-C1-4Alkylamino, 14) C1-4Alkanoylamino, 15) formyl, 16) C2-6Alkanoyl, 17) C1-4Alkylsulfonyl, 18) carbamoyl group, 19) mono- or di-C1-10Alkylcarbamoyl groups, 20) mono- or di-C6-14Arylcarbamoyl, 21) mono- or di-C7-16Aralkylcarbamoyl group, 22) sulfamoyl, 23) mono- or di-C1-10Alkylsulfamoyl radicals, 24) mono- or di-C6-14Arylsulfamoyl groups, 25) mono- or di-C7-16The compound according to the above (1), which is an aralkylsulfamoyl group or 26) a halogen atom
(In the above,
[0005]
The first group
Halogen atom, formyl group, C1-6An alkyl-carbonyl group and a nitro group,
The second group is
1) C1-6Alkyl groups, 2) C substituted with 1 to 5 halogen atoms1-4Alkyl groups, 3) 1 to 2 C1-4C substituted with alkoxy1-4Alkyl group, 4) hydroxyl group, 5) C1-4Alkoxy group, 6) C1-4Alkanoyloxy group, 7) carbamoyloxy group, 8) C1-4Carbamoyloxy group substituted with an alkyl group, 9) amino group, 10) mono- or di-C1-4Alkylamino group, 11) C1-4Alkanoylamino group, 12) formyl group, 13) C2-6Alkanoyl group, 14) C1-4Alkylsulfonyl group, 15) carbamoyl group, 16) mono- or di-C1-10Alkylcarbamoyl group, 17) C3-6Cycloalkylcarbamoyl group, 18) mono- or di-C6-14Arylcarbamoyl group, 19) mono- or di-C7-16Aralkylcarbamoyl group, 20) sulfamoyl group, 21) mono- or di-C1-10Alkylsulfamoyl radicals, 22) mono- or di-C6-14Arylsulfamoyl groups, 23) mono- or di-C7-16An aralkylsulfamoyl group and 24) a halogen atom, 25) a cyano group and 26) an oxo group,
The third group
2-thienyl group, 3-thienyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-furyl group, 3-furyl group, 2-quinolyl group, 4-quinolyl group, 8-quinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, pyrazinyl group, 2-pyrimidinyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 1-pyrazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5- Thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 3-pyridazinyl group, 1-indolyl group, 1-isoindolyl group, 2- Isoindolyl group, 1-tetrazolyl group, 2-tetrazolyl group and 5-tetrazolyl group,
Respectively. ),
(3) R is a hydrogen atom, R1Is C1-6Alkyl group or C3-6A cycloalkyl group, R2Are a phenyl group, a pyridyl group, a thienyl group, a freel group or an isoindolinyl group each optionally substituted by 1 to 4 groups selected from the fourth group, n is 0 or 1, and RThreeIs C1-4Lower alkoxy group, C1-4Alkanoyloxy group or C1-4The compound according to the above (1), which is an alkanoylamino group
(In the above,
The fourth group is
1) C1-6Alkyl groups, 2) C substituted with 1 to 5 halogen atoms1-4Alkyl groups, 3) 1 to 2 C1-4C substituted with alkoxy1-4Alkyl group, 4) C1-4Alkoxy group, 5) C1-4Alkanoylamino group, 6) C2-6Alkanoyl radicals, 7) mono- or di-C1-10Alkylcarbamoyl group, 8) C3-6Cycloalkylcarbamoyl group, 9) mono- or di-C1-10Alkylsulfamoyl group, 10) halogen atom, 11) cyano group and 12) oxo group
Indicates. ),
[0006]
(4) R2The compound according to the above (3), wherein is a phenyl group, pyridyl group, thienyl group, freel group or isoindolinyl group optionally substituted with one or two groups selected from Group 5
(In the above,
The fifth group is
1) C1-4Alkanoylamino group, 2) C2-6Alkanoyl group, 3) mono-C1-10Alkylcarbamoyl group, 4) mono-C1-10Alkylsulfamoyl group, 5) halogen atom and 6) oxo group
Indicates. ),
(5) R is a hydrogen atom, R1Is C1-6An alkyl group, R21) a phenyl group substituted with halogen or acetylamino, or 2) a pyridyl group substituted with halogen or acetylamino, and the compound according to the above (1), wherein n is 0,
(6) 1- (4′-fluoro [1,1′-biphenyl] -4-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol, (−)-N- (6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -2-pyridyl) acetamide, (−)-N- {4 ′-[1- Hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1′-biphenyl] -3-yl} acetamide, 4 ′-[1-hydroxy-1- (1H-imidazole-4] -Yl) -2-methylpropyl] -N-methyl [1,1'-biphenyl] -3-carboxamide, N- [4 '-[1-hydroxy-1- (1H-imidazol-4-yl) propyl] [1,1′-biphenyl] -3-yl] acetamide, or a salt thereof, the compound according to (1) above,
(7) Formula:
Embedded image
(Wherein R represents a hydrogen atom or a protecting group, R1Is a lower alkyl group or a cyclic hydrocarbon group, R2Represents an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, RThreeIs a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent, a thiol group which may have a substituent, an amino group which may have a substituent, an acyl A group or a halogen atom, n represents an integer of 0 to 4; ) Or a prodrug of a salt thereof,
(8) Formula:
Embedded image
(Wherein R represents a hydrogen atom or a protecting group, R1Is a lower alkyl group or a cyclic hydrocarbon group, R2Represents an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, RThreeIs a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent, a thiol group which may have a substituent, an amino group which may have a substituent, an acyl A group or a halogen atom, n represents an integer of 0 to 4; A pharmaceutical composition containing a compound represented by the following formula:
[0007]
(9) Steroid C17,20The composition according to (8) above, which is a lyase inhibitor,
(10) The composition according to the above (9), which is an antitumor agent,
(11) The antitumor agent composition according to the above (9), which is a prophylactic / therapeutic agent for breast cancer or prostate cancer,
(12) Formula:
Embedded image
(Wherein R represents a hydrogen atom or a protecting group, R1Is a lower alkyl group or a cyclic hydrocarbon group, R2Represents an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, RThreeIs a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent, a thiol group which may have a substituent, an amino group which may have a substituent, an acyl A group or a halogen atom, n represents an integer of 0 to 4; An androgen-lowering agent, characterized by using a compound represented by the following formula or a salt thereof or a prodrug thereof and an LHRH modulator:
(13) Formula:
Embedded image
(Wherein R1Is a lower alkyl group or a cyclic hydrocarbon group, R2Represents an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, RThreeIs a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent, a thiol group which may have a substituent, an amino group which may have a substituent, an acyl A group or a halogen atom, n represents an integer of 0 to 4; ) And a compound represented by the formula:
Embedded image
(Wherein X represents a leaving group, R represents a hydrogen atom or a protecting group) and a reaction product of a Grignard reagent or an alkyllithium with a compound represented by the formula:
Embedded image
(Wherein each symbol is as defined above), or a method for producing the salt thereof,
(14) For mammals, the formula:
Embedded image
(Wherein R represents a hydrogen atom or a protecting group, R1Is a lower alkyl group or a cyclic hydrocarbon group, R2Represents an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, RThreeIs a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent, a thiol group which may have a substituent, an amino group which may have a substituent, an acyl A group or a halogen atom, n represents an integer of 0 to 4; Steroid C characterized by administering an effective amount of a compound represented by the formula:17,20Lyase inhibition method, and
[0008]
(15) Steroid C17,20Formula for producing a lyase inhibitor:
Embedded image
(Wherein R represents a hydrogen atom or a protecting group, R1Is a lower alkyl group or a cyclic hydrocarbon group, R2Represents an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, RThreeIs a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent, a thiol group which may have a substituent, an amino group which may have a substituent, an acyl A group or a halogen atom, n represents an integer of 0 to 4; ) Or a salt thereof or a prodrug thereof,
And so on.
In the above formula, R1As the lower alkyl group represented by formula (1), a linear or branched group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl , Isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc.1-6An alkyl group etc. are mentioned. R1Examples of the cyclic hydrocarbon group represented by are C, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.3-6A cycloalkyl group etc. are mentioned. R1As C1-4Alkyl groups (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.) are preferred.
R2As the “aromatic hydrocarbon group” in the “optionally substituted aromatic hydrocarbon group” represented by the formula, for example, a monocyclic aromatic hydrocarbon group composed of 6 to 18 carbon atoms , Condensed polycyclic aromatic hydrocarbon groups and the like, specifically, C such as phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl and the like.6-14An aryl group, and C6-10An aryl group (such as phenyl) is preferred. R2Examples of the “aromatic heterocyclic group” in the “aromatic heterocyclic group optionally having substituent (s)” include 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl. 2-furyl, 3-furyl, 2-quinolyl, 4-quinolyl, 8-quinolyl, 3-isoquinolyl, 4-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 1-pyrazolyl 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 3-pyridazinyl, 1-indolyl, 1-isoindolyl, 2 -Isoindolyl, 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl and the like That.
[0009]
R2The “substituent” in the “optionally substituted aromatic hydrocarbon group” and the “optionally substituted aromatic heterocyclic group” represented by 1-4 may be substituted, and as the substituent, lower (C1-6) Alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, etc.), 1 to 5 halogen atoms (eg, Lower alkyl group substituted with fluorine, chlorine, etc. (chloromethyl, bromomethyl, fluoromethyl, trichloromethyl, 1-chloroethyl, 2-chloroethyl, 1,1-dichloroethyl, 1,2-dibromoethyl, 1,1, C 1-2 carbon atoms such as 2-trichloropropyl) 1-2 C1-4C substituted with alkoxy1-4Alkyl groups (eg, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, dimethoxymethyl, etc.), optionally substituted hydroxyl groups [eg, hydroxyl groups , Lower alkoxy (eg, C such as methoxy, ethoxy, propoxy, etc.)1-4Alkoxy group), lower alkanoyloxy (eg, acetyloxy, propionyloxy, etc.)1-4Alkanoyloxy), optionally substituted carbamoyloxy (eg, unsubstituted carbamoyloxy, for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy, methylethylcarbamoyloxy, etc. 1 or 2 C1-4Carbamoyloxy substituted with an alkyl group, etc.], an amino group optionally having a substituent [eg, amino, lower alkylamino (eg, C such as methylamino, ethylamino, propylamino, etc.)1-4Alkylamino group), di-lower alkylamino (eg, di-C such as dimethylamino, diethylamino)1-4Alkylamino), C1-4Alkanoylamino (eg, acetamide, propionamide, etc.)], acyl group [eg, optionally substituted carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.) -C1-10Alkylcarbamoyl groups, for example mono- or di-C such as phenylcarbamoyl, diphenylcarbamoyl6-14Aryl-carbamoyl, for example mono- or di-C such as benzylcarbamoyl, dibenzylcarbamoyl7-16Aralkylcarbamoyl groups, etc.), alkanoyl groups (eg C, such as formyl, acetyl, propionyl)1-6Alkanoyl), alkylsulfonyl groups (eg, C such as methylsulfonyl, ethylsulfonyl)1-4Alkylsulfonyl), optionally substituted carbamoyl group (eg, mono- or di-C such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl)1-10Alkylcarbamoyl groups such as cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl and the like3-6Mono- or di-C such as cycloalkylcarbamoyl, for example phenylcarbamoyl, diphenylcarbamoyl6-14Aryl-carbamoyl, for example mono- or di-C such as benzylcarbamoyl, dibenzylcarbamoyl7-16Aralkylcarbamoyl groups, etc.), optionally substituted sulfamoyl (eg, methyl-sulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, etc.) mono- or di-C1-10Alkylsulfamoyl groups, for example mono- or di-C such as phenylsulfamoyl, diphenylsulfamoyl6-14Arylsulfamoyl groups such as mono- or di-C such as benzylsulfamoyl, dibenzylsulfamoyl7-16Aralkylsulfamoyl group etc.)], halogen atoms (fluorine, chlorine, bromine, iodine) and the like.
[0010]
RThreeExamples of the hydrocarbon group which may have the substituent shown above include unsubstituted C, such as methyl, ethyl, propyl and the like.1-4In addition to alkyl, these alkyl groups include alkanoyl such as acetyl and propionyl, carboxyl, C1-4Examples include those substituted with alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc.) and the like.
RThreeExamples of the hydroxyl group which may have a substituent represented by the above are unsubstituted alkoxy, for example, lower alkoxy (eg, methoxy, ethoxy, propoxy, etc. C).1-4Alkoxy group), lower alkanoyloxy (eg, acetyloxy, propionyloxy, etc.)1-4Alkanoyloxy), optionally substituted carbamoyloxy (eg, unsubstituted carbamoyloxy, for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy, methylethylcarbamoyloxy, etc. 1 or 2 C1-4And carbamoyloxy substituted with an alkyl group.
RThreeIn addition to an unsubstituted thiol group, the thiol group which may have a substituent represented by, for example, a lower alkylthio (eg, C such as methylthio, ethylthio, propylthio, etc.)1-4Alkylthio group), lower alkanoylthio (eg, acetylthio, propionylthio, etc.)1-4Alkanoylthio) and the like.
RThreeAs the amino group which may have a substituent represented by the above, in addition to an unsubstituted amino group, for example, a lower alkylamino (eg, C such as methylamino, ethylamino, propylamino, etc.)1-4Alkylamino group), di-lower alkylamino (eg, di-C such as dimethylamino, diethylamino)1-4Alkylamino), C1-4Examples include alkanoylamino (eg, acetamide, propionamide, etc.).
RThreeAs the acyl group represented by, for example, an alkanoyl group (eg, C such as formyl, acetyl, propionyl, etc.)1-6Alkanoyl), alkylsulfonyl groups (eg, C such as methylsulfonyl, ethylsulfonyl)1-4Alkylsulfonyl), optionally substituted carbamoyl group (eg, mono- or di-C such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl)1-10Alkylcarbamoyl groups, for example mono- or di-C such as phenylcarbamoyl, diphenylcarbamoyl6-14Aryl-carbamoyl, for example mono- or di-C such as benzylcarbamoyl, dibenzylcarbamoyl7-16Aralkylcarbamoyl groups, etc.), optionally substituted sulfamoyl (eg, methyl-sulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, etc.) mono- or di-C1-10Alkylsulfamoyl groups, for example mono- or di-C such as phenylsulfamoyl, diphenylsulfamoyl6-14Arylsulfamoyl groups such as mono- or di-C such as benzylsulfamoyl, dibenzylsulfamoyl7-16Aralkylsulfamoyl group, etc.).
RThreeExamples of the halogen atom represented by are fluorine, chlorine, bromine and iodine.
[0011]
As the protective group represented by R, for example, formyl, each of which may have a substituent, C1-6Alkylcarbonyl (eg, acetyl, propionyl, etc.), phenylcarbonyl, C1-6Alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C7-10Aralkyloxy-carbonyl (eg, phenyl-C such as benzyloxycarbonyl1-4Alkyloxy-carbonyl, etc.), trityl, phthaloyl or N, N-dimethylaminomethylene. These substituents include halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C1-6Alkyl-carbonyl (for example, acetyl, propionyl, valeryl, etc.), a nitro group and the like are used, and the number of substituents is about 1 to 3.
The leaving group represented by X is a halogen atom (chlorine atom, bromine atom, iodine atom, etc.), alkyl or arylsulfonyloxy group (methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) Etc.
The compound represented by the formula (I) of the present invention may form a salt, and examples of the salt include acid addition salts such as inorganic acid salts (for example, hydrochloride, sulfate, hydrobromide, phosphorus Acid salts), organic acid salts (eg acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfone Acid salt, p-toluenesulfonate, etc.).
In addition, the compound represented by the general formula (I) or a salt thereof may be a hydrate, and hereinafter referred to as a compound (I) including a salt and a hydrate.
The prodrug of compound (I) is steroid C by reaction with enzymes, gastric acid, etc. in vivo.17,20This refers to a compound that is converted to compound (I) having a lyase inhibitory action.
As a prodrug of the compound (I), a compound in which the imidazole nitrogen of the compound (I) is acylated or alkylated (eg, dimethylaminosulfonylation, acetoxymethylation, (5-methyl-2-oxo-1,3 -Dioxolen-4-yl) methoxycarbonylmethylated, pivaloyloxymethylated, benzyloxymethylated compounds, etc.); hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, sulfated, borated And the like (eg, compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.). These compounds can be produced by a method known per se.
The prodrug of compound (I) may be itself or a pharmacologically acceptable salt. As such a salt, when the prodrug of the compound (I) has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, zinc, Transition metals such as iron and copper) and organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, organic amines such as N, N'-dibenzylethylenediamine, arginine , Basic amino acids such as lysine and ornithine) and the like.
[0012]
When the prodrug of the compound (I) has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid) Salt with fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), acidic amino acids such as aspartic acid, glutamic acid, etc. Can be mentioned.
In addition, the prodrug of compound (I) may be either a hydrate or a non-hydrate.
Compound (I) has 1 to more asymmetric carbon atoms in the molecule, and both R configuration and S configuration are included in the present invention with respect to these asymmetric carbons.
Throughout this specification the formulas (I), (I ′), (II), (III), (III ′), (IV), (IV ′), (V), (VI), (VIII), ( In the compounds represented by VIII ′) and (IX), a compound having a basic group or an acidic group can form a salt with an acid addition salt or a salt with a base, respectively. Examples of these acid addition salts and salts with bases are the same as those described for compound (I). Hereinafter, the compounds represented by the respective formulas are abbreviated as compounds (signs of formulas) including salts thereof. For example, a compound represented by formula (II) and a salt thereof are simply referred to as compound (II).
Compound (I) is produced, for example, by the method shown below.
The starting compound and the synthetic intermediate may be used as the same salt as the compound (I) in addition to the free form, or may be used in the reaction mixture as it is or after isolation according to known means.
Embedded image
[Wherein, M represents a metal or a salt thereof, and other symbols are as defined above. ]
Examples of the metal represented by M include lithium or magnesium, and examples of the salt thereof include metal halides such as magnesium chloride and magnesium bromide.
[Process A and B]
Compound (I) can be obtained by reacting compound (II) with organometallic compound (III '). That is, compound (I) can be obtained by reacting compound (III) with alkyllithium or alkylmagnesium halide to convert it to organometallic compound (III ') and subsequently reacting with compound (II).
Alkyllithium used in this reaction is C such as n-butyllithium, s-butyllithium and t-butyllithium.1-4Alkyllithium may be mentioned, and the amount used is 1 to 3 times mol, preferably 1 to 1.5 times mol per mol of the raw material compound (III) or (IV). The reaction temperature in the case of reacting alkyl lithium is -100 ° C to 0 ° C, preferably -80 ° C to -20 ° C. Examples of the alkylmagnesium halide include ethylmagnesium bromide, methylmagnesium chloride and the like, and the amount used is 1 mol to 10 times mol, preferably 1 mol to 4 mol, per mol of the raw material compound (III). When alkyl magnesium halide is reacted with compound (III), the reaction temperature is −40 ° C. to 20 ° C., preferably −20 ° C. to 0 ° C. The reaction time is about 5 minutes to 20 hours. This reaction is usually carried out in an organic solvent that does not affect the reaction. Examples of organic solvents that do not adversely affect the reaction include ethers such as diethyl ether, dioxane, and tetrahydrofuran (THF), saturated hydrocarbons such as hexane and pentane, halogenated hydrocarbons such as dichloromethane and chloroform, benzene, and toluene. Aromatic hydrocarbons, etc. are used, and these may be used singly or in combination at an appropriate ratio. Compound (II) is 0.1 to 10 equivalents, preferably 0.2 to 2 equivalents, relative to compound (III).
[0013]
[Processes C and D]
Compound (I) can also be obtained by reacting compound (IV) with a metal such as alkyl lithium or magnesium to convert it to organometallic compound (IV ') and then reacting with compound (V). Alkyllithium used in this reaction is C such as n-butyllithium, s-butyllithium and t-butyllithium.1-4Alkyllithium may be mentioned, and the amount used is 1 to 3 times mol, preferably 1 to 1.5 times mol per mol of the raw material compound (III) or (IV). The reaction temperature in the case of reacting alkyl lithium is -100 ° C to 0 ° C, preferably -80 ° C to -20 ° C. When metal magnesium is reacted with compound (IV), the amount used is 1 mol to 3 times mol, preferably 1 mol to 1.5 times mol per mol of compound (IV). The reaction temperature is -20 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time is about 5 minutes to 20 hours. This reaction is usually carried out in an organic solvent that does not affect the reaction. Examples of organic solvents that do not adversely affect the reaction include ethers such as diethyl ether, dioxane, and tetrahydrofuran (THF), saturated hydrocarbons such as hexane and pentane, halogenated hydrocarbons such as dichloromethane and chloroform, benzene, and toluene. Aromatic hydrocarbons, etc. are used, and these may be used singly or in combination at an appropriate ratio. Compound (V) is 0.1 to 10 equivalents, preferably 0.2 to 2 equivalents, relative to compound (IV).
[Process E]
Compound (I) can also be obtained by reacting compound (VI) with organometallic reagent (VII).
The amount of compound (VII) to be used is 1 to 10 times mol, preferably 1 to 5 times mol, per 1 mol of compound (VI). The reaction temperature is -80 ° C to 60 ° C, preferably -80 ° C to 50 ° C. The reaction time is about 5 minutes to 20 hours. This reaction is usually carried out in an organic solvent that does not affect the reaction. Examples of organic solvents that do not adversely affect the reaction include ethers such as diethyl ether, dioxane, and tetrahydrofuran (THF), saturated hydrocarbons such as hexane and pentane, halogenated hydrocarbons such as dichloromethane and chloroform, benzene, and toluene. Aromatic hydrocarbons, etc. are used, and these may be used singly or in combination at an appropriate ratio.
[Process F]
When R of compound (I) is a protecting group, compound (I ') can be obtained by removing the protecting group by a method known per se or a method analogous thereto. For example, when R is a trityl group, the trityl group can be removed by treatment under acidic conditions or hydrogenolysis. Examples of the acid include organic acids such as formic acid and acetic acid, and inorganic acids such as hydrochloric acid. The reaction can also be carried out using a solvent inert to the reaction, such as alcohols and ethers such as THF. The reaction temperature is usually from 0 ° C to 100 ° C.
Embedded image
[Wherein Y is a leaving group (such as a halogen atom, alkyl or arylsulfonyloxy group) or a substituent that can be converted into a leaving group (eg, a protected hydroxyl group), Z is a trialkyltin, boric acid, etc. Indicates a leaving group. Other symbols are as defined above. ]
[0014]
[Process G and H]
In step G and H, compound (IX) is obtained by reacting compound (VIII) with metal such as alkyllithium or magnesium to convert it to organometallic compound (VIII ′) and then reacting with compound (V). Can do. The reaction conditions are the same as in Steps A and B described above. When Y in compound (VIII) is a protected hydroxyl group that can be converted into a leaving group (eg, trialkylsilyloxy group), after conversion to compound (IX), Y is removed as a leaving group (eg, trifluoromethanesulfonyl). It is preferable to convert it into an oxy group. This conversion can be performed according to a conventional method.
[Process I]
Compound (I) is obtained by reacting Compound (IX) with Compound (X) in the presence of a palladium catalyst. As the palladium catalyst used in this reaction, zero-valent or divalent palladium complexes such as tetrakistriphenylphosphine palladium and 1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium are used. The reaction temperature is 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C. The reaction time is about 1 to 48 hours. This reaction is usually carried out in a solvent that does not affect the reaction. Examples of the solvent that does not adversely influence the reaction include ethers such as dimethoxyethane, dioxane, and tetrahydrofuran (THF), alcohols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane and chloroform, and aromatics such as benzene and toluene. Group hydrocarbons, water and the like are used, and these may be used singly or in combination of two or more at an appropriate ratio. When the compound (X) is a boron compound, it is preferable that a base (such as sodium carbonate) is present in the reaction system.
[Process J]
When R of compound (I) is a protecting group, compound (I ') can be obtained by removing the protecting group by a method known per se or a method analogous thereto. For example, when R is a trityl group, the trityl group can be removed by treatment under acidic conditions or hydrogenolysis. Examples of the acid include organic acids such as formic acid and acetic acid, and inorganic acids such as hydrochloric acid. The reaction can also be carried out using a solvent inert to the reaction, such as alcohols and ethers such as THF. The reaction temperature is usually from 0 ° C to 100 ° C.
When the desired product is obtained in the free state by the above reaction, it may be converted into a salt according to a conventional method. When it is obtained as a salt, it is converted into a free form or other salt according to a conventional method. You can also. The compounds (I) and (I ′) thus obtained can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography and the like. .
In each of the above reactions, a protecting group may be used for an amino group, a carboxyl group, or a hydroxy group that is not involved in the reaction in the compound subjected to the reaction or a salt thereof, and the addition or removal of the protecting group is publicly known. It can carry out by the means of.
[0015]
As a protecting group for amino group, for example, formyl, each of which may have a substituent, C1-6Alkylcarbonyl (eg, acetyl, propionyl, etc.), phenylcarbonyl, C1-6Alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C7-10Aralkyloxy-carbonyl (eg, phenyl-C such as benzyloxycarbonyl1-4Alkyloxy-carbonyl, etc.), trityl, phthaloyl or N, N-dimethylaminomethylene. These substituents include halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C1-6Alkyl-carbonyl (for example, acetyl, propionyl, valeryl, etc.), a nitro group and the like are used, and the number of substituents is about 1 to 3.
As the protective group for the carboxyl group, for example, C may have a substituent.1-6Alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like are used. These substituents include halogen atoms (eg, fluorine, chlorine, etc.), formyl, C1-6Alkyl-carbonyl (for example, acetyl, propionyl, valeryl, etc.), a nitro group and the like are used, and the number of substituents is about 1 to 3.
As a protective group for a hydroxy group, for example, C may have a substituent.1-6Alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C7-10Aralkyl (eg, phenyl-C such as benzyl)1-4Alkyl), formyl, C1-6Alkyl-carbonyl (eg, acetyl, propionyl, etc.), phenyloxycarbonyl, benzoyl, (C7-10Aralkyloxy) carbonyl (eg, phenyl-C such as benzyloxycarbonyl)1-4Alkyloxy-carbonyl etc.), pyranyl, furanyl or silyl etc. are used. These substituents include halogen atoms (for example, fluorine, chlorine, etc.), C1-6Alkyl (eg, methyl, ethyl, propyl, etc.), phenyl, C7-10Aralkyl (eg, phenyl-C such as benzyl)1-4Alkyl, etc.), nitro groups and the like are used, and the number of substituents is about 1 to 4.
In addition, as a method for removing the protecting group, a method known per se or a method equivalent thereto is used. For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride A method of treating with palladium acetate or the like is used.
Compound (I) has an excellent action as a medicine, and in particular steroid C17,20Excellent inhibitory activity against lyase. Since compound (I) has low toxicity and few side effects, it can be used against mammals (eg, humans, cows, horses, pigs, dogs, cats, monkeys, mice, rats, etc., particularly humans). Or (ii) diseases related to androgens or estrogen, such as (1) primary cancers of malignant tumors (eg, prostate cancer, breast cancer, uterine cancer, ovarian cancer, etc.), and their metastasis, recurrence, (2 ) Various symptoms associated with these cancers (eg, pain, cachexia, etc.), (3) Prostatic hypertrophy, masculinosis, hirsutism, androgenetic baldness, male prematurity, endometriosis, uterine fibroids It is useful as a therapeutic and prophylactic agent for various diseases such as uterine adenomyosis, mastopathy, polycystic ovary syndrome.
[0016]
Compound (I) exhibits an excellent effect even when used alone, but the effect can be further enhanced by further use in combination with other pharmaceutical preparations and therapies. Examples of the combination agent and therapy include, but are not limited to, sex hormone agents, alkylating agents, antimetabolites, anticancer antibiotics, plant alkaloids, immunotherapeutic agents and the like.
As hormonal drugs, for example, phosfestol, diethylstilbestrol, chlorotrianiserin, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, Olmelokifen, levormeloxifen, antiestrogens (eg, tamoxifen citrate, toremifene citrate), pill formulations, mepithiostan, test lactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, buserelin, leupro) Relin, etc.), LH-RH antagonists (eg, ganirelix, cetrorelix, abarelix), droloxifene, epithiostanol, sulfonic acid ester Nilestradiol, aromatase inhibitors (eg, fadrozole hydrochloride, anastrozole, letrozole, exemestane, borozole, formestane, etc.), antiandrogens (eg, flutamide, bicalutamide, nilutamide, etc.), 5α-reductase inhibitors (eg, Finasteride, epristeride, etc.), corticosteroids (eg, cortisol, dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (eg, abiraterone), retinoids and retinoids (eg, riarosol) ) And the like.
Examples of the alkylating agent include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, toprolate tosilate, busulfan, nimustine hydrochloride, mitoblonitol, melphalan, dacarbazine , Ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospium hydrochloride, fotemustine, pretempustine , Ribomustine, Temozolomide, Treossulfan, Trophosphamide, Dinos Chinsuchimarama, adozelesin, system scan Chin, Bizereshin and the like.
[0017]
Antimetabolites include, for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enositabine, cytarabine, cytarabine okphosphatate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur) , Galocitabine, emiteful, etc.), aminopterin, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexim, idoxyuridine, mitoguazone, thiazofurin and the like.
Anticancer antibiotics include, for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocalci Examples include nostatin, mythramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and the like.
Examples of plant alkaloids include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, vinorelbine and the like.
Examples of immunotherapeutic agents (BRM) include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium parvum , Levamisole, polysaccharide K, procodazole and the like.
In addition, L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin / cobalt complex, mercury hematoporphyrin / sodium, topoisomerase I inhibitor (for example, irinotecan, topotecan, etc.), topoisomerase II inhibitor (for example, sobuzoxane, etc.), differentiation inducer (Eg retinoids, vitamin Ds, etc.), growth factor inhibitors (eg suramin etc.), antibodies (eg herceptin etc.), angiogenesis inhibitors, α-blockers (eg tamsulosin hydrochloride etc.), tyrosine kinase inhibitors Etc. can also be used.
In addition to chemotherapy for administering Compound (I), for example, a therapy other than chemotherapy, such as surgery including ablation, hyperthermia, or radiation therapy, can be used in combination.
In particular, the compounds of the present invention can be used in combination with LHRH modulators (LHRH modulators) such as LHRH agonists (eg, goserelin acetate, buserelin, leuprorelin, etc.) or LHRH antagonists (eg, ganirelix, cetrorelix, abarelix, etc.). Androgen or estrogen in the blood can be effectively removed.
Thus, the compounds of the present invention are steroid C17,20It has high selectivity for lyase and has the effect of lowering androgen concentration without affecting drug-metabolizing enzymes such as CYP3A4.
[0018]
As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants, thickeners in solid preparations; solvents in liquid preparations Appropriate amounts are added as dispersing agents, solubilizers, suspending agents, tonicity agents, buffers, soothing agents, and the like. If necessary, additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used according to a conventional method. Preferable examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the thickener include natural gums, cellulose derivatives, acrylic acid polymers and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the dispersant include, for example, Tween 80, HCO 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate and the like. Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, xericelin monostearate; And hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol and the like.
Preferable examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, citrate and the like. Preferable examples of the soothing agent include benzyl alcohol. Preferable examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite and ascorbic acid.
The pharmaceutical composition and preparation of the present invention can be produced according to a conventional method, and the content ratio of compound (I) in the preparation is usually 0.1 to 100% (w / w). Specific examples are shown below.
(1) Tablets, powders, granules, capsules:
To compound (I), for example, an excipient, a disintegrant, a binder or a lubricant is added and compression-molded, and then, if necessary, coating for the purpose of taste masking, enteric property or durability is performed. Can be manufactured.
[0019]
(2) Injection:
Compound (I) is oily by dissolving, suspending or emulsifying compound (I) as an aqueous injection together with a dispersant, preservative, tonicity agent, etc., or in vegetable oils such as olive oil, sesame oil, cottonseed oil and corn oil, propylene glycol, etc. It can be manufactured by molding as an injection.
(3) Suppository:
The compound (I) is produced by forming an oily or aqueous solid, semi-solid or liquid composition. Examples of the oily base used in such a composition include glycerides of higher fatty acids (for example, cacao butter, witepsols), intermediate fatty acids (for example, miglyols), or vegetable oils (for example, sesame oil, soybean oil, Cottonseed oil, etc.). Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
The compounding ratio of compound (I) in these preparations varies depending on the kind of preparation, but is usually 0.01 to 50%.
The amount of the compound of the present invention to be used in the pharmaceutical preparation varies depending on the selected compound, the animal species selected as the administration subject, the number of administrations, etc., but exhibits effectiveness over a wide range. For example, when the pharmaceutical preparation of the present invention is orally administered to an adult solid tumor patient (for example, prostate cancer patient), the daily dose is usually an effective amount of the compound (I) of the present invention. About 0.001 to about 500 mg / kg body weight, preferably about 0.05 to about 40 mg / kg body weight, more preferably about 0.1 to about 10 mg / kg body weight. When used in combination with other anticancer agents, the dose is generally less than these doses. However, the amount of compound actually administered will be determined by the choice of compound, various dosage forms, patient age, weight, gender, disease severity, route of administration, duration and interval of administration, etc. It can be changed at any time according to the judgment of the doctor.
The administration route of the pharmaceutical preparation is not particularly limited depending on various situations. For example, it can be administered by oral or parenteral routes. As used herein, “parenteral” includes intravenous, intramuscular, subcutaneous, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, and the like.
The administration period and interval of the pharmaceutical preparation are changed according to various situations, and are determined at any time according to the judgment of a doctor, but divided administration, daily administration, intermittent administration, short-term large-scale administration, repeated administration There are methods such as administration. For example, in the case of oral administration, it is desirable to divide and administer 1 to several times a day (particularly 2 to 3 times a day). Moreover, it can be administered as a sustained-release preparation or can be administered by intravenous infusion over a long period of time.
[0020]
DETAILED DESCRIPTION OF THE INVENTION
The present invention is further described in detail in the following Examples, Formulation Examples, and Test Examples. However, these examples are merely implementations, do not limit the present invention, and change without departing from the scope of the present invention. You may let them. Abbreviations in the examples have the following meanings.
s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, m: multiplet, br: wide, J: coupling constant, room temperature: 0-30 ° C, DMF: Dimethylformamide, THF: tetrahydrofuran.
【Example】
Reference example 1
Preparation of 4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid
To a solution of p-dibromobenzene (66.0 g) in THF (700 ml) was added dropwise n-butyllithium hexane solution (1.6 M; 180 ml) at −78 ° C., and the mixture was stirred at the same temperature for 15 minutes. A solution of 2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanone (85.0 g) in THF (250 ml) was added dropwise, and the mixture was further stirred for 15 minutes. To this reaction solution was added dropwise n-butyllithium hexane solution (1.6M; 270 ml) at −78 ° C., and the mixture was stirred at the same temperature for 15 minutes, and then trimethyl borate (196 ml) was added. The reaction solution was stirred at room temperature for 2 hours, an aqueous ammonium chloride solution was added, and the mixture was stirred at room temperature for 12 hours. The organic layer was separated, washed with 1N sodium hydroxide and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a crude product (126 g) of the title compound as an amorphous powder. This product was used in the reaction without purification.
Example 1
Preparation of 1- (1H-imidazol-4-yl) -1- (4'-methoxy- [1,1'-biphenyl] -4-yl) -2-methyl-1-propanol
(i) Production of 4-bromo-4'-methoxy-1,1'-biphenyl
Under argon atmosphere, p-dibromobenzene (9.99 g), 4-methoxyphenylboronic acid (2.03 g) and tetrakistriphenylphosphine palladium (497 mg) were dissolved in dimethoxyethane (20 ml), and 2M aqueous sodium carbonate solution (20 ml) was dissolved. ) And heated to reflux for 14 hours. After cooling the reaction solution to room temperature, the precipitated crystals were filtered off. The obtained crystals were dissolved in ethyl acetate, insoluble matters were filtered off, and the solvent was evaporated. The obtained solid was washed with hexane to give the title compound (2.09 g) as a colorless solid.
1H-NMR (CDClThree) δ: 3.84 (3H, s), 6.97 (2H, d, J = 8.8 Hz), 7.37-7.56 (6H, m).
IR (KBr): 1483, 1291, 1258, 1038, 812 cm-1.
(ii) Preparation of 1- (1H-imidazol-4-yl) -1- (4'-methoxy- [1,1'-biphenyl] -4-yl) -2-methyl-1-propanol
4-Bromo-4′-methoxy-1,1′-biphenyl (1.95 g) was dissolved in THF (40 ml) and cooled to −78 ° C. A hexane solution of n-butyllithium (1.6 M; 5.5 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour, and then 1- (1H-imidazol-4-yl) -2-methyl-1-propanone (335 mg ) In THF (10 ml) was slowly added dropwise. After raising the temperature from −78 ° C. to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the obtained residue was recrystallized from ethyl acetate to give the title compound (322 mg) as a colorless solid.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.83 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 2.52-2.76 (1H, m), 3.85 (3H, s), 6.92-7.02 (3H, m), 7.38-7.62 (7H, m).
IR (KBr): 3218, 1497, 1252, 1038, 1007, 816 cm-1.
[0021]
Example 2
Preparation of 1- [1,1'-biphenyl] -4-yl-1- (1H-imidazol-4-yl) -2-methyl-1-propanol
4-Bromo-1,1′-biphenyl (5.17 g) was used for the same reaction as in Example 1- (ii) to obtain the title compound (1.76 g) as a colorless solid.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.83 (3H, d, J = 6.8 Hz), 0.99 (3H, d, J = 6.8 Hz), 2.57-2.74 (1H, m), 6.98 (1H, d, J = 1.2 Hz), 7.30 -7.47 (3H, m), 7.50-7.65 (7H, m).
IR (KBr): 3142, 2965, 1487, 826, 762 cm-1.
Example 3
Preparation of 1- (1H-imidazol-4-yl) -1- (2'-methoxy [1,1'-biphenyl] -4-yl) -2-methyl-1-propanol
(i) Production of 4-bromo-2'-methoxy-1,1'-biphenyl
Using 2-methoxyphenylboronic acid (3.15 g), the same reaction as in Example 1- (i) was carried out to obtain the title compound (4.77 g) as a colorless solid.
1H-NMR (CDClThree) δ: 3.81 (3H, s), 6.92-7.08 (2H, m), 7.21-7.44 (4H, m), 7.45-7.60 (2H, m).
IR (KBr): 1478, 1256, 1003, 754 cm-1.
(ii) Preparation of 1- (1H-imidazol-4-yl) -1- (2′-methoxy [1,1′-biphenyl] -4-yl) -2-methyl-1-propanol
4-Bromo-2′-methoxy-1,1′-biphenyl (1.58 g) was used to carry out the same reaction as in Example 1- (ii) to obtain the title compound (225 mg) as a colorless solid.
1H-NMR (CDClThree) δ: 0.85 (3H, d, J = 7.0 Hz), 0.98 (3H, d, J = 7.0 Hz), 2.52-2.72 (1H, m), 3.79 (3H, s), 6.92-7.06 (3H, m ), 7.26-7.36 (2H, m), 7.42-7.62 (5H, m).
IR (KBr): 3073, 2967, 1487, 1260, 1238, 1005, 752 cm-1.
[0022]
Example 4
Preparation of 1- (4'-fluoro [1,1'-biphenyl] -4-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) Preparation of 1- (4-bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol
To a solution of p-dibromobenzene (20.0 g) in diethyl ether-THF (4: 1) (210 ml), slowly add hexane solution of n-butyllithium (1.6 M; 34.6 ml) dropwise at -78 ° C. After stirring at −78 to −30 ° C. for 15 minutes, 2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propane (14.0 g) in THF (80 ml) The solution was slowly added dropwise and stirred at -78 to -50 ° C for 40 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to give the title compound (16.2 g) as colorless needle crystals.
1H-NMR (CDClThree) δ: 0.71 (3H, d, J = 6.6 Hz), 0.89 (3H, d, J = 6.6 Hz), 2.30-2.44 (1H, m), 3.50 (1H, s), 6.72 (1H, d, J = 1.2 Hz), 7.09-7.16 (6H, m), 7.30-7.38 (14H, m)
IR (KBr): 1489, 1445, 1159, 1009, 909, 812, 747, 735, 702, 660 cm-1
(ii) Preparation of 1- (4'-fluoro [1,1'-biphenyl] -4-yl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol
1- (4-Bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (3.60 g), 4-fluorophenylboronic acid (1.50 g), 2 M sodium carbonate Tetrakis (triphenylphosphine) palladium (0) (387 mg) was added to a suspension of an aqueous solution (26.8 ml) in dimethoxyethane (50 ml), and the mixture was heated to reflux for 12 hours under an argon atmosphere. The reaction mixture was extracted with ethyl acetate-THF (8: 3), washed with water and saturated brine, and dried. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 6: 1 → 4: 1) to obtain the title compound (3.16 g) as colorless needle crystals.
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.42-2.49 (1H, m), 3.53 (1H, s), 6.78 (1H, s), 7.06-7.15 (7H, m), 7.33-7.57 (17H, m)
IR (KBr): 1493, 1445, 1223, 1159, 818, 748, 733, 702 cm-1
(iii) Preparation of 1- (4'-fluoro [1,1'-biphenyl] -4-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
1- (4′-Fluoro [1,1′-biphenyl] -4-yl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (3.12 g), pyridine A methanol solution (75 ml) of hydrochloride (1.11 g) was stirred at 60 ° C. for 3.5 hours. The solvent of the reaction solution was evaporated under reduced pressure, diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, washed with saturated brine, and dried. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (eluent, hexane: ethyl acetate = 2: 1 → 1: 5) and recrystallized from ethyl acetate-hexane to give the title compound (1.34 g) as colorless Obtained as needles.
1H-NMR (CDClThree) δ: 0.85 (3H, d, J = 7.0 Hz), 1.00 (3H, d, J = 7.0 Hz), 2.60-2.74 (1H, m), 3.42 (1H, br s), 7.02-7.16 (3H, m), 7.48-7.66 (7H, m), 9.16 (1H, br s)
IR (KBr): 3241, 1493, 1397, 1242, 1009, 814, 781, 762, 623, 511 cm-1
[0023]
Example 5
Preparation of 1- (4'-chloro [1,1'-biphenyl] -4-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) Preparation of 1- (4'-chloro [1,1'-biphenyl] -4-yl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol
1- (4-Bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (3.60 g), 4-chlorophenylboronic acid (1.68 g), 2 M aqueous sodium carbonate solution (26.8 ml) and tetrakis (triphenylphosphine) palladium (0) (387 mg) were used for the same reaction as in Example 4- (ii) to obtain the title compound (3.04 g) as colorless needle crystals. It was.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 7.0 Hz), 0.92 (3H, d, J = 7.0 Hz), 2.42-2.49 (1H, m), 3.53 (1H, s), 6.78 (1H, s), 7.13-7.15 (6H, m), 7.32-7.59 (18H, m)
IR (KBr): 1485, 1445, 1094, 1005, 909, 812, 747, 733, 700 cm-1
(ii) Preparation of 1- (4'-chloro [1,1'-biphenyl] -4-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
1- (4′-chloro [1,1′-biphenyl] -4-yl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (3.00 g), pyridine The hydrochloride (1.04 g) was used for the same reaction as in Example 4- (iii) to obtain the title compound (1.18 g) as colorless plate crystals.
1H-NMR (CDClThree) δ: 0.83 (3H, d, J = 7.0 Hz), 0.98 (3H, d, J = 7.0 Hz), 2.58-2.75 (1H, m), 3.38 (1H, br s), 7.00 (1H, s) , 7.37 (2H, d, J = 8.4 Hz), 7.48-7.64 (7H, m), 9.24 (1H, br s)
IR (KBr): 3200, 1485, 1364, 1190, 1094, 1028, 1005, 808, 781 cm-1
Example 6
Preparation of 1- [1,1'-biphenyl] -3-yl-1- (1H-imidazol-4-yl) -2-methyl-1-propanol
Using 3-bromo-1,1′-biphenyl (0.98 g), the same reaction as in Example 1- (ii) was carried out to obtain the title compound (0.25 g) as a colorless solid.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.83 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.55-2.73 (1H, m), 6.97 (1H, d, J = 1.0 Hz), 7.28 -7.50 (7H, m), 7.54-7.62 (2H, m), 7.72-7.77 (1H, m).
IR (KBr): 3200, 1005, 799 cm-1.
[0024]
Example 7
Preparation of 1- (1H-imidazol-4-yl) -1- (2'-methoxy [1,1'-biphenyl] -3-yl) -2-methyl-1-propanol
(i) Production of 3-bromo-2'-methoxy-1,1'-biphenyl
The reaction was conducted in the same manner as in Example 1- (i) using 2-methoxyphenylboronic acid (2.90 g) to obtain the title compound (4.38 g) as a colorless oil.
1H-NMR (CDClThree) δ: 3.81 (3H, s), 6.97 (1H, d, J = 8.2 Hz), 7.02 (1H, dt, J = 1.0, 7.4 Hz), 7.21-7.49 (5H, m), 7.68 (1H, t , J = 1.8 Hz).
IR (KBr): 1466, 1254, 1235, 1028 cm-1.
(ii) Preparation of 1- (1H-imidazol-4-yl) -1- (2'-methoxy [1,1'-biphenyl] -3-yl) -2-methyl-1-propanol
Using 3-bromo-2'-methoxy-1,1'-biphenyl (2.10 g), the same reaction as in Example 1- (ii) was carried out to obtain the title compound (0.44 g) as a colorless solid.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.85 (3H, d, J = 6.8 Hz), 0.99 (3H, d, J = 6.8 Hz), 2.40-2.80 (1H, m), 3.77 (3H, s), 6.93-7.07 (3H, m), 7.25-7.49 (6H, m), 7.63 (1H, s).
IR (KBr): 2961, 1473, 1236, 1024 cm-1.
Example 8
Preparation of 1- (1H-imidazol-4-yl) -1- (3′-methoxy [1,1′-biphenyl] -3-yl) -2-methyl-1-propanol
(i) Production of 3-bromo-3'-methoxy-1,1'-biphenyl
The same reaction as in Example 1- (i) was performed using 3-methoxyphenylboronic acid (3.04 g) to obtain the title compound (3.10 g) as a colorless oil.
1H-NMR (CDClThree) δ: 3.85 (3H, s), 6.86-6.96 (1H, m), 7.04-7.17 (2H, m), 7.23-7.54 (4H, m), 7.70-7.75 (1H, m).
IR (KBr): 1591, 1559, 1470, 1213 cm-1.
(ii) Preparation of 1- (1H-imidazol-4-yl) -1- (3′-methoxy [1,1′-biphenyl] -3-yl) -2-methyl-1-propanol
Using 3-bromo-3′-methoxy-1,1′-biphenyl (2.09 g), the same reaction as in Example 1- (ii) was carried out to obtain the title compound (0.24 g) as a colorless solid.
1H-NMR (CDClThree) δ: 0.83 (3H, d, J = 6.7 Hz), 0.98 (3H, d, J = 6.7 Hz), 2.58-2.78 (1H, m), 3.86 (3H, s), 6.88 (1H, d, J = 8.4 Hz), 7.00 (1H, s), 7.08-7.24 (2H, m), 7.24-7.60 (6H, m), 7.79 (1H, s).
IR (KBr): 3202, 1472, 1044, 1005 cm-1.
[0025]
Example 9
Preparation of 1- (1H-imidazol-4-yl) -1- (4'-methoxy [1,1'-biphenyl] -3-yl) -2-methyl-1-propanol
(i) Production of 3-bromo-4'-methoxy-1,1'-biphenyl
Using 4-methoxyphenylboronic acid (3.08 g), the same reaction as in Example 1- (i) was carried out to obtain the title compound (3.84 g) as colorless needle crystals.
1H-NMR (CDClThree) δ: 3.85 (3H, s), 6.92-7.02 (2H, m), 7.22-7.32 (1H, m), 7.38-7.54 (4H, m), 7.69 (1H, t, J = 1.9 Hz).
IR (KBr): 1520, 1474, 1252, 837 cm-1.
(ii) Preparation of 1- (1H-imidazol-4-yl) -1- (4′-methoxy [1,1′-biphenyl] -3-yl) -2-methyl-1-propanol
Using 3-bromo-4′-methoxy-1,1′-biphenyl (2.01 g), the same reaction as in Example 1- (ii) was carried out to obtain the title compound (0.50 g) as a colorless solid.
1H-NMR (CDClThree) δ: 0.82 (3H, d, J = 6.9 Hz), 0.98 (3H, d, J = 6.9 Hz), 2.50-2.74 (1H, m), 3.83 (3H, s), 6.89-6.99 (3H, m ), 7.26-7.55 (6H, m), 7.71-7.76 (1H, m).
IR (KBr): 2969, 1516, 1480, 1248, 1181 cm-1.
Example 10
Preparation of 1- (1H-imidazol-4-yl) -1- (4-methoxy [1,1'-biphenyl] -3-yl) -2-methyl-1-propanol
(i) Preparation of 4-methoxy [1,1'-biphenyl] -3-carbaldehyde
The same reaction as in Example 1- (i) was performed using 5-bromo-o-anisaldehyde (8.00 g) to obtain the title compound (3.75 g) as a colorless solid.
1H-NMR (CDClThree) δ: 3.98 (3H, s), 7.08 (1H, d, J = 8.8 Hz), 7.28-7.48 (3H, m), 7.49-7.63 (2H, m), 7.80 (1H, dd, J = 2.5, 8.8 Hz), 8.08 (1H, d, J = 2.5 Hz), 10.52 (1H, s).
IR (KBr): 1680, 1609, 1483, 1271 cm-1.
(ii) Preparation of 1H-imidazol-4-yl (4-methoxy [1,1'-biphenyl] -3-yl) methanol 4-Bromo-1H-imidazole (5.20 g) was dissolved in THF (50 ml). After cooling to -78 ° C, a pentane solution of t-butyllithium (1.7 M; 50 ml) was added. After stirring at 0 ° C. for 1.5 hours, the mixture was again cooled to −78 ° C., and a THF solution (30 ml) of 4-methoxy [1,1′-biphenyl] -3-carbaldehyde (2.54 g) was added. After raising the temperature from -78 ° C to room temperature, the mixture was further stirred at room temperature for 24 hours. Aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (eluent, dichloromethane: methanol = 15: 1) and recrystallized from ethyl acetate to obtain the title compound (1.15 g) as a colorless solid.
1H-NMR (CDClThree) δ: 3.84 (3H, s), 6.15 (1H, s), 6.70 (1H, s), 6.96 (1H, d, J = 8.4 Hz), 7.23-7.44 (3H, m), 7.46-7.57 (4H , m), 7.69 (1H, d, J = 2.2 Hz).
IR (KBr): 3134, 1481, 1242, 1030 cm-1.
[0026]
(iii) Preparation of (1H-imidazol-4-yl) (4-methoxy [1,1'-biphenyl] -3-yl) methanone
1H-imidazol-4-yl (4-methoxy [1,1'-biphenyl] -3-yl) methanol (0.94 g) was dissolved in dichloromethane (100 ml), and manganese dioxide (5.52 g) was added at room temperature. Stir for 14 hours. The reaction mixture was filtered and concentrated, and ethyl acetate was added to the resulting residue for crystallization to give the title compound (0.84 g) as a colorless solid.
1H-NMR (CDClThree+ CDThreeOD) δ: 3.87 (3H, s), 7.11 (1H, d, J = 8.4 Hz), 7.28-7.49 (3H, m), 7.51-7.60 (3H, m), 7.67-7.76 (2H, m), 7.83 (1H, m).
IR (KBr): 3000, 1636, 1483, 1273 cm-1.
(vi) Preparation of 1- (1H-imidazol-4-yl) -1- (4-methoxy [1,1'-biphenyl] -3-yl) -2-methyl-1-propanol
1H-imidazol-4-yl (4-methoxy [1,1′-biphenyl] -3-yl) methanone (0.62 g) was dissolved in THF (15 ml) and cooled to −40 ° C. A THF solution of isopropylmagnesium chloride (0.6 M; 15 ml) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, diluted with water, and extracted with ethyl acetate. The extract was dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent, dichloromethane: methanol = 40: 1) to give the colorless amorphous title compound (0.16 g).
1H-NMR (CDClThree) δ: 0.92 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6 Hz), 2.70-2.95 (1H, m), 3.90 (3H, s), 6.97 (1H, d, J = 8.6 Hz), 7.06 (1H, s), 7.24-7.56 (7H, m), 7.73 (1H, d, J = 1.8 Hz).
IR (KBr): 2967, 1481, 1242, 1024 cm-1.
Example 11
Preparation of 1- (1H-imidazol-4-yl) -1- (6-methoxy [1,1'-biphenyl] -3-yl) -2-methyl-1-propanol
(i) Preparation of 6-methoxy [1,1'-biphenyl] -3-carbaldehyde
The same reaction as in Example 1- (i) was performed using 3-bromo-p-anisaldehyde (7.98 g) to obtain the title compound (7.78 g) as a colorless oil.
1H-NMR (CDClThree) δ: 3.90 (3H, s), 7.09 (1H, d, J = 9.2 Hz), 7.30-7.56 (5H, m), 7.85 (1H, s), 7.87 (1H, dd, J = 2.2, 7.8 Hz) ), 9.93 (1H, s).
IR (KBr): 1694, 1595, 1265, 1175 cm-1.
(ii) Preparation of (1H-imidazol-4-yl) (6-methoxy [1,1'-biphenyl] -3-yl) methanol
The same reaction as in Example 10- (ii) was performed using 6-methoxy [1,1′-biphenyl] -3-carbaldehyde (3.10 g) to obtain the title compound (3.84 g) as a colorless solid. .
1H-NMR (CDClThree+ CDThreeOD) δ: 3.81 (3H, s), 5.81 (1H, s), 6.73 (1H, s), 6.97 (1H, d, J = 8.8 Hz), 7.24-7.46 (5H, m), 7.46-7.58 ( 2H, m), 7.59 (1H, d, J = 1.0 Hz).
IR (KBr): 2996, 1487, 1175, 1022, 986 cm-1.
[0027]
(iii) Preparation of (1H-imidazol-4-yl) (6-methoxy [1,1'-biphenyl] -3-yl) methanone
Using (1H-imidazol-4-yl) (6-methoxy [1,1′-biphenyl] -3-yl) methanol (3.74 g), the same reaction as in Example 10- (iii) was carried out, and colorless The solid title compound (2.64 g) was obtained.
1H-NMR (CDClThree+ CDThreeOD) δ: 3.92 (3H, s), 7.10 (1H, d, J = 8.8 Hz), 7.35-7.60 (5H, m), 7.73 (1H, s), 7.83 (1H, s), 7.90-8.10 ( 2H, brs).
IR (KBr): 3004, 1644, 1343, 1264 cm-1.
(vi) Preparation of 1- (1H-imidazol-4-yl) -1- (6-methoxy [1,1'-biphenyl] -3-yl) -2-methyl-1-propanol
Using (1H-imidazol-4-yl) (6-methoxy [1,1′-biphenyl] -3-yl) methanone (1.10 g), the same reaction as in Example 10- (iv) was carried out to obtain colorless. The solid title compound (0.48 g) was obtained.
1H-NMR (CDClThree) δ: 0.84 (3H, d, J = 6.8 Hz), 0.96 (3H, d, J = 6.8 Hz), 2.45-2.70 (1H, m), 3.77 (3H, s), 6.86-6.96 (2H, m ), 7.26-7.56 (8H, m).
IR (KBr): 2969, 1505, 1487, 1264 cm-1.
Example 12
Preparation of 1- (4'-chloro [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) Preparation of 1- (3-bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol
Similar to Example 1- (ii) using 1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanone (34.90 g) and O-dibromobenzene (50.7 g) The reaction was performed to give the title compound (37.7 g) as a colorless solid.
1H-NMR (CDClThree) δ: 0.72 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6.8 Hz), 2.22-2.44 (1H, m), 6.73 (1H, d, J = 1.6 Hz), 7.06- 7.19 (7H, m), 7.26-7.39 (11H, m), 7.46 (1H, dt, J = 7.8, 1.3 Hz), 7.59 (1H, t, J = 1.8 Hz).
IR (KBr): 1493, 1472, 1445, 702 cm-1.
(ii) Preparation of 1- (4′-chloro [1,1′-biphenyl] -3-yl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol 4 Performed with 1-chlorophenylboronic acid (0.49 g) and 1- (3-bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.04 g) The same reaction as in Example 1- (i) was performed to give the title compound (0.77 g) as a colorless solid.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.7 Hz), 0.94 (3H, d, J = 6.7 Hz), 2.35-2.55 (1H, m), 6.78 (1H, d, J = 1.4 Hz), 7.05- 7.60 (23H, m), 7.65 (1H, s).
IR (KBr): 1493, 1476, 1445, 909 cm-1.
[0028]
(iii) Preparation of 1- (4′-chloro [1,1′-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
1- (4′-Chloro [1,1′-biphenyl] -3-yl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (0.71 g) and pyridine The hydrochloride (0.25 g) was dissolved in methanol (20 ml) and stirred at 60 ° C. for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was concentrated. The organic layer was dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent, dichloromethane: methanol = 40: 1) and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid ( 0.31 g) was obtained.
1H-NMR (CDClThree) δ: 0.82 (3H, d, J = 6.8 Hz), 0.98 (3H, d, J = 6.8 Hz), 2.50-2.78 (1H, m), 6.99 (1H, d, J = 1.0 Hz), 7.33- 7.44 (4H, m), 7.45-7.56 (4H, m), 7.78 (1H, s).
IR (KBr): 2969, 1476, 1092, 1013 cm-1.
Example 13
Preparation of 1- (4'-fluoro [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) Preparation of 1- (4′-fluoro [1,1′-biphenyl] -3-yl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol
Using 4-fluorophenylboronic acid (0.41 g) and 1- (3-bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.01 g) The same reaction as in Example 1- (i) was carried out to obtain the title compound (0.71 g) as a pale yellow solid.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.8 Hz), 2.35-2.52 (1H, m), 6.78 (1H, d, J = 1.0 Hz), 7.04- 7.18 (8H, m), 7.22-7.38 (12H, m), 7.44-7.55 (3H, m), 7.63 (1H, s).
IR (KBr): 1512, 1480, 1233, 1159 cm-1.
(ii) Preparation of 1- (4′-fluoro [1,1′-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
Using 1- (4'-fluoro [1,1'-biphenyl] -3-yl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (0.62 g) Then, the same reaction as in Example 4- (iii) was carried out to obtain the title compound (0.27 g) as a colorless solid.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.82 (3H, d, J = 6.8 Hz), 0.98 (3H, d, J = 6.8 Hz), 2.40-2.80 (1H, m), 6.70-7.16 (3H, m), 7.30-7.59 ( 6H, m), 7.72 (1H, s).
IR (KBr): 3187, 1514, 1236, 1005, 795 cm-1.
[0029]
Example 14
Preparation of 1- (2 ', 4'-dichloro [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) 1- (2 ′, 4′-dichloro [1,1′-biphenyl] -3-yl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol Manufacturing of
Using 2,4-dichlorophenylboronic acid (0.55 g) and 1- (3-bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.00 g) Then, the same reaction as in Example 1- (i) was carried out to obtain an amorphous title compound (0.85 g).
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.8 Hz), 2.30-2.52 (1H, m), 6.74 (1H, d, J = 1.4 Hz), 7.04- 7.50 (16H, m), 7.57 (1H, dt, J = 7.8, 1.5 Hz).
IR (KBr): 1493, 1464, 1445, 1165 cm-1.
(ii) Preparation of 1- (2 ′, 4′-dichloro [1,1′-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
1- (2 ′, 4′-Dichloro [1,1′-biphenyl] -3-yl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (0.80 g ) To give an amorphous title compound (0.30 g) in the same manner as in Example 12- (iii).
1H-NMR (CDClThree) δ: 0.81 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 6.7 Hz), 2.45-2.70 (1H, m), 6.94 (1H, s), 7.12-7.60 (8H, m ).
IR (KBr): 2969, 1466, 1103 cm-1.
Example 15
Preparation of 1- [2 '-(dimethoxymethyl) [1,1'-biphenyl] -3-yl] -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) Preparation of 3 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -2-carbaldehyde
With 2-formylphenylboronic acid (0.50 g) and 1- (3-bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.02 g) The same reaction as in Example 1- (i) was carried out to obtain an amorphous title compound (0.93 g).
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 6.7 Hz), 0.93 (3H, d, J = 6.7 Hz), 2.30-2.55 (1H, m), 6.73 (1H, d, J = 1.4 Hz), 7.05- 7.69 (23H, m), 8.03 (1H, dd, J = 1.4, 7.8 Hz), 9.92 (1H, d, J = 0.8 Hz).
IR (KBr): 1692, 1597, 1493, 1447 cm-1.
(ii) Preparation of 1- [2 '-(dimethoxymethyl) [1,1'-biphenyl] -3-yl] -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
With 3 ′-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1′-biphenyl] -2-carbaldehyde (0.89 g), The same reaction as in Example 12- (iii) was performed to obtain an amorphous title compound (0.28 g).
1H-NMR (CDClThree) δ: 0.82 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J = 6.7 Hz), 2.45-2.70 (1H, m), 3.10-3.40 (6H, m), 5.13 (1H, s ), 6.93 (1H, m), 7.10-7.75 (9H, m).
IR (KBr): 2969, 1472, 1092, 1073 cm-1.
[0030]
Example 16
Preparation of 1- [3 '-(dimethoxymethyl) [1,1'-biphenyl] -3-yl] -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) Preparation of 3 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-carbaldehyde
With 3-formylphenylboronic acid (0.45 g) and 1- (3-bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.05 g) The same reaction as in Example 1- (i) was carried out to obtain the amorphous title compound (0.80 g).
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 6.8 Hz), 0.95 (3H, d, J = 6.8 Hz), 2.35-2.58 (1H, m), 6.79 (1H, d, J = 1.6 Hz), 7.07- 7.64 (20H, m), 7.74-7.90 (3H, m), 8.06 (1H, t, J = 1.7 Hz), 10.07 (1H, s).
IR (KBr): 1698, 1445, 1163 cm-1.
(ii) Preparation of 1- [3 '-(dimethoxymethyl) [1,1'-biphenyl] -3-yl] -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
With 3 ′-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1′-biphenyl] -3-carbaldehyde (0.70 g), The same reaction as in Example 12- (iii) was performed to give the title compound (0.27 g) as a colorless solid.
1H-NMR (CDClThree) δ: 0.83 (3H, d, J = 6.7 Hz), 0.99 (3H, d, J = 6.7 Hz), 2.50-2.77 (1H, m), 3.37 (6H, m), 5.42 (1H, s), 6.93-7.01 (1H, m), 7.28-7.60 (7H, m), 7.66 (1H, s), 7.81 (1H, d, J = 1.6 Hz).
IR (KBr): 2967, 1198, 1107, 1055 cm-1.
Example 17
Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- (2'-methyl [1,1'-biphenyl] -3-yl) -1-propanol
(i) Preparation of 2-methyl-1- (2'-methyl [1,1'-biphenyl] -3-yl) -1- (1-trityl-1H-imidazol-4-yl) -1-propanol
Performed with o-tolylboronic acid (0.69 g) and 1- (3-bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.01 g) The same reaction as in Example 1- (i) was carried out to obtain an amorphous title compound (0.61 g).
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 6.7 Hz), 0.92 (3H, d, J = 6.7 Hz), 2.18 (3H, s), 2.30-2.55 (1H, m), 6.73 (1H, d, J = 1.4 Hz), 7.05-7.39 (23H, m), 7.54 (1H, dt, J = 7.8, 1.2 Hz).
IR (KBr): 1493, 1474, 1445, 1161 cm-1.
(ii) Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- (2'-methyl [1,1'-biphenyl] -3-yl) -1-propanol
Using 2-methyl-1- (2'-methyl [1,1'-biphenyl] -3-yl) -1- (1-trityl-1H-imidazol-4-yl) -1-propanol (0.55 g) Then, the same reaction as in Example 12- (iii) was performed to obtain an amorphous title compound (0.20 g).
1H-NMR (CDClThree) δ: 0.81 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 6.6 Hz), 2.19 (3H, s), 2.48-2.70 (1H, m), 6.85-6.97 (1H, m ), 7.10-7.54 (9H, m).
IR (KBr): 2970, 1474, 909 cm-1.
[0031]
Example 18
Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- (4'-methyl [1,1'-biphenyl] -3-yl) -1-propanol
(i) Preparation of 2-methyl-1- (4'-methyl [1,1'-biphenyl] -3-yl) -1- (1-trityl-1H-imidazol-4-yl) -1-propanol
Performed with p-tolylboronic acid (0.45 g) and 1- (3-bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.03 g) The same reaction as in Example 1- (i) was performed to give the title compound (0.76 g) as a colorless solid.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.7 Hz), 0.93 (3H, d, J = 6.7 Hz), 2.35-2.55 (1H, m), 2.40 (3H, s), 6.79 (1H, d, J = 1.4 Hz), 7.06-7.54 (23H, m), 7.66 (1H, t, J = 1.6 Hz).
IR (KBr): 1493, 1480, 1445, 1163 cm-1.
(ii) Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- (4'-methyl [1,1'-biphenyl] -3-yl) -1-propanol
Using 2-methyl-1- (4'-methyl [1,1'-biphenyl] -3-yl) -1- (1-trityl-1H-imidazol-4-yl) -1-propanol (0.61 g) Then, the same reaction as in Example 12- (iii) was carried out to obtain the title compound (0.23 g) as a colorless solid.
1H-NMR (CDClThree) δ: 0.82 (3H, d, J = 6.7 Hz), 0.98 (3H, d, J = 6.7 Hz), 2.38 (3H, s), 2.55-2.75 (1H, m), 6.98 (1H, s), 7.16-7.54 (8H, m), 7.77 (1H, t, J = 1.6 Hz).
IR (KBr): 2969, 1480, 791, 735 cm-1.
Example 19
Preparation of 1- (2 ', 4'-difluoro [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) 1- (2 ′, 4′-difluoro [1,1′-biphenyl] -3-yl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol Manufacturing of
1- (3-Bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (6.00 g), 2,4-difluorophenylboronic acid (2.82 g), 2 M The same reaction as in Example 4- (ii) was carried out using aqueous sodium carbonate solution (45 ml) and tetrakis (triphenylphosphine) palladium (0) (647 mg) to give the title compound (6.39 g) as a yellow amorphous product. Obtained.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.8 Hz), 2.35-2.49 (1H, m), 3.68 (1H, s), 6.76 (1H, d, J = 1.4 Hz), 6.83-6.97 (2H, m), 7.09-7.16 (6H, m), 7.26-7.35 (13H, m), 7.36-7.57 (2H, m)
IR (KBr): 1508, 1480, 1447, 1140, 909, 747, 735, 702 cm-1
(ii) Preparation of 1- (2 ', 4'-difluoro [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
1- (2 ', 4'-Difluoro [1,1'-biphenyl] -3-yl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (6.31 g ) And pyridine hydrochloride (2.17 g) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (2.93 g.) As colorless needle crystals.
1H-NMR (CDClThree) δ: 0.83 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 2.56-2.73 (1H, m), 6.84-6.98 (3H, m), 7..32- 7.52 (5H, m), 7.69 (1H, s) IR (KBr): 3202, 1508, 1478, 1385, 1364, 1142, 1005, 855, 845, 797 cm-1
[0032]
Example 20
Preparation of 1- (3'-fluoro [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) 1- (3'-Fluoro [1,1'-biphenyl] -3-yl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol
1- (3-Bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (2.62 g), 3-fluorophenylboronic acid (1.09 g), 2M aqueous sodium carbonate solution (19.5 ml) and tetrakis (triphenylphosphine) palladium (0) (281 mg) were used for the same reaction as in Example 4- (ii) to obtain the title compound (2.55 g) as a yellow amorphous.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 2.36-2.50 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J = 1.2 Hz), 6.98-7.43 (22H, m), 7.55 (1H, dt, J = 6.6, 2.0 Hz), 7.65 (1H, s)
IR (KBr) cm-1: 1493, 1472, 1445, 1159, 909, 781, 747, 735, 702 cm-1
(ii) Preparation of 1- (3'-fluoro [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
1- (3′-Fluoro [1,1′-biphenyl] -3-yl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (2.55 g), pyridine The hydrochloride (906 mg) was used for the same reaction as in Example 4- (iii) to obtain the title compound (1.15 g) as colorless needle crystals.
1H-NMR (CDClThree) δ: 0.83 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J = 7.0 Hz), 2.59-2.72 (1H, m), 3.52 (1H, br s), 7.00- 7.06 (2H, m), 7.30-7.40 (5H, m), 7.55 (2H, br s), 7.81 (1H, br s), 9.28 (1H, br s)
IR (KBr) cm-1: 3179, 1576, 1472, 1362, 1304, 1200, 1005, 777, 693 cm-1
Example 21
Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [4 '-(trifluoromethyl) [1,1'-biphenyl] -3-yl] -1-propanol
(i) 2-Methyl-1- [4 '-(trifluoromethyl) [1,1'-biphenyl] -3-yl] -1- (1-trityl-1H-imidazol-4-yl) -1- Propanol production
1- (3-Bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (3.01 g) 4-trifluoromethylphenylboronic acid (1.70 g), 2M sodium carbonate The same reaction as in Example 4- (ii) was performed using an aqueous solution (22.4 ml) and tetrakis (triphenylphosphine) palladium (0) (323 mg) to give the title compound (2.58 g) as colorless needle crystals. Obtained.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 7.0 Hz), 0.94 (3H, d, J = 7.0 Hz), 2.45-2.50 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J = 1.2 Hz), 7.09-7.14 (6H, m), 7.23-7.40 (12H, m), 7.55-7.69 (6H, m)
IR (KBr): 1447, 1327, 1167, 1125, 1073, 849, 793, 747, 735, 702 cm-1
(ii) Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [4 '-(trifluoromethyl) [1,1'-biphenyl] -3-yl] -1-propanol
2-Methyl-1- [4 '-(trifluoromethyl) [1,1'-biphenyl] -3-yl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol (2.55 g) and pyridine hydrochloride (831 mg) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (1.31 g) as colorless needle crystals.
1H-NMR (CDClThree) δ: 0.83 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.59-2.73 (1H, m), 3.37 (1H, br s), 7.01 (1H, s) , 7.35-7.46 (2H, m), 7.55-7.67 (6H, m), 7.84 (1H, s), 9.24 (1H, br s)
IR (KBr): 3252, 1327, 1171, 1119, 1073, 966, 845, 797 cm-1
[0033]
Example 22
Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [4 '-(trifluoromethoxy) [1,1'-biphenyl] -3-yl] -1-propanol
(i) 2-Methyl-1- [4 '-(trifluoromethoxy) [1,1'-biphenyl] -3-yl] -1- (1-trityl-1H-imidazol-4-yl) -1- Propanol production
1- (3-Bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (3.80 g) 4-trifluoromethoxyphenylboronic acid (2.33 g), 2M sodium carbonate The same reaction as in Example 4- (ii) was carried out using an aqueous solution (28.3 ml) and tetrakis (triphenylphosphine) palladium (0) (408 mg) to give the title compound (3.67 g) as colorless needle crystals. Obtained.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 7.0 Hz), 0.94 (3H, d, J = 7.0 Hz), 2.36-2.50 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J = 1.0 Hz), 7.10-7.16 (6H, m), 7.23-7.40 (14H, m), 7.50-7.64 (4H, m)
IR (KBr): 1493, 1481, 1445, 1264, 1225, 1165, 1015, 793, 747, 700 cm-1
(ii) Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [4 '-(trifluoromethoxy) [1,1'-biphenyl] -3-yl] -1-propanol
2-Methyl-1- [4 '-(trifluoromethoxy) [1,1'-biphenyl] -3-yl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol (3.63 g) and pyridine hydrochloride (1.22 g) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (3.76 g) as colorless needle crystals.
1H-NMR (CDClThree) δ: 0.82 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 2.57-2.71 (1H, m), 6.98 (1H, d, J = 0.8 Hz), 7.18- 7.39 (4H, m), 7.51-7.59 (4H, m), 7.78 (1H, s)
IR (KBr): 1510, 1478, 1271, 1227, 1167, 1105, 855, 829, 791, 708 cm-1
Example 23
Preparation of 1- [4'-fluoro-3 '-(methoxymethyl) [1,1'-biphenyl] -3-yl] -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) Production of 4-bromo-1-fluoro-2- (methoxymethyl) benzene
To a solution of (5-bromo-2-fluorophenyl) methanol (5.00 g) in THF (100 ml) was added 60% sodium hydride (1.08 g) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes, and then methyl iodide (3.80 ml) was added and stirred for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (eluent, hexane → hexane: ethyl acetate = 50: 1) to obtain the title compound (4.86 g) as a brown oil.
1H-NMR (CDClThree) δ: 3.42 (3H, s), 4.92 (2H, s), 6.93 (1H, dd, J = 8.8, 8.8 Hz), 7.34-7.42 (1H, m), 7.56 (1H, dd, J = 2.2, 6.2 Hz)
IR (KBr): 1485, 1456, 1383, 1238, 1177, 1123, 1101, 814, 623 cm-1
[0034]
(ii) 1- [4'-Fluoro-3 '-(methoxymethyl) [1,1'-biphenyl] -3-yl] -1- (1-trityl-1H-imidazol-4-yl) -2- Production of methyl-1-propanol
N-Butyllithium (1.6M; 15.3 ml) was added dropwise to a solution of 4-bromo-1-fluoro-2- (methoxymethyl) benzene (4.86 g) in THF (60 ml) at -78 ° C and stirred for 40 minutes. Triisopropoxyborane (10.2 ml) was added dropwise and stirred at room temperature for 15 hours. 2N Hydrochloric acid (20 ml) was added to the reaction mixture at 0 ° C., and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried. The solvent was distilled off under reduced pressure to obtain a crude product of 4-fluoro-3- (methoxymethyl) phenylboronic acid (4.50 g) as a yellow oil. This product (1.36 g), 1- (3-bromophenyl)-(1-trityl-1-1H-imidazol-4-yl) -2-methyl-1-propanol (1.50 g), 2M aqueous sodium carbonate solution (11.2 ml) and tetrakis (triphenylphosphine) palladium (0) (161 mg) were used to carry out the same reaction as in Example 4- (ii) to obtain the title compound (1.36 g) as a yellow amorphous.
1H-NMR (CDClThree) δ: 0.78 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 6.6 Hz), 2.43-2.50 (1H, m), 3.45 (3H, s), 4.58 (2H, s), 6.80 (1H, d, J = 1.2 Hz), 7.12-7.19 (7H, m), 7.28-7.52 (15H, m), 7.62 (1H, d, J = 2.2, 7.0 Hz), 7.71 (1H, s)
IR (KBr): 1493, 1478, 1445, 1188, 1159, 1121, 1094, 909, 748, 733, 702 cm-1
(iii) 1- [4'-Fluoro-3 '-(methoxymethyl) [1,1'-biphenyl] -3-yl] -1- (1H-imidazol-4-yl) -2-methyl-1- Propanol production
1- [4'-Fluoro-3 '-(methoxymethyl) [1,1'-biphenyl] -3-yl] -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1 The same reaction as in Example 4- (iii) was performed using -propanol (1.35 g) and pyridine hydrochloride (469 mg) to obtain the title compound (629 mg) as a colorless amorphous.
1H-NMR (CDClThree) δ: 0.79 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 6.4 Hz), 2.56-2.62 (1H, m), 3.41 (3H, s), 4.54 (2H, s), 6.88 (1H, s), 6.99-7.08 (1H, m), 7.30-7.57 (6H, m), 7.73 (1H, s) IR (KBr): 2971, 1505, 1478, 1385, 1229, 1192, 1123, 1092, 1007, 828, 793 cm-1
Example 24
Preparation of 1- (4'-fluoro-6-methoxy [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) Preparation of 4'-fluoro-6-methoxy [1,1'-biphenyl] -3-carbaldehyde
Using 3-bromo-p-anisaldehyde (14.0 g), 4-fluorophenylboronic acid (14.6 g), 2M aqueous sodium carbonate solution (260 ml), tetrakis (triphenylphosphine) palladium (0) (3.76 g) The same reaction as in Example 5- (ii) was carried out to obtain the title compound (11.9 g) as white needle crystals.
1H-NMR (CDClThree) δ: 3.91 (3H, s), 7.07-7.16 (3H, m), 7.46-7.53 (2H, m), 7.82-7.90 (2H, m), 9.94 (1H, s)
IR (KBr): 1694, 1599, 1497, 1265, 1225, 1177, 1020, 839, 814 cm-1
[0035]
(ii) Preparation of 1- (4'-fluoro-6-methoxy [1,1'-biphenyl] -3-yl) -2-methyl-1-propanol
4'-Fluoro-6-methoxy [1,1'-biphenyl] -3-carbaldehyde (5.00 g) in THF (80 ml) at 0 ° C with isopropylmagnesium bromide in THF (0.63; 44.8 ml) Was added dropwise and stirred for 1 hour 45 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (eluent, hexane: ethyl acetate = 6: 1 → 2: 1) to obtain the title compound (3.82 g) as a yellow oil.
1H-NMR (CDClThree) δ: 0.81 (3H, d, J = 6.6 Hz), 1.02 (3H, s, J = 6.6 Hz), 1.79 (1H, d, J = 3.2 Hz), 1.88-2.02 (1H, m), 3.81 ( 3H, s), 4.35 (1H, dd, J = 3.0, 7.0 Hz), 6.92-7.15 (3H, m), 7.24-7.29 (2H, m), 7.44-7.53 (2H, m)
IR (KBr): 1514, 1495, 1464, 1264, 1233, 1159, 1044, 1026, 837, 814 cm-1(iii) Preparation of 1- (4'-fluoro-6-methoxy [1,1'-biphenyl] -3-yl) -2-methyl-1-propanone
To a solution of 1- (4'-fluoro-6-methoxy [1,1'-biphenyl] -3-yl) -2-methyl-1-propanol (3.82 g) in dichloromethane (60 ml) was added manganese dioxide (IV) ( 12.1 g) was added, and after stirring at room temperature for 17 hours, manganese dioxide (IV) (17.7 g) was further added. After stirring at room temperature for 1.5 hours, the mixture was heated to reflux for 22 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound (3.73 g) as a yellow oil.
1H-NMR (CDClThree) δ: 1.23 (6H, d, J = 6.6 Hz), 3.55 (1H, m, J = 6.6 Hz), 3.89 (3H, s), 7.00-7.17 (3H, m), 7.44-7.54 (2H, m ), 7.92-8.01 (2H, m)
IR (KBr): 1674, 1599, 1514, 1497, 1267, 1208, 1159, 1150, 990, 839 cm-1(iv) 1- (4'-Fluoro-6-methoxy [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
To a solution of 4-iodo-1H-imidazole (2.13 g) and tetramethylethylenediamine (1.66 ml) in THF (50 ml) was added dropwise ethylmagnesium bromide in diethyl ether (3M; 14.7 ml) under ice cooling. The mixture was warmed to 0 ° C. and stirred for 1 hour, and then copper iodide (I) (178 mg) was added at 40 ° C. and stirred at 40 to 45 ° C. for 5 minutes. A solution of 1- (4′-fluoro-6-methoxy [1,1′-biphenyl] -3-yl) -2-methyl-1-propane (3.73 g) in THF (20 ml) was added dropwise at 30 ° C. Stir at room temperature for 4 hours. Saturated ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with 5% aqueous ethylenediamine solution and saturated brine, and dried. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (eluent, hexane: ethyl acetate = 1: 2 → ethyl acetate) to obtain the title compound (922 mg) as a colorless amorphous.
1H-NMR (CDClThree) δ: 0.84 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 7.0 Hz), 2.54-2.67 (1H, m), 3.78 (3H, s), 6.89-7.11 (4H, m ), 7.43-7.54 (5H, m) IR (KBr): 1514, 1493, 1464, 1264, 1227, 1157, 1026, 837, 818 cm-1
[0036]
Example 25
Preparation of 3 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methyl-1-propyl] [1,1'-biphenyl] -4-carbonitrile
(i) Preparation of 3 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propyl] [1,1'-biphenyl] -4-carbonitrile
1- (3-Bromophenyl)-(1-trityl-1-1H-imidazol-4-yl) -2-methyl-1-propanol (978 mg), 4-cyanophenylboronic acid (535 mg), 2M carbonic acid The same reaction as in Example 4- (ii) was carried out using aqueous sodium solution (7.28 ml) and tetrakis (triphenylphosphine) palladium (0) (105 mg), and the title compound (622 mg) was obtained as colorless needle crystals. Got as.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 7.0 Hz), 2.40-2.47 (1H, m), 3.68 (1H, s), 6.78 (1H, d, J = 1.6 Hz), 7.10-7.14 (6H, m), 7.29-7.40 (12H, m), 7.55-7.73 (6H, m)
IR (KBr): 2965, 2226, 1605, 1491, 1480, 1445, 845, 795, 754, 745, 700 cm-1
(ii) Preparation of 3 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methyl-1-propyl] [1,1'-biphenyl] -4-carbonitrile
3 ′-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propyl] [1,1′-biphenyl] -4-carbonitrile (590 mg), The same reaction as in Example 4- (iii) was performed using pyridine hydrochloride (111 mg) to obtain the title compound (261 mg) as colorless needle crystals.
1H-NMR (CDClThree) δ: 0.82 (3H, d, J = 7.0 Hz), 0.91 (3H, d, J = 6.6 Hz), 2.59-2.73 (1H, m), 6.99 (1H, s), 7.36-7.43 (2H, m ), 7.53-7.69 (6H, m), 7.83 (1H, s)
IR (KBr): 2232, 1605, 1478, 1103, 843, 791, 727, 708, 644 cm-1
Example 26
Preparation of 1- (4'-fluoro [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -1-ethanol
(i) Preparation of 1- (4'-fluoro [1,1'-biphenyl] -3-yl) -1- (1-trityl-1H-imidazol-4-yl) -1-ethanol
To a solution of 3-bromo-4'-fluoro-1,1'-biphenyl (1.50 g) in THF (20 ml) was added dropwise n-butyllithium hexane solution (1.6 M; 3.73 ml) at -78 ° C. After stirring for 1 min, a solution of 1- (1-trityl-1H-imidazol-4-yl) -1-ethanone (1.91 g) in THF (25 ml) was added dropwise at −78 ° C. The mixture was stirred at 35 to -10 ° C for 1 hour and at 0 ° C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (eluent, hexane: ethyl acetate = 3: 1 → 1: 1), recrystallized from ethyl acetate-hexane, Obtained as prismatic crystals.
1H-NMR (CDClThree) δ: 1.81 (3H, s), 3.44 (1H, s), 6.77 (1H, d, J = 1.4 Hz), 7.06-7.28 (8H, m), 7.30-7.55 (16H, m)
IR (KBr): 1514, 1483, 1441, 1221, 1163, 839, 797, 758, 750, 702 cm-1
[0037]
(ii) Preparation of 1- (4'-fluoro [1,1'-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -1-ethanol
1- (4′-Fluoro [1,1′-biphenyl] -3-yl) -1- (1-trityl-1H-imidazol-4-yl) -1-ethanol (1.51 g), pyridine hydrochloride (599 mg) was used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (559 mg.) as colorless plate crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 1.91 (3H, s), 6.89 (1H, s), 7.05-7.14 (2H, m), 7.35-7.42 (3H, m), 7.48-7.55 (3H, m), 7.65 (1H, s )
IR (KBr): 3166, 1514, 1481, 1456, 1231, 1190, 1067, 833, 799, 623 cm-1
Example 27
Preparation of 1- [4'-fluoro [1,1'-biphenyl] -3-yl] -1- (1H-imidazol-4-yl) -1-propanol
3-Bromo-4'-fluoro-1,1'-biphenyl (2.80 g), n-butyllithium in hexane (1.6 M; 6.96 ml), 1- (1H-imidazol-4-yl) -1-propanone (419 mg) was used for the same reaction as in Example 26- (i) to give the title compound (796 mg) as colorless plate crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.89 (3H, J = 7.2 Hz), 2.14-2.36 (2H, m), 6.90 (1H, s), 7.05-7.14 (2H, m), 7.37-7.56 (6H, m), 7.65 ( 1H, s)
IR (KBr): 3191, 1512, 1235, 1181, 1096, 963, 934, 835, 799, 619 cm-1
Example 28
Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [3- (2-thienyl) phenyl] -1-propanol
(i) Preparation of 2-methyl-1- [3- (2-thienyl) phenyl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol
1- (3-Bromophenyl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (1.70 g), tri-n-butyl (2-thienyl) tin (1.31 ml) in DMF (10 ml), tetrakis (triphenylphosphine) palladium (0) (110 mg) was added, and the mixture was stirred at 80 ° C. for 4 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed twice with water, washed with saturated brine, and dried. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 6: 1 → 3: 1) and recrystallized from ethyl acetate-hexane to give the title compound (1.32 g). Obtained as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.35-2.48 (1H, m), 3.68 (1H, s), 6.79 (1H, d, J = 1.0 Hz), 7.04-7.16 (6H, m), 7.24-7.35 (14H, m), 7.41-7.47 (2H, m), 7.72 (1H, s)
IR (KBr): 1493, 1445, 1165, 1003, 909, 747, 700 cm-1
[0038]
(ii) Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [3- (2-thienyl) phenyl] -1-propanol
Using 2-methyl-1- [3- (2-thienyl) phenyl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.21 g) and pyridine hydrochloride (465 mg) Then, the reaction similar to that of Example 4- (iii) was performed to obtain the title compound (585 mg) as colorless plate crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.82 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J = 6.4 Hz), 2.56-2.70 (1H, m), 6.98 (1H, d, J = 1.2 Hz), 7.06 (1H, dd, J = 3.8, 5.2 Hz), 7.24-7.49 (5H, m), 7.51 (1H, d, J = 1.2 Hz), 7.80 (1H, s)
IR (KBr): 3194, 2969, 1385, 1366, 1306, 1007, 822, 787, 693, 635 cm-1
Example 29
Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [3- (3-thienyl) phenyl] -1-propanol
(i) Preparation of 2-methyl-1- [3- (3-thienyl) phenyl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol
1- (3-Bromophenyl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (1.70 g), 3-thiopheneboronic acid (607 mg), 2 M carbonic acid Tetrakis (triphenylphosphine) palladium (0) (110 mg) was added to a toluene-ethanol (6: 1) (17.5 ml) suspension of an aqueous sodium solution (3.16 ml), and the mixture was heated to reflux for 3 hours under an argon atmosphere. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 6: 1 → 4: 1 → 3: 1), recrystallized from ethyl acetate-hexane, 1.48 g) was obtained as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.36-2.49 (1H, m), 3.67 (1H, s), 6.78 (1H, d, J = 1.4 Hz), 7.10-7.17 (6H, m), 7.25-7.48 (16H, m), 7.70 (1H, dd, J = 1.8, 1.8 Hz)
IR (KBr): 1493, 1445, 1163, 1003, 909, 775, 747, 733, 702 cm-1
(ii) Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [3- (3-thienyl) phenyl] -1-propanol
Using 2-methyl-1- [3- (3-thienyl) phenyl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.43 g) and pyridine hydrochloride (550 mg) Then, the reaction similar to that of Example 4- (iii) was performed to obtain the title compound (585 mg) as colorless plate crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.82 (3H, d, J = 7.0 Hz), 0.98 (3H, d, J = 7.0 Hz), 2.57-2.70 (1H, m), 6.96 (1H, d, J = 1.0 Hz), 7.28 -7.48 (7H, m), 7.79 (1H, s)
IR (KBr): 3196, 2969, 1358, 1304, 1007, 801, 787, 774 cm-1
[0039]
Example 30
Preparation of 1- [3- (2-furyl) phenyl] -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) Preparation of 1- [3- (2-furyl) phenyl] -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol
1- (3-Bromophenyl) -1- (1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (1.70 g), tri-n-butyl (2-furyl) tin (1.29 ml) and tetrakis (triphenylphosphine) palladium (0) (110 mg) were used to carry out the same reaction as in Example 28- (i) to obtain the title compound (1.62 g) as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.8 Hz), 2.36-2.50 (1H, m), 3.67 (1H, s), 6.46 (1H, dd, J = 1.8, 3.2 Hz), 6.60 (1H, d, J = 3.2 Hz), 6.79 (1H, d, J = 1.4 Hz), 7.10-7.15 (6H, m), 7.28-7.35 (11H, m), 7.41 -7.51 (3H, m), 7.79 (1H, dd, J = 1.8, 1.8 Hz)
IR (KBr): 1493, 1472, 1445, 1161, 1013, 910, 791, 733, 702, 660 cm-1
(ii) Preparation of 1- [3- (2-furyl) phenyl] -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
Using 1- [3- (2-furyl) phenyl] -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.54 g), pyridine hydrochloride (610 mg) Then, a reaction similar to that of Example 4- (iii) was performed to obtain the title compound (597 mg) as colorless plate crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.81 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.57-2.71 (1H, m), 6.46 (1H, dd, J = 1.8, 3.4 Hz) , 6.65 (1H, d, J = 1.8 Hz), 6.98 (1H, d, J = 3.4 Hz), 7.27-7.51 (5H, m), 7.85 (1H, s)
IR (KBr): 3200, 2975, 1306, 1188, 1007, 789, 729, 693, 635 cm-1
Example 31
Preparation of N- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} acetamide
(i) N- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} acetamide Manufacturing
1- (4-Bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.04 g), 3- (acetylamino) phenylboronic acid (571 mg) Using tetrakis (triphenylphosphine) palladium (0) (301 mg), the same reaction as in Example 4- (ii) was carried out to obtain the title compound (1.10 g) as a pale yellow amorphous powder.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.6Hz), 0.92 (3H, d, J = 6.6Hz), 2.20 (3H, s), 2.38-2.56 (1H, m), 3.55 (1H, s), 6.77 (1H, d, J = 1.2Hz), 7.06-7.20 (6H, m), 7.24-7.76 (18H, m).
IR (KBr): 3063, 1674, 1557, 1483, 1445 cm-1.
[0040]
(ii) Preparation of N- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} acetamide
N- {4 ′-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1′-biphenyl] -3-yl} acetamide (978 mg) Using pyridine hydrochloride (310 mg), the same reaction as in Example 4- (iii) was carried out to obtain the title compound (276 mg) as a colorless amorphous powder.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.82 (3H, d, J = 6.8Hz), 0.98 (3H, d, J = 6.8Hz), 2.17 (3H, s), 2.51-2.74 (1H, m), 6.96 (1H, d, J = 1.0Hz), 7.25-7.39 (3H, m), 7.42-7.56 (5H, m), 7.68 (1H, s).
IR (KBr): 3210, 2971, 1672, 1557, 1483 cm-1.
Example 32
Preparation of N- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -4-yl} acetamide
(i) N- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -4-yl} acetamide Manufacturing
1- (4-Bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.00 g), 4- (acetylamino) phenylboronic acid (510 mg) Using tetrakis (triphenylphosphine) palladium (0) (200 mg), the same reaction as in Example 4- (ii) was performed to obtain the title compound (350 mg) as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 6.6Hz), 0.93 (3H, d, J = 6.6Hz), 2.20 (3H, s), 2.30-2.56 (1H, m), 3.53 (1H, s), 6.77 (1H, d, J = 1.4Hz), 7.08-7.14 (6H, m), 7.27-7.38 (10H, m), 7.43-7.58 (8H, m).
IR (KBr): 2971, 1671, 1535, 1493 cm-1.
(ii) Preparation of N- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -4-yl} acetamide
N- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -4-yl} acetamide (601 mg) And pyridine hydrochloride (0.17 g) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (73 mg) as colorless powder crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.82 (3H, d, J = 6.8Hz), 0.98 (3H, d, J = 6.8Hz), 2.17 (3H, s), 2.49-2.70 (1H, m), 6.96 (1H, d, J = 0.8Hz), 7.44-7.60 (9H, m) .IR (KBr): 3173, 1667, 1534, 1499 cm-1.
[0041]
Example 33
Preparation of N- {4-fluoro-4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} acetamide
(i) Production of N- (5-bromo-2-fluorophenyl) acetamide
4-Bromo-1-fluoro-2-nitrobenzene (5.81 g), iron powder (6.20 g) and acetic anhydride (5 ml) were stirred in acetic acid (50 ml) at 60 ° C. for 16 hours. Acetic acid was distilled off under reduced pressure, and water and ethyl acetate were added. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (3.56 g) as colorless prism crystals.
1H-NMR (CDClThree) δ: 2.23 (3H, s), 6.87-7.03 (1H, m), 7.06-7.21 (1H, m), 7.43 (1H, brs), 8.53 (1H, d, J = 6.8 Hz).
IR (KBr): 3262, 1672, 1613, 1535, 1408 cm-1.
(ii) N- {4-Fluoro-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3- Ill} acetamide production
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.50 g), N- (5-bromo-2-fluorophenyl) acetamide ( 1.17 g) and tetrakis (triphenylphosphine) palladium (0) (0.17 g) were used to carry out the same reaction as in Example 4- (ii) to obtain the title compound (1.39 g) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 7.0 Hz), 0.92 (3H, d, J = 7.0 Hz), 2.24 (3H, s), 3.55 (1H, s), 6.77 (1H, d, J = 1.0 Hz), 7.06-7.20 (7H, m), 7.20-7.36 (11H, m), 7.47 (2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz), 8.55 (1H, d , J = 5.2 Hz).
IR (KBr): 2960, 1680, 1545, 1493 cm-1.
(iii) N- {4-Fluoro-4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} acetamide Manufacturing
N- {4-Fluoro-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} acetamide (1.29 g) and pyridine hydrochloride (297 mg) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (399 mg) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.81 (3H, d, J = 6.8 Hz), 0.97 (3H, d, J = 6.8 Hz), 2.23 (3H, s), 2.50-2.70 (1H, m), 6.95 (1H, s), 7.04-7.26 (2H, m), 7.38-7.60 (5H, m), 8.47 (1H, d, J = 7.8 Hz).
IR (KBr): 2971, 1682, 1669, 1609, 1487 cm-1.
[0042]
Example 34
Preparation of N- {6-fluoro-4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} acetamide
(i) Production of 2-bromo-1-fluoro-4-nitrobenzene
An aqueous solution (100 ml) of sodium nitrite (11.56 g) was added dropwise to a mixture of 2-fluoro-5-nitroaniline (25.90 g), 47% aqueous hydrogen bromide (100 ml), water (200 ml) and acetic acid (200 ml). And stirred at 0 ° C. for 1 hour. The mixture was added at 0 ° C. to a solution of 47% aqueous hydrogen bromide (100 ml) in which copper bromide (CuBr: 27.30 g) was dissolved, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane) and crystallized from hexane to give the title compound (4.01 g) as colorless needle crystals.
1H-NMR (CDClThree) δ: 7.22-7.35 (1H, m), 8.17-8.29 (1H, m), 8.51 (1H, dd, J = 2.4, 6.0 Hz).
IR (KBr): 1537, 1470, 1348 cm-1.
(ii) Production of N- (3-bromo-4-fluorophenyl) acetamide
2-Bromo-1-fluoro-4-nitrobenzene (2.27 g), iron powder (2.90 g) and acetic anhydride (2.0 ml) were used to carry out a reaction similar to Example 33- (i) to give the title compound (2.28 g ) Was obtained as colorless powder crystals.
1H-NMR (CDClThree) δ: 2.17 (3H, s), 7.06 (1H, t, J = 8.4 Hz), 7.26-7.43 (2H, m), 7.80 (1H, dd, J = 2.6, 5.6 Hz).
IR (KBr): 3306, 1669, 1609, 1549, 1493 cm-1.
(iii) N- {6-Fluoro-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3- Ill} acetamide production
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.19 g), N- (3-bromo-4-fluorophenyl) acetamide ( 990 mg) and tetrakis (triphenylphosphine) palladium (0) (0.21 g) were used to carry out the same reaction as in Example 33- (ii) to obtain the title compound (870 mg) as a pale yellow amorphous powder.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.11 (3H, s), 2.30-2.58 (1H, m), 3.59 (1H, s), 6.79 (1H, d, J = 1.0 Hz), 6.96-7.20 (7H, m), 7.25-7.70 (15H, m), 7.88 (1H, s).
IR (KBr): 3287, 2969, 1672, 1553, 1489 cm-1.
(iv) N- {6-Fluoro-4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} acetamide Manufacturing
N- {6-Fluoro-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} acetamide (820 mg) and pyridine hydrochloride (230 mg) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (250 mg) as a colorless amorphous powder.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.82 (3H, d, J = 7.0 Hz), 0.98 (3H, d, J = 7.0 Hz), 2.14 (3H, s), 2.56-2.70 (1H, m), 6.94-7.12 (2H, m), 7.40-7.58 (7H, m) .IR (KBr): 3158, 2973, 1667, 1489 cm-1.
[0043]
Example 35
Preparation of N- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -6-methoxy [1,1'-biphenyl] -3-yl} acetamide
(i) Production of N- (3-bromo-4-methoxyphenyl) acetamide
2-Bromo-4-nitroanisole (5.41 g), iron powder (6.49 g) and acetic anhydride (4.4 ml) were used for the same reaction as in Example 33- (i) to give the title compound (4.87 g). Obtained as colorless powder crystals.
1H-NMR (CDClThree) δ: 2.15 (3H, s), 3.87 (3H, s), 6.83 (1H, d, J = 8.8 Hz), 7.32 (1H, brs), 7.43 (1H, dd, J = 2.5, 8.8 Hz), 7.67 (1H, d, J = 2.5 Hz).
IR (KBr): 3173, 1667, 1597, 1495 cm-1.
(ii) N- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -6-methoxy [1,1'-biphenyl] -3- Ill} acetamide production
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.21 g), N- (3-bromo-4-methoxyphenyl) acetamide ( 1.05 g) and tetrakis (triphenylphosphine) palladium (0) (0.16 g) were used to carry out the same reaction as in Example 33- (ii) to obtain the title compound (1.14 g) as a colorless amorphous powder.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.77 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.14 (3H, s), 2.40-2.58 (1H, m), 3.77 (3H, s) , 6.79 (1H, d, J = 1.2 Hz), 6.92 (1H, d, J = 8.8 Hz), 7.06-7.20 (6H, m), 7.24-7.62 (16H, m).
IR (KBr): 2971, 1663, 1549, 1493 cm-1.
(iii) of N- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -6-methoxy [1,1'-biphenyl] -3-yl} acetamide Manufacturing
N- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -6-methoxy [1,1'-biphenyl] -3-yl} acetamide (975 mg) and pyridine hydrochloride (299 mg) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (290 mg) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.83 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 2.11 (3H, s), 2.40-2.70 (1H, m), 3.73 (3H, s), 6.87 (1H, d, J = 8.4 Hz), 6.93 (1H, s), 7.24 (2H, s), 7.34 (2H, d, J = 8.0 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 8.4 Hz).
IR (KBr): 3183, 2973, 1667, 1495 cm-1.
[0044]
Example 36
Preparation of N- [4 '-[1-hydroxy-1-(-1H-imidazol-4-yl) -2-methylpropyl] -2-methyl [1,1'-biphenyl] -3-yl] acetamide
(i) N- [4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -2-methyl [1,1'-biphenyl] -3- Ill] acetamide production
Crude of N- (3-bromo-2-methyl) acetamide (1.19 g), 4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid Using the product (3.40 g), 2 M aqueous sodium carbonate solution (5.20 ml), tetrakis (triphenylphosphine) palladium (0) (301 mg), the same reaction as in Example 33- (ii) was carried out to give the title compound (1.15 g) was obtained as a colorless amorphous.
1H-NMR (CDClThree) δ: 0,78 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 2.14 (3H, s), 2.24 (3H, s), 2.41-2.48 (1H, m ), 3.61 (1H, s), 6.77 (1H, d, J = 1.4 Hz), 7.00-7.38 (20H, m), 7.50-7.54 (2H, m), 7.22 (2H, d, J = 7.8 Hz) .
IR (KBr): 1667, 1535, 1491, 1468, 1445, 910, 733, 702 cm-1.
(ii) N- [4 '-[1-hydroxy-1-(-1H-imidazol-4-yl) -2-methylpropyl] -2-methyl [1,1'-biphenyl] -3-yl] acetamide Manufacturing of
N- [4 '-[1-Hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -2-methyl [1,1'-biphenyl] -3-yl] acetamide (1.10 g) and pyridine hydrochloride (378 mg) were used for the same reaction as in Example 4- (iii) to obtain the title compound (605 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.81 (3H, d, J = 7.0 Hz), 0.97 (3H, d, J = 6.6 Hz), 2.05 (3H, s), 2.20 (3H, s), 2.59-2.63 (1H, m) , 6.91 (1H, s), 7.03-7.19 (4H, m), 7.41-7.50 (4H, m).
IR (KBr): 1665, 1535, 1468, 1439, 1372, 997, 828, 793 cm-1.
Example 37
Preparation of N- [4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -5-methyl [1,1'-biphenyl] -3-yl] acetamide
(i) N- [4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -5-methyl [1,1'-biphenyl] -3- Ill] acetamide production
N- (3-Bromo-5-methylphenyl) acetamide (612 mg), 4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid Using the crude product (1.75 g), 2 M aqueous sodium carbonate solution (2.68 ml), tetrakis (triphenylphosphine) palladium (0) (310 mg), the same reaction as in Example 33- (ii) was carried out. Compound (1.07 g) was obtained as colorless amorphous.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.18 (3H, s), 2.39-2.48 (4H, m), 3.56 (1H, s), 6.78 (1H, s), 7.13-7.15 (7H, m), 7.32-7.72 (17H, m).
IR (KBr): 1674, 1615, 1559, 1447, 1121, 747, 725, 700 cm-1.
[0045]
(ii) N- [4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -5-methyl [1,1'-biphenyl] -3-yl] acetamide Manufacturing
N- [4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -5-methyl [1,1'-biphenyl] -3-yl] acetamide (1.02 g) and pyridine hydrochloride (350 mg) were used for the same reaction as in Example 4- (iii) to obtain the title compound (410 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.83 (3H, d, J = 6.8 Hz), 0.98 (3H, d, J = 7.0 Hz), 2.16 (3H, s), 2.37 (3H, s), 2.60-2.66 (1H, m) , 6.96 (1H, s), 7.13 (1H, s), 7.37 (1H, s), 7.46-7.50 (6H, m).
IR (KBr): 1669, 1613, 1599, 1559, 1435, 1372, 822 cm-1.
Example 38
N- [4 '-[1-Hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -5- (trifluoromethyl) [1,1'-biphenyl] -3-yl] acetamide Manufacturing of
(i) N- [4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -5- (trifluoromethyl) [1,1'-biphenyl ] -3-Il] acetamide production
N- [3-Bromo-5- (trifluoromethyl) phenyl] acetamide (1.00 g), 4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] Reaction similar to Example 33- (ii) using a crude product of phenylboronic acid (2.50 g), 2 M aqueous sodium carbonate solution (3.56 ml), tetrakis (triphenylphosphine) palladium (0) (221 mg) To give the title compound (1.80 g) as a colorless amorphous.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 2.42-2.49 (1H, m), 3.54 (1H, s), 6.79 (1H, d, J = 1.2 Hz), 7.10-7.15 (6H, m), 7.32-7.36 (10H, m), 7.45-7.64 (6H, m), 7.77 (1H, s), 7.86 (1H, s).
IR (KBr): 1682, 1456, 1364, 1262, 1167, 1127, 747, 735, 702 cm-1.
(ii) N- [4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -5- (trifluoromethyl) [1,1'-biphenyl] -3- Ill] acetamide production
N- [4 ′-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -5- (trifluoromethyl) [1,1′-biphenyl] -3 -Il] acetamide (1.85 g) and pyridine hydrochloride (551 mg) were used for the same reaction as in Example 4- (iii) to obtain the title compound (591 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.81 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.18 (3H, s), 2.50-2.62 (1H, m), 6.98 (1H, s) , 7.44-7.58 (6H, m), 7.85 (2H, s).
IR (KBr): 1678, 1566, 1460, 1366, 1264, 1169, 1127, 824 cm-1.
[0046]
Example 39
Preparation of N- [4 '-[1-hydroxy- (1H-imidazol-4-yl) ethyl] [1,1'-biphenyl] -3-yl] acetamide
(i) Preparation of (4-bromophenyl) (1-trityl-1H-imidazol-4-yl) methanol
Example 4- (i) using p-dibromobenzene (54.7 g), n-butyllithium in hexane (1.6 M; 94.7 ml), 1-trityl-1H-imidazole-4-carbaldehyde (34.2 g) The title compound (27.8 g) was obtained as colorless powder crystals.
1H-NMR (CDClThree) δ: 3.56 (1H, br s), 5.71 (2H, d, J = 4.4 Hz), 6.58 (1H, s), 7.07-7.13 (7H, m), 7.25-7.44 (12H, m).
IR (KBr): 1493, 1445, 1128, 1011, 909, 747, 733, 702 cm-1.
(ii) Preparation of (4-bromophenyl) (1-trityl-1H-imidazol-4-yl) methanone (4-bromophenyl) (1-trityl-1H-imidazol-4-yl) methanol (30.0 g), The same reaction as in Example 24- (iii) was performed using manganese dioxide (52.6 g), and the title compound (23.3 g) was obtained as colorless powder crystals.
1H-NMR (CDClThree) δ: 7.10-7.19 (6H, m), 7.31-7.41 (9H, m), 7.52 (1H, d, J = 1.4 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.77 (1H, d , J = 1.4 Hz), 8.21 (2H, d, J = 8.4 Hz).
IR (KBr): 1644, 1520, 1213, 887, 756, 747, 702 cm-1.
(iii) Preparation of N- [4 '-[(1-trityl-1H-imidazol-4-yl) carbonyl] [1,1'-biphenyl] -3-yl] acetamide
(4-Bromophenyl) (1-trityl-1H-imidazol-4-yl) methanone (12.0 g), 3-acetamidobenzeneboronic acid (5.66 g), 2 M aqueous sodium carbonate solution (24.3 ml), tetrakis (triphenyl The same reaction as in Example 29- (i) was performed using phosphine) palladium (0) (842 mg) to give the title compound (10.1 g) as colorless powder crystals.
1H-NMR (CDClThree) δ: 2.20 (3H, s), 7.14-7.21 (6H, m), 7.36-7.44 (12H, m), 7.54-7.77 (6H, m), 8.33 (2H, d, J = 8.4 Hz).
IR (KBr): 1671. 1645. 1603. 1553. 1524. 756. 702 cm-1.
(iv) Preparation of N- [4 '-[1-hydroxy-1- (1-trityl-1H-imidazol-4-yl) ethyl] [1,1'-biphenyl] -3-yl] acetamide
N- [4 ′-[(1-trityl-1H-imidazol-4-yl) carbonyl] [1,1′-biphenyl] -3-yl] acetamide (800 mg) in THF (14 ml) at 0 ° A solution of methylmagnesium bromide in THF (1.0 M; 4.38 ml) was added dropwise at C, and the mixture was stirred at 0 ° C. for 20 min. Saturated ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethyl acetate-methanol-hexane to obtain the title compound (823 mg) as colorless powder crystals.
1H-NMR (CDClThree) δ: 1.81 (3H, s), 2.20 (3H, s), 3.37 (1H, s), 6.79 (1H, d, J = 1.4 Hz), 7.12-7.20 (8H, m), 7.31-7.52 (16H) , m), 7.65 (1H, br s).
IR (KBr): 1672, 1553, 1483, 1445, 909, 747, 733, 700 cm-1.
[0047]
(v) Preparation of N- [4 '-[1-hydroxy- (1H-imidazol-4-yl) ethyl] [1,1'-biphenyl] -3-yl] acetamide
N- [4 ′-[1-hydroxy-1- (1-trityl-1H-imidazol-4-yl) ethyl] [1,1′-biphenyl] -3-yl] acetamide (775 mg), pyridine hydrochloride ( 286 mg) was used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (262 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 1.89 (3H, s), 2.16 (3H, s), 6.89 (1H, s), 7.27-7.52 (8H, m), 7.69 (1H, s).
IR (KBr): 3031, 1672, 1609, 1591, 1559, 1483, 1397, 1312, 791 cm-1.
Example 40
Preparation of N- [4 '-[cyclopropyl (hydroxy) (1H-imidazol-4-yl) methyl] [1,1'-biphenyl] -3-yl] acetamide
(i) Preparation of N- [4 '-[cyclopropyl (hydroxy) (1-trityl-1H-imidazol-4-yl) methyl] [1,1'-biphenyl] -3-yl] acetamide
N- [4 '-[(1-trityl-1H-imidazol-4-yl) carbonyl] [1,1'-biphenyl] -3-yl] acetamide (1.50 g), cyclopropylmagnesium bromide in THF (1.0 M; 9.59 ml), and the same reaction as in Example 39- (iv) was performed to give the title compound (996 mg) as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.41-0.49 (4H, m), 1.47-1.55 (1H, m), 2.20 (3H, s), 3.26 (1H, s), 6.82 (1H, d, J = 1.4 Hz), 7.11-7.41 (19H, m), 7.50-7.53 (5H, m), 7.65 (1H, s).
IR (KBr): 1671, 1591, 1559, 1483, 1445, 731, 702 cm-1.
(ii) N- [4 '-[cyclopropyl (hydroxy) (1H-imidazol-4-yl) methyl] [1,1'-biphenyl] -3-yl] acetamide
N- [4 '-[cyclopropyl (hydroxy) (1-trityl-1H-imidazol-4-yl) methyl] [1,1'-biphenyl] -3-yl] acetamide (946 mg), pyridine hydrochloride ( 334 mg) was used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (216 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.47-0.60 (4H, m), 1.57-1.64 (1H, m), 2.17 (3H, s), 7.00 (1H, s), 7.36-7.58 (8H, m), 7.71 (1H, s ).
IR (KBr): 3148, 1667, 1591, 1555, 1485, 831, 791 cm-1.
Example 41
Preparation of N- [4 '-[1-hydroxy-1- (1H-imidazol-4-yl) butyl] [1,1'-biphenyl] -3-yl] acetamide
(i) Preparation of N- [4 '-[1-hydroxy-1- (1-trityl-1H-imidazol-4-yl) -3-butenyl] [1,1'-biphenyl] -3-yl] acetamide
N- [4 '-[(1-trityl-1H-imidazol-4-yl) carbonyl] [1,1'-biphenyl] -3-yl] acetamide (1.00 g), allylmagnesium bromide in THF (1.0 M ; 5.48 ml) and the same reaction as in Example 39- (iv) was performed to give the title compound (909 mg,) as a colorless amorphous.
1H-NMR (CDClThree) δ: 2.19 (3H, s), 2.85 (1H, dd, J = 6.2, 14.0 Hz), 3.01 (1H, dd, J = 7.6, 14.0 Hz), 3.34 (1H, s), 5.04-5.11 (2H , m), 5.62-5.79 (1H, m), 6.78 (1H, d, J = 1.6 Hz), 7.11-7.18 (6H, m), 7.32-7.51 (18H, m), 7.65 (1H, s).
IR (KBr): 1669, 1609, 1593, 1485, 1445, 909, 747, 733, 702 cm-1.
[0048]
(ii) Preparation of N- [4 '-[1-hydroxy-1- (1H-imidazol-4-yl) butyl] [1,1'-biphenyl] -3-yl] acetamide
N- [4 ′-[1-hydroxy-1- (1-trityl-1H-imidazol-4-yl) -3-butenyl] [1,1′-biphenyl] -3-yl] acetamide (829 mg), A suspension of 10% palladium on carbon (829 mg) and 1N hydrochloric acid (1.41 ml) in ethanol (14 ml) was stirred at room temperature in a hydrogen atmosphere for 9.5 hours. After adding sodium bicarbonate (130 mg) and stirring, the reaction mixture was filtered through Celite, the filtrate was concentrated, and the residue was chromatographed on silica gel (eluent: chloroform → chloroform: methanol = 10: 1 → 7: 1 → 4: 1) To give the title compound (420 mg) as a colorless amorphous product.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.90 (3H, t, J = 7.0 Hz), 1.22-1.38 (2H, m), 2.16-2.36 (5H, m), 6.89 (1H, s), 7.29-7.56 (8H, m), 7.71 (1H, s).
IR (KBr): 3144, 1659, 1609, 1557, 1485, 1435, 791 cm-1.
Example 42
Preparation of N- [4 '-[1-hydroxy-1- (1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl] acetamide
(i) Preparation of N- [4 '-[1-hydroxy-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl] acetamide
N- [4 '-[(1-trityl-1H-imidazol-4-yl) carbonyl] [1,1'-biphenyl] -3-yl] acetamide (1.50 g), ethyl magnesium bromide in diethyl ether (3.0 M; 2.74 ml), and the same reaction as in Example 39- (iv) was performed to obtain the title compound (1.36 g) as a pale yellow amorphous.
1H-NMR (CDClThree) δ: 0.86 (3H, t, J = 7.6 Hz), 2.12-2.20 (5H, m), 3.35 (1H, s), 6.67 (1H, s), 7.13-7.22 (6H, m), 7.26-7.48 (18H, m), 7.66 (1H, s).
IR (KBr): 1674, 1609, 1557, 1485, 1445, 747, 733, 702 cm-1.
(ii) Preparation of N- [4 '-[1-hydroxy-1- (1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl] acetamide
N- [4 '-[1-hydroxy-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl] acetamide (1.31 g), 10% palladium The same reaction as in Example 41- (ii) was carried out using carbon (1.31 g) and 1N hydrochloric acid (2.27 ml) to obtain the title compound (640 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.89 (3H, t, J = 7.6 Hz), 2.17-2.32 (5H, m), 6.91 (1H, s), 7.30-7.53 (8H, m), 7.69 (1H, s).
IR (KBr): 3148, 1667, 1609, 1591, 1557, 1485, 831, 791 cm-1.
[0049]
Example 43
Preparation of N- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} propanamide
(i) Production of N- (3-bromophenyl) propanamide
To a solution of 3-bromoaniline (5.10 g) and triethylamine (8.3 ml) in THF (40 ml), propionyl chloride (2.8 ml) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The extract was washed with water and brine, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (5.60 g) as colorless needle crystals.
1H-NMR (CDClThree) δ: 1.24 (3H, t, J = 7.5 Hz), 2.39 (2H, q, J = 7.5 Hz), 7.11-7.30 (3H, m), 7.41 (1H, d, J = 7.8 Hz), 7.79 ( 1H, brs).
IR (KBr): 3243, 1661, 1593, 1539 cm-1.
(ii) N- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} propanamide Manufacturing
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.12 g), N- (3-bromophenyl) propanamide (1.56 g) and The reaction was conducted in the same manner as in Example 33- (ii) using tetrakis (triphenylphosphine) palladium (0) (0.133 g) to obtain the title compound (1.26 g) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 1.25 (3H, t, J = 7.5 Hz), 2.30-2.50 (3H, m), 3.55 ( 1H, s), 6.78 (1H, s), 7.08-7.44 (20H, m), 7.48 (2H, d, J = 8.3 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.72 (1H, brs ).
IR (KBr): 2973, 1669, 1557, 1485 cm-1.
(iii) Preparation of N- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} propanamide
N- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} propanamide (1.46 g) And pyridine hydrochloride (440 mg) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (280 mg) as a colorless amorphous powder.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.79 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 7.0 Hz), 1.22 (3H, t, J = 7.4 Hz), 2.39 (2H, q, J = 7.4 Hz) ), 2.40-2.70 (1H, m), 6.91 (1H, d, J = 1.2 Hz), 7.24-7.55 (8H, m), 7.67 (1H, s).
IR (KBr): 3196, 2975, 1669, 1557 cm-1.
[0050]
Example 44
Preparation of N- [4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -3-methylbutyl] [1,1'-biphenyl] -3-yl] acetamide
(i) Production of N- [4 '-[1-hydroxy-3-methyl-1- (1-trityl-1H-imidazol-4-yl) butyl] [1,1'-biphenyl] -3-yl] acetamido
N- [4 '-[(1-trityl-1H-imidazol-4-yl) carbonyl] [1,1'-biphenyl] -3-yl] acetamide (1.26 g), isobutylmagnesium bromide in THF (1.0 M 8.05 ml) was used to carry out the same reaction as in Example 39- (iv) to obtain the title compound (408 mg) as a pale yellow amorphous.
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 6.8 Hz), 0.88 (3H, d, J = 6.6 Hz), 1.68-1.74 (1H, m), 2.02 (2H, d, J = 5.2 Hz), 2.20 ( 3H, s), 3.43 (1H, s), 6.74 (1H, s), 7.12-7.17 (8H, m), 7.32-7.48 (16H, m), 7.65 (1H, s).
IR (KBr): 1672, 1607, 1557, 1485, 1445, 909, 747, 733, 702 cm-1.
(ii) Preparation of N- [4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -3-methylbutyl] [1,1'-biphenyl] -3-yl] acetamide
N- [4 '-[1-Hydroxy-3-methyl-1- (1-trityl-1H-imidazol-4-yl) butyl] [1,1'-biphenyl] -3-yl] acetamide (1.31 g) , 10% palladium on carbon (386 mg) and 1N hydrochloric acid (0.637 ml) were used to carry out the same reaction as in Example 41- (ii) to obtain the title compound (141 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.75 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 1.66-1.78 (1H, m), 2.13-2.16 (5H, m), 6.86 (1H, s), 7.30-7.53 (8H, m), 7.68 (1H, s).
IR (KBr): 1669, 1559, 1483, 1435, 1395, 1372, 791 cm-1.
Example 45
Preparation of 3 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
(i) Production of 3-bromophenylcarboxamide
To a solution of 3-bromobenzoyl chloride (21.75 g) in THF (20 ml) was added 40% methylamine methanol solution (50 ml) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hr, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and brine, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (18.6 g) as colorless powder crystals.
1H-NMR (CDClThree) δ: 2.99 (3H, d, J = 5.0Hz), 6.55 (1H, brs), 7.28 (1H, t, J = 7.9Hz), 7.56-7.72 (2H, m), 7.91 (1H, t, J = 1.8Hz).
IR (KBr): 3304, 1640, 1557 cm-1.
[0051]
(ii) Preparation of 3 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
3- [1-Hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (1.01 g), 3-bromophenylcarboxamide (567 mg) and tetrakis (triphenyl The same reaction as in Example 33- (ii) was performed using phosphine) palladium (0) (0.33 g), and the title compound (435 mg) was obtained as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.6Hz), 0.94 (3H, d, J = 6.6Hz), 2.36-2.58 (1H, m), 3.03 (3H, d, J = 4.6Hz), 3.66 ( 1H, s), 6.23 (1H, brs), 6.78 (1H, d, J = 1.2Hz), 7.06-7.17 (6H, m), 7.23-7.54 (14H, m), 7.62-7.80 (3H, m) , 7.88-7.93 (1H, m).
IR (KBr): 3378, 2969, 1644, 1549, 1447 cm-1.
(iii) Preparation of 3 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
3 ′-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -N-methyl [1,1′-biphenyl] -3-carboxamide (576 mg) and The same reaction as in Example 4- (iii) was performed using pyridine hydrochloride (0.22 g) to obtain the title compound (55 mg) as colorless powder crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.81 (3H, d, J = 6.6Hz), 0.97 (3H, d, J = 6.6Hz), 2.60-2.84 (1H, m), 3.02 (3H, s), 7.00 (1H, d, J = 1.0Hz), 7.30-7.55 (5H, m), 7.67-7.90 (3H, m), 8.01 (1H, t, J = 1.5Hz).
IR (KBr): 2967, 2872, 1644, 1541 cm-1.
Example 46
Preparation of 4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
(i) 4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -N-methyl [1,1'-biphenyl] -3-carboxamide.
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.44 g), 3-bromo-N-methylbenzamide (1.10 g) and tetrakis The same reaction as in Example 33- (ii) was performed using (triphenylphosphine) palladium (0) (0.21 g) to obtain the title compound (1.00 g) as a pale yellow amorphous powder.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.7 Hz), 0.93 (3H, d, J = 6.7 Hz), 2.30-2.54 (1H, m), 3.02 (3H, d, J = 4.8 Hz), 3.58 ( 1H, s), 6.33 (1H, brs), 6.78 (1H, d, J = 1.4 Hz), 7.04-7.20 (6H, m), 7.22-7.38 (9H, m), 7.39-7.76 (8H, m) , 7.98 (1H, t, J = 1.4 Hz).
IR (KBr): 3295, 2969, 1644, 1549, 1121 cm-1.
(ii) Preparation of 4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
4 ′-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -N-methyl [1,1′-biphenyl] -3-carboxamide (850 mg) and The same reaction as in Example 4- (iii) was performed using pyridine hydrochloride (270 mg) to obtain the title compound (210 mg) as a colorless amorphous powder.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.81 (3H, d, J = 6.9 Hz), 0.98 (3H, d, J = 6.9 Hz), 2.40-2.80 (1H, m), 3.00 (3H, s), 6.96 (1H, s) , 7.30 (1H, d, J = 1.4 Hz), 7.38-7.60 (5H, m), 7.60-7.74 (2H, m), 7.93 (1H, s).
IR (KBr): 3277, 2969, 1645, 1547 cm-1.
[0052]
Example 47
Preparation of N-ethyl-4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-carboxamide
(i) Production of 3-bromo-N-ethylbenzamide
To a solution of sodium hydroxide (3.80 g) in methanol (50 ml) -water (15 ml), ethylamine hydrochloride (7.80 g) was added little by little at 0 ° C. and stirred for 5 minutes. 3-Bromobenzoyl chloride (5.53 g) was added. The solution was added dropwise and stirred at room temperature for 1 hour. Methanol was distilled off under reduced pressure, and ethyl acetate was added to the residue for liquid separation. The organic layer was washed with water and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (5.47 g) as colorless powder crystals.
1H-NMR (CDClThree) δ: 1.26 (3H, t, J = 7.1 Hz), 3.40-3.59 (2H, m), 6.11 (1H, brs), 7.30 (1H, t, J = 8.2 Hz), 7.57-7.72 (2H, m ), 7.90 (1H, t, J = 1.4 Hz).
IR (KBr): 3308, 1638, 1541 cm-1.
(ii) N-ethyl-4 ′-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1′-biphenyl] -3-carboxamide.
4- [1-Hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (7.40 g, 14.7 mmol), 3-bromo-N-ethylbenzamide (2.20 g ) And tetrakis (triphenylphosphine) palladium (0) (0.441 g) were used to carry out the same reaction as in Example 33- (ii) to obtain the title compound (2.56 g) as a yellow amorphous powder.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.8 Hz), 1.27 (3H, t, J = 7.2 Hz), 2.36-2.54 (1H, m), 3.42- 3.61 (3H, m), 6.15 (1H, brs), 6.78 (1H, d, J = 1.6 Hz), 7.06-7.18 (6H, m), 7.27-7.38 (9H, m), 7.40-7.75 (8H, m), 7.97 (1H, t, J = 1.6 Hz).
IR (KBr): 3295, 2971, 1644, 1537 cm-1.
(iii) Preparation of N-ethyl-4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-carboxamide
N-ethyl-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-carboxamide (4.00 g) and The same reaction as in Example 4- (iii) was carried out using pyridine hydrochloride (1.14 g) to obtain the title compound (664 mg) as a colorless amorphous powder.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.79 (3H, d, J = 6.7 Hz), 0.96 (3H, d, J = 6.7 Hz), 1.23 (3H, t, J = 7.1 Hz), 2.48-2.70 (1H, m), 3.36 -3.56 (2H, m), 6.92 (1H, d, J = 1.2 Hz), 7.09 (1H, t, J = 5.5 Hz), 7.35-7.56 (6H, m), 7.58-7.72 (2H, m), 7.92 (1H, t, J = 1.6 Hz).
IR (KBr): 2973, 1644, 1537 cm-1.
[0053]
Example 48
Preparation of 4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -N-isopropyl [1,1'-biphenyl] -3-carboxamide
(i) Production of 3-bromo-N-isopropylbenzamide
The same reaction as in Example 45- (i) was performed using 3-bromobenzoyl chloride (5.70 g) and isopropylamine (4.10 g) to obtain the title compound (5.75 g) as colorless powder crystals.
1H-NMR (CDClThree) δ: 1.26 (6H, d, J = 6.6 Hz), 4.18-4.40 (1H, m), 5.97 (1H, brs), 7.23-7.34 (1H, m), 7.55-7.71 (2H, m), 7.84 -7.90 (1H, m).
IR (KBr): 3241, 2973, 1634, 1545 cm-1.
(ii) Preparation of 4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -N-isopropyl [1,1'-biphenyl] -3-carboxamide
4- [1-Hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.40 g), 3-bromo-N-isopropylbenzamide (1.70 g) and tetrakis (Triphenylphosphine) palladium (0) (0.220 g) was used for the same reaction as in Example 33- (ii) to obtain the title compound (1.88 g) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 6.4 Hz), 0.93 (3H, d, J = 6.4 Hz), 1.28 (6H, d, J = 6.6 Hz), 2.36-2.58 (1H, m), 3.56 ( 1H, s), 4.20-4.44 (1H, m), 5.95 (1H, d, J = 7.0 Hz), 6.78 (1H, d, J = 1.4 Hz), 7.06-7.20 (6H, m), 7.26-7.38 (10H, m), 7.42-7.74 (7H, m), 7.95 (1H, t, J = 1.6 Hz).
IR (KBr): 2971, 1636, 1537 cm-1.
(iii) Preparation of 4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -N-isopropyl [1,1'-biphenyl] -3-carboxamide
4 ′-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -N-isopropyl [1,1′-biphenyl] -3-carboxamide (1.67 g) and The same reaction as in Example 4- (iii) was performed using pyridine hydrochloride (490 mg) to obtain the title compound (480 mg) as colorless powder crystals.
1H-NMR (DMSO-d6) δ: 0.60-1.00 (6H, m), 1.19 (6H, d, J = 6.6 Hz), 2.54-2.78 (1H, m), 4.00-4.26 (1H, m), 7.42-7.68 (4H, m) , 7.68-7.88 (4H, m), 8.08 (1H, s), 8.24-8.40 (1H, m), 11.80 (1H, brs).
IR (KBr): 3243, 2975, 1628, 1547 cm-1.
[0054]
Example 49
Preparation of N-cyclopropyl-4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-carboxamide
(i) Production of 3-bromo-N-cyclopropylbenzamide
The same reaction as in Example 45- (i) was carried out using 3-bromobenzoyl chloride (5.50 g) and cyclopropylamine (4.30 g) to obtain the title compound (5.20 g) as colorless needle crystals.
1H-NMR (CDClThree) δ: 0.56-0.68 (2H, m), 0.82-0.96 (2H, m), 2.80-2.98 (1H, m), 6.20 (1H, brs), 7.30 (1H, t, J = 8.0 Hz), 7.58 -7.70 (2H, m), 7.87 (1H, t, J = 1.9 Hz).
IR (KBr): 3283, 1638, 1563, 1537 cm-1.
(ii) N-cyclopropyl-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-carboxamide Manufacturing
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.40 g), 3-bromo-N-cyclopropylbenzamide (1.53 g and tetrakis The same reaction as in Example 33- (ii) was performed using (triphenylphosphine) palladium (0) (0.290 g) to obtain the title compound (1.84 g) as a pale yellow amorphous powder.
1H-NMR (CDClThree) δ: 0.58-0.74 (2H, m), 0.76 (3H, d, J = 6.8 Hz), 0.83-0.98 (5H, m), 2.35-2.60 (1H, m), 2.81-3.01 (1H, m) , 3.56 (1H, s), 6.31 (1H, brs), 6.78 (1H, d, J = 1.4 Hz), 7.04-7.18 (6H, m), 7.26-7.38 (9H, m), 7.39-7.74 (8H , m), 7.93 (1H, t, J = 1.8 Hz).
IR (KBr): 3270, 2969, 1644, 1532 cm-1.
(iii) Preparation of N-cyclopropyl-4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-carboxamide
N-cyclopropyl-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-carboxamide (2.13 g) And pyridine hydrochloride (650 mg) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (375 mg) as colorless powder crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.56-0.90 (7H, m), 0.96 (3H, d, J = 6.6 Hz), 2.44-2.70 (1H, m), 2.78-2.96 (1H, m), 6.92 (1H, s), 7.00 (1H, brs), 7.31-7.57 (6H, m), 7.58-7.74 (2H, m), 7.89 (1H, s).
IR (KBr): 3183, 2969, 1645, 1532 cm-1.
[0055]
Example 50
Preparation of 4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -6-methoxy-N-methyl [1,1'-biphenyl] -3-carboxamide
(i) 4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -6-methoxy-N-methyl [1,1'-biphenyl] -3 -Production of carboxamide
Crude formation of 3-bromo-4-methoxy-N-methylbenzamide (934 mg), 4- [1-hydroxy-2-methyl-1- (1trityl-1H-imidazol-4-yl) propyl] phenylboronic acid Product (2.50 g), 2 M aqueous sodium carbonate solution (3.83 ml), tetrakis (triphenylphosphine) palladium (0) (221 mg), and the title compound ( 1.45 g) was obtained as a colorless amorphous.
1H-NMR (CDClThree) δ: 0.78 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 7.0 Hz), 2.42-2.49 (1H, m), 3.00 (3H, d, J = 4.8 Hz), 3.56 ( 3H, s), 3.85 (3H, s), 6.10 (1H, br s), 6.78 (1H, d, J = 1.0 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.13-7.16 (5H, m), 7.32-7.80 (15H, m).
IR (KBr): 1645, 1491, 1464, 1258, 1182, 747, 733, 702 cm-1.
(ii) Preparation of 4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -6-methoxy-N-methyl [1,1'-biphenyl] -3-carboxamide
4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -6-methoxy-N-methyl [1,1'-biphenyl] -3-carboxamide ( 1.40 g) and pyridine hydrochloride (468 mg) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (576 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.85 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 7.0 Hz), 2.58-2.71 (1H, m), 2.96 (3H, d, J = 4.4 Hz), 3.83 (3H, s), 6.96-7.00 (3H, m), 7.41-7.54 (5H, m), 7.68 (1H, d, J = 2.6 Hz), 7.77 (1H, dd, J = 2.6, 8.4 Hz).
IR (KBr): 1626, 1603, 1556, 1493, 1262, 1020, 829, 631 cm-1.
Example 51
Preparation of 6-fluoro-4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
(i) 6-Fluoro-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -N-methyl [1,1'-biphenyl] -3 -Production of carboxamide
Crude formation of 3-bromo-4-fluoro-N-methylbenzamide (889 mg), 4- [1-hydroxy-2-methyl-1- (1trityl-1H-imidazol-4-yl) propyl] phenylboronic acid Product (2.50 g), 2 M aqueous sodium carbonate solution (3.83 ml), tetrakis (triphenylphosphine) palladium (0) (221 mg), and the title compound ( 1.69 g) was obtained as a colorless amorphous.
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 7.0 Hz), 2.42-2.49 (1H, m), 3.02 (3H, d, J = 4.8 Hz), 3.58 ( 1H, s), 6.13 (1H, br s), 6.78 (1H, d, J = 1.4 Hz), 7.11-7.23 (7H, m), 7.31-7.35 (9H, m), 7.46-7.72 (7H, m ), 7.85 (1H, dd, J = 2.4, 7.2 Hz).
IR (KBr): 1647, 1487, 1447, 909, 747, 733, 702 cm-1.
[0056]
(ii) Preparation of 6-fluoro-4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
6-Fluoro-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] -N-methyl [1,1'-biphenyl] -3-carboxamide ( 1.64 g) and pyridine hydrochloride (559 mg) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (535 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.83 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J = 6.0 Hz), 2.67 (1H, br s), 2.97 (3H, s), 6.98 (1H, s), 7.17 (1H, dd, J = 8.8, 8.8 Hz), 7.51-7.57 (5H, m), 7.70-7.73 (1H, m), 7.87 (1H, dd, J = 2.6, 7.2 Hz).
IR (KBr): 1645, 1559, 1539, 1487, 1325, 1252, 829 cm-1.
Example 52
[4 '-[1-Hydroxy- (1H-imidazol-4-yl) ethyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
(i) Preparation of N-methyl- [4 '-[(1-trityl-1H-imidazol-4-yl) carbonyl] [1,1'-biphenyl] -3-carboxamide
To a solution of 3-bromo-N-methylbenzamide (16.0 g) in THF (180 ml), slowly add hexane solution of n-butyllithium (1.6 M; 103 ml) at -78 ° C and add it at -78 ° C. After stirring for 20 minutes, trimethoxyborane (50.2 ml) was added dropwise at −78 ° C., followed by stirring at −78 ° C. for 30 minutes and further at room temperature for 17 hours. 2N Hydrochloric acid (82.0 ml) was added to the reaction mixture, and the mixture was stirred for 1 hr, extracted with ethyl acetate, washed with saturated brine, and dried. The solvent was distilled off under reduced pressure to obtain a crude product of 3-[(methylamino) carbonyl] phenylboronic acid (22.5 g) as a pale yellow oil. This product (19.2 g), (4-bromophenyl) (1-trityl-1H-imidazol-4-yl) methanone (10.0 g), 2 M aqueous sodium carbonate solution (81.2 ml), tetrakis (triphenylphosphine) palladium ( 0) (1.17 g) was used for the same reaction as in Example 29- (i) to give the title compound (6.89 g) as colorless powder crystals.
1H-NMR (CDClThree) δ: 3.05 (3H, d, J = 4.6 Hz), 6.22 (1H, br s), 7.14-7.22 (6H, m), 7.36-7.55 (10H, m), 7.62-7.78 (6H, m), 8.03 (1H, s), 8.37 (2H, d, J = 8.8 Hz).
IR (KBr): 1644, 1526, 1186, 1119, 891, 725, 702 cm-1.
(ii) Preparation of [4 '-[1-hydroxy- (1-trityl-1H-imidazol-4-yl) ethyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
N-methyl- [4 '-[(1-trityl-1H-imidazol-4-yl) carbonyl] [1,1'-biphenyl] -3-carboxamide (700 mg), methylmagnesium bromide in THF (1.0 M 3.83 ml) was used for the same reaction as in Example 39- (iv) to give the title compound (557 mg) as colorless powder crystals.
1H-NMR (CDClThree) δ: 1.81 (3H, s), 3.04 (3H, d, J = 5.2 Hz), 3.36 (1H, s), 6.17 (1H, br s), 6.79 (1H, d, J = 1.4 Hz), 7.13 -7.18 (6H, m), 7.33-7.51 (15H, m), 7.66-7.71 (2H, m). 7.95 (1H, dd, J = 1.8, 1.8 Hz).
IR (KBr): 1644, 1547, 1445, 1159, 910, 735, 702 cm-1.
[0057]
(iii) Preparation of [4 '-[1-hydroxy- (1H-imidazol-4-yl) ethyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
[4 '-[1-Hydroxy- (1-trityl-1H-imidazol-4-yl) ethyl] -N-methyl [1,1'-biphenyl] -3-carboxamide (527 mg), 10% palladium on carbon ( 527 mg) and 1N hydrochloric acid (0.935 ml) were used to carry out the same reaction as in Example 41- (ii) to obtain the title compound (144 mg) as colorless powder crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 1.93 (3H, s), 3.00 (3H, s), 6.88 (1H, s), 7.44-7.74 (8H, m). 7.99 (1H, s).
IR (KBr): 3279, 1636, 1603, 1582, 1551, 737, 629 cm-1.
Example 53
Preparation of [4 '-[1-hydroxy- (1H-imidazol-4-yl) propyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
(i) Preparation of [4 '-[1-hydroxy- (1-trityl-1H-imidazol-4-yl) propyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
N-methyl- [4 ′-[(1-trityl-1H-imidazol-4-yl) carbonyl] [1,1′-biphenyl] -3-carboxamide (1.50 g), ethyl magnesium bromide in diethyl ether (3.0 M; 2.74 ml) and the same reaction as in Example 39- (iv) was performed to obtain the title compound (1.34 g) as a colorless amorphous.
1H-NMR (CDClThree) δ: 0.86 (3H, t, J = 7.2 Hz), 2.01-2.24 (2H, m), 3.04 (3H, d, J = 2.3 Hz), 3.39 (1H, s), 6.24 (1H, br s) , 6.78 (1H, d, J = 0.7 Hz), 7.13-7.19 (6H, m), 7.31-7.55 (15H, m), 7.67-7.78 (2H, m), 7.94-7.96 (1H, m).
IR (KBr): 1644, 1582, 1541, 1493, 1447, 909, 733, 700 cm-1.
(ii) Preparation of [4 '-[1-hydroxy- (1H-imidazol-4-yl) propyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
[4 '-[1-hydroxy- (1-trityl-1H-imidazol-4-yl) propyl] -N-methyl [1,1'-biphenyl] -3-carboxamide (1.29 g), 10% palladium on carbon ( 1.29 g) and 1N hydrochloric acid (2.23 ml) were used for the same reaction as in Example 41- (ii) to obtain the title compound (540 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.90 (3H, t, J = 7.6 Hz), 2.22-2.33 (2H, m), 3.00 (3H, s), 6.93 (1H, s), 7.43-7.71 (8H, m), 8.00 ( 1H, s).
IR (KBr): 3189, 1634, 1603, 1582, 1557, 835, 812, 627 cm-1.
Example 54
Preparation of [4 '-[1-hydroxy- (1H-imidazol-4-yl) butyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
(i) Preparation of [4 '-[1-hydroxy- (1-trityl-1H-imidazol-4-yl) -3-butenyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
N-methyl- [4 '-[(1-trityl-1H-imidazol-4-yl) carbonyl] [1,1'-biphenyl] -3-carboxamide (800 mg), allylmagnesium bromide in THF (1.0 M 6.57 ml) was used to carry out the same reaction as in Example 39- (iv) to obtain the title compound (770 mg) as a colorless amorphous.
1H-NMR (CDClThree) δ: 2.80-3.05 (5H, m), 3.36 (1H, s), 5.04-5.12 (2H, m), 5.66-5.82 (1H, m), 6.23 (1H, br s), 6.79 (1H, d , J = 1.4 Hz), 7.12-7.19 (6H, m), 7.32-7.54 (15H, m), 7.63-7.78 (2H, m), 7.95-7.96 (1H, m).
IR (KBr): 1644, 1541, 1445, 909, 747, 733, 702 cm-1.
[0058]
(ii) Preparation of [4 '-[1-hydroxy- (1H-imidazol-4-yl) butyl] -N-methyl [1,1'-biphenyl] -3-carboxamide
[4 '-[1-Hydroxy- (1-trityl-1H-imidazol-4-yl) -3-butenyl] -N-methyl [1,1'-biphenyl] -3-carboxamide (690 mg), 10% The same reaction as in Example 41- (ii) was performed using palladium on carbon (690 mg) and 1N hydrochloric acid (1.17 ml) to obtain the title compound (269 mg) as a colorless amorphous.
The title compound (420 mg) was obtained as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.91 (3H, t, J = 7.2 Hz), 1.21-1.43 (2H, m), 2.09-2.19 (2H, m), 3.00 (3H, s), 6.91 (1H, s), 7.38- 7.58 (6H, m), 7.70-7.74 (2H, m), 7.98 (1H, s).
IR (KBr): 3212, 1636, 1582, 1557, 831, 812, 737 cm-1.
Example 55
Preparation of 2- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} -N-methylacetamide
(i) Preparation of 2- (3-bromophenyl) -N-methylacetamide
3-bromophenylacetic acid (3.02 g), methylamine THF solution (2.0 M; 8.5 ml), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (3.20 g), 1-hydroxybenzotriazole A mixture of (2.60 g) and triethylamine (2.3 ml) was stirred in DMF (30 ml) at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, 1N aqueous sodium hydroxide solution, 1N hydrochloric acid, aqueous sodium bicarbonate, and brine, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent; ethyl acetate) and recrystallized from hexane-ethyl acetate to give the title compound (1.30 g) as colorless prism crystals.
1H-NMR (CDClThree) δ: 2.70 (3H, d, J = 4.8 Hz), 3.45 (2H, s), 5.34 (1H, brs), 7.04-7.20 (2H, m), 7.28-7.39 (2H, m).
IR (KBr): 3285, 1651, 1568 cm-1.
(ii) 2- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} -N -Methylacetamide production
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.47 g), 2- (3-bromophenyl) -N-methylacetamide (0.93 g) and tetrakis (triphenylphosphine) palladium (0) (0.21 g) were used to carry out the same reaction as in Example 33- (ii) to obtain the title compound (580 mg) as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.36-2.54 (1H, m), 2.76 (3H, d, J = 4.6 Hz), 3.55 ( 1H, s), 3.64 (2H, s), 5.41 (1H, brs), 6.78 (1H, d, J = 1.4 Hz), 7.08-7.24 (7H, m), 7.28-7.62 (17H, m).
IR (KBr): 3303, 2969, 1651, 1481, 1445 cm-1.
(iii) Preparation of 2- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} -N-methylacetamide
2- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} -N-methylacetamide ( The same reaction as in Example 4- (iii) was performed using 1.09 g) and pyridine hydrochloride (309 mg) to obtain the title compound (260 mg) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.80 (3H, d, J = 6.8 Hz), 0.96 (3H, d, J = 6.8 Hz), 2.44-2.66 (1H, m), 2.71 (3H, d, J = 4.8 Hz), 3.56 ( 2H, s), 5.88 (1H, brs), 6.89 (1H, s), 7.16 (1H, d, J = 7.8 Hz), 7.27-7.49 (6H, m), 7.53 (2H, d, J = 8.4 Hz ).
IR (KBr): 3071, 2969, 1651 cm-1.
[0059]
Example 56
Preparation of N-({4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} methyl) acetamide
(i) Production of N- (3-bromobenzyl) acetamide
Acetic anhydride (3.2 ml) was added to a solution of 3-bromobenzylamine hydrochloride (5.20 g) in pyridine (30 ml) at 0 ° C., and the mixture was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with 1N hydrochloric acid, aqueous sodium bicarbonate and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (4.00 g) as colorless needle crystals.
1H-NMR (CDClThree) δ: 2.02 (3H, d, J = 1.4 Hz), 4.38 (2H, d, J = 6.0 Hz), 6.04 (1H, brs), 7.10-7.26 (2H, m), 7.30-7.48 (2H, m ).
IR (KBr): 3283, 1636, 1549 cm-1.
(ii) N-({4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} methyl Acetamide production
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.30 g), N- (3-bromobenzyl) acetamide (1.05 g) and The reaction was conducted in the same manner as in Example 33- (ii) using tetrakis (triphenylphosphine) palladium (0) (0.18 g) to obtain the title compound (1.24 g) as a pale yellow amorphous powder.
1H-NMR (CDCl3) δ: 0.76 (3H, d, J = 6.7 Hz), 0.92 (3H, d, J = 6.7 Hz), 2.04 (3H, s), 2.36-2.54 (1H, m), 3.55 ( 1H, s), 4.49 (2H, d, J = 5.8 Hz), 5.80 (1H, brs), 6.78 (1H, d, J = 1.4 Hz), 7.06-7.24 (7H, m), 7.26-7.60 (17H , m).
IR (KBr): 3293, 2967, 1659, 1445 cm-1.
(iii) Preparation of N-({4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} methyl) acetamide
N-({4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} methyl) acetamide ( 1.05 g) and pyridine hydrochloride (278 mg) were used for the same reaction as in Example 4- (iii) to obtain the title compound (490 mg) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.82 (3H, d, J = 6.8 Hz), 0.98 (3H, d, J = 6.8 Hz), 2.02 (3H, s), 2.53-2.70 (1H, m), 4.46 (2H, d, J = 5.6 Hz), 5.94 (1H, brs), 6.96 (1H, d, J = 1.0 Hz), 7.19-7.26 (1H, m), 7.37 (1H, t, J = 7.7 Hz), 7.42-7.53 (5H , m), 7.58 (2H, d, J = 8.4 Hz).
IR (KBr): 3264, 1651, 1559 cm-1.
[0060]
Example 57
Preparation of 1- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} ethanone
(i) 1- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} ethanone Manufacturing
4- [1-Hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (6.22 g) and 3'-bromoacetophenone (2.30 g) and tetrakis (triphenyl The same reaction as in Example 33- (ii) was performed using phosphine) palladium (0) (0.210 g) to obtain the title compound (1.50 g) as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 7.0 Hz), 2.38-2.58 (1H, m), 2.66 (3H, s), 3.55 (1H, s), 6.78 (1H, d, J = 1.4 Hz), 7.07-7.20 (6H, m), 7.28-7.40 (9H, m), 7.46-7.71 (6H, m), 7.74-7.84 (1H, m), 7.87- 7.95 (1H, m), 8.17 (1H, t, J = 1.7 Hz).
IR (KBr): 2967, 1688, 1236 cm-1.
(ii) Preparation of 1- {4 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} ethanone
1- {4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} ethanone (3.30 g) And pyridine hydrochloride (870 mg) were used for the same reaction as in Example 4- (iii) to give the title compound (910 mg) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.83 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.50-2.80 (4H, m), 6.99 (1H, s), 7.44-7.69 (6H, m ), 7.76 (1H, d, J = 8.0 Hz), 7.90 (1H, d, J = 8.0 Hz), 8.15 (1H, s).
IR (KBr): 2971, 1682, 1238 cm-1.
Example 58
Preparation of (−)-1- (4′-fluoro [1,1′-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
1- (4′-Fluoro [1,1′-biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol obtained in Example 13 was optically active. It was subjected to liquid chromatography using a column (Chiralpak AD) (eluent; hexane: ethanol = 9: 1), and (-)-1- (4′-fluoro [1,1] '-Biphenyl] -3-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol was obtained.
Optical purity; 99% ee (Chiralpak AD)
[α]D 20 −47.1 ° (C = 0.31, methanol)
[0061]
Example 59
Preparation of 4-fluoro-4 '-[1-hydroxy-1-(-1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-carboxamide
(i) Preparation of 4-fluoro-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-carboxamide
5-Bromo-2-fluorobenzonitrile (1.04 g), crude product of 4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid ( 3.40 g), 2 M aqueous sodium carbonate solution (5.20 ml), tetrakis (triphenylphosphine) palladium (0) (211 mg), and the title compound (1.25 g ) Was obtained as colorless needle crystals.
1H-NMR (CDClThree) δ: 0,75 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.41-2.48 (1H, m), 3.54 (1H, s), 6.78 (1H, d , J = 1.0 Hz), 7.12-7.15 (4H, m), 7.22-7.35 (13H, m), 7.42 (2H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.74 -7.81 (2H, m).
IR (KBr): 2236, 1493, 1447, 910, 818, 747, 735, 702 cm-1.
(ii) 4-Fluoro-4 '-[1-hydroxy-1-(-1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-carboxamide
4-fluoro-4 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-carboxamide (1.20 g), The same reaction as in Example 4- (iii) was performed using pyridine hydrochloride (432 mg) to obtain the title compound (577 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.82 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 6.6 Hz), 2.57-2.67 (1H, m), 6.98 (1H, s), 7.29 (1H, d, J = 6.6 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.56-7.63 (3H, m), 7.76-7.79 (2H, m).
IR (KBr): 3133, 2973, 2236, 1493, 1273, 1244, 1119, 1015, 818 cm-1.
Example 60
Production of (−)-N- {4 ′-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1′-biphenyl] -3-yl} acetamide
The N- {4 ′-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1′-biphenyl] -3-yl} acetamide obtained in Example 31 was recovered. It was subjected to liquid chromatography using an optically active column (Chiralpak AD) (eluent; hexane: ethanol = 9: 1) and (-)-N- {4 '-[1- Hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1′-biphenyl] -3-yl} acetamide was obtained.
Optical purity; 99.9% ee (Chiralpak AD)
[α]D 20 −17.3 ° C (C = 1.0, methanol)
[0062]
Example 61
Preparation of 1- (3 ', 4'-dimethoxy [1,1'-biphenyl] -4-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) 1- (3 ′, 4′-dimethoxy [1,1′-biphenyl] -4-yl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol Manufacturing of
1- (4-Bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (1.50 g), 3,4-dimethoxyphenylboronic acid (762 mg), 2 M The same reaction as in Example 29- (i) was performed using an aqueous sodium carbonate solution (2.79 ml) and tetrakis (triphenylphosphine) palladium (0) (96.7 mg) to give the title compound (1.42 g) as a colorless amorphous product. It was.
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.40-2.53 (1H, m), 3.51 (1H, s), 3.92 (3H, s), 3.95 (3H, s), 6.78 (1H, d, J = 1.0 Hz), 6.93 (1H, d, J = 8.2 Hz), 7.11-7.16 (8H, m), 7.31-7.35 (10H, m), 7.46 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz).
IR (KBr): 1470, 1445, 1250, 1217, 1173, 747, 731, 702 cm-1.
(ii) Preparation of 1- (3 ', 4'-dimethoxy [1,1'-biphenyl] -4-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
1- (3 ′, 4′-dimethoxy [1,1′-biphenyl] -4-yl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.37 g ) And pyridine hydrochloride (479 mg) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (660 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.83 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.57-2.67 (1H, m), 3.91 (3H, s), 3.93 (3H, s) , 6.90-6.98 (2H, m), 7.10-7.15 (2H, m), 7.47-7.63 (5H, m).
IR (KBr): 1526, 1505, 1464, 1219, 1171, 1142, 1026, 829, 806 cm-1.
Example 62
Preparation of 1- (3'-methoxy [1,1'-biphenyl] -4-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
(i) Preparation of 1- (3'-methoxy [1,1'-biphenyl] -4-yl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol
1- (4-Bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (1.50 g), 3-methoxyphenylboronic acid (635 mg), 2 M sodium carbonate The same reaction as in Example 29- (i) was performed using an aqueous solution (2.79 ml) and tetrakis (triphenylphosphine) palladium (0) (96.7 mg) to obtain the title compound (1.01 g) as colorless powder crystals. .
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 7.0 Hz), 2.39-2.49 (1H, m), 3.54 (1H, s), 3.86 (3H, s), 6.77 (1H, d, J = 1.4 Hz), 6.87 (1H, dd, J = 2.4, 7.2Hz), 7.11-7.19 (8H, m), 7.30-7.38 (10H, m), 7.47-7.66 (5H, m).
IR (KBr): 1599, 1480, 1447, 1213, 1167, 909, 822, 747, 733, 702 cm-1.
[0063]
(ii) Preparation of 1- (3'-methoxy [1,1'-biphenyl] -4-yl) -1- (1H-imidazol-4-yl) -2-methyl-1-propanol
1- (3′-methoxy [1,1′-biphenyl] -4-yl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (960 mg), pyridine The hydrochloride (354 mg) was used for the same reaction as in Example 4- (iii) to obtain the title compound (483 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.82 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 2.59-2.69 (1H, m), 3.85 (3H, s), 6.86-6.96 (2H, m), 7.11-7.18 (2H, m), 7.29-7.65 (6H, m).
IR (KBr): 1481, 1296, 1219, 1171, 1032, 1015, 826, 775, 696 cm-1.
Example 63
Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [3- (4-pyridyl) phenyl] -1-propanol
(i) Preparation of 2-methyl-1- [3- (4-pyridyl) phenyl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol
1- (3-Bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (1.20 g), 4-pyridylboronic acid (754 mg), 2 M aqueous sodium carbonate solution (2.23 ml) and tetrakis (triphenylphosphine) palladium (0) (155 mg) were used to carry out the same reaction as in Example 29- (i) to obtain the title compound (1.13 g) as a pale yellow amorphous.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6 Hz), 2.05-2.50 (1H, m), 3.72 (1H, s), 7.86 (1H, d, J = 0.6 Hz), 7.10-7.15 (7H, m), 7.27-7.47 (12H, m), 7.51-7.75 (3H, m), 8.62-8.65 (2H, m).
IR (KBr): 1597, 1445, 909, 791, 747, 735, 702, 660 cm-1.
(ii) Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [3- (4-pyridyl) phenyl] -1-propanol
Using 2-methyl-1- [3- (4-pyridyl) phenyl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.08 g) and pyridine hydrochloride (419 mg) Then, the reaction similar to that in Example 4- (iii) was performed to obtain the title compound (477 mg) as a colorless amorphous.
1H-NMR (CDClThree) δ: 0.82 (3H, d, J = 7.0 Hz), 1.00 (3H, d, J = 7.0 Hz), 2.59-2.72 (1H, m), 7.00 (1H, s), 7.36-7.62 (6H, m ), 7.89 (1H, s), 8.57-8.60 (2H, m).
IR (KBr): 3073, 2969, 1599, 1476, 1005, 909, 831, 789, 733, 619 cm-1.
[0064]
Example 64
Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [3- (3-pyridyl) phenyl] -1-propanol
(i) Preparation of 2-methyl-1- [3- (3-pyridyl) phenyl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol
1- (3-Bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.01 g), diethyl (3-pyridyl) borane (0.497 g) and tetrakis (Triphenylphosphine) palladium (0) (0.170 g) was used for the same reaction as in Example 4- (ii) to obtain the title compound (0.657 g) as a pale yellow amorphous powder.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.7 Hz), 0.94 (3H, d, J = 6.7 Hz), 2.30-2.55 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J = 1.4 Hz), 7.05-7.46 (19H, m), 7.50-7.62 (1H, m), 7.69 (1H, s), 7.82 (1H, dt, J = 8.0, 2.0Hz), 8.59 (1H, dd, J = 2.0, 4.8 Hz), 8.80 (1H, d, J = 2.2 Hz).
IR (KBr): 1491, 1470, 1445, 912 cm-1.
(ii) Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [3- (3-pyridyl) phenyl] -1-propanol
Using 2-methyl-1- [3- (3-pyridyl) phenyl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol (0.57 g) and pyridine hydrochloride (208 mg) The same reaction as in Example 4- (iii) was performed to give the title compound (288 mg) as colorless powder crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.82 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.55-2.76 (1H, m), 6.99 (1H, d, J = 1.3 Hz), 7.34 -7.47 (3H, m), 7.52 (1H, d, J = 1.3 Hz), 7.50-7.59 (1H, m), 7.77 (1H, s), 7.88-7.98 (1H, m), 8.50 (1H, dd , J = 2.2, 5.0 Hz), 8.75 (1H, dd, J = 0.8, 2.2 Hz).
IR (KBr): 2971, 1470, 1022, 970 cm-1.
Example 65
Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [3- (2-pyridyl) phenyl] -1-propanol
(i) Preparation of 2-methyl-1- [3- (2-pyridyl) phenyl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol
1- (3-Bromophenyl)-(1-trityl-1H-imidazol-4-yl) -2-methyl-1-propanol (1.15 g), tri-n-butyl (2-pyridyl) tin (1.01 g) After degassing the DMF (10 ml) solution, tetrakis (triphenylphosphine) palladium (0) (73.1 mg) was added, and the mixture was stirred at 80 ° C for 5 hours under an argon atmosphere. mg) and tetrakis (triphenylphosphine) palladium (0) (48.7 mg) were added, and the mixture was stirred at 100 ° C. for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with 5% aqueous ethylenediamine solution, water (twice) and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent; hexane: ethyl acetate = 3: 1 → 2: 1) and recrystallized from ethyl acetate-hexane to give the title compound (577 mg, 51% ) Was obtained as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.45-2.52 (1H, m), 3.68 (1H, s), 6.86 (1H, d, J = 1.6 Hz), 7.10-7.43 (18H, m), 7.58-7.86 (4H, m), 8.09-8.10 (1H, m), 8.66-8.69 (1H, m).
IR (KBr): 1586, 1493, 1472, 1445, 909, 774, 747, 733, 702 cm-1.
[0065]
(ii) Preparation of 1- (1H-imidazol-4-yl) -2-methyl-1- [3- (2-pyridyl) phenyl] -1-propanol
Using 2-methyl-1- [3- (2-pyridyl) phenyl] -1- (1-trityl-1H-imidazol-4-yl) -1-propanol (527 mg) and pyridine hydrochloride (205 mg) The title compound (197 mg) was obtained as colorless plate crystals by the same reaction as in Example 4- (iii).
1H-NMR (CDClThree) δ: 0.80 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 6.6 Hz), 2.58-2.71 (1H, m), 6.89 (1H, s), 7.17-7.24 (1H, m ), 7.35-7.43 (2H, m), 7.59 (1H, d, J = 7.8 Hz), 7.67-7.79 (3H, m), 8.16 (1H, s), 8.62 (1H, d, J = 4.8 Hz) .
IR (KBr): 3187, 1584, 1460, 1362, 1304, 1007, 799, 768 cm-1.
Example 66
Preparation of N- {3 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} acetamide
(i) N- {3 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} acetamide Manufacturing
1- (3-bromophenyl) -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.02 g), 3-acetamidobenzeneboronic acid (0.531 g) and The reaction was conducted in the same manner as in Example 4- (ii) using tetrakis (triphenylphosphine) palladium (0) (0.170 g) to obtain the title compound (0.980 g) as a pale yellow amorphous powder.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.8 Hz), 2.16 (3H, s), 2.35-2.58 (1H, m), 3.68 (1H, brs), 6.80 (1H, d, J = 1.4 Hz), 7.04-7.18 (6H, m), 7.20-7.42 (13H, m), 7.44-7.56 (3H, m), 7.62-7.74 (2H, m).
IR (KBr): 3289, 1669, 1557, 1493 cm-1.
(ii) Preparation of N- {3 '-[1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -3-yl} acetamide
N- {3 '-[1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -3-yl} acetamide (0.781 g) And pyridine hydrochloride (290 mg) were used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (315 mg) as colorless powder crystals.
1H-NMR (DMSO-d6) δ: 0.69 (3H, d, J = 6.6 Hz), 0.82 (3H, d, J = 6.6 Hz), 2.07 (3H, s), 2.57-2.78 (1H, m), 5.12 (1H, brs), 6.96 (1H, s), 7.21-7.43 (4H, m), 7.50-7.66 (3H, m), 7.80 (1H, s), 7.88 (1H, s).
IR (KBr): 3295, 1667, 1557, 789 cm-1.
[0066]
Example 67
Preparation of 5- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -N-methylnicotinamide
(i) Production of 5-bromo-N-methylnicotinamide
5-bromonicotinic acid (5.01 g), methylamine THF solution (2.0 M; 30 ml), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (5.79 g) and 1-hydroxybenzotriazole (4.72 g) was used for the same reaction as in Example 55- (i) to give the title compound (2.30 g) as colorless prism crystals.
1H-NMR (CDClThree) δ: 3.04 (3H, d, J = 4.8 Hz), 6.45 (1H, brs), 8.27 (1H, t, J = 2.1 Hz), 8.78 (1H, d, J = 2.1 Hz), 8.86 (1H, d, J = 2.1 Hz).
IR (KBr): 3297, 3025, 1645, 1416 cm-1.
(ii) Preparation of 5- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -N-methylnicotinamide
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.0 g), 5-bromo-N-methylnicotinamide (1.01 g) and The reaction was conducted in the same manner as in Example 33- (ii) using tetrakis (triphenylphosphine) palladium (0) (0.177 g) to obtain the title compound (1.26 g) as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.76 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 Hz), 2.36-2.60 (1H, m), 3.07 (3H, d, J = 5.2 Hz), 3.59 ( 1H, s), 6.30 (1H, brs), 6.78 (1H, d, J = 1.4 Hz), 7.06-7.20 (6H, m), 7.26-7.38 (10H, m), 7.52 (2H, d, J = 8.4 Hz), 7.63 (2H, d, J = 8.4 Hz), 8.29 (1H, t, J = 2.2 Hz), 8.88 (1H, d, J = 2.2 Hz), 8.94 (1H, d, J = 2.2 Hz) ).
IR (KBr): 3227, 2969, 1651 cm-1.
(iii) Preparation of 5- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -N-methylnicotinamide
5- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -N-methylnicotinamide (1.44 g) and pyridine hydrochloride (466 mg ) Was used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (360 mg) as a colorless amorphous powder.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.80 (3H, d, J = 6.8 Hz), 0.98 (3H, d, J = 6.8 Hz), 2.40-2.80 (1H, m), 3.02 (3H, s), 6.98 (1H, d, J = 1.0 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.48 (1H, d, J = 1.0 Hz), 7.59 (2H, d, J = 8.4 Hz), 8.28 (1H, t, J = 2.1 Hz), 8.78 (1H, d, J = 2.1 Hz), 8.84 (1H, d, J = 2.1 Hz).
IR (KBr): 3200, 2971, 1651, 1557 cm-1.
[0067]
Example 68
Preparation of N- (6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -2-pyridyl) acetamide
(i) Production of N- (6-bromo-2-pyridyl) acetamide
The same reaction as in Example 56- (i) was performed using 2-amino-6-bromopyridine (2.97 g) and acetic anhydride (2.9 ml) to obtain the title compound (2.30 g) as colorless scaly crystals. .
1H-NMR (CDClThree) δ: 2.20 (3H, s), 7.21 (1H, d, J = 8.0 Hz), 7.56 (1H, t, J = 8.0 Hz), 8.05 (1H, brs), 8.15 (1H, d, J = 8.0 Hz).
IR (KBr): 3231, 1661, 1574, 1439, 1391 cm-1.
(ii) Preparation of N- (6- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -2-pyridyl) acetamide
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.01 g), N- (6-bromo-2-pyridyl) acetamide (1.05 g) and tetrakis (triphenylphosphine) palladium (0) (0.138 g) were used for the same reaction as in Example 33- (ii) to obtain the title compound (0.720 g) as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.74 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.8 Hz), 2.20 (3H, s), 2.34-2.58 (1H, m), 3.60 (1H, s), 6.77 (1H, d, J = 1.4 Hz), 7.06-7.20 (6H, m), 7.28-7.42 (10H, m), 7.44 (1H, dd, J = 0.8, 7.9 Hz), 7.59 (2H, d, J = 8.4 Hz), 7.75 (1H, t, J = 7.9 Hz), 7.83 (2H, d, J = 8.4 Hz), 8.05-8.16 (2H, m).
IR (KBr): 2969, 1732, 1690, 1447 cm-1.
(iii) Preparation of N- (6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -2-pyridyl) acetamide
N- (6- {4- [1-Hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -2-pyridyl) acetamide (1.48 g) and pyridine hydrochloride (520 mg) was used for the same reaction as in Example 4- (iii) to give the title compound (520 mg) as colorless powder crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.81 (3H, d, J = 6.7 Hz), 0.98 (3H, d, J = 6.7 Hz), 2.22 (3H, s), 2.52-2.74 (1H, m), 6.97 (1H, d, J = 1.0 Hz), 7.44 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 1.0 Hz), 7.59 (2H, d, J = 8.4 Hz), 7.76 (1H, t, J = 7.8 Hz), 7.83 (2H, d, J = 8.4 Hz), 8.09 (1H, d, J = 7.8 Hz).
IR (KBr): 3177, 2967, 1651, 1559, 1451 cm-1.
Example 69
Preparation of 6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -N-methyl-2-pyridinecarboxamide
(i) Preparation of 6-bromo-N-methyl-2-pyridinecarboxamide
6-bromopicolinic acid (3.00 g), methylamine THF solution (2.0 M; 18 ml), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (3.41 g) and 1-hydroxybenzotriazole (2.99 g) was used for the same reaction as in Example 55- (i) to give the title compound (2.60 g) as a pale brown oil.
1H-NMR (CDClThree) δ: 3.04 (3H, d, J = 5.2 Hz), 7.60 (1H, dd, J = 1.0, 7.6 Hz), 7.72 (1H, t, J = 7.6 Hz), 8.16 (1H, dd, J = 1.0 , 7.6 Hz).
IR (neat): 3391, 1682, 1669, 1557, 1539 cm-1.
[0068]
(ii) Preparation of 6- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -N-methyl-2-pyridinecarboxamide
4- [1-Hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (2.97 g), 6-bromo-N-methyl-2-pyridinecarboxamide (1.30 g) and tetrakis (triphenylphosphine) palladium (0) (0.110 g) were used to carry out the same reaction as in Example 33- (ii) to obtain the title compound (1.11 g) as colorless powder crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.76 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 2.44-2.64 (1H, m), 3.04-3.10 (3H, m), 6.83 (1H, d, J = 1.2 Hz), 7.08-7.20 (6H, m), 7.30-7.40 (10H, m), 7.63 (2H, d, J = 8.4 Hz), 7.82-7.98 (4H, m), 8.06-8.14 (1H, m), 8.33 (1H, brs).
IR (KBr): 3387, 2967, 1672, 1449 cm-1.
(iii) Preparation of 6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -N-methyl-2-pyridinecarboxamide
6- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -N-methyl-2-pyridinecarboxamide (1.44 g) and pyridine hydrochloride (550 mg) was used for the same reaction as in Example 4- (iii) to obtain the title compound (255 mg) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.81 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.48-2.70 (1H, m), 3.02 (3H, d, J = 5.2 Hz), 6.98 ( 1H, s), 7.48 (1H, s), 7.64 (2H, d, J = 8.4 Hz), 7.70-7.83 (2H, m), 7.88 (2H, d, J = 8.4 Hz), 8.04 (1H, d , J = 7.0 Hz), 8.16-8.30 (1H, m).
IR (KBr): 2969, 1667, 1537, 1449 cm-1.
Example 70
Preparation of N- (2- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -4-pyridyl) acetamide
(i) Preparation of 1- [4- (4-amino-2-pyridyl) phenyl] -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (5.78 g), 4-amino-2-chloropyridine (1.00 g), odor The reaction was conducted in the same manner as in Example 33- (ii) using sodium iodide (810 mg) and tetrakis (triphenylphosphine) palladium (0) (0.190 g) to give the title compound (2.30 g) as a yellow amorphous powder. It was.
1H-NMR (CDClThree) δ: 0.74 (3H, d, J = 6.5 Hz), 0.91 (3H, d, J = 6.5 Hz), 2.36-2.56 (1H, m), 3.61 (1H, s), 4.17 (2H, s), 6.46 (1H, dd, J = 2.2, 5.6 Hz), 6.77 (1H, s), 6.93 (1H, d, J = 2.2 Hz), 7.06-7.19 (6H, m), 7,27-7,39 ( 10H, m), 7.56 (2H, d, J = 8.2 Hz), 7.82 (2H, d, J = 8.2 Hz), 8.29 (1H, d, J = 5.6 Hz).
IR (KBr): 3335, 3210, 1599, 1445 cm-1.
[0069]
(ii) Preparation of N- (2- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -4-pyridyl) acetamide
1- [4- (4-Amino-2-pyridyl) phenyl] -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (1.40 g), acetic anhydride (0.46 ml ), Triethylamine (0.71 ml) and p-dimethylaminopyridine (20 mg) were stirred in THF (20 ml) at 60 ° C. for 16 hours. The solvent was distilled off, and ethyl acetate and water were added to the residue for liquid separation. The organic layer was washed with aqueous sodium bicarbonate and brine, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was dissolved in a mixture of acetonitrile (10 ml) -water (10 ml), tetrabutylammonium bromide (13 mg) was added, and the mixture was stirred at room temperature for 10 hours. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate to give the title compound (630 mg) as colorless powder crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.74 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.8 Hz), 2.19 (3H, s), 2.42-2.62 (1H, m), 6.82 (1H, d, J = 1.0 Hz), 7.06-7.20 (6H, m), 7.26-7.42 (10H, m), 7.50-7.62 (3H, m), 7.77-7.88 (3H, m), 8.46 (1H, d, J = (5.6 Hz).
IR (KBr): 3264, 2973, 1707, 1588 cm-1.
(iii) Preparation of N- (2- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -4-pyridyl) acetamide
N- (2- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -4-pyridyl) acetamide (0.590 g) and pyridine hydrochloride (190 mg) was used for the same reaction as in Example 4- (iii) to give the title compound (150 mg) as colorless powder crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.81 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.19 (3H, s), 2.50-2.78 (1H, m), 6.98 (1H, m) , 7.50-7.66 (4H, m), 7.74-7.86 (2H, m), 7.92 (1H, s), 8.43 (1H, dd, J = 2.6, 7.4 Hz).
IR (KBr): 3094, 1703, 1599, 1522 cm-1.
Example 71
Preparation of N-ethyl-6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -2-pyridinecarboxamide
(i) Preparation of 6-bromo-N-ethyl-2-pyridinecarboxamide
6-bromopicolinic acid (3.06 g), ethylamine hydrochloride (2.49 g), triethylamine (6 ml), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (3.61 g) and 1-hydroxy The reaction was carried out in the same manner as in Example 55- (i) using benzotriazole (2.66 g) to obtain the title compound (3.20 g) as a colorless oil.
1H-NMR (CDClThree) δ: 1.28 (3H, t, J = 7.3 Hz), 3.40-3.64 (2H, m), 7.60 (1H, d, J = 7.9 Hz), 7.72 (1H, t, J = 7.9 Hz), 7.82 ( 1H, brs), 8.16 (1H, d, J = 7.9 Hz).
IR (KBr): 2975, 1669, 1557, 1532, 1427 cm-1.
[0070]
(ii) Preparation of N-ethyl-6- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -2-pyridinecarboxamide
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.10 g), 6-bromo-N-ethyl-2-pyridinecarboxamide (1.20 g) and tetrakis (triphenylphosphine) palladium (0) (0.170 g) were used to carry out the same reaction as in Example 33- (ii) to obtain the title compound (1.89 g) as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 7.0 Hz), 1.31 (3H, t, J = 7.3 Hz), 2.40-2.60 (1H, m), 3.44- 3.64 (2H, m), 3.54 (1H, s), 6.79 (1H, d, J = 1.6 Hz), 7.08-7.19 (6H, m), 7.28-7.39 (10H, m), 7.66 (2H, d, J = 8.8 Hz), 7.79-7.96 (4H, m), 8.13 (1H, dd, J = 1.4, 7.4 Hz).
IR (KBr): 1671, 1524, 1449 cm-1.
(iii) Preparation of N-ethyl-6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -2-pyridinecarboxamide
N-ethyl-6- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -2-pyridinecarboxamide (1.82 g) and pyridine hydrochloride (570 mg) was used for the same reaction as in Example 4- (iii) to obtain the title compound (560 mg) as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.84 (3H, d, J = 6.6 Hz), 1.00 (3H, d, J = 6.6 Hz), 1.29 (3H, t, J = 7.3 Hz), 2.56-2.78 (1H, m), 3.44- 3.64 (2H, m), 7.01 (1H, d, J = 1.2 Hz), 7.55 (1H, d, J = 1.2 Hz), 7.69 (2H, d, J = 8.6 Hz), 7.77-7.88 (2H, m ), 7.93 (2H, d, J = 8.6 Hz), 8.10 (1H, dd, J = 1.4, 7.0 Hz), 8.18 (1H, brs).
IR (KBr): 3441, 3395, 2975, 1676, 1530, 1449 cm-1.
Example 72
Preparation of 6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -N-isopropyl-2-pyridinecarboxamide
(i) Preparation of 6-bromo-N-isopropyl-2-pyridinecarboxamide
6-bromopicolinic acid (3.04 g), isopropylamine (5 ml), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (3.44 g) and 1-hydroxybenzotriazole (2.70 g) Was used for the same reaction as in Example 55- (i) to give the title compound (3.10 g) as a colorless oil.
1H-NMR (CDClThree) δ: 1.29 (6H, d, J = 6.6 Hz), 4.10-4.40 (1H, m), 7.60 (1H, dd, J = 1.2, 7.8 Hz), 7.71 (1H, t, J = 7.8 Hz), 8.16 (1H, dd, J = 1.2, 7.8 Hz) .IR (KBr): 2973, 1674, 1557, 1520 cm-1.
[0071]
(ii) Preparation of 6- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -N-isopropyl-2-pyridinecarboxamide
4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (3.10 g), 6-bromo-N-isopropyl-2-pyridinecarboxamide (1.13 g) and tetrakis (triphenylphosphine) palladium (0) (0.160 g) were used for the same reaction as in Example 33- (ii) to obtain the title compound (1.67 g) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.78 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 1.32 (6H, d, J = 6.6 Hz), 2.40-2.58 (1H, m), 3.56 ( 1H, s), 4,20-4.42 (1H, m), 6.80 (1H, s), 7.00-7.20 (6H, m), 7.21-7.46 (10H, m), 7.66 (2H, d, J = 8.5 Hz), 7.79-7.86 (1H, m), 7.92 (2H, d, J = 8.5 Hz), 8.04 (1H, d, J = 7.4 Hz), 8.14 (1H, dd, J = 1.0, 6.2 Hz).
IR (KBr): 3382, 2969, 1667, 1524, 1447 cm-1.
(iii) Preparation of 6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -N-isopropyl-2-pyridinecarboxamide
6- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -N-isopropyl-2-pyridinecarboxamide (1.60 g) and pyridine hydrochloride (770 mg) was used for the same reaction as in Example 4- (iii) to give the title compound (350 mg) as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.80 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 6.6 Hz), 1.25 (6H, d, J = 6.6 Hz), 2.44-2.70 (2H, m), 6.93 ( 1H, d, J = 0.9 Hz), 7.41 (1H, d, J = 7.8 Hz), 7.46 (1H, d, J = 0.9 Hz), 7.60 (2H, d, J = 8.4 Hz), 7.73 (1H, t, J = 7.8 Hz), 7.84 (2H, d, J = 8.4 Hz), 8.15 (1H, d, J = 7.8 Hz), 8.15 (1H, brs).
IR (KBr): 2973, 1672, 1518,1447 cm-1.
Example 73
Preparation of 2- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -N-methylisonicotinamide
(i) Production of 2-bromo-N-methylisonicotinamide
2-bromoisonicotinic acid (2.69 g), methylamine THF solution (2.0 M; 15 ml), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (3.20 g) and 1-hydroxybenzo The same reaction as in Example 55- (i) was performed using triazole (2.59 g), and the title compound (361 mg) was obtained as colorless powder crystals.
1H-NMR (CDClThree) δ: 3.04 (3H, d, J = 4.6 Hz), 7.55 (1H, dd, J = 1.4, 5.1 Hz), 7.79-7.82 (1H, m), 8.49 (1H, d, J = 5.1 Hz).
IR (KBr): 3291, 1644, 1557, 1537 cm-1.
[0072]
(ii) Preparation of 2- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -N-methylisonicotinamide
4- [1-Hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid (1.30 g), 2-bromo-N-methylisonicotinamide (310 mg) Using tetrakis (triphenylphosphine) palladium (0) (0.110 g), the same reaction as in Example 33- (ii) was performed to obtain the title compound (480 mg) as a colorless amorphous powder.
1H-NMR (CDClThree) δ: 0.74 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.36-2.54 (1H, m), 3.06 (3H, d, J = 4.8 Hz), 3.61 ( 1H, s), 6.36 (1H, brs), 6,78 (1H, d, J = 1.4 Hz), 7.06-7.18 (6H, m), 7.28-7.38 (10H, m), 7.45 (1H, dd, J = 1.4, 5.2 Hz), 7.61 (2H, d, J = 8.4 Hz), 7.93 (2H, d, J = 8.4 Hz), 8.05-8.20 (1H, m), 8.75 (1H, dd, J = 0.6 , 5.2 Hz).
IR (KBr): 3304, 1651, 1549 cm-1.
(iii) Preparation of 2- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -N-methylisonicotinamide
2- {4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl} -N-methylisonicotinamide (0.450 g) and pyridine hydrochloride (230 mg) was used to carry out the same reaction as in Example 4- (iii) to obtain the title compound (110 mg) as a colorless amorphous powder.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.79 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 2.52-2.76 (1H, m), 3.02 (3H, s), 6.95 (1H, d, J = 1.0 Hz), 7.44-7.60 (4H, m), 7.81 (2H, d, J = 8.4 Hz), 7.97 (1H, s), 8.67 (1H, d, J = 5.2 Hz).
IR (KBr): 3175, 2973, 1651, 1549 cm-1.
Example 74
Preparation of N- [4'-fluoro-5- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -2-yl] acetamide
(i) Preparation of 4'-fluoro [1,1'-biphenyl] -2-yl methyl ether
Example 4 using 2-bromoanisole (8.91 g), 4-fluorophenylboronic acid (10.0 g), 2M aqueous sodium carbonate (47.6 ml), tetrakis (triphenylphosphine) palladium (0) (2.20 g) The title compound (8.14 g) was obtained as colorless needle crystals by the same reaction as-(ii).
1H-NMR (CDClThree) δ: 3.81 (3H, s), 6.96-7.13 (4H, m), 7.27-7.37 (2H, m), 7.45-7.33 (2H, m).
IR (KBr): 1514, 1487, 1260, 1236, 1223, 1159, 1028, 835, 754 cm-1.
[0073]
(ii) Preparation of 5-bromo-4'-fluoro [1,1'-biphenyl] -2-ol
4'-fluoro [1,1'-biphenyl] -2-yl methyl ether (107 g), pyridinium hydrobromide perbromide (34.0 g), water-acetic acid-diethyl ether mixture (1: 4: 5,500 ml) was stirred at room temperature for 18 hours. Hypo-water was added to the reaction solution, and the resulting crystals were filtered and the crude 5-bromo-4'-fluoro [1,1'-biphenyl] -2-ylmethyl ether product (15.2 g) was yellow. Obtained as a solid. To a solution of this product (14.1 g) in dichloromethane (150 ml) was added dropwise a solution of boron tribromide (5.69 ml) in dichloromethane (40 ml) at −78 ° C., and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured onto ice, the organic layer was separated, neutralized with aqueous sodium bicarbonate, washed with brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent; hexane → hexane: ethyl acetate = 5: 1) to obtain the title compound (13.2 g) as a colorless oil.
1H-NMR (CDClThree) δ: 5.11 (1H, s), 6.83-6.86 (1H, m), 7.13-7.24 (2H, m), 7.32-7.46 (4H, m).
IR (KBr): 1514, 1487, 1480, 1260, 1229, 1159, 839, 812 cm-1.
(iii) Preparation of 4'-fluoro-5- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -2-ol
5-Bromo-4'-fluoro [1,1'-biphenyl] -2-ol (13.2 g), imidazole (5.04 g) in DMF (60 ml) at 0 ° C with t-butyldimethylsilyl chloride (7.82 g) was added and stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed twice with water, washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 3-bromo-6-[[tert-butyl (dimethyl) silyl] oxy] -4'-fluoro-1,1'-biphenyl crude product (18.1 g) as a yellow oil. Got as. This product (18.1 g), hexane solution of n-butyllithium (1.6 M; 31.3 ml), 2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propane (12.0 g) The same reaction as in Example 4- (i) was carried out, and 1- [4′-fluoro-6-[[tert-butyl (dimethyl) silyl] oxy] [1,1′-biphenyl] -3- A crude product (18.2 g) of [yl] -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol was obtained as a colorless amorphous substance. A solution of tetrabutylammonium bromide in THF (1.0 M; 27.7 ml) was added dropwise to a THF (100 ml) solution of this product (18.2 g) at 0 ° C., and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added to the reaction solution and concentrated. Ethyl acetate and diisopropyl ether were added to the residue, and the precipitated crystals were collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give the title compound (11.2 g) as a colorless powder.
1H-NMR (DMSO-d6) δ: 0.65 (3H, d, J = 6.6 Hz), 0.73 (3H, d, J = 6.6 Hz), 2.44-2.51 (1H, m), 4.92 (1H, s), 6.78-6.83 (2H, m ), 7.04-7.08 (7H, m), 7.16-7.55 (15H, m), 9.37 (1H, s).
IR (KBr): 1501, 1271, 1223, 1184, 1157, 1001, 835, 756, 748, 702 cm-1.
[0074]
(iv) 4'-Fluoro-5- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -2-yl trifluoromethane Production of sulfonate
Of 4′-fluoro-5- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1′-biphenyl] -2-ol (1.10 g) Trifluoromethanesulfonic anhydride (0.423 ml) was added dropwise to a pyridine (7 ml) solution at 0 ° C, and the mixture was stirred at 0 ° C for 20 minutes and at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed 3 times with 5% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent; hexane: ethyl acetate = 5: 1) to obtain the title compound (1.06 g) as a colorless amorphous product.
1H-NMR (CDClThree) δ: 0.73 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.35-2.42 (1H, m), 3.74 (1H, s), 6.74 (1H, d, J = 1.6 Hz), 7.08-7.17 (7H, m), 7.24-7.40 (14H, m), 7.52-7.61 (2H, m).
IR (KBr): 1481, 1424, 1248, 1217, 1161, 1140, 885, 837, 747, 702 cm-1.
(v) 1- [6-[(Diphenylmethylene) amino] -4′-fluoro [1,1′-biphenyl] -3-yl] -2-methyl-1- (1-trityl-1H-imidazole-4 -Ill) -1-Propanol production
4'-Fluoro-5- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -2-yl trifluoromethanesulfonate (1.06 g), benzophenone imine (0.305 ml), cesium carbonate (1.23 g) in toluene (15 ml) and (RS) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (56.4 mg ) And tri (dibenzylideneacetone) dipalladium (0) (27.7 mg) were added, and the mixture was stirred at 80-90 ° C. for 26 hours. Add (RS) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (112 mg), tri (dibenzylideneacetone) palladium (0) (55.4 mg), and add 80-90 ° C. And stirred at 105 ° C. for 3.5 hours. The reaction solution was filtered through Celite, and the filtrate was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent; hexane: ethyl acetate = 5: 1 → 1: 1) to obtain the title compound (115 mg) as a yellow amorphous.
1H-NMR (CDClThree) δ: 0.69 (3H, d, J = 6.6 Hz), 0.88 (3H, d, J = 7.0 Hz), 2.28-2.35 (1H, m), 3.60 (1H, s), 6.60-6.66 (3H, m ), 6.82-7.44 (29H, m), 7.60-7.64 (2H, m).
IR (KBr): 1599, 1510, 1491, 1480, 1447, 1223, 1157, 909, 837, 747, 735, 700 cm-1.
[0075]
(vi) N- [4'-Fluoro-5- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -2- Ill] acetamide production
1- [6-[(Diphenylmethylene) amino] -4'-fluoro [1,1'-biphenyl] -3-yl] -2-methyl-1- (1-trityl-1H-imidazol-4-yl) To a solution of -1-propanol (110 mg) in THF-methanol (1: 1) (6 ml) was added anhydrous sodium acetate (29.6 mg) and hydroxyammonium chloride (18.7 mg) at room temperature, and the mixture was stirred for 22 hours. The reaction solution was concentrated, diluted with ethyl acetate, washed with 0.5N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1- [6-amino-4′-fluoro [1,1′-biphenyl] -3-yl] -2-methyl-1- (1-trityl-1H-imidazole-4- Yl) -1-propanol crude product (118 mg) was obtained as a yellow oil. Acetic anhydride (28.3 m l) was added dropwise to a THF (2 ml) solution of this product (116 mg) and pyridine (29.6 m l) at 0 ° C., and the mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent; hexane: ethyl acetate = 3: 1 → 3: 2) to give the title compound (79.6 mg) as a colorless amorphous product.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.6 Hz), 0.91 (3H, d, J = 6.6 Hz), 2.02 (3H, s), 2.30-2.41 (1H, m), 3.64 (1H, s), 6.73 (1H, d, J = 1.6 Hz), 6.96 (1H, br s), 7.09-7.19 (8H, m), 7.29-7.39 (14H, m), 8.09 (1H, d, J = 8.8 Hz).
IR (KBr): 1669, 1514, 1493, 1472, 1447, 1225, 1159, 747, 733, 702 cm-1.
(vii) of N- [4'-fluoro-5- [1-hydroxy-1- (1H-imidazol-4-imidazole) -2-methylpropyl] [1,1'-biphenyl] -2-yl] acetamide Manufacturing
N- [4'-Fluoro-5- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] [1,1'-biphenyl] -2-yl] acetamide (78.2 mg) and pyridine hydrochloride (26.7 mg) were used for the same reaction as in Example 4- (iii) to obtain the title compound (25.0 mg) as colorless needle crystals.
1H-NMR (CDClThree) δ: 0.83 (3H, d, J = 6.8 Hz), 0.95 (3H, d, J = 6.6 Hz), 2.02 (3H, s), 2.52-2.66 (1H, m), 6.95 (1H, br s) 7.10-7.19 (1H, m), 7.29-7.36 (3H, m), 7.47-7.52 (3H, m), 8.11 (1H, d, J = 8.8 Hz).
IR (KBr): 3169, 2973, 1665, 1514, 1491, 1304, 1225, 839, 820 cm-1.
Example 75
Preparation of 4'-fluoro-5- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -2-yl acetate
(i) Preparation of benzyl 5-bromo-4'-fluoro [1,1'-biphenyl] -2-yl ether
A solution of 5-bromo-4'-fluoro [1,1'-biphenyl] -2-ol (7.00 g), potassium carbonate (3.80 g), benzyl bromide (3.27 ml) in DMF (10 ml) at 60 ° C. Stir for 5 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent; hexane → hexane: ethyl acetate = 10: 1) to obtain the title compound (8.31 g) as a brown oil.
1H-NMR (CDThreeOD) δ: 5.05 (2H, s), 6.89 (1H, d, J = 8.8 Hz), 7.04-7.14 (2H, m), 7.25-7.55 (9H, m).
IR (KBr): 1512, 1483, 1454, 1265, 1227, 1159, 1024, 837, 737 cm-1.
[0076]
(ii) 1- [6-Benzyloxy-4′-fluoro [1,1′-biphenyl] -3-yl] -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1- Propanol production
Benzyl 5-bromo-4'-fluoro [1,1'-biphenyl] -2-yl ether (3.86 g), n-butyllithium solution in hexane (1.6 M; 7.29 ml), 1- (1H-imidazole-4 -Il) -2-methyl-1-propane (597 mg) was used to carry out the same reaction as in Example 4- (i) to obtain the title compound (672 mg) as a colorless amorphous.
1H-NMR (CDClThree) δ: 0.84 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 6.6 Hz), 2.53-2.67 (1H, m), 5.05 (2H, s), 6.94-7.10 (4H, m ), 7.30-7.33 (5H, m), 7.43-7.56 (5H, m).
IR (KBr): 1514, 1491, 1265, 1225, 1157, 1017, 837, 735 cm-1.
(iii) Preparation of 4'-fluoro-5- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -2-ol
1- [6-Benzyloxy-4′-fluoro [1,1′-biphenyl] -3-yl] -2-methyl-1- (1-trityl-1H-imidazol-4-yl) -1-propanol (647 mg), 10% palladium carbon (647 mg) in methanol (15 ml) was stirred for 4 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluent; ethyl acetate → ethyl acetate: methanol = 20: 1) and recrystallized from ethyl acetate-hexane to give the title compound (396 mg) was obtained as colorless powder crystals.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.83 (3H, d, J = 7.0 Hz), 0.95 (3H, d, J = 7.0 Hz), 2.52-2.65 (1H, m), 6.65 (1H, d, J = 8.4 Hz), 6.94 (1H, d, J = 1.2 Hz), 7.04-7.14 (2H, m), 7.26 (1H, d, J = 2.2, 8.4 Hz), 7.34 (1H, d, J = 2.2 Hz), 7.47-7.54 ( 3H, m).
IR (KBr): 1514, 1493, 1229, 1213, 1007, 841, 814, 627, 606 cm-1.
(iv) Preparation of 4'-fluoro-5- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -2-yl acetate
4'-Fluoro-5- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] [1,1'-biphenyl] -2-ol (390 mg) in pyridine (4 ml ) Acetic anhydride (0.135 ml) was added dropwise to the solution at room temperature, and after stirring for 4 hours, acetic anhydride (22.5 m l) was further added and stirred for 15 hours. The reaction solution was azeotroped with toluene, concentrated, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, acetic anhydride (0.209 ml) was added dropwise to a solution of the residue (414 mg) in pyridine (4 ml) at room temperature, and the mixture was stirred for 15 hours. The reaction solution was azeotroped with toluene and concentrated, and then a 0.1N p-toluenesulfonic acid aqueous solution (7.5 ml) was added to a methanol (15 ml) solution of the residue at room temperature, followed by stirring for 1 hour. The reaction mixture was concentrated, diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (eluent; ethyl acetate → ethyl acetate: methanol = 20: 1) to obtain the title compound (337 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.83 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 6.6 Hz), 2.08 (3H, s), 2.57-2.65 (1H, m), 6.96 (1H, d, J = 1.0 Hz), 7.03-7.11 (3H, m), 7.32-7.39 (2H, m), 7.50-7.59 (3H, m).
IR (KBr): 1748, 1516, 1487, 1372, 1223, 1196, 1161, 839 cm-1.
[0077]
Example 76
Preparation of 5- [4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl] -N-methyl-2-thiophenecarboxamide
(i) Preparation of 5- [4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl] -N-methyl-2-thiophenecarboxamide
5-Bromo-N-methyl-2-thiophenecarboxamide (1.01 g), crude 4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid Using the product (3.00 g), 2 M aqueous sodium carbonate solution (4.59 ml) and tetrakis (triphenylphosphine) palladium (0) (265 mg), the same reaction as in Example 33- (ii) was carried out. Compound (1.44 g) was obtained as colorless powder crystals.
1H-NMR (CDClThree) δ: 0.75 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 7.0 Hz), 2.43-2.47 (1H, m), 3.01 (3H, d, J = 4.8 Hz), 3.53 ( 1H, s), 5.93 (1H, br s), 6.76 (1H, d, J = 1.4 Hz), 7.10-7.15 (7H, m), 7.24-7.53 (15H, m).
IR (KBr): 1626, 1553, 1493, 1449, 810, 747, 733, 702 cm-1.
(ii) Preparation of 5- [4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl] -N-methyl-2-thiophenecarboxamide
5- [4- [1-Hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl] -N-methyl-2-thiophenecarboxamide (1.39 g), pyridine hydrochloride (484 mg) was used for the same reaction as in Example 4- (iii) to give the title compound (769 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.82 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 7.0 Hz), 2.59-2.66 (1H, m), 2.97 (3H, s), 6.96 (1H, d, J = 0.8 Hz), 7.22 (1H, d, J = 4.0 Hz), 7.47 (1H, d, J = 4.0 Hz), 7.54-7.56 (5H, m).
IR (KBr): 3079, 1626, 1557, 1528, 1451, 1410, 1314, 812 cm-1.
Example 77
Preparation of 5- [4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl] -N-methyl-2-thiophenesulfonamide
(i) Preparation of 5- [4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl] -N-methyl-2-thiophenesulfonamide
Of 5-bromo-N-methyl-2-thiophenesulfonamide (1.18 g), 4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid Using the crude product (3.00 g), 2 M aqueous sodium carbonate solution (4.59 ml), tetrakis (triphenylphosphine) palladium (0) (265 mg), the same reaction as in Example 33- (ii) was performed. Compound (1.67 g) was obtained as colorless needle crystals.
1H-NMR (CDClThree) δ: 0.74 (3H, d, J = 7.0 Hz), 0.92 (3H, d, J = 6.6 Hz), 2.40-2.47 (1H, m), 2.78 (3H, d, J = 5.6 Hz), 3.54 ( 1H, s), 4.44 (1H, q J = 5.6 Hz), 6.76 (1H, d, J = 1.2 Hz), 7.10-7.15 (6H, m), 7.22-7.35 (11H, m), 7.48-7.58 ( 5H, m).
IR (KBr): 1445, 1335, 1159, 808, 747, 733, 702, 594 cm-1.
[0078]
(ii) Preparation of 5- [4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl] -N-methyl-2-thiophenesulfonamide
5- [4- [1-Hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenyl] -N-methyl-2-thiophenesulfonamide (1.62 g), pyridine hydrochloride The salt (532 mg) was used for the same reaction as in Example 4- (iii) to obtain the title compound (884 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.80 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 6.6 Hz), 2.56-2.72 (4H, m), 6.97 (1H, s), 7.21 (1H, d, J = 4.0 Hz), 7.30 (1H, s), 7.48-7.58 (5H, m).
IR (KBr): 1435, 1327, 1157, 1134, 1090, 1015, 806, 594 cm-1.
Example 78
Preparation of 4- [4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl]]-1-isoindolinone
(i) Production of methyl 3-bromo-2-methylbenzoate
A solution of 3-bromo-2-methylbenzoic acid (9.95 g) and concentrated sulfuric acid (0.2 ml) in methanol (50 ml) was stirred at room temperature for 69 hours and then heated to reflux for 96 hours. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution and concentrated. The residue was diluted with ethyl acetate, washed 3 times with 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (10.2 g) as a colorless oil.
1H-NMR (CDClThree) δ: 2.65 (3H, s), 3.93 (3H, s), 7.12 (1H, dd, J = 8.0, 8.0 Hz), 7.69-7.77 (2H, m).
IR (KBr): 1728, 1435, 1285, 1256, 1215, 1098, 754 cm-1.
(ii) Production of methyl 3-bromo-2- (bromomethyl) benzoate
A solution of methyl 3-bromo-2-methylbenzoate (1.00 g), N-bromosuccinimide (855 mg), 2,2'-azobis (isobutyronitrile) (71.8 mg) in carbon tetrachloride (50 ml) Heated to reflux for 8 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (eluent; hexane: ethyl acetate = 20: 1) to give the title compound (1.29 g) as a colorless oil.
1H-NMR (CDClThree) δ: 3.96 (3H, s), 5.14 (2H, s), 7.23 (1H, dd, J = 6.8, 6.8 Hz), 7.77 (1H, dd, J = 1.2, 6.8 Hz), 7.89 (1H, dd , J = 1.2, 6.8 Hz).
IR (KBr): 1725, 1435, 1291, 1264, 1223, 1115, 760 cm-1.
(iii) Production of 4-bromo-1-isoindolinone
Methyl 3-bromo-2- (bromomethyl) benzoate (1.28 g) was dissolved in 11% ammonia methanol solution-THF mixed solution (3: 2, 25 ml) and stirred at room temperature for 16 hours. The reaction mixture was concentrated, the residue was washed with saturated brine, and recrystallized from ethyl acetate-hexane to give the title compound (671 mg, 76%) as colorless needle crystals.
1H-NMR (CDClThree) δ: 4.42 (2H, s), 7.42 (1H, dd, J = 7.8, 7.8 Hz), 7.48 (1H, br s), 7.73 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz).
IR (KBr): 3167, 1728, 1684, 1667, 1470, 1462, 1107, 745 cm-1.
[0079]
(iv) Preparation of 4- [4- [1-hydroxy-2-methyl 1- (1-trityl-1H-imidazol-4-yl) -propyl] phenyl]]-1-isoindolinone
4-Bromo-1-isoindolinone (620 mg), 4- [1-hydroxy-2-methyl-1- (1-trityl-1H-imidazol-4-yl) propyl] phenylboronic acid crude product ( 2.06 g), 2 M aqueous sodium carbonate solution (2.92 ml), tetrakis (triphenylphosphine) palladium (0) (169 mg), and the title compound (1.07 g ) Was obtained as colorless needle crystals.
1H-NMR (CDClThree) δ: 0.77 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 2.42-2.49 (1H, m), 3.60 (1H, s), 4.51 (2H, s), 6.38 (1H, br s), 6.79 (1H, d, J = 1.0 Hz), 7.11-7.16 (6H, m), 7.32-7.39 (12H, m), 7.55-7.62 (4H, m), 7.85 (1H , dd, J = 2.2, 6.2 Hz).
IR (KBr): 1694, 1491, 1478, 1445, 812, 756, 702 cm-1.
(v) Preparation of 4- [4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl]]-1-isoindolinone
4- [4- [1-hydroxy-2-methyl 1- (1-trityl-1H-imidazol-4-yl) -propyl] phenyl]]-1-isoindolinone (1.02 g) 90% formic acid The THF (1: 1, 8 ml) solution was heated to reflux for 1.5 hours. After the reaction solution was concentrated, the residue was diluted with a THF-ethyl acetate mixture (1: 1), washed with saturated aqueous sodium hydrogen carbonate-saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (eluent; dichloromethane → dichloromethane: methanol = 20: 1 → 7: 1) to obtain the title compound (503 mg) as a colorless amorphous.
1H-NMR (CDClThree+ CDThreeOD) δ: 0.83 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 2.58-2.72 (1H, m), 4.46 (2H, s), 7.01 (1H, d, J = 1.2 Hz), 7.37 (2H, d, J = 8.4 Hz), 7.50-7.57 (3H, m), 7.62 (2H, d, J = 8.6 Hz), 7.84 (1H, dd, J = 2.2, 6.2 Hz).
IR (KBr): 1682, 1480, 1456, 862, 812, 756, 741 cm-1.
Example 79
Preparation of (−)-N- (6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -2-pyridyl) acetamide
N- (6- {4- [1-hydroxy-1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -2-pyridyl) acetamide obtained in Example 68 was subjected to optically active column ( Chiralpak AD) was subjected to liquid chromatography (eluent; hexane: ethanol = 9: 1), and (-)-N- (6- {4- [1-hydroxy- 1- (1H-imidazol-4-yl) -2-methylpropyl] phenyl} -2-pyridyl) acetamide was obtained.
Optical purity;> 99.9% ee (Chiralpak AD)
[α]D 20 −11.8 ° (C = 1.02, methanol)
[0080]
The total amount of the above (1), (2) and (3) and 5 mg of (4) were mixed, granulated, 5 mg of the remaining (4) was added thereto, and the whole was enclosed in a gelatin capsule.
The total amount of the above (1), (2) and (3) and 20 mg of (4) and 2.5 mg of (5) were mixed and granulated, and the remaining (4) was added to 10 mg and (5) of this granule. Of 2.5 mg was added and pressed to form tablets.
Test example 1
Rat steroid C17,20Measurement of lyase inhibitory activity
This was performed according to The Prostate, Vol. 26, 140-150 (1995).
The testis was extracted from 13-week-old male SD rats, the testis was homogenized, and microsomes were prepared by centrifugation. [1.2-final concentration of 10 nMThreeH] -17α-hydroxyprogesterone, NADPH solution, and test compound were dissolved in 10 μl of 100 mM phosphate buffer at pH 7.4, 7 μg / 10 μl of microsomal protein was added and incubated at 37 ° C. for 7 minutes. 40 μl of ethyl acetate was added and centrifuged, and the substrate and products (androstenedione and testosterone) in the supernatant were separated by silica gel thin layer chromatography (TLC). Spot detection and quantification were performed with a BAS 2000 bioimage analyzer. The amount of product required to control the amount of product by 50% relative to the control (IC) when the amount of product when no test compound is added (control) is 100%.50Value). These are shown in [Table 1].
[0081]
[Table 1]
Test example 2
Measurement of testosterone synthesis inhibitory activity in vivo in rats
Test compounds (50 mg / kg) were orally administered to 9-week-old male SD (Sprague Dawley) rats. Blood was collected 2 hours after compound administration, and the testosterone concentration in the obtained serum was measured by radioimmunoassay. The ratio (T / C,%) of the testosterone concentration in the test drug administration group to the testosterone concentration in the control group was calculated to determine the testosterone synthesis inhibitory activity.
[Table 2]
[0082]
【The invention's effect】
The compound of the present invention or a salt thereof is steroid C17,20Primary cancers of malignant tumors affected by, for example, sex steroids and their metabolites, and their metastasis, recurrence, symptoms associated with these cancers, prostate hypertrophy, males It is useful for the treatment and prevention of various diseases such as keratosis, hirsutism, male pattern baldness, male prematurity, endometriosis, uterine fibroids, mastopathy, polycystic ovary syndrome.
Claims (12)
(上記において、
第1群は
ハロゲン原子、ホルミル基、C 1-6 アルキル−カルボニル基およびニトロ基、
第2群は
(1)C 1-6 アルキル基、(2)1ないし5個のハロゲン原子で置換されたC 1-4 アルキル基、(3)1ないし2個のC 1-4 アルコキシで置換されたC 1-4 アルキル基、(4)水酸基、(5)C 1-4 アルコキシ基、(6)C 1-4 アルカノイルオキシ基、(7)カルバモイルオキシ基、(8)C 1-4 アルキル基で置換されたカルバモイルオキシ基、(9)アミノ基、(10)モノまたはジC 1-4 アルキルアミノ基、(11)C 1-4 アルカノイルアミノ基、(12)ホルミル基、(13)C 2-6 アルカノイル基、(14)C 1-4 アルキルスルホニル基、(15)カルバモイル基、(16)モノ−またはジ−C 1-10 アルキルカルバモイル基、(17)C 3-6 シクロアルキルカルバモイル基、(18)モノ−またはジ−C 6-14 アリールカルバモイル基、(19)モノ−またはジ−C 7-16 アラルキルカルバモイル基、(20)スルファモイル基、(21)モノ−またはジ−C 1-10 アルキルスルファモイル基、(22)モノ−またはジ−C 6-14 アリールスルファモイル基、(23)モノ−またはジ−C 7-16 アラルキルスルファモイル基、(24)ハロゲン原子、(25)シアノ基および(26)オキソ基、
第3群は
2−チエニル基、3−チエニル基、2−ピリジル基、3−ピリジル基、4−ピリジル基、2−フリル基、3−フリル基、2−キノリル基、4−キノリル基、8−キノリル基、3−イソキノリル基、4−イソキノリル基、ピラジニル基、2−ピリミジニル基、3−ピロリル基、1−イミダゾリル基、2−イミダゾリル基、1−ピラゾリル基、2−チアゾリル基、4−チアゾリル基、5−チアゾリル基、3−イソチアゾリル基、4−イソチアゾリル基、2−オキサゾリル基、4−オキサゾリル基、5−オキサゾリル基、3−イソオキサゾリル基、3−ピリダジニル基、1−インドリル基、1−イソインドリル基、2−イソインドリル基、1−テトラゾリル基、2−テトラゾリル基および5−テトラゾリル基、
をそれぞれ示す。)。formula:
(In the above,
The first group
A halogen atom, a formyl group, a C 1-6 alkyl-carbonyl group and a nitro group,
The second group is
(1) a C 1-6 alkyl group, (2) a C 1-4 alkyl group substituted with 1 to 5 halogen atoms, and (3) a C 1 substituted with 1 to 2 C 1-4 alkoxy. -4 alkyl groups, (4) hydroxyl groups, (5) C 1-4 alkoxy groups, (6) C 1-4 alkanoyloxy groups, (7) carbamoyloxy groups, (8) substituted with C 1-4 alkyl groups Carbamoyloxy group, (9) amino group, (10) mono- or di-C 1-4 alkylamino group, (11) C 1-4 alkanoylamino group, (12) formyl group, (13) C 2-6 alkanoyl Group (14) C 1-4 alkylsulfonyl group, (15) carbamoyl group, (16) mono- or di-C 1-10 alkylcarbamoyl group, (17) C 3-6 cycloalkylcarbamoyl group, (18) Mono- or di-C 6-14 arylcarbamoyl group, (19) mono- or Or di-C 7-16 aralkylcarbamoyl group, (20) sulfamoyl group, (21) mono- or di-C 1-10 alkylsulfamoyl group, (22) mono- or di-C 6-14 arylsulfur group. A famoyl group, (23) a mono- or di-C 7-16 aralkylsulfamoyl group, (24) a halogen atom, (25) a cyano group and (26) an oxo group,
The third group
2-thienyl group, 3-thienyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-furyl group, 3-furyl group, 2-quinolyl group, 4-quinolyl group, 8-quinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, pyrazinyl group, 2-pyrimidinyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 1-pyrazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5- Thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 3-pyridazinyl group, 1-indolyl group, 1-isoindolyl group, 2- Isoindolyl group, 1-tetrazolyl group, 2-tetrazolyl group and 5-tetrazolyl group,
Respectively. )
(上記において、
第4群は
(1)C1-6アルキル基、(2)1ないし5個のハロゲン原子で置換されたC1-4アルキル基、(3)1ないし2個のC1-4アルコキシで置換されたC1-4アルキル基、(4)C1-4アルコキシ基、(5)C1-4アルカノイルアミノ基、(6)C2-6アルカノイル基、(7)モノ−またはジ−C1-10アルキルカルバモイル基、(8)C3-6シクロアルキルカルバモイル基、(9)モノ−またはジ−C1-10アルキルスルファモイル基、(10)ハロゲン原子、(11)シアノ基および(12)オキソ基
を示す。)。 formula:
The fourth group is (1) a C 1-6 alkyl group, (2) a C 1-4 alkyl group substituted with 1 to 5 halogen atoms, and (3) substituted with 1 to 2 C 1-4 alkoxy. C 1-4 alkyl group, (4) C 1-4 alkoxy group, (5) C 1-4 alkanoylamino group, (6) C 2-6 alkanoyl group, (7) mono- or di-C 1 -10 alkylcarbamoyl group, (8) C 3-6 cycloalkylcarbamoyl group, (9) mono- or di-C 1-10 alkylsulfamoyl group, (10) halogen atom, (11) cyano group and (12 ) Represents an oxo group. ).
(上記において、
第5群は
(1)C1-4アルカノイルアミノ基、(2)C2-6アルカノイル基、(3)モノ−C1-10アルキルカルバモイル基、(4)モノ−C1-10アルキルスルファモイル基、(5)ハロゲン原子および(6)オキソ基
を示す。)。R 2 is a 5 one or two selected from a group of good-phenyl group optionally substituted with a group, a pyridyl group, a thienyl group, a compound of claim 2 wherein the full drill group or an isoindolinyl group (in the above ,
The fifth group consists of (1) C 1-4 alkanoylamino group, (2) C 2-6 alkanoyl group, (3) mono-C 1-10 alkylcarbamoyl group, and (4) mono-C 1-10 alkylsulfa group. A moyl group, (5) a halogen atom, and (6) an oxo group. ).
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