TWI503120B - 23-alkyne-vitamin D 3 derivative - Google Patents
23-alkyne-vitamin D 3 derivative Download PDFInfo
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- TWI503120B TWI503120B TW100138462A TW100138462A TWI503120B TW I503120 B TWI503120 B TW I503120B TW 100138462 A TW100138462 A TW 100138462A TW 100138462 A TW100138462 A TW 100138462A TW I503120 B TWI503120 B TW I503120B
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- yne
- triol
- broken
- vitamin
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- 150000001875 compounds Chemical class 0.000 claims description 140
- -1 phenylcarbonyloxymethyl Chemical group 0.000 claims description 40
- 150000003704 vitamin D3 derivatives Chemical class 0.000 claims description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 208000001132 Osteoporosis Diseases 0.000 claims description 9
- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 5
- 201000004384 Alopecia Diseases 0.000 claims description 5
- 201000004624 Dermatitis Diseases 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 206010000496 acne Diseases 0.000 claims description 5
- 125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 claims description 5
- 231100000360 alopecia Toxicity 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 230000002757 inflammatory effect Effects 0.000 claims description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000006251 butylcarbonyl group Chemical group 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 189
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 121
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
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- 239000000243 solution Substances 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
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- 239000012453 solvate Substances 0.000 description 14
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- 238000000034 method Methods 0.000 description 11
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000011575 calcium Substances 0.000 description 9
- 229910052791 calcium Inorganic materials 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
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- 102000009310 vitamin D receptors Human genes 0.000 description 8
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- 210000002966 serum Anatomy 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
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- 230000002103 transcriptional effect Effects 0.000 description 4
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- 101100297347 Caenorhabditis elegans pgl-3 gene Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- MUXOBHXGJLMRAB-UHFFFAOYSA-N Dimethyl succinate Chemical compound COC(=O)CCC(=O)OC MUXOBHXGJLMRAB-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101001086210 Homo sapiens Osteocalcin Proteins 0.000 description 1
- 101000641550 Homo sapiens Vitamin D3 receptor Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- JGFFTJDJHXLDNJ-UHFFFAOYSA-L [O-]OOO[O-].[K+].[K+] Chemical compound [O-]OOO[O-].[K+].[K+] JGFFTJDJHXLDNJ-UHFFFAOYSA-L 0.000 description 1
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
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- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008416 bone turnover Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- YFTMLUSIDVFTKU-UHFFFAOYSA-M bromomethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CBr)C1=CC=CC=C1 YFTMLUSIDVFTKU-UHFFFAOYSA-M 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
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- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
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- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004821 effect on bone Effects 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 102000051544 human VDR Human genes 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002350 laparotomy Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 210000004705 lumbosacral region Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- CRSOQBOWXPBRES-UHFFFAOYSA-N neopentane Chemical group CC(C)(C)C CRSOQBOWXPBRES-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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- A—HUMAN NECESSITIES
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- A61P11/06—Antiasthmatics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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Description
本發明係關於作為醫藥品而有用之維生素D3
衍生物或其醫藥上容許之溶劑合物、使用該等之治療劑、含有該等之醫藥組成物、及該等之製造中間體。更詳而言之,係關於23-炔-維生素D3
衍生物或其醫藥上容許之溶劑合物、含有該等之醫藥組成物、及以該等為有效成分之骨質疏鬆症、惡性腫瘤、乾癬症、副甲狀腺機能亢進症、發炎性呼吸器疾病、關節風濕性疾病、真性糖尿病、高血壓症、脫毛症、面皰、或皮膚炎之治療劑、以及該等的製造中間體。
活性型維生素D3
衍生物,具有調節以骨形成、骨破壊來構成之骨更新,與增加骨密度的作用。因此,係作為有用之骨質疏鬆症治療劑來使用。然而,該等之活性型維生素D3
衍生物、例如1α,25-二羥基維生素D3
,其骨密度增加量並不必然滿足需求,為了增加骨密度而增加投藥量時,比起骨密度進一步增加,反而較會引起血清鈣值的上昇,其係為臨床上不佳的基準之一,由引起1mg/dL以上之血清鈣值的上昇來看,係散見有無法得到充分骨密度增加之作用的病例(國際公開WO01/62723號小冊子)。
因此,係期望有在血清鈣值不上昇的範圍內,顯示強力的骨密度增加作用之活性型維生素D3
衍生物,雖然到現在為止為了取得如此之衍生物,已合成了大量的維生素D3
衍生物,但仍然未發現完全滿足要求的衍生物。
本發明的目的在提供異於以血中鈣濃度上昇作用為目的之藥理作用的新穎維生素D3
衍生物或其醫藥上容許之溶劑合物。
又,本發明的目的為提供含有以該等維生素D3
衍生物或其醫藥上容許之溶劑合物作為有效成分之骨質疏鬆症、惡性腫瘤、乾癬症、副甲狀腺機能亢進症、發炎性呼吸器疾病、關節風濕性疾病、真性糖尿病、高血壓症、脫毛症、面皰、或皮膚炎的治療劑。
進一步地,本發明之目的在提供含有該等維生素D3
衍生物或其醫藥上容許之溶劑合物而成的醫藥組成物。
進一步地,本發明之目的在提供適合用於製造該等維生素D3
衍生物或其醫藥上容許之溶劑合物之維生素D3
衍生物的中間體。
本發明者等以上述目的進行戮力研究的結果,達成了以下之發明。
亦即,本發明係一種以下述式(1)表示之維生素D3
衍生物或其醫藥上容許之溶劑合物。
【化1】
此處,R1
表示氫原子、碳數1~6之烷基、烷基羰基氧烷基(各烷基之碳數為1~6)、或芳基羰基氧烷基(芳基之碳數為6~10、烷基之碳數為1~6)。R2
表示氫原子或碳數1~6之烷基、或亦可與另一R2
及該等所鍵結之碳原子一起形成碳數3~6之環狀烷基。R3
表示碳數1~6之烷基,或亦可與另一R3
及該等所鍵結之碳原子一起形成碳數3~6之環狀烷基。X表示氧原子或亞甲基、n表示1或2之整數。
又,本發明為一種醫藥組成物,其係由以上述式(1)表示之維生素D3
衍生物或其醫藥上容許之溶劑合物、與製藥學上容許的載體所構成。
又,本發明為一種疾病之治療劑,其係含有以上述式(1)表示之維生素D3
衍生物或其醫藥上容許之溶劑合物作為有效成分,且該疾病為骨質疏鬆症、惡性腫瘤、乾癬症、副甲狀腺機能亢進症、發炎性呼吸器疾病、關節風濕性疾病、真性糖尿病、高血壓症、脫毛症、面皰、及皮膚炎所構成群組中選出之一者以上之疾病。
進一步地,本發明為以式(2)表示之維生素D3
衍生物的製造中間體。
【化2】
此處,R2
、X及n為與上述式(1)相同。又,R4
係表示上述式(1)中之R1
、甲氧基甲基、甲氧基乙氧基甲基、四氫呋喃基、四氫吡喃基、或苄基氧甲基。R5
表示氫氧基之保護基。
依據本發明,係提供有效於以骨質疏鬆症、惡性腫瘤、乾癬症、副甲狀腺機能亢進症、發炎性呼吸器疾病、關節風濕性疾病、真性糖尿病、高血壓症、脫毛症、面皰、皮膚炎等為代表之各種疾病的治療之新穎維生素D3
衍生物或其醫藥上容許之溶劑合物。又,本發明之以上述式(2)表示的製造中間體,係有用於製造本發明之維生素D3
衍生物等。
本發明中之用語定義係如以下所述。
所謂烷基,係指直鏈、支鏈、或環狀之脂肪族烴基。作為碳數1~6之烷基者,可列舉例如甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、戊基、異戊基、己基、環丙基、環丙基甲基、環己基作為具體的基。
作為烷基羰基氧烷基者,可列舉第三丁基羰基氧甲基作為具體的基。
作為芳基羰基氧烷基者,可列舉苯基羰基氧甲基。
上述式(1)中、R1
表示氫原子、碳數1~6之烷基、烷基羰基氧烷基(各烷基之碳數為1~6)、或芳基羰基氧烷基(芳基之碳數為6~10、烷基之碳數為1~6)。其中尤以氫原子、甲基、乙基、丙基、異丙基或第三丁基為佳、特佳為氫原子或異丙基。作為烷基羰基氧烷基者,較佳為第三丁基羰基氧甲基。再者作為芳基羰基氧烷基者,較佳為苯基羰基氧烷基。
上述式(1)中,R2
表示氫原子或碳數1~6之烷基、或亦可與另一R2
及該等所鍵結之碳原子一起形成碳數3~6之環狀烷基。其中尤其是在R2
為氫原子或甲基、或與另一R2
及該等所鍵結之碳原子形成環狀烷基的情況時,較佳為環丙基。
上述式(1)中,R3
表示碳數1~6之烷基、或亦可與另一R3
及該等所鍵結之碳原子一起形成環狀烷基。作為碳數1~6之烷基者,較佳為甲基、乙基。又,與另一R3
及該等所鍵結之碳原子一起形成環狀烷基的情況時,較佳為環戊基。
又,上述式(1)中,X表示氧原子或亞甲基。
又,上述式(1)中,n表示1或2之整數,特佳為n=1。
本發明之以式(1)表示之維生素D3
衍生物的適宜之具體例,可列舉次表所示之化合物。
【化3】
[表1]
本發明之維生素D3
衍生物,能夠依照需要轉換為其醫藥上容許之溶劑合物。作為如此之溶劑,較佳者可列舉水、甲醇、乙醇、1-丙醇、2-丙醇、丁醇、第三丁醇、乙腈、丙酮、甲乙酮、氯仿、乙酸乙酯、二乙醚、第三丁基甲醚、苯、甲苯、DMF、DMSO等。特佳者可列舉水、甲醇、乙醇、1-丙醇、2-丙醇、乙腈、丙酮、甲乙酮、乙酸乙酯。
又,上述式(2)中之R5
係表示氫氧基之保護基。作為氫氧基之保護基者,可列舉甲氧基甲基、碳數1~3之醯基(碳數係包含羰基碳)、三甲基矽烷基、三乙基矽烷基、第三丁基二甲基矽烷基、第三丁基二苯基矽烷基等。其中較佳的例子可列舉三乙基矽烷基、第三丁基二甲基矽烷基。
又,上述式(2)中之R4
係表示上述式(1)中之R1
,或表示甲氧基甲基、甲氧基乙氧基甲基、四氫呋喃基、四氫吡喃基、或苄基氧甲基。其中尤以甲基、乙基、丙基、異丙基或第三丁基、第三丁基羰基氧甲基、苯基羰基氧烷基、或苄基氧甲基較佳。
又上述式(2),n表示1或2之整數,特佳為n=1。
以上述式(1)表示的維生素D3
衍生物的合成,可以任意方法進行,例如能夠以下述流程1來進行。亦即,能夠使化合物(2)與化合物(3)偶合之後、使氫氧基之保護基脫保護、及依照需要使酯基水解,藉以得到目標物(1)。
【化4】
上述式中之化合物(1)、化合物(2)中之R1
至R5
,係與上述式(1)、上述式(2)相同。又上述式中化合物(3)之R3
,係與上述式(1)之R3
相同。又化合物(3)中之OPG,係表示被保護的氫氧基。具體而言,可列舉三甲基矽烷基、三乙基矽烷基、甲氧基甲基。
上述流程1中、R2
為氫原子的情況時,化合物(2)可由例如文獻(高山等人、Vitamin D Analog in Cancer Prevention and Therapy、Recent Results in Cancer Research、164卷、Springer出版、289-317頁、2003年等)所記載之烯炔化合物(4),依照下述流程2來合成。亦即能夠將(4)之1級氫氧基之保護基(第三丁基二甲基矽烷基;TBS基)選擇性地脫保護而得到化合物(5),將此氫氧基氧化成為羧基,接著藉由酯化,而得到目標之(2)(R2
=TBS)。
【化5】
另一方面,上述流程1中、R3
為甲基時,化合物(3)能夠由如以下流程3的方式來合成。
亦即,能夠藉由將文獻(例如、美國專利第4804502號說明書)所記載之化合物(6)溴亞甲基化而得。
【化6】
又,以上述式(1)表示之維生素D3
衍生物中,R2
為氫原子之化合物,除了上述流程1以外,亦能夠以下述流程4所示之方法來合成。亦即,將流程2中之化合物(5)以三甲基乙醯基保護,而得到化合物(7),藉由進行將之與流程1中之化合物(3)偶合、與將A環2位取代基末端之氫氧基脫保護,而得到化合物(8)。可將所得之化合物的氫氧基氧化為羧酸,最後藉由將全部的氫氧基保護基脫保護而得。
【化7】
又上述流程1中,R2
被取代時,化合物(2)中例如R2
與另一R2
及該等所鍵結之碳原子一起形成環烷基時,係與文獻(高山等人、Vitamin D Analog in Cancer Prevention and Therapy、Recent Results in Cancer Research、164卷、Springer出版、289-317頁、2003年等)所記載之烯炔化合物(4)同樣地,將市售之4,6-O-亞苄基-αD-甲基-吡喃葡萄糖苷(9)作為起始物質,予以環氧化後,在鹼條件下進行環氧化物的開環,而得到化合物(10)。以氫氧基之保護而得到化合物(11)後,進行亞苄基環之開環、進一步進行葡萄糖1位的還原,而得到化合物(12)。接著,由二醇形成環氧化物而得到化合物(13),藉由環氧化物與乙炔的反應而得到經導入3鍵部位之化合物(14)。藉由進行氫氧基之適切的保護,可取得化合物(15)。藉由使化合物(15)與上述式流程1記載之CD環中間體(3)偶合與選擇性地脫保護,而得到化合物(16),進一步地氧化1級氫氧基而成為羧酸後,藉由脫保護,能夠取得目標之化合物(1)。
【化8】
含有本發明之維生素D3
衍生物或其醫藥上容許之溶劑合物作為有效成分之骨質疏鬆症等的治療劑,通常係使用製劑化中所用的載體或賦形劑、其他添加劑來調製。製劑用之載體或賦形劑可為固體或液體,可列舉例如乳糖、硬脂酸鎂、澱粉、滑石、明膠、寒天、果膠、阿拉伯膠、橄欖油、芝麻油、可可脂、乙二醇等或其他常用者。投藥可為錠劑、丸劑、膠囊劑、顆粒劑、散劑、液劑等口服;或靜脈注射、肌肉注射等注射劑;栓劑、經皮等非口服之任意形態。
本發明之治療劑中之有效成分的治療有效量,係隨著投藥經路、患者年齡、性別、疾病之程度而不同,但通常為0.01~10μg/天左右,投藥次數通常為1~3次/天至1~3次/週,較佳為將製劑調製為滿足如此條件。
以下,藉由實施例以進一步詳細地說明本發明,但本發明並不受此限定。又,本發明之縮寫符號係如以下所示。
TBS=第三丁基二甲基矽烷基
TES=三乙基矽烷基
TESC1=氯三乙基矽烷
TMS=三甲基矽烷基
TMSC1=氯三甲基矽烷
Piv=三甲基乙醯基
PivC1=三甲基乙醯基氯化物
TBAF=氟化四丁基銨
CSA=(+/-)-樟腦-10-磺酸
PDC=重鉻酸吡啶鎓鹽
TBSOTf=三氟甲磺酸第三丁基二甲基矽烷酯
DIBAL=氫化二丁基鋁
DMF=N,N-二甲基甲醯胺
THF=四氫呋喃
TsCl=p-甲苯磺醯基氯化物
Ts=p-甲苯磺醯基
【化9】
(1)將文獻(例如、Kittaka等人、J.Org.Chem.、2004年、69卷、7463-7471頁)已知之化合物A-1(2.29 g,4.11 mmol)溶解於乙醇(20 mL),於冰浴之下添加(+/-)-樟腦-10-磺酸(954 mg,4.11 mmol),在0℃攪拌1小時。添加飽和碳酸氫鈉水溶液以停止反應,以乙酸乙酯稀釋反應液。將其以水、飽和食鹽水洗淨,以無水硫酸鈉乾燥。將減壓濃縮而得之殘渣以二氧化矽凝膠管柱層析法(正己烷/乙酸乙酯=9/1)精製而得到化合物A-2(1.64 g,產率90%)。
1
H-NMR(CDCl3
)δ:5.96-5.88(1H,m),5.27-5.21(2H,m),4.29(1H,dd,J=6.8,3.9 Hz),3.88-3.72(5H,m),3.45(1H,dd,J=5.4,4.1 Hz),3.00(1H,t,J=6.0 Hz),2.50-2.46(1H,m),2.38-2.33(1H,m),2.01(1H,t,J=2.6 Hz),1.85-1.68(2H,m),0.91(9H,s),0.91(9H,s),0.10(9H,s),0.07(3H,s).
(2)將(1)中得到之化合物A-2(1.0 g,2.26 mmol)溶解於吡啶(10 mL),在0℃添加三甲基乙醯基氯化物(0.69 mL,5.65 mmol)後,在室溫攪拌。添加無水甲醇(3 mL),在室溫進一步攪拌30分鐘攪拌。添加甲苯以減壓濃縮。於所得之殘渣中添加乙酸乙酯,以飽和食鹽水洗淨,將有機層以無水硫酸鎂乾燥。將減壓濃縮而得之殘渣以二氧化矽凝膠管柱層析法(正己烷/乙酸乙酯=9/1)精製而得到化合物A-3(1.072 g,產率90%)。
1
H-NMR(CDCl3
)δ:5.95(1H,ddd,J=17.0,11.0,6.0 Hz),5.21(1H,ddd,J=17,2.0,1.0 Hz),5.14(1H,ddd,J=11.0,2.0,1.0 Hz),4.32-4.28(1H,m),4.18-4.10(2H,m),3.86(1H,q,J=5.6 Hz),3.81-3.74(1H,m),3.68-3.60(1H,m),3.39(1H,dd,J=5.4,3.4 Hz),2.49(1H,dq,J=17.0,2.7 Hz),2.35(1H,dq,J=16.9,2.8 Hz),1.96(1H,t,J=2.7 Hz),1.87(2H,dt,J=14.0,7.0 Hz),1.19(9H,s),0.90(9H,s),0.89(9H,s),0.10(3H,s),0.08(3H,s),0.07(5H,s),0.03(3H,s).
(3)將(溴甲基)三苯基溴化鏻(1.25 g,2.87 mmol)溶解於四氫呋喃(7 mL),在氮氣環境下冷卻至0℃。於此,添加鈉雙(三甲基矽烷基)醯胺(1.0 M四氫呋喃溶液,2.90 mL,2.87 mmol),在冰浴下攪拌30分鐘。將反應液冷卻至-78℃,將文獻(例如、Uskokovic等人、美國專利第4804502號說明書)已知之化合物B-1(200 mg,0.574 mmol)溶解於四氫呋喃(1.5 mL)而添加。於-78℃攪拌1小時後,在0℃進一步攪拌1小時。於反應液中添加二氧化矽凝膠(2.5 g),在室溫激烈攪拌10分鐘後,以矽藻土過濾。將所得之濾液減壓濃縮,將殘渣以二氧化矽凝膠管柱層析法(正己烷/乙酸乙酯=9/1)精製而得到化合物B-2(161 mg,產率67%)。
1
H-NMR(CDCl3
)δ:5.65(1H,s),2.90-2.86(1H,m),2.28-1.24(20H,m),1.08(3H,d,J=6.3 Hz),0.58(3H,s),0.18(9H,s).
(4)將(3)中所得之化合物B-2(1.2 g,2.82 mmol)溶解於四氫呋喃(10 mL),添加氟化四丁基銨(1 M四氫呋喃溶液,4.23 mL,4.23 mmol),於50℃攪拌30分鐘。添加乙酸乙酯、以水洗淨,將有機層以無水硫酸鎂乾燥。將減壓濃縮而得之殘渣,以二氧化矽凝膠層析法(正己烷/乙酸乙酯=19/1)精製。將精製物溶解於無水吡啶(10 mL),於氮氣環境下,冷卻至0℃。於此添加氯三乙基矽烷(0.944 mL,5.70 mmol),昇溫至室溫,攪拌2.5小時。將反應液冷卻至0℃,添加飽和氯化銨水溶液、水,以甲苯萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鎂乾燥。將減壓濃縮而得之殘渣,以二氧化矽凝膠層析法(正己烷/乙酸乙酯=99/1)精製,而得到化合物B-3(783 mg,產率88%)。
1
H-NMR(CDCl3
)δ:5.65(1H,s),2.92-2.85(1H,m),2.23(1H,dd,J=16.5,3.4 Hz),2.07-
1.24(19H,m),1.08(3H,d,J=6.6 Hz),0.96(9H,t,J=7.9 Hz),0.66(6H,q,J=7.9 Hz),0.57(3H,s).
(5)將(4)中所得之化合物B-3(783 mg,1.67 mmol)及(2)中所得之化合物A-3(733 mg,1.39 mmol)溶解於無水甲苯/三乙基胺(1/1,11.1 mL),添加肆三苯基膦化鈀(289 mg,0.25 mmol),在氮氣環境下、於105℃攪拌2小時。冷卻至室溫後,添加二胺二氧化矽凝膠(富士SILYSIA公司製,6 g)、正己烷(20 mL),於室溫攪拌1小時後,使用乙酸乙酯過濾。將所得到之濾液減壓濃縮,將殘渣以二氧化矽凝膠層析法(正己烷/乙酸乙酯=100/0→95/5)精製。將所得到之精製物溶解於無水四氫呋喃(5.5 mL)、無水甲醇(4.6 mL),添加甲氧化鈉、甲醇溶液(0.91 mL,5.46 mmol),回流1小時。添加飽和氯化銨水溶液以減壓濃縮。於所得到之殘渣中添加乙酸乙酯,以飽和食鹽水洗淨,將有機層以無水硫酸鎂乾燥。將減壓濃縮而得之殘渣,以二氧化矽凝膠層析法(正己烷/乙酸乙酯=100/0→50/50)精製,而得到化合物AB-1(609 mg,產率67%)。
1
H-NMR(CDCl3
)δ:6.18(1H,d,J=11.2 Hz),6.02(1H,d,J=11.2 Hz),5.30(1H,brs),5.00(1H,brs),4.46(1H,brs),4.05(1H,m),3.88-3.69(4H,m),3.36(1H,brs),2.94(1H,brs),2.83-2.77(1H,m),2.62-2.56(1H,m),2.24(1H,dd,J=16.5,3.4 Hz),2.10(1H,dd,J=13.9,4.4 Hz),2.06-1.21(21H,m),1.07(3H,d,J=6.6 Hz),0.96(9H,t,J=7.9 Hz),0.93(9H,s),0.87(9H,s),0.67(6H,q,J=7.9 Hz),0.55(3H,s),0.10(3H,s),0.10(3H,s),0.08(3H,s),0.07(3H,s).
(6)將(5)中所得之化合物AB-1(427 mg,0.514 mmol)溶解於無水二氯甲烷(5.2 mL),冷卻至0℃後,添加Dess-Martin試藥(523 mg,1.23 mmol),於冰浴下攪拌2小時之後,昇溫至室溫攪拌1小時。添加飽和硫代硫酸鈉水溶液、飽和碳酸氫鈉水溶液,以二氯甲烷萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥且減壓濃縮。將所得到之殘渣溶解於第三丁醇(21 mL)中,添加四氫呋喃(37 mL)與2-甲基-2-丁烯(6.47 mL)且冰浴。添加次氯酸鈉(純度80%,580 mg,5.14 mmol)與磷酸2氫鈉‧2水和物(400 mg,2.57 mmol)之水溶液(7.3 mL),在冰浴下攪拌45分鐘。添加飽和硫代硫酸鈉水溶液、飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。將減壓濃縮而得之殘渣,以二氧化矽凝膠層析法(正己烷/乙酸乙酯=100/0→80/20)精製,而得到化合物AB-2(341 mg,產率78%)。
1
H-NMR(CDCl3
)δ:6.22(1H,d,J=11.2 Hz),6.00(1H,d,J=11.2 Hz),5.27(1H,brs),4.99(1H,brs),4.45(1H,brs),4.07(1H,m),3.91(2H,t,J=6.1 Hz),3.36(1H,brs),2.84-2.77(1H,m),2.64(2H,d,J=6.1,1.5 Hz),2.60-2.53(1H,m),2.24(1H,dd,J=16.5,3.4 Hz),2.13(1H,dd,J=13.9,5.4 Hz),2.07-1.21(19H,m),1.07(3H,d,J=6.3 Hz),0.96(9H,t,J=7.9 Hz),0.90(9H,s),0.87(9H,s),0.67(6H,q,J=7.9 Hz),0.55(3H,s),0.09(3H,s),0.09(6H,s),0.07(3H,s).
(7)將(6)中所得到之化合物AB-2(140 mg,0.165 mmol)溶解於丙酮(1.65 mL),冷卻至0℃後,添加鹽酸(6當量、0.332 mL)之丙酮稀釋液(1.65 mL),在室溫攪拌4小時。添加正己烷(3.3 mL),以二氧化矽凝膠層析法(正己烷/丙酮=1/1)、薄層二氧化矽凝膠層析法(正己烷/丙酮=4/5)粗精製,進一步以逆相HPLC(A=0.1%甲酸/1%甲醇/4%乙腈/水;B=0.1%甲酸/5%水/19%甲醇/乙腈;0-2min.:B=20%,2-20min.:B=20%→98%,20-25min.:B=98%,25-30min.:B=20%)精製,藉以得到化合物C-1(34.9 mg,產率42%)。
1
H-NMR(CDCl3
)δ:6.42(1H,d,J=11.2 Hz),6.00(1H,d,J=11.2 Hz),5.39(1H,d,J=1.9 Hz),5.09(1H,d,J=1.9 Hz),4.50(1H,d,J=2.9 Hz),4.36-3.58(6H,m),3.35(1H,dd,J=8.1,3.2 Hz),2.86-2.79(1H,m),2.72-2.57(3H,m),2.29-2.19(2H,m),2.04-1.20(19H,m),1.06(3H,d,J=6.6 Hz),0.54(3H,s).
【化10】
(1)將實施例1(1)中得到之化合物A-2(1.45 g,3.27 mmol)溶解於無水二甲基甲醯胺(15 mL),添加重鉻酸吡啶鎓鹽(6.17 g,16.4 mmol),攪拌12小時。添加水,以二乙醚萃取,將所得之有機層以無水硫酸鎂乾燥。將減壓濃縮而得到之殘渣以二氧化矽凝膠管柱層析法(20%乙酸乙酯/正己烷)精製而得到化合物A-4(0.82 g,產率55%)。
1
H-NMR(CDCl3
)δ:5.90(1H,ddd,J=17.0,6.0,11.0 Hz),5.30-5.20(2H,m),4.33(1H,ddt,J=7.0,3.0,1.0 Hz),3.96(2H,td,J=6.0,1.2 Hz),3.85-3.75(1H,m),3.55(1H,dd,J=6.3,3.7 Hz),2.63(2H,td,J=5.9,1.9 Hz),2.50-2.32(2H,m),2.02(1H,t,J=2.7 Hz),0.91(9H,s),0.90(9H,s),0.11(3H,s),0.10(3H,s),0.09(3H,s),0.08(3H,s).
(2)將(1)中得到之化合物A-4(0.82 g,1.79 mmol)溶解於無水甲醇(8 mL),添加濃硫酸(74 μL,1.5 mmol),攪拌2.5小時。冷卻至室溫後,添加飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將所得到之有機層以無水硫酸鈉乾燥。將減壓濃縮後的殘渣溶解於無水二氯甲烷,在冰浴下添加2,6-二甲基砒啶(1.01 mL,9 mmol)、三氟甲磺酸第三丁基二甲基矽烷酯(1.65 mL,7.2 mmol)後,在室溫攪拌1小時。添加無水甲醇(1.5 mL),在室溫進一步攪拌10分鐘。添加正己烷/乙酸乙酯(9/1),以水洗淨,將所得到之有機層以無水硫酸鈉乾燥。將減壓濃縮後的殘渣以二氧化矽凝膠管柱層析法(3%乙酸乙酯/正己烷)精製,而得到化合物A-5(683.4 mg,產率81%)。
1
H-NMR(CDCl3
)δ:5.94(1H,ddd,J=10.0,17.2,6.5 Hz),5.21(1H,dt,J=17.3,1.3 Hz),5.14(1H,dt,J=10.0,1.3 Hz),4.30(1H,dd,J=6.8,3.4 Hz),4.00-3.97(1H,m),3.88-3.82(2H,m),3.68(3H,s),3.40(1H,dd,J=5.5,3.5 Hz),2.57(2H,t,J=6.6 Hz),2.48(1H,dq,J=16.8,2.7 Hz),2.35(1H,dq,J=17.0,2.8 Hz),1.96(1H,t,J=2.6 Hz),0.90(9H,s),0.89(9H,s),0.09(3H,s),0.08(3H,s),0.07(3H,s),0.03(3H,s).
(3)將(2)中得到之化合物A-5(47.0 mg,0.1 mmol)及實施例1(3)中得到之化合物B-2(46.2 mg,0.11 mmol)溶解於甲苯/三乙基胺(1/1,2 mL),添加肆三苯基膦化鈀(12.5 mg,0.0108 mmol),在氮氣環境下、於110℃攪拌3小時。冷卻至室溫後,減壓濃縮。將殘渣以薄層二氧化矽凝膠層析法(正己烷/乙酸乙酯=19/1)粗精製。將所得到之粗精製物溶解於無水二氯甲烷/乙腈(1/1,1 mL),在氮氣環境下、於0℃添加四氟硼酸鋰(78 mg,0.8 mmol)、硫酸(1M乙腈溶液,0.08 mL,0.08 mmol),攪拌30分鐘。添加飽和碳酸氫鈉水溶液,將以乙酸乙酯萃取其而得之有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。將減壓濃縮而得之殘渣,以薄層二氧化矽凝膠層析法(正己烷/乙酸乙酯=1/2)粗精製,進一步以逆相HPLC(A=95%水/乙腈;B=0.5%水/40%甲醇/乙腈;B=75%)精製,藉以得到化合物C-2(6.8 mg,13%)。
1
H-NMR(CDCl3
)δ:6.42(1H,d,J=11.2 Hz),6.03(1H,d,J=11.2 Hz),5.40(1H,d,J=1.2 Hz),5.09(1H,d,J=2.2 Hz),4.45(1H,t,J=3.3 Hz),4.06-3.79(3H,m),3.73(3H,s),3.36(1H,dd,J=7.7,3.3 Hz),2.85-2.60(7H,m),2.24(2H,dt,J=18.8,5.9 Hz),2.02-1.96(3H,m),1.89-1.82(2H,m),1.72-1.54(6H,m),1.51(6H,s),1.47-1.24(4H,m),1.06(3H,d,J=6.3 Hz),0.54(3H,s).
MS m/z 537.2(M+23)+523.3(M+18)+
【化11】
(1)以實施例2(1)中得到之化合物A-4(240 mg,0.525 mmol)為原料,且以與實施例2(2)相同之方法將甲醇替換為丙醇來進行,而得到化合物A-6(18.5 mg,產率27%)。
(2)以(1)中得到之化合物A-6(40.5 mg,0.081mmol)與實施例1(3)中得到之化合物B-2(47 mg,0.11mmol)為原料,藉由與實施例2(3)相同之方法,得到化合物C-4(6.8 mg,15%)。
1H-NMR(CDCl3)δ:6.42(1H,d,J=11.2 Hz),6.03(1H,d,J=11.2 Hz),5.39(1H,d,J=1.2 Hz),5.09(1H,d,J=2.2 Hz),4.45(1H,t,J=3.5 Hz),4.08(2H,t,J=6.7 Hz),4.06-3.95(2H,m),3.85-3.77(1H,m),3.36(1H,dd,J=7.8,3.2 Hz),2.85-2.82(1H,m),2.79(1H,d,J=4.1 Hz),2.70-2.62(4H,m),2.26-2.22(2H,m),2.03-1.98(3H,m),1.90-1.80(3H,m),1.70-1.64(7H,m),1.58-1.53(4H,m),1.51(6H,s),1.48-1.45(2H,m),1.40-1.20(4H,m),1.06(3H,d,J=6.6 Hz),0.94(4H,t,J=7.4 Hz),0.54(3H,s).
【化12】
(1)以實施例2(1)中所得到之化合物A-4(240 mg,0.525 mmol)為原料,且以與實施例2(2)相同之方法將甲醇替換為異丙醇來進行,而得到化合物A-7(157.4 mg,產率60%)。
(2)以(1)中所得到之化合物A-7(35 mg,0.07mmol)與實施例1(3)中所得到之化合物B-2(44 mg,0.11mmol)為原料,藉由與實施例2(3)相同之方法,得到化合物C-5(6.8 mg,17%)。
1H-NMR(CDCl3)δ:6.42(1H,d,J=11.0 Hz),6.03(1H,d,J=11.5 Hz),5.39(1H,d,J=1.5 Hz),5.09-5.02(2H,m),4.45(1H,t,J=3.5 Hz),4.05-3.78(3H,m),3.35(1H,dd,J=7.7,3.3 Hz),2.85-2.58(6H,m),2.28-1.53(18H,m),1.51(6H,s),1.46-1.30(5H,m),1.26(3H,d,J=1.7 Hz),1.24(3H,d,J=1.5 Hz),1.06(3H,d,J=6.3 Hz),0.54(3H,s).
【化13】
(1)將從文獻(例如、Saito等人、四面體(Tetrahedron)、2004年、60卷、7951-7961頁))已知之化合物(3R,4R,5S)-3,5-Bis[(t-butyldimethylsilyl)oxy]-4-[3-{(t-butyldimethylsilyl)oxy}propyl]oct-1-ene-7-yne藉由與實施例1(1)相同之方法所得到之化合物A-8(0.72 g,1.69 mmol)溶解於二氯甲烷(6.8 mL),在0℃添加三乙基胺(0.47 mL,3.37 mmol)、鹽酸三甲基胺(16 mg,0.169 mmol)、p-甲苯磺醯基氯化物(0.48 g,2.53 mmol),在室溫攪拌1小時。添加飽和碳酸氫鈉水溶液,以乙酸乙酯萃取,將有機層以無水硫酸鎂乾燥。將減壓濃縮而得到之殘渣溶解於二甲基甲醯胺(3 mL),添加氰化鈉(199 mg,4.06 mmol)、碘化鈉(380 mg,2.53 mmol),於50℃攪拌2小時。添加水,以乙酸乙酯萃取,將有機層以飽和食鹽水洗淨,以無水硫酸鎂乾燥,減壓濃縮而得到粗產物之化合物A-9。將其溶解於四氫呋喃(5 mL),添加氟化四丁基銨(1M四氫呋喃溶液,5.07 mL,5.07 mmol),於60℃攪拌1小時。添加乙酸乙酯,以水洗淨,將有機層以無水硫酸鎂乾燥。將減壓濃縮而得到之殘渣溶解於二甲基甲醯胺(5 mL),在0℃添加咪唑(460 mg,6.76 mmol)、二甲基胺吡啶(21 mg,0.169 mmol)、氯三乙基矽烷(0.851 mL,5.07 mmol)在50℃攪拌40分鐘。添加飽和碳酸氫鈉水溶液、以乙酸乙酯萃取、將有機層以無水硫酸鎂乾燥。將減壓濃縮而得到之殘渣以二氧化矽凝膠管柱層析法(1%乙酸乙酯/正己烷→2%乙酸乙酯/正己烷→5%乙酸乙酯/正己烷→10%乙酸乙酯/正己烷)精製,而得到化合物A-10(531.3 mg,產率72%)。
1
H-NMR(CDCl3
)δ:5.82(1H,ddd,J=17.0,10.0,7.0 Hz),5.17(1H,dd,J=17.2,1.1 Hz),5.11(1H,ddd,J=10.0,2.0,1.0 Hz),4.00-3.95(1H,m),2.42-2.37(2H,m),2.32(2H,t,J=7.8 Hz),1.97(1H,t,J=2.6 Hz),1.85-1.65(3H,m),1.43-1.29(2H,m),1.26(2H,t,J=7.2 Hz),0.89(19H,s),0.09(3H,s),0.06(3H,s),0.06(3H,s),0.03(3H,s).
(2)將(1)中所得到之化合物A-10(449.4 mg,1.03 mmol)溶解於二氯甲烷(5 mL),在-78℃冷卻下,添加氫化二異丁基鋁(1M甲苯溶液,2.08 mL,2.08 mmol)並於-78度攪拌50分鐘。添加無水甲醇(0.3 mL)且在室溫攪拌20分鐘,進一步添加飽和酒石酸鈉鉀水溶液,攪拌10分鐘。添加乙酸乙酯,以飽和食鹽水洗淨,將有機層以無水硫酸鎂乾燥。將減壓濃縮而得到之殘渣溶解於四氫呋喃(6.9 mL),添加第三丁醇(6.9 mL)與2-甲基-2丁烯(4.5 g)且冰浴。添加次氯酸鈉(931 mg,10.3 mmol)與磷酸2氫鈉(803 mg,5.15 mmol)之水溶液(6.9 mL),攪拌1小時。添加飽和硫代硫酸鈉水溶液,進一步添加飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。將減壓濃縮而得之殘渣,以二氧化矽凝膠層析法(正己烷/乙酸乙酯=100/1→50/1→20/1→10/1→5/1→2/1)精製,而得到化合物A-11(220 mg,47%)。
1
H-NMR(CDCl3
)δ:5.82(1H,ddd,J=17.0,10.0,7.0 Hz),5.17(1H,dd,J=17.2,1.1 Hz),5.11(1H,ddd,J=10.0,2.0,1.0 Hz),4.00-3.95(1H,m),2.42-2.37(2H,m),2.32(2H,t,J=7.8 Hz),1.97(1H,t,J=2.6 Hz),1.85-1.65(3H,m),1.43-1.29(2H,m),1.26(2H,t,J=7.2 Hz),0.89(19H,s),0.09(3H,s),0.06(3H,s),0.06(3H,s),0.03(3H,s).
(3)將(2)中所得到之化合物A-11(126.6 mg,0.278 mmol)溶解於二甲基甲醯胺(1.2 mL),於0℃冷卻下,添加三乙基胺(0.126 mL,0.9 mmol)並攪拌40分鐘。添加飽和碳酸氫鈉水溶液,以乙酸乙酯萃取,將有機層以無水硫酸鎂乾燥。將減壓濃縮而得之殘渣,以二氧化矽凝膠層析法(正己烷/乙酸乙酯=95/5)精製,而得到化合物A-12(126.5 mg,79%)。
1
H-NMR(CDCl3
)δ:5.82(1H,ddd,J=17.0,10.0,7.0 Hz),5.17(1H,dd,J=17.2,1.1 Hz),5.11(1H,ddd,J=10.0,2.0,1.0 Hz),4.00-3.95(1H,m),2.42-2.37(2H,m),2.32(2H,t,J=7.8 Hz),1.97(1H,t,J=2.6 Hz),1.85-1.65(3H,m),1.43-1.29(2H,m),1.26(2H,t,J=7.2 Hz),0.89(19H,s),0.09(3H,s),0.06(3H,s),0.06(3H,s),0.03(3H,s).
(4)將(3)中所得到之化合物A-12(46 mg,0.08 mmol)及實施例1(3)中所得到之化合物B-2(47 mg,0.1 mmol)溶解於甲苯/三乙基胺(1/1,2 mL),添加肆三苯基膦化鈀(12 mg,0.01 mmol),在氮氣環境下、於110℃攪拌3小時。冷卻至室溫後,減壓濃縮。將殘渣以薄層二氧化矽凝膠層析法(正己烷/乙酸乙酯=19/1)粗精製。將所得到之粗精製物溶解於丙酮,添加鹽酸(6N,0.1 mL,0.6 mmol)且於0℃攪拌50分鐘,進一步添加鹽酸(6N,0.2 mL,1.2 mmol)且在室溫攪拌40分鐘。添加飽和碳酸氫鈉水溶液以乙酸乙酯萃取,將有機層以無水硫酸鎂乾燥。將減壓濃縮而得到之殘渣以Bond Elut SI(Varian製正己烷/乙酸乙酯=1/2→乙酸乙酯→乙酸乙酯/乙酸=99/1)粗精製。進一步將粗精製物以逆相HPLC(A=95%水/乙腈;B=0.5%乙酸/5%水/乙腈;B=65%)精製,藉以得到化合物D-1(14.6 mg,36%)。
1
H-NMR(CDCl3
)δ:6.40(1H,d,J=11.5 Hz),6.00(1H,d,J=11.2 Hz),5.27(1H,d,J=1.5 Hz),4.99(1H,d,J=2.0 Hz),4.39(1H,t,J=4.0 Hz),3.92-3.84(1H,m),2.86-2.79(1H,m),2.65(1H,dd,J=13.3,4.3 Hz),2.30-2.20(4H,m),2.05-1.96(3H,m),1.88(2H,t,J=10.0 Hz),1.81-1.64(8H,m),1.56(6H,dt,J=15.3,4.5 Hz),1.51(6H,s),1.49-1.46(3H,m),1.45(9H,s),1.40-1.24(5H,m),1.06(3H,d,J=6.6 Hz),0.54(3H,s),0.54(3H,s).
【化14】
(1)將實施例5(1)中得到之化合物A-9(565 mg,1.29 mmol)溶解於二氯甲烷,在-78℃冷卻下,添加氫化二異丁基鋁(1M甲苯溶液,2 mL,2 mmol)且於-78度攪拌2小時。添加無水甲醇(1 mL)在室溫攪拌20分鐘,進一步添加飽和酒石酸鈉鉀水溶液,攪拌10分鐘。添加乙酸乙酯,以飽和食鹽水洗淨,將有機層以無水硫酸鎂乾燥。將減壓濃縮而得到之殘渣溶解於四氫呋喃(18.3 mL),添加第三丁醇(18.3 mL)與2-甲基-2丁烯(6 mL)且冰浴。添加次氯酸鈉(1.47 g,13 mmol)與磷酸2氫鈉(1.01 g,6.5 mmol)之水溶液(5 mL),攪拌1小時。添加飽和硫代硫酸鈉水溶液,進一步添加飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。將減壓濃縮而得之殘渣,以二氧化矽凝膠層析法(正己烷/乙酸乙酯=9/1→7/1→5/1)精製,而得到化合物A-13(233.7 mg,38%)。
1
H-NMR(CDCl3
)δ:5.82(1H,ddd,J=17.0,10.0,7.0 Hz),5.17(1H,dd,J=17.2,1.1 Hz),5.11(1H,ddd,J=10.0,2.0,1.0 Hz),4.00-3.95(1H,m),2.42-2.37(2H,m),2.32(2H,t,J=7.8 Hz),1.97(1H,t,J=2.6 Hz),1.85-1.65(3H,m),1.43-1.29(2H,m),1.26(2H,t,J=7.2 Hz),0.89(19H,s),0.09(3H,s),0.06(3H,s),0.06(3H,s),0.03(3H,s).
(2)於(1)中所得到之化合物A-13(228.4 mg,0.5mmol)添加甲苯(5 mL),且添加N,N-二甲基甲醯胺二第三丁基縮醛(1.1 mL,4 mmol),於80℃攪拌1小時。添加乙酸乙酯,以飽和食鹽水洗淨,將有機層以硫酸鎂乾燥。將減壓濃縮而得之殘渣以二氧化矽凝膠層析法(3%乙酸乙酯/正己烷)精製,而得到化合物A-14(118.5 mg,46%)。
1
H-NMR(CDCl3
)δ:5.83(1H,ddd,J=17.0,10.0,7.0 Hz),5.15(1H,dq,J=17.2,1.0 Hz),5.10(1H,dq,J=10.0,1.0 Hz),4.12(1H,dd,J=8.0,5.0 Hz),4.00(1H,td,J=6.2,3.8 Hz),2.39(2H,dd,J=6.1,2.7 Hz),2.17(2H,t,J=8.0 Hz),1.79-1.63(3H,m),1.44(9H,s),1.40-1.20(4H,m),0.89(18H,s),0.09(3H,s),0.06(3H,s),0.05(3H,s),0.03(3H,s).
(3)將(2)中所得到之化合物A-14(59.6 mg,0.12 mmol)及實施例1(3)中所得到之化合物B-2(60 mg,0.14 mmol)溶解於甲苯/三乙基胺(1/1,2 mL),添加肆三苯基膦化鈀(17 mg,0.0147 mmol),在氮氣環境下、於110℃攪拌3.5小時。冷卻至室溫後,減壓濃縮。將殘渣以薄層二氧化矽凝膠層析法(正己烷/乙酸乙酯=19/1)粗精製。將所得之粗精製物溶解於四氫呋喃,添加氟化四丁基銨(1M四氫呋喃溶液,0.84 mL,0.84 mmol),在60℃攪拌2小時。添加乙酸乙酯,以水洗淨,將有機層以無水硫酸鎂乾燥。將減壓濃縮而得之殘渣,以薄層二氧化矽凝膠層析法(正己烷/乙酸乙酯=1/1)粗精製,進一步以逆相HPLC(A=95%水/乙腈;B=0.5%水/40%甲醇/乙腈;B=85%)精製,藉以得到化合物D-6(5.0 mg,7%)。
1
H-NMR(CDCl3
)δ:6.40(1H,d,J=11.5 Hz),6.00(1H,d,J=11.2 Hz),5.27(1H,d,J=1.5 Hz),4.99(1H,d,J=2.0 Hz),4.39(1H,t,J=4.0 Hz),3.92-3.84(1H,m),2.86-2.79(1H,m),2.65(1H,dd,J=13.3,4.3 Hz),2.30-2.20(4H,m),2.05-1.96(3H,m),1.88(2H,t,J=10.0 Hz),1.81-1.64(8H,m),1.56(6H,dt,J=15.3,4.5 Hz),1.51(6H,s),1.49-1.46(3H,m),1.45(9H,s),1.40-1.24(5H,m),1.06(3H,d,J=6.6 Hz),0.54(3H,s),0.54(3H,s).
【化15】
(1)將實施例2(1)中所得到之化合物A-4(164.3 mg,0.360 mmol)溶解於無水N,N-二甲基甲醯胺(1.2 mL),冷卻至0℃,添加三乙基胺(0.15 mL,1.08 mmol)、三甲基乙醯基氧甲基氯化物(0.104 mL,0.719 mmol),在室溫攪拌1小時。1小時後,添加碘化鈉(150 mg,1.008 mmol)、碳酸鉀(140 mg,1.008 mmol),於50℃進一步加熱攪拌30分鐘。冷卻至室溫,以水稀釋後,以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鎂乾燥後,減壓濃縮。將所得到之殘渣以二氧化矽凝膠管柱層析法(正己烷/乙酸乙酯=5/1)精製,而得到化合物A-15(158.0 mg,產率77%)。
1
H-NMR(CDCl3
)δ:5.98-5.90(1H,m),5.76(2H,s),5.21(1H,dt,J=17.32,1.46 Hz),5.14(1H,dt,J=10.37,1.10 Hz),4.30(1H,dd,J=8.00,3.00 Hz),4.02-3.82(3H,m),3.42(1H,dd,J=5.61,3.41 Hz),2.62(2H,t,J=6.71 Hz),2.47(1H,ddd,J=16.83,2.68,5.50 Hz),2.34(1H,ddd,J=16.83,2.76,5.50 Hz),1.96(1H,t,J=2.68 Hz),1.21(9H,s),0.90(9H,s),0.89(9H,s),0.09(3H,s),0.08(3H,s),0.07(3H,s),0.03(3H,s).
(2)以(1)中所得到之化合物A-15(40 mg,0.07mmol)與實施例1(3)中所得到之化合物B-2(36 mg,0.085mmol)為原料,藉由與實施例2(3)相同之方法,而得到化合物C-7(7.8 mg,18%)。
1
H-NMR(CDCl3
)δ:6.42(1H,d,J=11.47 Hz),6.02(1H,d,J=11.22 Hz),5.81-5.76(2H,m),5.39(1H,d,J=1.46 Hz),5.09(1H,d,J=2.20 Hz),4.44(1H,s),4.04-3.95(2H,m),3.85-3.80(1H,m),3.36(1H,dd,J=7.56,3.17 Hz),2.85-2.57(6H,m),2.28-1.81(8H,m),1.59-1.24(16H,m),1.23(9H,s),1.06(3H,d,J=6.59 Hz),0.54(3H,s).
【化16】
以實施例2(1)中所得到之化合物A-4(175 mg,0.383 mmol)為原料,將實施例7(1)中之三甲基乙醯基氧甲基氯化物替換為苯甲醯基氧甲基氯化物,以與實施例7(1)相同的方式進行而得到化合物A-16之後,以化合物A-16(41.3 mg,0.07 mmol)與實施例1(3)中所得到之化合物B-2(34 mg,0.08 mmol)作為起始物質,以與實施例7(2)相同的方式,而得到化合物C-8(4.9 mg,11%)。
1
H-NMR(CDCl3
)δ:8.09-8.07(2H,m),7.62-7.44(3H,m),6.41(1H,d,J=10.98 Hz),6.05-6.01(3H,m),5.38(1H,d,J=1.46 Hz),5.07(1H,d,J=1.95 Hz),4.44(1H,d,J=2.93 Hz),4.05-3.97(2H,m),3.87-3.82(1H,m),3.36(1H,dd,J=7.56,3.17 Hz),2.85-2.64(4H,m),2.32-2.18(2H,m),2.05-1.53(9H,m),1.49-1.24(4H,m),1.06(3H,d,J=6.34 Hz),0.55(3H,s).
【化17】
將(1)文獻(例如、Kittaka等人、J.Org.Chem.、2004年、69卷、7463-7471頁)所記載之化合物A-17(6.03 g,22.8 mmol)溶解於N-甲基吡咯啶酮(60 mL),添加第三丁氧化鉀(11.88 g,114 mmol),於130度加熱攪拌4小時。冷卻至室溫,添加水(240 mL),添加Diaion HP-20SS(三菱化學製、30 g(乾燥重量)),於室溫攪拌一夜。過濾且將固體以飽和氯化銨水溶液(100 mL)、水(200 mL)洗淨,以丙酮(500 mL)溶出。將溶出液減壓濃縮,以乙酸乙酯稀釋後,以飽和食鹽水洗淨,以無水硫酸鎂乾燥。將減壓濃縮有機層而得到之殘渣以二氧化矽凝膠管柱層析法(正己烷/乙酸乙酯=1/4)精製,而得到化合物A-18(1.78 g,21%)。
1
H NMR(CDCl3
)δ:7.51-7.36(5H,m),5.54(1H,s),4.61(1H,s),4.40-4.29(2H,m),4.08(1H,t,J=4.27 Hz),4.01(1H,dd,J=9.27,2.68 Hz),3.93(1H,br s),3.83-3.75(3H,m),3.60-3.50(3H,m),3.41(3H,s),0.59-0.41(3H,m).
(2)將(1)中所得到之化合物A-18(2.97 g,8.10 mmol)溶解於無水吡啶(30 mL)並冷卻至0℃,添加三甲基乙醯基氯化物(1.15 mL,9.32 mmol)在同溫度下攪拌1小時。添加無水甲醇(3 mL),在室溫攪拌5分鐘,減壓濃縮。溶解於甲苯且以飽和食鹽水洗淨後,將有機層以無水硫酸鎂乾燥。將有機層減壓濃縮、乾燥。將此粗產物溶解於無水二氯甲烷(20 mL)且冷卻至0℃,添加2,6-二甲基砒啶(1.3 mL,11.6 mmol)、三氟甲磺酸第三丁基二甲基矽烷酯(2.14 mL,9.32 mmol)之後,在室溫攪拌1小時。添加無水甲醇(5 mL)後,減壓濃縮。溶解於甲苯,以水洗淨後,將有機層以無水硫酸鈉乾燥。將減壓濃縮後的殘渣以二氧化矽凝膠管柱層析法(5%乙酸乙酯/正己烷→10%乙酸乙酯/正己烷)精製,而得到化合物A-19(3.19 g,產率69%)。
1
H NMR(CDCl3
)δ:7.49-7.34(5H,m),5.56(1H,s),4.45(1H,s),4.29-4.25(2H,m),4.18(1H,d,J=11.22 Hz),3.98-3.92(3H,m),3.75(1H,t,J=12.08 Hz),3.65(1H,t,J=2.68 Hz),3.56(2H,dd,J=29.76,9.51 Hz),3.35(3H,s),1.19(9H,s),0.91(9H,s),0.61-0.51(4H,m),0.10(3H,s),0.10(3H,s).
(3)將(2)中所得到之A-19(3.17 g,5.61 mmol)溶解於環己烷(63 mL),添加碳酸鋇(775 mg,3.92 mmol)、過氧化苯甲醯基(136 mg,0.56 mmol)、N-溴琥珀醯亞胺(1.21 g,6.73 mmol),加熱回流1小時。冷卻後,以矽藻土過濾,將有機層以飽和小蘇打水、飽和食鹽水的順序洗淨後,以無水硫酸鎂乾燥。將有機層減壓濃縮,而得到粗產物(4.0 g)。將此粗產物溶解於1-丙醇(36 mL)與水(4 mL)的混合溶劑,添加經活化之鋅(7.38 g,112.2 mmol)與氰基硼氫化鈉(1.42 g,22.4 mmol),加熱回流1小時。冷卻後,以矽藻土過濾,將固體以1-丙醇洗淨後,將液體減壓濃縮。將所得到之殘渣以乙酸乙酯稀釋,以飽和食鹽水洗淨,將有機層以無水硫酸鎂乾燥。將減壓濃縮有機層而得到之殘渣以二氧化矽凝膠管柱層析法(己烷/乙酸乙酯=90/10→80/20)精製,而得到化合物A-20(1.50 g,產率50%)。
1
H NMR(CDCl3
)δ:8.05-8.02(2H,m),7.59-7.43(3H,m),6.11(1H,ddd,J=11.00,17.32,6.00 Hz),5.78-5.75(1H,m),5.41(1H,dt,J=17.32,1.34 Hz),5.30(1H,dt,J=10.49,1.22 Hz),4.17(1H,d,J=11.47 Hz),3.96-3.93(2H,m),3.81(1H,dd,J=11.47,5.12 Hz),3.73-3.68(2H,m),3.64(1H,d,J=9.76 Hz),3.50(1H,d,J=9.76 Hz),1.18(9H,s),0.90(9H,s),0.55(4H,t,J=1.95 Hz),0.09(3H,s),0.07(3H,s).
(4)將(3)中所得到之A-20(2.41 g,4.5mmol)溶解於乙腈(25 mL),以三乙基胺(1.26 mL,9 mmol)、三甲基胺鹽酸鹽(86 mg,0.9 mmol)、p-甲苯磺醯基氯化物(1.30 g,6.8 mmol)之順序添加,在室溫攪拌1小時。添加飽和碳酸氫鈉水溶液,減壓濃縮,以乙酸乙酯稀釋後,以飽和食鹽水洗淨。將有機層以無水硫酸鎂乾燥,減壓濃縮。將此粗產物(3.31 g)溶解於四氫呋喃(18 mL),添加氟化四丁基銨(1M四氫呋喃溶液,13.5 mL,13.5mmol),加熱回流1.5小時。冷卻後、減壓濃縮後以甲苯稀釋,以飽和食鹽水洗淨,將有機層以無水硫酸鎂乾燥,減壓濃縮。將所得到之殘渣以二氧化矽凝膠管柱層析法(己烷/乙酸乙酯=90/10)精製,而得到化合物A-21(851 mg,產率47%)。
1
H NMR(CDCl3
)δ:8.06-8.02(2H,m),7.61-7.44(3H,m),6.10-6.01(1H,m),5.67-5.64(1H,m),5.42(1H,dt,J=17.24,1.34 Hz),5.32(1H,dt,J=10.57,1.22 Hz),4.04(2H,dd,J=27.32,11.22 Hz),3.65(1H,d,J=10.24 Hz),3.53(1H,d,J=10.24 Hz),3.17(1H,dd,J=7.32,5.37 Hz),3.10-3.06(1H,m),2.75(1H,t,J=4.39 Hz),2.60(1H,dd,J=4.88,2.93 Hz),1.19(9H,s),0.55(4H,s).
(5)使三甲基矽烷基乙炔(1.62 mL,11.5 mmol)之四氫呋喃溶液(3 mL)處於氮氣環境下,將溶液以乾冰-丙酮冷卻。於此添加正丁基鋰己烷溶液(2.64 M,3.97 mL,10.5 mmol),攪拌45分鐘。於此添加(4)中所得到之化合物A-21(846 mg,2.1 mmol)之四氫呋喃溶液(6 mL)、三氟硼烷-二乙醚錯合物(0.343 mL,2.73 mmol),在乾冰-丙酮冷卻下2小時、在0℃攪拌1小時。添加飽和氯化銨水溶液且回到室溫,以乙酸乙酯稀釋。將溶液以飽和碳酸氫鈉、飽和食鹽水的順序洗淨,將有機層以無水硫酸鎂乾燥。將有機層減壓濃縮。將所得到之殘渣溶解於無水甲醇(10 mL),添加甲氧化鈉(870 mg,6.3 mmol),於50℃加熱攪拌1小時。冷卻後,減壓濃縮。將殘渣以乙酸乙酯稀釋後,以飽和食鹽水洗淨,將有機層以無水硫酸鎂乾燥。將有機層減壓濃縮,將所得到之殘渣以二氧化矽凝膠管柱層析法(己烷/乙酸乙酯=60/40→50/50→35/65)精製,而得到化合物A-22(311.5 mg,產率62%)。
1
H NMR(CDCl3
)δ:5.57(1H,ddd,J=17.00,11.00,6.00 Hz),4.88(1H,dt,J=17.00,1.70 Hz),4.73(1H,dt,J=11.00,1.70 Hz),3.85-3.81(1H,m),3.51(1H,ddd,J=8.42,5.73,2.07 Hz),3.16(1H,d,J=9.50 Hz),3.05(1H,d,J=9.50 Hz),2.85(2H,dd,J=4.63,2.20 Hz),2.12-1.92(2H,m),1.85(1H,t,J=2.68 Hz).
(6)將(5)中所得到之化合物A-22(534.4 mg,2.26 mmol)溶解於無水吡啶(7.5 mL),在0℃添加三甲基乙醯基氯化物(0.276 mL,2.26 mmol),在同溫度攪拌45分鐘。添加飽和碳酸氫鈉水溶液。以甲苯稀釋,以飽和食鹽水洗淨後,將有機層以無水硫酸鎂乾燥,減壓濃縮。將所得到之殘渣溶解於無水二氯甲烷(10 mL),在0℃添加2,6-二甲基砒啶(1.1 mL,9.22 mmol)、三氟甲磺酸第三丁基二甲基矽烷酯(1.7 mL,7.55 mmol),在同溫度攪拌1.5小時。添加乙酸乙酯、以飽和食鹽水洗淨,將有機層以無水硫酸鎂乾燥,減壓濃縮。將所得到之殘渣以二氧化矽凝膠管柱層析法(己烷/乙酸乙酯=99/1→85/15)精製,而得到化合物A-23(1.08 g,產率91%)。
1
H-NMR(CDCl3
)δ:6.00-5.91(1H,m),5.21(1H,d,J=17.32 Hz),5.13(1H,d,J=11.00 Hz),4.32(1H,dd,J=7.07,3.90 Hz),4.03(2H,dd,J=19.03,11.22 Hz),3.94(1H,dd,J=10.73,5.85 Hz),3.64(1H,d,J=9.76 Hz),3.45(1H,d,J=9.76 Hz),3.39(1H,t,J=4.27 Hz),2.51(1H,ddd,J=16.83,6.00,3.00 Hz),2.36(1H,ddd,J=16.71,6.10,2.56 Hz),1.95(1H,t,J=2.56 Hz),1.19(9H,s),0.90(9H,s),0.88(9H,s),0.55-0.48 3H,m),0.11(3H,s),0.09(3H,s),0.06(3H,s),0.03(3H,s).
(7)以(6)中所得到之化合物A-23(70 mg,0.15 mmol)與實施例1(4)中所得到之化合物B-3(69 mg,0.16 mmol)為起始物質,以與實施例1(5)相同的方式反應,以得到化合物AB-3(48.1 mg,37.4%)。
1
H-NMR(CDCl3
)δ:6.18(1H,d,J=10.98 Hz),6.02(1H,d,J=11.47 Hz),5.32(1H,s),5.01(1H,s),4.47(1H,s),4.03(1H,q,J=4.15 Hz),3.91(1H,d,J=9.03 Hz),3.58(1H,dd,J=11.10,4.03 Hz),3.46-3.39(2H,m),3.32(1H,d,J=9.51 Hz),3.21(1H,br s),2.80(1H,t,J=7.81 Hz),2.61(1H,d,J=13.42 Hz),2.24(1H,dd,J=16.34,3.42 Hz),2.10(1H,dd,J=13.66,4.15 Hz),2.05-1.84(4H,m),1.66-1.49(12H,m),1.43-1.30(4H,m),1.07(4H,d,J=6.59 Hz),0.98-0.83(36H,m),0.82-0.81(2H,m),0.70-0.64(9H,m),0.57-0.54(6H,m),0.51-0.36(6H,m),0.11(3H,s),0.10(3H,s),0.08(3H,s),0.07(3H,s).
(8)以(7)中所得到之化合物AB-3(48.1 mg,0.056 mmol)作為原料,以與實施例1(6)相同之方法處理。將此反應物(28.5 mg,0.0327 mmol)溶解於無水二氯甲烷/乙腈(1/1 1 mL)之混合溶劑且冷卻至0℃後,添加對甲基苯磺酸一水和物(31 mg,0.163 mmol)、四氟硼酸鋰(30 mg,0.327 mmol),在同溫度攪拌30分鐘。添加飽和碳酸氫鈉水溶液、以乙酸乙酯萃取,以無水硫酸鎂乾燥。將減壓濃縮而得到之殘渣以薄層二氧化矽凝膠層析法(乙酸乙酯/丙酮=9/1+0.5%乙酸)粗精製,進一步以逆相HPLC(A=95%水/乙腈;B=0.5%水/40%甲醇/乙腈;B=85%)精製,藉以得到化合物E-1(4.9 mg,16.6%)。
1
H-NMR(CDCl3
)δ:6.41(1H,d,J=11.22 Hz),6.01(1H,d,J=10.98 Hz),5.37(1H,s),5.08(1H,d,J=1.46 Hz),4.48(1H,d,J=2.68 Hz),4.06-3.82(2H,m),3.55-3.25(2H,m),2.88-2.60(2H,m),2.28-1.54(13H,m),1.42-1.20(10H,m),1.10-1.08(1H,m),1.06(3H,d,J=6.59 Hz),0.91(3H,d,J=4.88 Hz),0.54(3H,s).
【化18】
(1)將三甲基矽烷基乙炔(1.84 mL,13.0 mmol)溶解於1,4-二噁烷(15 mL),在氬氣環境下、一邊以冰浴冷卻,一邊花費10分鐘滴下正丁基鋰(1.59 M正己烷溶液,8.18 mL,13.0 mmol)。於此使用Tanaka等人的方法(國際公開WO98/58909說明書)將被合成之化合物B-4(1.91 g,4.33 mmol)溶解於1,4-二噁烷(10 mL)而添加,於110℃加熱回流24小時。冷卻至室溫後,添加飽和氯化銨水溶液並攪拌後,以正己烷萃取。將所得到之有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥,將之減壓濃縮。將殘渣溶解於四氫呋喃-甲醇(1:1,20 mL),添加碳酸鉀(718 mg,5.20 mmol)並在室溫攪拌一夜。於反應液中添加水後以正己烷萃取,將所得到之有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。將減壓濃縮而得之殘渣,以二氧化矽凝膠管柱層析法(正己烷)精製,而得到化合物B-5(1.14 g,產率89%)。
1
H-NMR(CDCl3
)δ:5.65(1H,s),2.90-2.86(1H,m),2.25(1H,dt,J=16.6,3.0 Hz),2.10-1.88(5H,m),1.72-1.25(9H,m),1.11(3H,d,J=6.6 Hz),0.58(3H,s)ppm.
(2)將(1)中所得到之化合物B-5(301 mg,1.02 mmol)溶解於四氫呋喃(10 mL),在氬氣環境下、一邊冷卻至-78℃一邊滴下正丁基鋰(1.59 M正己烷溶液,0.673 mL,1.02 mmol),攪拌30分鐘。於此添加3-戊酮(0.216 mL,2.04 mmol),維持在-78℃攪拌1小時。於反應液中添加飽和氯化銨水溶液且昇溫至室溫。以乙酸乙酯萃取反應液,將所得到之有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。將減壓濃縮而得到之殘渣以二氧化矽凝膠管柱層析法(正己烷/乙酸乙酯=9/1)精製,而得到化合物B-6(205 mg,產率53%)。
1
H-NMR(CDCl3
)δ:6.42(1H,d,J=11.2 Hz),6.02(1H,d,J=11.2 Hz),5.39(1H,s),5.10(1H,s),4.44(1H,t,J=3.9 Hz),4.11-4.07(1H,m),3.84-3.81(1H,m),3.75-3.68(2H,m),3.39(1H,dd,J=7.4,3.3 Hz),2.84-2.81(1H,m),2.68(1H,dd,J=13.7,4.4 Hz),2.52(2H,t,J=6.8 Hz),2.29-2.20(3H,m),2.15-1.83(6H,m),1.70-1.22(14H,m),1.08-1.01(9H,m),0.55(3H,s)ppm.
(3)將(2)中所得到之化合物B-6(396 mg,1.04 mmol)溶解於無水N,N-二甲基甲醯胺(4 mL),添加氯三乙基矽烷(0.283 mL,1.68 mmol)、咪唑(152 mg,2.23 mmol)、4-二甲基胺吡啶(27 mg,0.22 mmol),於50℃加熱攪拌1小時。冷卻至室溫,添加無水甲醇(1 mL),攪拌30分鐘。以甲苯稀釋,以飽和食鹽水洗淨後,以無水硫酸鎂乾燥。將減壓濃縮有機層而得到之殘渣以二氧化矽凝膠管柱層析法(正己烷/乙酸乙酯=90/10)精製,而得到化合物B-7(454.8 mg,產率88%)。
1
H-NMR(CDCl3
)δ:5.65(1H,s),2.91-2.85(1H,m),2.24(1H,dd,J=16.46,3.54 Hz),2.10(1H,dd,J=16.58,6.83 Hz),2.02-1.88(4H,m),1.71-1.58(9H,m),1.54-1.24(7H,m),1.08(3H,d,J=8.00 Hz),0.98-0.91(22H,m),0.73-0.64(9H,m),0.58(3H,s),0.52(2H,q,J=7.97 Hz).
(4)將實施例2(1)中所得到之化合物A-4(457 mg,1 mmol)溶解於無水N,N-二甲基甲醯胺(5 mL),添加三乙基胺(0.421 mL,3 mmol)、氯甲基苄基醚(0.276 mL,2 mmol),於0℃攪拌1小時45分鐘。添加飽和碳酸氫鈉水溶液,以乙酸乙酯萃取,以飽和食鹽水洗淨。將有機層以無水硫酸鎂乾燥後,減壓濃縮。將所得到之殘渣以二氧化矽凝膠管柱層析法(正己烷/乙酸乙酯=95/5)精製,而得到化合物A-24(485 mg,產率84%)。
(5)以(3)中所得到之化合物B-7(44 mg,0.09 mmol)與(4)中所得到之化合物A-24(43 mg,0.075 mmol)為出發原料,依據實施例5(4)所記載之方法,進行偶合反應與脫保護反應。將所得到之反應粗產物以薄層二氧化矽凝膠層析法(乙酸乙酯/丙酮=4/1+乙酸(1.5v/v%))粗精製之後,進一步以逆相HPLC(A=95%水/乙腈;B=0.5%水/40%甲醇/乙腈;B=75%)精製,藉以得到化合物F-1(4.7 mg,12%)。
1
H-NMR(CDCl3
)δ:6.42(1H,d,J=10.98 Hz),6.00(1H,d,J=10.98 Hz),5.37(1H,d,J=1.46 Hz),5.08(1H,d,J=1.95 Hz),4.47(1H,d,J=2.93 Hz),4.08-3.94(2H,m),3.82-3.74(1H,m),3.33(1H,dd,J=8.17,3.05 Hz),2.83(1H,d,J=12.20 Hz),2.69-2.60(3H,m),2.30-2.20(2H,m),1.98(2H,d,J=11.71 Hz),1.91-1.80(1H,m),1.72-1.24(16H,m),1.07(3H,d,J=6.34 Hz),1.03(8H,t,J=7.44 Hz),0.54(3H,s).
【化19】
(1)以實施例10(1)中所得到之化合物B-5(442 mg,1.5 mmol)為起始物質,遵照與實施例10(2)相同之方法,得到化合物B-8與環戊酮之混合物(427.2 mg)。將此粗產物作為起始物質,使用無水N,N-二甲基甲醯胺(4.5 mL)、氯三乙基矽烷(0.283 mL,1.68 mmol)、咪唑(152 mg,2.23 mmol)、4-二甲基胺吡啶(27 mg,0.22 mmol),藉由與實施例10(3)相同之方法,得到化合物B-9(506.2 mg,產率68%)。
1
H-NMR(CDCl3
)δ:5.65(1H,s),2.92-2.85(1H,m),2.24(1H,dd,J=16.46,3.29 Hz),2.08(1H,dd,J=16.10,6.83 Hz),2.02-1.57(19H,m),1.54-1.26(7H,m),1.07(4H,d,J=7.56 Hz),0.98-0.91(15H,m),0.73-0.63(8H,m),0.57(3H,s),0.52(3H,q,J=7.97 Hz).
(2)以(1)中所得到之化合物B-9(44 mg,0.09 mmol)與實施例10(4)中所得到之化合物A-24(43 mg,0.075 mmol)為起始物質,藉由與實施例10(5)相同之方法,得到化合物F-2(2.0 mg,產率5%)。
1
H-NMR(CDCl3
)δ:6.41(1H,d,J=10.98 Hz),6.00(1H,d,J=10.98 Hz),5.36(1H,s),5.07(1H,s),4.46(1H,s),4.10-3.93(2H,m),3.78(1H,br s),3.30(1H,d,J=6.59 Hz),3.07-2.62(9H,m),2.30-2.19(2H,m),2.05-1.24(25H,m),1.06(3H,d,J=6.59 Hz),0.54(3H,s).
VDR之評估係使用市售之測定評估套組、例如Invitrogen社販賣之POLARSCREEN VITAMIN D RECEPTOR COMPETITOR ASSAY,RED(invitrogen)Cat.No.PV4569),由以下順序來進行評估。
於384孔黑盤每次2孔,各添加化合物溶液10μL。將套組中所含之VDR/Fluoromone VDR Complex於每孔各添加10μL,在室溫反應2小時。2小時後、測定螢光偏光,以評估親和性。
再者,親和性係以1,25-(OH)2-維生素D3
之親和性為1時的相對值(1/X)來評估。
[表2]
本發明中所得到之化合物確認了具有強的VDR親和性。且可知尤以化合物C-1、化合物D-1具有非常強的VDR親和性。
(1)報導載體係使用pGL3載體(promega公司),於螢光酵素(luciferase)基因的上游,將以文獻已知的方法(Ozono等人、The Journal of Biological Chemistry、265卷、21881-21888頁、1990年)得到之人類骨鈣化素基因促進子(promoter)部分序列,由從HOS細胞(自ATCC得到)取得之cDNA進行選殖(cloning),重組而構築。表現載體係於pCDNA3載體(Invitrogen公司)插入編碼有人類VDR及人類RXR之DNA序列來構築。HOS細胞係在含有10% FBS之DMEM培養基,於37℃、5% CO2
之條件下培養,每2天或3天繼代。
(2)將繼代培養之細胞離心回收,在無血清、不含酚紅之DMEM培養基中以4×105
cells/ml之密度分散,於96孔盤以0.1mL/孔播種。於此系統中將(1)所記載之各種載體,使用Lipofectamine2000(Invitrogen公司)試藥於每孔添加0.05mL。在37℃培養3小時後,於各孔中添加各種濃度之被試驗化合物乙醇溶液或控制組的乙醇各2μL。於37℃培養24小時後,去除培養基,以PBS(-)洗淨一次之後,使用DualGlo-Luciferase Assay kit(Promega公司),藉由光度計(Berthold公司)來測定螢光酵素活性。
結果,可知本發明之化合物均具有EC50
值在20nM以下之轉錄活性。進一步,可知化合物C-1、C-2、D-1、E-1、F-1、F-2,具有EC50
值在0.2nM以下之轉錄活性。特別是可知化合物D-1、F-1、F-2,具有EC50
值在0.02nM以下之轉錄活性。
將12週齡之SD系雌性大鼠(Charles River Japan)之兩側卵巢摘出,放置4週後,分別口服本發明之化合物、以及國際公開WO01/62723號小冊子所記載之2α-(3-羥丙基)氧-1α,25-二羥基維生素D3
,每週5次、共4週。最終投藥24小時後,在醚麻醉下進行採血,使其安樂死。於麻醉下,使用雙重X射線骨鹽量測定裝置(QDR-2000,HOLOGIC)來測定第4第5腰椎之骨密度。為了比較,針對偽手術(sham)群(雖進行開腹手術但不摘出卵巢、不進行試驗化合物的投藥)與卵巢摘出(OVX)群(雖摘出卵巢但不進行試驗化合物之投藥)亦於解剖時進行測定腰椎之骨密度。又,亦進行各群之血清中鈣濃度的測定。
[表3]
[表4]
確認了藉由施行手術,OVX群之骨密度相較於偽手術群(sham)群更低。藉由投予維生素D衍生物,確認了骨密度的回復。但是,國際公開WO01/62723號小冊子所記載之2α-(3-羥丙基)氧-1α,25-二羥基維生素D3
投藥群,隨著骨密度增加,血中鈣值會上昇,可知為了使骨密度成為sham群以上所必要之投藥量(25ng/kg)當中,血清鈣值上昇幅度係1mg/dL以上,即為大幅度地上昇。
另一方面,可知本發明之化合物,血清鈣值之上昇範圍在比OVX之血清鈣值高1mg/dL以下的範圍內,且骨密度增強至與sham群同等以上之骨密度。
由以上結果,可知本發明之維生素D3
衍生物或其醫藥上容許之溶劑合物,相較於以往被報導之維生素D3
衍生物,具有對骨頭更優良的作用。
本發明之維生素D3
衍生物或其醫藥上容許之溶劑合物可使用作為醫藥品。
Claims (13)
- 一種維生素D3 衍生物,其係以下述式(1)表示;
- 如申請專利範圍第1項之維生素D3 衍生物,其中X表示氧原子。
- 如申請專利範圍第1項之維生素D3 衍生物,其中X表示亞甲基。
- 如申請專利範圍第1至3項中任一項之維生素D3 衍生物,其中n為1。
- 如申請專利範圍第1至3項中任一項之維生素D3 衍生物,其中R2 表示氫原子。
- 如申請專利範圍第1至3項中任一項之維生素D3 衍生物,其中R1 表示氫原子、甲基、乙基、丙基、異丙基、第三丁基、第三丁基羰基氧甲基、或苯基羰基氧甲基。
- 如申請專利範圍第1至3項中任一項之維生素D3 衍生物,其中R2 表示氫原子、且n為1。
- 如申請專利範圍第1項之維生素D3 衍生物,其中R1 表示氫原子、甲基、乙基、丙基、異丙基、第三丁基、第三丁基羰基氧甲基、或苯基羰基氧甲基、R2 表示氫原子、或與另一R2 及該等所鍵結之碳原子形成環丙基、R3 表示甲基、乙基;或與另一R3 及該等所鍵結之碳原子形成環丙基、X表示氧原子或亞甲基、n=1。
- 一種維生素D3 衍生物,其係下述任一之維生素D3 衍生物:(5Z,7E)-(1R,2S,3R,20R)-2-(2-羧基乙氧基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-(2-甲氧基羰基乙氧基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-(2-乙氧基羰基乙氧基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-(2-丙氧基羰基乙氧 基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-(2-(1-甲基)乙氧基羰基乙氧基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-(2-(1,1-二甲基)乙氧基羰基乙氧基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-((第三丁基羰基氧)甲氧基羰基乙氧基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-((苯基羰基氧)甲氧基羰基乙氧基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1S,2S,3R,20R)-2-(2-羧丙基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1S,2S,3R,20R)-2-(2-甲氧基羰基丙基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1S,2S,3R,20R)-2-(2-乙氧基羰基丙基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1S,2S,3R,20R)-2-(2-丙氧基羰基丙基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1S,2S,3R,20R)-2-(2-(1-甲基)乙氧基羰基丙基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇 (5Z,7E)-(1S,2S,3R,20R)-2-(2-(1,1-二甲基)乙氧基羰基丙基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-((2-羧基-2,2-橋亞乙基)乙氧基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-((2-甲氧基羰基-2,2-二甲基)乙氧基)-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-(2-羧基乙氧基)-26,27-二甲基-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇(5Z,7E)-(1R,2S,3R,20R)-2-(2-羧基乙氧基)-26,27-失碳-25-環戊基-23-炔-9,10-斷-5,7,10(19)-膽甾三烯-1,3,25-三醇。
- 一種醫藥組成物,其係由如申請專利範圍第1至9項中任一項之維生素D3 衍生物、與製藥學上容許之載體所構成。
- 一種由骨質疏鬆症、惡性腫瘤、乾癬症、發炎性呼吸器疾病、關節風濕性疾病、真性糖尿病、高血壓症、脫毛症、面皰、及皮膚炎所構成群組中選出之一者以上的疾病之治療劑,其係含有如申請專利範圍第1至9項中任一項之維生素D3 衍生物作為有效成分。
- 如申請專利範圍第11項之疾病之治療劑,其中 疾病係骨質疏鬆症。
- 一種以下述式(2)表示之化合物;
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SG70010A1 (en) | 1996-05-23 | 2000-01-25 | Hoffmann La Roche | Fluorinated vitamin d3 analogs |
SG70009A1 (en) * | 1996-05-23 | 2000-01-25 | Hoffmann La Roche | Vitamin d3 analogs |
GB9611603D0 (en) | 1996-06-04 | 1996-08-07 | Leo Pharm Prod Ltd | Chemical compounds |
CA2263940A1 (en) | 1997-06-25 | 1998-12-30 | Teijin Limited | Vitamin d3 derivatives and remedies for inflammatory respiratory diseases prepared from the same |
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JP4357114B2 (ja) * | 1998-02-24 | 2009-11-04 | 中外製薬株式会社 | 24−ヒドロキシビタミンd誘導体 |
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