NZ227641A - 16-dehydro-vitamin d 3 (dehydrocholecalciferol) derivatives; medicaments and preparatory processes - Google Patents
16-dehydro-vitamin d 3 (dehydrocholecalciferol) derivatives; medicaments and preparatory processesInfo
- Publication number
- NZ227641A NZ227641A NZ227641A NZ22764189A NZ227641A NZ 227641 A NZ227641 A NZ 227641A NZ 227641 A NZ227641 A NZ 227641A NZ 22764189 A NZ22764189 A NZ 22764189A NZ 227641 A NZ227641 A NZ 227641A
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- formula
- treatment
- mixture
- hydroxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 239000003814 drug Substances 0.000 title claims 4
- 229940046008 vitamin d Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 86
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 11
- 230000003463 hyperproliferative effect Effects 0.000 claims description 9
- 230000001613 neoplastic effect Effects 0.000 claims description 8
- 201000004681 Psoriasis Diseases 0.000 claims description 7
- 208000032839 leukemia Diseases 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 2
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 2
- 239000012876 carrier material Substances 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims 1
- 229920001214 Polysorbate 60 Polymers 0.000 claims 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N beta-monoglyceryl stearate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims 1
- 229960000541 cetyl alcohol Drugs 0.000 claims 1
- 239000012153 distilled water Substances 0.000 claims 1
- 229940124274 edetate disodium Drugs 0.000 claims 1
- 229940075507 glyceryl monostearate Drugs 0.000 claims 1
- 229940100242 glycol stearate Drugs 0.000 claims 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims 1
- 229960002216 methylparaben Drugs 0.000 claims 1
- 239000002480 mineral oil Substances 0.000 claims 1
- 235000010446 mineral oil Nutrition 0.000 claims 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims 1
- 229920000059 polyethylene glycol stearate Polymers 0.000 claims 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims 1
- 229940113124 polysorbate 60 Drugs 0.000 claims 1
- AKJDMMRCSCGXFD-UHFFFAOYSA-N propane-1,2-diol;propyl 4-hydroxybenzoate Chemical compound CC(O)CO.CCCOC(=O)C1=CC=C(O)C=C1 AKJDMMRCSCGXFD-UHFFFAOYSA-N 0.000 claims 1
- 239000001587 sorbitan monostearate Substances 0.000 claims 1
- 235000011076 sorbitan monostearate Nutrition 0.000 claims 1
- 229940035048 sorbitan monostearate Drugs 0.000 claims 1
- 239000000600 sorbitol Substances 0.000 claims 1
- 238000011200 topical administration Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 53
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 28
- 239000000047 product Substances 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
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- 229910002027 silica gel Inorganic materials 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 14
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- 239000003960 organic solvent Substances 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 11
- -1 alkyl lithium Chemical compound 0.000 description 10
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
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- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 208000017520 skin disease Diseases 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000004069 differentiation Effects 0.000 description 5
- 210000002510 keratinocyte Anatomy 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 4
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
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- 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 2
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- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 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
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- SQKZZFWTOOPCDQ-UHFFFAOYSA-N dichloromethane;ethyl acetate;hexane Chemical compound ClCCl.CCCCCC.CCOC(C)=O SQKZZFWTOOPCDQ-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- FQTIYMRSUOADDK-UHFFFAOYSA-N ethyl 3-bromopropanoate Chemical compound CCOC(=O)CCBr FQTIYMRSUOADDK-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004673 fluoride salts Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- HJHVQCXHVMGZNC-JCJNLNMISA-M sodium;(2z)-2-[(3r,4s,5s,8s,9s,10s,11r,13r,14s,16s)-16-acetyloxy-3,11-dihydroxy-4,8,10,14-tetramethyl-2,3,4,5,6,7,9,11,12,13,15,16-dodecahydro-1h-cyclopenta[a]phenanthren-17-ylidene]-6-methylhept-5-enoate Chemical compound [Na+].O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C([O-])=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C HJHVQCXHVMGZNC-JCJNLNMISA-M 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Substances CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 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 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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
- C07F7/1804—Compounds having Si-O-C linkages
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
<div class="application article clearfix" id="description">
<p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number £27641 <br><br>
^ Patents Form No. 5 _ ^ <br><br>
* 227641 <br><br>
NO DRAWINGS <br><br>
Priority Oate(s): <br><br>
Compl«M Specification Filed: .9P... Dim: f&l £)7? Jp.Q,. t-P.1. <br><br>
£Q1 f.1 J.[k> Jgj <br><br>
PubUc, 0.,.: .8.5.JIJN.8SI. <br><br>
P.O. -n»!, No: <br><br>
NEW ZEALAND <br><br>
PATENTS ACT, 1953 <br><br>
No.: Date. <br><br>
o '. <br><br>
COMPLETE SPECIFICATION 16-DEHYDRO-VITAMIN D3-DERIVATIVES <br><br>
*17JANt98» 1 <br><br>
We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT 124-184 Grenzacherstrasse, Basle, Switzerland a Swiss company hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- <br><br>
- 1 - <br><br>
(followed by page -la-) <br><br>
m 22 76 4 1 <br><br>
^; <br><br>
- 1 O^r <br><br>
RAN 4212/54 <br><br>
The invention relates to compounds of the formula <br><br>
10 <br><br>
15 <br><br>
wherein R is hydrogen or hydroxy, and A is -C=C-, 20 -CHaCH- with E-configuration or -CH2-CH2~, <br><br>
to pharmaceutical compositions comprising one, two or more compounds of formula I, and to the use of said compounds for <br><br>
\ ^ the manufacture of such compositions useful in the treatment of hyperproliferative skin diseases, such as psoriasis, and 25 for the treatment of neoplastic diseases, such as leukemia. <br><br>
Examples of ^-alkyl groups as referred to below, are methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Examples of aryl-C1_4-alkyl groups are benzyl, phenethyl 30 and phenylpropyl. Examples of aryl groups are phenyl and p-tolyl. Halogen denotes bromine, chlorine, fluorine or iodine. <br><br>
35 <br><br>
Compounds of formula I of the invention are compounds A Me/14.12.88 <br><br>
20 <br><br>
£27641 <br><br>
- 2 - <br><br>
to F as defined below: <br><br>
A: 1,25-dihydroxy-16-dehydrocholecalci£erol; <br><br>
B: 25-hydroxy-16-dehydrocholecalciferol; <br><br>
5 C: 1.25-dihydroxy-16,23E-bisdehydrocholecalciferol; <br><br>
D: 25-hydroxy-16,23E-bisdehydrocholecalciferol; <br><br>
E: l.25-dihydroxy-16-dehyro-23-didehydrocholecalciferol; and <br><br>
F: 25-hydroxy-16-dehydro-23-didehydrocholecalciferol; <br><br>
10 among which Che 1.25-dihydroxylated compounds A. C and E are preferred. <br><br>
The compounds of formulae la and lb (encompassed by formula I) can be prepared as described in the Schemes 1. 2 15 and 3 by reacting a corresponding compound of formula I <br><br>
containing instead of the two or three hydroxy groups two or three protected hydroxy groups of the formula <br><br>
-OSi(R1.R2.R3) <br><br>
wherein R^ and R3 are c14-alkyl and R2 is 4~alkyl, aryl or aryl-C14-alkyl. <br><br>
with an agent capable of removing the protecting groups <br><br>
25 <br><br>
30 <br><br>
35 <br><br>
- 3 - <br><br>
22 7 6 4 1 <br><br>
Scheme 1 <br><br>
o "I <br><br>
wherein A is as described above and R, and R_ are <br><br>
1 3 <br><br>
independently ^-alkyl and R2 is independently C^^-alkyl, aryl, or aryl-C^^-alkyl. <br><br>
o o <br><br>
c <br><br>
22 7 6 4 1 <br><br>
- 4 - <br><br>
Scheme 2 <br><br>
wherein R^, R2 and R3 are as described above. <br><br>
Wf. <br><br>
1 <br><br>
- 5 - <br><br>
Scheme 3 <br><br>
22 764 1 <br><br>
n <br><br>
*1 <br><br>
C <br><br>
10 <br><br>
15 <br><br>
20 <br><br>
25 <br><br>
30 <br><br>
"— <br><br>
H| ' S*C <br><br>
i <br><br>
. Ct> i <br><br>
H <br><br>
35 <br><br>
wherein R , R2 and R3 are as described above. X is chlorine, bromine or iodine and Ts is tosyl. <br><br>
- 6 - <br><br>
227641 <br><br>
In Scheme 1. the compound of formula II is converted to a compound of formula IVa or IVb by reaction with the corresponding compound of formula where Ph is phenyl; R4 is H or -OSi(R1< R2# R3), <br><br>
and R^, R2 and R^ are as described above. <br><br>
The reaction is carried out at -60 to 90°C, preferably -75°C. in a polar, aprotic. organic solvent, e.g. dry ether or preferably dry tetrahydrofuran (THF), in the presence of a strong base, such as an alkyl lithium, e.g. butyl lithium. <br><br>
The protecting groups of a compound of formula IVa or IVb are removed by reaction with a fluorine salt, e.g. tetrabutylammonium fluoride in a polar, organic solvent, e.g. ether or preferably THF, to yield a corresponding compound of formula la or lb. <br><br>
In Scheme 2, the compound the compound of focmula VI by agent, e.g. 2,2'-bipyridinium pyridinium chlorochromate. in such as methylene chloride. <br><br>
of formula V is oxidized to treatment with an oxidizing chlorochromate or preferably, an aprotic, organic solvent <br><br>
I <br><br>
I I <br><br>
i <br><br>
mwiNitr <br><br>
22 76 4 1 <br><br>
7 - <br><br>
The compound of formula VI is converted to a compound of formula lib, by reaction with, e.g.. a (trialkylsilyl)-imidazole such as (trimethylsilyl)imidazole, in an aprotic organic solvent such as THF. or preferably, methylene chloride. <br><br>
The compound of formula V may also be partially hydrogenated to the compound of formula VII by reaction with a reducing agent, e.g. lithium aluminium hydride, preferably 10 in the presence of an alkali metal alkoxide. e.g. sodium methoxide. in an aprotic organic solvent e.g. ether, or preferably THF. at reflux temperature (about 68°C for THF). for about 10-20 hours. <br><br>
15 The resulting compound of formula VII is oxidized to the compound of formula VIII by treatment with an oxidizing agent as described above for the oxidation of V to VI. <br><br>
The compound of formula VIII is converted to a compound 20 of formula Ha. by reaction with a (trialkylsilyl) imidazole, as described above for the conversion of VI to lib. <br><br>
In Scheme 3. the compound of formula X is reacted in ether, preferably THF, at reflux temperature with magnesium. 25 The resulting Grignard solution is treated with cuprous iodide and then the compound of formula IX is added. <br><br>
O <br><br>
The resulting compound of formula XI is reacted with a fluoride salt, e.g. tetrabutylammonium fluoride in ether or 30 preferably THF. <br><br>
The obtained compound of formula XII may be oxidized as described above for the oxidation of V to VI. <br><br>
35 <br><br>
22 7 641 <br><br>
- 8 - <br><br>
The resulting compound of formula XIII is converted to a compound of formula lie, by reaction with a (trialkylsilyl)-imidazole as described above for the conversion of VI to lib. <br><br>
To prepare a compound of formula IX, the compound of formula <br><br>
HO <br><br>
(Tetrahedron 40, 1984,2283) can be reacted with a tosylating agent, such as a p-toluenesulfonyl halide, e.g. the chloride, in an organic base, e.g. collidine or preferably pyridine. The resulting compound of formula is then converted to a compound of formula IX by reaction of a trialkylsilyl chloride, e.g. trimethylsilyl chloride, in the presence of imidazole and in an aprotic organic solvent, e.g. THF or methylene chloride. <br><br>
To prepare a compound of formula X, a compound of formula x-ch2ch2coch3 <br><br>
xvi <br><br>
22 7 6 4 1 <br><br>
9 <br><br>
can be converted to a compound of focmula <br><br>
X-CH2CH2C(CH3)2-OH <br><br>
XVII <br><br>
wherein X is as above, by reaction with a methyl Grignard reagent such as methylmagnesium bromide in ether. The compound of formula XVII is converted to a compound of formula X, by reaction with a trialkylsilyl chloride, as described above for converting XV to IX. <br><br>
Foe preparing the compound of formula V, the compound of formula XV above is reacted with a cyanide forming agent, e.g. sodium cyanide, in an aprotic organic solvent, e.g. dimethyl sulfoxide (DMSO), at a temperature between 80 and 100°C for 1 to 5 hours to give a compound of formula <br><br>
XVIII <br><br>
ho <br><br>
This is converted to the compound of formula cho xix ho by reaction with a reducing agent, e.g. diisobutylaluminium hydride, followed by hydrolysis with, e.g. a mineral acid. <br><br>
227641 <br><br>
- 10 - <br><br>
such as hydrochloric acid. The reduction is conducted in an aprotic organic solvent, e.g. methylene chloride, at about -10 to 10°C for about 20 to 90 minutes. The compound of formula XIX is converted to the compound of formula by reaction with a mixture of triphenylphosphine, carbon tetrabromide and zinc dust, in an aprotic organic solvent, e.g. methylene chloride, for about 1 to 30 hours. <br><br>
The compound of formula XX is converted to the compound of formula by reaction with a strong base, e.g. butyllithium, in a polar aprotic solvent, e.g. THF, at about -80 to -70°C, for about 1 to 3 hours. The compound of formula XXI is converted to the compound of formula <br><br>
- 11 - <br><br>
22 764 1 <br><br>
H <br><br>
XXII <br><br>
MejSiO <br><br>
by- reaction with (trimethylsilyl)imidazole in an apcotic organic solvent, e.g. THF or methylene chloride. This compound is converted to the compound of formula by reaction with a strong base, e.g. butyllithium and then with acetone. The reaction is conducted in an aprotic organic solvent, e.g. THF at about -80 to -60°C. The compound of formula XXIII is deprotected to give the compound of formula V (in Scheme 2) by reaction with a fluorine salt, e.g. tetrabutylammonium fluoride in an organic solvent, e.g. ether or THF. <br><br>
The compound of formula I stimulate differentiation and decrease proliferation of human keratinocytes. Accordingly, they ace useful as agents in the treatment of hyper-proliferative skin disorders, such as psoriasis, basal cell carcinomas, disorders or keratinization and keratosis. The compound of formula I are also useful as agents in the treatment of neoplastic diseases, such as leukemia. <br><br>
XXIII <br><br>
Me3SiO <br><br>
22 7 6 4 1 <br><br>
12 - <br><br>
The activity of compounds of focmula I as agents foe the treatment of hyperproliferative skin diseases can be demonstrated e.g. by test procedures known in the art, such as set forth in The Society for Investigative Dermatology 5 1986, 709-714. The effects of the compounds A to F above on the morphologic differentiation of cultured human keratinocytes compared to the effect of 1.25-dihydroxy- <br><br>
cholecalciferol (compound X) are expressed in the Tables 1 <br><br>
' 4 <br><br>
to 4 below, as number (xlO ) of human keratinocytes in <br><br>
10 culture. A compound which induces the differentiation of <br><br>
' basal cells to squamous and envelope cells is useful as an agent in the treatment of skin diseases characterized by disorders of keratinization, such as psoriasis. <br><br>
<* <br><br>
15 <br><br>
20 <br><br>
25 <br><br>
Table <br><br>
1 <br><br>
Compound <br><br>
Dose (M) <br><br>
Number of cells (xlO4): <br><br>
total basal squamous enve <br><br>
Control <br><br>
13315 <br><br>
11814 <br><br>
15tl <br><br>
1812 <br><br>
X <br><br>
lo-io <br><br>
10"8 10~6 <br><br>
122±4 112±6 95±7 <br><br>
10312 8912 6416 <br><br>
1912 2314 3111 <br><br>
2311 3013 3412 <br><br>
A <br><br>
10-10 <br><br>
10"8 10-6 <br><br>
132±8 <br><br>
128110 <br><br>
10117 <br><br>
11517 10618 7115 <br><br>
1711 2212 3012 <br><br>
2712 3312 3912 <br><br>
B <br><br>
10-10 <br><br>
10-8 <br><br>
10"6 <br><br>
13316 13114 10414 <br><br>
11515 10912 7413 <br><br>
1811 2212 3011 <br><br>
2511 2912 3311 <br><br>
30 <br><br>
35 <br><br>
22 76 4 1 <br><br>
- 13 - <br><br>
Table 2 <br><br>
Compound <br><br>
Dose <br><br>
Number of cells <br><br>
(xlO4): <br><br>
(M) <br><br>
total basal squamous envelope <br><br>
Contcol <br><br>
123±7 <br><br>
10516 <br><br>
18tl <br><br>
7417 <br><br>
X <br><br>
10-10 <br><br>
116±9 <br><br>
9518 <br><br>
2 111 <br><br>
9 ll4 <br><br>
10-8 <br><br>
101±10 <br><br>
7518 <br><br>
2612 <br><br>
122111 <br><br>
IO"6 <br><br>
8315 <br><br>
5714 <br><br>
2611 <br><br>
146116 <br><br>
c <br><br>
10-10 <br><br>
11714 <br><br>
9212 <br><br>
2512 <br><br>
10316 <br><br>
10-8 <br><br>
10813 <br><br>
8012 <br><br>
2811 <br><br>
12813 <br><br>
10-6 <br><br>
8017 <br><br>
5416 <br><br>
2611 <br><br>
15311 <br><br>
D <br><br>
10-10 <br><br>
11317 <br><br>
9316 <br><br>
2011 <br><br>
104110 <br><br>
lO-8 <br><br>
11117 <br><br>
8613 <br><br>
2512 <br><br>
12815 <br><br>
io-6 <br><br>
9413 <br><br>
68ll <br><br>
2612 <br><br>
14417 <br><br>
Table <br><br>
3 <br><br>
Compound <br><br>
Dose <br><br>
Numbec of cells <br><br>
(xlO4): <br><br>
(M) <br><br>
total basal squamous envelope <br><br>
Control <br><br>
108110 <br><br>
9318 <br><br>
1512 <br><br>
8818 <br><br>
X <br><br>
10-10 <br><br>
10617 <br><br>
8616 <br><br>
18H <br><br>
10019 <br><br>
IO'8 <br><br>
8418 <br><br>
6115 <br><br>
2313 <br><br>
12218 <br><br>
10-8 <br><br>
7317 <br><br>
5115 <br><br>
2212 <br><br>
142111 <br><br>
E <br><br>
10-1° <br><br>
8614 <br><br>
6312 <br><br>
2312 <br><br>
11415 <br><br>
IO"8 <br><br>
8213 <br><br>
5312 <br><br>
2911 <br><br>
14115 <br><br>
io-6 <br><br>
7813 <br><br>
4111 <br><br>
2712 <br><br>
14714 <br><br>
F <br><br>
10-10 <br><br>
10315 <br><br>
8113 <br><br>
2212 <br><br>
10314 <br><br>
IO-8 <br><br>
9713 <br><br>
6712 <br><br>
2911 <br><br>
12116 <br><br>
IO"6 <br><br>
8414 <br><br>
5512 <br><br>
2911 <br><br>
13717 <br><br>
The activity of compounds of formula I as agents for the treatment of hyperpcoliferative skin diseases can also be demonstrated by determining the number of human keratinocytes grown and the number of envelopes formed, as well as the number squamous carcinoma cell lines (SCC-115) grown in <br><br>
i <br><br>
! i n <br><br>
CD <br><br>
22 76 4 1 <br><br>
- 14 - <br><br>
cultures, in the presence of said compounds. The results are given in the Tables 4 and 5: <br><br>
Table 4 <br><br>
C <br><br>
Treatment <br><br>
Dose (M) <br><br>
10 Control <br><br>
(0.1% ethanol) <br><br>
Number of keratinocytes <br><br>
(xlO4) <br><br>
189.49122.3 <br><br>
Number of envelopes (xlO2) <br><br>
858.281185.70 <br><br>
15 <br><br>
Compound E <br><br>
10 10 10 10 <br><br>
-12 -10 -8 -6 <br><br>
187.36115.33 175.34110.19 145.79115.66 41.951 7.53 <br><br>
1136.631 383.66 1444.871 312.47 2113.6211049.33 1916.831 887.66 <br><br>
C <br><br>
20 <br><br>
25 <br><br>
Control (0.1% ethanol) <br><br>
Compound A <br><br>
10 10 10 10 <br><br>
-12 -10 -8 -6 <br><br>
148.73116.23 <br><br>
114.91110.95 130.37124.32 120.67116.87 109.22115.87 <br><br>
2193.71 921.9 <br><br>
1662.21 420.1 3973.81 126.99 7235.21 55.5 8323.51 157.6 <br><br>
30 <br><br>
35 <br><br>
22 76 4 1 <br><br>
- 15 - <br><br>
Table 5 <br><br>
Treatment Dose Number of <br><br>
O (M) cell lines (SCC-15) <br><br>
5 (xlO-5) <br><br>
Control <br><br>
7.35±1.75 <br><br>
10 <br><br>
Compound E <br><br>
12 <br><br>
10" <br><br>
10 <br><br>
10" <br><br>
8 <br><br>
10 <br><br>
6 <br><br>
10 <br><br>
6.98 tl. 68 5.89±1.58 5.76±1.53 0.4010.98 <br><br>
C <br><br>
15 <br><br>
20 <br><br>
Compound A <br><br>
10 <br><br>
0.4910.13 <br><br>
The above results show that the compounds of formula I induce differentiation of skin cells and, accordingly, are useful in the treatment of hyperproliferative disorders of the skin, such as psoriasis. <br><br>
In order to demonstrate the activity of the compounds of formula I as agents for the treatment of neoplastic diseases, the anti-proliferative (AP) and differentiation--inducing (DI) effects of the compounds A to F and human 25 promyelocytic HL-60 tumor cells were evaluated. In Table 6 the AP effect is given in percent reduction of cell number and in concentration ID5Q of the compound which reduced the cells number by 50%. The DI effect is expressed as the percentage of differentiated cells and as the concentration 30 EDCA of the compounds which induced a 50% differentiation bU <br><br>
of the cells. <br><br>
35 <br><br>
22 7 6 4 1 <br><br>
- 16 - <br><br>
Table 6 <br><br>
Concentration (X10~8M) <br><br>
% Reduction in cell number lD" e <br><br>
(X 10 M) <br><br>
Differentiated cells(%) <br><br>
ED*° . <br><br>
(XlO" M <br><br>
Compound X <br><br>
0.01 <br><br>
6 <br><br>
3 <br><br>
0.1 <br><br>
5 <br><br>
11 <br><br>
1 <br><br>
16 <br><br>
2 <br><br>
19 <br><br>
2 <br><br>
10 <br><br>
66 <br><br>
68 <br><br>
100 <br><br>
84 <br><br>
98 <br><br>
Compound A <br><br>
rH <br><br>
o • <br><br>
o <br><br>
10 <br><br>
3 <br><br>
0.1 <br><br>
33 <br><br>
16 <br><br>
1 <br><br>
84 <br><br>
0.2 <br><br>
92 <br><br>
0.2 <br><br>
10 <br><br>
85 <br><br>
97 <br><br>
100 <br><br>
85 <br><br>
98 <br><br>
Compound B <br><br>
0.1 <br><br>
10 <br><br>
5 <br><br>
1 <br><br>
8 <br><br>
4 <br><br>
10 <br><br>
14 <br><br>
35 <br><br>
6 <br><br>
32 <br><br>
100 <br><br>
82 <br><br>
93 <br><br>
1000 <br><br>
95 <br><br>
95 <br><br>
22 7 6 4 1 <br><br>
- 17 - <br><br>
Compound C <br><br>
0.01 0.1 1 10 100 <br><br>
Compound D <br><br>
0.1 1 10 100 1000 <br><br>
Compound E <br><br>
0.01 0.1 1 10 <br><br>
Compound F <br><br>
0.1 1 10 100 1000 <br><br>
18 20 81 <br><br>
85 <br><br>
86 <br><br>
12 12 17 46 95 <br><br>
6 59 <br><br>
80 <br><br>
81 <br><br>
13 10 8 58 95 <br><br>
0.3 <br><br>
150 <br><br>
0.07 <br><br>
70 <br><br>
3 19 92 97 99 <br><br>
1 <br><br>
2 17 31 97 <br><br>
9 <br><br>
50 96 98 <br><br>
4 <br><br>
12 21 55 91 <br><br>
These data indicate that each of the compounds in question restrains the proliferation of human promyelocytic cells, in vitro, even though they are not toxic to the cells. Furthermore, the cells differentiate toward a more mature phenotype at the same doses which inhibit proliferation. From these results it can be seen that each <br><br>
o <br><br>
***** <br><br>
22 764 1 <br><br>
- 18 - <br><br>
of the compounds tested is useful as an agent in the treatment of neoplastic diseases, such as leukemia. <br><br>
The compounds of formula I can be administered orally 5 for the treatment of neoplastic diseases or for the treatment of hyperproliferative skin diseases, to warmblooded animals, which need such treatment, e.g. to an adult human, in dosage that are in the range of about 0.1 to 10 ug per day. <br><br>
10 <br><br>
For the treatment of hyperproliferative skin diseases the compounds of formula I can also be administered topically to warmblooded animals which need such treatment, in dosage of about 1 to 1000 ug per gram of topical 15 formulation per day. <br><br>
Oral dosage forms comprising compounds of formula I may be incorporated e.g. in capsules or tablets with pharmaceutical^ acceptable carriers. Examples of such 20 carrier materials which may be incorporated into capsules are binders, such as gum tragacanth or gelatin; excipients. such as dicalcium phosphate; disintegrating agents, such as corn starch; lubricants, such as magnesium stearate; sweetening agents, such as sucrose; flavoring agents, such 25 as peppermint. Tablets may be coated with shellac, sugar or both. A syrup or elixir may contain a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring agent. <br><br>
30 Topical dosage forms comprising compounds of formula I <br><br>
include ointments and creams encompassing formulations having oleaginous, adsorbable. water soluble and emulsion-type bases, such as lanolin and polyethylene glycols. Topical dosage forms also comprise gels, lotions. 35 powders and aerosols. The topical compositions can also be employed in the treatment of inflammations of the skin or of raucous membranes, e.g. the mucous lining of the mouth or <br><br>
\ n i <br><br>
s <br><br>
30 <br><br>
22 7 6 4 1 <br><br>
- 19 - <br><br>
lower colon. <br><br>
Lotions, i.e. liquid preparations varying from simple solutions to aqueous of hydroalcoholic preparations 5 containing finely divided substances, can contain suspending or dispersing agents, such as cellulose derivatives, e.g. ethyl or methyl cellulose; gelatin or gums, which incorporate the active ingredient in a vehicle made up of water, alcohol or glycerin. Gels are semi-solid preparations 10 made by gelling a solution or suspension of the active ingredient in a carrier vehicle. The vehicles, which can be hydrous or anhydrous, are gelled using a gelling agent, e.g. carboxy polymethylene, and neutralized to a proper gel consistency with the use of alkalies, e.g. sodium hydroxide, 15 or amines, such as polyethylenecocoamine. <br><br>
Example 1 <br><br>
a) A mixture of 3.24 g of [1(R*),3aR*-(3afl,4a.7aa)]-20 3a.4.5.6.7.7a-hexahydro-4-hydroxy-fl.7a-dimethyl-3H-indene-1-ethanol. 30 ml of pyridine and 3.51 g of p-toluenesulfonyl chloride is stirred at 0° for 18 hr. After addition of ice and dilution with water, the mixture is extracted with methylene chloride. The organic phase is washed with IN 25 H2S04, saturated NaHC03, then dried and evaporated. <br><br>
The residue is chromatographed on silica gel with ethyl acetate-hexane (1:1:5) to afford 4.61 g (82%) of [1(R*),3aR*-(3afi.4a,7aa)]-3a,4,5.6,7,7a-hexahydro- <br><br>
4-hydroxy-fl,7a-dimethyl-3H-indene-1-ethanol -4-methy1-benzenesulfonate, + 31.9° (c 0.53. CHClj). <br><br>
b) To a solution of 4.61 g of the product of a) in 22 ml of DMSO is added 1.10 g of sodium cyanide and the mixture is heated at 90°C for 2 hours. After cooling to room 35 temperature, the mixture is pumped to remove the solvent, then diluted with water. The mixture is extracted with ether. The organic phase is washed with saturated brine. <br><br>
3 <br><br>
4 <br><br>
- 20 - <br><br>
22 7 6 A 1 <br><br>
deled and evaporated. The residue is chromatographed on silica gel with methylene chloride-hexane-ethyl acetate <br><br>
(86:7:7) to give 2.52 g (91*) of [l(R*).3aR*- <br><br>
(3aB,4a,7aa)J-3a,4.5,6.7,7a-hexahydro-4-hydroxy-fl.7a- <br><br>
21 <br><br>
dimethyl-3H- indene-l-propanenitr ile, [<*3^ + 29.2° (C 0.65, CHC13). <br><br>
c) To a mixture of 6.85 ml of diisobutylalurainium hydride in hexane and 5.2 ml of methylene chloride at -6°C is added a solution of 0.430 g of the product of b) in 10 ml of methylene chloride. The mixture is stirred at -6°C for 55 minutes. After addition of saturated ammonium chloride, the mixture is hydrolyzed with 3N HCl-ether (2:1). The aqueous layer is extracted with ether. The organic layers are washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:2) to afford 260 mg (60*) [1(R*),3aR*-(3afl,4a,7aa)]- <br><br>
-3 a,4,5,6,7,7a-hexahydr o-4- hydroxy-fl,7a-dimethyl-3H-indene--1-propanal, [a]22 + 43.1° (c 0.32. CHC13). <br><br>
d) A mixture of 1.77 g of triphenylphosphine. 2.23 g of carbon tetrabromide, 441 mg of Zn dust and 23 ml of methylene chloride is stirred at 25°c for 31 hours. To this mixture is added a solution of 0.430 g of the product of c) in 38 ml of methylene chloride and the mixture is stirred for 18 hours. The mixture is diluted with pentane and insoluble material is filtered off. The insoluble fraction is dissolved in methylene chloride and the solution is again diluted with pentane. After filtration, the combined filtrates are evaporated. The residue is purified on silica gel with 1:4 ethyl acetate-hexane to give 0.490 g (67%) of <br><br>
[ 1 (R*), 3aR*- (3aJ3 , 4a,7aa) ]-1- (4, 4-dibromo- 1-methyl -3-butenyl)-3a,4,5,6,7,7a-hexahydro-7a- methyi-3H-indene-4-ol, [a]^2 + 14.4° (c 0.55, CHC13). <br><br>
e) To a solution of 0.680 g of the product of d) in 31 ml of THF at -75°C are added dropwise 3.77 ml of 1.6M solution <br><br>
22 7 641 <br><br>
- 21 - <br><br>
of butyllithium in hexane. The mixture is stirred at -75°C for 1 hour and at 25°C for 1 hr. After addition of saturated brine, the mixture is diluted with saturated aqueous NaHCO^ and extracted with ether. The organic phase is washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:4) to afford 0.350 g (89*) of [1(R*).3aR*- <br><br>
(3aB.4a,7aa)]-3a,4,5,6,7,7a-hexahydro -7a-methyl-1-(l-methyl-3-but: <br><br>
10 (c 0.42. CH£13) <br><br>
(l-methyl-3-butynyl)-3H-inden-4-ol, [a]22 + 30.7° <br><br>
f) To a solution of 1.29 g of the product of e) in 80 ml of methylene chloride are added 3.59 g of l-(trimethylsilyl)-imidazole. The mixture is stirred at 25°C for 3 hours. After <br><br>
15 adding 40 ml of water and stirring for 20 minutes, the mixture is extracted with ethyl acetate. The organic phase is washed with water and saturated brine, dried and evaporated. The residue is purified on silica gel with ethyl acetate-hexane (1:15) to give 1.70 g (99*) of [1(R*),3aR*-20 (3afl.4a,7aa)]-3a,4,5,6,7,7a-hexahydro -7a-methyl-1- <br><br>
(l-methyl-3-butynyl)-4-[(triraethylsilyl)oxy] -3H-indene, [a]20 + 39.7° (c 0.30, CHC13). <br><br>
g) To a solution of 1.70 g of the product of f) in 48 ml of 25 THF at -75°C are added dropwise 6.01 ml of 1.6M butyllithium in hexane. After stirring for 40 minutes, 3.05 ml of acetone are added and the mixture is stirred at -75°C for 20 minutes and at 25°C for 75 minutes. After addition of 40 ml of a 1:1 <br><br>
mixture of 2M KHCC>3 and 1M potassium sodium tartrate, the <br><br>
30 mixture is stirred for 20 minutes and then extracted with ethyl acetate. The organic phase is washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate hexane (1:5) to give 1.62 g <br><br>
(89%) of [ 1 (R*) , 3aR*- ( 3aJ3,4a,7aa) ]- 6 - ( 3a , <br><br>
35 4,5,6,7,7a-hexahydro-7a-methyl-4-[(trimethylsilyl)oxy]- <br><br>
20 <br><br>
3H-inden-l-yl)-2-methyl-3-heptyn-l-ol, [a]D + 39.7° <br><br>
22 7 6 4 1 <br><br>
- 22 - <br><br>
(c 0.30, chc13). <br><br>
h) To a solution of 1.62 g of the product of 9) in 53 ml of THF are added 15.5 ml of 1M tetrabutylammonium fluoride in THF. The mixture is stirred for 50 minutes. After dilution with half saturated NaHCO^. the mixture is evaporated to remove most of the solvent and extracted with ethyl acetate. The organic phase is washed with half saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:1) to give 1.17 g (82%) of <br><br>
[1 (R*),3aR*-(3afl,4a,7aa)J-3a.4.5.6,7,7a-hexahydro <br><br>
-1-(1,5-dimethy1-5-hydroxy-3-hexynyl)-7a-methyl-3H-inden-4-ol, <br><br>
m.p. 105-107°. <br><br>
i) To a solution of 0.720 g of the product of h) in 44 ml of methylene chloride are added 1.59 g of sodium acetate and <br><br>
3.18 g of 2.21-bipyridinium chlorochromate. The mixture is stirred for 2 hours. Additional 1.59 g of 2,2'-bipyridinium chlorochromate are then added and the stirring continued for <br><br>
2 hours. Then, after the addition of 6 ml of 2-propanol, the mixture is diluted with water and extracted with ether-ethyl acetate (1:1). The organi? phase is washed with water, IN <br><br>
H.SO., saturated NaHCO. and saturated brine. After 2 4 3 <br><br>
drying, the solution is evaporated and the residue chromatographed on silica gel with ethyl acetate-hexane (1:1) to give 0.560 g (78%) of [1(R«).3aR*-(3afl.7aa)]- <br><br>
-3.3a.5.6.7.7a-hexahydro-l-(5-hydroxy-1.5-dimethy1- <br><br>
20 <br><br>
-3-hexynyl)-7a-methyl-4H-inden-4-one, [a]D +35.3° (c 0.36, CHC13). <br><br>
j) To a solution of 0.552 g of the product of i) in 70 ml of methylene chloride are added 2.00 g of l-(trimethyl-silyl)imidazole. After stirring for 17 hours and addition of 22 ml of water, the mixture is extracted with ethyl acetate. The organic phase is washed with water and saturated brine, then dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:4) to give 0.693 g <br><br>
-4* <br><br>
227641 <br><br>
n i W <br><br>
- 23 - <br><br>
(99%) of [1(R*).3aR«-(3afl,7aa)]-3.3a.5, 6.7,7a~hexahydro <br><br>
-1-(1.5-dimethyl-5-[(tc imethylsilyl)oxy] - 3-hexynyl) <br><br>
20 <br><br>
-7a-methyl-4H-inden-4-one. [a]D + 29.5° (c 0.20, <br><br>
O CHC13). <br><br>
5 <br><br>
k) To a solution of 2.00 g of [ 3S-(IZ, 3a. 5J3) ]-[2-[3,5-bis[[(l,l-dimethyl)dimethylsilyl]oxy]-2-raethylene-cyclohexylidene]ethyl]diphenylphosphine oxide in 45 ml of THF at -75°C ace added dcopwise 1.87 ml of 1. 6M butyllithium ( 10 i-n hexane. After stirring for 6 minutes a solution of <br><br>
"j 0.693 g of the product of j) in 26 ml of THF are added <br><br>
J dropwise. After stirring at -75°C for 70 minutes and <br><br>
/( addition of a 1:1 mixture of IM potassium sodium tartrate <br><br>
| and 2M KHC03, the mixture is extracted with ethyl acetate, <br><br>
i 15 The organic phase is washed with saturated brine, dried and <br><br>
| evaporated. The residue is chromatogcaphed on silica gel <br><br>
; with ethyl acetate-hexane (1:15) to give 1.23 g (87%) of <br><br>
| (la.3J3,5Z.7E)-1.3-bis[(l. 1-d imethylethy 1) dime thy Is i ly 1 ] <br><br>
I -oxy-2 5-[(trimethylsilyl)oxy]-9,10-secocholesta-5,7,10(19), 16- <br><br>
? 20 tetraene-3-yne, + 47.1° (c 0.21, CHC13). <br><br>
1) To a solution of 0.228 g of the product of k) in 11 ml of THF are added 1.92 ml of IM tetcabutylammonium fluoride in THF. The mixture is stirred for 16 hours. After dilution 25 with water, the mixture is extracted with ethyl acetate. The organic phase is washed with half saturated brine and saturated brine, dried and evaporated. The residue is purified on silica gel with ethyl acetate-hexane (3:1) to afford 0.126 g (96%) of 1,25-dihydcoxy-l6-dehydro-23~dide-30 hydrocholecalciferol, + 21.5+ (c 0.20, MeOH). <br><br>
Example 2 <br><br>
a) As described in Example lk), but starting from 0.343 g 35 of [5S-(1Z)]-[2-[5-[[(1.1-dimethylethyl)dimethylsilyl]oxy] -2-methylenecyclohexylideneJ ethyl]d iphenylphos phine oxide and 0.186 g of thTe/^^pdUct of Example Ij). there were <br><br>
fvi.* <br><br>
y'y"-'rz-fK^. <br><br>
22 7 6 4 1 <br><br>
24 - <br><br>
10 <br><br>
obtained 0.205 g (80*) of (3B.5Z.7E)-3-[[(1.1-dimethyl-ethy1)dimethylsilyl]oxy]-25-[(trimethylsilyl)oxy] -9,10-secocholesta-5,7.10(19),16- tetraen-23-yne. MS m/e 580 (M+). <br><br>
b) By treating 0.248 g of the product of a) as described in Example 11). there were obtained 0.153 g (91*) of 25-hydroxy-16-dehydro-23-didehydrocholecalciferol. [a]21 +99.6° (c 0.25). MeOH). <br><br>
Example 3 <br><br>
a) To a mixture of 0.146 g of lithium aluminum hydride, <br><br>
0.211 g of sodium methoxide and 6.5 ml of THF at 0°C is <br><br>
15 added dropwise a solution of 0.180 g of the product of <br><br>
Example lh) in 13 ml of THF. The mixture is heated at 68°C <br><br>
for 16 hours and recooled at 0°C. After dilution with 13 ml of ether and addition of 0.30 mi of water and 0.26 ml of 10* <br><br>
aqueous NaOH, the mixture is stirred at room temperature for <br><br>
20 I hour and filtered. The solids are triturated with ether and filtered. The combined filtrates are evaporated and chromatographed on silica gel with ethyl acetate-hexane <br><br>
(1:2) to give 0.179 g (99*) of [1(R*),1(3E).3afl.4a,- <br><br>
7aa)]-(3a,4,5,6,7,7a-hexahydro-1-(5-hydroxy-1.5-dimethy1- <br><br>
21 <br><br>
25 -3-hexenyl)-7a-methyl-lH-inden-4-ol. [aj^ +11.5° (c <br><br>
0.33. CHC13). <br><br>
b) To a solution of 0.120 g of the product of a) in 10 mi of methylene chloride are added 0.500 g of pyridiniura 30 dichromate and 25 rag of pyridinium p-toluenesulfonate. The mixture is stirred for 135 minutes. After addition of 40 ml of ether, the mixture is stirred for 5 minutes and filtered. The solids are triturated with ether and filtered. The combined filtrates are washed with saturated aqueous 35 CuS04. water, half saturated aqueous NaHC03 and saturated brine. The organic phase is dried and evaporated. The residue is chromatographed on silica gel with 35% ethyl <br><br>
22 7 6 A 1 <br><br>
- 25 - <br><br>
acetate-hexane to give 90 mg (76*) of [1(R*).l(3E).(3afl. 7aa)]-3.3a.5.6.7,7a-hexahydro-l-(5 -hydroxy-1.5-dimethyl-3-hexenyl)-7a-methyl-4H-inden-4-one, <br><br>
[a]25 +30.6° (c 0.17. CHC13). <br><br>
c) By treating 0.099 g of the product of b) as described in Example lj)» there are obtained 0.111 g (89*) of <br><br>
[1 (R*).1(3E).(3afl.7aa)]-3.3a.5.6,7.7a-hexahydro-1-(1.5--dimethy1-5-[(trimethylsilyl)oxy]-3-hexenyl)-7a-methy1--4H-inden-4-one. [a]24 +26.4° (c 0.22. CHC13). <br><br>
d) As described in Example lk). starting from 0.265 g of [3S-(1Z.3a.5B)]-[2-[3,5-bis[[(1.1 -dimethyl)dimethyl- <br><br>
si lyl ] oxy] -2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.095 g of the product of c). there are obtained 0.162 g (83*) of (lfl.3a,5Z.7E.23E)-1,3-bis[[(1.1 -dimethylethy1)dimethylsilyl]oxy]-25-[(trimethylsilyl)oxy] -9,10-secocholesta-5.7.10(19).16,23-pentaene, MS m/e 712 (M+) . <br><br>
e) By treating 0.159 g of the product of d) as in Example <br><br>
11), there are obtained 0.077 g (84) of 1,25-dihydroxy- <br><br>
24 <br><br>
16,23E-bisdehydrocholecalciferol. [aJD +46.5° (c 0.20. MeOH). <br><br>
Example 4 <br><br>
a) As described in Example lk). starting from 0.225 g of [5S—(1Z)]-[2 — [5—C C(1.1-dimethylethy1)dimethylsilyl]oxy] -2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.110 g of the product of Example 3c), there are obtained 0.150 g (81*) of (3fi.5Z.7E.23E)-3-[[(1.1-dimethylethyl)-dimethylsilyl]oxy] -25-[(trimethylsilyl)-oxy]-9.10-secocholesta -5.7.10(19),16,23-pentaene. [a]24 +68.3° (c 0.18, CHC13). <br><br>
- 26 - <br><br>
22 7 6 4 1 <br><br>
b) By treating 0.144 g of the product of a) as described in Example 11). there are obtained 0.076 g (78%) of 25-hydroxy-16,2 3E-bisdehydrocholecalciferol. <br><br>
[a]22 +62.5° (c 0.20, MeOH). <br><br>
Example 5 <br><br>
a) To a solution of 6.25 g of ethyl 3-bromopropionate in 28 ml of THF at -20°C are added 28.8 ml of 2.8M methylmagnesium bromide in ether. The mixture is stirred at room temperature for 170 minutes. After addition of 15 ml of saturated aqueous ammonium chloride and of 42 ml of IN HC1, the organic phase is separated and the aqueous phase extracted with ether. The organic extracts are washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with 30% ethyl acetate-hexane to give 2.57 g (45%) of 4-bromo-2-methyl-2-butanol. MS m/e 151 (M+-CH3). <br><br>
b) To a solution of 2.56 g of 4-bromo-2-methyl-2-butano1 and 4.86 g of imidazole in 15 ml of N.N-dimethylformamide at 0°C are added 6.48 g of chlorotriethylsilane. The mixture is stirred at room temperature for 200 minutes. After adding ice, the mixture is diluted with water and extracted with pentane. The organic phase is washed with water and saturated brine, dried and evaporated. The residue is chromatogrpahed on silica gel with pentane to give 4.02 g (93%) of (3-brorao-l,1-dimethylpropoxy)triethylsilane, MS m/e 265 (M+-CH3). <br><br>
c) To a solution of 0.930 g of [1(R*),3aR*(3afi,4a, 7aa)]-3a,4,5,6.7,7a-hexahydro -4-hydroxy-fl.7a-dimethy1-3H-indene-l-ethanol 4-methyl-benzenesulfonate and 1.10 g of imidazole in 73 ml of methylene chloride at 0°C are added 0.580 g of chlorotriethylsilane. The mixture is stirred at room temperature for 1.5 hours. After adding ice, the mixture is diluted with water and stirred for 20 minutes. <br><br>
22 7 6 4 1 <br><br>
- 27 - <br><br>
The organic layer is extracted with methylene chloride. The extracts are washed with water. IN N2S04< saturated <br><br>
^ aqueous NaHC03 and saturated brine. After drying and evaporation, the residue is purified on silica gel with <br><br>
5 ethyl acetate-hexane (1:5) to afford 1.22 g (100%) of <br><br>
[1(R*).3aR*-(3afl.4a.7aa)]-3a.4.5,6.7,7a-hexahydro <br><br>
-4-[(triethylsilyl)oxy]-fl.7a-dimethy1-3H-indene-l-ethanol <br><br>
20 <br><br>
4-methylbenze sulfonate. [a]D +46.1° (c 0.31. <br><br>
v <br><br>
CHC13). <br><br>
10 <br><br>
d) To a solution of 3.08 g of (3-bromo-1.1-dimethylpropoxy) triethylsilane in 31 ml of THF are added 0.282 g of magnesium. The mixture is heated at 68°C for 3.5 hours. Then a mixture of 0.686 g of cuprous iodide and the above <br><br>
15 mentioned Grignard solution are stirred at 3°C for 30 minutes. To this is added a solution of 1.02 g of the product of c) and the mixture is stirred at room temperature for 40 minutes. After adding a mixture of ice and water, the mixture is extracted with ether. The organic phase is washed 20 with IN H2S04 and saturated aqueous NaHC03< dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:15) to afford 1.80 g of [1 (R*),3aR*-(3afl,4a,7aa)J- 3a.4.5,6,7,7a-hexahydro--l-[1.5-dimethyl-5-[(triethylsilyl)- oxy]hexyl]-25 -4-[(triethyIsily1)oxy]-7a-methy1-3H-indene. MS m/e 479 (M+-Et). <br><br>
e) To a solution of 1.60 g of the product of d) in 5 ml of THF are added 2.00 ml of IM tetrabutylammonium fluoride in <br><br>
30 THF. The mixture is heated at 68°C for 50 minutes. After cooling to room temperature, the mixture is diluted with water and extracted with methylene chloride. The organic phase is washed with brine, dried and evaporated. The residue is purified on silica gel with ethyl acetate-hexane <br><br>
35 (1:1) to afford 0.420 g (79%) of [1(R*),3aR*-(3ai3, 4aa, <br><br>
7aa)]-3a.4,5,6.7.7a-hexahydro-4-hydroxy-a,a- e ,7a- <br><br>
21 <br><br>
tetramethyl-lH-indene-l-pentanol. [a]^ =+12.0° <br><br>
o <br><br>
A <br><br>
227641 <br><br>
- 28 - <br><br>
(C 0.25, CHC13). <br><br>
£) To a solution o£ 0.210 g of the product of e) in 18 ml of methylene chloride are added 0.870 g of pyridinium 5 dichromate and 44 mg of pyridinium p-toluenesulfonate. The mixture is stirred for 175 minutes. After addition of 50 ml of ether, the mixture is stirred for 5 minutes and filtered. The solids are washed with saturated aqueous CuSO.. water, <br><br>
4 <br><br>
half saturated aqueous NaHC03 and saturated brine. The 10 organic phase is dried and evaporated. The residue is chromatographed on silica gel with 35% ethyl acetate-hexane to give 0.175 g (84%) of [1(R*).3aR*-(3afl.7aa)]- <br><br>
3.3a.5.6,7,7a-hexahydro-1-(5-hydroxy-1,5-dimethylhexyl)-7a-meth: <br><br>
15 CHC13). <br><br>
7a-methyl-4H-inden-4-one, [cO^1 +28.2° (c 0.22, <br><br>
g) By treating 0.168 g of the product of f) as described in Example lj). there are obtained 0.211 g (100%) of <br><br>
[1(R*),3aR*-(3afl.7aa)]-3,3a.5.6.7.7a-hexahydro-l-(1.5- <br><br>
20 dimethy1-5-[(trimethyIsilyl)oxy]hexyl) - 7a-methyl-4H-inden-20 <br><br>
4-one, [a]£ +21.9° (c 0.27, CHC13). <br><br>
h) As described in Example Ik), starting from 0.581 g of [3S-(1Z,3a.5fl)]-[2-[3.5-bis[[(1.1-dimethy1)dimethylsily1]- <br><br>
25 oxy]-2-methylenecyclohexylidene]ethyl]diphenyl phosphine oxide and 0.210 g of the product of g). there are obtained 0.358 g (83%) of (la.3fl.5Z.7E)-1.3-bis[[(1.1-dimethyl-ethyl)dimethylsilyl]oxy]-25-[(trimethylsilyl)oxy]-9,10-secocholesta-5,7,10(19),16-tetraene, MS m/e 714 (M+). <br><br>
30 <br><br>
i) Treating 0.350 g of the product of h) as described in <br><br>
Example 11), there are obtained 0.168 g (83%) of <br><br>
1,25-dihydroxy-16-dehydrocholecalciferol, <br><br>
20 <br><br>
[a]£ +40.0° (c 0.17. MeOH). <br><br>
35 <br><br>
i i) <br><br>
fj <br><br>
< <br><br>
- 29 - <br><br>
22 7 6 4 1 <br><br>
Example 6 <br><br>
a) As described in Example Ik) starting from 0.383 g of [5S-(1Z)]-[2-[5-[[(l.l-dimethylethyl)dimethylsilyl]oxyJ-2-methylenecyclohexylidene]ethylJdiphenylphosphine oxide and 0.188 g of the product of Example 5g), there are obtained 0.245 g (78*) of (3a.5Z.7E)-3-[[(l.l-dimethylethyl)- <br><br>
dimethyIsilylJ oxyJ - 25-[(trimethylsilyl)oxy]-9,10-seco-cholesta-5.7.10(19),16-tetraene, [a]24 +67.5° (c 0.20. CHC13). <br><br>
b) Treating 0.239 g of the product of a) as described in Example 11) affords 0.135 g (83*) of 25-hydroxy-16-dehydro-cholecalcif erol. +75.4° (c ».13, Me OH). <br><br>
The following Example A and B illustrate the composition of soft gelatine capsules for oral administration and of a topical cream: <br><br>
Example A <br><br>
Butylated hydroxytoluene Butylated hydroxyanisole Fractionated coconut oil <br><br>
Compound E <br><br>
mq/capsule 0.0001-0.010 0.016 <br><br>
0.016 <br><br>
160.0 <br><br></p>
</div>
Claims (1)
- <div class="application article clearfix printTableText" id="claims"> <p lang="en"> 22 7 6 4 1<br><br> - 30 -Example B<br><br> Comppound E Cetyl alcohol Stearyl alcohol Sorbitan monostearate Glyceryl monostearate and polyoxyechylene glycol stearate Polysorbate 60 Mineral oil Propylene glycol Propylparaben Butylated hydroxyanisole Sorbitol solution Edetate disodium Methylparaben Distilled water mq/q of cream 0.001-1.0 1.5 2.5 2.0<br><br> 4.0 1.0 4.0 5.0 0.05 0.05 2.0 0.01 0.18 q.s. to 100 g<br><br> 727641<br><br> 31<br><br> WHAT WE CLAIM IS:<br><br> 1. A compound of the formula ho'*;r;I;wherein R is hydrogen or hydroxy and A is -CEC--CH=CH- with E-configuration or -CH2-CH2-.;2. A compound in accordance with claim 1, of the group consisting of:;1.25-d ihydroxy-16-dehydro-23-didehydrocholecalciferol, 1.25-d ihydroxy-16,2 3E-bisdehydrocholecalc ifero1 and 1.25-dihydroxy-16-dehydrocholecalciferol.;3. A compound in accordance with claim 1 or 2 for use as a therapeutically active substance, particularly for the treatment of hyperproliferative diseases of the skin, especially psoriasis, or for the treatment of neoplastic diseases, especially leukemia.;4. A process for the preparation of a compound according to claim 1 or 2, which process comprises reacting a corresponding compound of formula I containing instead of : three hydroxy groups two or three protected wherein Rn and R, are C. .-alkyl and R_ is 1 3 1-4 2;C1_4-alkyl, aryl or aryl-C^ 4-alkyl.;with an agent capable of removing the protecting groups.;xy\groups of the formula;-OSi(R1,R2,R3);32;227641;5. A medicament, particularly for the treatment of hyperproliferative diseases of the skin, especially psoriasis, or for the treatment of neoplastic diseases, especially leukemia, comprising an effective amount of a compound according to claim 1 or 2 and a pharmaceutically effective carrier material, particularly for oral or topical administration.;6. The use of a compound in accordance with claim 1 or 2 for the manufacture of a medicament for the treatment of hyperproliferative diseases of the skin, especially psoriasis, oc for the treatment of neoplastic diseases, especially leukemia.;7 . A compound in accordance with claim 1 substantially as described herein, particularly with reference to any one of Examples 1 to 6.;8. The process for the preparation of a compound according to claim 1, substantially as described herein, particularly with reference to any one of Examples 1 to 6.;g . A medicament comprising a compound according to claim 1 substantially as described herein, particularly with reference to either Example A or Example B.;DATED THIS 22. DAY OF*<br><br> </p> </div>
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US14593288A | 1988-01-20 | 1988-01-20 |
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NZ227641A true NZ227641A (en) | 1991-06-25 |
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NZ227641A NZ227641A (en) | 1988-01-20 | 1989-01-17 | 16-dehydro-vitamin d 3 (dehydrocholecalciferol) derivatives; medicaments and preparatory processes |
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EP (1) | EP0325279B1 (en) |
JP (1) | JPH0764806B2 (en) |
KR (1) | KR960009119B1 (en) |
AR (1) | AR247551A1 (en) |
AT (1) | ATE74350T1 (en) |
AU (1) | AU622139B2 (en) |
BG (1) | BG60530B2 (en) |
CA (1) | CA1337529C (en) |
DE (1) | DE58901056D1 (en) |
DK (1) | DK169945B1 (en) |
ES (1) | ES2033467T3 (en) |
FI (1) | FI90764C (en) |
GR (1) | GR3004786T3 (en) |
HU (1) | HU201007B (en) |
IE (1) | IE60921B1 (en) |
IL (1) | IL88989A (en) |
MC (1) | MC1998A1 (en) |
NO (1) | NO175429C (en) |
NZ (1) | NZ227641A (en) |
PH (1) | PH25605A (en) |
PT (1) | PT89486B (en) |
YU (1) | YU47298B (en) |
ZA (1) | ZA8923B (en) |
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US4804502A (en) * | 1988-01-20 | 1989-02-14 | Hoffmann-La Roche Inc. | Vitamin D compounds |
EP0398217B1 (en) * | 1989-05-18 | 1994-01-12 | F. Hoffmann-La Roche Ag | Dehydrocholecalciferol derivatives |
AU650751B2 (en) * | 1991-05-28 | 1994-06-30 | Wisconsin Alumni Research Foundation | Novel synthesis of 19-nor vitamin D compounds |
ES2091515T3 (en) * | 1992-05-20 | 1996-11-01 | Hoffmann La Roche | FLUORATED ANALOGS OF VITAMIN D3. |
US5753638A (en) * | 1992-10-07 | 1998-05-19 | Hoffmann-La Roche Inc. | Method of treating hyperproliferative skin disease with Vitamin D3 fluorinated analogs |
CA2096105A1 (en) * | 1992-10-07 | 1994-04-08 | Enrico Giuseppe Baggiolini (Deceased) | Vitamin d3 fluorinated analogs |
TW267161B (en) * | 1992-11-20 | 1996-01-01 | Hoffmann La Roche | |
US5401733A (en) * | 1993-10-01 | 1995-03-28 | Hoffmann-La Roche Inc. | Stable and active metabolites of 1,25-dihydroxy-16-ene-cholecalciferol |
US5428029A (en) * | 1993-11-24 | 1995-06-27 | Hoffmann-La Roche Inc. | Vitamin D3 fluorinated analogs |
TW403735B (en) * | 1995-11-22 | 2000-09-01 | Hoffmann La Roche | 25-hydroxy-16-ene-26, 27-bishomo-cholecalciferol |
AU708679B2 (en) * | 1996-03-21 | 1999-08-12 | F. Hoffmann-La Roche Ag | 1,25-dihydroxy-16,22,23-trisdehydro-cholecalciferol derivatives |
SG70009A1 (en) * | 1996-05-23 | 2000-01-25 | Hoffmann La Roche | Vitamin d3 analogs |
US5939408A (en) * | 1996-05-23 | 1999-08-17 | Hoffman-La Roche Inc. | Vitamin D3 analogs |
EP0884308B1 (en) * | 1997-05-02 | 2003-04-16 | Duphar International Research B.V | A method of preparing 16-dehydro vitamin D compounds |
US6331642B1 (en) * | 1999-07-12 | 2001-12-18 | Hoffmann-La Roche Inc. | Vitamin D3 analogs |
US9221753B2 (en) * | 2004-02-03 | 2015-12-29 | Chugai Seiyaku Kabushiki Kaisha | Process for the synthesis of vitamin D compounds and intermediates for the synthesis of the compounds |
EP1883626B1 (en) * | 2005-04-25 | 2017-10-11 | OPKO Ireland Global Holdings, Ltd. | Low-calcemic 16,23-diene 25-oxime analogs of 1alpha,25-dihydroxy vitamin d3 |
CA2619311A1 (en) * | 2005-08-18 | 2007-02-22 | Bioxell S.P.A. | Synthesis of 1.alpha.-fluoro-25-hydroxy-16-23e-diene-26,27-bishomo-20-epi-cholecalciferol |
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DE2812741C2 (en) * | 1977-03-24 | 1987-03-12 | Wisconsin Alumni Research Foundation, Madison, Wis. | Vitamin D↓3↓ derivatives, processes and intermediates for their preparation and medicinal products containing them |
FR2426044A2 (en) * | 1978-05-19 | 1979-12-14 | Wisconsin Research Foundation | VITAMIN D3 DERIVATIVES WITH ANTI-VITAMIN D ACTIVITY |
US4360471A (en) * | 1981-12-11 | 1982-11-23 | Wisconsin Alumni Research Foundation | 23-Dehydro-25-hydroxyvitamin D3 |
US4508651A (en) * | 1983-03-21 | 1985-04-02 | Hoffmann-La Roche Inc. | Synthesis of 1α,25-dihydroxyergocalciferol |
US4505906A (en) * | 1984-01-30 | 1985-03-19 | Wisconsin Alumni Research Foundation | Hydroxyvitamin D2 isomers |
US4612308A (en) * | 1984-11-29 | 1986-09-16 | Hoffmann-La Roche Inc. | 25,26-Dehydro-1α,23(S,R)-dihydroxycholecalciferol and its epimers |
US4898855A (en) * | 1987-09-14 | 1990-02-06 | Hoffman-La Roche Inc. | Deuterated analogs of 1,25-dihydroxycholecalciferol |
US4804502A (en) * | 1988-01-20 | 1989-02-14 | Hoffmann-La Roche Inc. | Vitamin D compounds |
EP0398217B1 (en) * | 1989-05-18 | 1994-01-12 | F. Hoffmann-La Roche Ag | Dehydrocholecalciferol derivatives |
-
1989
- 1989-01-03 ZA ZA8923A patent/ZA8923B/en unknown
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