NO300209B1 - Analogous Process for Preparation of Side-Chain Homologous Vitamin D Derivatives - Google Patents
Analogous Process for Preparation of Side-Chain Homologous Vitamin D Derivatives Download PDFInfo
- Publication number
- NO300209B1 NO300209B1 NO913913A NO913913A NO300209B1 NO 300209 B1 NO300209 B1 NO 300209B1 NO 913913 A NO913913 A NO 913913A NO 913913 A NO913913 A NO 913913A NO 300209 B1 NO300209 B1 NO 300209B1
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- denotes
- hydroxy
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- 238000000034 method Methods 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims description 12
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- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
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- 125000004423 acyloxy group Chemical group 0.000 claims description 5
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- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 2
- 235000005282 vitamin D3 Nutrition 0.000 description 2
- 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 2
- CLNKPEBBYRPFKN-UHFFFAOYSA-M (2-oxo-4-propan-2-yloxybutyl)-triphenylphosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC(=O)CCOC(C)C)C1=CC=CC=C1 CLNKPEBBYRPFKN-UHFFFAOYSA-M 0.000 description 1
- WUAOFWYIMBQLIU-UHFFFAOYSA-M (4-methyl-2-oxopentyl)-triphenylphosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC(=O)CC(C)C)C1=CC=CC=C1 WUAOFWYIMBQLIU-UHFFFAOYSA-M 0.000 description 1
- CSXGZXSMJNQAOP-UHFFFAOYSA-N 1-(cyclopropylmethoxy)-3-(triphenyl-$l^{5}-phosphanylidene)propan-2-one Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)=CC(=O)COCC1CC1 CSXGZXSMJNQAOP-UHFFFAOYSA-N 0.000 description 1
- VXEXQQZXNUFFCG-UHFFFAOYSA-N 1-bromo-4-propan-2-yloxybutan-2-one Chemical compound CC(C)OCCC(=O)CBr VXEXQQZXNUFFCG-UHFFFAOYSA-N 0.000 description 1
- LAIOKBCBCQXLNI-UHFFFAOYSA-N 1-bromo-5-methylhexan-2-one Chemical compound CC(C)CCC(=O)CBr LAIOKBCBCQXLNI-UHFFFAOYSA-N 0.000 description 1
- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 description 1
- XARVANDLQOZMMJ-CHHVJCJISA-N 2-[(z)-[1-(2-amino-1,3-thiazol-4-yl)-2-oxo-2-(2-oxoethylamino)ethylidene]amino]oxy-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)O\N=C(/C(=O)NCC=O)C1=CSC(N)=N1 XARVANDLQOZMMJ-CHHVJCJISA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- JWUBBDSIWDLEOM-UHFFFAOYSA-N 25-Hydroxycholecalciferol Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CCC1=C JWUBBDSIWDLEOM-UHFFFAOYSA-N 0.000 description 1
- 239000003872 25-hydroxy-cholecalciferol Substances 0.000 description 1
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
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- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 235000021318 Calcifediol Nutrition 0.000 description 1
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- 206010009944 Colon cancer Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000011785 NMRI mouse Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 101710183568 Serine/threonine-protein kinase PknK Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- RIJGYYOKRFBBGY-UHFFFAOYSA-J [Cl-].[Ce+3].[Na+].[Cl-].[Cl-].[Cl-] Chemical compound [Cl-].[Ce+3].[Na+].[Cl-].[Cl-].[Cl-] RIJGYYOKRFBBGY-UHFFFAOYSA-J 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- PNZVFASWDSMJER-UHFFFAOYSA-N acetic acid;lead Chemical compound [Pb].CC(O)=O PNZVFASWDSMJER-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- JWUBBDSIWDLEOM-DTOXIADCSA-N calcidiol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DTOXIADCSA-N 0.000 description 1
- 150000001668 calcitriol derivatives Chemical class 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic 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
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical compound C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 108010007093 dispase Proteins 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- XCSNRICUVQIXEM-UHFFFAOYSA-N ethyl 2-(2-diethoxyphosphorylethoxy)acetate Chemical compound CCOC(=O)COCCP(=O)(OCC)OCC XCSNRICUVQIXEM-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- VBQCHPIMZGQLAZ-UHFFFAOYSA-N phosphorane Chemical class [PH5] VBQCHPIMZGQLAZ-UHFFFAOYSA-N 0.000 description 1
- 210000004765 promyelocyte Anatomy 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 1
- 229960000342 retinol acetate Drugs 0.000 description 1
- 235000019173 retinyl acetate Nutrition 0.000 description 1
- 239000011770 retinyl acetate Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 229960005322 streptomycin Drugs 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
- 229940104230 thymidine Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 1
- 150000004072 triols Chemical class 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
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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
- A61P35/00—Antineoplastic agents
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)
- 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)
- Lubricants (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pyrane Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
Foreliggende oppfinnelse angår en analogifremgangsmåte for fremstilling av sidekjede-homologe vitamin-D-derivater med formel I The present invention relates to an analogue method for the production of side-chain homologous vitamin D derivatives of formula I
hvori in which
R<1> betegner et hydrogenatom, en hydroksy- eller R<1> denotes a hydrogen atom, a hydroxy or
acyloksygruppe med 1 til 9 karbonatomer, acyloxy group with 1 to 9 carbon atoms,
R<2> betegner et hydrogenatom eller en acylgruppe med 1 R<2> denotes a hydrogen atom or an acyl group with 1
til 9 karbonatomer, to 9 carbon atoms,
R<3> eller R4 betegner en hydroksy- eller acyloksygruppe med 1 R<3> or R4 denotes a hydroxy or acyloxy group with 1
til 9 karbonatomer og den andre substituenten betegner et hydrogenatom, eller R3 og R4 betegner sammen et oksygenatom, to 9 carbon atoms and the second substituent represents a hydrogen atom, or R3 and R4 together represent an oxygen atom,
R<5> og R6 betegner uavhengig av hverandre en lineær eller for-grenet alkylrest med inntil 5 karbonatomer, en tri-fluormetylgruppe eller danner med det tertiære karbonatom sammen en mettet, umettet eller aromatisk karbosyklisk, eller ved inkludering ved 1 eller 2 N-, 0- eller S-atomer, en heterosyklisk 3-, 4-, 5- eller 6-leddet ring, R<5> and R6 independently denote a linear or branched alkyl residue with up to 5 carbon atoms, a trifluoromethyl group or form together with the tertiary carbon atom a saturated, unsaturated or aromatic carbocyclic, or by inclusion at 1 or 2 N- , 0 or S atoms, a heterocyclic 3-, 4-, 5- or 6-membered ring,
B og D betegner enten et hydrogenatom eller sammen en andre B and D denote either a hydrogen atom or together another
binding (E-konfigurert dobbeltbinding) og bond (E-configured double bond) and
A betegner enten en direkte binding mellom karbon-at omene 20 og 22 og A denotes either a direct bond between carbon atoms 20 and 22 and
X betegner en alkylenoksyrest -(CH2)nO- hvor n = 1 til 3; X denotes an alkyleneoxy acid residue -(CH2)nO- where n = 1 to 3;
eller or
A betegner en metylenbro (-CH2-) mellom karbonatomene A denotes a methylene bridge (-CH2-) between the carbon atoms
20 og 22 og 20 and 22 and
X betegner en alkylenrest -(CH2)n- eller en alkylenoksyrest -(CH2)n0- hvor n = 1 til 3; X denotes an alkylene residue -(CH2)n- or an alkyleneoxy acid residue -(CH2)n0- where n = 1 to 3;
eller; or;
når A betegner en direkte binding og B og D sammen be- when A denotes a direct bond and B and D together denote
tegner en andre binding, betegner draws a second bond, denotes
en av restene kjennetegnet ved at en forbindelse med generell formel IV one of the residues characterized in that a compound of general formula IV
hvori in which
R<1>' betegner et hydrogenatom eller en beskyttet hydroksygruppe og R<1>' denotes a hydrogen atom or a protected hydroxy group and
R2 betegner en hydroksybeskyttelsesgruppe og R 2 denotes a hydroxy protecting group and
A, X, R<5> og R6 har betegnelsene angitt for formel I, A, X, R<5> and R6 have the designations given for formula I,
om ønskelig etter selektiv hydrering av dobbeltbindingen i sidekjeden, omdannes til en forbindelse med generell formel IVa if desired after selective hydration of the double bond in the side chain, is converted into a compound of general formula IVa
hvori R<1>', R<2>', A, X, R<5> og R6 har betegnelsen angitt i formel IV og om ønskelig, et reduksjon av karbonyl funksjonen og eventuelt etter atskillelse av blandingen av de ved reduksjonen dannede epimere hydroksyforbindelser med generell formel Illa og Illb in which R<1>', R<2>', A, X, R<5> and R6 have the designation indicated in formula IV and, if desired, a reduction of the carbonyl function and optionally after separation of the mixture of the epimers formed by the reduction hydroxy compounds of general formula Illa and Illb
hvori in which
R<1>', R<2>', A, X, R<5> og R6 har betegnelsene angitt i formel IV, og B og D har betegnelsene angitt i formel I, ved bestråling med ultrafiolett lys under invertering av stereoisomerien ved 5,6-dobbeltbindingen, omdannes til en forbindelse med generell formel II R<1>', R<2>', A, X, R<5> and R6 have the designations indicated in formula IV, and B and D have the designations indicated in formula I, upon irradiation with ultraviolet light while inverting the stereoisomerism by The 5,6-double bond is converted into a compound of general formula II
hvori in which
R<1>', R<2>', A, B, D, X, R<5> og R6 har betegnelsene angitt i formel Illa/IIIb, R<1>', R<2>', A, B, D, X, R<5> and R6 have the designations given in formula Illa/IIIb,
og denne forbindelse deretter, ved avspalting av foreliggende hydroksybeskyttelsesgrupper og eventuelt ved delvis eller fullstendig forestring av hydroksygruppene, overføres til en forbindelse med generell formel I. and this compound then, by splitting off the present hydroxy protecting groups and optionally by partial or complete esterification of the hydroxy groups, is transferred to a compound of general formula I.
De for restene R<1>, R2, og innen restene R<3> eller R<4>, mulige acyloksygrupper, henholdsvis acylgrupper, er spesielt avledet fra mettede karboksylsyrer eller også benzosyre. Andre egnede acylrester i R<1>, R2, R3 og R<4> omfatter sykliske, asykliske, karbosykliske eller heterosykliske rester, hvilke alle eventuelt også kan være umettet. De foretrukne rester er avledet fra Cx- til C9-, fortrinnsvis C2- til C5-alkankarboksyl-syrer, som f.eks. eddiksyre, propionsyre og smørsyre. Those for the residues R<1>, R2, and within the residues R<3> or R<4>, possible acyloxy groups, respectively acyl groups, are especially derived from saturated carboxylic acids or also benzoic acid. Other suitable acyl residues in R<1>, R2, R3 and R<4> include cyclic, acyclic, carbocyclic or heterocyclic residues, all of which may optionally also be unsaturated. The preferred residues are derived from Cx- to C9-, preferably C2- to C5-alkanecarboxylic acids, such as e.g. acetic acid, propionic acid and butyric acid.
Når R<5> og R6 sammen med det tertiære karbonatom danner en mettet karbosyklisk ring, kommer spesielt en syklopropylring eller sykloheksylring i betraktning. Som alkyl-grupper for R<5> og R<6> kommer spesielt slike med 1 til 5 karbonatomer i betraktning, hvilke kan være rettkjedede eller for-grenede. Eksempelvis nevnes metyl-, etyl-, propyl-, såvel som When R<5> and R6 together with the tertiary carbon atom form a saturated carbocyclic ring, in particular a cyclopropyl ring or cyclohexyl ring comes into consideration. As alkyl groups for R<5> and R<6> in particular those with 1 to 5 carbon atoms come into consideration, which can be straight-chain or branched. Examples include methyl, ethyl, propyl, as well as
t-butylgruppen. the t-butyl group.
Foretrukne forbindelser fremstilt ifølge foreliggende oppfinnelse er sidekjede-homologe vitamin-D-derivater med generell formel I, hvori Preferred compounds prepared according to the present invention are side chain homologous vitamin D derivatives of general formula I, wherein
R<1>, R<3> eller R<4> betegner en hydroksygruppe eller, R<1>, R<3> or R<4> denotes a hydroxy group or,
R<5> og R<6> betegner en metylgruppe eller betegner sammen med det tertiære karbonatom en syklopropylring, R<5> and R<6> denote a methyl group or together with the tertiary carbon atom denote a cyclopropyl ring,
R<2> betegner et hydrogenatom og n er 1 eller 2. R<2> denotes a hydrogen atom and n is 1 or 2.
Mellom karbonatomene 22 og 23 (når A betegner en direkte binding) eller mellom karbonatomene 23 og 24 (når A betegner en metylengruppe) befinner det seg fortrinnsvis en dobbeltbinding. Spesielt foretrukne er forbindelsene Between carbon atoms 22 and 23 (when A denotes a direct bond) or between carbon atoms 23 and 24 (when A denotes a methylene group) there is preferably a double bond. Particularly preferred are the compounds
24-(1(R)-hydroksy-4-metylpentyl)-9,10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(R)-diol, 24-(1(R)-hydroxy-4-methylpentyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol,
24-(1(S)-hydroksy-4-metylpentyl)-9,10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(R)-diol, 24-(1(S)-hydroxy-4-methylpentyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol,
24-(1(R)-hydroksy-3-metylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(R)-diol, 24-(1(R)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol,
24-(1(S)-hydroksy-3-metylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(R)-diol, 24-(1(S)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol,
24-(l(R)-hydroksy-3-metylbutyl)-9,10-secochola-5Z,7E,10(19)trien-1(S),3(R)-diol, 24-(1(R)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19)triene-1(S),3(R)-diol,
24-(1(S)-hydroksy-3-metylbutyl)-9,10-secochola-5Z,7E,10(19)trien-1(S),3(R)-diol, 24-(1(S)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19)triene-1(S),3(R)-diol,
24-(l(R)-hydroksy-3-isopropoksypropyl)-9,10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(R)-diol, 24-(1(R)-hydroxy-3-isopropoxypropyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol,
24-(l(S)-hydroksy-3-isopropoksypropyl)-9,10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(R)-diol, 24-(1(S)-hydroxy-3-isopropoxypropyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol,
24-isopropoksymetyl-9,10-secochola-5Z,7E,10(19),22E-tetraen-l(S),3(R),24(R)-triol, 24-isopropoxymethyl-9,10-secochola-5Z,7E,10(19),22E-tetraene-1(S),3(R),24(R)-triol,
24-isopropoksymetyl-9,10-secochola-5Z,7E,10(19),22E-tetraen-1(S),3(R),24(S)-triol, 24-isopropoxymethyl-9,10-secochola-5Z,7E,10(19),22E-tetraene-1(S),3(R),24(S)-triol,
24-(2-isopropoksyetyl)-9,10-secochola-5Z,7E,10(19),22E-tetraen-1(S),3(R),24(R)-triol, 2 4-(2-i sopropoksyety1)-9,10-secochola-5Z,7E,10(19),22E-tetraen-l(S),3(R),24(S)-triol, 24-(2-isopropoxyethyl)-9,10-secochola-5Z,7E,10(19),22E-tetraene-1(S),3(R),24(R)-triol, 2 4-(2- i sopropoxyethyl 1)-9,10-secochola-5Z,7E,10(19),22E-tetraene-1(S),3(R),24(S)-triol,
26,27-syklo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23E-tetraen-l(S),3(R),24a(R)-triol, 26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23E-tetraene-1(S),3(R),24a(R)-triol,
26,27-syklo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23E-tetraen-1(S),3(R),24a(S)-triol, 26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23E-tetraene-1(S),3(R),24a(S)-triol,
De naturlige vitaminer D2 og D3 (se generell formel IV) er i seg selv biologisk inaktive og omdannes først etter hydroksylering i 25-posisjonen i leveren, henholdsvis i 1-posisjonen i nyrene, til deres biologisk aktive metabolit-ter. Virkningen av vitamin D2 og D3 består i stabiliseringen av plasma-Ca<++->speilet og plasma-fosfatspeilet: de motvirker en senkning av plasma-Ca<++->speilet. The natural vitamins D2 and D3 (see general formula IV) are in themselves biologically inactive and are only converted after hydroxylation in the 25-position in the liver, respectively in the 1-position in the kidneys, into their biologically active metabolites. The effect of vitamins D2 and D3 consists in the stabilization of the plasma Ca<++->mirror and the plasma phosphate mirror: they counteract a lowering of the plasma Ca<++->mirror.
Ergocalciferol: R<a>=R<b>=H, R<C>=CH3, Vitamin D2Ergocalciferol: R<a>=R<b>=H, R<C>=CH3, Vitamin D2
dobbeltbinding C 22/23 double bond C 22/23
Cholecalciferol: Ra=R<b>=R<c>=H Vitamin D3Cholecalciferol: Ra=R<b>=R<c>=H Vitamin D3
25-hydroksycholecalciferol: R<a>=R<c>=H, R<b>=0H la-hydroksycholecalciferol: R<a>=0H, R<b>=Rc=H la,25-dihydroksycholecalciferol: R<a>=R<b>=0H, R<C>=H Calcitriol 25-hydroxycholecalciferol: R<a>=R<c>=H, R<b>=0H 1a-hydroxycholecalciferol: R<a>=0H, R<b>=Rc=H 1a,25-dihydroxycholecalciferol: R<a >=R<b>=0H, R<C>=H Calcitriol
Foruten deres markerte virkning på kalsiumstoff-skiftet og fosfatstoffskiftet besitter vitamin D2 og D3, og deres syntetiske derivater, også proliferasjonshemmende og celledifferensierende virkninger (H.F. De Luca, The Metabolism and Function of Vitamin D in Biochemistry of Steroid Hormones, Hrgs. H.L.J. Makin, 2nd Edition, Blackwell Scientific Publi-cations 1984, S. 71-116). In addition to their marked effect on calcium metabolism and phosphate metabolism, vitamins D2 and D3, and their synthetic derivatives, also possess proliferation-inhibiting and cell-differentiating effects (H.F. De Luca, The Metabolism and Function of Vitamin D in Biochemistry of Steroid Hormones, Ed. H.L.J. Makin, 2nd Edition, Blackwell Scientific Publications 1984, pp. 71-116).
Ved anvendelse av vitamin D kan det imidlertid også forekomme overdoseringsfenomener (hypercalcemia). When using vitamin D, however, overdose phenomena (hypercalcemia) can also occur.
la-cholecalciferol hydroksylert i 24-stilling er allerede beskrevet i DE-AS-25 26 981; denne forbindelse har en lavere toksisitet enn det tilsvarende ikke-hydroksylerte la-cholecalciferol. De hydroksylerte forbindelser oppviser en selektiv aktivering av den intestinale kalsiumabsorpsjon og en svakere knokkelabsorpsjonsvirkning enn la-cholecalciferol. Den i den internasjonale patentsøknad WO 87/00834 beskrevne 24-hydroksy-vitamin-D-analog kan anvendes til behandling av for-styrrelser hos mennesker og dyr som stammer fra abnorm celle-proliferasjon og/eller celledifferensiering. la-cholecalciferol hydroxylated in the 24-position is already described in DE-AS-25 26 981; this compound has a lower toxicity than the corresponding non-hydroxylated la-cholecalciferol. The hydroxylated compounds show a selective activation of intestinal calcium absorption and a weaker bone absorption effect than la-cholecalciferol. The 24-hydroxy-vitamin D analogue described in the international patent application WO 87/00834 can be used to treat disorders in humans and animals that originate from abnormal cell proliferation and/or cell differentiation.
For forskjellige 1,25-dihydroksy-homo-vitamin-D-derivater er en dissosiasjon med hensyn til egenskapene knokkelabsorpsjonsvirkning og HL-60-celledifferensiering allerede kort nevnt av De Luca. Knokkelabsorpsjonsvirkningen in vltro er derved et direkte mål for kalsiummobilisering in vivo. For various 1,25-dihydroxy-homo-vitamin D derivatives, a dissociation with regard to the properties of bone absorption action and HL-60 cell differentiation has already been briefly mentioned by De Luca. The bone absorption effect in vitro is thus a direct measure of calcium mobilization in vivo.
Det er nå funnet at de sidekjede-homologe vitamin-D-derivater med generell formel I fremstilt ifølge foreliggende oppfinnelse overraskende oppviser et gunstigere virknings-spektrum sammenlignet med vitamin-D-derivatet calcitriol (la,25-dihydroksycholecalciferol). Mens effekten på kalsium-stoffskiftet og fosfatstoffskiftet betydelig svekkes (reduksjon av bivirkningene ved overdosering eller nødvendig høyere It has now been found that the side-chain homologous vitamin-D derivatives of general formula I produced according to the present invention surprisingly exhibit a more favorable spectrum of action compared to the vitamin-D derivative calcitriol (1α,25-dihydroxycholecalciferol). While the effect on calcium metabolism and phosphate metabolism is significantly weakened (reduction of side effects in case of overdose or necessary higher
dosering), forblir de proliferasjonshemmende og celledifferensierende virkninger tilnærmet opprettholdt (dissosiasjon). dosage), the proliferation-inhibiting and cell-differentiating effects remain almost maintained (dissociation).
Vitamin D-aktiviteten av forbindelsene fremstilt ifølge foreliggende oppfinnelse bestemmes ved hjelp av calcitriol-reseptortesten. Testen utføres ved anvendelse av et The vitamin D activity of the compounds prepared according to the present invention is determined by means of the calcitriol receptor test. The test is carried out using a
spesifikt reseptorprotein fra tarmen hos rakittiske høner. Reseptorholdig bindingsprotein inkuberes med <3>H-calcitriol (0,5 ng/ml) i et reaksjonsvolum på 0,575 ml,i fravær og i nærvær av prøvematerialet, i en time i et lite testrør. For atskillelse av fritt og reseptorbundet calcitriol utføres en specific receptor protein from the intestine of rickety hens. Receptor-containing binding protein is incubated with <3>H-calcitriol (0.5 ng/ml) in a reaction volume of 0.575 ml, in the absence and presence of the sample material, for one hour in a small test tube. For the separation of free and receptor-bound calcitriol, a
adsorbsjon med aktivt karbon-dekstran. Dertil tilføres 200 ul av en aktivt kull-dekstransuspensjon til hvert testrør og det inkuberes ved 22 "C i 30 min. Deretter sentrifugeres prøvene ved 1500 x g i 10 min ved 4 °C. Supernatanten dekanteres og telles etter ca. en times ekvilibrering i "Atom-Light" i en (3- adsorption with activated carbon-dextran. In addition, 200 ul of an activated charcoal-dextran suspension is added to each test tube and it is incubated at 22 "C for 30 min. The samples are then centrifuged at 1500 x g for 10 min at 4 °C. The supernatant is decanted and counted after approx. one hour of equilibration in the "Atom -Light" in a (3-
teller. counting.
De erholdte kompetitive kurver med forskjellige konsentrasjoner av prøvemateriale, såvel som refereranse-materiale, (umerket calcitriol) ved konstant konsentrasjon av referansematerialet (<3>H-calcitriol), ble sammenlignet med hverandre og en kompetitiv faktor (KF) ble bestemt. The competitive curves obtained with different concentrations of sample material, as well as reference material, (unlabeled calcitriol) at a constant concentration of the reference material (<3>H-calcitriol), were compared with each other and a competitive factor (KF) was determined.
Denne faktor er definert som det forholdstall mellom konsentrasjonen av det respektive prøvemateriale og referansematerialet som fordres for 50 % kompetitivitet: This factor is defined as the ratio between the concentration of the respective sample material and the reference material required for 50% competitiveness:
Etter dette besitter After this possess
24-(l-hydroksy-3-metylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(R)-diol (forbindelse A) en KF-verdi på 2,0 og 24-(1-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol (compound A) a KF value of 2.0 and
24-(l-hydroksy-3-metylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(S)-diol (forbindelse B) en KF-verdi på 3,6. 24-(1-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(S)-diol (compound B) a KF value of 3.6.
For å bestemme den antiproliferative styrke av forbindelsene fremstilt ifølge foreliggende oppfinnelse utføres den etterfølgende beskrevne test med forbindelsene A og B som alternerende prøvematerialer: Keratinocytter fra nyfødte mus ble fremstilt og dyrket ved modifisering av metoden ifølge Yuspa, S. und Harris, CC, "Altered differentiation of mouse epidermal cells treated with retinyl acetat in vitro", Exp. Cell Res. 86:95-105, 1974. In order to determine the antiproliferative potency of the compounds produced according to the present invention, the following described test is performed with compounds A and B as alternating test materials: Keratinocytes from newborn mice were prepared and cultured by modification of the method according to Yuspa, S. und Harris, CC, "Altered differentiation of mouse epidermal cells treated with retinyl acetate in vitro", Exp. Cell Res. 86:95-105, 1974.
Nyfødte NMRI-mus av begge kjønn ble avlivet ved dekapitering, huden ble dissekert fra, vasket i en anti-biotika-antimykotika-løsning og inkubert med den dermale side nederst i dispase II-løsning (1,2 U/ml i vevkulturmedium M199 + 25 mmol/1 HEPES + 15 % kalvefosterserum (FCS) + 50 U/ml penicillin/streptomycin (P/S) (prepareringsmedium, PM) ved 4 °C over natten. Epidermis ble fjernet og ved behandling med trypsin ble det fremstilt en éncellesuspensjon. Etter sentri-fugering ble cellebunnfallet resuspendert, antall levende, små, runde celler ble bestemt etter farging med trypanblått og cellene ble inokulert i en tykkelse av 4 x IO<5> celler/cm<2> i primaria-24 perforerte plater i vevkulturmedium (M199 + 15 % FCS + 50 U/ml P/S). Etter inkubasjon i 24 timer ved 37 °C ble Newborn NMRI mice of both sexes were sacrificed by decapitation, the skin was dissected from, washed in an antibiotic-antimycotic solution and incubated with the dermal side down in dispase II solution (1.2 U/ml in tissue culture medium M199 + 25 mmol/l HEPES + 15% fetal calf serum (FCS) + 50 U/ml penicillin/streptomycin (P/S) (preparation medium, PM) at 4 °C overnight Epidermis was removed and by treatment with trypsin a single cell suspension was prepared After centrifugation, the cell pellet was resuspended, the number of live, small, round cells was determined after trypan blue staining and the cells were inoculated at a thickness of 4 x 10<5> cells/cm<2> in primaria-24 perforated plates in tissue culture medium (M199 + 15% FCS + 50 U/ml P/S).After incubation for 24 h at 37 °C,
i cellene med fosfatbufret saltløsning (PBS) vasket og inkubert i ytterligere 24 timer i serumfritt vevkulturmedium (Ml99 + 50 U/ml P/S + 0,5 % etanol) med og uten testforbindelser. Deretter ble det tilsatt 0,4 uCi/50 ul <3>H-metyltymidin (40 Ci/mmol). Etter 4 timer ble mediet avsuget og reaksjonen ble stanset ved tilsetning av 500 ul iskald 10 % trikloreddik-syre (TCA). Cellene ble vasket med TCA og PBS, lysert ved inkubering i en proteinase K-løsning (10 mmol/1 tris-HCl, in the cells with phosphate-buffered saline (PBS) washed and incubated for an additional 24 h in serum-free tissue culture medium (Ml99 + 50 U/ml P/S + 0.5% ethanol) with and without test compounds. Then 0.4 µCi/50 µl <3>H-methylthymidine (40 Ci/mmol) was added. After 4 hours, the medium was aspirated and the reaction was stopped by adding 500 ul of ice-cold 10% trichloroacetic acid (TCA). The cells were washed with TCA and PBS, lysed by incubation in a proteinase K solution (10 mmol/l tris-HCl,
10 mmol/1 EDTA, 10 mmol/1 NaCl, 0,2 % triton-X 100, pH 8,0, 10 mmol/1 EDTA, 10 mmol/1 NaCl, 0.2% triton-X 100, pH 8.0,
50 ug/ml proteinkinase K), og lysatet ble klaret ved sentri-fugering. I supernatanten ble radioaktiviteten bestemt scintillasjonsfotometrisk og, etter spesifikk farging av DNA med diamidinofenylindol (DAPI), ble DNA-konsentrasjonen bestemt fluorescensfotometrisk. 50 ug/ml protein kinase K), and the lysate was cleared by centrifugation. The radioactivity was determined in the supernatant scintillation photometrically and, after specific staining of DNA with diamidinophenylindole (DAPI), the DNA concentration was determined fluorescence photometrically.
Avhengig av dosen hemmer således både calcitriol og forbindelsene A og B inkorporeringen av <3>H-tymidin i DNA med de følgende IC50<->verdier: Depending on the dose, both calcitriol and compounds A and B thus inhibit the incorporation of <3>H-thymidine into DNA with the following IC50<->values:
De differensieringsstimulerende virkninger av både calcitriol og forbindelsene fremstilt ifølge foreliggende oppfinnelse 26,27-syklo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23E-tetraen-l(S),3(R),24a(R)-triol (forbindelse C) og 26,27-syklo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23E-tetraen-l(S),3(R),24a(S)-triol (forbindelse D) er praktisk talt ikke forskjellige. The differentiation-stimulating effects of both calcitriol and the compounds prepared according to the present invention 26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23E-tetraene-1(S),3( R),24a(R)-triol (compound C) and 26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23E-tetraene-1(S), 3(R),24a(S)-triol (compound D) are practically not different.
Det er kjent i litteraturen (Mangelsdorf, D.J. et al, i J. Cell. Biol. 98: 391-398 (1984)), at behandlingen av humane leukemiceller (promyelozyttcellelinje HL 60) in vitro med calcitriol induserer differensieringen av cellene til makrofager. It is known in the literature (Mangelsdorf, D.J. et al, in J. Cell. Biol. 98: 391-398 (1984)) that the treatment of human leukemia cells (promyelocyte cell line HL 60) in vitro with calcitriol induces the differentiation of the cells into macrophages.
For kvantifisering av den differensieringsstimulerende virkning av calcitriolanaloger ble den etterfølgende beskrevne test utført: For quantification of the differentiation-stimulating effect of calcitriol analogues, the test described below was carried out:
HL 60-celler ble dyrket i vevkulturmedium (RPMI - HL 60 cells were grown in tissue culture medium (RPMI -
10 % kalvefosterserum) ved 37 °C i en atmosfære av 5 % C02 i luft. 10% fetal calf serum) at 37 °C in an atmosphere of 5% CO2 in air.
For testing av forbindelsene ble cellene frasentri-fugert og 2,8 x 10<5> celler/ml ble overført i et vevkulturmedium uten innhold av fenolrødt. Testforbindelsene ble løst i etanol og fortynnet til den ønskede konsentrasjon med vevkulturmedium uten innhold av fenolrødt. De forskjellige fortynnede løs-ninger ble blandet med cellesuspensjonen i et forhold på 1:10 og porsjoner å 100 ul av cellesuspensjonen tilsatt forbindelse ble pipettert over i fordypninger på en 96 brønners plate. Som kontroll ble det tilsatt en analog cellesuspensjon med kun løsningsmiddel. For testing the compounds, the cells were centrifuged and 2.8 x 10<5> cells/ml were transferred into a tissue culture medium without phenol red. The test compounds were dissolved in ethanol and diluted to the desired concentration with tissue culture medium without phenol red. The various diluted solutions were mixed with the cell suspension in a ratio of 1:10 and portions of 100 µl of the cell suspension spiked with compound were pipetted into wells of a 96-well plate. As a control, an analogous cell suspension with only solvent was added.
Etter inkubasjon i 96 timer ved 37 °C i 5 % C02 i luft, ble det til hver cellesuspensjon i brønnene på den 96 brønners platen pipettert 100 pl av en NBT-TPA-løsning (nitro-blå tetrazolium (NBT), sluttkonsentrasjon i preparatet 1 mg/ml, tetradecanoylforbolmyristat-13-acetat (TPA), sluttkonsentrasjon i preparatet 2 x IO"<7> mol/l). After incubation for 96 hours at 37 °C in 5% CO2 in air, 100 µl of an NBT-TPA solution (nitro-blue tetrazolium (NBT), final concentration in the preparation) was pipetted into each cell suspension in the wells of the 96-well plate 1 mg/ml, tetradecanoylphorbol myristate-13-acetate (TPA), final concentration in the preparation 2 x 10"<7> mol/l).
Ved inkubasjon i 2 timer ved 37 °C og 5 % C02 i luft ble, som følge av den intracellulære oksygenradikalfrigivelse, stimulert gjennom TPA i cellene differensiert til makrofager, NTB redusert til uløselig formazan. Upon incubation for 2 hours at 37 °C and 5% C02 in air, as a result of the intracellular oxygen radical release, stimulated through TPA in the cells differentiated into macrophages, NTB was reduced to insoluble formazan.
For å avslutte reaksjonen ble brønnene på den 96 brønners plate avsuget og de vedhengende celler ble fiksert ved tilsetning av metanol og tørket etter fiksering. To terminate the reaction, the wells of the 96-well plate were aspirated and the adherent cells were fixed by adding methanol and dried after fixation.
For å oppløse de dannede intracellulære formazan-krystaller ble det til hver brønn pipettert 100 ul kalium-hydroksid (2 val/l) og 100 ul dimetylsulfoksid, etterfulgt av behandling med ultralyd i et minutt. Konsentrasjonen av formazan ble målt spektrofotometrisk ved 650 nm. To dissolve the formed intracellular formazan crystals, 100 ul of potassium hydroxide (2 val/l) and 100 ul of dimethylsulfoxide were pipetted into each well, followed by treatment with ultrasound for one minute. The concentration of formazan was measured spectrophotometrically at 650 nm.
Som mål for differensieringsinduksjonen av HL 60-cellene til makrofager gjelder konsentrasjonen av dannet formazan. Den relative aktivitet av testforbindelsen er gitt fra kvotienten ED50 testforbindelse/ED50 calcitriol. As a measure for the differentiation induction of the HL 60 cells into macrophages, the concentration of formed formazan applies. The relative activity of the test compound is given from the quotient ED50 test compound/ED50 calcitriol.
Ut fra dette har calcitriol, forbindelse C og forbindelse D ED50-verdiene 1,8 x IO"<9> mol/l, 2,2 x IO'<9>, henholdsvis 2,5 x IO"<9> mol/l. Based on this, calcitriol, compound C and compound D have ED50 values of 1.8 x IO"<9> mol/l, 2.2 x IO'<9>, 2.5 x IO"<9> mol/l respectively .
På grunn av den reduserte risiko for hypercalcemia er forbindelsene fremstilt ifølge foreliggende oppfinnelse spesielt egnet til fremstilling av legemidler for behandling av sykdommer, hvilke er kjennetegnet ved en hyperproliferasjon, f.eks. hyperproliferative sykdommer i huden (psoriasis) og maligne tumorer (leukemi, tykktarmskreft, brystkreft). I en spesielt foretrukket utførelsesform påvises calcitriolresep-torer i målorganet før behandlingen. Due to the reduced risk of hypercalcemia, the compounds produced according to the present invention are particularly suitable for the production of drugs for the treatment of diseases, which are characterized by a hyperproliferation, e.g. hyperproliferative diseases of the skin (psoriasis) and malignant tumors (leukaemia, colon cancer, breast cancer). In a particularly preferred embodiment, calcitriol receptors are detected in the target organ before the treatment.
Foreliggende oppfinnelse angår dessuten anvendelse av forbindelsene ifølge formel I til fremstilling av legemidler. The present invention also relates to the use of the compounds according to formula I for the production of medicinal products.
Fremstillingen av de sidekjede-homologe vitamin-D-derivater av formel I utføres ifølge foreliggende oppfinnelse ved at en forbindelse med generell formel IV The production of the side-chain homologous vitamin D derivatives of formula I is carried out according to the present invention in that a compound of general formula IV
hvori in which
R<1>' betegner et hydrogenatom eller en beskyttet hydroksygruppe og R<1>' denotes a hydrogen atom or a protected hydroxy group and
R2 betegner en hydroksybeskyttelsesgruppe og R 2 denotes a hydroxy protecting group and
A, X, R<5> og R6 har betegnelsene angitt for formel I, A, X, R<5> and R6 have the designations given for formula I,
om ønskelig etter selektiv hydrering av dobbeltbindingen i sidekjeden, omdannes til en forbindelse med generell formel IVa if desired after selective hydration of the double bond in the side chain, is converted into a compound of general formula IVa
hvori R<1>', R<2>', A, X, R<5> og R6 har betegnelsen angitt i formel IV og om ønskelig, et reduksjon av karbonylfunksjonen og eventuelt etter atskillelse av blandingen av de ved reduksjonen dannede epimere hydroksyforbindelser med generell formel Illa og Illb in which R<1>', R<2>', A, X, R<5> and R6 have the designation given in formula IV and, if desired, a reduction of the carbonyl function and optionally after separation of the mixture of the epimeric hydroxy compounds formed by the reduction with general formula Illa and Illb
hvori in which
R<1>, R<2>, A, X, R<5> og R6 har betegnelsene angitt i formel IV, og B og D har betegnelsene angitt i formel I, R<1>, R<2>, A, X, R<5> and R6 have the designations given in formula IV, and B and D have the designations given in formula I,
ved bestråling med ultrafiolett lys under invertering av stereoisomerien ved 5,6-dobbeltbindingen, omdannes til en forbindelse med generell formel II upon irradiation with ultraviolet light during inversion of the stereoisomerism at the 5,6-double bond, is converted into a compound of general formula II
hvori in which
R<1>', R<2>', A, B, D, X, R<5> og R6 har betegnelsene angitt i formel Illa/IIIb, R<1>', R<2>', A, B, D, X, R<5> and R6 have the designations given in formula Illa/IIIb,
og denne forbindelse deretter, ved avspalting av foreliggende hydroksybeskyttelsesgrupper og eventuelt ved delvis eller fullstendig forestring av hydroksygruppene, overføres til en forbindelse med generell formel I. and this compound then, by splitting off the present hydroxy protecting groups and optionally by partial or complete esterification of the hydroxy groups, is transferred to a compound of general formula I.
Reduksjon av sidekjede-karbonylfunksjonene i forbindelse med generell formel IV utføres fortrinnsvis med cerium-(III)klorid-natriumborhydrid i et polart løsningsmiddel. Ved reduksjonen dannes både R-hydroksyisomeren og S-hydroksyisomeren med generell formel Illa, henholdsvis Illb. Disse begge isomerer kan atskilles kromatografisk. Reduction of the side chain carbonyl functions in connection with general formula IV is preferably carried out with cerium-(III) chloride-sodium borohydride in a polar solvent. During the reduction, both the R-hydroxy isomer and the S-hydroxy isomer with general formula Illa and Illb respectively are formed. Both of these isomers can be separated chromatographically.
Om ønskelig kan dobbeltbindingen i sidekjeden selek-tivt hydreres før reduksjon av karbonylfunksjonen. Som hydrer-ingsmiddel er blant annet egnet litium-tri-tertiær-butoksy-aluminiumhydrid i et polart løsningsmiddel. If desired, the double bond in the side chain can be selectively hydrogenated before reduction of the carbonyl function. Lithium-tri-tertiary-butoxy-aluminium hydride in a polar solvent is suitable as a hydrogenating agent.
Den etterfølgende omdannelse av en forbindelse med generell formel Illa/IIIb til en forbindelse med generell formel II, utføres f.eks. ved bestråling med ultrafiolett lys i nærvær av en såkalt "triplett sensibilisator". Til dette anvendes innen rammen for foreliggende oppfinnelse anthracen. Ved spaltning av 5,6-dobbeltbindingens pi-binding, rotasjon av A-ringen 180 <0> rundt 5,6-enkeltbindingen og reetablering av 5,6-dobbeltbindingen, blir stereoisomerien ved 5,6-dobbeltbindingen invertert. The subsequent conversion of a compound of general formula IIa/IIIb into a compound of general formula II is carried out, e.g. by irradiation with ultraviolet light in the presence of a so-called "triplet sensitizer". For this, within the scope of the present invention, anthracene is used. By cleavage of the pi bond of the 5,6-double bond, rotation of the A-ring 180 <0> around the 5,6-single bond and re-establishment of the 5,6-double bond, the stereoisomerism of the 5,6-double bond is inverted.
I forbindelse med dette avspaltes foreliggende hydroksybeskyttelsesgrupper, fortrinnsvis ved anvendelse av tetra-n-butyl-ammoniumfluorid, og om ønskelig forestres de frie hydroksygrupper delvis eller fullstendig med det tilsvarende karboksylsyrehalogenid (halogenid = klorid, bromid) eller karboksylsyreanhydrid, etter vanlige fremgangsmåter. In connection with this, the present hydroxy protecting groups are split off, preferably by using tetra-n-butyl-ammonium fluoride, and if desired, the free hydroxy groups are partially or completely esterified with the corresponding carboxylic acid halide (halide = chloride, bromide) or carboxylic acid anhydride, according to usual methods.
Fremstilling av utqanqsmaterialer Production of output materials
1. 1(S),3(R)-bis-(tert.-butylmetylsilyloksy)-20(S)-formyl-9,10-secopregna-5E,7E,10(19)-trien 1: Fremstillingen av 1. utføres etter M.J. Calverley, tetrahydron 43, 4609 (1987); se også internasjonal patent-søknad WO 87/00834. I denne publikasjon er også fremstillingen av utgangsforbindelsen, hvori R<1>' er et hydrogenatom, beskrevet . 2. 1(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-20(R)-metyl-9,10-secopregna-5E,7E,10(19)-trien-21-carbalde-hyd 2. 1. 1(S),3(R)-bis-(tert-butylmethylsilyloxy)-20(S)-formyl-9,10-secopregna-5E,7E,10(19)-triene 1: The preparation of 1. performed according to M.J. Calverley, Tetrathron 43, 4609 (1987); see also international patent application WO 87/00834. In this publication, the preparation of the starting compound, in which R<1>' is a hydrogen atom, is also described. 2. 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-5E,7E,10(19)-triene-21-carbaldehyde 2.
Aldehydet 2 fremstilles ifølge en ny fremgangsmåte. a. Til en suspensjon av 1,8 g natriumhydrid (80 % i olje) i 70 ml absolutt THF dryppes ved 25 "C en løs-ning av 15,57 g dietylfosfonoetoksyeddiksyreetylester (fremstilt etter W. Grell und H. Machleidt, Liebigs Ann. Chem. 699, 53 (1966)) i 200 ml THF. Etter til-setningen omrøres ytterligere i 90 min ved 60 °C. Deretter avkjøles til 25 °C og det tilsettes dråpevis en løsning av 6,2 g forbindelse 1 i 70 ml THF. Det omrøres i 2 timer under tilbakeløpskjøling, den av-kjølte reaksjonsløsning helles deretter ned i vann og ekstraheres med etylacetat. Etter tørking (Na2S04) og inndamping kromatograferes det erholdte råprodukt på kiselgel med heksan/etylacetat. Hovedfraksjonen gir 5,2 g 1(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-23-(etoksy-9,10-secochola-5E,7E,10(19)-tetraen-24-syre-etylester i form av en oljeaktig blanding av C-22-dobbeltbindingsi someren. The aldehyde 2 is produced according to a new method. a. To a suspension of 1.8 g of sodium hydride (80% in oil) in 70 ml of absolute THF, a solution of 15.57 g of diethylphosphonoethoxyacetic acid ethyl ester (prepared according to W. Grell und H. Machleidt, Liebigs Ann . Chem. 699, 53 (1966)) in 200 ml of THF. After the addition, the mixture is stirred for a further 90 min at 60 °C. It is then cooled to 25 °C and a solution of 6.2 g of compound 1 in 70 ml of THF. It is stirred for 2 hours under reflux, the cooled reaction solution is then poured into water and extracted with ethyl acetate. After drying (Na2SO4) and evaporation, the crude product obtained is chromatographed on silica gel with hexane/ethyl acetate. The main fraction gives 5.2 g 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-23-(ethoxy-9,10-secochola-5E,7E,10(19)-tetraene-24-acid ethyl ester in the form of a oily mixture of C-22 double bonds in the sommer.
b. 5,2 g av produktet erholdt under punkt a. løses i 120 ml toluen og tilsettes ved 0 °C langsomt 20 ml b. Dissolve 5.2 g of the product obtained under point a. in 120 ml of toluene and slowly add 20 ml at 0 °C
av en 20 % løsning av diisobutylaluminiumhydrid i toluen. Etter 30 min ved 0 °C helles reaksjonsløs-ningen forsiktig over i NH4Cl-løsning og ekstraheres med etylacetat. Etter vanlig opparbeidelse erholdes 4,88 g 1(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-23-etoksy-9,10-secochola-5E, 7E, 10( 19), 22-tetraen-24-ol i form av en fargeløs, oljeaktig isomerblanding som anvendes i de etterfølgende trinn uten ytterligere rensning. c. Forbindelsen fremstilt under punkt b. (4,88 g) om-røres i en blanding av 55 ml diklormetan og 55 ml 70 % vandig eddiksyre i 4 timer ved romtemperatur. of a 20% solution of diisobutylaluminum hydride in toluene. After 30 min at 0 °C, the reaction solution is carefully poured into NH4Cl solution and extracted with ethyl acetate. After usual work-up, 4.88 g of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-23-ethoxy-9,10-secochola-5E, 7E, 10(19), 22-tetraen- 24-ol in the form of a colourless, oily isomer mixture which is used in the subsequent steps without further purification. c. The compound prepared under point b. (4.88 g) is stirred in a mixture of 55 ml of dichloromethane and 55 ml of 70% aqueous acetic acid for 4 hours at room temperature.
Blandingen nøytraliseres ved tilsetning av NH3-løs-ning og ekstraheres med diklormetan. Råproduktet kromatograferes på kiselgel med heksan/etylacetat. På denne måte erholdes 2,02 g l(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-24-hydroksy-9,10-secochola-5E,7E,10(19)-trien-23-on 5 i form av en fargeløs olje. The mixture is neutralized by adding NH3 solution and extracted with dichloromethane. The crude product is chromatographed on silica gel with hexane/ethyl acetate. In this way, 2.02 g of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-24-hydroxy-9,10-secochola-5E,7E,10(19)-trien-23-one are obtained 5 in the form of a colorless oil.
<1>H-NMR (CDC13): Y = 0,01 ppm (s, 12H, Si-CH3), 0,52 (s,3H,H-18), 0,81 og 0,84 (s,9H-Si-t-butyl), 0,90 (d,J=7Hz,3H,H-21), 3,09 (t,J=5Hz,1H,OH), 4,10 (dd,lH,H-24), 4,16 (m,lH,H-3), 4,21 (dd,1H,H-24), 4,39 (m,lH,H-l), 4,88, 4,93 (s,je 1H,H-19), 5,77, 6,39 (d,J=HHz, lH,H-6,H-7). d. Produktet erholdt under punkt c. (2,02 g) oppløses i 25 ml metanol og 25 ml THF og tilsettes 300 mg natriumborhydrid ved 0 °C. Det omrøres i 1,5 time ved 0 °C, reaksjonsblandingen helles deretter over i NH4Cl-løsning og ekstraheres med etylacetat. Det erholdes 1,75 g l(S),3(R)-bis-(tert.-butyldimetylsilyl-oksy ) -9, 10-secochola-5E, 7E,10(19)-trien-23,24-diol 6. 1 form av fargeløs, oljeaktig blanding av 23-epimerene, som tilsettes som sådan i den etterfølg-ende reaksjon. <1>H-NMR (CDC13): Y = 0.01 ppm (s, 12H, Si-CH3), 0.52 (s,3H,H-18), 0.81 and 0.84 (s,9H -Si-t-butyl), 0.90 (d,J=7Hz,3H,H-21), 3.09 (t,J=5Hz,1H,OH), 4.10 (dd,lH,H- 24), 4.16 (m,lH,H-3), 4.21 (dd,1H,H-24), 4.39 (m,lH,H-l), 4.88, 4.93 (s, ie 1H,H-19), 5.77, 6.39 (d,J=HHz, 1H,H-6,H-7). d. The product obtained under point c. (2.02 g) is dissolved in 25 ml of methanol and 25 ml of THF and 300 mg of sodium borohydride is added at 0 °C. It is stirred for 1.5 hours at 0 °C, the reaction mixture is then poured into NH4Cl solution and extracted with ethyl acetate. 1.75 g of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-secochola-5E,7E,10(19)-triene-23,24-diol 6 are obtained. 1 form of colorless, oily mixture of the 23-epimers, which is added as such in the subsequent reaction.
e. 1,75 g av det erholdte produkt under punkt d. opp-løses i 40 ml toluen og 1,23 g blytetraacetat tilsettes porsjonsvis under avkjøling med isvann. Det omrøres i 30 min, tilsettes ytterligere 1,0 g e. 1.75 g of the product obtained under point d. is dissolved in 40 ml of toluene and 1.23 g of lead tetraacetate is added in portions while cooling with ice water. It is stirred for 30 min, a further 1.0 g is added
Pb(0Ac)4 og omrøres i ytterligere 15 min ved + 5 til + 10 °C. Pb(0Ac)4 and stirred for a further 15 min at + 5 to + 10 °C.
Blandingen tilsettes NaHC03-løsning, den dannede suspensjon filtreres over celitt og filtratet ekstraheres med etylacetat. Råproduktet kromatograferes på kiselgel med heksan/etylacetat. Etter krystallisering av hovedfraksjonen fra etanol erholdes 560 mg 1(S),-3 (R) -bis- (tert. -butyldimetylsilyloksy) -20 (R) -metyl-9,10-secopregna-5E,7E, 10( 19)-trien-21-karbaldehyd med smeltepunkt 101-104 °C. Omsetningen av aldehydet 1, henholdsvis 2, med et fosforan med formel NaHCO 3 solution is added to the mixture, the resulting suspension is filtered over celite and the filtrate is extracted with ethyl acetate. The crude product is chromatographed on silica gel with hexane/ethyl acetate. After crystallization of the main fraction from ethanol, 560 mg of 1(S),-3(R)-bis-(tert.-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-5E,7E, 10( 19) are obtained -triene-21-carbaldehyde with melting point 101-104 °C. The reaction of the aldehyde 1, respectively 2, with a phosphorane of formula
gir forbindelser med generell formel IV (Wittig-reaksjon). gives compounds of general formula IV (Wittig reaction).
Fremstilling av de anvendte fosforylider: Preparation of the phosphorylides used:
1. Isobutylkarbonylmetylentrifenylfosforan a. Brommety1isobutylketon 50 ml isobutyImetylketon i 240 ml metanol tilsettes 20 ml brom ved 0 °C og omrøres i 1,5 timer ved 10 °C. 1. Isobutylcarbonylmethylenetriphenylphosphorane a. Bromomethylisobutylketone 50 ml of isobutylmethylketone in 240 ml of methanol is added to 20 ml of bromine at 0 °C and stirred for 1.5 hours at 10 °C.
Deretter tilsettes 360 ml vann og det omrøres ytterligere i 16 timer ved romtemperatur. 360 ml of water are then added and the mixture is stirred for a further 16 hours at room temperature.
Reaksjonsblandingen tilsettes mettet koksaltoppløs-ning, den utskilte organiske fase frasepareres og den vandige fase ekstraheres med etere. De sammenslåtte organiske faser vaskes med 10 % Na2C03-løsning og tørkes over Na2S04. Etter filtrering avsuges løs-ningsmidlet i vannstrålevakuum og bunnfallet destil-leres. Hovedfraksjonen inneholder 53,7 g brommetyl-isobutylketon med Kp<15>'<20> 67-69 <6>C. Saturated sodium chloride solution is added to the reaction mixture, the separated organic phase is separated and the aqueous phase is extracted with ethers. The combined organic phases are washed with 10% Na 2 CO 3 solution and dried over Na 2 SO 4 . After filtration, the solvent is sucked off in a water jet vacuum and the precipitate is distilled. The main fraction contains 53.7 g of bromomethyl isobutyl ketone with Kp<15>'<20> 67-69 <6>C.
b. Isobutylkarbonylmetyltrifenylfosfoniumbromid Bronunetylisobutylketon (53,6 g) og tri f enylf osf in (78,5 g) blandes grundig i en 500 ml rundkolbe og etter at den innledende sterke reaksjonsvarmeutvik-ling har opphørt hensettes blandingen i 12 timer under nitrogenatmosfære ved romtemperatur. Deretter ekstraheres den faste reaksjonsmasse med 330 ml metylenklorid og oppvarmes i 30 min under tilbake-løpskjøling. Etter tilsetning av 500 ml eter avkjøles til romtemperatur og produktet isoleres ved filtrering. Etter tørking erholdes 111,7 g av fosfoniumsaltet med smeltepunkt 244-245 °C. c. Isobutylkarbonylmetylentrifenylfosforan 111,6 g av fosfoniumbromidet erholdt under punkt b. tilsettes suksessivt 1500 ml metylenklorid og 1500 ml 2N-NaOH og omrøres i 30 min ved romtemperatur. Den organiske fase adskilles, vaskes med vann og tørkes over Na2S04. Det faste bunnfall erholdt etter inndamping omkrystalliseres fra tertiært butylmetyleter og gir 72,2 g av ylidet med smeltepunkt 120-121 °C. 2. Isoamylkarbonylmetylentrifenylfosforan Fremstillingen av tittelforbindelsen utføres analogt med fremgangsmåten beskrevet under punkt 1, ved bromering av isoamylmetylketon, omsetning av bromidet med trifenylfosfin til fosfoniumsalt og dannelse av ylidet med 2N NaOH. b. Isobutylcarbonylmethyltriphenylphosphonium bromide Bronuethyl isobutyl ketone (53.6 g) and triphenyl phosphine (78.5 g) are thoroughly mixed in a 500 ml round bottom flask and after the initial strong reaction heat development has ceased, the mixture is allowed to stand for 12 hours under a nitrogen atmosphere at room temperature. The solid reaction mass is then extracted with 330 ml of methylene chloride and heated for 30 min under reflux cooling. After adding 500 ml of ether, cool to room temperature and the product is isolated by filtration. After drying, 111.7 g of the phosphonium salt with melting point 244-245 °C are obtained. c. Isobutylcarbonylmethylenetriphenylphosphorane 111.6 g of the phosphonium bromide obtained under point b. is successively added to 1500 ml of methylene chloride and 1500 ml of 2N-NaOH and stirred for 30 min at room temperature. The organic phase is separated, washed with water and dried over Na 2 SO 4 . The solid precipitate obtained after evaporation is recrystallized from tertiary butyl methyl ether and gives 72.2 g of the ylide with a melting point of 120-121 °C. 2. Isoamylcarbonylmethylenetriphenylphosphorane The preparation of the title compound is carried out analogously to the method described under point 1, by bromination of isoamylmethyl ketone, reaction of the bromide with triphenylphosphine to a phosphonium salt and formation of the ylide with 2N NaOH.
Fra 50,0 ml isoamylmetylketon og 18,2 ml brom erholdes etter rensing ved destillering 54,68 g 1-brom-5-metyl-heksan-on med Kp<15>"<20> 80-86 °C. From 50.0 ml of isoamyl methyl ketone and 18.2 ml of bromine, 54.68 g of 1-bromo-5-methyl-hexan-one with Kp<15>"<20> 80-86 °C are obtained after purification by distillation.
Fra 54,58 g av bromidet og 74,14 g difenylfosfin erholdes 91,6 g av fosfoniumsalt med smeltepunkt 230-233 °C. From 54.58 g of the bromide and 74.14 g of diphenylphosphine, 91.6 g of a phosphonium salt with a melting point of 230-233 °C is obtained.
Fra 91,6 g av fosfoniumsaltet erholdes etter behandling med NaOH og omkrystallisering av råproduktet fra metylenklorid/ester, 69,8 g av tittelforbindelsen med smeltepunkt 64-67 °C. 3. Isopropoksymetylkarbonylmetylentrifenylfosforan 2,43 g natrium oppløst i 150 ml isopropanol. Etter tilsetning av 20,0 g klormetylkarbonylmetylentri-fenylfosforan (R.F. Hudson et al., J. Org. Chem. 24 2446, 1963), løst i 200 ml isopropanol, oppvarmes i 8 timer under tilbakeløpskjøling. From 91.6 g of the phosphonium salt, after treatment with NaOH and recrystallization of the crude product from methylene chloride/ester, 69.8 g of the title compound with a melting point of 64-67 °C are obtained. 3. Isopropoxymethylcarbonylmethylenetriphenylphosphorane 2.43 g sodium dissolved in 150 ml isopropanol. After addition of 20.0 g of chloromethylcarbonylmethylenetriphenylphosphorane (R.F. Hudson et al., J. Org. Chem. 24 2446, 1963), dissolved in 200 ml isopropanol, heated for 8 hours under reflux.
Den avkjølte reaksjonsblanding helles over i kok-salt løsning og ekstraheres med etylacetat. Den olje-aktige rest erholdt etter inndamping kromatograferes på kiselgel med etylacetat. Det erholdes 9,53 g av tittelforbindelsen med smeltepunkt 134 °C. The cooled reaction mixture is poured into sodium chloride solution and extracted with ethyl acetate. The oily residue obtained after evaporation is chromatographed on silica gel with ethyl acetate. 9.53 g of the title compound with a melting point of 134 °C are obtained.
4. (2-isopropoksyetyl)-karbonylmetylentrifenylfosforan a. l-brom-4-isopropoksy-butan-2-on 4. (2-isopropoxyethyl)-carbonylmethylenetriphenylphosphorane a. 1-bromo-4-isopropoxy-butan-2-one
En oppløsning av 68,2 g 4-isopropoksy-2-butanon (F.B. Hassan et al., J. Biolog. Chem. 256. 7781, 1981) i 315 ml metanol tilsettes 26,9 ml brom dråpevis ved 0 °C og omrøres deretter i 1,5 time ved + 10 °C. Deretter dryppes 470 ml vann til reaksjonsløsningen og det omrøres i 16 timer ved romtemperatur. Det tilsettes mettet koksaltløsning og ekstraheres med eter. Destillering av råproduktet gir 78,07 g av brom-derivatet med Kp<15>'<20> 95 °C. A solution of 68.2 g of 4-isopropoxy-2-butanone (F.B. Hassan et al., J. Biolog. Chem. 256. 7781, 1981) in 315 ml of methanol is added 26.9 ml of bromine dropwise at 0 °C and stirred then for 1.5 hours at + 10 °C. Then 470 ml of water is added to the reaction solution and it is stirred for 16 hours at room temperature. Saturated sodium chloride solution is added and extracted with ether. Distillation of the crude product gives 78.07 g of the bromine derivative with Kp<15>'<20> 95 °C.
b. 4-isopropoksy-2-okso-butyl-trifenylfosfoniumbromid Fra 78,0 g av bromidet erholdt under punkt a. og 97,85 g trifenylfosfin erholdes etter fremgangsmåten beskrevet under punkt 1 133,35 g av fosfoniumsaltet med smeltepunkt 183 °C. b. 4-isopropoxy-2-oxo-butyl-triphenylphosphonium bromide From 78.0 g of the bromide obtained under point a. and 97.85 g of triphenylphosphine, 133.35 g of the phosphonium salt with a melting point of 183 °C is obtained according to the method described under point 1.
c. (2-isopropoksyetyl)-karbonylmetylentrifenylfosforan Fosfoniumbromidet (133,2 g) erholdt under punkt b. behandles med 2N-NaOH i metylenklorid som beskrevet under punkt 1. Etter omkrystallisering av råproduktet fra etylacetat erholdes 64,38 g av tittelforbindelsen med smeltepunkt 97 °C. 5. (1-etylpropoksymetyl) -karbonylmetylentrif enylf osf oran En løsning av 3,04 g natrium i 100 ml 3-pentanol omsettes med 25,0 g klormetylkarbonylmetylentrifenyl-fosforan analogt med fremstilling av isopropoksy-metylkarbonylmetylentri feny1fos foran. Tittelforbindelsen erholdes som krystallisert olje med smeltepunkt 66-70 °C. 6. Syklopropylmetoksymetylkarbonylmetylentrif enylf os-foran c. (2-isopropoxyethyl)-carbonylmethylenetriphenylphosphorane The phosphonium bromide (133.2 g) obtained under point b. is treated with 2N-NaOH in methylene chloride as described under point 1. After recrystallization of the crude product from ethyl acetate, 64.38 g of the title compound with melting point 97 is obtained °C. 5. (1-Ethylpropoxymethyl)-carbonylmethylenetriphenylphosphorane A solution of 3.04 g of sodium in 100 ml of 3-pentanol is reacted with 25.0 g of chloromethylcarbonylmethylenetriphenylphosphorane analogously to the preparation of isopropoxymethylcarbonylmethylenetriphenylphosphorane. The title compound is obtained as a crystallized oil with a melting point of 66-70 °C. 6. Cyclopropylmethoxymethylcarbonylmethylenetriphenylfuran
En løsning av 5,58 g natrium i 25,0 g syklopropyl-metanol og 200 ml toluen, omsettes med 30,0 g klor-metylkarbonylmetylentrifenylfosforan analogt med fremstilling av isopropoksymetylkarbonylmetylentrifenylfosforan. Tittelforbindelsen erholdes som fast stoff med smeltepunkt 121 °C. A solution of 5.58 g of sodium in 25.0 g of cyclopropyl methanol and 200 ml of toluene is reacted with 30.0 g of chloromethylcarbonylmethylenetriphenylphosphorane analogously to the preparation of isopropoxymethylcarbonylmethylenetriphenylphosphorane. The title compound is obtained as a solid with a melting point of 121 °C.
7. (3-butinyl)-karbonylmetylentrifenylfosforan 20,0 g metylkarbonylmetylentrifenylfosforan oppløses i 628 ml tetrahydrofuran og tilsettes dråpevis 41,3 ml butyllitium (1,6 molar løsning heksan) ved -78 °C. Reaksjonsblandingen tilføres etter oppvarming til romtemperatur is/koksaltløsning og blandingen ekstraheres med eddikester. Etter tørking av den organiske fase med natriumsulfat erholdes 23,4 g fast stoff. Søylekromatografisk rensing (kiselgel/eddikester) gir 15,4 g av tittelforbindelsen med smeltepunkt 135-136 °C. 7. (3-Butynyl)-carbonylmethylenetriphenylphosphorane Dissolve 20.0 g of methylcarbonylmethylenetriphenylphosphorane in 628 ml of tetrahydrofuran and add dropwise 41.3 ml of butyl lithium (1.6 molar solution hexane) at -78 °C. After heating to room temperature, the reaction mixture is added to the ice/common salt solution and the mixture is extracted with vinegar. After drying the organic phase with sodium sulfate, 23.4 g of solid material is obtained. Column chromatographic purification (silica gel/ethyl acetate) gives 15.4 g of the title compound with melting point 135-136 °C.
8. (3-butenyl)-karbonylmetylentrifenylfosf oran 8. (3-butenyl)-carbonylmethylenetriphenylphosphorane
Ved reaksjon av 15,0 g metylkarbonylmetylentrifenyl-f osf oran i 471 ml tetrahydrofuran med 31,0 ml butyllitium og 4,28 ml allylbromid erholdes analogt med punkt 7. Tittelforbindelsen som krystallisert olje med smeltepunkt 92-93 °C. By reaction of 15.0 g of methylcarbonylmethylenetriphenylphosphorane in 471 ml of tetrahydrofuran with 31.0 ml of butyllithium and 4.28 ml of allyl bromide, the title compound is obtained as a crystallized oil with a melting point of 92-93 °C.
Ved variasjon av de anvendte keto-bestanddeler for fremstilling av Wittig-reagensene kan det, som beskrevet i det etterfølgende, fremstilles ytterligere fosforaner, som med aldehyd 1 eller 2 kan omsettes til ytterligere forbindelser med generell formel IV. By varying the keto components used for the preparation of the Wittig reagents, as described below, further phosphoranes can be produced, which can be converted with aldehyde 1 or 2 into further compounds of general formula IV.
Eksempel 1 Example 1
En løsning av 1,6 g 1(S),3(R)-bis-(tert.-butyl-dimetylsilyloksy )-20(R)-metyl-9,10-secopregna-5E,7E,10(19)-trien-21-karbaldehyd i 50 ml toluen omrøres etter tilsetning av 3,02 g isoamylkarbonylmetylentrifenylfosforan i 16 timer ved 80 °C under argon. Deretter avsuges løsningsmidlet under redusert trykk og residuet kromatograferes på kiselgel med heksan/etylacetat. Hovedfraksjonen gir 1,15 g [1(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-9,10-secochola-5E,7E,10(19),-23(E)-tetraen-24-yl]-4-metyl-pentan-l-on som fargeløs olje. A solution of 1.6 g of 1(S),3(R)-bis-(tert-butyl-dimethylsilyloxy)-20(R)-methyl-9,10-secopregna-5E,7E,10(19)- triene-21-carbaldehyde in 50 ml of toluene is stirred after the addition of 3.02 g of isoamylcarbonylmethylenetriphenylphosphorane for 16 hours at 80 °C under argon. The solvent is then suctioned off under reduced pressure and the residue is chromatographed on silica gel with hexane/ethyl acetate. The main fraction gives 1.15 g of [1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-secochola-5E,7E,10(19),-23(E)-tetraene-24 -yl]-4-methyl-pentan-1-one as a colorless oil.
<1>H-NMR (CDC13); 6 = 0,01 ppm (s, 12H, Si-CH3); 0,56 (s,3H,H-18); 0,87 (s,18H.Sit.-butyl); 0,88 (d,J=7Hz,6H,C-(CH3)2); 0,95 (d,J=7Hz,3H,H-21); 4,25 (m, lH,H-3); 4,55 (m,lH,H-l); 4,94 og 5,00 (s,lH,H-19), 5,82 og 6,46 (d,J=llHz, lH,H-6,H-7); 6,10 (d,J=16Hz,lH,H-24); 6,80 (m,lH,H-23). <1>H-NMR (CDCl3); 6 = 0.01 ppm (s, 12H, Si-CH3); 0.56 (s,3H,H-18); 0.87 (s,18H.Sit.-butyl); 0.88 (d,J=7Hz,6H,C-(CH3)2); 0.95 (d,J=7Hz,3H,H-21); 4.25 (m, 1H,H-3); 4.55 (m,1H,H-1); 4.94 and 5.00 (s,1H,H-19), 5.82 and 6.46 (d,J=11Hz, 1H,H-6,H-7); 6.10 (d,J=16Hz,1H,H-24); 6.80 (m,1H,H-23).
' Eksempel 2 ' Example 2
572 mg cerium(III)-klorid-heptahydrat oppløses i Dissolve 572 mg of cerium(III) chloride heptahydrate in
10 ml metanol og forbindelsen fremstilt ifølge eksempel 1 10 ml of methanol and the compound prepared according to example 1
(1,10 g) oppløst i 5 ml metanol, tilsettes. Etter tilsetning (1.10 g) dissolved in 5 ml of methanol, is added. After addition
av 61 mg natriumborhydrid omrøres i 30 min ved 0 °C. Det til-< settes vann, ekstraheres med diklormetan, tørkes (Na2S04) og inndampes. Den således erholdte blanding av diastereomere alkoholer adskilles ved kromatografering på kiselgel med heksan/etylacetat. Det erholdes i elueringsrekkefølge 290 mg 1(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-24-(l-hydroksy-4-1 metylfenyl)-9,10-seco-5E,7E,10(19),23(E)-cholatetraen (epimer A) og 120 mg epimer B. Epimerene oppviser identiske NMR-spektre. of 61 mg of sodium borohydride is stirred for 30 min at 0 °C. Water is added, extracted with dichloromethane, dried (Na 2 SO 4 ) and evaporated. The thus obtained mixture of diastereomeric alcohols is separated by chromatography on silica gel with hexane/ethyl acetate. 290 mg of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-24-(1-hydroxy-4-1 methylphenyl)-9,10-seco-5E,7E,10( 19),23(E)-cholatetetraene (epimer A) and 120 mg of epimer B. The epimers show identical NMR spectra.
<4>I-NMR (CDC13): 6 = 0,01 ppm (s, 12H, Si-CH3), 0,49 (s,3H,H-18), 0,86 (s,18H.Si-t.-butyl), 0,86 (d,J=7Hz,6H,C-(CH3)2), 0,88 (d,J=7Hz, 3H,H-21); 4,16 (m, lH,H-3); 4,48 <4>1-NMR (CDC13): 6 = 0.01 ppm (s, 12H, Si-CH3), 0.49 (s,3H,H-18), 0.86 (s,18H.Si-t .-butyl), 0.86 (d,J=7Hz,6H,C-(CH3)2), 0.88 (d,J=7Hz,3H,H-21); 4.16 (m, 1H,H-3); 4.48
(m,lH,H-l), 4,88 og 4,93 (s,lH,H-19), 5,40 (dd,J=15,5 og 7Hz, lH,H-24); 5,55 (m,1H,H-23); 5,77 og 6,40 (d,J=llHz,lH,H-6, H-7). (m,1H,H-1), 4.88 and 4.93 (s,1H,H-19), 5.40 (dd,J=15.5 and 7Hz, 1H,H-24); 5.55 (m, 1H, H-23); 5.77 and 6.40 (d,J=11Hz,1H,H-6,H-7).
Eksempel 3 Example 3
En løsning av 290 mg av det erholdte produkt ifølge eksempel 2 (epimer A) i 80 ml toluen blir etter tilsetning av 44 mg anthracen og 0,01 ml trietylamin bestrålt i en pyrex-immersjonsreaktor ved hjelp av en kvikksølv-høytrykkslampe (Philips HPK 125). Bestrålingstiden er 3,5 min, en grundig blanding av løsningen sikres ved tilførsel av en nitrogen-strøm. Etter inndamping og kromatografering på kiselgel med heksan/etylacetat erholdes 241 mg 1(S),3(R)-bis-(tert.-butyl-dimetylsilyloksy )-24-(l-hydroksy-4-metylpentyl)-9,10-secochola-5Z,7E,10(19),23(E)-tetraen i form av en fargeløs olje. A solution of 290 mg of the product obtained according to example 2 (epimer A) in 80 ml of toluene is, after the addition of 44 mg of anthracene and 0.01 ml of triethylamine, irradiated in a pyrex immersion reactor by means of a mercury high-pressure lamp (Philips HPK 125 ). The irradiation time is 3.5 min, a thorough mixing of the solution is ensured by supplying a nitrogen stream. After evaporation and chromatography on silica gel with hexane/ethyl acetate, 241 mg of 1(S),3(R)-bis-(tert-butyl-dimethylsilyloxy)-24-(1-hydroxy-4-methylpentyl)-9,10- secochola-5Z,7E,10(19),23(E)-tetraene in the form of a colorless oil.
[o]?° + 49,6 0 (CHC13, o = 0,425. [o]?° + 49.6 0 (CHCl 3 , o = 0.425.
Analog behandling av 120 mg av den polare isomere (epimer B), erholdt ifølge eksempel 2, gir 113 mg i form av fargeløs olje. Analogous treatment of 120 mg of the polar isomer (epimer B), obtained according to Example 2, gives 113 mg in the form of a colorless oil.
[a]2° + 41,4 <0> (CHC13, o = 0,285. [α]2° + 41.4 <0> (CHCl 3 , o = 0.285.
Eksempel 4 Example 4
En løsning av 225 mg av det erholdte produkt fra epimer A ifølge eksempel 3 i 5 ml THF omrøres etter tilsetning av 1,31 ml av en 1M-Iøsning av tetrabutylammoniumfluorid i THF, i 60 min ved 60 °C. Etter avkjøling tilsettes mettet kok-saltløsning og det ekstraheres med etylacetat. Råproduktet kromatograferes på kiselgel med heksan/etylacetat og gir 85 mg 24-(l-hydroksy-4-metylpentyl)-9,10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(R)-diol i form av et hvitt skum. A solution of 225 mg of the product obtained from epimer A according to example 3 in 5 ml of THF is stirred after the addition of 1.31 ml of a 1 M solution of tetrabutylammonium fluoride in THF for 60 min at 60 °C. After cooling, saturated sodium chloride solution is added and it is extracted with ethyl acetate. The crude product is chromatographed on silica gel with hexane/ethyl acetate and gives 85 mg of 24-(1-hydroxy-4-methylpentyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3( R)-diol in the form of a white foam.
<1>H-NMR (CDCI3): 6 = 0,57 ppm (s, 3H,H-18); 0,84 (d,J=7Hz,3H,H-21); 0,92 (d,J=7Hz 6H,C-(CH3)2; 4,03 (m,lH,H-25); 4,23 (m,lH,H-3); 4,43 (m,lH,H-l); 5,00 og 5,33 (s,1H,H-19 ) ; 5,45 (dd,J=15,5 og 7Hz,1H,H-24); 5,60 (m,1H,H-23); 6,02 og 6,38 (d,J=lH,llH,H-6,H-7). <1>H-NMR (CDCl3): δ = 0.57 ppm (s, 3H,H-18); 0.84 (d,J=7Hz,3H,H-21); 0.92 (d,J=7Hz 6H,C-(CH3)2; 4.03 (m,1H,H-25); 4.23 (m,1H,H-3); 4.43 (m, 1H,H-1); 5.00 and 5.33 (s,1H,H-19 ); 5.45 (dd,J=15.5 and 7Hz,1H,H-24); 5.60 (m,1H ,H-23); 6.02 and 6.38 (d,J=1H,11H,H-6,H-7).
En analog behandling av produktet erholdt fra epimer B ifølge eksempel 3 (95 mg) gir 35 mg av de epimere trioler som fargeløs olje. NMR-spektrene av epimerene er identiske. An analogous treatment of the product obtained from epimer B according to example 3 (95 mg) gives 35 mg of the epimeric triols as a colorless oil. The NMR spectra of the epimers are identical.
Eksempel 5 Example 5
Analogt med fremgangsmåten beskrevet i eksempel 1 omsettes 2,05 g 1(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-20- (R) -metyl-9,10-secopregna-5E, 7E, 10 (19) -trien-21 -karbaldehyd i 53 ml toluen med 3,4 g isobutylkarbonylmetylentrifenylfosforan. Etter kromatografisk rensning erholdes [1(S),3(R)-bis-(tert. -butyldimetylsilyloksy)-9,10-secochola-5E, 7E, 10(19 ), - 23(E)-tetraen-24-yl]-3-metyl-butan-l-on med smeltepunkt 79-81 °C (fra etanol), Analogous to the procedure described in example 1, 2.05 g of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20-(R)-methyl-9,10-secopregna-5E, 7E, 10 (19)-triene-21-carbaldehyde in 53 ml of toluene with 3.4 g of isobutylcarbonylmethylenetriphenylphosphorane. After chromatographic purification, [1(S),3(R)-bis-(tert.-butyldimethylsilyloxy)-9,10-secochola-5E, 7E, 10(19 ), - 23(E)-tetraen-24-yl is obtained ]-3-methyl-butan-l-one with melting point 79-81 °C (from ethanol),
[a]2,<0>+ 52,6 ° (CHC13, o = 0,500). [α]2.<0>+ 52.6° (CHCl 3 , δ = 0.500).
Eksempel 6 Example 6
Ved reduksjon av 1,75 g av produktet erholdt fra eksempel 5, under betingelsene ifølge eksempel 2, erholdes 1 (S),3(R)-bis-(tert.-butyldimetylsilyloksy)-24-(1(R,S)-hydroksy-3-metylbutyl )-9,10-secopregna-5E, 7E, 10(19),23E-tetraen i form av en oljeaktig blanding av epimerene. Ved kromatografi på kiselgel med heksan/etylacetat erholdes i elueringsrekkefølge 780 mg epimer A og 600 mg epimer B, i form av fargeløse oljer som ikke kan sjeldnes NMR-spektroskopisk. By reducing 1.75 g of the product obtained from example 5, under the conditions according to example 2, 1 (S),3(R)-bis-(tert-butyldimethylsilyloxy)-24-(1(R,S)- hydroxy-3-methylbutyl )-9,10-secopregna-5E, 7E, 10(19),23E-tetraene in the form of an oily mixture of the epimers. Chromatography on silica gel with hexane/ethyl acetate yields in order of elution 780 mg of epimer A and 600 mg of epimer B, in the form of colorless oils which cannot be rarefied by NMR spectroscopy.
Eksempel 7 Example 7
Ved triplettsensibilisert fotoisomerisering analogt med eksempel 3, og etterfølgende silyleterspaltning analogt med eksempel 4, erholdes fra 700 mg av den ifølge eksempel 6 fremstilte epimer A 240 mg 24-(l-hydroksy-3-metylbutyl)9-10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(R)-diol (forbindelse A) med dekomponeringstemperatur i området 119-125 °C, By triplet sensitized photoisomerization analogous to example 3, and subsequent silyl ether cleavage analogous to example 4, 240 mg of 24-(1-hydroxy-3-methylbutyl)9-10-secochola-5Z,7E are obtained from 700 mg of the epimer A prepared according to example 6 ,10(19),23E-tetraene-1(S),3(R)-diol (compound A) with a decomposition temperature in the range 119-125 °C,
[a]<2>,<0> + 38,8 0 (metanol, o = 0,505). [a]<2>,<0> + 38.8 0 (methanol, o = 0.505).
Analog behandling av 330 mg epimer B gir 129 mg 24-(l-hydroksy-3-metylbutyl )9-10-secochola-5Z,7E,10(19),23E-tetraen-l(S),3(S)-diol (forbindelse B) med dekomponeringstemperatur i området 139-145 °C, [a]<2>,<0> + 54,8 (metanol, Analogous treatment of 330 mg of epimer B yields 129 mg of 24-(1-hydroxy-3-methylbutyl)9-10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(S)- diol (compound B) with decomposition temperature in the range 139-145 °C, [a]<2>,<0> + 54.8 (methanol,
o = 0,505). o = 0.505).
Eksempel 8 Example 8
En løsning av 170 mg av produktet erholdt ifølge A solution of 170 mg of the product obtained according to
i eksempel 5 i 5 ml THF omrøres etter tilsetning av 200 mg litium-tri-tertiær-butoksy-aluminiumhydrid i 90 min ved romtemperatur. Det tilsettes 0,8 ml mettet NH4C1-løsning, filtreres og filtratet inndampes. Kromatografering av råproduktet på A1203 (Merck, nøytral, trinn III) gir 108 mg in example 5, 5 ml of THF is stirred after the addition of 200 mg of lithium-tri-tertiary-butoxy-aluminium hydride for 90 min at room temperature. 0.8 ml of saturated NH4C1 solution is added, filtered and the filtrate evaporated. Chromatography of the crude product on A1203 (Merck, neutral, stage III) gives 108 mg
1-[1(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-9,10-secochola-5E,7E,10(19)-trien-24-yl]-3-metyl-butan-l-on i form av farge-løs olje. 1-[1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-secochola-5E,7E,10(19)-trien-24-yl]-3-methyl-butan- l-on in the form of colorless oil.
^-NMR (CDCI3): 6 = 0,53 ppm (s, 3H, H-18); 4,22 (m,lH,H-3); 4,54 (m,lH,H-l); 4,93 og 4,98 (m,1H,H-19); 5,82 og 6,46 (d,J=llHz,lH,H-6,H-7). 3-NMR (CDCl 3 ): δ = 0.53 ppm (s, 3H, H-18); 4.22 (m,1H,H-3); 4.54 (m,1H,H-1); 4.93 and 4.98 (m,1H,H-19); 5.82 and 6.46 (d,J=11Hz,1H,H-6,H-7).
Eksempel 9 Example 9
Fotokjemisk dobbeltbindingsisomerisering analogt med eksempel 3 og silyleterspaltning analogt med eksempel 4, gir fra 100 mg av produktet fra eksempel 8 50 mg 1-[1(S),3(R)-di-hydroksy-9,10-secochola-5Z,7E,10(19)-trien-24-yl]-3-metyl-butan-l-on. Photochemical double bond isomerization analogously to example 3 and silyl ether cleavage analogously to example 4 gives from 100 mg of the product from example 8 50 mg of 1-[1(S),3(R)-di-hydroxy-9,10-secochola-5Z,7E ,10(19)-trien-24-yl]-3-methyl-butan-1-one.
UV (metanol): = 212 nm (e = 14 300), 265 (15 860). UV (methanol): = 212 nm (e = 14,300), 265 (15,860).
Eksempel 10 Example 10
Omsetning av 1,6 g 1(S),3(R)-bis-(tert.-butyldimetyl-silyloksy )-20(R)-metyl-9, 10-secopregna-5E, 7E, 10(19)-trien-21-karbaldehyd med (2-isopropoksyetyl)-karbonylmetylentrifenyl-fosforan analogt med eksempel 1, gir 1,15 g l-[l(S),3(R)-bis-(tert. -butyldimetylsilyloksy)-9,10-secochola-5E,7E,10(19 )-23(E)-tetraen-24-yl]-3-isopropoksy-propan-l-on i form av fargeløs olje. Conversion of 1.6 g of 1(S),3(R)-bis-(tert-butyldimethyl-silyloxy)-20(R)-methyl-9, 10-secopregna-5E, 7E, 10(19)-triene -21-carbaldehyde with (2-isopropoxyethyl)-carbonylmethylenetriphenyl-phosphorane analogously to example 1, gives 1.15 g of l-[l(S),3(R)-bis-(tert.-butyldimethylsilyloxy)-9,10- secochola-5E,7E,10(19 )-23(E)-tetraen-24-yl]-3-isopropoxy-propan-1-one in the form of a colorless oil.
^-NMR (CDCI3): 6 = 0,01 ppm ( s, 12H, Si-CH3); 0,55 (s,3H,H-18); 0,86 og 0,90 (s,9H,Si-t.-butyl); 0,96 (d,J=7Hz, 3H,H-21); 1,15 (d,J=7Hz,6H,C-(CH3)2); 3,60 (m,1H,CH-0); 3,73 (t, J=7Hz,2H,CH2-0); 4,23 (m,lH,H-3); 4,55 (m,lH,H-l), 4,95 og 5,00 (m,lH,H-19); 5,83 og 6,46 (d,J=llHz,lH,H-6,H-7); 6,11 (d,J=15,5Hz,lH,H-24); 6,87 (m,lH,H-23). 3-NMR (CDCl 3 ): δ = 0.01 ppm (s, 12 H, Si-CH 3 ); 0.55 (s,3H,H-18); 0.86 and 0.90 (s,9H,Si-t-butyl); 0.96 (d,J=7Hz, 3H,H-21); 1.15 (d,J=7Hz,6H,C-(CH3)2); 3.60 (m, 1H, CH-O); 3.73 (t, J=7 Hz, 2 H, CH 2 -O); 4.23 (m,1H,H-3); 4.55 (m,1H,H-1), 4.95 and 5.00 (m,1H,H-19); 5.83 and 6.46 (d,J=11Hz,1H,H-6,H-7); 6.11 (d,J=15.5Hz,1H,H-24); 6.87 (m,1H,H-23).
Eksempel 11 Example 11
Ved redusering analogt med eksempel 2, fotoisomerisering analogt med eksempel 3, og silyleterspaltning analogt med eksempel 4, erholdes fra 1,05 g av produktet fremstilt ifølge eksempel 10 143 mg 24-(l(R,S)-hydroksy-3-isopropoksy-propyl)-9,10-secochola-5Z,7E,10(19),23-tetraen-l(S),3(R)-diol i form av en l:l-blanding av diastereomerer som kan adskilles ved høytrykks-væskekromatografi. Isomerene oppviser identiske NMR-spektre. By reduction analogous to example 2, photoisomerization analogous to example 3, and silyl ether cleavage analogous to example 4, 1.05 g of the product prepared according to example 10 yield 143 mg of 24-(1(R,S)-hydroxy-3-isopropoxy- propyl)-9,10-secochola-5Z,7E,10(19),23-tetraene-1(S),3(R)-diol in the form of a 1:1 mixture of diastereomers which can be separated by high-pressure liquid chromatography. The isomers exhibit identical NMR spectra.
^-NMR (CDCI3): 6 = 0,57 ppm (s,3H,H-18), 0,94 (d,J=7Hz,3H,H-21); 1,15 (d. J=7Hz, 6H,C(CH3)2), 4,17 (m,lH,H-3); 3-NMR (CDCl 3 ): δ = 0.57 ppm (s,3H,H-18), 0.94 (d,J=7Hz,3H,H-21); 1.15 (d. J=7Hz, 6H,C(CH3)2), 4.17 (m,1H,H-3);
4,21 (m,lH,H-25); 4,38 (m,lH,H-l); 4,98 og 5,29 (m,1H,H-19); 4.21 (m,1H,H-25); 4.38 (m,1H,H-1); 4.98 and 5.29 (m,1H,H-19);
5,45 (dd, J=15,5 og 7Hz,lH,H-24); 5,63 (m,1H,H-23); 6,02 og 5.45 (dd, J=15.5 and 7Hz,1H,H-24); 5.63 (m, 1H, H-23); 6.02 and
i 6,38 (d,J=llHz,lH,H-6,H-7). in 6.38 (d,J=11Hz,1H,H-6,H-7).
Eksempel 12 Example 12
Med utgangspunkt i aldehyd 1 og isopropoksymetylkarbonylmetylentrifenylfosforan erholdes analogt med rekke- Starting from aldehyde 1 and isopropoxymethylcarbonylmethylenetriphenylphosphorane is obtained analogously to series
> følgen ifølge eksempel 1-4 isomer B (5Z,7E,22E-1(S),3(R),-24(S)-9,10-seco-24a,24b-dihomo-24b-oksacholestra-5,7,10(19)22-tetraen-l,3,24-triol) med smeltepunkt 131-132 "C. > the sequence according to example 1-4 isomer B (5Z,7E,22E-1(S),3(R),-24(S)-9,10-seco-24a,24b-dihomo-24b-oxacholestra-5, 7,10(19)22-tetraene-1,3,24-triol) with melting point 131-132 "C.
Eksempel 13 Example 13
> Med utgangspunkt i aldehyd 1 og (2-isopropoksyetyl)-karbonylmetylentrifenylfosforan erholdes analogt med rekke-følgen ifølge eksempel 1-4 isomer B (5Z,7E,22E-1(S),3(R),-24(S)-9,10-seco-24a,24b,24c-trihomo-24c-oksacholestra-5,7,10-(19)22-tetraen-l,3,24-triol) med smeltepunkt 125-126 °C. > Starting from aldehyde 1 and (2-isopropoxyethyl)-carbonylmethylenetriphenylphosphorane, isomer B (5Z,7E,22E-1(S),3(R),-24(S)- 9,10-seco-24a,24b,24c-trichomo-24c-oxacholestra-5,7,10-(19)22-tetraene-1,3,24-triol) with melting point 125-126 °C.
Eksempel 14 Example 14
Analogt med eksempel 1 omsettes 0,85 g l(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-20(R)-metyl-9,10-secopregna-5E,7E,10(19)-trien-21-karbaldehyd med 4,5 g syklopropylmetyl-5 karbonyltrifenylfosforan. Etter kromatografisk rensning på kiselgel med heksan/eddikester erholdes 500 mg 1(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-26,27-syklo-24a, 24b-dihomo-9,10-secocholesta-5E,7E,10(19)-23E-tetraen-24a-on i form av et Analogous to example 1, 0.85 g of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-5E,7E,10(19)-triene is reacted -21-carbaldehyde with 4.5 g of cyclopropylmethyl-5-carbonyltriphenylphosphorane. After chromatographic purification on silica gel with hexane/acetic ester, 500 mg of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-26,27-cyclo-24a, 24b-dihomo-9,10-secocholesta-5E is obtained ,7E,10(19)-23E-tetraen-24a-one in the form of a
fargeløst skum. colorless foam.
3<X>H-NMR (CDCI3): 6 = 0,01 ppm (s, 12H, Si-CH3); 0,09 og 0,50 (m,2H,H-26 og H-27); 0,50 (s,3H,H-18); 0,83 og 0,85 (s, 9H,Si-t.-butyl); 0,91 (d,J=7,3Hz,3H,H-21; 0,96 (m,lH,H-25); 3<X>H-NMR (CDCl 3 ): δ = 0.01 ppm (s, 12 H, Si-CH 3 ); 0.09 and 0.50 (m,2H,H-26 and H-27); 0.50 (s,3H,H-18); 0.83 and 0.85 (s, 9H,Si-t-butyl); 0.91 (d,J=7.3Hz,3H,H-21; 0.96 (m,1H,H-25);
2,47 (d,J=6Hz,2H,H-24b); 4,16 (m,lH,H-3); 4,47 (m,lH,H-l); 2.47 (d,J=6Hz,2H,H-24b); 4.16 (m,1H,H-3); 4.47 (m,1H,H-1);
4,89 og 4,93 (s. 1H,H-19); 5,77 og 6,40 (d. J=llHz,1H,H-6 og 4.89 and 4.93 (pp. 1H,H-19); 5.77 and 6.40 (d. J=11Hz,1H,H-6 and
5 H-7); 6,08 (d. J=15,5Hz,H-24); 6,75 (ddd. J=15,5, 9, 6,5Hz, lH,H-23). 5H-7); 6.08 (d. J=15.5Hz, H-24); 6.75 (ddd. J=15.5, 9, 6.5Hz, 1H,H-23).
Eksempel 15 Example 15
Redusering av det erholdte produkt ifølge eksempel 14, analogt med eksempel 2, gir 200 mg l(S),3(R)-bis-(tert.-butyldimetylsilyloksy)-26,27-syklo-24a,24b-dihomo-9,10-secocholesta-5E,7E,10(19),23E-tetraen-24a(R,S)-ol i form av en oljeaktig blanding av epimerer, som ikke kan sjeldnes NMR-spektroskopisk. Reduction of the product obtained according to example 14, analogously to example 2, gives 200 mg of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-26,27-cyclo-24a,24b-dihomo-9, 10-secocholesta-5E,7E,10(19),23E-tetraen-24a(R,S)-ol in the form of an oily mixture of epimers, which cannot be rarefied NMR spectroscopically.
<1>H-NMR (CDC13): 6 = 0,01 ppm (s, 12H, Si-CH3), 0,09 og 0,40 (m,2H,H-26 og H-27); 0,50 (s,3H,H-18); 0,68 (m,1H,H-25); 0,81 og 0,86 (s,9H,Si-t.-butyl); 0,88 (d,J=7Hz,3H,H-21); 1,40 (t,J=7Hz,H-24b); 4,13 (m,lH,H-24a); 4,17 (m,lH,H-3); 4,49 (m, 1H,H-1); 4,88 og 4,93 (s. 1H,H-19); 5,45 (dd. J=15,5, 6,5Hz, lH,H-24); 5,59 (ddd. J=15,5, 7, 6,5Hz,lH,H-23); 5,77 og 6,40 (d. J=llHz,lH,H-6 og H-7). <1>H-NMR (CDCl 3 ): δ = 0.01 ppm (s, 12H, Si-CH 3 ), 0.09 and 0.40 (m, 2H, H-26 and H-27); 0.50 (s,3H,H-18); 0.68 (m, 1H, H-25); 0.81 and 0.86 (s,9H,Si-t-butyl); 0.88 (d,J=7Hz,3H,H-21); 1.40 (t,J=7Hz,H-24b); 4.13 (m,1H,H-24a); 4.17 (m,1H,H-3); 4.49 (m, 1H,H-1); 4.88 and 4.93 (pp. 1H,H-19); 5.45 (dd. J=15.5, 6.5Hz, 1H,H-24); 5.59 (ddd. J=15.5, 7, 6.5Hz, 1H, H-23); 5.77 and 6.40 (d. J=11Hz,1H,H-6 and H-7).
Eksempel 16 Example 16
Analogt med eksempel 3 erholdes det, ved triplettsensibilisert fotoisomerisering og avspalting av beskyttelses-gruppene analogt med eksempel 4, fra 190 mg av forbindelsen beskrevet under eksempel 15, 85 mg 26,27-syklo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23(E)-tetraen-1(S),3(R),24a-(R,S)-triol i form av en l:l-blanding av diastereomerer, som adskilles ved høytrykks-væskekromatografering. NMR-spektrene av begge diastereomerer er identiske. Analogous to example 3, by triplet sensitized photoisomerization and removal of the protective groups analogously to example 4, from 190 mg of the compound described under example 15, 85 mg of 26,27-cyclo-24a,24b-dihomo-9,10-secocholesta is obtained -5Z,7E,10(19),23(E)-tetraene-1(S),3(R),24a-(R,S)-triol in the form of a 1:1 mixture of diastereomers, which separate by high pressure liquid chromatography. The NMR spectra of both diastereomers are identical.
^-NMR (CDCI3): 6 = 0,09 og 0,49 (m,2H,H-26 og H-27); 0,53 (s,3H,H-18); 0,70 (m,lH,H-25); 0,93 (d,J=7Hz,3H, H-21); 4,18 (m,lH,H-24a); 4,22 (m,lH,H-3); 4,43 (m,lH,H-l); 5,00 og 5,32 (s,lH,H-19); 5,50 (dd,J=15,5, 6,5Hz,H-24); 5,64 (ddd. J=15,5, 7, 6,5Hz,lH,H-23); 6,02 og 6,38 (d. J=llHz,lH, H-6 og H-7). 3-NMR (CDCl 3 ): δ = 0.09 and 0.49 (m, 2H, H-26 and H-27); 0.53 (s,3H,H-18); 0.70 (m,1H,H-25); 0.93 (d,J=7Hz,3H,H-21); 4.18 (m,1H,H-24a); 4.22 (m,1H,H-3); 4.43 (m,1H,H-1); 5.00 and 5.32 (s,1H,H-19); 5.50 (dd,J=15.5, 6.5Hz,H-24); 5.64 (ddd. J=15.5, 7, 6.5Hz, 1H, H-23); 6.02 and 6.38 (d. J=11Hz,1H, H-6 and H-7).
Eksempel 17 Example 17
Med utgangspunkt i aldehyd 1. og (1-etylpropoksymetyl)-karbonylmetylentrifenylfosforan erholdes analogt med rekkefølgen ifølge eksemplene 1-4 isomer B (5Z,7E,22E-1(S),3(R),24(S)-26,27-dimetyl-24a,24b-dihomo-24b-oksa-9,10-secocholesta-5,7,10(19)22-tetraen-l,3,24-triol) med smeltepunkt 103-105 °C. Starting from aldehyde 1. and (1-ethylpropoxymethyl)-carbonylmethylenetriphenylphosphorane, isomer B is obtained analogously to the sequence according to examples 1-4 (5Z,7E,22E-1(S),3(R),24(S)-26,27 -dimethyl-24a,24b-dihomo-24b-oxa-9,10-secocholesta-5,7,10(19)22-tetraene-1,3,24-triol) with melting point 103-105 °C.
Eksempel 18 Example 18
Med utgangspunkt i aldehyd 1 og syklopropylmetoksy-metylkarbonylmetylentrifenylfosforan erholdes analogt med rekkefølgen ifølge eksempel 1-4 isomer B (5Z,7E,22E-1(S),-3(R),24(S)-26,27-syklo-24a,24b,24c-trihomo-24b-oksa-9,10-secocholesta-5,7,10(19)22-tetraen-1,3,24-triol). Starting from aldehyde 1 and cyclopropylmethoxymethylcarbonylmethylenetriphenylphosphorane, isomer B (5Z,7E,22E-1(S),-3(R),24(S)-26,27-cyclo-24a) is obtained analogously to the sequence according to example 1-4 ,24b,24c-trihomo-24b-oxa-9,10-secocholesta-5,7,10(19)22-tetraene-1,3,24-triol).
<X>H-NMR (DMS0-d3): S=0,16 ppm (m,2H); 0,43 (m,2H); 0,53 (S,3H); 1,00 (d,J=6Hz,3H); 3,21 (m,4H); 4,00 (m,2H); 4,19 (m,lH); 4,51 (d,J=5Hz,1H); 4,70 (d,J=5Hz,1H); 4,75 (m,lH); 4,82 (d,J=5Hz,1H); 5,21(m,lH); 5,39 (m,2H); 5,98 (d, J=llHz,-1H); 6,18 (d,J=llHz,lH). <X>H-NMR (DMS0-d3): S=0.16 ppm (m,2H); 0.43 (m, 2H); 0.53 (S.3H); 1.00 (d,J=6Hz,3H); 3.21 (m, 4H); 4.00 (m, 2H); 4.19 (m, 1H); 4.51 (d,J=5Hz,1H); 4.70 (d,J=5Hz,1H); 4.75 (m,1H); 4.82 (d,J=5Hz,1H); 5.21(m,1H); 5.39 (m, 2H); 5.98 (d, J=11Hz, -1H); 6.18 (d,J=11Hz,1H).
Eksempel 19 Example 19
Med utgangspunkt i aldehyd 1 og (3-butinyl)-karbonyl-metylentrifenylfosforan erholdes analogt med rekkefølgen ifølge eksempler 1-4 isomer B (5Z,7E,22E-l(S),3(R),24(S)-24-(3-butinyl)-9,10-secochola-5,7,10(19)22-tetraen-l,3,24-triol) med smeltepunkt 115-118 °C. Starting from aldehyde 1 and (3-butynyl)-carbonyl-methylenetriphenylphosphorane, isomer B (5Z,7E,22E-1(S),3(R),24(S)-24- (3-butynyl)-9,10-secochola-5,7,10(19)22-tetraene-1,3,24-triol) with melting point 115-118 °C.
Eksempel 20 Example 20
Med utgangspunkt i aldehyd 1 og (3-butenyl)-karbonyl-metylentrifenylfosforan erholdes analogt med rekkefølgen ifølge eksempel 1-4 isomer B (5Z,7E,22E-l(S),3(R),24(S)-24-(3-butenyl)-9,10-secochola-5,7,10(19)22-tetraen-l,3,24-triol) med smeltepunkt 146-147 °C. Starting from aldehyde 1 and (3-butenyl)-carbonyl-methylenetriphenylphosphorane, isomer B (5Z,7E,22E-1(S),3(R),24(S)-24- (3-butenyl)-9,10-secochola-5,7,10(19)22-tetraene-1,3,24-triol) with melting point 146-147 °C.
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DE4003854A DE4003854A1 (en) | 1990-02-06 | 1990-02-06 | New vitamin=D derivs. - are cell differentiators and proliferation inhibitors useful for treating psoriasis and malignant tumours |
DE19904034730 DE4034730A1 (en) | 1990-10-30 | 1990-10-30 | New vitamin=D derivs. with modified side chain |
PCT/DE1991/000104 WO1991012238A1 (en) | 1990-02-06 | 1991-02-06 | Side-chain-homologous vitamin d derivatives, process for producing them, pharmaceutical preparations containing these derivatives and their use as medicaments |
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DE4221961A1 (en) * | 1992-06-30 | 1994-01-05 | Schering Ag | 22-en-25-oxa derivatives in the vitamin D series, processes for their preparation, pharmaceutical preparations containing these derivatives and their use as medicines |
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CA2296145A1 (en) * | 1997-07-17 | 1999-01-28 | F. Hoffmann-La Roche Ag | Dihomo-seco-cholestanes with two unsaturated bonds in the side chain |
DE19935771A1 (en) | 1999-07-23 | 2001-02-01 | Schering Ag | New vitamin D derivatives with cyclic substructures in the side chains, processes and intermediates for their manufacture and their use in the manufacture of pharmaceuticals |
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DE59101738D1 (en) | 1994-07-07 |
FI100598B (en) | 1998-01-15 |
CA2058637A1 (en) | 1991-08-07 |
CN1029400C (en) | 1995-08-02 |
HUT59665A (en) | 1992-06-29 |
PT96679B (en) | 1998-07-31 |
ATE106391T1 (en) | 1994-06-15 |
EP0441467A1 (en) | 1991-08-14 |
IL97158A (en) | 1994-12-29 |
IL97158A0 (en) | 1992-05-25 |
HU913475D0 (en) | 1992-05-28 |
CZ280203B6 (en) | 1995-11-15 |
WO1991012238A1 (en) | 1991-08-22 |
AU652739B2 (en) | 1994-09-08 |
AU7216191A (en) | 1991-09-03 |
JPH05501718A (en) | 1993-04-02 |
FI914677A0 (en) | 1991-10-04 |
CS28191A3 (en) | 1992-04-15 |
ES2055521T3 (en) | 1994-08-16 |
EP0441467B1 (en) | 1994-06-01 |
DK0441467T3 (en) | 1994-10-03 |
NO913913D0 (en) | 1991-10-04 |
PT96679A (en) | 1991-10-31 |
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