MXPA99009555A - Arylsecocholadiene derivatives - Google Patents
Arylsecocholadiene derivativesInfo
- Publication number
- MXPA99009555A MXPA99009555A MXPA/A/1999/009555A MX9909555A MXPA99009555A MX PA99009555 A MXPA99009555 A MX PA99009555A MX 9909555 A MX9909555 A MX 9909555A MX PA99009555 A MXPA99009555 A MX PA99009555A
- Authority
- MX
- Mexico
- Prior art keywords
- methyl
- phenyl
- ethyl
- cola
- hydroxy
- Prior art date
Links
- 201000010099 disease Diseases 0.000 claims abstract description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 150000003710 vitamin D derivatives Chemical class 0.000 claims abstract description 13
- 229940046008 Vitamin D Drugs 0.000 claims abstract description 12
- 229930003316 Vitamin D Natural products 0.000 claims abstract description 12
- 235000019166 vitamin D Nutrition 0.000 claims abstract description 12
- 239000011710 vitamin D Substances 0.000 claims abstract description 12
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 201000004681 psoriasis Diseases 0.000 claims abstract description 8
- 206010004146 Basal cell carcinoma Diseases 0.000 claims abstract description 7
- 206010020649 Hyperkeratosis Diseases 0.000 claims abstract description 7
- 208000001126 Keratosis Diseases 0.000 claims abstract description 7
- 206010024324 Leukaemias Diseases 0.000 claims abstract description 7
- 201000002980 hyperparathyroidism Diseases 0.000 claims abstract description 7
- 230000003780 keratinization Effects 0.000 claims abstract description 7
- 230000001419 dependent Effects 0.000 claims abstract description 6
- 206010038435 Renal failure Diseases 0.000 claims abstract description 5
- 201000006370 kidney failure Diseases 0.000 claims abstract description 5
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 3
- 230000002265 prevention Effects 0.000 claims abstract 5
- -1 1-Hydroxy-1-methyl-1-ethyl Chemical group 0.000 claims description 157
- 150000001875 compounds Chemical class 0.000 claims description 127
- 239000000203 mixture Substances 0.000 claims description 18
- 229910004759 OSi Inorganic materials 0.000 claims description 12
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 8
- 238000003776 cleavage reaction Methods 0.000 claims description 7
- 239000000543 intermediate Substances 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 210000003734 Kidney Anatomy 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 abstract 2
- 206010052779 Transplant rejections Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 146
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 64
- 239000011541 reaction mixture Substances 0.000 description 57
- 239000008079 hexane Substances 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 239000000243 solution Substances 0.000 description 38
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- 229910052938 sodium sulfate Inorganic materials 0.000 description 30
- 235000011152 sodium sulphate Nutrition 0.000 description 30
- 239000012267 brine Substances 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 238000003818 flash chromatography Methods 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 125000004494 ethyl ester group Chemical group 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- NFILHPVBZNKVNP-UHFFFAOYSA-N ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate Chemical compound ClC1=CC(Cl)=C2C(C=O)=C(C(=O)OCC)NC2=C1 NFILHPVBZNKVNP-UHFFFAOYSA-N 0.000 description 14
- 239000003480 eluent Substances 0.000 description 13
- 150000002576 ketones Chemical class 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 101700050775 oct-1 Proteins 0.000 description 11
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 210000003491 Skin Anatomy 0.000 description 9
- 239000012300 argon atmosphere Substances 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- KRHYYFGTRYWZRS-UHFFFAOYSA-N HF Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 7
- 239000005711 Benzoic acid Substances 0.000 description 7
- LXCIHXPVYQKJAG-UHFFFAOYSA-N N-[aziridin-1-yl-(2-methylaziridin-1-yl)phosphoryl]-N-prop-2-enylprop-2-en-1-amine Chemical compound CC1CN1P(=O)(N(CC=C)CC=C)N1CC1 LXCIHXPVYQKJAG-UHFFFAOYSA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- LMYWWPCAXXPJFF-UHFFFAOYSA-P Cornforth reagent Chemical compound C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O LMYWWPCAXXPJFF-UHFFFAOYSA-P 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- LEHBURLTIWGHEM-UHFFFAOYSA-N Pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- GMRQFYUYWCNGIN-NKMMMXOESA-N (1R,3S,5Z)-5-{2-[(1R,3aS,4E,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-octahydro-1H-inden-4-ylidene]ethylidene}-4-methylidenecyclohexane-1,3-diol 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)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000000875 corresponding Effects 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229960005084 CALCITRIOL Drugs 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- JSPLKZUTYZBBKA-UHFFFAOYSA-N Trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 230000035492 administration Effects 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 235000020964 calcitriol Nutrition 0.000 description 4
- 239000011612 calcitriol Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- 238000006884 silylation reaction Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000001808 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 3
- 230000003463 hyperproliferative Effects 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- GNVMUORYQLCPJZ-UHFFFAOYSA-M thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- HWBIQJOWCBKZJW-UHFFFAOYSA-N $l^{1}-silanyloxysilicon Chemical compound [Si]O[Si] HWBIQJOWCBKZJW-UHFFFAOYSA-N 0.000 description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-Diazabicyclo(4.3.0)non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L Bis(triphenylphosphine)palladium(II) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 210000000987 Immune System Anatomy 0.000 description 2
- RQNMYNYHBQQZSP-UHFFFAOYSA-M Methylmagnesium chloride Chemical compound C[Mg]Cl RQNMYNYHBQQZSP-UHFFFAOYSA-M 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-Methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 240000002799 Prunus avium Species 0.000 description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 2
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 2
- NBRKLOOSMBRFMH-UHFFFAOYSA-N Tert-Butyl chloride Chemical compound CC(C)(C)Cl NBRKLOOSMBRFMH-UHFFFAOYSA-N 0.000 description 2
- DBGVGMSCBYYSLD-UHFFFAOYSA-N Tributyltin hydride Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- YSLUMOXQTAXULO-MUPNANLLSA-N [(1R,3aR,4S,7aR)-1-[(2R)-but-3-yn-2-yl]-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-4-yl]oxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@]2(C)[C@@H]([C@H](C#C)C)CC[C@H]21 YSLUMOXQTAXULO-MUPNANLLSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- QOUFDDUDXYJWHV-UHFFFAOYSA-N ethyl 2-iodobenzoate Chemical compound CCOC(=O)C1=CC=CC=C1I QOUFDDUDXYJWHV-UHFFFAOYSA-N 0.000 description 2
- JHYNXXDQQHTCHJ-UHFFFAOYSA-M ethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC)C1=CC=CC=C1 JHYNXXDQQHTCHJ-UHFFFAOYSA-M 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- KLGZELKXQMTEMM-UHFFFAOYSA-N hydride Chemical compound [H-] KLGZELKXQMTEMM-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N methyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
- 230000000051 modifying Effects 0.000 description 2
- 230000001613 neoplastic Effects 0.000 description 2
- 230000003000 nontoxic Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- 229960003415 propylparaben Drugs 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
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- 229910052905 tridymite Inorganic materials 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 150000004072 triols Chemical class 0.000 description 1
- KLGZELKXQMTEMM-NJFSPNSNSA-N tritide Chemical compound [3H-] KLGZELKXQMTEMM-NJFSPNSNSA-N 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Abstract
24-Nor-secochola-5,7-diene derivatives of formula (I) wherein A is a single or double bond, B is a group CH2CH2, CH=CH or C=C, T is a group CH2 or CH2CH2, R1 and R3 are H or OH, C(R,R) is CH2 or C=CH2, R2 is CH3 and R4 is H, or R2 is H and R4 is CH3, L is phenyl and R5 is OH or C(C1-4-alkyl)2OH, or L-R5 is 2-furyl which is 5-substituted by C(C1-4-alkyl)2OH, with the proviso that when L is phenyl, A is a single bond, B is C=C, T is CH2, each R1 and R3 are OH, C(R,R) is C=CH2, R2 is CH3, R4 is H, and R5 is C(CH3)2OH, then R5 must be in position ortho or para, are useful in the treatment or prevention of vitamin D dependent disorders, particularly psoriasis, basal cell carcinomas, disorders of keratinization and keratosis, leukemia, osteoporosis, hyperparathyroidism accompanying renal failure, transplant rejection and graft vs. host disease.
Description
ARILSECOCOLADIENE DERIVATIVES
FIELD OF THE INVENTION The invention relates to dry cocacolans, in particular derivatives of nor-secocola-5,7-diene, of formula (I)
where A is a single bond or a double bond, B is a group CH CH, CH = CH or C = C, T is a group CH or CH CH, R1 and R are H or OH, C (R, R) is CH ^ or C = CH,
REF .: 31367
R: is CH. and R 4 is H, or R- is H and R "is CH., L is phenyl, and R" is OH or C (alkyl of 1 to 4 carbon atoms) OH, or L-R; is 2-furyl which is substituted at the 5-position with C (alkyl of 1 carbon atoms) OH, with the proviso that when L is phenyl c, A is ui: single bond, B is C = C, T is CH;, each R ^ and R 'sin OH, C (R, R) is C = CH;, R- is CH3, R ^ is H, and R is C (CH; -) _ OH, then R5 must be in the ortho or para position.
Brief Description of the Invention
The present invention further relates to a process for the preparation of the compound of formula I, pharmaceutical compositions containing the compound of formula I, and the use of the compound of formula I for the treatment of disorders dependent on vitamin D, and for the preparation of pharmaceutical compositions for the treatment of disorders dependent on vitamin D. The term "disorders dependent on vitamin D" refers to disorders that can be treated or prevented by administration of
compounds having the activity of vitamin L, such as vitamin D or derivatives, in particular, the hydroxylated derivatives thereof, for example, calcitriol or calcol triol. Examples of such disorders are skin hyperproliferative diseases such as psoriasis, basal cell carcinomas, keratinization disorders and keratosis; neoplastic diseases such as leukemia; disorders of the cebaceous glands such as acne and seborrheic dermatitis, os t eopor s i s; hyperparathyroidism that accompanies renal failure; and diseases that require a modulation of the immune system, such as rejection of a transplant and graft disease versus the recipient. Preferred alkyl groups of 1 to 4 carbon atoms are straight chain alkyl groups such as ethyl, propyl and particularly methyl. Preferred compounds of formula I are those in which: a) R: is H or OH and R: is OH, and / or
b) L is phenyl, B is CH "CH or C = C, R and R 'are OH and RL is C (CHJ): OH, preferably c) A is a single bond B is C = C and T is CH , such as :
(7E) - (1R, 3R, 20R) -23- [2- (1-Hydroxy-1-methyl-1-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, " 7-dien-22-in-1, 3-diol
Preferred other compounds are
(7E) - (1R, 3R) -23- [2- (1-hydroxy-1-methylethyl) -phenyl] -19,24-dinor-9, 10-seco-cola-5, 7- dien-1,3-diol, (7E) - (lR, 3R) -23- [2- (1-hydroxy-1-meth i 1 -ethyl) -phenyl] -19, 24-dinor-9,10- dry-cola-5,7-dien-22 'in-1, 3-diol, (7E) -. { IR, 3R) -23- [3- (1-Hydroxy-1-methyl-1-ethyl) -phenyl] -19,24-dinor-9, 10-seco-cola-5,7-dien-1, 3 -diol, (5Z, 7E) - (1S, 3R, 20R) -23- [3- (1-hydroxy? -l-methyl-ethyl) -phenyl] -24-nor-9, 10-seco-cola- 5, 7, 10 (19) -trien-22-in-l, 3-diol,
(5Z, 7E) - (1S, 3R, 20R) -23- [2- (1-hydroxy-1-methyl-ethyl) -phenyl] -24-nor-9, 1 O-seco-col a-5, 7, 10; 1 trien-22-in-l, 3-diol, (7E) - (IR, 3R, 20S) -23- [3- (1-hydroxy-1-methyl-1-ethyl) -phenyl] -19, 24- dinor-9, 10-seco-cola-5, 7, -dien-1, 3-diol, (7E) - (IR, 3R) -23- [2- (1-hydroxy-l-methyl-ethyl) - phenyl] -D-homo-19, 24-dinor-9, 10-seco-cola-5, 7, 17-trien-22-in-l, 3-diol, (5Z, 7E) - (lS, 3R, 21R) -23- [2- (l-hydroxy-l-methyl-ethyl) -phenyl] -D-homo-24-nor-9 ', 10-seco-cola-5,7,10 (19) -trien -22-in-l, 3-diol.
Other preferred compounds are those in which L is 2-furyl, A is a single bond, B is C = C, T is CH, R is CH, and R4 is H, such as
(7E) - (IR, 3R) -23- [5- (1-Hydroxy-1-methyl-1-ethyl) -furan-2-yl] -19, 24-dinor-9, 10-seco-cola- 5, 7-dien-22-in-l, 3-diol. The compounds of formula I can be obtained by cleavage of the group (s) pro tector (s) of the silyl group, contained (s) in a compound of the formula:
where A, B, L, T, R, R ~ and R4 are as defined above, R: and R * are H or OSi (CH) _ - 1 erc-but i lo, and R is OSi ( CH3)., OSi (CH .. tert -butyl or C (alkyl of 1 to 4 carbon atoms) .OSi (CHO,.
The intermediates of formula II above, and those of formulas IV, IVa and V are new and as such are another object of the present invention. The cleavage can be effected by tetrabutylammonium fluoride (TBAF) in a solvent such as THF.
The compounds of formula II are obtained by coupling a phosphine oxide of formula
With a formula ketone
The coupling can be effected by reacting a solution of the phosphine oxide of THF with butyllithium and then with a ketone IV to
Ketones IV in which R "" is C (alkylene of 1 to 4 carbon atoms); OSi (CH.)., Can be obtained by oxidation followed by silylation of the diols of the formula
wherein R is C (alkyl of 1 to 4 carbon atoms) OH. The products of this oxidation are hidroxice tonas of formula IVa
IVa
The oxidation can be carried out in DMF c in CH.C1. they are pyridinium dichromate (PDC) Silylation can be carried out by reaction of the intermediate ketone in THF or in CH.Cl at 0 ° C with 1-trimethylsilyl imidazole, optionally in mixture with imidazole and trimeric chloride 1 if 1 i lo.
Ketones IV where R is OSi (CH)
OSi (CH.sub.-tert.-butyl) can be obtained by silylation of the alcohols phenols of formula V, where R is OH, followed by oxidation Silylation of the phenolic hydroxyl can be carried out in DMF or in CHjCl; of tert-butyldimethylsilyl and imidazole Oxidation can be carried out in DMF with PDC The diols V, wherein R ~ is C (alkylene of 1 to 4 carbon atoms), OH, can be obtained by the ester-alcohol reaction of formula
SAW
with methylmagnesium chloride in THF at 0 ° C. The alcohol phenols V in which L is phenyl, R is OH and R is C = C or CH = CH, can be obtained by coupling the alcohols of formula VII or
V I I I
with iodophenol in the presence of a palladium and copper (I) iodide catalyst in piperidine or in 2,2,6,6-tetramethylpiperidine. Similarly, esters alcohols of formula VI, wherein B is C = C or CH = CH, can be obtained by reacting a solution of alcohols of formula VII or VIII with a
Hal-L-COOEt formula, such as et ilyodoben zoa or in the presence of bis (triphenylphosphine) palladium (II) dichloride and cooper iodide
The alcohol esters VI, wherein B is CH_CH_, can be obtained by catalytic hydrogenation, for example by Pd / C in ethanol, of the corresponding alcohol-esters in which B is C = C. Compounds VIII are obtained from compounds VII by reaction in toluene with tributyltin hydride and azobisi sobut ironi tri lo. The compounds of formula VII are obtained by deprotection of the corresponding ones of formula
IX
for example, in THF with hydrofluoric acid or TBA? anhydrous A compound of formula IX can be reacted with a halide of formula Hal-L-COOEt, such as e. 2-bromo-furan-? In the presence of the bis- (tri-phenyl phosph) palladium dichloride (11) and copper iodide, the ester obtained can be deprotected, for example in THF with hydrofluoric acid, to give the corresponding tert-alcohol. Formula VI The compounds of formula IX are obtained from compounds of formula
by reaction in THF at -78 ° C with butyllithium. The compounds of formula X are obtained from aldehydes of formula
by reaction with tertibromometry in dichloromethane in the presence of triphenylphosphine at -20 ° C. The aldehydes of formula IX can be obtained by oxidation of the alcohols of formula
XII
XII
for example, in dichloromethane, with catalytic amounts of tetrapropyl ammon perruthenate
(TPAP), in the presence of a molecular sieve and with N-methyl morpholine oxide as a co-oxidant, c. 00: 1 oxalyl chloride, DMSO and Net, in CH_C1_. An alcohol-ether XII with the non-natural configuration (R "= H), R" = CHO, can be obtained by epimerization of the corresponding aldehyde XI with natural configuration, with 1,5-diazabi cyano [4.3.0] non 5-ene (DNB) in THF, followed by reduction with sodium borohydride and chromatographic separation of the desired alcohol XII. The compounds of formula XII wherein T is CH CH, can be prepared as described in European patent application No. 95117037.2 (RAN 4212/67) as shown in the scheme of formula 1 below: According to the scheme 1, compound (1) [Synthesis 957 (1933)] is reduced to give equatorial alcohol (2), which is transformed into (4) by thiocarbamate (3). The compound (4) can be hydroborated to give the compound (5). Oxidation of alcohol, for example with pyridinium chlorochromate or TPAP and balanced with t-butoxide
potassium, gives the compound (6) which can be reduced to give the compound (7). Acetylation of the compound (7) and cleavage of the tert-butyl ether function gives the compound (8) which is oxidized and deacylated to give the ketoalcohol (9). To form the side chain of vitamin E > 3 the alcohol group of the compound (9) is suitably protected, for example by a protecting group Z of the silyl ether, preferably by a tert-butyl-dimethylsilyo group, to obtain the compound (10). The ketone (10) is converted by a Wittig reaction into the compound (11) from which the compound (12) is obtained by an ene reaction, with couple of formaldehyde and dimethyl ilaluminium chloride, or with formaldehyde and BF .Et O. Catalytic hydrogenation of compound (12) gives compound (13).
Esoruema and butyl butyl
(8) (9) (10)
The phosphine oxides of formula III are already known or can be obtained analogously to the known compounds. Thus, those in which
C (R, R) is CH_ can be prepared as shown in the scheme of formulas 2, which follows:
Scheme ?
XDI
XIV
XV
X \ l III -
According to scheme 2, ketone XIII is converted by a Peterson reaction into the
ester XIV from which alcohol XV is obtained by reduction. The reaction of the compound XV with the N-chlorosuccinimide in the presence of the dimethyl sulfide gives the chloride XVI. Reaction of compound XVI with diphenylphosphine-lithium and treatment with 5% H.sub.2 in ethyl acetate gives phosphine oxide III '. The following examples describe the preparation of compounds of formula I in more detail. In the following examples 1 to 26, the compounds of formula I were obtained by cleavage of the silyl protection group (s), in compounds of formula II:
Example 1
(7E, 22E) - (1R, 3R) -23- [4- (1-Hydroxy-1-methyl-1-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7, 22-trien-1, 3-diol, from (7E, 22E) - (1 R, 3P) -1,3 bis- (tert-butyldimethyl-silanyloxy) -23- [4- (1 -met i 1-1 trimethylsilanyloxy-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7, 22-triene.
MS: (M) "464 IR: cm" 1 3432; 2931; 2878; 1452; 1371; 1257; 1214;
1169; 1134; 1094; 1050; 967; 863; 813
2
(7E, 22E) - (1R, 3R) -23- [2- (1-hydroxy-1-methyl-ethyl) -phenyl] -19,24-dinor-9, 10-seco-cola-5, 7, 22-trien-1, 3-diol, from (7E, 22E) - (IR, 3R) -1,3-bis- (tert-butyldi ethyl-silanyloxy) -23- [2- (1-methyl- 1-trimethylsilanyloxy-ethyl) -phenyl] -19,24-dinor-9, 10-seco-cola-5, 7, 22-triene.
MS: (M) * 464 IR: cm ~: 3424; 29477 2870; 1621; 1444; 1371; 1 4 H; 974; 757. Example 3
(7E, 22E) - (1R, 3R) -23- (3-hydroxy-phenyl) -19,24-dinor-9, 10-seco-cola- 5, 7, 22-trien-l, 3-diol, from (7E, 22E) - (IR, 3R) -1,3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -19 , 24-dinor-9, 10-seco-cola-5, 7, 22-triene.
MS: (M) t 422 IR: cm 3419, 3042, 2947, 2869, 1613, 1585, 1451, 1375, 1286, 1260, 1229, 1156, 1044, 970, 777. Example 4
(7E, 22E) - (1R, 3R) -23- [3- (1-Hydroxy-1-methyl-1-methyl) -phenyl] -19,24-dmor-9,10-dry -cola-5,7,22-tpen-1, 3-dαol, from (7E, 22E) - (IR, 3R) -1,3-bis- (tert-buty 1 dimet i 1 -s ? lan? lox) -23- [3- (1-met? II -trimethylsilanyloxy-ethyl) -phenyl] -19, 24-dmor-9, 10-seco-cola-5, 7, 22-tpeno.
MS: (M: 464 IR: cm "3431; 2947; 2871; 1627; 1050; 970; 702
Example 5
(7E) - (1R, 3R) -23- [2- (1-Hydroxy-1-methyl-1-ethyl) -phenyl] -19, 24-d-nor-9, 10-seco-cola-5, 7-d? En-1,3-d? Ol, from (7E) - (IR, 3R) -1,3-b? S- (t-butyldimethyl-silanyloxy) -23- [2- ( 1-meth? II -trimethylsilanyloxy-ethyl) -phenyl] -19,24-dmor-9,10-seco-cola-5,7-d? Ene.
MS: (M) * 466 IR: cm ": 3422; 2944; 2871; 1619; 1442; 1376; 1047;
761. E j em lo 6
(7E) - (1R, 3R) -23- [2- (1-hydroxy-1-methyl-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7-dien- 22-ino- 1, 3-diol, from (7E) - (IR, 3R) -1,3-bi s- (tert-butyldimethyl-silanyloxy) -23- [2- (1-methyl-1-methyl) trimethylsilanyloxy-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5,7-diene-22-yne.
MS: (M) "462 IR cm 3415 1931 2872 1623 1441 1362 1046
759. Example 7
(7E) - (1R, 3R) -23- [3- (1-Hydroxy-1-methyl-1-ethyl) -phenyl] -19, 24-di-non-9, 10-seco-cola-5, 7-Dien-1,3-diol, from (7E) - (IR, 3R) -1,3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (1-methyl-1-trimethylsilanyloxy) -ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7-diene.
MS: (M) '466 IR: cm "1 3409; 2944; 2870; 1620; 1442; 1376; 104»; 793; 709. Example 8
(7E) - (IR, 3R) -23- [3- (1-Hydroxy-1-methyl-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7-dien -22-ino-1, 3-diol, from (7E) - (IR, 3R) -1, 3-bi s- (tert-butyl-1-dimethylsilyloxy) -23- [3- ( 1-methyl-l-trimethylsilanyloxy-ethyl) -phenyl] -19,24-dinor-9, 10-seco-cola-5,7-dien-22-ino.
MS: (M) * 462 IR: cm "? 3410; 2931; 2872; 1619; 1451; 1415; 1366; 1309; 1272; 1217; 1174; 1142; 1081; 1047; 975; 795;
700.
Example 9
(7E) - (1R, 3R) -23- [4- (1-Hydroxy-1-methyl-1-ethyl) -phenyl] -19,24-dinor-9, 10-seco-cola-5, 7- dien-1,3-diol, from (7E) - (IR, 3R) -1,3-bis- (tert-butyldimethyl-silanyloxy) -23- [4- (1-methyl-l-
trimethylsilanyloxy-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7-d? ene
MS: (M) "466 IR: cm" - 3396; 2944; 2870; 1617; 1511; 1450; 1409; 1376; 1258; 1215; 1170; 1145; 1118; 1048; 976; 954;
63 13
Example 10
(7E) - (IR, 3R) -23- [4- (1-hydroxy-l-methyl-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7-d? en-22-ino-1, 3-diol, from (7E) - (1 R, 3R) -1,3-bi s- (tert-butyldimethyl-silanyloxy) -23- [4- (1-methyl -l-tr ime t ils i nanoyloxy-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7-d? en-22-ino.
MS: (M) * 462 IR: cm "1 3422; 2966; 2931; 2872; 2238; 1619; 1503; 1451; 1365; 1308; 1255; 1217; 1172; 1142; 1110;
1092; 1047; 958; 862; 836
Example 11
(7E) - (1R, 3R) -23- (3-Hydroxy-phenyl) -19,24-dinor-9, 10-seco-cola-5,7-dien-22-ino-l, 3-diol , from (7E) - (IR, 3R) -1, 3-bis- (t erc-but i ldimet i 1-silanyloxy) -23- [3- (tert-butyldimethylethi-silanyloxy) -phenyl] -19 , 24-dinor-9, 10-seco-cola-5, 7-dien-22-ino. MS: (M) * 420 IR: cm 1 3345, 2931, 2873, 2226, 1578, 1445, 1347, 1286, 1183, 1079, 1042, 977, 871, 782, and 692.
Example 12
(7E) - (1R, 3R) -23- (3-hydrox i -f eni 1) -19,24-dinor-9, 10-seco-cola-5,7-dien-1,3-diol, from (7E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (tert-butyldimethylethyl-silanyloxy) -phenyl] -19, 24-dinor-9 , 10-seco-cola-5, 7-dieno. MS: (M) * 424 IR: cm "3434; 2945; 2870; 1591; 1454; 1376; 1272; 1234; 1155; 1045; 975; 781; 695.
Example 13
(7E) - (1R, 3R) -23- [4-hydroxy-phenyl] -19,24-dinor-9, 10-seco-cola-5,7-dien-22-ino-l, 3-diol, a - from (7E) -. (IR, 3R) -1, 3-bis- (t erc-butyldi et i 1- silanyloxy) -23- [4- (tert-butyldimethylethylsilanyloxy) -phenyl] - 19, 24-dinor-9, 10-seco-cola-5, 7- dien-22-ino. MS: (M) "420 IR: cm" 1 3429; 2932; 2872; 1609; 1511; 1263; 1218;
1044; 832.
Example 14
(5Z, 7E) - (1S, 3R, 20R) -23- [3- (1-hydroxy-1-methyl-ethyl) phenyl] -24-nor-9, 10-seco-cola-5, 7, 10 (19) -trien-22-ino-1,3-diol, from (5Z, 7E) - (1S, 3R, 20R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [ 3- (1-methyl-l-trimethyl-silanyloxy-ethyl) -phenyl] -24-dinor-9, 10-seco-cola-5, 7, 10 (19) -trien-22-ino. MS: (M) + 474 IR: cm 1 3428, 2931, 2872, 2218, 1635, 1053, 897, 796, 700.
Example 15
(7E) - (1R, 3R, 20R) -23- [3- (1-hydroxy-1-methyl) phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7- dien-2 ^ ino-1, 3-diol, from (7E) - (IR, 3R, 2 OR i-1, 3-b: (tert-butyldimethyl-silanyloxy) -23- [3- (1- methyl-l-trimethylsilanyloxy-ethyl) -phenyl] -19,24-dinor-9,10-seco-cola-5,7-trien-22-yn. MS: (M) '462 IR: cm "' 3413; 2930; 2873; 2230; 1620; 1487; 104"\ - 66 801; 703
Example 16
(5Z, 7E) - (1S, 3R, 20R) -23- [2- (1-hydroxy-1-methyl-ethyl) phenyl] -24-dinor-9, 10-seco-cola-5, 7, 10 (19) -trien-22-ino- 1, 3-diol, from (5Z, 7E) - (1S, 3R, 20R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [2- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -24-nor-9,10-seco-cola-5,7,10 (19) -trien-22-ino. EM: (M) * 474
IR cm 3422; 2930 2872 1634 147 '1442 4;
1173; 1053; 954 914 859; 759
Example 17
(7E) - (1R, 3R, 20R) -23- [2- (1-Hydroxy-1-methyl-1-ethyl) phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7 -dien-22-ino-1, 3-diol, from (7E) - (IR, 3R, 2 OR) - 1, 3-bi s - (tert-buty Idimet i 1-silanyloxy) -23- [ 2- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -19,24-dinor-9, 10-seco-cola-5,7-dien-22-ino. MS: (M) * 462 IR: cm "1 3417; 2930; 2872; 1620; 1445; 1363; 1307;
1230; 1173; 1119; 1046; 976; 953; 858; 759
Example 18
(5Z, 7E) - (1S, 3R, 20S) -23- [3- (1-hydroxy-1-methyl-ethyl) phenyl] 24-nor-9, 10-seco-cola-5, 7, 10 ( 19) -trien-1,3-diol, from (5Z, 7E) - (SS, 3R, 2 OS) -1,3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (1 -methyl-l-trimethylsilanyloxy-ethyl) -phenyl] -24-dinor-9, 10-seco-cola-5,7, 10 (19) -triene. EM: (M) '478
IR c 3425 2930 2871 1632 1380 1055 95 '
899; 708. Example 19
(7E) - (1R, 3R, 20S) -23- [3- (1-Hydroxy-1-methyl-1-ethyl) phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7 -dien-l, 3-diol, from (7E) - (IR, 3R, 2 OS) - 1, 3-bi s- (tert-butyldimethyl-silanyloxy) -23- [3- (1-methyl- 1-trimethylsilanyloxy-ethyl) -phenyl] -19,24-dinor-9, 10-seco-cola-5,7-diene. MS: (M) * 466 IR: cm ": 3414; 2933; 2871; 1616; 1490; 1450; 137; 1175; 1082; 1047; 978; 959; 798; 708.
Example 20
(5Z, 7E) - (lS, 3R, 20R) -23- (3-hydroxy-phenyD-24-nor-9,10-seco-cola-5,7,10 (19) -trien-22-ino- 1, 3-diol, from (5Z, 7E) - (1 S, 3R, 20R) - 1, 3-bi s - (t erc-butyldimethyl-silanyloxy) -23- [3- (tert-butyldimethyl- silanyloxy) -phenyl] -24-nor-9, 10-seco-cola-5, 7, 10 (19) -tr ieno-22-ino. MS: (M) + 432
IR: c "- 3415; 2945; 2872; 2232; 1612; 1595; 15 '1446: 1286; 1189; 1051; 782; 688.
Example 21
(7E) - (IR, 3R, 20R) -23- [3-hydroxy-phenol] -19, 24-dinor-9, 10-seco-cola-5, 7-dien-22-ino-i, 3-diol, from (7E) - (IR, 3R, 2 OR) - 1, 3-b is- (erc-butyldimethyl-silanyloxy) -23- [3- (tert-butyldimethyl-silanyloxy) - phenyl] -19, 24-dinor-9, 10-seco-cola-5, "-diene-22- ino. EM: (M)" 420 IR: cm "1 3422; 2932; 2873; 2240; 1611; 1594; 1579; 1448; 1287; 1184; 1044; 872; 788; 691.
Example 22
(5Z, 7E, 22E) - (1S, 3R, 20S) -23- [3-hydroxy-phenyl) -24-nor-9, 10-seco-cola-5, 7, 10 (19) -22-tetraen -1,3-diol, from (5Z, 7E, 22E) - (1 S, 3R, 2 OS) -1,3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (tert- butyldimethyl-silanyloxy) -phenyl] -24-nor-9, 10-seco-cola-5, 7, 10 (19), 22-tetraene. EM: (M) t 434
IR: m 3432; 2950 2869 1612 1586? c- '125
1258; 1153; 1052; 970; 957; 870; 773; 688
Example 23
7E, 22E) - (1R, 3R, 20S) -23- [3-hydroxy-fe; 19, 24-dinor-9, 10-seco-cola-5, 7, 22-trien-l, 3-diol, from (7E, 22E) - (IR, 3R, 2 OS) -1, 3- bis- (tert-butyldimethyl-silanyloxy) -23- [3- (tert-butyldimethyl-silanyloxy) -phenyl] -19,24-dinor-9, 10-seco-cola-5, 7, 22-triene. MS: (M) + 422 IR: cm 1 3432, 2953, 2929, 2869, 1613, 1585, 1451, 1374, 1284, 1155, 1079, 1044, 972, 870, 972, 777, and 691.
Example 24
(7E) - (1R, 3R) -23- [S- (1-hydroxy-1-methyl-ethyl) -furan-2-yl] -19,24-dinor-9,10-seco-cola-5, 7-dien-22-in-l, 3-diol, from (7E) - (IR, 3R) -1,3-bis- (tert-butyldimethyl-silanyloxy) -23- [5- (1-trimethylsilanyloxy) -1-methyl) furan-2-yl] -19, 24-dinor-9,10-seco-cola-5,7,10 (19) -trien-22-in-l, 3-diol.
MS: (M) * 452 IR: c "1 3345; 2954; 2922; 2855; 2240; 1617; 1534;
1456; 1377; 1366: 1305; 1262; 1200; 1189; 1169;
1149; 1119; 1080; 1047; 1024; 978; 963; 940; 789
Example 25
(5Z, 7E) - (1S, 3R) -23- [5- (1-hydroxy-l-ethyl-ethyl) -fur-an-2-yl] -24-non-9, 10-dry-cola- 5, 7, 10 (19) -trien-22-in-l, 3-diol, from (5 z, 7E) - (1 S, 3R ^ -1, 3-bis- (tert-butyl-dimethyl) -silyloxy) -23- [5- (1-trimethyl-silanyloxy-1-methyl-ethyl) -furan-2-yl] -19-nor-9, 10-seco-cola-577, 10 (19) -trien -22-in-l, 3 -diol EM: (M) + 464 IR: cm "1 3360, 2934; 2880; 1538; 1453; 1380; 1366; 1309; 1264; 1203; 1183; 1170; 1148; 1121;; 1052; 1023; 966; 899; 847; 791.
Example 26
(5Z, 7E) - (3S,) -23- [5- (1-hydroxy-l-methyl-ethyl) -furan-2-yl] -24- not r-9, 10-seco-cola-5, 7, 10 (19) -trien-22-in-3-ol, from (5Z, 7E) - (3S) -3- (tert: butyl-dimethylsilanyloxy) -23- [5- (1-
trimethylsilanyloxy-1-methyl-ethyl) -furan-2-yl] -19-nor-9, 10-seco-cola-5, 7, 10 (19) -trien-22-in-3-ol. MS: (M) "448 IR: cm" 1 3360; 2940; 2880; 1540; 1443; 1380; 3 c "; 1267; 1203; 1172: 1150; 1122; 1052; 1028; 968; 94";
898; 870; 848; 791. Typically, the product of formula II,
(5z, 7E) - (1S, 3R, 20R) -l, 3-bis (t erc-but i Id imet i 1-silanyloxy) -23- [2- (1-methyl-1-trimethylsilanyloxy-ethyl) ) -phenyl] -24- not r-9, 10-seco-cola-5, 7, 10 (19) -trien-22-ino, was dissolved in a 1 molar solution of TBAF tetrabutylammonium fluoride in THF my mmoles; 10 equivalents and stirred overnight at room temperature. The reaction mixture was then poured onto an ice-cold salt, extracted twice with ethyl acetate, washed twice with brine, dried over anhydrous sodium sulfate and the solvent was removed. After flash chromatography (eluent: hexanes / isopropanol 73/27), the product from the previous example 16, (5Z, 7E) - (1S, 3R, 20R) -23- [2- (1-hydroxy-1 - me ti 1-ethyl) -phenyl] -24-nor-9, 10-seco-cola-5, 7, 10 (19) -trien-
22-ino-l, 3-diol, in the form of a colorless foam, "1 mg, 73% yield.
A) The following compounds of formula II,
were obtained from compounds of formula III and IV:
»Example ÍA
(7E, 22E) - (IR, 3R) -1, 3-bis- (tertbutyldimethyl-silanyloxy) -23- [4- (1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -19, 24- dinor-9, 10-dry-cola- 5, 7, 22-triene, from (E) - (IR, 3R, 7 aR) - 7 a-met i 1 -1- [(R) -1- methyl-3- [4- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -prop-2-enyl] -octahydro-inden-4-one.
MS: (M) "765 IR: cm" 1 4331; 2955; 2886; 2856; 1616; 1468; 1361; 1253; 1174; 1093; 1048; 917; 837; 775
Example 2A
(7E, 22E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [2- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -19, 24- dinor-9, 10-seco-cola-5, 7, 22-triene, from (E) - (IR, 3R, 7aR) -7a-met i 1 - 1 - [(R) -
l-methyl-3- [2- (l-methyl-l-trimethylsilanyloxy-ethyl-phenyl] -allyl] -octahydro-inden-4-one MS: (M) * 765 IR: cm "1 3058; 2953; 2885, 2856, 1612, 1468, 1379, 1361, 1252, 1212, 1158, 1085, 1026, 960, 918, 83, 776, 697, 669.
3A
(7E, 22E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl)
-silyloxy) -23- [4- (1-methyl-1-trimethyl-ils-ynyloxy-ethyl) -phenyl] -19,24-dino-r-9, 10-seco-cola-5, 7,22-triene, a starting from (E) - (IR, 3R, 7aR) -7a-meti 1- 1 - [(R) -l-methyl-3- [2- (tert-butyldimethylsilanyloxy) -phenyl] -alyl] -octahydro-inden -4-one. MS: (M) ^ 765 IR: cm "2954; 2931; 2886; 2857; 1598; 1577; 1471; 1440; 1360; 1281; 1253; 1155; 1087; 1051; 1036; 1003; 963; 922; 836; 777 692.
Example A
(7E, 22E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (1-methyl-1-trimethyl silanyloxy)
ethyl) -phenyl] -19, 24-dinor-9,10-seco-cola-5, ~, 22-triene, from (E) - (IR, 3R, 7aR) - 7a-met i i- 1 l-methyl-3- [3- (1-methyl-1-trimethylsilanyloxy? -eti: phenyl] -allyl] -octahydro-inden-4-one MS: (M-tBu-Si-OH 632 IR: m 2954; 2887; 2856; 1602; 1467; 1361 52;
1172; 1086; 1048; 963; 922,903,837; 775
Example 5A
(7E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [2- (1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -1, 24- dinor-9, 10-seco-cola-5, 7-dieno, from (IR, 3R, 7 aR) -7 a-me ti 1- 1 - [(S) - 1 -me ti 1 - 3 - [2 - (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -propeni 1] -octahydro-inden-4-one. MS: (M) + 767 IR: cm "1 2952; 2856; 1620; 1468; 1378; 1358; 1251; 1158; 1086; 1026; 837; 775; 752.
Example 6A
(7E) - (1R, 3R) -1, 3-bis- (tert-butyldimethyl silanyloxy) -23- [2- (1-methyl-1-trimethylsilanyloxy)
ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7-dien-22-ino, from (lR, 3aR, 7aR) -7a-methyl-l- [(S ) -l-methyl-3- [2- (1-methyl-1-trimethylsilanyloxy-ethyl: -phenyl] -prop-2-ynyl] -octahydro-inden-4-one MS: (M) * 762 IR: cm "1 2953; 2930; 2884; 2857; 1621; 1470; 1359;
1252; 1080; 1048; 836; 775; 75
Example 7A
(7E) - (1R, 3R) -l, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -19, 24-dinor-9 , 10-seco-cola-5, 7, -diene, from (IR, 3aR, 7 aR) -7 a-me ti 1 - 1 - [(R) - 1 -me ti I-3- [3 - (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -propeni 1] -octahydro-inden-4-one. MS: (M) t 767 IR: cm "1 2953; 2929; 2885; 2856; 1600; 1467; 1372; 1355; 1248; 1086; 1028; 837; 767.
Example 8A
(7E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl silanyloxy) -23- [3- (1-methyl-1-trimethyl silanyloxy)
ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, 7-die, -22-ino, from (IR, 3aR, 7aR) -7 a-met i 1- 1 - [iSi-1-methyl-3- [3- (1-methyl-1-trimethylsilanedioxy-ethyl) -phenyl] -prop-2-enyl] -octahydro-inden-4-one. MS: (M) * 763 IR: cm "1 2953; 2929; 2884; 2855; 1470; 1358; 1252; 1084; 1046; 835; 774; 696.
Example 9A
(7E) - (1R, 3R) -l, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [4- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -19, 24-dinor- 9, 10-seco-cola-5, 7-dieno, from (IR, 3 aR, 7aR) -7a-me ti 1- 1 - [(R) - 1 -me ti 1 -3- [- ( 1-methyl-l-trimethyl-silanyloxy-ethyl) -phenyl] -propeni 1] -octahydro-inden-4-one. MS: (M) '767 IR: cm "1 2953; 2884; 2856; 1620; 1380; 1861; 1252; 1172; 1086; 1030; 917; 836; 775.
Example 10A
(7E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [4- (1-methyl-1-trimethylsilanyloxy)
ethyl / -phenyl] -19,24-dinor-9, l 0-seco-cola-5, "7-die:, -22-mo, from (IR, 3 aR, 7 aR) - 7 a- met ii-1 - [ { S -1-methyl-3- [4- (1-methyl-1-trimethyl-silanyloxy-ethyl: -phenyl] -prop-2-ynyl] -octahydro-inden-4- ona EM: (M) * 763 IR: cm "'2954; 2931; 2885; 2857; 1620; 1502; 1 ^;
1377; 1359; 1253; 1173; 1091; 1046; 961; 916; 83o;
775.
Example 1 ÍA
(7E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (tert-buty-idimethyl-silanyloxy-phenyl] -19,24-dinor-9, 10 -seco-cola-5, 7-dien-22-ino, from (IR, 3aR, 7aR) -7a-methyl-l- [(R) -3- [4- (tert-butyldimethyl-silanyloxy) - 1-methyl-phenyl] -propeni 1] -octahydro-inden-4-one MS: (MH) * 762 IR: cm 1 2954, 2930, 2885, 2857, 1596, 1574, 1475, 1426, 1360, 1289; 1254; 1195; 1086; 1025; 939; 878; 837; 777; 687.
Example 12A
(7E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (tert-butyldimethyl-silanyloxy-phenyl] -19, 24-dinor-9, 10-dry -cola-5, 7-diene, starting from (IR, 3aR, 7aR) -7a-met il-1 - [(R) -1-met i -3- (tert-but i 1 dimethylsilanyloxy) -1-methyl-phenyl] -propyl] -octahydro-inden-4-one MS: (M) t 767 IR: cm "-2,952; 2930; 2885; 2857; 1604; 1583; 1468; 1441; 1376; 1360; 1253; 1156; 1086; 1050; 1026; 1004; 960; 922; 837; 777; 696; 664.
Example 13A
(7E) - (1R, 3R) -l, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [4- (tert-butyldimethyl-silanyloxy-phenyl] -19, 24-dinor-9, 10- dry-cola-5, 7-dien-22-ino, from (IR, 3aR, 7aR) -1- [(S) -3- [4- (tert-butyldimethyl-silanyloxy) -1-methyl-phenyl ] -prodinyl] -7a-methyl-octahydro-inden-4-one EM: (M) * 763 IR: c "1 2956; 2930; 2886; 2857; 1602; 1507; 1469; 1360; 1255; 1089; 1051; 1026; 915; 837; 805; 777.
Example 14A
(5Z, 7E) - (1S, 3R, 20R) -l, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -24- dinor-9, 10-sec-tail-5, 7, 10 (19-trien-22-ino, from (IR, 3aR, 7aR) -7-methyl-l- [(R) -l-methyl- 3- [3- (1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -prop-2-ynyl] -octahydro-inden-4-one MS: (M) t 774.7 IR: cm " 2954; 2930; 2885; 2857; 1652; 1602; 1468; 1377; 1361; 1317; 1253; 1223; 1177; 1084; 1043;
1006 909; 885; 836; 775; 701
Example 15A
(7E) - (IR, 3R, 20R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -19, 24- dinor-9, 10-seco-cola-5, 7-dien-22-ino, from (lR, 3aR, 7aR! 7a-methyl-l- [(R) -l-methyl-3- [3- (1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -prop-2-ynyl] -octahydro-inden-4-one MS: (M) * 762.6
IR: cm "1 2953; 2929; 2885; 2856; 2241; 1625; ZZ Z; 1468; 1378; 1360; 1252; 1221; 1176; 1086; 1048; 961; 902; 836; 800; 774; 699.
Example 16A
(5Z, 7E) - (1S, 3R, 20R) -l, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [2- (1-methyl-1-trimethyl-yl-ynyloxy-yl) -phenyl] -24-R-9, 10-sec-tail-5,7,10 (19) -trien-22-yne, from (IR, 3aR, 7aR) -7a-methyl-l- [(R) -l-methyl-3- [2- (1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -prop-2-ynyl] -octahydro-inden-4-one. MS: (M) '774.5 IR: cm 1 2953, 2930, 2886, 2857, 1645, 1470, 14 0, 1376, 1360, 1253, 1176, 1078, 1045, 1006, 909, 87 and 835; 777; 702; 683.
Example 17A
(7E) - (IR, 3R, 20R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [2- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -19, 24- dinor-9, 10-seco-cola-5, 7 -dien-22 -ino, from (! R, 3aR, 7aR
7 a-me i 1-1- [(R) -l-methyl-3- [2- (1-met il-1-1 r imet i 1-silanyloxy-ethyl) -phenyl] -prop-2-ynyl ] -octahydro-inden-4-one. MS: (M) * 762, 6 IR: cm "1 2954 2930; 2857; 1620; 1470; 1359; i
1175; 1085; 1048; 960; 908; 836; 776; 757 98 or c
Example 18A
(5Z, 7E) - (1S, 3R, 20R) -l, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -24- Dino r-9, 10-seco-cola-5, 7, 10 (19) -triene, from (IR, 3aR, 7 aR) - 7 a-methyl-1- [(S) -l-methyl- 3- [3- (1-methyl-1-tr imet i 1-silanyloxy-ethyl) -phenyl] -propyl] -octahydro-inden-4-one. MS: (M) * 778.7 IR: cm ": 2954; 2930; 2884; 2856; 1645; 1603; 1468; 1459; 1377; 1360; 1252; 1175; 1085; 1043; 909; 875; 837; 775; 706
Example 19A
(7E) - (IR, 3R, 20R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -19, 24- dinor-9, 1 -seco-cola-5, 7, -diene, from (IR, 3aR, 7aR1 '-methyl-1- [(S) -l-methyl-3- [3- (1-methyl -l-tr imet il-silanyloxy-ethyl) -phenyl] -propyl] -octahydro-inden-4-one MS: (M) "766.7 IR: cm" 1 2953; 2929; 2885; 2856; 1602; 1468; 1462; 1379; 1358; 1252; 1177; 1087; 1048; 1030; 962; 922;
37; 775 706
Example 2 OA
(5Z, 7E) - (1S, 3R, 20R) -l, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (tert-butyldimethyl-silanyloxy) -phenyl] -24-nor-9, 10-seco-cola-5, 7, 10 (19) -tri en- 22-ino, from (IR, 3aR, 7 aR) -7 a-me ti 1 - 1 [(R) -l-methyl -3- [3- (tert-Butyl-dimethyl-s i-lanyloxy) -phenyl] -prop-2-ynyl] -octahydro-inden-4-one. EM: (MP 774.7
IR: c "-2,954; 2930; 2885; 2857; 1596; 1574; 14"; 1424; 1360; 1288; 1254; 1198; 1087; 1050; 02"; 1004; 980; 960; 941; 904; 878; 836; 777; 687.
Example 21A
(7E) - (IR, 3R, 20R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (tert-butyldimethyl-silanyloxy) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, "-dien-22-ino, from (IR, 3aR, 7aR) -7 a-met i 1- 1 - [(R) -l-methyl-3- [3- (tert-Butyldimethylsilanyloxy) -phenyl] -prop-2-ynyl] -octahydro-inden-4-one MS: (M) * 762.6 IR: cm "" 2954; 2931; 2885; 2857; 1596; 1574; 1475; 1424; 1376; 1360; 1289; 1254; 1198; 1156; 1086; 1051; 1027; 1004; 981; 961; 942; 905; 878; 836; 778; 688; 664.
Example 22A
(5Z, 7E, 22E) - (1S, 3R, 20S) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [3- (tert-butyldimethyl-silanyloxy) -phenyl] -24-yr- 9, 10-dry-cola- 5, 7, 10 (19), 22-tetraene from E- (1 R, 3aR, 7 aP) -
7 a-me ti 1-1- [(S) -l-methyl-3- [3- (tert-but i 1 -dimet i 1-silanyloxy) -phenyl] -alyl] -octahydro-inden-4-one . MS: (M) "776.5 IR: cm" 1 2955; 2930; 2888; 2857; 1599; 1577; 14 ^ 0; 1438; 1362; 1280; 1254; 1158; 1081; 989; 909; 835; 777; 687. Example 23A
(7E, 22E) - (IR, 3R, 20S) -1, 3-bis- (tertbutyldimethyl-silanyloxy) -23- [3- (tert-butyldimethyl-silanyloxy) -phenyl] 19,24-dinor-9, 10-seco-cola-5, 7, 22 -trieno from E- (IR, 3aR, 7aR) -7a-me ti 1- 1 - [(S) -1-methyl-3- [3- (tert. -butyl-dimethyl-silanyloxy) -phenyl] -alyl] -octahydro-inden-4-one.
Example 24A
(7E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [5 (1- (trimethyl-silanyloxy-1-methyl-ethyl) -furan-2-yl] - 19,24-dinor-9,10-seco-cola-5,7-dien-22-in-l, 3-diol, from (IR, 3R, 7aR) -7 a-methyl-1- [( S) -l-methyl-3- [5- (1-methyl-1-trimethyl-silanyloxy-ethyl) -furan-2-yl] -prop-2-ynyl] -octahydro-inden-4-one.
MS: (M) t 753.7 IR: cm "1 2994, 2929, 2885, 2856, 1472, 1463, 1449, 1434, 1379, 1361, 1251, 1185, 1162, 1088, 1C51, 1023, 1006; 960; 899; 875; 837; 774.
Example 25A
(5Z, 7E) - (1S, 3R) -1, 3-bis- (tere-butyl-methyl-tyl-si-lanyloxy) -23- [5- (1- (trimethyl-si-lanyloxy-1-methyl-ethyl) -furan. -2-il] -19-nor-9, 10-seco-cola-5, 7, 10 (19 i -trien-22-in-1, 3-diol from (IR, 3R, 7aR) - ~ a-methyl-1- [(S) -l-methyl-3- [5- (1-methyl-1-trimethyl-silanyloxy-ethyl) -furan-2-yl] -prop-2-ynyl] -octahydro- inden- 4 -one EM: (M) + 764.7
Example 26A
(5Z, 7E) - (3R) -3- (tert-Butyldimethyl-silanyloxy) -23- [5- (1- (trimethyl-silanyloxy-1-methyl-ethyl) -furan-2-yl] -19-nor -9, 10-seco-cola-5,7, 10 (19) -tr? En-22- in-3-ol from (IR, 3R, 7aR) - 7 a-met i 1 - 1 [( S) -l-methyl-3- [5- (1-methyl-1-trimethyl-silanyloxy)
ethyl) -furan-2-yl] -prop-2-ynyl] -octahydro-inden-4-one. EM: (M! 634, 5
Typically, the product of formula TT (3R, 5R) - [2- [3,5-bis- (tert-butyl-1-dimet-1-silanyloxy) -cyclohexylidene] -ethyl] -di-phenyl-fos oxide , Te t rah edron lett. 1991, 3_2, 7666) (399 mg; ú, r 9? Mmol), was dissolved in anhydrous THF (3 mL). 7.6M butyl lithium in hexane was added slowly; 0.530 mi; 0.848 mmoles The reaction mixture turned to an intense red color and was stirred for 30 minutes. Then compound (E) - (1R, 3R, 7 aR) -7 a-me ti 1- 1 - [(R) -l-methyl-3- [4- (1-methyl-1) was added slowly. -trimethylsilanyloxy-ethyl) -phenyl] -prop-2-enyl] -octahydro-inden-4-one (144 mg, 0.349 mmol). After one hour at -78 ° C the reaction mixture was allowed to slowly reach room temperature. The reaction mixture was then poured into ice-cold brine, extracted twice with ether, washed twice with brine, dried over anhydrous sodium sulfate and the solvents were removed. After flash chromatography
(eluant: hexanes / ethyl acetate 95/5) the compound of formula II of Example A above is obtained: (7E, 22E) - (IR, 3R) -1, 3-bis- (tert-butyldimethyl-silanyloxy) -23- [4- (1-Methyl-l-trimethylsilanyloxy-ethyl) -phenyl] -19,24-di-n-9, 10-seco-cola-5, 7,22-triene (228 mg, yield 85 %), in the form of a colorless foam. For the preparation of compounds II containing a methylene group in ring A, (3S, 5R) - [2- [3,5-bis- (tert-butyl-1-dimethyl-yl-ynyloxy) -oxide) - 2-methylene-cyclohexylidene] -ethyl] -di-phenyl-fos, instead of the phosphine oxide used above. B) The following compounds of formula IV were obtained from compounds of formula V:
Example IB
(E) - (lR, 3R, 7aR) -7 a-me ti 1-1- [(R) -methyl-3- [4- (1-methyl-l-trimethyl-silanyloxy-ethyl) -phenyl] - prop-2-eni 1] -oct ahydro-inden-4-one, from (E) - (lR, 3aR, 4S, 7aR) -l - [(R) -l-methyl-3- [4- (l-hydroxy-l-methyl-ethyl) -phenyl-propenyl] -7a-methyl-octahydro-indene-1.
MS: (M) "412 IR: cm" 1 2959; 2874; 1714; 1507; 1458; 1379; 1254;
1173; 1098; 1039; 969; 912; 840; 755
Example 2B
(E) - (lR, 3R, 7aR) -7 a-me ti 1-1- [(R) -l-methyl-3- [2- (1-methyl-l-trimethyl-silanyloxy-ethyl) -phenyl) ] -ali 1] -oct ahydro-inden-4-one, from (The (IR, 3aR, 4S, 7aR) -1- [(R) -l-methyl-3- [2- (l-hydroxy -l-methyl-ethyl) -phenyl-propenyl] -7 a-me t -l-octahydro-inden--ol MS: (M) + 412 IR: c "1 2958, 2873, 1714, 1457, 1380, 1248; 1158; 1025; 913; 838; 757.
Example 3B
(E) - (lR, 3R, 7aR) -7 a-me ti 1-1- [(R) -1-methyl -3- [3- (1-methyl-1-trimethyl-s i-lanyloxy-ethyl) -phenyl] -al-yl] -octahydro-inden-4-one, from (E) (! R, 3aR, 4S, 7aR) -l- [(R) -3- [3- (1-hydroxy) 1 -me thi 1 -ethyl) -phenyl-propenyl] -7a-methyl-octahydro-inden-4-ol MS: (M) * 412
IR: cm "1 2959; 2874; 1714; 1500; 1458; 1379; 1251;
1175; 1085; 1039; 968; 878; 841; 790; 754 703
Example B
(LR, 3R, 7aR) -7a-methyl-l- [(S) -l-methyl-3- [2- (1-methyl-l-trimethyl-silanyloxy-ethyl) -phenyl] -propenyl] -oct ahydrous - inden-4 -one, from (IR, 3aR, 4S, 7aR) -7a-methyl-l- [(S) -l-methyl-3- [2- (1-hydroxy-1-methyl-ethyl ) -phenyl-propenyl] -octahydro-inden-4-ol. MS: (M) * 399 IR: cm "-2,958; 2875; 1715; 1465; 1380; 1248; 1159; 1026; 912; 839; 757.
Example 5B
(IR, 3aR, 7aR) -7a-methyl-l- [(S) -l-methyl-3- [2- (1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -prop-2-ynyl ] -octahydro-inden-4-one, from (IR, 3aR, 4S, 7aR) -7a-methyl-l- [(R) -l-methyl-3- [2- (1-hydroxy-1 - methyl-ethyl) -phenyl-propynyl] -octahydro-inden-4-o 1. MS: (M) + 410
IR: cm "1 2964; 2876; 1715; 1476; 1455; 1379; 1249; 1176; 1073; 1044; 910; 841; 759.
Example 6B
(IR, 3aR, 7aR) -7a-methyl-l- [. { R) -l-methyl-3- [3- 1-methyl-l-trimethyl-silanyloxy-ethyl) -phenyl] -propeni 1] -oct ahydro-indenone -one, from [IR, 3aR, 4S, 7aR] -7a-methyl-l- [(S) -l-methyl-3- [3- (1-hydroxy-1-methyl-ethyl) -phenyl-propenyl] -octahydro-inden-4-o 1. MS : (M + H) "415 IR: cm" 1 2958; 2874; 1715; 1607; 1458; 1380; 1251;
1175; 1088; 1037; 840; 796; 755; 707
Example 7B
(IR, 3aR, 7aR) -7 a-met 11-1- [(S) -met i 1-3- [3 (1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -prop-2-innyl ] -octahydro-inden-4-one, from
[LR, 3aR, 4S, 7aR] -7a-methyl-l- [(R) -l-methyl-3- [3- (1-hydroxy-1-methyl-ethyl) -phenyl-propynyl] -octahydro-inden - 4 -o 1. EM: (M) + 410
IR: cm "-2963; 2876; 1715; 1598; 1470; 1455; 1380; 1307; 1250; 1176; 1083; 1040; 904; 841; 796;" 55
701
Example 8B
(IR, 3aR, 7aR) -7a-methyl-l- [(R) -methyl-3- [4-1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -propenill-octahydro-inden-4 -one, from [IR, 3 aR, 4 S, 7 aR] -7a-methyl-l - [(S) -l-methyl-3- [4- (1-hydroxy-l-methyl-ethyl) phenyl-propenyl] -octahydro-inden-4-ol. MS: (M-CH,) + 399 IR: cm "-2958; 2874; 1715; 1512; 1458; 1379; 1252; 1173; 1101; 1037; 913; 840; 757.
Example 9B
(IR, 3aR, 7aR) -7a-methyl-l- [(S) -l-methyl-3- [4- (1-met il- 1 -trimet i 1 -synyloxy-et i 1) -phenyl ] -prop-2-ynyl] -octahydro-inden-4-one, from [IR, 3aR, 4S, 7aR] -7a-methyl-l- [(R) -l-methyl-3- [4- (l-hydroxy-1-methyl-ethyl) -phenyl-propynyl] -octahydro-inden-4-o 1. MS: (M) + 410
IR: cm "1 2963; 2876; 1715; 1502; 1455; 1380; 1253; 1174; 1096; 912; 839; 755.
Example 10B
(IR, 3aR, 7aR) -7a-methyl-l- [(R) -l-methyl-3- [3- (1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -prop-2-ini 1] -octahydro-inden-4-one, from
[1 R, 3aR, 4S, 7aR] -7 a-methyl-1- [(R) -3- [3- (1-hydroxy-1-methyl-ethyl) -phenyl-1-methyl-prop-2 inyl] -octahydro-inden-4-o 1. MS: (M) * 410 IR: cm "1 2964; 2875; 1714; 1600; 1480; 1455; 1381;
1315; 1250; 1225; 1176; 1084; 1039; 841; 799; 756 701.
Example 11B
(IR, 3aR, 7aR) -7a-methyl-l- [(R) -l-methyl-3- [2- (1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -prop-2-ynyl ] -octahydro-inden-4-one, from [lR, 3aR, 4S, 7aR] -7 a-me ti 1-1- [(R) -3- [2- (l-hydroxy-l-methyl ethyl) -phenyl] -l-methyl-prop-2-ynyl] -octahydro-inden-4-ol.
MS: (M) "410 IR: cm" 1 2964; 2875; 1715; 1476; 1455; 1379; 1313;
1248-1175; 1071; 1045; 909; 842; 759
Example 12B
(IR, 3aR, 7aR) -7a-methyl-l- [(S) -l-methyl-3- [3- (1-methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -propyl] -octahydro- inden-4-one, from [IR, 3aR, 4S, 7 aR] -7 to -me ti 1-1- [(S) -3- [3- (1-hydroxy-1-methyl-ethyl) ) -phenyl] -1-methyl-propyl] -octahydro-inden-4-ol. MS: (M + H) "415 IR: cm" 1 2960; 2875; 1715; 1462; 1383; 1250; 1175; 1096; 1038; 840; 800; 762; 712
Example 13B
(LR, 3R, 7aR) -7a-methyl-l- [(S) -methyl-3- [5- (l-methyl-1-trimethyl-silanyloxy-ethyl) -furan-2-yl] -prop-2 -inyl] -octahydro-inden-4-one, from [IR, 3aR, 4S, 7aR] -7a-methyl-l- [(R) -l-methyl-3- [5- (1-methyl- 3- [5- (1-methyl-l-hydroxy-ethyl) furan-2-yl] -prop-2-ynyl] -octahydro-inden-4-ol MS: (M) + 400
IR: m 2963; 2876; 1716; 1542 1455 1380 1364
1262; 1251; 1217; 1206; 1184; 1162; 1123; 1036; 42; 791; 756
Typically, the compound of formula V, (E) - (IR, 3aR, 4S, 7 aR) - 1 - [(R) -1-methyl 1 -3- [4 - (1-hydroxy-1) -methyl-ethyl) -phenyl-propenyl] -7a-methyl-octahydro-inden-4-ol (137 mg, 0.40 mmol is), in DMF (6 mL). PDC (226 mg, 0.60 mmol) was added portionwise at room temperature, and stirring was continued for one hour. The reaction mixture was then poured into ice-cold salt, extracted twice with ethyl acetate, washed twice with brine, dried over anhydrous sodium sulfate and the solvent was removed. After flash chromatography (eluent: hexanes / ethyl acetate 67/33), the obtained intermediate was dissolved in anhydrous THF (6 ml). Then, they were added sequentially at 0 ° C, 1- t r i -me t i 1 s i 1 i 1 - imide zo 1
(57.7 μl, 0.394 mmol), imidazole 13.4 mg; 0.197 mmole) and t r ime t i ls chloride (24.9 1, 0.197 mmol). After twenty minutes at 0 ° C, it was left
that the reaction mixture slowly reach room temperature. The reaction mixture was then poured into ice-cold brine, extracted twice with ethyl acetate, washed twice with brine, dried with anhydrous sodium sulfate and the solvents were removed after 1? flash chromatography (eluent: hexanes / ethyl acetate 85/15), the compound of formula IV of example IB above was obtained, (E) - (1R, 3R, 7 aR) - 7 a-me ti 1 -1 - [ (R) -1-methyl-3- [4- (1-meth i 1-1 -tr imet i 1-silanyl-oxy-ethyl) -phenyl] -prop-2-enyl] -octahydro-inden-4- ona, (148 mg; 89% yield), in the form of a yellow oil. C) The following compounds of formula IV were obtained from compounds of formula V: Example 1C
(E) - (1R, 3R, 7aR) -7a-methyl-1 - [(R) -methyl-3- [3- (tert-but-1-dimethyl-1-silanyloxy-phenyl) -alyl] -octahydro-inden - 4-one, from (E) (lR, 3aR, 4S, 7aR) -l - [(R) -l-methyl-3- [3- (hydroxy-phenyl) propeni 1] -7 a-me til-octahydro-inden--ol. MS: (M) * 412
IR cm 2956; 2931 2888 2861 1708 1599 15 '
1485; 1465; 1429; 1382; 1282; 156; 1160; Q7"Q. 782; 692.
Example 2C
(lR, 3aR, 7aR) -l - [(S) -l-methyl-3- [3- (tert-buty 1 -dimet i 1- si lanyloxyphenyl]) -prop-2-iniI] -Carnet i 1-oct ahydro-indenone -one, from [! R, 3aR, 4S, 7aR] -l - [(S) -l-methyl-3- (3- (hydroxy-f eni -prop-2- inyl] -7 a-methyl-octahydro-inden-4-ol.
Example 3C
(! R, 3aR, 7aR) -l - [(R) -l-methyl-3- [3- (tert-butyldimethyl-silanyloxy-phenyl] -prop-2-ynyl] -7-methyl-oct-ahydro-inden- 4-one, from (IR, 3 aR, S, 7 aR) -1- [(R) -l-Methyl-3- [3- (hydroxy-phenyl) -prop-2-ynyl] -7a- methyl-octahydro-inden-4-ol MS: (M) t 414 IR: cm ": 2957; 2858; 1714; 1603; 1583; 1483; 1442; 1379; 1273; 1260; 1157; 976; 889; 842; 782; 696.
Example C
(! R, 3aR, aR) -l - [(S) -l-methyl-3- [4- (tert-butyl-di-ethyl-silanyloxy) -phenyl] -prop-2-ynyl] -7-a-methyl -octahydro-inden-4-one, from
(1 R, 3aR, 4S, 7aR) -l- [(S) -3- [4- (tert-but i 1 -dimet i 1 -sylanyloxy) -phenyl] -1-met-il-prop-2-ynyl] -7a-met? L-octahydro-inden-4-ol. MS: (M) * 410 IR cm 2958; 2932; 2882; 2858 1715 1602 1506
1469; 1380; 1262; 1166; 1096; 911; 841; 805; 781
Example 5C
(IR, 3aR, 7aR) -7a-methyl-l- [(R) -l-methyl-3- [3- (tert-butyl-1-dimethyl-s-lanyl-oxy) -phenyl] -prop- 2 -inyl] -octahydro-inden-4-one, from (lR, 3aR, 4S, 7aR) -l - [(R) -l-methyl-3- [3- (hydroxy-phenyl) -prop-2 -inyl] -7a-methyl-octahydro-inden-4-ol. MS: (M) 1 4 l 0 IR: cm "1 2957; 2932; 2883; 2859; 2215; 1715; 1596; 1573; 1477; 1422; 1380; 1289; 1256; 1196; 1004; 976; 945; 913; 877; 839; 785; 689.
Example 6C
(E) - (IR, 3aR, 7aR) -7a-methyl-l- [(S) -l- et? L-3- [3- (tert-butyl-dimethylsilanyl-oxy) -phenyl-allyl] -octahydro -inden-4-one, from (E - [lR, 3aR, 4S, 7aR] -l - [(S) -l-methyl-3- [3- (tert-butyldimethyl-silanyloxy) -phenyl] - alyl] -7a-methyl-octahydre-inden-4-ol MS: (M) * 412 IR: cm "1 2958; 2859; 1714; 1598; 1576; 1477; 1380; 1280; 1254; 1156; 973; 853; 842; 783; 691. Typically the alcohol of formula V, (IR, 3aR, 4S, 7 aR) - 1 - [(R) -1-methyl-3- (3-hydroxy-phenyl) - prop-2-ynyl] -α-methyl-octahydro-inden-4-ol (236 mg, 0.78 mmol) in DMF (5 ml) T erc-butyl chloride was added, if 1 (130 mg, 0.86 mmol) and imidazole (133 mg, 1.95 mmol) at room temperature, stirring was continued for 24 hours, then the reaction mixture was poured into ice cold HCl aqueous solution. extracted twice with ethyl acetate, washed twice with brine, dried with anhydrous sodium sulfate and the solvent was removed. After the
flash chromatography (eluent: hexanes / acet ethyl acetate 85/15), the intermediate product (ketone of formula IV-A) was obtained, in the form of a yellow oil lo. The intermediate product was dissolved in DMF
(6 mi) PDC (333 mg, 0.885 mmol) was added in portions at room temperature, and stirring was continued for 1 hour. The reaction mixture was then poured onto an ice-cold salt, extracted twice with ethyl acetate, washed twice with brine, dried over anhydrous sodium sulfate and the solvent was removed. After flash chromatography (eluent: hexanes / ethyl acetate 88/12) the compound of formula IV was obtained in the above example 3C (lR, 3aR, 7aR) - a-me ti 1-1- [(R) - 3- [3- (tert-Butyldimethyl-s -laryloxy) -1-methyl-phenyl] -prop-2-ynyl] -octahydro-indenone -one (236 mg, total yield: 73--), in the form of a colorless oil. D) The following compounds of formula V were obtained from the compounds of formula VI:
Example ID
(E) - (1R, 3aR, 4S, 7aR) -l- [(R) -l-methyl-3- [4-hydroxy-1-methyl-ethyl) -phenyl-propenyl] -7a-methyl-octahydro -inden-4-ol, from the ethyl ester of (E) -4- [(R) -3- [(lR, 3aR, 4S, 7aR) -4-hydroxy-7a-methyl-octahydro-inden- 1-yl] -but-1-enyl] -benzoic acid. MS: (M) * 342 IR: c "1 3413; 2931; 2867; 1640; 1510; 1458; 1366; 1257; 1161; 1093; 961; 862; 814; 565.
Example 2D
(E) - (1R, 3aR, 4S, 7aR) -l- [(R) -l-methyl-3- [2- (1-hydroxy-1-methyl-ethyl) -phenyl-propenyl] -7a-methyl -octahydro-inden-4-ol from the ethyl ester of (E) -2- [(R) -3- [(lR, 3aR, 4S, 7aR) -4-hydroxy-7a-methyl-octahydro-inden -1-yl] -but-1-enyl] -benzoic acid. MS: (M) + 342 IR: cm "3426, 2934, 2867, 1640, 1448, 1368, 1245, 1163, 1067, 989, 945, 761, 751.
3D Example
(E) - (1R, 3aR, 4S, 7aR) -l- [(R) -3- [3- (1-hydroxy-1-methyl-ethyl) -phenyl-propenyl] -7a-methyl-octahydre-inden -4-ol from the ethyl ester of the acid (E) -3- [(R) -3- [(! R, 3aR, 4S, 7aR) -4-hydroxy-7a-methyl-octahydro-inden-1- il] -but-1-enyl] -benzoic acid. MS: (M) '342 IR: cm 1 3406, 2933, 2868, 1600, 1455, 1370, 1252, 1164, 963, 790, 700.
Example D
(IR, 3aR, 4S, 7aR) -7a-methyl-l- [(S) -l-methyl-3- [2- (1-hydroxy-1-methyl-yl-ethyl) -phenyl-propenyl] -octahydro- inden-4-ol from (IR, 3 aR, 4S, 7 aR) -7a-methyl-1- [(S) -l-methyl-3- [2- (carboxylic acid ethyl ester) phenyl- propenyl] -octahydro-inden-4-ol. MS: (M-H20) * '326 IR: cm 1 3405, 2936, 2870, 1468, 1442, 1373, 1241, 1065, 992, 943, 759.
Example 5D
(IR, 3aR, 4S, 7aR) -7a-methyl-l- [(R) -1-met il-3- [2- (1-hydroxy-l-methyl-ethyl) -phenyl-propinyl] -octahydro- inden-4-ol from [IR, 3 aR, 4 S, 7 aR] -4-hydroxy-l- [(S) -3- [2- (ethyl ester of carboxylic acid co) - phenyl 1- 1-methyl-propini 1-7 a-met i 1-octahydro-indene. MS: (M) ~ 340 IR: cm 1 3422, 2919, 2850, 2213, 1470, 1429, 1398, 1340, 1283, 1219, 1122, 1095, 1059, 1031, 948, 721.
Example 6D
[IR, 3aR, 4S, 7aR] -7 a-me ti 1-1- [(S) -1-met 11-3- [3- (1-hydroxy-l-methyl-ethyl) -phenyl-propenyl] -octahydro-inden-4-ol from [IR, 3 aR, 4 S, 7 aR] -7a-methyl-l- [(S) -l-methyl-3- [3- (carboxylic acid ethyl ester ) -phenyl-propenyl] -octahydro-inden-4 - or 1. MS: (M) "344 IR: cm" 1 3398; 2930; 2868; 1604; 1487; 1441; 1371;
1263; 1163; 1068; 990; 952; 940; 886; 790; 706
Example 7D
[IR, 3aR, 4S, 7aR] -7a-methyl-l- [(R) -l-methyl-3- [3- (1-hydroxy-1-methyl-ethyl) -phenyl-propinyl] -octahydro-inden -4-ol from [IR, 3 aR, 4S, 7 aR] - 4-hydroxy-1 - [(S) -3- [3- (ethyl ester of carboxylic acid) - f-enyl-1-met i 1-propynyl] -7a-methyl-octahydro-indene. MS: (M) * 340 IR: cm "3424; 2970; 2934; 2872; 2218; 1600; 1470;
1455; 1372; 1268; 1167; 992; 951; 894; 862; 796;
701.
Example 8D
(! R, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(S) -1-met il-3- [3- (1-hydroxy-l-methyl-ethyl) -phenyl-propenyl ] -octahydro-inden-4-ol from [IR, 3 aR, 4 S, 7 aR] -7a-methyl-l- [(S) -l-methyl-3- [4- (ethyl acid ester carboxyl ico) -feni 1-propenyl] -octahydro-inden-4-ol. MS: (M) + 344
IR: cm "-3377; 2974; 2938; 2867; 1510; 1459; 140 ~; 1376; 1316; 1261; 1165; 1141; 1098; 1078; 994; 952; 861; 810. Example 9D
(IR, 3aR, 4S, 7aR) -7a-methyl-l- [(R) -l-methyl-5- [4- (1-hydroxy-1-methyl-ethyl) -phenyl-propynyl] -octahydro-inden -4-ol from [IR, 3 aR, 4S, 7 aR] - 4-hydroxy-1 - [(S) -3- [4- (ethyl ester of carboxylic acid) - f eni 1- 1- met i 1-propynyl] -7a-methyl-octahydro-indene. MS: (M) * 340 IR: cm "1 3412; 2970; 2870; 2214; 1602; 1502; 1455; 1365; 1257; 1167; 1107; 1042; 988; 950; 857; 835; 569
Example 10D
(lR, 3aR, 4S, 7aR) -7a-methyl-l- [(S) -3- [3- (l-hydroxy-1-methyl-ethyl) -phenyl] -1-methyl-propyl] -oct ahydrous -inden- 4 -ol from the ethyl ester of the acid 3- [(S) -3- [(lR, 3aR, 4S, 7 R) -4-hydroxy-7a-methyl-octahydro-inden-1-yl] -butyl] -benzoic acid. EM: (M) t 344
IR: cm "- 3406; 2932; 2869; 1726; 1608; 1490; 1 57;
1374; 1261; 1166; 1087; 989; 951; 890; 837; 792;
707. Example 11D
(IR, 3aR, 4S, 7aR) -7a-methyl-l- [(R) -3- [3- (l-hydroxy-1-methyl-ethyl) -phenyl] -l-methyl-prop-2-ynyl ] -octahydro-inden-4-ol from [IR, 3 aR, 4 S, 7 aR] - 4 -hydroxy- 1- [(R) -3- [3- (carboxylic acid ethyl ester) phenyl] -1-methyl-propynyl] -7a-methyl-octahi dro -indeno. MS: (M) * 340 IR: cm "3397; 2969; 2933; 2870; 2230; 1600; 1480;
1454; 1415; 1370; 1310; 1268; 1082; 1068; 987; 952; 892; 862; 794; 708
Example 12D
(lR, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(R) -3- [2- (l-hydroxy-1-methyl-ethyl) -phenyl] -l-methyl-prop- 2-inyl] -octahydro-inden-4-ol from (IR, 3 aR, 4S, 7aR) -4-hydroxy-1 - [(R) -3- [2 - (carboxylic acid ethyl ester ) -phenyl-1-methyl-propynyl] -7a-methyl-octahydro-indene.
MS: (M) * 340 IR: cm "1 3439; 2931; 2869; 2220; 1477; 1450; 1438;
1366; 1307; 1265; 1231; 1166; 1119 106. 103 98
949; 855; 759 Example 13D
(IR, 3aR, 4S, 7aR) -7a-methyl-l- [(R) -l-methyl-3- [5- (1-meth i 1-1 -hydroxy-ethyl) -furan-2-yl] -prop-2-ini 1] -oct ahydro-inden-4-ol from [lR, 3aR, 4S, 7aR] -7 a-me ti 1-4- (tert-butyl-dime til-si lani loxi ) - 1 - [(R) - 1-met i 1- 3- [5- (carboxyl-furan-2-yl] -prop-2-ynyl] -octahydro-indene ethyl ester EM: (M) + 330 IR: cm "-3409; 2969; 2934; 2872; 1732; 1719; 1504; 1455; 1373; 1305; 1256; 1201; 1166; 1145; 1120; 1021; 963; 946; 789.
Typically, the compound of formula VI, ethyl ester of (E) -4- [(R) -3- [(IR, 3aR, 4S, 7aR) -4-hydroxy-7a-methyl-octahydro-inden- 1-i 1] -but-1-eni 1] -benzoic acid (177 mg, 0.496 mmol) in
THF anhydrous (6 ml). Methylmagnesium chloride (3M solution in THF, 1.0 ml, 2.98 g.
Immoles) at 0 ° C, and the reaction was stirred for three hours at room temperature. The reaction mixture was then poured into ice-cold brine, extracted twice with ethyl acetate, washed twice with water. Salt was dried, dried with anhydrous sodium sulfate and the solvent was removed. After flash chromatography (eluent: hexanes / ethyl acetate 67/33), the compound of formula V of example ID above was obtained, (E) - (1R, 3aR, 4S, 7aR) -l- [(R) -l-methyl-3- [4- (1-hydroxy-l-methyl-ethyl) -phenyl-propenyl] -7a-methyl-octahydro-inden-4-ol (144 mg, yield: 85.), in the form of a colorless foam. E) The following compounds of formula VI were obtained by hydrogenation of the side chain:
Example ÍE
(IR, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(S) -1-methyl-3- [2- (carboxylic acid ethyl ester) -phenyl-propenyl] -octahydro-inden- 4-ol from (IR, 3aR, 4S, 7aR) - -hydroxy- 1 - [(S) -3- [2- (ethyl ester
of the carboxylic acid) -pheni 1- 1 -methyl-propynyl methyl-octahydro-indene. MS: (M) "358 IR: cm" 1 3500; 1720; 1602; 1577; 1447; 1368; 1167; 1136, 1098; 1069; 990; 942; 750; 711
Example 2E
(IR, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(S) - 1-met i 1-3- [3- (carboxylic acid ethyl ester) - pheni 1-propeni 1 ] -octahydro-inden--ol from
(! R, 3aR, 4S, 7aR) -4-hydroxy-l- [(S) -3- [3- (carboxylic acid ethyl ester) -pheni 1- 1 -methyl 1-propinyl]] - 7 a-met i 1-octahydro-indeno. MS: (M) * 358 IR: cm "; 3528; 2939; 2868; 1719; 1608; 1590; 1444;
1369; 1280; 1197; 1104; 1024; 992; 946; 862; 751;
698. Example 3E
(IR, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(S) -1-methyl -3- [4- (carboxylic acid ethyl ester) -phenyl-propenyl] -octahydro-inden- 4-ol from (! R, 3aR, 4S, 7aR) -4-hydroxy-l- [(S) -3- [4- (ethyl ester
of the carboxylic acid) -pheni 1- 1 -methyl-1-propinyl] -α-methyl-octahydro-indene. MS: (M) t 358 IR: cm "1 3538; 2935; 2868; 1718; 1611; 1463; 13o6; 1276; 1177; 1106; 1022; 993; 943; 850; 768; 706.
Example 4E
Ethyl 3- [(S) -3- [(IR, 3aR, 4S, 7aR) - Hydroxy-a-methyl-1-octylhydro-inden-1-yl] -butyl] -benzoic acid ester, from of (IR, 3aR, 4S, 7 aR> -4-hydroxy- 1- [(R) -3- [3- (carboxyl-carboxylic acid ethyl ester) -phenyl-1-methyl-propynyl] -7a-methyl- Octahydro-indene MS: (M) + 358 IR: cm 1 3528, 2932, 2870, 1719, 1609, 1591, 1445, 1370, 1282, 1197, 1105, 1024, 990, 947, 751, 695.
Example 5E
3- [(R) -3- [(IR, 3aR, 4S, 7 aR) -4-hydr oxidant ti 1-oct ahydro-inden-1-i 1] -but i 1] - pheno 1, from [LR, 3aR, 4S, 7aR] -7a-methyl-l- [(S) -l-methyl-3- (3-hydroxy-phenyl) -propinyl] -octahydro-inden-4-ol.
MS: (M) + 302 IR: cm "1 3523; 3224; 3034; 2996; 2936; 2867; 1619;
1585; 1480, 1372; 1349; 1295; 1249; 1153; 1063; 962;
956 941; 784, 695
Typically, the compound of formula VI
(IR, 3aR, 4S, 7aR) - 4-hydroxy-1 - [(S) -3- [2- (carboxylic acid ethyl ester) -phi] -1-methyl-1-propyne-7- -met i 1-oct ahydro-indene (218 mg, 0.615 mmol) was dissolved in anhydrous ethanol 812 ml). Palladium on carbon (10%, 55 mg) was added and the reaction mixture was subjected to a stream of hydrogen at one atmosphere for 12 hours at room temperature. The catalyst was prepared by filtration and the solvent was evaporated. The compound of formula VI of the previous example 1E, the [IR, 3aR, 4S, 7aR] -7 a-me ti 1-1- [(S) -l-methyl-3- [2- (ethyl ester of the carboxy li co) - pheni 1 -propeni 1] -octahydro-inden-4-ol, (226 mg, yield: 100), in the form of a yellowish oil.
F) The following compounds of formula * t or
VI were obtained from formab compounds
VII or IX:
1F
(lR, 3aR, 4S, 7aR) -4-h? drox? -l- [(S) -3- [2- (carboxylic acid 1-yl ethyl ester) - fem 1 - 1 -me ti 1 -propini 1 ] - 7a-me ti 1-oc tahidro-indene, from (IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethyl-silanyloxy) -7 a-met i 1-1- [(S ) - 1-metí 1-prop-mil] -octahidro-indenc. MS: (M) + 354 IR: cm "-3530; 3440; 2934; 2872, 2218; 1726; 159"; 1568; 1481; 1446; 1367; 1292; 1248; 1165; 1131; 1080; 1042; 758
Example 2F
(lR, 3aR, 4S, 7aR) -4-h? drox? -l- [(S) -3- [3- (carboxylic acid 1-ethyl ester) - phenyl-1-met i 1-propini 1 ] -7a-met 11-oct ahydro-mdene, from (IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethylsilanyloxy) -7a-met? Ll- [(S) -1- met? l-prop-m? l] -octahydro-mdeno. MS: (M) + 354
IR: c 1 3531, 2934, 2872, 2216, 1721, 1600, 15 8, 1451, 1369, 1290, 1228, 1166, 1105, 1079, 1024, and 992;
756; 685
Example 3F
(lR, 3aR, 4S, 7aR) -4-hydroxy-l- [(S) -3- [4- (carboxylic acid ethyl ester) -pheni 1- 1 -met i 1 -propini 1] -7a- me ti 1-oct ahydro-indene, from (IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethyl-silanyloxy) -7a-methyl-l- [(S) -1-methyl- prop-inyl] -octahydro-indene. MS: (M) * 354 IR: cm 1 3530, 2934, 2872, 2216, 1719, 1605, 1451, 1405, 1368, 1272, 1174, 1106, 1022, 857, 770, and 698.
Example 4F
(IR, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(S) -3- [3-hydroxyphenyl] -propinyl] -octahydro-inden-4-o 1, from (IR , 3aR, 4S, 7 aR) -7 a-meti 1- 1 - [(S) -1-met i 1-prop-2-ynyl] -octahydro-inden-4-o 1. MS: (MH) * 297
IR: c 1 3441, 3140, 2946, 2881, 2220, 1611, 1571, 1479, 1450, 1359, 1327, 1285, 1182, 1157, 1064, 968;
947 783 689
Example 5F
(LR, 3aR, 4S, 7aR) -l - [(S) -l-methyl-3- [4-tert-butyl-dimethyl-silanyloxy) -phenyl] -prop-2-ynyl] -7a-methyl-octahydro -inden-4-ol, from
[LR, 3aR, 4S, 7aR] -7 a-me ti 1-1- [(S) -1-me t i 1 -prop-2-ynyl] -octahydro-inden-4-ol. MS: (M-H) + 412 IR: cm "3400, 2931, 2859, 1602, 1506, 1470, 1362, 1258, 1165, 1097, 1062, 912, 840, 806, 781, 675.
Example 6F
(lR, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(R) -3- [3-hydroxy-phenyl) -l-methyl-prop-2-ynyl] -octahydro-inden-4 -ol, from (IR, 3aR, 4S, 7 aR) -7 a-me ti 1 - 1 - [(R) l-methyl-prop-2-ynyl] -octahydro-inden-4-ol. EM: (M) "298
IR cm 3561 3226 2938 2875 2228 1611 1471; 1453; 1377; 1328; 1291; 1234; 1183; 153, 1085; 1000; 989; 936; 888; 880; 789; 692
Example 7F
(lR, 3aR, 4S, 7aR) -4-hydroxy-1 - [(R) -3- [3- (carboxylic acid ethyl ester) -phi] -1-met-1 -prop-2-ini 1 ] - 7 a-met i 1-oct ahydro-indene, from (IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethyl-silanyloxy) -7a-methyl-l- [(R) - l-methyl-prop-2-ynyl] -octahydro-indene. MS: (M) t 354 IR: cm "1 3524; 3468; 2934; 2870; 2238; 1721; 1602; 1582; 1476; 1453; 1428; 1370; 1291; 1229; 1167;
1106; 1080; 1025; 989; 960; 756; 685.
Example 8F
(lR, 3aR, 4S, 7aR) -4-hydroxy-l- [(R) -3- [2- (carboxylic acid ethyl ester) -phi] 1-methyl-1-prop-2-ynyl ] -7a-met il-octahydro-indene, from (IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethylsilanyloxy) -
7a-methyl-l- [(R) -l-methyl-prop-2-ynyl] -octahydro-indene. MS: (M) * 354 IR: cm "1 3538; 3468; 2933; 2870; 2240; 1714; 1 PU l 1570; 1482; 1447; 1369; 1292; 1249; 1167; 1 1076; 1042; 989; 949; 758; 701.
Example 9F
(IR, 3aR, 4S, 7aR) -7 a-me ti 1-4- (tert-butyl-dimethyl-silanyloxy-1- [(R) -l-methyl-3- [5- (carboxylic acid ethyl ester 1 ico-fur an-2-i 1] -prop-2-yl] -octahydro-indene, from (IR, 3aR, 4S, 7 aR i -4- (tert-butyl-dimethyl-silanyloxy) -7a -methyl-l- [(S) -1-methyl-prop-inyl] -octahydro-indene MS: (M) * 330 IR: cm "-3540, 2935, 2873, 2242, 1722, 1589, 1508, 1470; 1457; 1445; 1436; 1361; 1302; 1244; 1142; 991; 761.
Typically, the compound of formula IX, (IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethylsilanyloxy) -7a-methyl-l- [(S) -1-methyl-propinyl] -octahydro- indene (1000 mg, 3.12 mmol) and ethyl 2-iodobenzoate
(1290 mg, 4.68 mmol), were dissolved in piperidma (15 ml). The reaction mixture was degassed and bis- (tri-phenylphosph) -palladium (II) dichloride (219 mg, 0.312 mmol) and copper iodide (I> - The reaction mixture was stirred at room temperature. The reaction mixture was poured into ice-cold aqueous hydrochloric acid, extracted twice with ethyl acetate, washed several times with brine, dried with sulphate and then heated to 50 ° C. overnight. of anhydrous sodium and the solvent was removed.After flash chromatography (eluent: hexanes / ethyl acetate 96/4) the impure adduct was obtained in the form of a brown oil.The brown oil was dissolved in THF ( 25 ml) Hydrofluoric acid (40 ml aqueous solution, 13 ml) was added and the reaction mixture was stirred at room temperature for forty hours, then the reaction mixture was poured onto ice cold salt, extracted twice. with ethyl acetate , washed twice with brine, dried with anhydrous sodium sulfate and the solvent was removed. After chromatography
flash (eluent: hexanes / ethyl acetate 82/18) there was obtained the compound of formula VI of example 1F above, (! R, 3aR, 4S, 7aR) -4-hydroxy-l- [(S) - 3 - [ 2 - (Carboxylic acid ethyl ester) - phenyl-1-met i 1 -propini 1] - 7 a-me ti 1-oct ahydro-indene (642 mg, yield: 58: t) in the form of a yellow colcrum oil). G) The following compounds of formula V or VI were obtained from compounds of formula VIII:
Example 1G
Ethyl ester of (E) -4- [(R) - 3 - [(lR, 3aR, 4S, 7aR) - 4 -hi drox i-7 a-me ti 1-oct ahydro-inden-1-yl] -but-1-enyl] -benzoic, from (E) - (R1- (1R, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(S) -methyl-3-tributylstannyl- alyl] -octahydro-inden-4-ol EM: (M + H) * 357 IR: cm "1 3522; 2934; 2869; 1715; 1646, 1606; 1456; 1411; 1368; 1275, 1178; 1106; 1068; 1022; 969; 873; 705; 704.
Example 2G
Ethyl ester of (E) -2 - [(R > - 3- [(IR, 3aR, 4S, 7aR) -4-hydroxy-7 a-met i 1-octylhydro-inden-1-yl] - but-l-enyl] -benzoic, from (E - (P '- (lR, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(S) -me ti 1 - 3 -tributylstannyl -alyl] -octahydro-inden-4-ol MS: (M) * 356 IR: cm "1 3527; 2933; 2869; 1716; 1646; 1602; 1571; 1477; 1449; 1367; 1294; 1251; 1166; 1127; 1074;
1023 990; 751; 709
3G example
Ethyl ester of (E) -3 - [(R j - 3 - [(IR, 3aR, 4S, 7aR) -4-hydroxy-7a-methyl-octahydro-inden-1-yl] -but-1-enyl ester ] -benzoic acid, starting from (E) - (R) - (1R, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(S) -methyl-3-tributylstannyl-allyl] -octahydro- inden- -ol MS: (M) + 356 IR: cm 1 3524, 2934, 2868, 1719, 1648, 1601, 1582, 1443, 1369, 1286, 1201, 1167, 1106, 1025, 965, 752.
Example 4G
(E) - (1R, 3aR, 4S, 7aR) -l- [(R) -l-methyl-3- [3- (hydroxy-phenyl) -prop-2-enyl] -7a-methyl-octahydro-inden -4-ol], from (E) - (R) - (IR, 3aR, 4S, 7 aR) -7a-methyl-1- [(S) -methyl-3-tributylstannyl-allyl] -octahydro -inden-4-ol. MS: (M) * 300 IR: cm "1 3430; 3259; 2940; 2863; 1613; 1579; 1500;
1454; 1364; 1331; 1250; 1159; 1060; 963; 778 686
E j us 5G
(E) - (1R, 3R, 4S, 7aR) -7a-methyl-l- [(S) -1-met-11-3- [2- (tert-butyl-dimethyl-silanyl-oxy) -phenyl] allyl ] -octahydro-inden-4-ol, from (E) - (R) - (! R, 3aR, 4S, 7aR) -7a-methyl-l- [(R) -methyl-3-tributylstannyl-ally] ] -octahydro-inden-4-ol. NMR (CDC1, J in Hz, 250 MHz): 7.14 (t, J = 8, 1, 1H); 6.91 (dm; J = 8, 1; 1H); 6.81 (sbr; 1H); 6.67 (dm; J = 8, 1; 1H); 6.24 (d (AB); J = 16.2; 1H); 6.00 (d (AB) d; J = 16.2, 9.6; 1H); 4.07 (m; 1H); 2.31-0.86 (m, 13H); 0.99 (d; J = 6, 1; 3 H); 0.98 (s; 9H); 0.93 (s; 3 H); 0.19 (s; 3H).
Typically the compound of formula VIII, (E) - (R) - (IR, 3aR, 4S, 7aR) -7a-methyl-l- [(S) -methyl-3-tributyl-tannil-ali 1] -octahydro- inden- 4-ol (437 mg, 0.858 mmol) and -yodobenzoato acetate (24 mg,? 0.90 mmol) were dissolved in toluene \ 8 mi '. The reaction mixture was degassed, bi-s (tri-phenyl-fos) -palladium (II) dichloride was added.
mg; 0.043 mmol), and the reaction mixture was heated to 75 ° C overnight. The reaction mixture was then poured onto an ice-cold salt, extracted twice with ethyl acetate, washed twice with brine, dried over anhydrous sodium sulfate and the solvent was removed. After flash chromatography (eluent: hexanes / ethyl acetate 8/2), the compound of formula VI of example 1G, ethyl ester of (E) -4 - [(R) -3- (IR, 3aR) , 4 S, 7aR) -4-hydroxy-7a-methyl-octahydro-inden-1-yl] -but-1-enyl] -benzoic acid (182 mg, yield: 60"), in the form of a brown oil . in the example 5G, using the 3- (tert-but i 1-dimethyl-s ílaniloxi) iodobenzene instead of 4 - iodobenzoate.
H) The following compound of formula VII was obtained from the compounds of formula VII
Example 1H
(E) - (R) - (LR, 3aR, 4S, 7aR) -7a-methyl-l- [(S) -methyl-3-tributylstannyl-allyl] -octahydro-inden -o-1, from ( IR, 3aR, 4S, 7aR) -7a-me t il- 1- [(S) -1-met i 1 -prop-2-nyl] -octahydro-inden-4-ol. NMR (CDC1, J in Hz, 250 MHz): 5.74 (m, 2H); 4.08 (m; 1H); 2.18-0.82 (m; 47H).
Example 2H
(E) - (R) - (1R, 3aR, 4S, 7aR) -7a-methyl-1 - [(R) -methyl-3-tributylstannyl-allyl] -octahydro-inden--ol, from [IR , 3aR, S, 7aR] -7a-me t il- 1- [(R) -1-met i 1 -prop-2-nyl] -octahydro-inden-4-ol. MS: (MC H) + 441 IR: cm 1 3408, 2954, 2926, 2870, 1594, 1458, 1374, 1160, 1069, 990, 942, 882. Typically, the compound of formula VII was dissolved, [1 R , 3aR, S, 7 aR] - 7 a-met i 1- 1 - [(S) -met i 1 -
prop-2-ni 1] -oct ahydro-inden-4-ol (494 mg;, 39 mmol) in toluene (16 ml). Then tributyltin hydride (698 μl, 2.63 mmol) and azobi sisobut ironi trilo (39 mg, C, 24 mmol) were added and the reaction mixture was heated to S0CC for three hours. The reaction mixture was then poured onto an ice-cold salt, extracted twice with ethyl acetate, washed twice with brine, dried over anhydrous sodium sulfate and the solvent was removed. After flash chromatography (eluent: hexanes / ethyl acetate 9/1), compound (E) - (R) - (IR, 3aR, S, 7aR) -7 a-methyl-1- [(S ) -methyl-3-tributylstannyl-allyl] -oct ahidro- inden- 4-ol] (908 mg; yield: 74), as a colorless oil. I) The following compounds of formula VII were obtained from compounds of formula
IX
Example II
IR, 3aR, 4S, 7aR) -7 a-me ti 1-1- [(S) -1-met i 1-prop-2-nil] -octahydro-inden-4-ol, from
(IR, 3aR, 4S, 7aR) -4- (tert-Butyl-dimethyl-silanyloxy -7a-methyl-1 - [(S) -1-methyl-propynyl] -octahydro-mdene.
IR: cm "- 3429; 3307; 2935; 2872; 2118; 1454; 13 4;
1268 1233; 1163; 1066; 989; 943 625
Example 21
[IR, 3aR, 4S, 7aR] -7a-methyl-l- [(R) -1-met? L-prop-2-n? 1] -octahydro-mden-4-ol, from (IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethylsilanyloxy) -7a-met? Ll- [(R) -1-met i 1-propynyl] -octahydro-indene. MS: (M) 206 IR: cm "3356; 3306; 2932; 2879; 2120; 1453; 1376; 1268; 1168; 1066; 990; 946; 643; 621. Typically, the compound of formula IX was dissolved, ( IR, 3 aR, 4 S, 7 aR) - 4- (ter c-but 11-d? Me 111-silanyloxy) -7a-met? Ll - [(S) -1-met-il-propini 1] -octahydro Inden (900 mg, 2.81 mmol) in THF (35 ml), hydrofluoric acid (40% aqueous solution, 18 ml) was added and the reaction mixture was stirred at room temperature for three hours. the reaction mixture was poured over
brine ice, extracted twice with ethyl acetate, washed twice with brine, dried over anhydrous sodium sulfate and the solvent removed. After flash chromatography (eluent: hexanes / ethyl acetate 82/18!, Compound ((IR, aR, 4S, 7aR) -7 a-met il-1 - [(S "-l-methyl- prop-2-nil] -octahydro-inden-4-o-1 (497 mg, yield: 86%) in the form of a yellow coke oil lo J) The following compounds of formula IX were obtained from compounds of formula X :
Example 1J
(LR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethi-silanyloxy) -7a-methyl-1 - [(S) -1-methyl-propynyl] -octahydro-indene, from (IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethyl-silanyloxy) -1- [(S) -3,3-dibromo-1-methyl-allyl] -7 a-methyl-octahydro - indeno. MS: (M-tBu) * 263 IR: cm "1 3312; 2932; 2858; 2120; 1252; 1165; 1083; 1029; 836; 774.
Example 2J
(IR, 3aR, 4S, 7aR) -4- (tert-Butyl-dimethyl-silanyloxy) -7a-methyl-1 - [(R) -1-methyl-1-propyne] -octahydro-indene, from (IR, 3aR, 4S, 7 aR) -4- (tert-butyl-dimethyl-silanyloxy) -1- [(R) -3,3-dibromo-1-methyl-allyl] -7a-methyl-octahydro- indeno. MS: (M) * 320 IR: cm "1 3313; 2954; 2931; 2859; 2120; 1469; 1375; 1253; 1166; 1079; 1020; 973; 953; 924; 836; 774; 687; 629. Typically, the compound of formula X, (IR, 3aR, S, 7aR) -4- (tert-but i 1-dime ti 1-si lanyloxy) -1- [(S) -3,3-dibromo-l- was dissolved methyl-allyl] -7a-met il-octahydro-indene (8.94 g, 18.6 mmol) in anhydrous THF (80 mL) and cooled to -78 ° C. Butyl lithium (28.6 mL of 1.6 M solution in hexane, 42.8 mmol) dropwise The reaction mixture was allowed to rise to room temperature and then poured into ice cold aqueous citric acid, The mixture was extracted twice with ethyl acetate (150 g. mi), the organic phase was washed twice with brine (50 ml), and dried with sodium sulfate, after evaporating the solvents and
After flash chromatography on silica gel (hexanes / ethyl acetate 99: 1), the compound ((IR, 3aR, 4S, aR) -4- (tert-butyl-dimethylsilanyloxy) -7a-methyl- was obtained. l- [(S) -1-methyl-propynyl] -octahydro-indene (5.85 g, yield: 98), in the form of a yellow oil K) The following compounds of formula X were obtained from aldehydes of Formula XI:
Example 1K
(lR, 3aR, 4S, 7aR) -4- (tert-but i 1-dime thi 1-silanyloxy) -l- [(S) -3,3-dibromo-1-met i 1-al i 1] - 7 a-met i 1-oct ahydro-indene, from (S) -2- [(IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethyl-silanyloxy) -7a-methyl-octahydro- inden-l-il] -propan-1-al. MS: (M-tBu) "423 IR: cm": 2932; 2857; 1626; 1467; 1375; 1252; 1165; 1080; 1029; 952; 922; 835; 776
Example 2K
(lR, 3aR, 4S, 7aR) -4- (tert-but i 1 -dimet i 1 -sylanyloxy) -1- [(R) -3, 3-dibromo-1-met il-ali 1] -7a-
I tet-oct ahydro-indene, from? R -2- [(IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethylsilyloxy> -7a-methyl-octahydro-inden-l- il] -propan-1-al. MS: (M-Me) t 463 IR: cm "1 2930; 2858; 1627; 1465; 1375; 1252; lie" 7; 1082; 1021; 960; 920; 873; 836; 775; 686. Typically, tetrabromomethane (16.8 g, 50.6 mmol) was dissolved in dichloromethane (80 mL), and 1-phosphate (26.5 g, 101.1 mmol) in solution was added. in dichloromethane (40 ml) dropwise The reaction mixture was cooled to -20 ° C, and the compound (S) -2- [(IR, 3aR, 4S, 7aR) -4- was added dropwise. (tert-butyl-dimethyl-silanyloxy) -7a-met i 1 -oct ahydro-inden-1 -i 1] -propan-1 -al (J. Org Ch em: 1992, 5_7_, 3173) in solution in dichloromethane
(30 mi). The reaction mixture was allowed to reach room temperature and then poured on ice. The mixture was extracted twice with ethyl acetate (250 ml); the organic phase was washed twice with brine (100 ml), and dried with sodium sulfate. After evaporating the solvents and subjecting them to flash chromatography on silica gel (hexanes / ethyl acetate 98/2), the compound was obtained ((IR, 3aR, 4S, 7aR) -4 -
(tert-butyl-dimethyl-silanyloxy) -1- [(S) -3,3-dibromo-1-methyl-allyl] -7 a-met i 1-octylhydro-indene? 8.94 g; performance: 81- ':. ), in the form of a colorless oil. L) The starting aldehyde used in the above example 2K is obtained as follows: The alcohol is diluted (R) -2- ((IR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethyl-silanyloxy) -7a-methyl-octahydro-inden-1-yl] -propan-1-ol (10.00 g, 30.6 mmol), in dichloromethane (120 ml) and 4 ° molecular sieve powder (6.35 g. g) and N-methyl morpholine oxide (6.21 g, 45.9 mmol), and the mixture is stirred for 30 minutes, the mixture is cooled to -10 ° C and tetrapropylammonium perruthenate is added.
(538 mg, 1.53 mmol). The reaction mixture is allowed to reach room temperature and is stirred for an additional hour. The mixture is purified by chromatography with silica gel using n-hexanes / ethyl acetate 98/2 as eluent. 7.46 g (yield 76.4'-) of the intermediate aldehyde are obtained: (R) -2- [(lR, 3aR, 4S, 7aR) -4- (tert-butyl-dimethylsilanyl-oxy) -7a-methyl -octahydro-inden-1-yl] -propan-al.
M) The (R) -basic alcohol used in example L, is obtained as follows: The aldehyde (S) -2- [(IR, 3aR, S, 7 aR) -4- (tert-butyl-dimethylsi) lanyloxy) -7 a-met i 1-octahydro-inden-1-yl] -propan-1-al (7.63 g, 23.5 mmol) is diluted in
Absolute THF (120 mmol) and 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) (2.81 mL, 23.5 mmol) is added. The mixture is heated to reflux for 6 hours. The reaction mixture is poured into a freezing solution of citric acid and extracted with ethyl acetate. The organic phase is dried with sodium sulfate and the solvents are removed. The
* H-NMR of the crude product of the reaction indicates a mixture of about 1/1 of the diastereomeric isomers. The crude product is diluted in isopropanol (100 ml) and at 0 ° C NaBH (978 mg, 25.9 mmol) is added. The mixture is stirred for half an hour at 0 ° C and at room temperature overnight. The reaction mixture is then poured into ice-cold brine and extracted twice with ethyl acetate. The organic layer is washed with brine and dried with sodium sulfate. HE
The solvents are removed and the crude product is purified by two consecutive flash chromatographies (n-hexanes / ethyl acetate 95/5> 20-epi (R) -2- [IR, 3aR, 4S, 7aR >.; - 4 - (tert-butyl-dimethyl-silanyloxy) -7a-methyl-octahydroinden-1-yl] -propan-1-ol, with yield 41 (3, 135 g) .MS (M-Me) "311 IR: cm" 1 3352; 2931; 2858; 1469; 1374; 1252; 1166;
1081-1025; 919; 835; 774
The following compounds of formula I were obtained from hydroxyketone of formula IVa (4aR, 5R, 8aR) -5 - ((S) -3- [2- (l-hydroxy-l-methyl-ethyl) -phenyl] -l-methyl-prop-2-ynyl) -α-methyl-octahydro-na to en-1 -one, by protection of the alcohol as trimethylsilyl ether of formula IV, Wittig reaction with a phosphine oxide of formula III, followed by the cleavage of the silyl groups by treatment with an excess of fluoride, according to the experimental procedure given below:
Example 27
(7E) - (IR, 3R) -23- [2-hydroxy-l-methyl-ethyl phenyl] -D-hom-19, 24-dinor-9, 10-seco-cola-5, 7 -di en- 22-in-l, 3-diol. MS: (M) "476 NMR 1H, d, TMS) 0.87 (s, 3H), 1.32 (d, 3H), 1.69.
(s, 6H), 1, 15-1, 85 (m, 14H), 1, 9 (m, 3H), 2.22 (m, 2 H i,
2, 49 (dd, lH), 2, 75 (dd, lH), 2, 9 (m, lH), 3, 13 (q, lH), 3, 94 (s, 0H), 4, 1 (m , lH), 4, 2 (m, lH), 5, 85 (d, lH), 6, 31 (d, lH), 7, 1-7, 25 (m, 2H), 7, 41 (dxt, 2H).
Example 28
(5Z, 7E) - (1R, 3R) -23- [2- (1-Hydroxy-1-meth i 1 -ethyl) -phenyl] -D-homo-24-nor-9, 10-seco-cola- 5,7, 10 (19) -trien-22-in-l, 3-diol. MS: (M) * 488 NMR: (1H, d, TMS) 0.86 (s, 3H), 1.34 (d, 3H), 1.69
(s, 6H), 1, 15-2, 0 (m, 17H), 2, 31 (dd, lH), 2, 61
(dd, lH), 2, 75 (dd, lH), 2, 9 (M, 1H), 3, 13 (q, lH), 3, 94
(s, OH), 4.24 (m, lH), 4, 43 (m, lH), 4, 99 (s, lH), 5, 33
(S, 1H), 5.33 (S, 1H), 6.02 (d, lH), 6.36 td, lH), ", 1-7, 25 (, 2H), 7, 41 (dxt, 2H).
Example 29
(5Z, 7E) - (3S) -23- [2- (1-hydroxy-1-methyl-ethyl) -phenyl] -D-homo-24-nor-9, 10-seco-cola-5, 7, 10 (19) -trien-22-in-l, 3-ol. MS: (M) "472 NMR: (1H, d, TMS) 0.86 (s, 3H), 1.32 (d, 3H), 1.69 (s, 6H), 1.15-2.7 (m, 20H), 2.9 (m, 'lH), 3.11 (q, lH), 3.94 (s, OH and 1H), 4.81 (s, lH), 5.06 (s) , lH), 6.04 (d, lH), 6.22 (d, lH), 7.1-7.25 (m, 2H), 7.40 (dxt, 2H).
Typically, the compound of Example 28 was prepared as follows: a) The hydroxyketone of formula IVa, (4aR, 5R, 8aR) -5- ((S) -3- [2- (1-Hydroxy-1-met i 1 - eti 1) -phenyl] -l-methyl-prop-2-ynyl) -4a-methyl-octahydro-naphthalen-1-one (419 mg, 1.19 mg, 1.19 mmol), was dissolved in CH_C1; (10 ml) and treated with trimeth il s i li limidazole (0.889 ml, 6.07 mmol). The mixture was kept at 35-40 ° C for 5 hours, poured on crushed ice, extracted twice
with ether, washed with water, dried with sodium sulfate and evaporated to dryness. Flash chromatography (SiO_, hexane / AcOEt = 9/1), gave 504 na of (aR, 5R, 8aR) -4 a-me ti 1-5- ((S) -l-methyl-3- 2- J methyl-1-trimethyl-silanyloxy-ethyl) -phenyl] -prop-2-ynyl) -octahydro-naphthalen-1-one. b) Phosphine oxide, (3S, 5R- (Z) - [2 - [3, 5-bis (tert-butyl-dimethyl-silanyloxy) -2-methylene-cyclohexy-1-iden] ethyl] -di-pheni oxide. 1 Phosphine (563 mg, 0.965 mmol) was dissolved in anhydrous THF (5 mL) and treated at -78 ° C with 0.772 mL of 1.57 M nBuLi (hexane). After 10 minutes, the prepared ketone was added. above (205 mg, 0.482 mmol), dissolved in a minuscule quantity of THF, to the deep red solution.The reaction temperature was maintained at -78 ° C for 0.75 hours and then allowed to slowly warm up to reach The temperature of 0 ° C. After 2.5 hours the reaction mixture was poured onto tri-ice / NH.Cl, extracted twice with ether, washed with water and brine, dried with sodium sulfate. and evaporated to dryness Flash chromatography (SIO2, hexane / AcOEt = 9/1) afforded less polar fractions, 129 mg ((5Z, 7E) - (lS, 3R) -l, 3-bis (tert. -butyl dimethyl-
silanyloxy) -23- [2- (1-methyl-1-trimethylsilanyloxy-ethyl) -phenyl] -D-homo-24-nor-9, 10-seco-cola-5, 7, 10 (19) -trien- 22-ino in the form of a colorless oil and in the more polar fractions, 111 mg of the starting ketone. c) 619 mg 81.96 mmol: of TBAF trihydrate in 4 ml of THF were dried, by stirring at room temperature with 0.6 g of molecular sieve 3a for 2 hours. Next, the resulting solution was added to the 129 mg of the vitamin D protected derivative prepared above, and the mixture was maintained for 1.5 hours at 50 ° C. The reaction mixture was then poured onto ice cold / NH, Cl, extracted twice with ether, washed with water and brine, dried with sodium sulfate and evaporated to dryness. Flash chromatography (SiO, hexane / AcOEt = 1/2) afforded 80 mg of ((5Z, 7E) - (1 S, 3R) -23- [2- (1-hydroxy-1-methyl-ethyl-phenyl) -D-homo-24-nor-9, 10-seco-cola-5, 7, 10 (19) -trien-22-in-1, 3-diol), in the form of a colorless gum N) starting hydroxy cetane, of formula IVa, used in paragraph a) above, (4 aR, 5R, 8 aR) - 5- ((S) -3- [2- (1-hydroxy-1-methyl-ethyl ) -phenyl] -1-methyl-
prop-2-ynyl) -4a-methyl-octahydro-naphthalene-1-one, was prepared from the corresponding alcohol-ether of formula XII, (S) -2- [(IR, 4aR, 5S, 8 aR) - 5- [tert-but-1-dimethylsilanyloxy) -8a-methyl-decahydro-naphthalene-li 1] -propan-l-ol (Example 15 of European Patent Application No. 95117037.2) (RAN 4212/067-OQi) as follows: a) S wern reagent was prepared at -60 ° C by slowly adding DMSO (0.899 ml, 11.5 mmol, dissolved in 2 ml of CH? Cl2) to oxalyl chloride
(0.503 mL, 5.85 mmol) in 10 mL of CH.C1. After 15 minutes, S [(IR, 4aR, 5S, 8aR) -5- (tert-butyl-dimethylsilanyloxy) was slowly added. -8a-methyl-decahydro-naphthalen-1-yl] -propan-1-ol, (1.81 g, 5.31 mmol), dissolved in 7 ml of CH_C1. After 1/2 hour, NEt (5.18 ml, 37.2 mmol) was added, and the temperature was allowed to reach -25 ° C. The reaction was quenched by pouring onto tri-tide ice / NH / Cl, extracted twice with ether, washed with water and brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO_, hexane / AcOEt = 97/3) yielded 1.583 g of (S) -2 - [(IR, 4aR, 5S, 8 aR) -5- (tert-butyl-dimethyl-silanyloxy) -8 a-methyl-decahydro-
naphthalen-1-yl] -propionaldehyde in the form of an isomerically pure, colorless oil. b) CBr (3.10 g, 9.35 mmol) was dissolved in 21 ml of CH_.dc and treated at -15 ° C with Ph, P (4.7 g, 18.7 mmol). After 10 minutes, the aldehyde prepared above (1.583 g, 4.675 mmol) dissolved in 5 ml of Ch_Cl_ was slowly added and allowed to react with the ylide for 1/2 hour.The crude reaction mixture was distributed twice between Hexane and EtOH / water = 8/2, the upper layer was dried with sodium sulfate and the solvent was evaporated. Flash chromatography (SiO., Hexane) yielded 2.18 g of tert-but i 1- [(SS, 4 aR, 5R, 8 aR) -5- ((S) -3,3-dibromo-l- methyl-allyl) 4a-methyl-decahydro-naphthalen-1-yloxy-dimethyl-tin, in the form of a colorless oil. c) The dibromide synthesized above (2.18 g, 4.41 mmol) was dissolved in anhydrous THF (26 ml) and treated at -78 ° C with nBuLi (9.55 ml [1.5M (hexane)] , 14.3 mmol). After 60 minutes the reaction mixture was poured onto ice triturated / NH, Cl, extracted twice with ether, washed with brine, dried with sodium sulfate and evaporated to dryness. Flash chromatography (SiO_, hexane)
provided 1.37 g of the desired compound, tert-but i 1-dimethyl- [(1S, 4aR, 5R, 8aR) -4a-methyl-5; S) -1-methyl-prop-2-ynyl) -decahydro-naphthalene-1-yloxy-silane, in the form of a colorless, pure oil. d) The acetylene prepared above (1.37 g, 4.09 mmol), dissolved in 20 ml of piperidine, was mixed under scrupulous absence of air, with ethyl 2-iodobenzoate (1.69 g, 6.14 g). mmoles), Cul? ^ mg, 0.408 mmoles), and (Ph_.P) _Pd (472 mg, 0.408 mmoles) and allowed to react at 50 ° C for 2 hours. The mixture was poured onto ice cold / HCl, extracted twice with ether, washed with water and brine, dried with sodium sulfate and evaporated to dryness. Flash chromatography (SiO, hexane / AcOEt = 98/2) gave 1.841 g of the ethyl ester of 2- ((S) -3- [(SS, 4 aR, 5R, 8aR) - 5- (tert-butyl- dimethylsilanyloxy) -8a-methyl-decahydro-naphthalen-1-yl] -but-1-ynyl) -benzoic acid, containing some amount of the starting iodine-ester, as an impurity, which was removed after the next step. e) The Gri gn a rd reagent was prepared according to the standard procedure, starting with Mel (2.27 g, 16 mmol) and Mg shavings (0.365 g, 15 g).
mmoles) in 50 ml of anhydrous ether. After cooling to -78 ° C, 1.437 g (<3 mmol, corrected ur) of the ester prepared above, dissolved in 10 ml of anhydrous THF, were added dropwise and the mixture was stirred at room temperature for 2 hours. . Cooling and in argon current, the excess reagent was carefully destroyed with NH C1 solution, the layers were separated, the aqueous phase was extracted with ether, the combined organic layers were washed with NH4CI solution, dried with sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane / AcOEt = 93/7) gave 862 mg of 2- ((S) -3- [(SS, 4 aR, 5R, 8aR) -5- (tert-but-yl-dimethyl-s i-lanyloxy) -8a-met i 1-decahydro-naph talen-1-yl] -but-1-ynyl) -phenyl) -propan-2-ol, in the form of a colorless oil. f) 2.90 g (9.19 mmol of TBAF trihydrate in 18 ml of THF was dried by stirring at room temperature with 2.5 g of 3A molecular sieve for 1.5 hours.) The resulting solution was then added to the 862 mg of silyl ether prepared above After stirring for 44 hours at 75 ° C, the reaction mixture was poured onto crushed ice, the usual finishes followed by chromatography
Flash (SiO_, hexane / AcOEt = 8/2) gave in the less polar fractions, 174 mg of the starting material and in the more polar fractions, 424 s of (lS, 4aR, 5R, 8aR) -5- ((S ) -3- [2- (1-Hydroxy-1-meth i 1 -ethyl) -phenyl] -l-methyl-prop-2-ynyl) -4a-methyl-decahydro-naphthalene-ol, in the form of pf yellowish crystals 126-128 ° C. g) 423 mg of the alcohol synthesized above, was dissolved in 10 of CHcCl. and treated with pyridinium dichromate (1.86 g, 4.95 mmol). After stirring for 3 hours at room temperature the reaction mixture was filtered and then washed thoroughly with ether. The combined organic washings were evaporated to dryness and purified by flash chromatography (SiO_, hexane / AcOEt = 8/2) to obtain 420 mg of (4 aR, 5R, 8 aR) - 5- ((S) -3- [ 2- (1-Hydroxy-1-methyl-ethyl) -phenyl] -l-methyl-prop-2-ynyl) -4 a-me ti 1 -oct ahi dro-na alen-1 -one in the form of a colorless oil MS: (M) ~ 352 1 H NMR, d, TMS 0.95 3 H 1, 35 d, 3H; 69
(s, 6H), 1.2-2.2 (m, 12H), 2.35 (m, 2H), 3.13 (q, lH), 3.80 (s, OH), 7.14- 7.3 (m, 2H), 7.37.747 (m, 2H).
Example 30
The compound of formula I, (7E) - (1R, 3R-23- [2- (1-hydroxy-1-methyl-ethyl) -phenyl] -D-homo-19, 24-dinor-9, 10- dry-cola-5, 7, 17-trien-22-in-l, 3-d? cl EM: (M) + 474 NMR: (1H, d, TMS) 0.95 (s, 3H), 1 , 42 (d, 3H), 1.69
(s, 6H), 1.25-2.3 (m), 2.48 (m, lH), 2.7-2.9 (m, 2H ?, 3.42 (q, lH), 3, 84 (s, OH), 4.0-4.2 (m, 2H), 5.81
(m, lH), 5.91 (d, lH), 6.31 (d, lH), 7.1-7.3 (m, 2H),
7.43 (m, 2H),
It was prepared following the experimental procedures described in examples 27, 28 and 29, but starting from the alcohol-ether of formula XII, (S) -2- [(4aR, 5S, 8aS) -5- (tert-butyl-dimethyl- silanyloxy) -8a-methyl-3, 4, a, 5, 6, 7, 8, 8a-octahydro-naphthalen-1-yl] -propan-l-ol (example 14 of European patent application no. 95117037.2, RAN 4212 / 067-00). The following compounds of formula I were obtained from the hydroxyketone of formula IVa, (aR, 5R, 8aR) -5- ((R) -3- [2- (l-hydroxy-l-methyl-ethyl) - phenyl] -l-methyl-prop-2-ynyl) -4 a-me ti 1-
oct ahydro-naphthal en-1-one, by protecting the alcohol as trimet i 1 s il i 1- e er of formula IV, reaction of Wi ttig with a phosphine oxide of formula III, followed by cleavage of Silyl groups by treatment with an excess of fluoride, according to the experimental procedure described above for the product of example 28:
Example 31
(7E) - (1R, 3R, 20R) -23- [2- (1-Hydroxy-1-methyl-ethyl) -phenyl] -D-homo- 19,24-dinor-9, 10-seco-cola- 5, 7-di-22-in-l, 3-diol. MS: (M + NH.j) * 494, (M + Na) + 499 NMR: (lH, d, TMS) 0.74 (s, 3H), 1.20 (d, 3H), 1.71 ( s, 6H), 1.2-2.0 (m, 17H), 2.24 (m, 2H), 2.50 (dd, lH), 2.75 (dd, 1H), 2.88 (m , lH), 3.10 (dq, lH), 3.90 (s, OH), 4.0-4.2 (m, 2H), 5.87 (d, lH), 6.31 (d, lH), 7.15-7.25 (m, 2H), 7.44 (m, 2H).
Example 32
(5Z, 7E) - (1S, 3R, 21R) -23- [2- (1-hydroxy? -l-methyl-ethyl) -phenyl] -D-homo-24-nor-9, 10-dry-cola -5,7, 10 (19) -trien-22-in-l, 3-diol. MS: (M) * 488 NMR: (lH, d, TMS) 0.74 (s, 3H), 1.20 (d, 3H), 1.71 (s, 6H), 1.25-2.05 (m, 17H), 2.32 (dd, lH), 2, ol (dd, lH), 2.89 (m, lH), 3.10 (qd, lH), 3.90 (s, OH: , 4.24 (m, lH), 4.45 (m, lH), 5.00 (s, lH), 5.34 (s, lH), 6.02 (d, lH), 6.39 ( d, IH), 7.1-7.3 (m, 2H), 7.44 (m, 2H).
Example 33
(5Z, 7E) - (3S, 21R) -23- [2- (l-hydroxy-l-methyl-ethyl) -phenyl] -D-homo-24-nor- 9, 10-seco-cola-5, 7, 10 (19) -trien-22-in-3-ol. MS: (M) "472 NMR: (1H, d, TMS) 0.74 (s, 3H), 1.20 (d, 3H), 1.71 (s, 6H), 1.25-2.5 (m, 19H), 2.57 (dd, 1H), 2.88 (m, 1H), 3.10 (dq, 1H), 3.91 (s, 0H), 3.94 (m, 1H) , 4.82 (s (br), lH), 5.07 (s (br), lH), 6.03 (d, lH), 6.22 (d, lH), 7.1-7.3 (m, 2H), 7.44 (m, 2H).
The starting hydroxyketone of formula IVa (4aR, 5R, 8aR) -5- ((R) -3- [2- (l-hydroxy-l-methyl-ethyl'-phenyl] -l-methyl-prop-2- inyl) -4a-methyl-octahydro-naphthalen-1-one, used for example 31, 32 and 33, was prepared from (R) -2- [(IR, 4 aR, 53, 8 aR) -5 - (tert-butyl-dimethyl-silanyloxy) -8a-methyl-decahydre-naphthalene-1-y1] -propan-l-ol following a method similar to that described in Example N) above. 0) The alcohol ethers of formula XII used as starting material in the preceding paragraph N), and in examples 27-33, can be obtained as follows: a) A solution of 30.1 g (0.13 moles) of (4aS, 5S) -5-tert-butoxy-4a-methyl-4, 4a, 5, 6, 7, 8-hexahydro-2 (3H) -naphthalenone in 600 ml of tetrahydrofuran, cooled with stirring and argon atmosphere at -78 ° C. After the dropwise addition of 140 ml (0.14 mole) of L-selectride (1 molar in tetrahydrofuran), the reaction mixture was kept at -78 ° C for an additional hour, then warmed to room temperature and kept at this temperature for 4.5 hours. After cooling to -15 ° C, 12 ml of H.O, 90 ml of 4N NaOH were added sequentially and
100 ml of H_0_ (30? -) and drop by drop keeping the temperature between -10 ° C and 15 ° C. After the addition was complete, the reaction mixture was warmed to room temperature, poured into water and extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulphate and evaporated after filtration, yielding 30 g of the crude product (2S, 4 aS, 5S) -5- t erc-butoxy-4 a-methyl-2, 3, 4 , 4a, 5, 6, 7, 8-octahydro-naphthalen-2-ol in the form of an amorphous product, which by means of thin layer chromatography and NMR proved to be sufficiently pure for subsequent transformations. b) To a solution of 13 g (54.54 mmoles1 of (2S, 4aS, 5S) - 5- 1 er c-butoxy-4 a-me ti 1- 4, 4a, 5, 6, 7, 8-octahydro Naphthalene-2-ol in 150 ml of tetrahydrofuran, 20 g (112 mmoles) of 1, 1'-t-carboncarbonate were added. The reaction mixture was heated to reflux for two hours, cooled to room temperature The residue was chromatographed on silica gel with hexane / ethyl acetate 4/1 to obtain 14.8 g of the ester (2S, 4aS, 5S) -0- (5-tert-butoxy-4a- methyl-2,3,4,4a, 5,6,7,8-octahydro-naphthalene-2-yl) of the
Imidazole-1-carbothio acid, in the form of an amorphous material. c) To a stirred solution of 9.95 g, 28.5 mmol) of the ester (2S, 4 aS, 5S) -O- (5-1 er c-butox i-4 a-met i 1-2, 3 , 4, 4a, 5, 6, 7, 8-octahydro-naphthalen-2-ylco >; of the zol-1-carbohydrate imide acid, in 285 ml of toluene, kept under an argon atmosphere, were added 75.7 ml (285 mmoles) of tributyl hydride and 75.7 ml of a solution molar of triet-ilborane in tetrahydrofuran. The reaction mixture was heated at 120 ° C for 4 hours and 20 ml of tributyl hydride as well as 20 ml of triethyloborane solution (one molar in tetrahydrofuran) were added. The reaction mixture was kept at 120 ° C for 3 days, cooled to room temperature and evaporated in vacuo. The residue was chromatographed twice in 900 g of silica gel with toluene / hexane 1/1 to obtain 4.3 g of the pure compound (4S, 4aS) -4- tert -butoxy-4 a-met i 1, 2,3,4,4a, 5,6,7,8-octahydro-naphthalene (liquid). d) A solution of 6.15 g (27.6 mmoles) of (4aS, 4aS) -5-tert-butoxy-4a-methyl-1, 2, 3, 4, 4a, 5, 6, 7, -oct Ahydro-na to ene in 180 ml of tetrahydrofuran was cooled in an argon atmosphere and stirred.
they added 55.3 ml (55.3 mmol) of a molar solution of borane in tetrahydrofuran. The reaction mixture was maintained for a further hour at ° C, warmed to room temperature and kept stirring - overnight. After cooling to __ 0 ° C, 421 ml of water were added dropwise, followed by the addition of 25.3 g of NaBO-, 4 H_O. The suspension was stirred at room temperature for 4 hours, and then the reaction mixture was extracted three times with diethyl ether. The combined organic phases were washed once with brine, dried over sodium sulfate and evaporated in vacuo to obtain 12.07 g of crude product, which was chromatographed on 500 g of silica gel with hexane / ethyl acetate. 4/1 to give 3.4 g of a 2: 1 mixture of (1S, 4 aS, 5S, 8 aS) - and (IR, 4 aS, 5S, 4 aR) - 5- t er c-butoxy - 4 a-me ti 1- decahydro-na to en-1, in the form of an oily material. e) To a solution of 3.4 g (14.1 mmol) of (1RS, 4aS, 5S, 8aRS) - 5-tert-butoxy-4-a-meth i 1 -decahydro-naphthalenol in 34 ml of methylene chloride, 3.66 g (17.0 mmol) of pyridinium chlorochromate were added with stirring, and the reaction mixture was kept stirring during the
night. The reaction was then diluted with 33 ml of diethyl ether, the stirring was maintained for 15 minutes and filtered through florisil. The filtrate was evaporated in vacuo to dryness and the residue was dissolved in 33 ml of tetrahydrofuran. While stirring and under an argon atmosphere, 1.65 ml of a one molar solution of potassium t-butoxide in tetrahydrofuran was added, and the reaction was maintained overnight. The equilibration is controlled by TLC (silica gel, hexane / ethyl acetate 4/1), which shows the almost complete disappearance of one of the two epimers. The reaction mixture was evaporated in vacuo to dryness, the residue was dissolved in water and extracted three times with diethyl ether. The combined organic phases were washed with water and brine, dried over sodium sulphate and evaporated in vacuo. The residue was chromatographed on 120 g of silica gel with hexane / ethyl acetate 9/1 to obtain 2.39 g (71) of the pure compound (4 aS, 5S, 8 aR) - 5- 1 er c-butox i - 4a-methyl-octahydro-naphthalene-l-one. An analytical sample was obtained by crystallization with hexane, with a m.p. from 78-79 ° C.
f) A solution of 2.12 g (8.9 mmol / g) of (4aS, 5S, 8aR) -5-tert-butoxy-4a-methyl-octahydro-naphthalen-1-one, in 44.5 ml of tetrahydrofuran it was cooled to -78 ° C and 9.8 ml (9.8 mmol) of a one molar solution of L-selectride in tetrahydrofuran was added dropwise with stirring and argon atmosphere.The reaction mixture was kept at this temperature for one hour more, it was warmed to room temperature and kept overnight, then the temperature was lowered to -15 ° C and 0.17 ml of H_O was added dropwise, then 7.60 was added dropwise. ml of 3N NaOH and 6.36 ml of H_0_ The reaction temperature was maintained between -10 and -15 ° C. The reaction mixture was then poured into water and extracted three times with ethyl acetate. They were washed with brine, and evaporated in vacuo to dryness, The residue was chromatographed on 120 g of silica gel with hexane / ethyl acetate 4/1 to obtain 1.03 g (48 [deg.]). of the pure compound (SS, 4aS, 5S, 8aR) -5-tert-butoxy-4a-methyl-decahydro-naphthalene-ol, in the form of an amorphous product. g) A solution of 4.11 g (17.1 mmol) of (SS, 4aS, 5S, 8aR) -5-tert-butoxy-4a-methyl-decahydro-
Naphthalene-ol and 313.6 mg (2.6 mmol) of 4-dimethylaminopyridine in 26 ml of pyridine was treated with 13 ml of acetic anhydride with stirring and under an argon stream for two hours. The reaction mixture was poured onto ice and water and extracted three times with diethyl ether. The combined organic layers were washed twice with water, dried with sodium sulfate and evaporated in vacuo to obtain 1.26 g of the crude product which was chromatographed in 60 g of silica gel with hexane / ethyl acetate 9 / 1 obtaining 464 g (91%) of the ester (IS, 4 aS, 5S, 8 aR: -5-tert-butoxy-4a-methyl-decahydro-naphthalene-1-yl acetic acid, in the form of a pure amorphous product. h) A solution of 4.08 g (14.45 mmolesi) of the ester (1S, 4 aS, 5S, 8 aR) - 5-tert-butoxy-4 a-meth i 1 -decahydronaphthalene-1-yl acid acetic acid, in 7.25 ml of carbon tetrachloride is treated dropwise with stirring and argon atmosphere, with 2.56 ml (18.8 mmol) of triodide iodide 1 if 1 i, maintaining at room temperature After the addition was complete, the reaction mixture was stirred for another 30 minutes, then 1.79 ml of methanol was added and the reaction was
kept for 15 min. The reaction mixture was evaporated in vacuo to dryness to obtain 5.52 g. The residue was chromatographed on 500 g of silica gel with hexane / ethyl acetate 4/1 to obtain 2.8 g (88-) of the pure ester compound (1 S, 4 aS, 5S, 8 aR '- 5-hydroxy). -4-a-met i 1-decahydronaf talen-1-yl of acetic acid i) 3.73 g (17.3 mmoles1 pyridinium chlorochromate) were added, with stirring, to a solution of 3.25 g (14%). 35 mmoles) of the ester (SS, aS, 5S, 8aR) -5-hydroxy-4a-methyl-decahydro-na to the 1-yl of acetic acid in 32.5 ml of dichloromethane. it was stirred overnight, diluted with 70 ml of diethyl ether, stirred for 15 minutes and filtered through florisil using diethyl ether for complete elution.Vacuum evaporation gave 3.34 g of a residue, which chromatographed on 200 g of silica gel with hexane / ethyl acetate 4/1 to obtain 3.02 g (94%) of the pure ester compound (1S, 4 aS, 8 aR) -4 a-met i 1- 5-oxo-decahydro-na to a-1-acid acid ico acid tico, in the form of an oil.
j) A solution of 2.99 g (13.3 mmcles of the ester (lS, 4aS, 8aR) -4a-methyl-5-oxo-decah? dre-naphthalene-1-yl acetic acid, in 13.3 ml of ethanol, were treated with stirring and argon atmosphere with sodium ethylate prepared from 0.67 g (29.4 gram atoms) of sodium and 29.4 ml of ethanol and the reaction mixture was kept overnight. The solvent was evaporated in vacuo to dryness, the residue was dissolved in water and after cooling to 0 ° C, the pH was adjusted to 3-4 with 1N HCl After extracting three times with diethyl ether, the combined organic extract was washed with brine, dried with sodium sulfate and the solvent was evaporated in vacuo The residue was triturated with hexane, the crystals were separated by filtration and dried: 1.07 g (95) of the pure compound (4aR, 5S , 8 aS) - 5-hydroxy-8 a-met i 1 -octahidr onaf talen- 1 -one, mp: 109, 5-lll ° C. k) To a solution of 2.3 g (12.6 mmol) of (4aR, 5S, 8aS) -5-hydroxy-8a-methyl-octahydro-naphthalene - 1-one, in 63 ml of dimethylformamide, 3.74 g (24.8 mmoles) of tert-butyl chloride and 1-dimethyl-1-silyl chloride and 1.94 g were added under stirring and under an argon atmosphere. (28.5 mmoles) of imidazole. The
The reaction mixture was heated at 100 ° C for 4 hours, then an additional 3 g of tert-butyl chloride and 1-dimethanol were added, and 1.94 g of imidazole were added and the reaction mixture was stirred.
-5- kept for. the night at 100 ° C. The reaction mixture was poured into ice-water and extracted three times with diethyl ether. The combined organic extract was washed once with water and dried, dried with sodium sulfate and evaporated in vacuo. The residue was chromatographed on 250 g of silica gel with hexane / ethyl acetate 9/1 to obtain 3.17 g (85-) of the low-melting compound (4aR, 5S, 8aS) -5- butyl-dimethyl-silanyloxy) -8a-methyl-octahydro-naphthalen-1-one. 5 1) A suspension of 11.8 g (31.7 mmol) of ethyl tri-phenyl phosphonium bromide in 64 ml of tetrahydrofuran was treated with stirring and argon atmosphere, with 31.9 ml of a molar solution of tetrahydrofuran. potassium butylate and the resulting orange suspension was treated with a solution of 3.17 g (10.7 mmol) of (4 aR, 5 S, 8 a S) - 5- (t erc-but i 1-dimet 1-if lanoxy) -8a-methyl-1-octahydro-naphthalene-1 -one, in 64 ml of tetrahydrofuran and kept at room temperature for 3 hours. 11.8 g were added
additional (31.7 mmol) of ethyltriphenylphosphonium bromide and 31.9 ml of a one molar solution of potassium tert-butylate in tetrahydrofuran, and the reaction mixture was kept overnight. Isobutyric aldehyde (5.4 ml) was added, the reaction was stirred for 1 minute, diluted with diethyl ether and filtered through Florisil using diethyl ether as eluent. After evaporating in vacuo, the residue (4.79 g) was chromatographed on 120 g of silica gel with hexane to obtain 3.15 g (95%) of the pure compound (1S, 4aS, 8aR) -tert-butyl- ( 5-ethylidene-4a-methyl-decahydro-naphthalen-1-yloxy) -dimethylsilane (E / Z 4/1), in the form of an oil. m To a stirring solution of 3.11 g
, 1 mms of 1S, aS, 8aR) -tert-butyl ethylidene-4a-methyl-decahydro-naphthalene-1-yloxy) -dime ti 1 if 1 yr, in 125 ml of toluene, 0.33 g was added (11.1 mmol) of par to finely divided powdered ldehyde form. The reaction mixture was cooled to 0 ° C and 12.56 ml of a one molar solution of dimethyl chloride and 1 aluminum in hexane were added, and held for one hour at this temperature. The reaction mixture was stirred at room temperature
overnight, it was diluted with diethyl ether, washed with 1N HCl and water, then dried with sodium sulfate and evaporated in vacuo. The residue was chromatographed on a medium pressure column in 250 g of silica gel with hexane / ethyl acetate 9/1 to obtain 2.31 g (67.50 of the pure compound (S) -2- [(4aR, 5S, 8aS) -5- (tert-but? I-dimet? I-silanyloxy) -8 a-methyl-3,, 4a, 5, 6, 7, 8, 8a-octah? Drc-naphthalen-1-yl) -propan- 1 -ol, in the form of an oil. By carrying out the reaction with BFj.Et O in CHCl. Small amounts of the primer (R), the starting material of Examples 31-33, can be isolated. n) To a solution of 2.27 g (6.7 mmol) of (S) -2 - [(4aR, 5S, 8aS) -5- (tert-butyl-dimethyl-1-silanyloxy) -8a-methyl- 3, 4, 4a, 5, 6, 7, 8, 8a-octahydro-na to en-1-y1] -propan-1-ol, in 22.7 ml of ethyl acetate were added 227 mg of Pd / C 10 and 227 mg of sodium bicarbonate. The reaction mixture was stirred under hydrogen atmosphere overnight, filtered through Speedex using ethyl acetate for a complete wash, and the solvent was evaporated in vacuo. The residue was chromatographed on a Lobar 250 g column with hexane / ethyl acetate 9/1 to obtain 2.18 g (95.5) of (S) -2-
[(IR, 4aR, 5S, 8aR) -5- (tert-Butyl-dimethylsilyloxy> -8a-methyl-decahydro-naphthalen-1-yl) -propan-1-ol as an oily product. The pharmacological properties of the compounds of formula I can be determined by the following test procedures: Calcium tolerance (tolerance test in mice): This assay provides a global picture of calcemic tolerance. Deep changes in calcium homeostasis strongly affect the weight development of animals. This parameter was used as a primary test for tolerance.
Mice (25-30 g body weight) received subcutaneous daily administration of the vitamin D derivative for 4 consecutive days. Body weight was recorded just before and at the end of the day
of the treatment period. The highest tolerated dose "(HTD) in the mouse is the dose that results in a zero weight increase during the treatment period.For calcitriol, an HTD of 0.5 μg / kg was observed. for the compounds of formula I specifically named
As products of the previous examples, HTD values of 4, 5, 12 and 100 μg-g were observed for the four least tolerated compounds, up to 6800, 7000, 7500 and 8500 μg / kg for the four best tolerated compounds. From the above results, it can be deduced that the compounds of formula I are better tolerated than 1,25-dihydroxycholecalcoferol. Vitamin D analogues administered orally can lead to thickening of the epidermis in hairless mice (acanthosis). This effect on the skin is considered as indicative for the antipsoriatic potential of the analogous compounds of vitamin D. The analogues were tested for 4 days in different dosages in order to detect the compounds that showed this epidermal effect at subtoxic and non-toxic doses (dosages that lead to a slight weight loss or no weight loss). The calcitriol itself could not be dosed for 4 days high enough to obtain this effect on the skin. Hairless mice (Moro hr / hr) received daily administrations of the compound of
peanut oil test by esophageal tube for 4 days, using 2-5 different dosages (triple increments); groups of 2 animals per dosage). The mice were sacrificed on day 5 and skin biopsies were performed, fixed in formalin and treated for histological evaluation. Daily measurements of body weight allow the diagnosis of toxicity (calcium tolerance) and determine the level of the non-toxic dose defined as the dose that is tolerated without weight loss. The results of the table below show that the compounds in question, although less potent, are much superior to calcitrol due to a better relationship between the effective dose and the maximum tolerated dose (HTD) pointing towards a greater therapeutic window between the effect on the skin (ED ,,,) and the toxic calémic effects.
ED,,: dose (μg / kg) that yields half of. maximum epidermal thickening
HTD: Maximum tolerated oral dose (μgV-kg weight loss
TI variation: The variation of the "therapeutic index" is defined as the quotient between the ratio ED50 / HTD for calcitriol and the ratio ED =, / HTD for the test compound.
The compounds of formula I, as described above, can be administered orally for the treatment of hyperproliferative diseases of the skin such as psoriasis, basal cell carcinomas, keratinization disorders, and keratosis, or for treatment of neoplastic diseases such as leukemia, or for the treatment of diseases that require the modulation of the immune system, such as the rejection of transplants, graft disease against the recipient, or for the treatment of osteoporosis and hyperparathyroidism
in warm-blooded animals that need such treatment. More specifically, the compounds of formula I as described above can be administered orally to an adult human in dosages ranging from 0.5 to 1000 μg per day for the treatment of the above diseases.
The compounds of formula I as described above can be administered topically, for the treatment of hyperproliferative diseases of the skin such as psoriasis in warm-blooded animals in need of such treatment. More specifically, the compounds of formula I, as described above, can be administered topically in dosages ranging approximately between
0.5 and 1000 μg per gram of topical formulation per day, for the treatment of the above diseases. The dosage of the compounds of formula I can vary within wide limits depending on the disease to be treated, the age and the individual condition of the patient and the mode of treatment.
administration and, of course, will be appropriate to the individual requirements of each particular case. Oral dosage forms comprising the compounds of formula I of the invention may be incorporated into capsules, tablets and the like with pharmaceutically acceptable carrier materials. Examples of such support materials that can be incorporated into capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, algenic acid, and the like; a lubricant such as magnesium stearate, a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as mint essence, gualteria essence or cherry. Various other materials may be present as a coating or otherwise to modify the physical form of the dosage unit. For example, the tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound,
sucrose as a sweetening agent, methyl and propyl paraben as preservatives, a dye and a flavoring agent such as cherry or orange essence. Topical dosage forms comprising the compounds of formula I of the invention include: ointments and creams comprising formulations having oleaginous, absorbable, water-soluble and emulsion-type bases such as petrolatum, lanolin, polyethylene glycols and the like. Lotions are liquid preparations and vary from simple solutions to aqueous or hydroalcoholic preparations containing finely divided substances. The lotions may contain suspending or dispersing agents, for example, cellulose derivatives such as ethers, methylcellulose and the like; gelatin or gums, which incorporate the active ingredient in a vehicle composed of water, alcohol, glycerin and the like. Gels are semi-solid preparations made by gelling a solution or suspension of the active ingredient in a carrier vehicle. The vehicles, which can be hydrated or anhydrous, are gelled using a gelling agent, such as carboxy polymethylene, and neutralized to have a
Appropriate gel consistency with the use of alkalis, such as sodium hydroxide and amines, such as polyethylencocoamine.
As used so far, the term
"Topical" means the use of the active ingredient incorporated in a suitable pharmaceutical support, and applied to the site of the disorder for local action to take place. Accordingly, the topical composition includes those pharmaceutical forms in which the compound is applied - externally by direct contact with the skin. Topical dosage forms comprise gels, creams, lotions, ointments, powders, aerosols and other conventional forms for the application of the medication on the skin, obtained by mixing the compounds of formula I with known topical carrier pharmaceutical materials. The following pharmaceutical compositions can be prepared in a manner known per se:
Example A
Soft gelatin capsule mg / capsule Compound I 0.0001 - Butylated hydroxytoluene (BHT 0.01 Butylated hydroxyanisole (BHA) 0.016 Fractionated coconut oil Neobee M-5) or Miglyol 812 c. s 160.0
Example B Soft gelatin capsule mg / capsule Compound I 0, 0001-1 a-tocopherol 0,016
Miglyol 812 c. s 160, 0 Example C Topical cream Compound I 0.005 - 1 Cetyl alcohol 1.5 Stearic alcohol 2.5 Span 60 (sorbitan monostearate) 2.0 Arlacel 165 (glyceryl monostearate and 4.0 mixture of polyethylene glycol stearate ) Tween 60 (polysorbate 60) 1, or mineral oil 4, 0
Propylene glycol 5, 0 Propylparaben 0.05 BHA 0.05 Sorbitol solution 2.0 Disodium edetate- 0.01 Meti lparaben 0.18 Distilled water
Example D Topical ointment mg / g Compound I 0.005 - 1 Propylene glycol exc. ad ung. for 1 g
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content in the following is claimed as property:
Claims (4)
- R E I V I N D I C A C I O N S Derivatives of 24-nor-secocola-5, • -diene, of formula (I characterized in that A is a single bond or a double bond, B is a group CH.CH_, CH = CH or C = C, T is a CH group. or CH_CH ", R1 and R 'are H or OH, C (R, R) is CH, or C = CH_, R is CH. and R "1 is H, or R" is H and R is CH ,, L is phenyl, and R ° is OH or C (alkyl of 1 to 4 carbon atoms); 0H, or LR "is 2-furyl which is substituted in the 5-position with C (alkyl of 1 to 4 carbon atoms); 0H, with the proviso that when L is phenyl, A is a single bond, B is C = C, T is CH ,, each R "and R are OH, C (R, R) is C = CH_, R - is CH ?, R is H, and R is C (CH,): OH, then R ~ must be in the ortho or pair a position.
- 2. Compounds as in claim 1, characterized in that R1 is H or OH, and R "is OH.
- 3. Compounds as in claim 1 or 2, characterized in that L is phenyl, B is CH CH or C = C, R: and R 'are OH and R! is C (CH,) _ OH.
- 4. Compounds as in claim 3, characterized in that A is a single bond, B is C-C, and T is CH,. The compound as in the claim 4, namely: (7E) - (1 R, 3R, 20R) -23- [2- (1-hydroxy? -I-meth? L-ethyl) -phenyl] -19,24-dinor-9,10-seco-cola-5 , 7-dien-22-in-1,3-diol Compounds as in claim viz. (7E) - (lR, 3R) -23- [2- (l-hydroxy-l-methyl-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5, -dien-1, 3-diol, (7E) - (lR, 3R) -23- [2- (1-hydroxy-1 -met i 1 -et? L) -phenyl] -19,24-dinor-9,10-seco-cola-5,7-d? En-22-in-1,3-diol, (7E) - (lR, 3R ) -23- [3- (l-hydroxy-l-methyl-ethyl) -phenyl] -19, 24-dinor-9, 10-seco-cola-5,7-dien-1,3-diol, (5Z) , 7E) - (lS, 3R, 20R) -23- [3- (l-hydroxy-l-methyl-ethyl) -phenyl] -24- not r-9, 10-seco-cola-5, 7, 10 (19) -trien-22-in-l, 3-diol, (5Z, 7E) - (lS, 3R, 20R) -23- [2- (l-hydroxy-l-methyl-ethyl) -phenyl] - 24-nor-9, 10-seco-cola-5, 7, 10 (19) -trien-22-in-l, 3-diol, (7E) - (lR, 3R, 20S) -23- [3- (1-Hydroxy-1-methyl-1-ethyl) -phenyl] -19,24-dinor-9, 10-seco-cola-5,7-dien-1,3-diol, (7E) - (1R, 3R) -23- [2- (1-Hydroxy-1-meth i 1 -ethyl) -phenyl] -D-homo-19, 24-dinor-9, 10-seco-cola- 5, 7, 17-trien-22-in-l, 3-diol, (5Z, 7E) - (lS, 3R, 21R) -23- [2- (lh? Drox? -l-methyl-ethyl) - phenyl] -D-homo-24-nor-9, 10-seco-cola-5,7,10 (19) -trien-22-in-l, 3-diol. 7. Compounds as in claim 1 or 2, characterized in that L is 2-furyl, A is a single bond, B is C = C, T is CH ,, R- is CH, and R is H. 8. The compounds as in claim 7, namely: (7E) - (lR, 3R) -23- [5- (l-hydroxy-l-methyl-ethyl) -furan-2-yl] -19,24-dinor -9,10-seco-cola-5,7-dien-22-in-l, 3-diol. The compounds of the formulas II IV, IV characterized because A, B, T, R, R R '! and L, are as defined in claim 1, R 'and R' are H ú OS i (CH O, -terc-but i lo, and R'1 is OSi (CH,) - ,, OSi (CHj ) ^ -tere-butyl or C (C _ -alkyl), OSi (CHO •. 10. Pharmaceutical compositions for the treatment or prevention of disorders that depend on vitamin D, particularly psoriasis, basal cell carcinomas, keratinization and keratosis disorders, leukemia, osteoporosis, hyperparathyroidism accompanying the kidney failure, rejection of a transplant graft disease versus the recipient. 11. Process for the preparation of compounds of formula I as in claim 1, characterized in that it comprises the cleavage of the i) protecting silyl group (s) contained in a compound of formula wherein A, B, T, R, RR ^ and L, are as defined in claim 1, R: and R 'are H or OS i (CH 0 -.- 1 erc-but i lo, and Rr is OSi (CHO-, OSi (CH3), -tert-butyl or C (alkyl of 1 to 4 carbon atoms) 2OSi (CH3),. 12. The compounds of any one of claims 1 to 8 for use in the treatment or prevention of disorders which are dependent on vitamin D, in particular, on psoriasis, basal cell carcinomas, disorders of keratinization and keratosis. , leukemia, teoporosis, hyperparathyroidism that accompanies renal failure, rejection of a transplant and graft disease against the recipient. 13. The use of the compounds of any one of claims 1 to 8 for the production of pharmaceutical compositions for the treatment or prevention of disorders dependent on vitamin D, particularly psoriasis, basal cell carcinomas, disorders of keratinization and keratosis, leukemia, teoporosis, hyperparathyroidism that accompanies renal failure, rejection of a transplant and graft disease against the recipient. 14. New compounds, intermediates, formulations and uses substantially as described. SUMMARY OF THE INVENTION The invention relates to novel secocoladienes, in particular the derivatives of 24-nor-seco-cola-5, 7-diene, of formula (I), wherein A is a single bond or a double bond, B is a CH group , .CH_, CH = CH or C = C, T is a group CH or CH.CH ,, R: and R3 are H or OH, C (R, R) is CH. or C = CH, R is CHj and R "is H, or R ~ is H and R4 is CH .., L is phenyl, and R5 is OH or C (alkyl of 1 to 4 carbon atoms): OH, or LR "is 2-furyl which is substituted in the 5-position with C (C 1 -C 4 -alkyl), OH, with the proviso that when L is phenyl, A is a single bond, B is C = C, T is CH, each R and R 'are OH, C (R, R) is C = CH_, R is CH., R' is H, and R is C (CHO.OH, then R "'must be in the ortho or para position, are useful in the treatment or prevention of disorders that depend on vitamin D, particularly psoriasis, basal cell carcinomas, keratinization and keratosis disorders, leukemia, osoporosis, hyperparathyroidism accompanying to insufficiency kidney, and rejection of a transplant and graft disease against the recipient.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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EP97106547.9 | 1997-04-21 |
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MXPA99009555A true MXPA99009555A (en) | 2000-07-01 |
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