24-HOMO-26,27-HEXAFLUORO-CHOLECALCIFEROLS

Abstract: The invention relates to a compound of formula (I) wherein A is a carbon double bond having the stereochemical configuration E or Z, i.e. of formula (a) or (b), respectively, R is hydroxy and R<1> is hydrogen or =CH2 or R is hydrogen or fluoro and R<1> is =CH2. Compounds of formula (I) induce differentiation and inhibition of proliferation in certain skin and cancer cell lines. Accordingly, the compounds of formula (I) are useful as agents for the treatment of hyperproliferative skin diseases such as psoriasis. Compounds of formula (I) are also useful as agents for the treatment of neoplastic diseases, such as leukemia.

Description: 24-Homo-26.27-hexafluoro-cholecalciferols The invention relates to a compound of the formula wherein A is a carbon double bond having the stereochemical configuration E or Z, i.e. of the formula: respecti vel y , R is hydroxy and R is hydrogen or =CH2 or R is hydrogen or fluoro and R * is =CH2- Compounds of formula I induce differentiation and inhibition of proliferation in certain skin and cancer cell lines. Accordingly, the compounds of formula I are useful as agents for the treatment of hyperproliferative skin diseases such as, psoriasis. Compounds of formula I are also useful as agents for the treatment of neoplastic diseases, such as leukemia. As used herein, the term "lower alkyl" denotes a straight or branched-chain alkyl group containing 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. The term "ar-lower alkyl" are p-tolyl, benzyl, phenylethyl, phenylpropyl, and the like. The term "aryl" denotes a group derived from an aromatic hydrocarbon which may be unsubstituted or substituted by one or more lower alkyl groups. Exemplary of "aryl" are phenyl and p-methyl phenyl. The term "halogen" denotes the halogens, that is, bromine, chlorine, fluorine, or iodine. The invention relates to a composition comprising a compound of formula I, or a mixture of two or more compounds of formula I. The invention also relates to a method for treating the above¬ mentioned disease states by administration of a compound of formula I, or a mixture of two or more compounds of formula I. The invention also relates to a process for preparing compounds of formula I and intermediates of formulas X, XI, XII and V. In a preferred embodiment of the compounds of formula I, R is hydroxy and Rl is =CH2 - In another compound of formula I, Rl is hydrogen. Most preferred compounds of formula I are: l ,25-dihydroxy-22E,24Z-diene-24-homo-26,27-hexafluoro- cholecalciferol; l ,25-dihydroxy-22E,24E-diene-24-homo-26,27-hexafluoro- cholecalciferol; l ,25-dihydroxy-22E,24Z-diene-24-homo- 19-nor-26,27- hexafluorocholecalciferol; l ,25-dihydroxy-22E,24E-diene-24-homo- 19-nor-26,27- hexafluorocholecalciferol; l α-fluoro-25-hydroxy-22E,24Z-diene-24-homo-26,27 - hexafluorocholecalciferol; and l α-fluoro-25-hydroxy-22E,24E-diene-24-homo-26,27- hexafluorocholecalciferol. The compounds of formula I are prepared as hereafter described, with particular reference to Formula Schemes I-III and the Examples below, by removing the protecting groups of formula -Si(R ,R 5 ,R 6 ) from correspondingly protected compounds.. 4 - FORMULA SCHEME I Ia Ib Ic wherein Rl and A are as described above and R4 and R6 are independently lower alkyl and R-5 is independently lower alkyl, aryl, or ar-lower alkyl. In the above Formula Scheme I, the compound of formula II is converted to a compound of formula IVa, IVb, or IVc by reaction with the corresponding compound of formula where Ph is phenyl; and Rl , R^, R5 and R'S are as described above; R^ is hydrogen, fluorine or O— Si— R 5 I R 6 wherein R^, R-5 and R^ are as described above. The reaction is carried out at -60°C to - 90°C, preferably -78°C, in a polar, aprotic, organic solvent, such as dry ether or more preferably dry tetrahydrofuran, in the presence of a strong base such as an alkyl lithium like butyl lithium. Compounds of formula III are known or can be prepared in accordance with known methods. The protecting groups of a compound of formula IVa, IVb or IVc are removed by reaction with a fluorine salt, such as tetrabutyl- ammonium fluoride in a polar, organic solvent such as ether, or more preferably tetrahydrofuran to yield a corresponding compound of formula Ia, Ib or Ic. The intermediates of formula II as described above are prepared as hereinafter described with particular reference to Formula Scheme II below. FORMULA SCHEME II π VU wherein R^, R-5 and R*5 are as described above. In the above Formula Scheme II, when the compounds of formula I, wherein A is are prepared, the compound of formula V is reduced to a corresponding compound of formula VI by reaction with hydrogen and Lindlar catalyst in an organic solvent, such as, a combination of ethyl acetate, hexane and ethanol. In the above Formula Scheme II, when the compound of formula I, wherein A is are prepared, the compound of formula V is partially hydrogenated to obtain the corresponding compound of formula VI by reaction with a reducing agent such as lithium aluminum hydride, preferably in the presence of an alkali metal alkoxide, like sodium methoxide, in an aprotic organic solvent like dry ether, or more preferably dry tetrahydrofuran, at reflux temperature (about 80°C for tetrahydrofuran) for about 2.5 hours, cooled to about 0°C, and worked up by conventional means. The resulting compound of formula VI is oxidized to the compound of formula VII by treatment with an oxidizing agent such as 2,2'-bipyridinium chlorochromate, or pyridinium dichromate, at room temperature, in an aprotic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride. The compound of formula VII is converted to a compound of formula II, by reaction with, for example, a (trialkylsilyl)imidazole such as (trimethylsilyl)imidazole in an aprotic, organic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride. The compound of formula II is worked up by conventional means such as extraction followed by chromatography. The compound of formula V is prepared as hereafter described with particular reference to formula Scheme III below. FORMULA SCHF.MK TTT vm DC XI XII In the above Formula Scheme III, the compound of formula VIII, a known compound (Wovkulich, P.M. et al., Proceedings of the 6th Workshop of Vitamin D, 1985, p. 755-764), is converted to a compound of formula IX by treatment with an oxidizing agent, such as, 2,2'-bipyridinium chlorochromate, or pyridinium chlorochromate, in an aprotic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride under an argon atmosphere. The compound of formula IX is converted to a compound of formula X by reaction with Wittig reagent, such as, (3-trimethyl-silyl- 2-propynyl)-triphenyl-phosphonium bromide, in an aprotic solvent, such as dry tetrahydrofuran or dry methylene chloride, and a base such as butylithium. The reaction is carried out at -78°C . The compound of formula X is converted to a compound of formula XI by reaction with silver nitrate in a alcohol solvent, such as ethanol . The compound of formula XI is converted to the compound of formula XII by reaction with a fluorinated acetone, such as hexafluoroacetone. The reaction is carried out at -78° C. The compound of formula XII is converted to the compound of formula V by reaction with a disilylating reagent, such as hydrofluoric acid, in an organic solvent, such as a combination of acetonitrile and te trah ydrofuran . The compounds of formula I as described above can be administered orally, for the treatment of neoplastic diseases such as leukemia, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be administered orally to an adult human in dosages that are in the range of about .05 to 50 μg per day for the treatment of neoplastic diseases such as leukemia. The compounds of formula I as described above can be administered orally, for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratination, and keratosis, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be administered orally to an adult human in dosages that are in the range of about 0.5 to 50 μg per day for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis. These compounds can be administered orally for the treatment of acne in humans at a dosage of about .05 to 50 μg per day; preferably 0.5 to 50 μg per day. The compounds of formula I as described above can be administered topically, for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be administered topically in dosages that are in the range of about 0.5 to about 50 μg per gram of topical formulation per day, for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis. The useful activity of compounds of formula I as agents for the treatment of neoplastic diseases can be demonstrated by the following test procedures. HL-60 Cell Differentiation The induction of differentiation of HL-60 cells was assayed by measuring their oxidative burst potential via the reduction of nitrobluetetrazolium (NBT). HL-60 cells were maintained in RPMI 1640 medium supplemented with 10% fetal calf serum (FCS), 2mM L-glutamine, ImM sodium pyruvate, 1 % non-essential amino acids, 50 U/ml penicillin, and 50 μg/ml streptomycin. HL-60 cells (30,000 cells in 90 μl of supplemented RPMI medium) were seeded into flat-bottomed microliter wells. Immediately after seeding, 10 μl of test compounds listed below in Table I diluted in supplemented RPMI medium were added to the wells to yield final concentrations of between 10" ! and 10 ~ 6 M (starting from stock solutions of 10 * 3 M in ethanol, stored at -20°C and protected from light). After 3 days, medium was removed from the wells with a multichannel pipette and replaced with 100 μl of NBT solution ( 1 mg/ml in phosphate buffered saline with 200 nM phorbol myristate acetate). Following an additional hour incubation at 37°C the NBT solution was removed and 100 μl of 10% sodium dodecyl sulfate in 0.01 N HC l was added. The amount of the reduced NBT was quantified photometrically at 540 nm using an automated plate reader. The mean of 3 wells was calculated. S.E.M. were between 5 and 10%. Values were expressed as percent of maximal differentiation achieved with 100-1000 nM calcitriol in the same experiment. The concentration (nM) leading to 50% of this maximal value is determined graphically and given in Table I as ED50. TABLE I COMPOUND ED50 (nM) 1 ,25-Dihydroxy-cholecalciferol 6.0 l ,25-Dihydroxy-22E,24Z-diene-24- 1 .6 homo-26,27-hexafluoro-cholecalciferol l ,25-Dihydroxy-22E,24E-diene-24- 0.9 homo-26,27-hexafluoro-cholecalciferol From the above results, it can be seen that compounds of formula I induce differentiation of HL-60 cells and thereby stop these tumor cells from growing. Accordingly, compounds of formula I are useful in the treatment of neoplastic diseases such as leukemia. The useful activity of compounds of formula I as agents for the treatment of hyperproliferative skin disease can be demonstrated by the following. Inhibition of Keratinocytes Proliferation HaCaT cell line - The immortalized human cell line HaCaT was used (originally obtained from N.E. Fusenig, German Cancer Research Center, Heidelberg, Germany). ^H-thymidine incorporation was measured in exponentially growing cultures after 6 days of culture in presence of the test compound. Cell culture - HaCaT cells were cultured in a mixture of Dulbecco's Modified Eagle Medium containing 4.5 g glucose and Nutrient Mixture Ham's F12, 3: 1 (v/v). This mixture was supplemented with 10% FCS, 2mM L-glutamine, 50 Ul/ml, penicillin, 50 μg/ml streptomycin, 10 ng/ml EGF, 400 ng/ml hydrocortisone, 8.5 ng/ml cholera toxin, and 5 ng/ml insulin. The cells were maintained in a humidified atmosphere containing 5% CO2 and 95% air and passaged every 3-4 days. Inhibition of ^H-thymidine uptake - HaCaT cells (250 cells in 180 μl of the supplemented mixture) were seeded into 96-well culture dishes and incubated at 37°C with 5% CO2 and 95% air. Immediately after seeding, 20 μl of test compounds listed below in Table II, diluted in the supplemented mixture containing 1 % ethanol, were added to the wells to yield final concentrations of between 10" and 10" 6 M (starting from 1 mM stock solutions in ethanol, stored at -20°C and protected from light). After 6 days, ^ H-thymidine (5 Ci/mmol) was added to the wells at a concentration of 1 μCi/well . Cells were pulse-labeled for the last 6 hours of the growth period. Cells were then trypsinized for 10 minutes at 37°C under a vigorous agitation and harvested on to a 96-well filter plate using a cell harvester. After drying at 40°C under vacuum for 20-30 minutes, 20 μl of scintillator was added and the radioactivity bound to the filters was counted. Values are expressed as percent of controls (samples without test compound). The concentration leading to 50% of control values is determined graphically and given as IC50 (inhibitory concentration) in Table II. TABLE II COMPOUND IC50 (nM) 1 ,25-Dihydroxy-cholecalciferol 55.0 l ,25-Dihydroxy-22E,24Z-diene-24-homo- 2. 1 26,27-hexafluoro-cholecalciferol l ,25-Dihydroxy-22E,24E-24-homo-diene- 5. 1 26,27-hexafluoro-cholecalciferol From the above results, it can be seen that compounds of formula I inhibit proliferation of keratinocytes. Accordingly, compounds of formula I are useful in the treatment of hyperproliferative skin diseases, such as psoriasis. Calcium tolerance test in mice Profound changes in calcium homeostasis strongly affect the weight development of mice. Mice (25-30 g body weight) received daily subcutaneous administrations of the compound for 4 consecutive days. Body weight was registered just before and at the end of a 5 day treatment period. The "highest tolerated dose" (HTD) is the dose which results in zero weight gain during this treatment period. The results are set forth in Table III. TABLE III COMPOUND HTD (μg/kg) 1 ,25-Dihydroxycholecalciferol 0.5 l ,25-Dihydroxy-22E,24Z-24-homo-26,27- 0.4 hexafluoro-cholecalciferol l ,25-Dihydroxy-22E,24Z-24-homo-23E- 0.8 diene-26,27-hexafluoro-cholecalciferol From the above results, it can be seen that the compounds of formula I exhibit approximately the same HTD as 1 ,25- dihydroxycholecalciferol. The following Examples are provided to further describe the invention and are not intended to limit it in any way. Oral dosage forms comprising compounds of formula I of the invention may be incorporated in capsules, tablets and the like with pharmaceutically acceptable carrier materials. Illustrative of the pharmaceutically acceptable carrier materials which may 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 peppermint, oil of wintergreen or cherry. Various other materials may be present as coating or to otherwise modify the physical form of the dosage unit. For instance, 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 parabens as preservatives, a dye, and a flavoring such as cherry or orange flavor. Topical dosage forms comprising compounds of formula I of the invention include: ointments and creams encompassing formulations having oleaginous, adsorbable, 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. Lotions can contain suspending or dispersing agents, for example, cellulose derivatives such as ethyl cellulose, methyl cellulose, and the like; gelatin or gums, which incorporate the active ingredient in a vehicle made up 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 hydrous or anhydrous, are gelled using a gelling agent, such as, carboxy polymethylene, and neutralized to a proper gel consistency with the use of alkalies, such as, sodium hydroxide and amines, such as, polyethylenecocoamine. As used herein, the term "topical" denotes the use of the active ingredient, incorporated in a suitable pharmaceutical carrier, and applied at the site of the inflammation for the exertion of local action. Accordingly, the topical composition include those pharmaceutical forms in which the compound is applied externally by direct contact with the skin. The topical dosage forms comprise gels, creams, lotions, ointments, powders, aerosols and other conventional forms for applying medication to the skin obtained by admixing the compounds of formula I with known pharmaceutical topical carrier materials. In addition to application to the skin, the topical compositions of this invention can also be employed in the treatment of inflammations of mucous membranes, where such membranes are accessible to topical application of medication. For example, the topical composition can be applied to the mucous lining of the mouth or lower colon. EXAMPLE I [ l R-[ l α(S *),3aβ,4α,7aα]]-4-[[ l , l -Dimethylethyl) dimethylsilyl]- oxy]octahydro-β,7α-dime thy 1- l H-indene- l -acetaldehyde To a stirred suspension of 5.37g (25 mmole) of pyridinium chlorochromate in 50 ml of anhydrous methylene chloride under argon atmosphere was added dropwise 3.26 g ( 10 mmole) of [1R- [ l α(S *),3aβ,4α,7aα]]-4-[[ l , l -dimethylethyl)dimethylsilyl]- oxy]octahydro- β,7a-dimethyl- lH-indene- l -ethanol in 15 ml anhydrous methylene chloride. The reaction mixture was stirred for one hour, then diluted with 120 ml of ether, and purified on a 100 g Florosil column to give 3.04 g (94%) of the title compound. 1 H-NMR (CDCl3):δ0.02 (s,6H, 2CH3), 0.88 (s, 9H, 3CH3), 1.09 (d, 3H, J = 7 Hz, CH3), 4.02 (brm, IH, CH) 9.58 (d, IH, J= 3 Hz, CH). EXAMPLE 2 [ l R-[ l α( l R*,2E),3aβ,4α,7aα]]-( l , l -Dimethylethyl) dimethyl- [ [octahydro-7a-me thy 1- 1 - [ 1 -methy l-5-(trime thy lsilyl)-2-penten-4- ynyl]- l H-inden-4-yl]oxy]silane To a stirred suspension of 1 g (2.2 mmole) of (3-trimethylsilyl- 2-propynyl)-triphenyl-phosphonium bromide in 20 ml anhydrous tetrahydrofuran at -78°C was added 1.4 ml (2.2 mmole) of 1.6M n- butyllithium in hexane. After addition was complete, the reaction mixture was warmed up to 40°C, stirred for 0.5 hour when it turned to a red solution. It was then cooled to -78°C and 478 mg ( 1.47 mmole) of [ lR-[l αS*), 3aβ, 4α,7aα]]-4-[[( l , l -dimethylethyl)dimethyl- silyl]oxy]octahydro-β,7a-dimethyl- lH-indene- l -acetaldehyde in 6 ml anhydrous tetrahydrofuran was added, then stirred at room temperature for one hour, and quenched by addition of water. It was thoroughly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate, and evaporated to dryness. The residue was triturated with hexane and the soluble part was purified by FLASH chromatography with hexane. It gave 396 mg (64%) of the title compound. Analytical sample was purified by preparative HPLC with hexane, and was crystallized from ethanol, m.p. 81-83°C; [ ] 2 ^D + 80.5° (c 0.2) CHCI3); UVλ (hexane): shoulder 227nm (ε 17,000, max 236-237 nm (ε21 ,800), shoulder 295 nm (εl6,600); H-NMR (CDCI3): δθ.01 (s, 6H, 2CH3), 0.19 (s,9H, 3CH3), 0.89 (s, 9H, 3CH3), 0.93 (s, 3H, CH3), 1.02 (d, 3H, J = 6.7 Hz, CH3), 1.80 (m, IH, CH of CH2), 1.91 (dm, IH, Jgem = 12.5 Hz, CH or CH2), 2.1 1 (m, IH, CH), 3.99 (m, IH, CH), 5.42 (d, IH, Jtrans = 15.9 Hz, CH), 6.06 (dd, IH, Jvic = 8.8 Hz, Jtrans = 15.9 CH). The structure of this compound was confirmed by an X-ray analysis; Analysis: Calcd for C25H46OSi2'. C 71.70, H 1 1.07; Found: C 71..23; H 1 1.04. EXAMPLE 3 [lR-[lα(lR*,2E), 3aβ,4α,7aα]]-(l,l-Dimethylethyl) dimethyl- [[octahydro-7a-methyl-l-[l-methyl-2-penten-4-ynyl)-lH-inden-4- yl]oxy]silane To a stirred suspension of 1.5 g (3.58 mmole) of [1R- [lα(lR*,2E),3aβ,4α,7aα]]-(l,l-dimethylethyl)dimethyl-[[octahydro-7a- me thy 1-1 -[1 -me thy 1-5 -trimethylsilyl )- 2 -penten-4-y nyl)- lH-inden-4- yl]oxy]silane in 9 ml anhydrous tetrahydrofuran and 60 ml ethanol at room temperature was added dropwise a solution of 3.65 g (21.4 mmole) silver nitrate in 72 ml of 3:1 ethanol-water., A yellowish- white precipitate developed, and such a formed mixture was stirred for one hour. This was followed by addition of 4.19 g (64.4 mmole) potassium cyanide in 60 ml water, when the precipitate dissolved. After 0.5 hour t.l.c. indicated that the reaction was complete. The mixture was diluted with 500ml of water and brine (1:1), and extracted thoroughly with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane, followed by preparative HPLC with hexane using a YMC column (50 mm x 50 cm). It have 1.26 g (100%) of the title compound. 1 H-NMR (CDCI3) 50.00 (s, 6H, 2CH3), 0.89 (s, 9H, 3CH3), 0.94 (s, 3H, CH3), 1.02 (d, 3H, J = 7Hz, CH3), 2.13 (m, IH, CH), 2.75 (d, IH, J = 2.5 Hz, CH), 3.99 (brs, IH, CH), 5.25 (dd, IH, Jvic = 2.5 Hz, Jtrans = 16 Hz, CH), 6.09 (dd, IH, Jvic = 8 Hz, Jtrans = 16 Hz, CH). EXAMPLE 4 [lR-[lα(lR*,2E),3aβ,4α,7aα]]-7-[4-[[(l,l-Dimethylethyl)-dimethyl- silyl] oxy] octahydro-7a-methyl-lH-inden- l-yl] -1,1,1 -trif luoro- 2(trifluoromethyl)-5-octen-3-yn-2-ol To a stirred solution of 0.91 g (2.63 mmole) of [1R- [lα(lR*,2E),3aβ,4α,7aα]]-(l,l-dimethylethyl)dimethyl[[octahydro-7a- me thy 1-1-(1 -me thy l-2-penten-4-ynyl)-lH-inden-4-yl] oxy] silane in 15 ml anhydrous tetrahydrofuran at -78°C was added 1.65 ml 1.6M n- butyllithium in hexane, and the mixture was stirred for 0.5 hour. At this point in time gaseous hexafluoroacetone was introduced by a dispersion tube for 2 minutes, and the reaction mixture was stirred for additional 1.5 hours, when t.l.c. indicated that the reaction was complete. The reaction mixture was then diluted with 400 ml water and extracted thoroughly with hexane. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 19: 1 to give 1.27 (95%) of the title compound. H-NMR (CDCI3) δO.OO (s, 6H, 2CH3), 0.88 (s, 9H, 3CH3), 1.03 (d, 3H, CH3), 2.18 (m, IH, CH), 4.00 (brs, IH, CH), 5.42 (d, IH, Jtrans = 16 Hz, CH), 6.26 (dd, IH, Jvic = 9 Hz, Jtrans = 16 Hz, CH). EXAMPLE 5 [ l R-[ l α( l R*,2E),3aβ,4α,7aα]]-Octahydro-7a-methyl- l -[7,7,7-trifluoro- 6-hydroxy- l -methy l-6-( trif luoro-methyl)-2-hepten-4-y nyl] - 1 H- inden-4-ol] To a stirred solution of 1.648 g (3.21 mmole) of JT R- [ l α( l R*,2E),3aβ,4α,7aα]]-7-[4-[[( l , l -dimethylethyl)-dimethylsilyl]- oxy ] octahydro-7 a-me thy 1- 1 H-inden- l -yl] - 1 , 1 , 1 -trifluoro-2- (trifluoromethyl)-5-octen-3-yn-2-ol in 30 ml acetonitrile and 24 ml anhydrous tetrahydrofuran was added at room temperature 30 ml 49% hydrofluoric acid, and thus obtained reaction mixture was stirred for 3 hours. It was then diluted with 400ml water and extracted thoroughly with ethyl acetate. The combined extracts were washed with 2N potassium bicarbonate and water, and finally with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 2: 1 the title compound, which was crystallized from ether- petroleum ether (2:25) to give 1.087 g (85%), m.p. 108-109°C; [α] 25 D + 47° (c 0.2, CHCI3); UVλ (EtOH): max 224 nm (ε20,060), shoulder 230- 231 nm (εl 8,600); IH-NMR (CDC13): δθ.96 (s, 3H, CH3), 1.05 (d, 3H, J = 6.41 Hz, CH3), 1.96 (brd, IH, Jgem = 13 Hz, CH of CH2), 2.19 (m, IH, CH), 4.10 (brs, IH, CH), 5.44 (d, IH, Jtrans = 16Hz, CH), 6.25 (dd, IH, Jvic = 8.9 Hz J trans = 16Hz, CH). Analysis: Calcd. for C19H24F6O2: C57.28, H 6.07; Found: C 57.29, H 6.19. EXAMPLE 6 [ l R-[ l α( l R*,2E,4E),3aβ,4α,7aα]]-Octahydro-7a-methyl- l -[7,7,7- trif luoro-6-hydroxy- l -methy l-6-( trif luoro-methyl)-2 ,4-heptadienyl ] - l H-inden-4-ol] To a 100 ml three necked flask fitted with a dropping funnel, condenser and argon inlet tube was added 143 mg (3.75 mmole) of lithium aluminum hydride suspended in 1.5 ml anhydrous tetrahydrofuran. The flask was cooled in an ice-bath and with stirring was added carefully first 203 mg (3.75 mmole) of solid sodium methoxide, and then dropwise the solution of 300mg (0.753 mmole) of [ l R-[ l α( l R*,2E),3aβ,4α,7aα]]-Octahydro-7α-methyl- l - [7,7,7-trifluoro- 6- hydroxy- 1 - me thy 1-6- (trif luoromethyl )-2-hepten-4-y nyl] - 1 H- inden-4-ol in 6 ml anhydrous tetrahydrofuran. After addition was completed, the ice-bath was removed, and the reaction mixture was heated under reflux at 80°C for 2.5 hours. It was then cooled in ice- bath, quenched with 1 ml water and 1 ml 2N sodium hydroxide; 20 ml of ether was added, stirred for 0.5 hr., 2.2 g of MgSO4 was added, stirred for 0.5 hr, filtered, filter was washed with ether, and the filtrates were evaporated to dryness. The crude product was purified by preparative HPLC with hexane-ethyl acetate 4: 1 , to give, after recrystallization from methylene chloride-hexane mixture, 251 mg (83.2%) of crystalline title compound, m.p. 146- 148°C. UV λmax (EtOH): 228-229 nm (ε 32,100); 1 H-NMR (CDCI3): δθ.907 (s, 3H, CH3), 1.05 (d, 3H, J = 6.5 Hz, CH3), 1.69 (m, IH, CH), 1.98 (brd, IH, Jgem = 13 Hz, CH of CH2), 2.17 (m, IH, CH), 4.09 (brs, IH, CH), 5.59 (d, IH, Jtrans = 15.4 Hz, CH), 5.79 (dd, IH, Jvic = 8.6 Hz, Jtrans = 15.3 Hz, CH), 6.05 (dd, IH, Jvic = 10.5 Hz, Jtrans = 15.3 Hz, CH) , 6.68 (dd, IH, Jvic = 10.6 Hz, Jtrans = 15.3 Hz, CH). Analysis: Calcd. for C19H26F6O2: C 56.99, H 6.55; Found C 56.64, H 6.41. EXAMPLE 7 [ l R-[ l α( l R*,2E,4E),3aβ,7aα]]-Octahydro-7a-methyl- l -[7,7,7-trinuoro- 6-hydroxy- l -methy l-6-( trif luoro-methyl)-2,4-heptadienyl] -4H- inden-4-one To a stirred solution of 300 mg (0.75 mmole) of [1R- [ l α( l R*,2E,4E),3aβ,4α,7aα]]-octahydro-7α-methyl- l - [7,7,7-trifluoro-6- hydroxy- 1 -methy l-6-( trif luorome thy l)-2,4-heptadieny l] -4H-inden-4- ol in 15 ml anhydrous methylene chloride was added 1.465 g (3.9 mmole) pyridinium dichromate, and stirred at room temperature for 3.5 hours. After addition of 25 ml ether and stirring for 15 minutes, the mixture was filtered through a celite pad, which was washed with 3 x 25 ml ethyl acetate. The combined filtrates were washed with 2N potassium bicarbonate, water and brine, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 3: 1 to give 267 mg (89.5%) of the title compound. 1 H-NMR (CDCI3): δθ.66 (s, 3H, CH3), 1.08 (d, 3H, J = 6.5 Hz, CH3), 2.46 (dd, IH, J = 8 and 1 1 Hz, CH) 5.58 (d, IH, Jtrans = 15 Hz, CH), 5.77 (dd, IH, Jvic = 8.5 Hz, Jtrans = 15 Hz, CH), 6.04 (dd, IH, Jvic = 10.5 Hz, Jtrans = 15 Hz, CH), 6.68 (dd, IH, Jvic = 10.5 Hz, Jtrans = 15 Hz, CH). EXAMPLE 8 [ l R-[ l α( l R*,2E,4E),3aβ,7aα]]-Octahydro-7a-methyl- l -[7,7,7-trifluoro- l -methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy] -2,4- heptadienyl]-4H-inden-4-one To a stirred solution of 267 mg (0.67 mmole) of [1R- [ l α( l R* ,2E,4E),3aβ,7aα]]-octahydro-7α-methyl- l -[7,7,7-trifluoro-6- hydroxy- 1 -methy l-6-( trif luoromethyl)-2,4-heptadienyl]-4H-inden-4- one in 10 ml anhydrous methylene chloride was added 0.885ml (6.03 mmole) of l -(trimethyl-silyl)imidazole and stirred at room temperature overnight. The reaction was then quenched by addition of water, and was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 5: 1 to give 307 mg (97.3%) of the title compound. 1 H-NMR (CDCI3): δθ.20 (s, 9H, 3CH3), 0.66 (s, 3H, CH3), 1.10 (d, 3H, J = 6.5 Hz, CH3), 2.45 (dd, IH, J = 8 and 11 Hz, CH of CH2), 5.55 (dd, IH, Jtrans = 15 Hz, CH), 5.73 (dd, IH, Jvic = 8.5 Hz, Jtrans = 15 Hz, CH), 6.01 (dd, IH, Jvic = 10 Hz, Jtrans = 15 Hz, CH), 6.51 (dd, IH, Jvic = 10 Hz, Jtrans = 15 Hz, CH). EXAMPLE 9 l ,25-Dihydroxy-22E,24E-diene-26,27-hexafluoro-24-homo- cholecalciferol To a stirred solution of 0.608 g (1.04 mmole) of [3S-( lZ,3α,5β)]- [2- [3 ,5-bis [[( l , l -dimethylethyl)dimethylsilyl]oxy]-2-methylene- cyclohexylidene]ethyl]diphenylphosphine oxide in 10 ml anhydrous tetrahydrofuran at -78°C was added 0.652 ml (1.04 mmole) of 1.6M n-butyllithium in hexane. The solution turned red and the color persisted during the entire addition of 307 mg (0.652 mmole) of [ 1R- [ l α( l R* ,2E,4E),3aβ,7aα]]-octahydro-7a-methyl- l -[7,7,7-trifluoro- l - methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy]-2,4-heptadienyl]- 4H-inden-4-one in 8 ml anhydrous tetrahydrofuran. The reaction mixture was stirred at -78°C for 0.5 hr and then quenched with water. It was extracted with 4 x 50 ml ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 10: 1 to give 337 mg of trisilylated intermediate. To the solution of 337 mg of trisilylated intermediate in 8 ml anhydrous tetrahydrofuran stirred at room temperature under argon was added in portions 3 ml (3 mmole) of IM tetrabutyl ammonium fluoride in tetrahydrofuran. The reaction mixture was stirred overnight, then diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 1 :3, and preparative HPLC with hexane-ethyl acetate 1 :4 to give 235 mg (67.4%) of the title compound as white foam, [ ^D + 64.5° (cθ.2, EtOH); UV λmax (EtOH): 229 nm (ε 40,500), 262-263 nm (ε 17,600); H-NMR (CDC13): δθ.57 (s, 3H,CH3), 1.08 (d, 3H, J= 6.5 Hz, CH3) 2.18 (m, IH, CH), 2.32, 2.60 (AB of ABX, 2H, Jvic = 6.5 and 3 Hz, Jgem = 13 Hz, CH2), 2.83 (brdd, IH, Jgem = 12.5 Hz, CH of CH2), 4.23 (brm, IH, CH), 4.44 (brm, IH, CH), 5.00, 5.23 (2s, 2H, CH2), 5.60 (d, IH, Jtrans = 15.5 Hz, CH), 5.82 (dd, IH, Jvic = 9 Hz, Jtrans = 15 Hz, CH), 6.01 , 6.36 (AB, 2H, Jvic = 11 Hz, CHCH), 6.05 (dd, IH, Jvic = 10.5 Hz, Jtrans = 15 Hz, CH), 6.69 (dd, IH, Jvic = 10.5 Hz, Jtrans = 15.5 Hz, CH). Analysis: Calcd:. for C28H36F6O3 : C 62.91 , H 6.79; Found C 61.83, H 7.02 EXAMPLE 1 [ l R- [ l α( l R*,2E,4Z),3aβ,7aα]]-Octahydro-7a-methyl- l -[7,7,7-trifluoro- 6-hydroxy- l -methyl-6-(trifluoro-methyl)-2 ,4-heptadienyl] - l H- inden-4-ol] The mixture of 392 mg (0.98 mmole) of [lR-[lα( l R*,2E) 3 aβ,4α,7aα]]-octahydro-7α-methyl- l - [7,7,7-trifluoro-6-hydroxy- l - methyl-6-(trifluoromethyl)-2-hepten-4-ynyl]- l H-inden-4-ol] , 5 ml ethylacetate, 12.5 ml hexane, 0.35 ml absolute ethanol, 0.017 ml quinoline and 63 mg Lindlar catalyst (5% Pd on CaCO3) was hydrogenated for 2 hrs at 1 atm. and room temperature. The reaction mixture was filtered through a celite pad and the pad was washed with hexane. The combined filtrates were washed with dilute acid, brine, 2N potassium bicarbonate and water, dried over sodium sulfate and evaporated to dryness. The crude product was recrystallized from hexane. The first crop and mother liquors were separately purified by preparative HPLC with hexane-ethyl acetate 3: 1. Ultimately 220 mg (56% of the title compound was obtained, mm.p. 140-141°C; UV λmax (EtOH): 231-232 nm (ε 30,600); H-NMR (CDCI3) : δθ.97 (s, 3H, CH3), 1.05 (d, 3H, J = 6.7 Hz, CH3) 1.98 (brd, IH, Jgem = 13 Hz, CH of CH2), 2.21 (m, IH, CH), 4.08 (brs, IH, CH), 5.25 (d, IH, Jcis = 1 1.5 Hz, CH), 5.75 (dd, IH, Jvic = 8.8 Hz, Jtrans = 15 Hz, CH), 6.43 (t, IH, Jvic and Jcis = 11.5 Hz, CH), 6.71 (dd, IH, Jvic = 1 1.5 Hz, Jtrans = 15 Hz, CH). Analysis: Calcd. for C19H26F6O2: C 56.99, H 6.55; Found: C 57.03, H 6.69 EXAMPLE 11 [lR-[lα(lR*,2E,4Z),3aβ,7aα]]-Octahydro-7a-methyl-l-[7,7,7-trifluoro- 6-hydroxy-l-methyl-6-(trifluoro-methyl)-2,4-heptadienyl]-4H- inden-4-one To the at room temperature stirred soluton of 202 mg (0.52 mmole) [lR-[lα(lR*,2E,4Z),3aβ,4α,7aα]]-octahydro-7a-methyl-l- [7,7,7-trifluoro-6-hydroxy-l-methyl-6-(trifluoromethyl)-2,4- heptadienyl]-lH-inden-4-ol in 10 ml anhydrous methylene chloride was added 886 mg (2.36 mmole) pyridinium dichromate, and stirred for 0.5 hr. Then 25 ml of ether was added, stirred for 15 minutes, and filtered through a celite pad. The pad was washed with 3 x 25 ml ethyl acetate. The combined filtrates were washed with 2N potassium bicarbonate, water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with methylene chloride-ethyl acetate 20:1 to give 196 mg (96%) of the title compound. 1 H-NMR (CDCI3): 60.67 (s, 3H, CH3), 1.10 (d, IH, J = 6.5 Hz, CH3), 2.45 (dd, IH, J = 8 and 11 Hz, CH), 5.26 (d, IH, Jcis = 11.5 Hz, CH), 5.76 (dd, IH, Jvic = 8.5 Hz, Jtrans = 15 Hz, CH), 6.43 (t, IH, Jvic and Jcis = 11.5 Hz, CH), 6.73 (dd, IH, Jvic = 11.5 Hz, Jtrans = 15 Hz, CH). EXAMPLE 12 [lR-[lα(lR*,2E,4Z),3aβ,7aα]]-Octahydro-7a-methyl-l-[7,7,7-triΩuoro- l-methyl-6-(trifluoromethyl)-6-[(trimethylsilyl)oxy]-2,4- heptadienyl]-4H-inden-4-one To a stirred solution of 196 mg (0.49 mmole) [lR-[lcc(lR*,2E, 4Z),3aβ,7aα]]-octahydro-7α-methyl-l-[7,7,7-trifluoro-6-hydroxy-l- methyl-6-(trifluoromethyl)-2,4-heptadienyl]-4H-inden-4-one in 10 ml anhydrous methylene chloride under argon was added 0.67 ml (4.42 mmole) of l-(trimethylsilyl)-imidazole, and thus was obtained reaction mixture was stirred at room temperature overnight. It was then diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by FLASH chromatography with hexane-ethyl acetate 5: 1 to give 229 mg (99%) of the title compound. EXAMPLE 1 l ,25-Dihydroxy-22E,24Z-diene-26,27-hexafluoro-24-homo- cholecalciferol To a stirred solution of 467 mg (0.80 mmole) of [3S-(l Z,3α,5β)]- [2- [3 ,5-bis[[( l , l -dimethylethyl)dimethylsilyl]-oxy]-2-methylene- cyclohexylidene]ethyl]diphenylphosphine oxide in 10 ml anhydrous tetrahydrofuran at -78°C was added 0.5 ml (0.80 mmole) of 1.6M n- butyllithium in hexane. The solution turned red and the color persisted during the entire addition of 229 mg (0.486 mmole) of [1R- [ l α( l R* ,2E,4Z),3aβ,7aα]]-octahydro-7a-methyl- l -[7,7,7-trifluoro- l - methyl-6-(trifluoromethyl)-6- [(trimethylsilyl)oxy] -2,4-heptadienyl] - 4H-inden-4-one in 8 ml anhydrous tetrahydrofuran. The reaction mixture was stirred at -78°C for 1.5 hrs and quenched with water. It was extracted thoroughly with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude residue was purified by FLASH chromatography with hexane-ethyl acetate 10: 1. This gave 310 mg of the trisilylated intermediate. To the solution of 310 mg of trisilylated intermediate in 8 ml anhydrous tetrahydrofuran stirred at room temperature under argon was added in portions 4.5 ml of IM tetrabutyl ammonium fluoride in tetrahydrofuran. The reaction mixture was stirred for 48 hrs, then diluted with water and extracted thoroughly with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified first by FLASH chromatography with hexane-ethyl acetate 1 :3, and preparative HPLC with hexane-ethyl acetate 1 :4 and then by preparative HPLC with hexane-ethyl acetate 1 :4 to give 206 mg (79.2%) of the title compound as white foam, [α] 25 D + 17.5° (c 0.2, EtOH); UVλ (EtOH): max 232-233 nm (ε 38,700), shoulder 265 nm (εl7,200); H-NMR (CDCI3); δθ.57 (s, 3H, CH3), 1.07 (d, 3H, J = 6.5 Hz, CH3), 2.22 (m, IH, CH), 2.32, 2..60 (AB of ABX, 2H, Jvic = 6.5 and 3.5 Hz Jgem = 13 Hz, CH2), 2.84 (dd, IH, Jvic = 4Hz, Jgem - 12.5 Hz, CH of CH2), 4.23 (brm, IH, CH), 4.43 (brm, IH, CH), 5.00, 5.33 (2s, 2H, CH2) 5.25 (d, IH, Jcis = 12 Hz, CH) , 5.76 (dd, IH, Jvic = 8.5 Hz, Jtrans = 15 Hz, CH), 6.02, 6.38 (AB, 2H, Jvic = 11.3 Hz, CHCH), 6.43 (t, IH, Jvic and Jtrans = 12 Hz, CH), 6.71 (dd, IH, Jvic = 12 Hz, Jtrans = 15 Hz, CH). Analysis: Calcd. for C28H36F6O3: C 62.91, H 6.79; Found: C 61.73, H 6.74 EXAMPLE 14 Oral Dosage Form Soft Gelatin Capsule mg/c apsule l ,25 -dihydroxy-22E,24E-diene-24- homo-26,27-hexafluoro-cholecalciferol 0.0005 - 0.050 (Compound A) Butylated Hydroxytoluene (BHT) 0.016 Butylated Hydroxyanisole (BHA) 0.0 1 6 Myglyol®-812 qs 1 60 1 . Suspend BHT and BHA in Myglyol®-812. Warm to about 50° C, and stir until dissolved. 2. Dissolve Compound A in the solution from Step 1. 3. Fill the solution from Step 2 in a soft gelatin cap. All steps are performed under a nitrogen atmosphere and protected from light. EXAMPLE 15 Oral Dosage Form Soft Gelatin Capsule mg/capsule Compound A 0.0005 - 0.050 α-Tocopherol 0.016 Myglyol®-812 qs 1 60 1 . Suspend α-Tocopherol in Myglyol®-812. Warm to about 50° C, and stir until dissolved. 2. Dissolve Compound A in the solution from Step 1. 3. Fill the solution from Step 2 in a soft gelatin cap. All steps are performed under a nitrogen atmosphere and protected from light. EXAMPLE 16 Topical Dosage Form Cream % w/w Compound A 0.00005-5.0 Cetyl Alcohol 1 .50 Stearyl Alcohol 2.50 Sorbitan Monostearate (Span 60) 2.00 Mineral Oil 2.00 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate 4.00 Blend (Arlacel 165) Polysorbate 60 (Tween 60) 1 .00 Caprylic/Capric Triglyceride 5.00 Sorbitol Solution 4.00 Edetate Disodium 0. 10 Butylated Hydroxyanisole (BHA) 0.02 Sorbic Acid 0.20 Potassium Sorbate 0.1 - 0.2 Water q.s. to 1 00.00 1 . Stir Compound A until dissolved. 2. Warm mixture of cetyl alcohol, stearyl alcohol, Span 60, mineral oil, Arlacel 165, Tween 60 and BHA to about 70-75°C, to form oily solution. 3. Add solution from Step 1 to solution from Step 2 while mixing. 4. Warm mixture of water, sorbitol solution, edetate disodium, sorbic acid, and potassium sorbate to 70-75°C . 5. Add solution from Step 3 to solution from Step 4 while emulsifying with a high speed mixer. 6. Cool emulsion from Step 5 to room temperature until emulsion congeals. EXAMPLE 17 Topical Dosage Form Gel % w/w Compound A 0.00005 - 5.0 Butylated Hydroxyanisole (BHA) 0.02 Hydroxypropyl Cellulose 3.00 Ethyl Alcohol, USP 45.00 Water q.s. to 100.00 1 . Dissolve BHA in mixture of ethyl alcohol and water. 2. Dissolve Compound A in solution from Step 1. 3. Disperse hydroxypropyl cellulose in solution from Step 2. EXAMPLE 1 Topical Dosage Form Solution % w/w Compound A 0.00005 - 5.0 Propylene Glycol 10.00 Caprylic/Capric Triglyceride 30.00 Butylated Hydroxyanisole (BHA) 0.02 Ethyl Alcohol, Absolute q.s. to 100.00 1 . Dissolve Compound A in ethyl alcohol. 2. Add BHA to solution from Step 1 and dissolve. 3. Add propylene glycol and caprylic/capric triglyceride to solution from Step 2 and mix until solution becomes clear.

Claims: Claims 1. A compound of the formula wherein A is a carbon double bond having the stereochemical configuration E or Z, i.e. of the formula: respectively, R is hydroxy and R is hydrogen or =CH2 or R is hydrogen or fluoro and Rl is =CH2- 2. A compound in accordance with claim 1, wherein A is 3. A compound in accordance with Claim 2, wherein R is hydroxy. 4. A compound in accordance with Claim 2, wherein R is fluoro. 5. A compound in accordance with Claim 2, wherein Rl is =CH2- 6. A compound in accordance with Claim 3, wherein Rl is hydrogen. 7. A compound in accordance with Claim 3, 1 ,25-dihdyroxy- 22E,24E-diene-26,27-hexafluoro-24-homo-cholecalciferol. 8. A compound in accordance with Claim 6, 1,25-dihydroxy- 22E,24E-diene- 19-nor-26,27-hexafluoro-24-homo-cholecalciferol. 9. A compound in accordance with Claim 4, lα-fluoro-25-hydroxy- 22E,24E-diene-26,27-hexafluoro-24-homo-cholecalciferol. 10. A compound in accordance with claim 1, wherein A is 1 1 . A compound in accordance with Claim 10, wherein R is hydroxy. 12. A compound in accordance with Claim 10, wherein R is fluoro. 13. A compound in accordance with Claim 10, wherein Rl is =CH2- 14. A compound in accordance with Claim 11, wherein Rl is hydrogen. 15. A compound in accordance with Claim 11, 1,25-dihydroxy- 22E,24Z-diene-26,27-hexafluoro-24-homo-cholecalciferol. 16. A compound in accordance with Claim 14, 1,25-dihydroxy- 22E,24Z-diene- 19-nor-26,27-hexafluoro-24-homo-cholecalciferol. 17. A compound in accordance with Claim 12, lα-fluoro-25- hydroxy-22E,24Z-diene-26,27-hexafluoro-24-homo-cholecalciferol. 1 8. A compound of the formula or of the formula or of the formula or of the formula 19. A pharmaceutical composition, particularly for inducing differentiation and inhibiting proliferation in certain skin and cancer cell lines, specially for the treatment of hyperproliferative skin disorders, such as psoriasis, and for the treatment of neoplastic diseases such as leukemia, comprising (a) an effective amount of a compound of the formula I in claim 1 , a n d (b) an inert carrier. 20. The compounds of claims 1 to 17 for use as agent for inducing differentiation and inhibiting proliferation in certain skin and cancer cell lines, specially for the treatment of hyperproliferative skin disorders, such as psoriasis, and for the treatment of neoplastic diseases such as leukemia. 2 1 . The use of the compounds of claims 1 to 17 for the production of medicaments for inducing differentiation and inhibiting proliferation in certain skin and cancer cell lines, specially for the treatment of hyperproliferative skin disorders, such as psoriasis, and for the treatment of neoplastic diseases such as leukemia. 22. Novel compounds, intermediates, formulations, processes and methods substantially as described herein.

Inventors: IACOBELLI JEROME ANTHONY, USKOKOVIC MILAN RADOJE, IACOBELLI, JEROME, ANTHONY, USKOKOVIC, MILAN, RADOJE
Applicants: HOFFMANN LA ROCHE, F.HOFFMANN-LA ROCHE AG
Application year: 1996
Main classification: C07C401
IPC codes: A61K31, A61P17, A61P35, C07C35, C07C401, C07F7