NZ227641A

NZ227641A - 16-dehydro-vitamin d 3 (dehydrocholecalciferol) derivatives; medicaments and preparatory processes

Info

Publication number: NZ227641A
Application number: NZ227641A
Authority: NZ
Inventors: Enrico Giuseppe Baggiolini; Bernard Michael Hennessy; Shian-Jan Shiuey; Gary Arthur Truitt; Milan Radoje Uskokovic
Original assignee: Hoffmann La Roche
Priority date: 1988-01-20
Filing date: 1989-01-17
Publication date: 1991-06-25
Also published as: DE58901056D1; FI890283A0; HU201007B; JPH029861A; NO175429B; AR247551A1; IE890157L; NO175429C; EP0325279A1; GR3004786T3; IL88989A; FI890283A; EP0325279B1; ATE74350T1; FI90764B; JPH0764806B2; CA1337529C; PT89486B; BG60530B2; DK169945B1

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £27641 ^ Patents Form No. 5 _ ^ * 227641 NO DRAWINGS Priority Oate(s): Compl«M Specification Filed: .9P... Dim: f&l £)7? Jp.Q,. t-P.1. £Q1 f.1 J.[k> Jgj PubUc, 0.,.: .8.5.JIJN.8SI. P.O. -n»!, No: NEW ZEALAND PATENTS ACT, 1953 No.: Date. o '. COMPLETE SPECIFICATION 16-DEHYDRO-VITAMIN D3-DERIVATIVES *17JANt98» 1 We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT 124-184 Grenzacherstrasse, Basle, Switzerland a Swiss company hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page -la-) m 22 76 4 1 ^; - 1 O^r RAN 4212/54 The invention relates to compounds of the formula 10 15 wherein R is hydrogen or hydroxy, and A is -C=C-, 20 -CHaCH- with E-configuration or -CH2-CH2~, to pharmaceutical compositions comprising one, two or more compounds of formula I, and to the use of said compounds for \ ^ the manufacture of such compositions useful in the treatment of hyperproliferative skin diseases, such as psoriasis, and 25 for the treatment of neoplastic diseases, such as leukemia. Examples of ^-alkyl groups as referred to below, are methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Examples of aryl-C1_4-alkyl groups are benzyl, phenethyl 30 and phenylpropyl. Examples of aryl groups are phenyl and p-tolyl. Halogen denotes bromine, chlorine, fluorine or iodine. 35 Compounds of formula I of the invention are compounds A Me/14.12.88 20 £27641 - 2 - to F as defined below: A: 1,25-dihydroxy-16-dehydrocholecalci£erol; B: 25-hydroxy-16-dehydrocholecalciferol; 5 C: 1.25-dihydroxy-16,23E-bisdehydrocholecalciferol; D: 25-hydroxy-16,23E-bisdehydrocholecalciferol; E: l.25-dihydroxy-16-dehyro-23-didehydrocholecalciferol; and F: 25-hydroxy-16-dehydro-23-didehydrocholecalciferol; 10 among which Che 1.25-dihydroxylated compounds A. C and E are preferred. The compounds of formulae la and lb (encompassed by formula I) can be prepared as described in the Schemes 1. 2 15 and 3 by reacting a corresponding compound of formula I containing instead of the two or three hydroxy groups two or three protected hydroxy groups of the formula -OSi(R1.R2.R3) wherein R^ and R3 are c14-alkyl and R2 is 4~alkyl, aryl or aryl-C14-alkyl. with an agent capable of removing the protecting groups 25 30 35 - 3 - 22 7 6 4 1 Scheme 1 o "I wherein A is as described above and R, and R_ are 1 3 independently ^-alkyl and R2 is independently C^^-alkyl, aryl, or aryl-C^^-alkyl. o o c 22 7 6 4 1 - 4 - Scheme 2 wherein R^, R2 and R3 are as described above. Wf. 1 - 5 - Scheme 3 22 764 1 n *1 C 10 15 20 25 30 "— H| ' S*C i . Ct> i H 35 wherein R , R2 and R3 are as described above. X is chlorine, bromine or iodine and Ts is tosyl. - 6 - 227641 In Scheme 1. the compound of formula II is converted to a compound of formula IVa or IVb by reaction with the corresponding compound of formula where Ph is phenyl; R4 is H or -OSi(R1< R2# R3), and R^, R2 and R^ are as described above. The reaction is carried out at -60 to 90°C, preferably -75°C. in a polar, aprotic. organic solvent, e.g. dry ether or preferably dry tetrahydrofuran (THF), in the presence of a strong base, such as an alkyl lithium, e.g. butyl lithium. The protecting groups of a compound of formula IVa or IVb are removed by reaction with a fluorine salt, e.g. tetrabutylammonium fluoride in a polar, organic solvent, e.g. ether or preferably THF, to yield a corresponding compound of formula la or lb. In Scheme 2, the compound the compound of focmula VI by agent, e.g. 2,2'-bipyridinium pyridinium chlorochromate. in such as methylene chloride. of formula V is oxidized to treatment with an oxidizing chlorochromate or preferably, an aprotic, organic solvent I I I i mwiNitr 22 76 4 1 7 - The compound of formula VI is converted to a compound of formula lib, by reaction with, e.g.. a (trialkylsilyl)-imidazole such as (trimethylsilyl)imidazole, in an aprotic organic solvent such as THF. or preferably, methylene chloride. The compound of formula V may also be partially hydrogenated to the compound of formula VII by reaction with a reducing agent, e.g. lithium aluminium hydride, preferably 10 in the presence of an alkali metal alkoxide. e.g. sodium methoxide. in an aprotic organic solvent e.g. ether, or preferably THF. at reflux temperature (about 68°C for THF). for about 10-20 hours. 15 The resulting compound of formula VII is oxidized to the compound of formula VIII by treatment with an oxidizing agent as described above for the oxidation of V to VI. The compound of formula VIII is converted to a compound 20 of formula Ha. by reaction with a (trialkylsilyl) imidazole, as described above for the conversion of VI to lib. In Scheme 3. the compound of formula X is reacted in ether, preferably THF, at reflux temperature with magnesium. 25 The resulting Grignard solution is treated with cuprous iodide and then the compound of formula IX is added. O The resulting compound of formula XI is reacted with a fluoride salt, e.g. tetrabutylammonium fluoride in ether or 30 preferably THF. The obtained compound of formula XII may be oxidized as described above for the oxidation of V to VI. 35 22 7 641 - 8 - The resulting compound of formula XIII is converted to a compound of formula lie, by reaction with a (trialkylsilyl)-imidazole as described above for the conversion of VI to lib. To prepare a compound of formula IX, the compound of formula HO (Tetrahedron 40, 1984,2283) can be reacted with a tosylating agent, such as a p-toluenesulfonyl halide, e.g. the chloride, in an organic base, e.g. collidine or preferably pyridine. The resulting compound of formula is then converted to a compound of formula IX by reaction of a trialkylsilyl chloride, e.g. trimethylsilyl chloride, in the presence of imidazole and in an aprotic organic solvent, e.g. THF or methylene chloride. To prepare a compound of formula X, a compound of formula x-ch2ch2coch3 xvi 22 7 6 4 1 9 can be converted to a compound of focmula X-CH2CH2C(CH3)2-OH XVII wherein X is as above, by reaction with a methyl Grignard reagent such as methylmagnesium bromide in ether. The compound of formula XVII is converted to a compound of formula X, by reaction with a trialkylsilyl chloride, as described above for converting XV to IX. Foe preparing the compound of formula V, the compound of formula XV above is reacted with a cyanide forming agent, e.g. sodium cyanide, in an aprotic organic solvent, e.g. dimethyl sulfoxide (DMSO), at a temperature between 80 and 100°C for 1 to 5 hours to give a compound of formula XVIII ho This is converted to the compound of formula cho xix ho by reaction with a reducing agent, e.g. diisobutylaluminium hydride, followed by hydrolysis with, e.g. a mineral acid. 227641 - 10 - such as hydrochloric acid. The reduction is conducted in an aprotic organic solvent, e.g. methylene chloride, at about -10 to 10°C for about 20 to 90 minutes. The compound of formula XIX is converted to the compound of formula by reaction with a mixture of triphenylphosphine, carbon tetrabromide and zinc dust, in an aprotic organic solvent, e.g. methylene chloride, for about 1 to 30 hours. The compound of formula XX is converted to the compound of formula by reaction with a strong base, e.g. butyllithium, in a polar aprotic solvent, e.g. THF, at about -80 to -70°C, for about 1 to 3 hours. The compound of formula XXI is converted to the compound of formula - 11 - 22 764 1 H XXII MejSiO by- reaction with (trimethylsilyl)imidazole in an apcotic organic solvent, e.g. THF or methylene chloride. This compound is converted to the compound of formula by reaction with a strong base, e.g. butyllithium and then with acetone. The reaction is conducted in an aprotic organic solvent, e.g. THF at about -80 to -60°C. The compound of formula XXIII is deprotected to give the compound of formula V (in Scheme 2) by reaction with a fluorine salt, e.g. tetrabutylammonium fluoride in an organic solvent, e.g. ether or THF. The compound of formula I stimulate differentiation and decrease proliferation of human keratinocytes. Accordingly, they ace useful as agents in the treatment of hyper-proliferative skin disorders, such as psoriasis, basal cell carcinomas, disorders or keratinization and keratosis. The compound of formula I are also useful as agents in the treatment of neoplastic diseases, such as leukemia. XXIII Me3SiO 22 7 6 4 1 12 - The activity of compounds of focmula I as agents foe the treatment of hyperproliferative skin diseases can be demonstrated e.g. by test procedures known in the art, such as set forth in The Society for Investigative Dermatology 5 1986, 709-714. The effects of the compounds A to F above on the morphologic differentiation of cultured human keratinocytes compared to the effect of 1.25-dihydroxy- cholecalciferol (compound X) are expressed in the Tables 1 ' 4 to 4 below, as number (xlO ) of human keratinocytes in 10 culture. A compound which induces the differentiation of ' basal cells to squamous and envelope cells is useful as an agent in the treatment of skin diseases characterized by disorders of keratinization, such as psoriasis. <* 15 20 25 Table 1 Compound Dose (M) Number of cells (xlO4): total basal squamous enve Control 13315 11814 15tl 1812 X lo-io 10"8 10~6 122±4 112±6 95±7 10312 8912 6416 1912 2314 3111 2311 3013 3412 A 10-10 10"8 10-6 132±8 128110 10117 11517 10618 7115 1711 2212 3012 2712 3312 3912 B 10-10 10-8 10"6 13316 13114 10414 11515 10912 7413 1811 2212 3011 2511 2912 3311 30 35 22 76 4 1 - 13 - Table 2 Compound Dose Number of cells (xlO4): (M) total basal squamous envelope Contcol 123±7 10516 18tl 7417 X 10-10 116±9 9518 2 111 9 ll4 10-8 101±10 7518 2612 122111 IO"6 8315 5714 2611 146116 c 10-10 11714 9212 2512 10316 10-8 10813 8012 2811 12813 10-6 8017 5416 2611 15311 D 10-10 11317 9316 2011 104110 lO-8 11117 8613 2512 12815 io-6 9413 68ll 2612 14417 Table 3 Compound Dose Numbec of cells (xlO4): (M) total basal squamous envelope Control 108110 9318 1512 8818 X 10-10 10617 8616 18H 10019 IO'8 8418 6115 2313 12218 10-8 7317 5115 2212 142111 E 10-1° 8614 6312 2312 11415 IO"8 8213 5312 2911 14115 io-6 7813 4111 2712 14714 F 10-10 10315 8113 2212 10314 IO-8 9713 6712 2911 12116 IO"6 8414 5512 2911 13717 The activity of compounds of formula I as agents for the treatment of hyperpcoliferative skin diseases can also be demonstrated by determining the number of human keratinocytes grown and the number of envelopes formed, as well as the number squamous carcinoma cell lines (SCC-115) grown in i ! i n CD 22 76 4 1 - 14 - cultures, in the presence of said compounds. The results are given in the Tables 4 and 5: Table 4 C Treatment Dose (M) 10 Control (0.1% ethanol) Number of keratinocytes (xlO4) 189.49122.3 Number of envelopes (xlO2) 858.281185.70 15 Compound E 10 10 10 10 -12 -10 -8 -6 187.36115.33 175.34110.19 145.79115.66 41.951 7.53 1136.631 383.66 1444.871 312.47 2113.6211049.33 1916.831 887.66 C 20 25 Control (0.1% ethanol) Compound A 10 10 10 10 -12 -10 -8 -6 148.73116.23 114.91110.95 130.37124.32 120.67116.87 109.22115.87 2193.71 921.9 1662.21 420.1 3973.81 126.99 7235.21 55.5 8323.51 157.6 30 35 22 76 4 1 - 15 - Table 5 Treatment Dose Number of O (M) cell lines (SCC-15) 5 (xlO-5) Control 7.35±1.75 10 Compound E 12 10" 10 10" 8 10 6 10 6.98 tl. 68 5.89±1.58 5.76±1.53 0.4010.98 C 15 20 Compound A 10 0.4910.13 The above results show that the compounds of formula I induce differentiation of skin cells and, accordingly, are useful in the treatment of hyperproliferative disorders of the skin, such as psoriasis. In order to demonstrate the activity of the compounds of formula I as agents for the treatment of neoplastic diseases, the anti-proliferative (AP) and differentiation--inducing (DI) effects of the compounds A to F and human 25 promyelocytic HL-60 tumor cells were evaluated. In Table 6 the AP effect is given in percent reduction of cell number and in concentration ID5Q of the compound which reduced the cells number by 50%. The DI effect is expressed as the percentage of differentiated cells and as the concentration 30 EDCA of the compounds which induced a 50% differentiation bU of the cells. 35 22 7 6 4 1 - 16 - Table 6 Concentration (X10~8M) % Reduction in cell number lD" e (X 10 M) Differentiated cells(%) ED*° . (XlO" M Compound X 0.01 6 3 0.1 5 11 1 16 2 19 2 10 66 68 100 84 98 Compound A rH o • o 10 3 0.1 33 16 1 84 0.2 92 0.2 10 85 97 100 85 98 Compound B 0.1 10 5 1 8 4 10 14 35 6 32 100 82 93 1000 95 95 22 7 6 4 1 - 17 - Compound C 0.01 0.1 1 10 100 Compound D 0.1 1 10 100 1000 Compound E 0.01 0.1 1 10 Compound F 0.1 1 10 100 1000 18 20 81 85 86 12 12 17 46 95 6 59 80 81 13 10 8 58 95 0.3 150 0.07 70 3 19 92 97 99 1 2 17 31 97 9 50 96 98 4 12 21 55 91 These data indicate that each of the compounds in question restrains the proliferation of human promyelocytic cells, in vitro, even though they are not toxic to the cells. Furthermore, the cells differentiate toward a more mature phenotype at the same doses which inhibit proliferation. From these results it can be seen that each o ***** 22 764 1 - 18 - of the compounds tested is useful as an agent in the treatment of neoplastic diseases, such as leukemia. The compounds of formula I can be administered orally 5 for the treatment of neoplastic diseases or for the treatment of hyperproliferative skin diseases, to warmblooded animals, which need such treatment, e.g. to an adult human, in dosage that are in the range of about 0.1 to 10 ug per day. 10 For the treatment of hyperproliferative skin diseases the compounds of formula I can also be administered topically to warmblooded animals which need such treatment, in dosage of about 1 to 1000 ug per gram of topical 15 formulation per day. Oral dosage forms comprising compounds of formula I may be incorporated e.g. in capsules or tablets with pharmaceutical^ acceptable carriers. Examples of such 20 carrier materials which may be incorporated into capsules are binders, such as gum tragacanth or gelatin; excipients. such as dicalcium phosphate; disintegrating agents, such as corn starch; lubricants, such as magnesium stearate; sweetening agents, such as sucrose; flavoring agents, such 25 as peppermint. Tablets may be coated with shellac, sugar or both. A syrup or elixir may contain a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring agent. 30 Topical dosage forms comprising compounds of formula I include ointments and creams encompassing formulations having oleaginous, adsorbable. water soluble and emulsion-type bases, such as lanolin and polyethylene glycols. Topical dosage forms also comprise gels, lotions. 35 powders and aerosols. The topical compositions can also be employed in the treatment of inflammations of the skin or of raucous membranes, e.g. the mucous lining of the mouth or \ n i s 30 22 7 6 4 1 - 19 - lower colon. Lotions, i.e. liquid preparations varying from simple solutions to aqueous of hydroalcoholic preparations 5 containing finely divided substances, can contain suspending or dispersing agents, such as cellulose derivatives, e.g. ethyl or methyl cellulose; gelatin or gums, which incorporate the active ingredient in a vehicle made up of water, alcohol or glycerin. Gels are semi-solid preparations 10 made by gelling a solution or suspension of the active ingredient in a carrier vehicle. The vehicles, which can be hydrous or anhydrous, are gelled using a gelling agent, e.g. carboxy polymethylene, and neutralized to a proper gel consistency with the use of alkalies, e.g. sodium hydroxide, 15 or amines, such as polyethylenecocoamine. Example 1 a) A mixture of 3.24 g of [1(R*),3aR*-(3afl,4a.7aa)]-20 3a.4.5.6.7.7a-hexahydro-4-hydroxy-fl.7a-dimethyl-3H-indene-1-ethanol. 30 ml of pyridine and 3.51 g of p-toluenesulfonyl chloride is stirred at 0° for 18 hr. After addition of ice and dilution with water, the mixture is extracted with methylene chloride. The organic phase is washed with IN 25 H2S04, saturated NaHC03, then dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:1:5) to afford 4.61 g (82%) of [1(R*),3aR*-(3afi.4a,7aa)]-3a,4,5.6,7,7a-hexahydro- 4-hydroxy-fl,7a-dimethyl-3H-indene-1-ethanol -4-methy1-benzenesulfonate, + 31.9° (c 0.53. CHClj). b) To a solution of 4.61 g of the product of a) in 22 ml of DMSO is added 1.10 g of sodium cyanide and the mixture is heated at 90°C for 2 hours. After cooling to room 35 temperature, the mixture is pumped to remove the solvent, then diluted with water. The mixture is extracted with ether. The organic phase is washed with saturated brine. 3 4 - 20 - 22 7 6 A 1 deled and evaporated. The residue is chromatographed on silica gel with methylene chloride-hexane-ethyl acetate (86:7:7) to give 2.52 g (91*) of [l(R*).3aR*- (3aB,4a,7aa)J-3a,4.5,6.7,7a-hexahydro-4-hydroxy-fl.7a- 21 dimethyl-3H- indene-l-propanenitr ile, [<*3^ + 29.2° (C 0.65, CHC13). c) To a mixture of 6.85 ml of diisobutylalurainium hydride in hexane and 5.2 ml of methylene chloride at -6°C is added a solution of 0.430 g of the product of b) in 10 ml of methylene chloride. The mixture is stirred at -6°C for 55 minutes. After addition of saturated ammonium chloride, the mixture is hydrolyzed with 3N HCl-ether (2:1). The aqueous layer is extracted with ether. The organic layers are washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:2) to afford 260 mg (60*) [1(R*),3aR*-(3afl,4a,7aa)]- -3 a,4,5,6,7,7a-hexahydr o-4- hydroxy-fl,7a-dimethyl-3H-indene--1-propanal, [a]22 + 43.1° (c 0.32. CHC13). d) A mixture of 1.77 g of triphenylphosphine. 2.23 g of carbon tetrabromide, 441 mg of Zn dust and 23 ml of methylene chloride is stirred at 25°c for 31 hours. To this mixture is added a solution of 0.430 g of the product of c) in 38 ml of methylene chloride and the mixture is stirred for 18 hours. The mixture is diluted with pentane and insoluble material is filtered off. The insoluble fraction is dissolved in methylene chloride and the solution is again diluted with pentane. After filtration, the combined filtrates are evaporated. The residue is purified on silica gel with 1:4 ethyl acetate-hexane to give 0.490 g (67%) of [ 1 (R*), 3aR*- (3aJ3 , 4a,7aa) ]-1- (4, 4-dibromo- 1-methyl -3-butenyl)-3a,4,5,6,7,7a-hexahydro-7a- methyi-3H-indene-4-ol, [a]^2 + 14.4° (c 0.55, CHC13). e) To a solution of 0.680 g of the product of d) in 31 ml of THF at -75°C are added dropwise 3.77 ml of 1.6M solution 22 7 641 - 21 - of butyllithium in hexane. The mixture is stirred at -75°C for 1 hour and at 25°C for 1 hr. After addition of saturated brine, the mixture is diluted with saturated aqueous NaHCO^ and extracted with ether. The organic phase is washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:4) to afford 0.350 g (89*) of [1(R*).3aR*- (3aB.4a,7aa)]-3a,4,5,6,7,7a-hexahydro -7a-methyl-1-(l-methyl-3-but: 10 (c 0.42. CH£13) (l-methyl-3-butynyl)-3H-inden-4-ol, [a]22 + 30.7° f) To a solution of 1.29 g of the product of e) in 80 ml of methylene chloride are added 3.59 g of l-(trimethylsilyl)-imidazole. The mixture is stirred at 25°C for 3 hours. After 15 adding 40 ml of water and stirring for 20 minutes, the mixture is extracted with ethyl acetate. The organic phase is washed with water and saturated brine, dried and evaporated. The residue is purified on silica gel with ethyl acetate-hexane (1:15) to give 1.70 g (99*) of [1(R*),3aR*-20 (3afl.4a,7aa)]-3a,4,5,6,7,7a-hexahydro -7a-methyl-1- (l-methyl-3-butynyl)-4-[(triraethylsilyl)oxy] -3H-indene, [a]20 + 39.7° (c 0.30, CHC13). g) To a solution of 1.70 g of the product of f) in 48 ml of 25 THF at -75°C are added dropwise 6.01 ml of 1.6M butyllithium in hexane. After stirring for 40 minutes, 3.05 ml of acetone are added and the mixture is stirred at -75°C for 20 minutes and at 25°C for 75 minutes. After addition of 40 ml of a 1:1 mixture of 2M KHCC>3 and 1M potassium sodium tartrate, the 30 mixture is stirred for 20 minutes and then extracted with ethyl acetate. The organic phase is washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate hexane (1:5) to give 1.62 g (89%) of [ 1 (R*) , 3aR*- ( 3aJ3,4a,7aa) ]- 6 - ( 3a , 35 4,5,6,7,7a-hexahydro-7a-methyl-4-[(trimethylsilyl)oxy]- 20 3H-inden-l-yl)-2-methyl-3-heptyn-l-ol, [a]D + 39.7° 22 7 6 4 1 - 22 - (c 0.30, chc13). h) To a solution of 1.62 g of the product of 9) in 53 ml of THF are added 15.5 ml of 1M tetrabutylammonium fluoride in THF. The mixture is stirred for 50 minutes. After dilution with half saturated NaHCO^. the mixture is evaporated to remove most of the solvent and extracted with ethyl acetate. The organic phase is washed with half saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:1) to give 1.17 g (82%) of [1 (R*),3aR*-(3afl,4a,7aa)J-3a.4.5.6,7,7a-hexahydro -1-(1,5-dimethy1-5-hydroxy-3-hexynyl)-7a-methyl-3H-inden-4-ol, m.p. 105-107°. i) To a solution of 0.720 g of the product of h) in 44 ml of methylene chloride are added 1.59 g of sodium acetate and 3.18 g of 2.21-bipyridinium chlorochromate. The mixture is stirred for 2 hours. Additional 1.59 g of 2,2'-bipyridinium chlorochromate are then added and the stirring continued for 2 hours. Then, after the addition of 6 ml of 2-propanol, the mixture is diluted with water and extracted with ether-ethyl acetate (1:1). The organi? phase is washed with water, IN H.SO., saturated NaHCO. and saturated brine. After 2 4 3 drying, the solution is evaporated and the residue chromatographed on silica gel with ethyl acetate-hexane (1:1) to give 0.560 g (78%) of [1(R«).3aR*-(3afl.7aa)]- -3.3a.5.6.7.7a-hexahydro-l-(5-hydroxy-1.5-dimethy1- 20 -3-hexynyl)-7a-methyl-4H-inden-4-one, [a]D +35.3° (c 0.36, CHC13). j) To a solution of 0.552 g of the product of i) in 70 ml of methylene chloride are added 2.00 g of l-(trimethyl-silyl)imidazole. After stirring for 17 hours and addition of 22 ml of water, the mixture is extracted with ethyl acetate. The organic phase is washed with water and saturated brine, then dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:4) to give 0.693 g -4* 227641 n i W - 23 - (99%) of [1(R*).3aR«-(3afl,7aa)]-3.3a.5, 6.7,7a~hexahydro -1-(1.5-dimethyl-5-[(tc imethylsilyl)oxy] - 3-hexynyl) 20 -7a-methyl-4H-inden-4-one. [a]D + 29.5° (c 0.20, O CHC13). 5 k) To a solution of 2.00 g of [ 3S-(IZ, 3a. 5J3) ]-[2-[3,5-bis[[(l,l-dimethyl)dimethylsilyl]oxy]-2-raethylene-cyclohexylidene]ethyl]diphenylphosphine oxide in 45 ml of THF at -75°C ace added dcopwise 1.87 ml of 1. 6M butyllithium ( 10 i-n hexane. After stirring for 6 minutes a solution of "j 0.693 g of the product of j) in 26 ml of THF are added J dropwise. After stirring at -75°C for 70 minutes and /( addition of a 1:1 mixture of IM potassium sodium tartrate | and 2M KHC03, the mixture is extracted with ethyl acetate, i 15 The organic phase is washed with saturated brine, dried and | evaporated. The residue is chromatogcaphed on silica gel ; with ethyl acetate-hexane (1:15) to give 1.23 g (87%) of | (la.3J3,5Z.7E)-1.3-bis[(l. 1-d imethylethy 1) dime thy Is i ly 1 ] I -oxy-2 5-[(trimethylsilyl)oxy]-9,10-secocholesta-5,7,10(19), 16- ? 20 tetraene-3-yne, + 47.1° (c 0.21, CHC13). 1) To a solution of 0.228 g of the product of k) in 11 ml of THF are added 1.92 ml of IM tetcabutylammonium fluoride in THF. The mixture is stirred for 16 hours. After dilution 25 with water, the mixture is extracted with ethyl acetate. The organic phase is washed with half saturated brine and saturated brine, dried and evaporated. The residue is purified on silica gel with ethyl acetate-hexane (3:1) to afford 0.126 g (96%) of 1,25-dihydcoxy-l6-dehydro-23~dide-30 hydrocholecalciferol, + 21.5+ (c 0.20, MeOH). Example 2 a) As described in Example lk), but starting from 0.343 g 35 of [5S-(1Z)]-[2-[5-[[(1.1-dimethylethyl)dimethylsilyl]oxy] -2-methylenecyclohexylideneJ ethyl]d iphenylphos phine oxide and 0.186 g of thTe/^^pdUct of Example Ij). there were fvi.* y'y"-'rz-fK^. 22 7 6 4 1 24 - 10 obtained 0.205 g (80*) of (3B.5Z.7E)-3-[[(1.1-dimethyl-ethy1)dimethylsilyl]oxy]-25-[(trimethylsilyl)oxy] -9,10-secocholesta-5,7.10(19),16- tetraen-23-yne. MS m/e 580 (M+). b) By treating 0.248 g of the product of a) as described in Example 11). there were obtained 0.153 g (91*) of 25-hydroxy-16-dehydro-23-didehydrocholecalciferol. [a]21 +99.6° (c 0.25). MeOH). Example 3 a) To a mixture of 0.146 g of lithium aluminum hydride, 0.211 g of sodium methoxide and 6.5 ml of THF at 0°C is 15 added dropwise a solution of 0.180 g of the product of Example lh) in 13 ml of THF. The mixture is heated at 68°C for 16 hours and recooled at 0°C. After dilution with 13 ml of ether and addition of 0.30 mi of water and 0.26 ml of 10* aqueous NaOH, the mixture is stirred at room temperature for 20 I hour and filtered. The solids are triturated with ether and filtered. The combined filtrates are evaporated and chromatographed on silica gel with ethyl acetate-hexane (1:2) to give 0.179 g (99*) of [1(R*),1(3E).3afl.4a,- 7aa)]-(3a,4,5,6,7,7a-hexahydro-1-(5-hydroxy-1.5-dimethy1- 21 25 -3-hexenyl)-7a-methyl-lH-inden-4-ol. [aj^ +11.5° (c 0.33. CHC13). b) To a solution of 0.120 g of the product of a) in 10 mi of methylene chloride are added 0.500 g of pyridiniura 30 dichromate and 25 rag of pyridinium p-toluenesulfonate. The mixture is stirred for 135 minutes. After addition of 40 ml of ether, the mixture is stirred for 5 minutes and filtered. The solids are triturated with ether and filtered. The combined filtrates are washed with saturated aqueous 35 CuS04. water, half saturated aqueous NaHC03 and saturated brine. The organic phase is dried and evaporated. The residue is chromatographed on silica gel with 35% ethyl 22 7 6 A 1 - 25 - acetate-hexane to give 90 mg (76*) of [1(R*).l(3E).(3afl. 7aa)]-3.3a.5.6.7,7a-hexahydro-l-(5 -hydroxy-1.5-dimethyl-3-hexenyl)-7a-methyl-4H-inden-4-one, [a]25 +30.6° (c 0.17. CHC13). c) By treating 0.099 g of the product of b) as described in Example lj)» there are obtained 0.111 g (89*) of [1 (R*).1(3E).(3afl.7aa)]-3.3a.5.6,7.7a-hexahydro-1-(1.5--dimethy1-5-[(trimethylsilyl)oxy]-3-hexenyl)-7a-methy1--4H-inden-4-one. [a]24 +26.4° (c 0.22. CHC13). d) As described in Example lk). starting from 0.265 g of [3S-(1Z.3a.5B)]-[2-[3,5-bis[[(1.1 -dimethyl)dimethyl- si lyl ] oxy] -2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.095 g of the product of c). there are obtained 0.162 g (83*) of (lfl.3a,5Z.7E.23E)-1,3-bis[[(1.1 -dimethylethy1)dimethylsilyl]oxy]-25-[(trimethylsilyl)oxy] -9,10-secocholesta-5.7.10(19).16,23-pentaene, MS m/e 712 (M+) . e) By treating 0.159 g of the product of d) as in Example 11), there are obtained 0.077 g (84) of 1,25-dihydroxy- 24 16,23E-bisdehydrocholecalciferol. [aJD +46.5° (c 0.20. MeOH). Example 4 a) As described in Example lk). starting from 0.225 g of [5S—(1Z)]-[2 — [5—C C(1.1-dimethylethy1)dimethylsilyl]oxy] -2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.110 g of the product of Example 3c), there are obtained 0.150 g (81*) of (3fi.5Z.7E.23E)-3-[[(1.1-dimethylethyl)-dimethylsilyl]oxy] -25-[(trimethylsilyl)-oxy]-9.10-secocholesta -5.7.10(19),16,23-pentaene. [a]24 +68.3° (c 0.18, CHC13). - 26 - 22 7 6 4 1 b) By treating 0.144 g of the product of a) as described in Example 11). there are obtained 0.076 g (78%) of 25-hydroxy-16,2 3E-bisdehydrocholecalciferol. [a]22 +62.5° (c 0.20, MeOH). Example 5 a) To a solution of 6.25 g of ethyl 3-bromopropionate in 28 ml of THF at -20°C are added 28.8 ml of 2.8M methylmagnesium bromide in ether. The mixture is stirred at room temperature for 170 minutes. After addition of 15 ml of saturated aqueous ammonium chloride and of 42 ml of IN HC1, the organic phase is separated and the aqueous phase extracted with ether. The organic extracts are washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with 30% ethyl acetate-hexane to give 2.57 g (45%) of 4-bromo-2-methyl-2-butanol. MS m/e 151 (M+-CH3). b) To a solution of 2.56 g of 4-bromo-2-methyl-2-butano1 and 4.86 g of imidazole in 15 ml of N.N-dimethylformamide at 0°C are added 6.48 g of chlorotriethylsilane. The mixture is stirred at room temperature for 200 minutes. After adding ice, the mixture is diluted with water and extracted with pentane. The organic phase is washed with water and saturated brine, dried and evaporated. The residue is chromatogrpahed on silica gel with pentane to give 4.02 g (93%) of (3-brorao-l,1-dimethylpropoxy)triethylsilane, MS m/e 265 (M+-CH3). c) To a solution of 0.930 g of [1(R*),3aR*(3afi,4a, 7aa)]-3a,4,5,6.7,7a-hexahydro -4-hydroxy-fl.7a-dimethy1-3H-indene-l-ethanol 4-methyl-benzenesulfonate and 1.10 g of imidazole in 73 ml of methylene chloride at 0°C are added 0.580 g of chlorotriethylsilane. The mixture is stirred at room temperature for 1.5 hours. After adding ice, the mixture is diluted with water and stirred for 20 minutes. 22 7 6 4 1 - 27 - The organic layer is extracted with methylene chloride. The extracts are washed with water. IN N2S04< saturated ^ aqueous NaHC03 and saturated brine. After drying and evaporation, the residue is purified on silica gel with 5 ethyl acetate-hexane (1:5) to afford 1.22 g (100%) of [1(R*).3aR*-(3afl.4a.7aa)]-3a.4.5,6.7,7a-hexahydro -4-[(triethylsilyl)oxy]-fl.7a-dimethy1-3H-indene-l-ethanol 20 4-methylbenze sulfonate. [a]D +46.1° (c 0.31. v CHC13). 10 d) To a solution of 3.08 g of (3-bromo-1.1-dimethylpropoxy) triethylsilane in 31 ml of THF are added 0.282 g of magnesium. The mixture is heated at 68°C for 3.5 hours. Then a mixture of 0.686 g of cuprous iodide and the above 15 mentioned Grignard solution are stirred at 3°C for 30 minutes. To this is added a solution of 1.02 g of the product of c) and the mixture is stirred at room temperature for 40 minutes. After adding a mixture of ice and water, the mixture is extracted with ether. The organic phase is washed 20 with IN H2S04 and saturated aqueous NaHC03< dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:15) to afford 1.80 g of [1 (R*),3aR*-(3afl,4a,7aa)J- 3a.4.5,6,7,7a-hexahydro--l-[1.5-dimethyl-5-[(triethylsilyl)- oxy]hexyl]-25 -4-[(triethyIsily1)oxy]-7a-methy1-3H-indene. MS m/e 479 (M+-Et). e) To a solution of 1.60 g of the product of d) in 5 ml of THF are added 2.00 ml of IM tetrabutylammonium fluoride in 30 THF. The mixture is heated at 68°C for 50 minutes. After cooling to room temperature, the mixture is diluted with water and extracted with methylene chloride. The organic phase is washed with brine, dried and evaporated. The residue is purified on silica gel with ethyl acetate-hexane 35 (1:1) to afford 0.420 g (79%) of [1(R*),3aR*-(3ai3, 4aa, 7aa)]-3a.4,5,6.7.7a-hexahydro-4-hydroxy-a,a- e ,7a- 21 tetramethyl-lH-indene-l-pentanol. [a]^ =+12.0° o A 227641 - 28 - (C 0.25, CHC13). £) To a solution o£ 0.210 g of the product of e) in 18 ml of methylene chloride are added 0.870 g of pyridinium 5 dichromate and 44 mg of pyridinium p-toluenesulfonate. The mixture is stirred for 175 minutes. After addition of 50 ml of ether, the mixture is stirred for 5 minutes and filtered. The solids are washed with saturated aqueous CuSO.. water, 4 half saturated aqueous NaHC03 and saturated brine. The 10 organic phase is dried and evaporated. The residue is chromatographed on silica gel with 35% ethyl acetate-hexane to give 0.175 g (84%) of [1(R*).3aR*-(3afl.7aa)]- 3.3a.5.6,7,7a-hexahydro-1-(5-hydroxy-1,5-dimethylhexyl)-7a-meth: 15 CHC13). 7a-methyl-4H-inden-4-one, [cO^1 +28.2° (c 0.22, g) By treating 0.168 g of the product of f) as described in Example lj). there are obtained 0.211 g (100%) of [1(R*),3aR*-(3afl.7aa)]-3,3a.5.6.7.7a-hexahydro-l-(1.5- 20 dimethy1-5-[(trimethyIsilyl)oxy]hexyl) - 7a-methyl-4H-inden-20 4-one, [a]£ +21.9° (c 0.27, CHC13). h) As described in Example Ik), starting from 0.581 g of [3S-(1Z,3a.5fl)]-[2-[3.5-bis[[(1.1-dimethy1)dimethylsily1]- 25 oxy]-2-methylenecyclohexylidene]ethyl]diphenyl phosphine oxide and 0.210 g of the product of g). there are obtained 0.358 g (83%) of (la.3fl.5Z.7E)-1.3-bis[[(1.1-dimethyl-ethyl)dimethylsilyl]oxy]-25-[(trimethylsilyl)oxy]-9,10-secocholesta-5,7,10(19),16-tetraene, MS m/e 714 (M+). 30 i) Treating 0.350 g of the product of h) as described in Example 11), there are obtained 0.168 g (83%) of 1,25-dihydroxy-16-dehydrocholecalciferol, 20 [a]£ +40.0° (c 0.17. MeOH). 35 i i) fj < - 29 - 22 7 6 4 1 Example 6 a) As described in Example Ik) starting from 0.383 g of [5S-(1Z)]-[2-[5-[[(l.l-dimethylethyl)dimethylsilyl]oxyJ-2-methylenecyclohexylidene]ethylJdiphenylphosphine oxide and 0.188 g of the product of Example 5g), there are obtained 0.245 g (78*) of (3a.5Z.7E)-3-[[(l.l-dimethylethyl)- dimethyIsilylJ oxyJ - 25-[(trimethylsilyl)oxy]-9,10-seco-cholesta-5.7.10(19),16-tetraene, [a]24 +67.5° (c 0.20. CHC13). b) Treating 0.239 g of the product of a) as described in Example 11) affords 0.135 g (83*) of 25-hydroxy-16-dehydro-cholecalcif erol. +75.4° (c ».13, Me OH). The following Example A and B illustrate the composition of soft gelatine capsules for oral administration and of a topical cream: Example A Butylated hydroxytoluene Butylated hydroxyanisole Fractionated coconut oil Compound E mq/capsule 0.0001-0.010 0.016 0.016 160.0 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 22 7 6 4 1 - 30 -Example B Comppound E Cetyl alcohol Stearyl alcohol Sorbitan monostearate Glyceryl monostearate and polyoxyechylene glycol stearate Polysorbate 60 Mineral oil Propylene glycol Propylparaben Butylated hydroxyanisole Sorbitol solution Edetate disodium Methylparaben Distilled water mq/q of cream 0.001-1.0 1.5 2.5 2.0 4.0 1.0 4.0 5.0 0.05 0.05 2.0 0.01 0.18 q.s. to 100 g 727641 31 WHAT WE CLAIM IS: 1. A compound of the formula ho'*;r;I;wherein R is hydrogen or hydroxy and A is -CEC--CH=CH- with E-configuration or -CH2-CH2-.;2. A compound in accordance with claim 1, of the group consisting of:;1.25-d ihydroxy-16-dehydro-23-didehydrocholecalciferol, 1.25-d ihydroxy-16,2 3E-bisdehydrocholecalc ifero1 and 1.25-dihydroxy-16-dehydrocholecalciferol.;3. A compound in accordance with claim 1 or 2 for use as a therapeutically active substance, particularly for the treatment of hyperproliferative diseases of the skin, especially psoriasis, or for the treatment of neoplastic diseases, especially leukemia.;4. A process for the preparation of a compound according to claim 1 or 2, which process comprises reacting a corresponding compound of formula I containing instead of : three hydroxy groups two or three protected wherein Rn and R, are C. .-alkyl and R_ is 1 3 1-4 2;C1_4-alkyl, aryl or aryl-C^ 4-alkyl.;with an agent capable of removing the protecting groups.;xy\groups of the formula;-OSi(R1,R2,R3);32;227641;5. A medicament, particularly for the treatment of hyperproliferative diseases of the skin, especially psoriasis, or for the treatment of neoplastic diseases, especially leukemia, comprising an effective amount of a compound according to claim 1 or 2 and a pharmaceutically effective carrier material, particularly for oral or topical administration.;6. The use of a compound in accordance with claim 1 or 2 for the manufacture of a medicament for the treatment of hyperproliferative diseases of the skin, especially psoriasis, oc for the treatment of neoplastic diseases, especially leukemia.;7 . A compound in accordance with claim 1 substantially as described herein, particularly with reference to any one of Examples 1 to 6.;8. The process for the preparation of a compound according to claim 1, substantially as described herein, particularly with reference to any one of Examples 1 to 6.;g . A medicament comprising a compound according to claim 1 substantially as described herein, particularly with reference to either Example A or Example B.;DATED THIS 22. DAY OF* </div>