CA1337529C - 16-dehydro-vitamin d -derivatives - Google Patents
16-dehydro-vitamin d -derivativesInfo
- Publication number
- CA1337529C CA1337529C CA000588384A CA588384A CA1337529C CA 1337529 C CA1337529 C CA 1337529C CA 000588384 A CA000588384 A CA 000588384A CA 588384 A CA588384 A CA 588384A CA 1337529 C CA1337529 C CA 1337529C
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- mixture
- treatment
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Abstract
The novel compounds of the formula wherein R is hydrogen or hydroxy and A is -C ? C-;
-CH=CH- with E-configuration or -CH2-CH2-, are useful as agents for the treatment of hyperproliferative disorders of the skin and as agents for the treatment of neo-plastic diseases.
-CH=CH- with E-configuration or -CH2-CH2-, are useful as agents for the treatment of hyperproliferative disorders of the skin and as agents for the treatment of neo-plastic diseases.
Description
1 33752~
The invention relates to compounds of the focmula ~ A ~ I
H0` R
wherein R is hydrogen or hydroxy, and ~ is -C-C-, -CH=CH- with E-configuration or -CH2-CHz-, 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 for the treatment of neoplastic diseases, such as leukemia.
Examples of Cl 4-alkyl groups as referred to below, are methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
Examples of aryl-Cl 4-alkyl groups are benzyl, phenethyl and phenylpropyl. Examples of aryl groups are phenyl and p-tolyl. Halogen denotes bromine, chlorine, fluocine or iodine.
Compounds of formula I of the invention are compounds - 2 _ 1 337 529 to F as defined below:
A: 1,25-dihydroxy-16-dehydrocholecalciferol;
B: 25-hydroxy-16-dehydrocholecalciferol:
C: 1,25-dihydroxy-16,23E-bisdehydrocholecalciferol:
D: 25-hydroxy-16,23E-bisdehydrocholecalciferol:
E: 1,25-dihydroxy-16-dehyro-23-didehydrocholecalciferol: and F: 25-hydroxy-16-dehydro-23-didehydrocholecalciferol:
among which the 1,25-dihydroxylated compounds A, C and E are preferred.
The compounds of formulae la and Ib (encompassed by formula I) can be prepared as described in the Schemes 1, 2 and 3 by reacting a corresponding compound of formula I
containing instead of the two or three hydroxy groups two o~
three protected hydroxy groups of the formula -OSi(Rl,R2,R3) wherein Rl and R3 are Cl 4-alkyl and R2 is Cl_4-alkyl, aryl or aryl-Cl_4-alkyl, with an agent capable of removing the protecting groups.
~ - 3 - ~ 33~ 529 Scheme 1 =~
H
O ~l ~CS~ 2 ~ R~
~ ~c~ ~ I R2-5 a~ ~
R~ R~ R~
lV~
IVb C ~ A '~
HO-`` ~CH HO `~
wherein A is as described above and RL and R3 are independently Cl 4-alkyl and R2 is inde~endently Cl 4-alkyl. aryl, or aryl-Cl_4-alkyl.
_ 4 _ 1 337529 Scheme 2 ~ ~OH
~/
Lo '~.,~
~CH ~ I OH
O Vl HO Vll . "'~0~
~'1~ 2 Ç~
o H R3 Vlll llb ..
~CS~--R2 lla wherein Rl, R2 and R3 are as described above.
_ - 5 - 1 337 52 9 Scheme 3 ~ orS si--R2 R. ~/ X R~
R~ \~
IX
~ f ~ r ~ 2 ~ I
R ~ ~?/ ~
R2--SiO H
H Xll HO
~" ~r H Xlll I
~" ~`l R~
~ I 05;_R2 ~ lle o H
wherein Rl, R2 and R3 are as described above, X is chlorine, bromine or iodine and Ts is tosyl.
~ - 6 - 1337529 The intermediates of formula II, encompassing those of formulae IIa, lIb and IIc, are novel and are part of the invention.
In Scheme l, the compound of formula II is converted to a compound of formula IVa or IVb by reaction with the corresponding compound of formula ~ POPh2 R2 SlO` ~ ~ III
where Ph is phenyl: R4 is H or -OSi(Rl, R2, R3), and Rl, R2 and R3 are as described above.
The reaction is carried out at -60 to 90C, preferably -75C, 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 Ib.
In Scheme 2, the compound of formula V is oxidized to the compound of formula VI by treatment with an oxidizing agent, e.g. 2,2'-bipyridinium chlorochromate or preferably, pyridinium chlorochromate, in an aprotic, organic solvent such as methylene chloride.
- 7 - 1 337 52q The compound of formula VI is converted to a compound of formula IIb, 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 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 68C for THF), for about 10-20 hours.
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 of formula IIa, by reaction with a (trialkylsilyl)imidazole.
as described above for the conversion of VI to IIb.
In Scheme 3, the compound of formula X is reacted in ether, preferably THF, at reflux temperature with magnesium.
The resulting Grignard solution is treated with cuprous iodide and then the compound of formula IX is added.
The resulting compound of formula XI is reacted with a fluoride salt, e.g. tetrabutylammonium fluoride in ether or preferably THF.
The obtained compound of formula XII may be oxidized as described above for the oxidation of V to VI.
- 8 - 1 33752~
The resulting compound of formula XIII is converted to a compound of formula IIc, by reaction with a (trialkylsilyl)-imidazole as described above for the conversion of VI to IIb.
To prepare a compound of formula IX, the compound of focmula " ~ OH
~ XIV
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 ~ OTs XV
HO
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. T~IF or methylene chloride.
To prepare a compound of formula X, a compound of focmula ~ - 9 - 1 33752q can be converted to a compound of formula X-CH2CH2C(CH3)2-OH XVII
wherein X is as above, by ceaction with a methyl Grignard eeagent 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.
For 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 a~rotic organic solvent, e.g.
dimethyl sulfoxide (DMS0), at a temperature between 80 and 100C for l to 5 hours to give a compound of formula - CN
~ 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, -- lo - 1 337529 such as hydrochloric acid. The reduction is conducted in an aprotic organic solvent, e.g. methylene chloride, at about -10 to 10C for about 20 to 90 minutes. The compound of formula XIX is converted to the compound of formula H
4`c--Br ~> Ir XX
~--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 ~ XXI
by reaction with a strong base, e.g. butyllithium, in a polar aprotic solvent, e.g. THF, at about -80 to -70C, for about 1 to 3 hours. The compound of formula XXI is converted to the compound of formula ~ H
~ XXII
H
Me3 SiO
by reaction with (trimethylsilyl)imidazole in an aprotic organic solvent, e.g. THF or methylene chloride. This compound is converted to the compound of formula ' ~
OH XXIII
~ H
Me3 SiO
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 -60C. The compound of formula XXIII is deprotected to give the compound of formula ~ (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 are 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.
- L2 - 1 33752q The activity of compounds of formula I as agents for 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 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 L,25-dihydroxy-cholecalciferol (compound X) are expressed in the Tables 1 to 4 below, as number (xlO ) of human keratinocytes in 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.
Table 1 Compound Dose Number of cells (xlO ):
(M) total basal squamous envelope Control 133i5118i4 15il 18i2 X lO_lo 122i4103i2 l9i2 23il -8 112i689i2 23+4 30~3 lo-6 95i764i6 31+1 34+2 A lO_lo 132i8115i7 17il 27+2 -8 128ilO106i8 22~2 33+2 lo-6 lOli771i5 30i2 39~2 B lO_lo 133i6115i5 18il 25+1 -8 131i4lO9i2 22i2 2gi2 lo-6 104i474i3 30il 33il - 13 _ 1 33752q Table 2 Compound Dose Number of cells (xlO ):
(M) total basal squamous envelope Control 123i7 105i6 18il 74i7 X 10-1 116i9 95i8 21il 91i4 10-8lOlilO 75i8 26i2 122ill 1o-6 83i5 57i4 26il 146il6 C 10-1 117i4 92i2 25i2 103i6 10-8 108i3 80i2 28il 128+3 10-6 80i7 54i6 26+1 153il D 10-1113i7 93i6 20il 104ilO
10-8 llli7 86+3 25i2 128i5 1o-6 94i3 68il 26i2 144i7 Table 3 Compound Dose Number of cells (xlO ):
(M) total basal squamous envelope Control 108ilO 93i8 15i2 88i8 X lo-lo106i7 86i6 18il lOOi9 10-8 84i8 61i5 23i3 122+8 10-6 73i7 51i5 22i2 142ill E }o~l 86i4 63i2 23i2 114i5 10-8 82i3 53i2 29il 141i5 10-6 78i3 41il 27i2 147+4 3o F lO_lo103i5 81i3 22i2 103i4 10-8 97i3 67i2 29il 121+6 10-6 84i4 55i2 29il 137i7 The activity of compounds of formula I as agents for the treatment of hyperproliferative skin diseases can also be demonstrated by determining the number of human keratino--cytes grown and the number of envelopes formed, as well as the number squamous carcinoma cell lines (SCC-L15) grown in cultures, in the presence of said compounds. The results are given in the Tables 4 and 5:
Table 4 Treatment Dose Number of Number of (M) keratinocytes envelopes (x104) (x102) Control 189.49+22.3 858.28+185.70 (0.1% ethanol) Compound E lo~l2 187.36~15.33 1136.63i 383.66 10-1 175.34+10.19 1444.87+ 312.47 1o~8 145.79il5.66 2113.62ilO49.33 41.95i 7.53 1916.83 887.66 Control 148.73il6.23 2193.7i 921.9 (0.1% ethanol) Compound ~ lo~l2 114.91ilO.95 1662.2i 420.1 10-1 130.37i24.32 3973.8i 126.99 10 8 120.67il6.87 7235.2i 55.5 10 6 109.22il5.87 8323.5i 157.6 Table 5 Treatment Dose Number of (M) cell lines (SCC-15) (xlO
Control 7.35+1.75 Compound E lo~l2 6.98il.68 5.89+1.58 10 8 5.76il.53 lo~6 0.40iO.98 Compound A 10 0.49iO.13 The above results show that the compounds of foemula 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 promyelocytic HL-60 tumor cells were evaluated. In Table 6 the AP effect is given in percent reduction of cell number and in concentration ID50 f the compound which reduced the cells number by 50%. The DI effect is expressed as the percentage of differentiated cells and as the concentration ED50 of the compounds which induced a 50% differentiation of the cells.
Table 6 Concentration % Reduction ID50 Differen- ED50 (xlO M) in cell number (x 10 M) tiated (xlO M
cells(%) Compound X
0.01 6 3 0.1 5 11 COmPound A
0.01 10 3 0.1 33 16 1 84 0.2 92 0.2 Compound B
0.1 10 5 - 17 - 1 337 52~
Compound C
0.01 18 3 0.1 20 19 1 81 0.3 92 0.3 Compound D
0.1 12 looo 95 97 Compound E
0.01 6 9 0.1 59 50 1 80 0.0796 0.1 Compound F
0.1 13 4 These data indicate that each of the compounds in ~uestion 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 prolifecation. From these results it can be seen that each - 18 - 1 337 52q 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 for the treatment of neoplastic diseases or for the tceatment 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 ~g per day.
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 L000 ~g per gram of topical formulation per day.
Oral dosage forms comprising compounds of formula I may be incorporated e.g. in capsules or tablets with pharmaceutically acceptable carriers. Examples of such 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 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.
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, powders and aerosols. The topical compositions can also be employed in the treatment of inflammations of the skin or of mucous membranes, e.g. the mucous lining of the mouth or - 19 - I 33752q lower colon.
Lotions, i.e. liquid preparations varying from simple solutions to aqueous of hydroalcoholic preparations 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 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, or amines, such as polyethylenecocoamine.
Example 1 a) A mixture of 3.24 g of [l(R~),3aR~-(3a~,4,7aa)]-3a,4,5,6,7,7a-hexahydro-4-hydroxy-~,7a-dimethyl-3H-indene--l-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 lN
H2SO4, saturated NaHCO3, 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 [l(R~),3aR~-(3a~,4a,7aa)]-3a,4,5,6,7,7a-hexahydro-4-hydroxy-~,7a-dimethyl-3H-indene-l-ethanol -4-methyl-benzenesulfonate, [a]D + 31.9 (c 0.53, CHC13).
b) To a solution of 4.61 g of the product of a) in 22 ml ofDMSO is added 1.10 g of sodium cyanide and the mixture is heated at 90C for 2 hours. After cooling to room 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, - 20 _ 1 33 75 29 dried 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*-(3a~,4a,7aa)]-3a,4,5,6,7,7a-hexahydro-4-hydroxy-~,7a-dimethyl-3H-indene-l-propanenitrile, [a]D + 29.2 (c 0.65, CHC13).
c) To a mixture of 6.85 ml of diisobutylaluminium hydride in hexane and 5.2 ml of methylene chloride at -6C is added a solution of 0.430 g of the product of b) in 10 ml of methylene chloride. The mixture is stirred at -6C 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%) [l(R*),3aR*-(3a~,4a,7aa)]--3a,4,5,6,7,7a-hexahydro-4-hydroxy-~,7a-dimethyl-3H-indene--l-propanal, [a]D + 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 25C 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 ~iltrates are evaporated. The residue is purified on silica gel with 1:4 ethyl acetate-hexane tO give 0.490 g (67%) of [l(R*),3aR*-(3a~,4a,7aa)]-1-(4,4-dibromo- l-methyl -3-butenyl)-3a,4,5,6,7,7a-hexahydro-7a-methyl-3H-indene-4-ol, [a]D + 14.4 (c 0.55, CHC13).
e) To a solution of 0.680 g of the product of d) in 3L ml of THF at -75C are added dropwise 3.77 ml of 1.6M solution - 1 33752~
of butyllithium in hexane. The mixture is stirred at -75C
for 1 hour and at 25C for 1 hr. After addition of saturated brine, the mixture is diluted with saturated aqueous NaHC03 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 [l(R*),3aR~-(3aB,4a,7aa)]-3a,4,5,6,7,7a-hexahydro -7a-methyl-1-(l-methyl-3-butynyl)-3H-inden-4-ol, [a]D + 30.7 (c 0.42, CHC13).
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 25C for 3 hours. After 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 [l(R*),3aR*-(3aB,4a,7aa)]-3a,4,5,6,7,7a-hexahydro -7a-methyl-1-(l-methyl-3-butynyl)-4-[(trimethylsilyl)oxy] -3H-indene, [a]2 + 39.7O (c 0.30, CHC13).
g) To a solution of 1.70 g of the product of f) in 48 ml of THF at -75C 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 --75C for Z0 minutes and at 25C for 75 minutes. After addition of 40 ml of a 1:1 mixture of 2M KHCO3 and lM potassium sodium tartrate, the 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 [l(R*),3aR*-(3aB,4a,7aa)]-6-(3a, 4,5,6,7,7a-hexahydro-7a-methyl--4-[(tcimethylsilyl)oxy]-3H-inden-l-yl)-2-methyl--3-heptyn-1-ol, [a]2 + 39.7O
- 22 - ~ 337 529 (c 0.30, CHC13).
h) To a solution of 1.62 g of the product of g) in 53 ml of THF are added 15.5 ml of lM tetrabutylammonium fluoride in THF. The mixture is stirred for 50 minutes. After dilution with half saturated NaHC03, 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 [l(R*),3aR*-(3aB,4a,7aa)]-3a,4,5,6,7,7a-hexahydro -1-(1,5-dimethyl-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 2,2'-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 organic phase is washed with water, lN
H2S04, saturated NaHCO3 and saturated brine. After drying, the solution is evaporated and the residue chroma-tographed on silica gel with ethyl acetate-hexane (1:1) to give 0.560 g (78%) of [l(R*),3aR*-(3aB,7aa)]--3,3a,5,6,7,7a-hexahydro-1-(5-hydroxy-1,5-dimethyl--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 chcomatographed on silica gel with ethyl acetate-hexane (1:4) to give 0.693 g - 23 - 1 33 7 52~
(99%) of [l(R~),3aR~-(3a~,7aa)]-3,3a,5,6,7,7a-hexahydro -1-(1,5-dimethyl-5-[(teimethylsilyl)oxy]-3-hexynyl) -7a-methyl-4H-inden-4-one, [a~D + 29.5 (c 0.20, CHC13).
k) To a solution of 2.00 g of ~3S-(lZ,3a,5~)]-[2-[3,5-bis[[(l,l-dimethyl)dimethylsilyl]oxy~-2-methylene-cyclohexylidene]ethyl]diphenylphosphine oxide in 45 ml of THF at -75C are added dropwise 1.87 ml of 1.6M butyllithi~m in hexane. After stirring for 6 minutes a solution of 0.693 g of the product of j) in 26 ml of THF are added dropwise. After stirring at -75C for 70 minutes and addition of a 1:1 mixture of lM potassium sodium tartrate - and 2M KHC03, the mixture is 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 (1:15) to give 1.23 g (87%) of (la,3~,5Z,7E)-1,3-bis[[l,l-dimethylethyl)dimethylsilyl]
-oxy-25-[(trimethylsilyl)oxy]-9,~0-secocholesta-5,7,10(19),16-tetraene-3-yne, ~a]D + 47.1 (c 0.2L, 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 lM tetrabutylammonium fluoride in THF. The mixture is stirred for 16 hours. After dilution 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-dihydroxy-16-dehydro-23-dide-hydeocholecalciferol, [a]D + 21.5+ (c 0.20, MeOH).
E~ 2 a) As described in Example lk), but starting from 0.343 g of [5S-(lZ)]-[2-[5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]
-2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.186 g of the product of Example Lj), thece were , obtained 0.205 g (80%) of (3~,5Z,7E)-3-[[(L,l-dimethyl-ethyl)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]D +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 0C is added dropwise a solution of 0.180 g of the product of Example lh) in 13 ml of THF. The mixture is heated at 68C
for 16 hours and recooled at 0C. ~fter dilution with 13 ml of ether and addition of 0.30 ml of water and 0.26 ml of 10 aqueous NaOH, the mixture is stirred at room temperature for 1 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 [l(R~),1(3E),3a~,4,-7aa)]-(3a,4,5,6,7,7a-hexahydro--1-(5-hydroxy-1,5-dimethyl--3-hexenyl)-7a-methyl-lH-inden-4-ol, [a]D +11.5~ (c 0.33, CHC13).
b) To a solution of 0.120 g of the product of a) in 10 ml of methylene chloride are added 0.500 g of pyridinium dichromate and 25 mg of pyridinium p-toluenesulfonate. The mixture is stirred for 135 minutes. ~fter addition of 40 ml of ether, the mixture is sticred for 5 minutes and filtered.
The solids are triturated with ether and filtered. The combined filtrates are washed with saturated aqueous CUSO4, water, half saturated aqueous NaHCO3 and saturated brine. The organic phase is dried and evaporated.
The residue is chromatographed on silica gel with 35% ethyl acetate-hexane to give 90 mg (76%) of [l(R~),1(3E),(3a~, 7a)]-3,3a,5,6,7,7a-hexahydro-1-(5 -hydroxy-1,5-dimethyl-3-hexenyl)-7a-methyl-4H-inden-4-one, ~a]D +30.6 (c 0.17, CHC13).
c) By treating 0.099 g of the product of b) as desccibed in Example li), there are obtained 0.111 g (89%) of [l(R~),1(3E),(3a~,7aa)]-3,3a,5,6,7,7a-hexahydro-L-(1,5--dimethyl-5-[(trimethylsilyl)oxy]-3-hexenyl)-7a-methyl--4H-inden-4-one, [a]D +26.4 (c 0.22, CHC13).
d) As described in Example lk), starting from 0.265 g of [3S-(lZ,3a,5~)]-[2-[3,5-bis[[(l,l -dimethyl)dimethyl-silyl]oxy] -2-methylenecyclohexylidene]ethyl]diphenyl-phosphine oxide and 0.095 g of the product of c), there areobtained 0.162 g (83%) of (lB,3a,5Z,7E,23E)-1,3-bis[[(l,l -dimethylethyl)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-16,23E-bisdehydrocholecalciferol, []24 +46.5 (c 0.20, MeOH).
Example 4 a) As described in Example lk), starting from 0.225 g of [5S-(lZ)]-[2-[5-[[(1,1-dimethylethyl)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 (3~,5Z,7E,23E)-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy] -25-[(t~imethylsilyl)-oxy]-9,10-secocholesta -5,7,10(19),16,23 pentaene, [a]D +68.3 (c 0.18, CHC13).
- 26 _ 1 33 7529 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-16,23E-bisdehydrocholecalciferol, [a]22 +6Z 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 -20C 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 lN HCl, 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-butanol and 4.86 g of imidazole in 15 ml of N,N-dimethylformamide at 0C 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-bromo-1,1-dimethylpropoxy)triethylsilane, MS m/e 265 (M -CH3).
c) To a solution of 0.930 g of [l(R~),3aR~(3a~,4a, 7aa)]-3a,4,5,6,7,7a-hexahydro -4-hydroxy-~,7a-dimethyl-3H-indene-l-ethanol 4-methyl-benzenesulfonate and 1.10 g of imidazole in 73 ml of methylene chloride at 0C are added 0.580 g of chlorotriethylsilane. The mixture is stirred at room temperature for 1.5 houcs. After adding ice, the mixture is diluted with water and stirred foc 20 minutes.
- 27 _ 1 337 52~
The organic layer is extracted with methylene chloride. The extracts are washed with water, lN N2SO4, satucated aqueous NaHC03 and saturated bcine. After drying and evaporation, the residue is purified on silica gel with ethyl acetate-hexane (l:S) to afford 1.22 g (100%) of [l(R*),3aR*-(3aB,4a,7aa)]-3a,4,5,6,7,7a-hexahydro -4-[(triethylsilyl)oxy]-~,7a-dimethyl-3H-indene-l-ethanol 4-methylbenze sulfonate, [a]D +46.1 (c 0.3L, CHC13).
d) To a solution of 3.08 g of (3-bromo-1,1-dimethyl-propoxy)triethylsilane in 31 ml of THF are added 0.282 g of magnesium. The mi-xture is heated at 68C for 3.5 hours. Then a mixture of 0.686 g of cuprous iodide and the above mentioned Grignard solution are stirred at 3C 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 tempecature for 40 minutes. After adding a mixture of ice and water, the mixture is extracted with ether. The organic phase is washed with lN H2S04 and saturated aqueous NaHC03, deied and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (l:lS) to afford 1.80 g of [l(R*),3aR*-(3a~,4a,7aa)]- 3a,4,5,6,7,7a-hexahydro--1-[1,5-dimethyl-5-[(triethylsilyl)- oxy]hexyl]--4-[(triethylsilyl)oxy]-7a-methyl-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 lM tetrabutylammonium fluoride in THF. The mixture is heated at 68C for 50 minutes. After cooling to coom 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 [l(R*),3aR*-(3a~,4aa, 7aa)]-3a,4,5,6,-7,7a-hexahydro-4-hydroxy-a,a-- F, 7a-tetramethyl-lH-indene-l-pentanol, [a]D =~12.0 - 28 - 1 337 52~
(c 0.25, CHC13).
f) To a solution of 0.210 g of the product of e) in 18 ml of methylene chloride are added 0.870 g of pyridinium 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 CUSO4, water, half saturated a~ueous NaHCO3 and saturated brine. The 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 [L(R*),3aR*--(3a~,7aa)]-3,3a,5,6,7,7a-hexahydro-1-(5-hydroxy-1,5-dimethylhexyl)-7a-methyl-4H-inden--4-one, ~a]D +28.2 (c 0.22, cHc13).
g) By treating 0.168 g of the product of f) as described in Example lj), there are obtained 0.211 g (100%) of [l(R*),3aR*-(3a~,7aa)]-3,3a,5,6,7,7a-hexahydro-1-(1,5-dimethyl-5-[(trimethylsilyl)oxy~hexyl)--7a-methyl-4H-inden-4-one, [a]2 +21.9 (c 0.27, CHC13).
h) As described in Example Lk), starting from 0.581 g of [3S-(lZ,3a,5B)]-[2-[3,5-bis[[(l,l-dimethyl)dimethylsilyl]-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,3~,5Z,7E)-1,3-bis[[(l,l-dimethyl-ethyl)dimethylsilyl]oxy]-25-[(trimethylsilyl)oxy]-9,10-secocholesta--5,7,10(19),16-tetraene, MS m/e 714 (M ).
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, [a]D +40 0 (c 0.17, MeOH).
- 29 _ 1 337 529 Example 6 a) As described in Example lk) staeting from 0.383 g of [5S-(lZ)]-[2-[5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]--2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.188 g of the product of Example 5g), there are obtained 0.245 g (78%) of (3a,5Z,7E)-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-25-[(trimethylsilyl)oxy]-9,10-seco-cholesta-5,7,10(19),16-tetraene, []D +67.5 lo (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 Z5-hydroxy-16-dehydro-cholecalciferol, [a]D +75.4 (c =.13, MeOH).
The following Example A and B illustrate the composi-tion of soft gelatine capsules for oral administration and of a topical cream:
Example A
. mq/capsule Compound E 0.000L-0.010 Butylated hydroxytoluene 0.016 25 Butylated hydroxyanisole 0.016 Fractionated coconut oil 160.0 _ 30 _ 1337529 Example B
mq/q of cream Com~pound E O.OOl-l.0 5 Cetyl alcohol l.5 Stearyl alcohol 2.5 Soebitan monostearate 2.0 Glyceryl monostearate and polyoxyethylene glycol stearate 4.0 10 P0lysorbate 60 l.0 Mineral oil 4.0 Propylene glycol 5.0 Propylparaben 0.05 Butylated hydroxyanisole 0.05 15 Sorbitol solution 2.0 Edetate disodium O.Ol Methylparaben 0.18 Distilled water q.s. to lO0 g
The invention relates to compounds of the focmula ~ A ~ I
H0` R
wherein R is hydrogen or hydroxy, and ~ is -C-C-, -CH=CH- with E-configuration or -CH2-CHz-, 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 for the treatment of neoplastic diseases, such as leukemia.
Examples of Cl 4-alkyl groups as referred to below, are methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
Examples of aryl-Cl 4-alkyl groups are benzyl, phenethyl and phenylpropyl. Examples of aryl groups are phenyl and p-tolyl. Halogen denotes bromine, chlorine, fluocine or iodine.
Compounds of formula I of the invention are compounds - 2 _ 1 337 529 to F as defined below:
A: 1,25-dihydroxy-16-dehydrocholecalciferol;
B: 25-hydroxy-16-dehydrocholecalciferol:
C: 1,25-dihydroxy-16,23E-bisdehydrocholecalciferol:
D: 25-hydroxy-16,23E-bisdehydrocholecalciferol:
E: 1,25-dihydroxy-16-dehyro-23-didehydrocholecalciferol: and F: 25-hydroxy-16-dehydro-23-didehydrocholecalciferol:
among which the 1,25-dihydroxylated compounds A, C and E are preferred.
The compounds of formulae la and Ib (encompassed by formula I) can be prepared as described in the Schemes 1, 2 and 3 by reacting a corresponding compound of formula I
containing instead of the two or three hydroxy groups two o~
three protected hydroxy groups of the formula -OSi(Rl,R2,R3) wherein Rl and R3 are Cl 4-alkyl and R2 is Cl_4-alkyl, aryl or aryl-Cl_4-alkyl, with an agent capable of removing the protecting groups.
~ - 3 - ~ 33~ 529 Scheme 1 =~
H
O ~l ~CS~ 2 ~ R~
~ ~c~ ~ I R2-5 a~ ~
R~ R~ R~
lV~
IVb C ~ A '~
HO-`` ~CH HO `~
wherein A is as described above and RL and R3 are independently Cl 4-alkyl and R2 is inde~endently Cl 4-alkyl. aryl, or aryl-Cl_4-alkyl.
_ 4 _ 1 337529 Scheme 2 ~ ~OH
~/
Lo '~.,~
~CH ~ I OH
O Vl HO Vll . "'~0~
~'1~ 2 Ç~
o H R3 Vlll llb ..
~CS~--R2 lla wherein Rl, R2 and R3 are as described above.
_ - 5 - 1 337 52 9 Scheme 3 ~ orS si--R2 R. ~/ X R~
R~ \~
IX
~ f ~ r ~ 2 ~ I
R ~ ~?/ ~
R2--SiO H
H Xll HO
~" ~r H Xlll I
~" ~`l R~
~ I 05;_R2 ~ lle o H
wherein Rl, R2 and R3 are as described above, X is chlorine, bromine or iodine and Ts is tosyl.
~ - 6 - 1337529 The intermediates of formula II, encompassing those of formulae IIa, lIb and IIc, are novel and are part of the invention.
In Scheme l, the compound of formula II is converted to a compound of formula IVa or IVb by reaction with the corresponding compound of formula ~ POPh2 R2 SlO` ~ ~ III
where Ph is phenyl: R4 is H or -OSi(Rl, R2, R3), and Rl, R2 and R3 are as described above.
The reaction is carried out at -60 to 90C, preferably -75C, 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 Ib.
In Scheme 2, the compound of formula V is oxidized to the compound of formula VI by treatment with an oxidizing agent, e.g. 2,2'-bipyridinium chlorochromate or preferably, pyridinium chlorochromate, in an aprotic, organic solvent such as methylene chloride.
- 7 - 1 337 52q The compound of formula VI is converted to a compound of formula IIb, 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 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 68C for THF), for about 10-20 hours.
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 of formula IIa, by reaction with a (trialkylsilyl)imidazole.
as described above for the conversion of VI to IIb.
In Scheme 3, the compound of formula X is reacted in ether, preferably THF, at reflux temperature with magnesium.
The resulting Grignard solution is treated with cuprous iodide and then the compound of formula IX is added.
The resulting compound of formula XI is reacted with a fluoride salt, e.g. tetrabutylammonium fluoride in ether or preferably THF.
The obtained compound of formula XII may be oxidized as described above for the oxidation of V to VI.
- 8 - 1 33752~
The resulting compound of formula XIII is converted to a compound of formula IIc, by reaction with a (trialkylsilyl)-imidazole as described above for the conversion of VI to IIb.
To prepare a compound of formula IX, the compound of focmula " ~ OH
~ XIV
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 ~ OTs XV
HO
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. T~IF or methylene chloride.
To prepare a compound of formula X, a compound of focmula ~ - 9 - 1 33752q can be converted to a compound of formula X-CH2CH2C(CH3)2-OH XVII
wherein X is as above, by ceaction with a methyl Grignard eeagent 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.
For 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 a~rotic organic solvent, e.g.
dimethyl sulfoxide (DMS0), at a temperature between 80 and 100C for l to 5 hours to give a compound of formula - CN
~ 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, -- lo - 1 337529 such as hydrochloric acid. The reduction is conducted in an aprotic organic solvent, e.g. methylene chloride, at about -10 to 10C for about 20 to 90 minutes. The compound of formula XIX is converted to the compound of formula H
4`c--Br ~> Ir XX
~--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 ~ XXI
by reaction with a strong base, e.g. butyllithium, in a polar aprotic solvent, e.g. THF, at about -80 to -70C, for about 1 to 3 hours. The compound of formula XXI is converted to the compound of formula ~ H
~ XXII
H
Me3 SiO
by reaction with (trimethylsilyl)imidazole in an aprotic organic solvent, e.g. THF or methylene chloride. This compound is converted to the compound of formula ' ~
OH XXIII
~ H
Me3 SiO
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 -60C. The compound of formula XXIII is deprotected to give the compound of formula ~ (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 are 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.
- L2 - 1 33752q The activity of compounds of formula I as agents for 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 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 L,25-dihydroxy-cholecalciferol (compound X) are expressed in the Tables 1 to 4 below, as number (xlO ) of human keratinocytes in 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.
Table 1 Compound Dose Number of cells (xlO ):
(M) total basal squamous envelope Control 133i5118i4 15il 18i2 X lO_lo 122i4103i2 l9i2 23il -8 112i689i2 23+4 30~3 lo-6 95i764i6 31+1 34+2 A lO_lo 132i8115i7 17il 27+2 -8 128ilO106i8 22~2 33+2 lo-6 lOli771i5 30i2 39~2 B lO_lo 133i6115i5 18il 25+1 -8 131i4lO9i2 22i2 2gi2 lo-6 104i474i3 30il 33il - 13 _ 1 33752q Table 2 Compound Dose Number of cells (xlO ):
(M) total basal squamous envelope Control 123i7 105i6 18il 74i7 X 10-1 116i9 95i8 21il 91i4 10-8lOlilO 75i8 26i2 122ill 1o-6 83i5 57i4 26il 146il6 C 10-1 117i4 92i2 25i2 103i6 10-8 108i3 80i2 28il 128+3 10-6 80i7 54i6 26+1 153il D 10-1113i7 93i6 20il 104ilO
10-8 llli7 86+3 25i2 128i5 1o-6 94i3 68il 26i2 144i7 Table 3 Compound Dose Number of cells (xlO ):
(M) total basal squamous envelope Control 108ilO 93i8 15i2 88i8 X lo-lo106i7 86i6 18il lOOi9 10-8 84i8 61i5 23i3 122+8 10-6 73i7 51i5 22i2 142ill E }o~l 86i4 63i2 23i2 114i5 10-8 82i3 53i2 29il 141i5 10-6 78i3 41il 27i2 147+4 3o F lO_lo103i5 81i3 22i2 103i4 10-8 97i3 67i2 29il 121+6 10-6 84i4 55i2 29il 137i7 The activity of compounds of formula I as agents for the treatment of hyperproliferative skin diseases can also be demonstrated by determining the number of human keratino--cytes grown and the number of envelopes formed, as well as the number squamous carcinoma cell lines (SCC-L15) grown in cultures, in the presence of said compounds. The results are given in the Tables 4 and 5:
Table 4 Treatment Dose Number of Number of (M) keratinocytes envelopes (x104) (x102) Control 189.49+22.3 858.28+185.70 (0.1% ethanol) Compound E lo~l2 187.36~15.33 1136.63i 383.66 10-1 175.34+10.19 1444.87+ 312.47 1o~8 145.79il5.66 2113.62ilO49.33 41.95i 7.53 1916.83 887.66 Control 148.73il6.23 2193.7i 921.9 (0.1% ethanol) Compound ~ lo~l2 114.91ilO.95 1662.2i 420.1 10-1 130.37i24.32 3973.8i 126.99 10 8 120.67il6.87 7235.2i 55.5 10 6 109.22il5.87 8323.5i 157.6 Table 5 Treatment Dose Number of (M) cell lines (SCC-15) (xlO
Control 7.35+1.75 Compound E lo~l2 6.98il.68 5.89+1.58 10 8 5.76il.53 lo~6 0.40iO.98 Compound A 10 0.49iO.13 The above results show that the compounds of foemula 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 promyelocytic HL-60 tumor cells were evaluated. In Table 6 the AP effect is given in percent reduction of cell number and in concentration ID50 f the compound which reduced the cells number by 50%. The DI effect is expressed as the percentage of differentiated cells and as the concentration ED50 of the compounds which induced a 50% differentiation of the cells.
Table 6 Concentration % Reduction ID50 Differen- ED50 (xlO M) in cell number (x 10 M) tiated (xlO M
cells(%) Compound X
0.01 6 3 0.1 5 11 COmPound A
0.01 10 3 0.1 33 16 1 84 0.2 92 0.2 Compound B
0.1 10 5 - 17 - 1 337 52~
Compound C
0.01 18 3 0.1 20 19 1 81 0.3 92 0.3 Compound D
0.1 12 looo 95 97 Compound E
0.01 6 9 0.1 59 50 1 80 0.0796 0.1 Compound F
0.1 13 4 These data indicate that each of the compounds in ~uestion 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 prolifecation. From these results it can be seen that each - 18 - 1 337 52q 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 for the treatment of neoplastic diseases or for the tceatment 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 ~g per day.
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 L000 ~g per gram of topical formulation per day.
Oral dosage forms comprising compounds of formula I may be incorporated e.g. in capsules or tablets with pharmaceutically acceptable carriers. Examples of such 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 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.
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, powders and aerosols. The topical compositions can also be employed in the treatment of inflammations of the skin or of mucous membranes, e.g. the mucous lining of the mouth or - 19 - I 33752q lower colon.
Lotions, i.e. liquid preparations varying from simple solutions to aqueous of hydroalcoholic preparations 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 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, or amines, such as polyethylenecocoamine.
Example 1 a) A mixture of 3.24 g of [l(R~),3aR~-(3a~,4,7aa)]-3a,4,5,6,7,7a-hexahydro-4-hydroxy-~,7a-dimethyl-3H-indene--l-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 lN
H2SO4, saturated NaHCO3, 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 [l(R~),3aR~-(3a~,4a,7aa)]-3a,4,5,6,7,7a-hexahydro-4-hydroxy-~,7a-dimethyl-3H-indene-l-ethanol -4-methyl-benzenesulfonate, [a]D + 31.9 (c 0.53, CHC13).
b) To a solution of 4.61 g of the product of a) in 22 ml ofDMSO is added 1.10 g of sodium cyanide and the mixture is heated at 90C for 2 hours. After cooling to room 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, - 20 _ 1 33 75 29 dried 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*-(3a~,4a,7aa)]-3a,4,5,6,7,7a-hexahydro-4-hydroxy-~,7a-dimethyl-3H-indene-l-propanenitrile, [a]D + 29.2 (c 0.65, CHC13).
c) To a mixture of 6.85 ml of diisobutylaluminium hydride in hexane and 5.2 ml of methylene chloride at -6C is added a solution of 0.430 g of the product of b) in 10 ml of methylene chloride. The mixture is stirred at -6C 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%) [l(R*),3aR*-(3a~,4a,7aa)]--3a,4,5,6,7,7a-hexahydro-4-hydroxy-~,7a-dimethyl-3H-indene--l-propanal, [a]D + 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 25C 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 ~iltrates are evaporated. The residue is purified on silica gel with 1:4 ethyl acetate-hexane tO give 0.490 g (67%) of [l(R*),3aR*-(3a~,4a,7aa)]-1-(4,4-dibromo- l-methyl -3-butenyl)-3a,4,5,6,7,7a-hexahydro-7a-methyl-3H-indene-4-ol, [a]D + 14.4 (c 0.55, CHC13).
e) To a solution of 0.680 g of the product of d) in 3L ml of THF at -75C are added dropwise 3.77 ml of 1.6M solution - 1 33752~
of butyllithium in hexane. The mixture is stirred at -75C
for 1 hour and at 25C for 1 hr. After addition of saturated brine, the mixture is diluted with saturated aqueous NaHC03 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 [l(R*),3aR~-(3aB,4a,7aa)]-3a,4,5,6,7,7a-hexahydro -7a-methyl-1-(l-methyl-3-butynyl)-3H-inden-4-ol, [a]D + 30.7 (c 0.42, CHC13).
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 25C for 3 hours. After 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 [l(R*),3aR*-(3aB,4a,7aa)]-3a,4,5,6,7,7a-hexahydro -7a-methyl-1-(l-methyl-3-butynyl)-4-[(trimethylsilyl)oxy] -3H-indene, [a]2 + 39.7O (c 0.30, CHC13).
g) To a solution of 1.70 g of the product of f) in 48 ml of THF at -75C 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 --75C for Z0 minutes and at 25C for 75 minutes. After addition of 40 ml of a 1:1 mixture of 2M KHCO3 and lM potassium sodium tartrate, the 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 [l(R*),3aR*-(3aB,4a,7aa)]-6-(3a, 4,5,6,7,7a-hexahydro-7a-methyl--4-[(tcimethylsilyl)oxy]-3H-inden-l-yl)-2-methyl--3-heptyn-1-ol, [a]2 + 39.7O
- 22 - ~ 337 529 (c 0.30, CHC13).
h) To a solution of 1.62 g of the product of g) in 53 ml of THF are added 15.5 ml of lM tetrabutylammonium fluoride in THF. The mixture is stirred for 50 minutes. After dilution with half saturated NaHC03, 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 [l(R*),3aR*-(3aB,4a,7aa)]-3a,4,5,6,7,7a-hexahydro -1-(1,5-dimethyl-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 2,2'-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 organic phase is washed with water, lN
H2S04, saturated NaHCO3 and saturated brine. After drying, the solution is evaporated and the residue chroma-tographed on silica gel with ethyl acetate-hexane (1:1) to give 0.560 g (78%) of [l(R*),3aR*-(3aB,7aa)]--3,3a,5,6,7,7a-hexahydro-1-(5-hydroxy-1,5-dimethyl--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 chcomatographed on silica gel with ethyl acetate-hexane (1:4) to give 0.693 g - 23 - 1 33 7 52~
(99%) of [l(R~),3aR~-(3a~,7aa)]-3,3a,5,6,7,7a-hexahydro -1-(1,5-dimethyl-5-[(teimethylsilyl)oxy]-3-hexynyl) -7a-methyl-4H-inden-4-one, [a~D + 29.5 (c 0.20, CHC13).
k) To a solution of 2.00 g of ~3S-(lZ,3a,5~)]-[2-[3,5-bis[[(l,l-dimethyl)dimethylsilyl]oxy~-2-methylene-cyclohexylidene]ethyl]diphenylphosphine oxide in 45 ml of THF at -75C are added dropwise 1.87 ml of 1.6M butyllithi~m in hexane. After stirring for 6 minutes a solution of 0.693 g of the product of j) in 26 ml of THF are added dropwise. After stirring at -75C for 70 minutes and addition of a 1:1 mixture of lM potassium sodium tartrate - and 2M KHC03, the mixture is 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 (1:15) to give 1.23 g (87%) of (la,3~,5Z,7E)-1,3-bis[[l,l-dimethylethyl)dimethylsilyl]
-oxy-25-[(trimethylsilyl)oxy]-9,~0-secocholesta-5,7,10(19),16-tetraene-3-yne, ~a]D + 47.1 (c 0.2L, 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 lM tetrabutylammonium fluoride in THF. The mixture is stirred for 16 hours. After dilution 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-dihydroxy-16-dehydro-23-dide-hydeocholecalciferol, [a]D + 21.5+ (c 0.20, MeOH).
E~ 2 a) As described in Example lk), but starting from 0.343 g of [5S-(lZ)]-[2-[5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]
-2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.186 g of the product of Example Lj), thece were , obtained 0.205 g (80%) of (3~,5Z,7E)-3-[[(L,l-dimethyl-ethyl)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]D +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 0C is added dropwise a solution of 0.180 g of the product of Example lh) in 13 ml of THF. The mixture is heated at 68C
for 16 hours and recooled at 0C. ~fter dilution with 13 ml of ether and addition of 0.30 ml of water and 0.26 ml of 10 aqueous NaOH, the mixture is stirred at room temperature for 1 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 [l(R~),1(3E),3a~,4,-7aa)]-(3a,4,5,6,7,7a-hexahydro--1-(5-hydroxy-1,5-dimethyl--3-hexenyl)-7a-methyl-lH-inden-4-ol, [a]D +11.5~ (c 0.33, CHC13).
b) To a solution of 0.120 g of the product of a) in 10 ml of methylene chloride are added 0.500 g of pyridinium dichromate and 25 mg of pyridinium p-toluenesulfonate. The mixture is stirred for 135 minutes. ~fter addition of 40 ml of ether, the mixture is sticred for 5 minutes and filtered.
The solids are triturated with ether and filtered. The combined filtrates are washed with saturated aqueous CUSO4, water, half saturated aqueous NaHCO3 and saturated brine. The organic phase is dried and evaporated.
The residue is chromatographed on silica gel with 35% ethyl acetate-hexane to give 90 mg (76%) of [l(R~),1(3E),(3a~, 7a)]-3,3a,5,6,7,7a-hexahydro-1-(5 -hydroxy-1,5-dimethyl-3-hexenyl)-7a-methyl-4H-inden-4-one, ~a]D +30.6 (c 0.17, CHC13).
c) By treating 0.099 g of the product of b) as desccibed in Example li), there are obtained 0.111 g (89%) of [l(R~),1(3E),(3a~,7aa)]-3,3a,5,6,7,7a-hexahydro-L-(1,5--dimethyl-5-[(trimethylsilyl)oxy]-3-hexenyl)-7a-methyl--4H-inden-4-one, [a]D +26.4 (c 0.22, CHC13).
d) As described in Example lk), starting from 0.265 g of [3S-(lZ,3a,5~)]-[2-[3,5-bis[[(l,l -dimethyl)dimethyl-silyl]oxy] -2-methylenecyclohexylidene]ethyl]diphenyl-phosphine oxide and 0.095 g of the product of c), there areobtained 0.162 g (83%) of (lB,3a,5Z,7E,23E)-1,3-bis[[(l,l -dimethylethyl)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-16,23E-bisdehydrocholecalciferol, []24 +46.5 (c 0.20, MeOH).
Example 4 a) As described in Example lk), starting from 0.225 g of [5S-(lZ)]-[2-[5-[[(1,1-dimethylethyl)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 (3~,5Z,7E,23E)-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy] -25-[(t~imethylsilyl)-oxy]-9,10-secocholesta -5,7,10(19),16,23 pentaene, [a]D +68.3 (c 0.18, CHC13).
- 26 _ 1 33 7529 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-16,23E-bisdehydrocholecalciferol, [a]22 +6Z 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 -20C 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 lN HCl, 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-butanol and 4.86 g of imidazole in 15 ml of N,N-dimethylformamide at 0C 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-bromo-1,1-dimethylpropoxy)triethylsilane, MS m/e 265 (M -CH3).
c) To a solution of 0.930 g of [l(R~),3aR~(3a~,4a, 7aa)]-3a,4,5,6,7,7a-hexahydro -4-hydroxy-~,7a-dimethyl-3H-indene-l-ethanol 4-methyl-benzenesulfonate and 1.10 g of imidazole in 73 ml of methylene chloride at 0C are added 0.580 g of chlorotriethylsilane. The mixture is stirred at room temperature for 1.5 houcs. After adding ice, the mixture is diluted with water and stirred foc 20 minutes.
- 27 _ 1 337 52~
The organic layer is extracted with methylene chloride. The extracts are washed with water, lN N2SO4, satucated aqueous NaHC03 and saturated bcine. After drying and evaporation, the residue is purified on silica gel with ethyl acetate-hexane (l:S) to afford 1.22 g (100%) of [l(R*),3aR*-(3aB,4a,7aa)]-3a,4,5,6,7,7a-hexahydro -4-[(triethylsilyl)oxy]-~,7a-dimethyl-3H-indene-l-ethanol 4-methylbenze sulfonate, [a]D +46.1 (c 0.3L, CHC13).
d) To a solution of 3.08 g of (3-bromo-1,1-dimethyl-propoxy)triethylsilane in 31 ml of THF are added 0.282 g of magnesium. The mi-xture is heated at 68C for 3.5 hours. Then a mixture of 0.686 g of cuprous iodide and the above mentioned Grignard solution are stirred at 3C 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 tempecature for 40 minutes. After adding a mixture of ice and water, the mixture is extracted with ether. The organic phase is washed with lN H2S04 and saturated aqueous NaHC03, deied and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (l:lS) to afford 1.80 g of [l(R*),3aR*-(3a~,4a,7aa)]- 3a,4,5,6,7,7a-hexahydro--1-[1,5-dimethyl-5-[(triethylsilyl)- oxy]hexyl]--4-[(triethylsilyl)oxy]-7a-methyl-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 lM tetrabutylammonium fluoride in THF. The mixture is heated at 68C for 50 minutes. After cooling to coom 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 [l(R*),3aR*-(3a~,4aa, 7aa)]-3a,4,5,6,-7,7a-hexahydro-4-hydroxy-a,a-- F, 7a-tetramethyl-lH-indene-l-pentanol, [a]D =~12.0 - 28 - 1 337 52~
(c 0.25, CHC13).
f) To a solution of 0.210 g of the product of e) in 18 ml of methylene chloride are added 0.870 g of pyridinium 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 CUSO4, water, half saturated a~ueous NaHCO3 and saturated brine. The 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 [L(R*),3aR*--(3a~,7aa)]-3,3a,5,6,7,7a-hexahydro-1-(5-hydroxy-1,5-dimethylhexyl)-7a-methyl-4H-inden--4-one, ~a]D +28.2 (c 0.22, cHc13).
g) By treating 0.168 g of the product of f) as described in Example lj), there are obtained 0.211 g (100%) of [l(R*),3aR*-(3a~,7aa)]-3,3a,5,6,7,7a-hexahydro-1-(1,5-dimethyl-5-[(trimethylsilyl)oxy~hexyl)--7a-methyl-4H-inden-4-one, [a]2 +21.9 (c 0.27, CHC13).
h) As described in Example Lk), starting from 0.581 g of [3S-(lZ,3a,5B)]-[2-[3,5-bis[[(l,l-dimethyl)dimethylsilyl]-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,3~,5Z,7E)-1,3-bis[[(l,l-dimethyl-ethyl)dimethylsilyl]oxy]-25-[(trimethylsilyl)oxy]-9,10-secocholesta--5,7,10(19),16-tetraene, MS m/e 714 (M ).
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, [a]D +40 0 (c 0.17, MeOH).
- 29 _ 1 337 529 Example 6 a) As described in Example lk) staeting from 0.383 g of [5S-(lZ)]-[2-[5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]--2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.188 g of the product of Example 5g), there are obtained 0.245 g (78%) of (3a,5Z,7E)-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-25-[(trimethylsilyl)oxy]-9,10-seco-cholesta-5,7,10(19),16-tetraene, []D +67.5 lo (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 Z5-hydroxy-16-dehydro-cholecalciferol, [a]D +75.4 (c =.13, MeOH).
The following Example A and B illustrate the composi-tion of soft gelatine capsules for oral administration and of a topical cream:
Example A
. mq/capsule Compound E 0.000L-0.010 Butylated hydroxytoluene 0.016 25 Butylated hydroxyanisole 0.016 Fractionated coconut oil 160.0 _ 30 _ 1337529 Example B
mq/q of cream Com~pound E O.OOl-l.0 5 Cetyl alcohol l.5 Stearyl alcohol 2.5 Soebitan monostearate 2.0 Glyceryl monostearate and polyoxyethylene glycol stearate 4.0 10 P0lysorbate 60 l.0 Mineral oil 4.0 Propylene glycol 5.0 Propylparaben 0.05 Butylated hydroxyanisole 0.05 15 Sorbitol solution 2.0 Edetate disodium O.Ol Methylparaben 0.18 Distilled water q.s. to lO0 g
Claims (5)
1. A compound of the formula wherein R is hydrogen or hydroxy and A is -C ? C-, -CH=CH- with E-configuration or -CH2-CH2-.
2. A compound in accordance with claim 1, of the group consisting of:
1,25-dihydroxy-16-dehydro-23-didehydrocholecalciferol, 1,25-dihydroxy-16,23E-bisdehydrocholecalciferol and 1,25-dihydroxy-16-dehydrocholecalciferol.
1,25-dihydroxy-16-dehydro-23-didehydrocholecalciferol, 1,25-dihydroxy-16,23E-bisdehydrocholecalciferol and 1,25-dihydroxy-16-dehydrocholecalciferol.
3. 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 the two or three hydroxy groups two or three protected hydroxy qroups of the formula -OSi(R1,R2,R3) wherein R1 and R3 are C1-4-alkyl and R2 is C1-4-alkyl, aryl or aryl-C1-4-alkyl, with an agent capable of removing the protecting groups.
4. 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.
5. 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, or for the treatment of neoplastic diseases, especially leukemia.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14593288A | 1988-01-20 | 1988-01-20 | |
| US145,932 | 1988-01-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1337529C true CA1337529C (en) | 1995-11-07 |
Family
ID=22515181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000588384A Expired - Fee Related CA1337529C (en) | 1988-01-20 | 1989-01-17 | 16-dehydro-vitamin d -derivatives |
Country Status (23)
| Country | Link |
|---|---|
| EP (1) | EP0325279B1 (en) |
| JP (1) | JPH0764806B2 (en) |
| KR (1) | KR960009119B1 (en) |
| AR (1) | AR247551A1 (en) |
| AT (1) | ATE74350T1 (en) |
| AU (1) | AU622139B2 (en) |
| BG (1) | BG60530B2 (en) |
| CA (1) | CA1337529C (en) |
| DE (1) | DE58901056D1 (en) |
| DK (1) | DK169945B1 (en) |
| ES (1) | ES2033467T3 (en) |
| FI (1) | FI90764C (en) |
| GR (1) | GR3004786T3 (en) |
| HU (1) | HU201007B (en) |
| IE (1) | IE60921B1 (en) |
| IL (1) | IL88989A (en) |
| MC (1) | MC1998A1 (en) |
| NO (1) | NO175429C (en) |
| NZ (1) | NZ227641A (en) |
| PH (1) | PH25605A (en) |
| PT (1) | PT89486B (en) |
| YU (1) | YU47298B (en) |
| ZA (1) | ZA8923B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4804502A (en) * | 1988-01-20 | 1989-02-14 | Hoffmann-La Roche Inc. | Vitamin D compounds |
| DK0398217T3 (en) * | 1989-05-18 | 1994-02-14 | Hoffmann La Roche | Dehydrocholecalciferol derivatives |
| AU650751B2 (en) * | 1991-05-28 | 1994-06-30 | Wisconsin Alumni Research Foundation | Novel synthesis of 19-nor vitamin D compounds |
| ATE141914T1 (en) * | 1992-05-20 | 1996-09-15 | Hoffmann La Roche | FLUORINATED ANALOGUE VITAMINS D3 |
| CA2096105A1 (en) * | 1992-10-07 | 1994-04-08 | Enrico Giuseppe Baggiolini (Deceased) | Vitamin d3 fluorinated analogs |
| US5753638A (en) * | 1992-10-07 | 1998-05-19 | Hoffmann-La Roche Inc. | Method of treating hyperproliferative skin disease with Vitamin D3 fluorinated analogs |
| TW267161B (en) * | 1992-11-20 | 1996-01-01 | Hoffmann La Roche | |
| US5401733A (en) * | 1993-10-01 | 1995-03-28 | Hoffmann-La Roche Inc. | Stable and active metabolites of 1,25-dihydroxy-16-ene-cholecalciferol |
| US5428029A (en) * | 1993-11-24 | 1995-06-27 | Hoffmann-La Roche Inc. | Vitamin D3 fluorinated analogs |
| TW403735B (en) * | 1995-11-22 | 2000-09-01 | Hoffmann La Roche | 25-hydroxy-16-ene-26, 27-bishomo-cholecalciferol |
| AU708679B2 (en) * | 1996-03-21 | 1999-08-12 | F. Hoffmann-La Roche Ag | 1,25-dihydroxy-16,22,23-trisdehydro-cholecalciferol derivatives |
| US5939408A (en) * | 1996-05-23 | 1999-08-17 | Hoffman-La Roche Inc. | Vitamin D3 analogs |
| SG70009A1 (en) * | 1996-05-23 | 2000-01-25 | Hoffmann La Roche | Vitamin d3 analogs |
| DK0884308T3 (en) * | 1997-05-02 | 2003-07-21 | Duphar Int Res | Process for Preparation of 16-Dehydro Vitamin D Compounds |
| US6331642B1 (en) * | 1999-07-12 | 2001-12-18 | Hoffmann-La Roche Inc. | Vitamin D3 analogs |
| US9221753B2 (en) * | 2004-02-03 | 2015-12-29 | Chugai Seiyaku Kabushiki Kaisha | Process for the synthesis of vitamin D compounds and intermediates for the synthesis of the compounds |
| US8906888B2 (en) * | 2005-04-25 | 2014-12-09 | Cytochroma Inc. | Low-calcemic 16,23-diene 25-oxime analogs of 1α,25-dihydroxy vitamin D3 |
| JP2009508813A (en) * | 2005-08-18 | 2009-03-05 | ビオクセル エッセ ピ ア | Synthesis of 1α-fluoro-25-hydroxy-16-23E-diene-26,27-bishomo-20-epi-cholecalciferol |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1574685A (en) * | 1977-03-24 | 1980-09-10 | Wisconsin Alumni Res Found | Vitamin d3 derivatives |
| GB2021115B (en) * | 1978-05-19 | 1982-10-06 | Wisconsin Alumni Res Found | Vitamin d derivatives |
| US4360471A (en) * | 1981-12-11 | 1982-11-23 | Wisconsin Alumni Research Foundation | 23-Dehydro-25-hydroxyvitamin D3 |
| US4508651A (en) * | 1983-03-21 | 1985-04-02 | Hoffmann-La Roche Inc. | Synthesis of 1α,25-dihydroxyergocalciferol |
| US4505906A (en) * | 1984-01-30 | 1985-03-19 | Wisconsin Alumni Research Foundation | Hydroxyvitamin D2 isomers |
| US4612308A (en) * | 1984-11-29 | 1986-09-16 | Hoffmann-La Roche Inc. | 25,26-Dehydro-1α,23(S,R)-dihydroxycholecalciferol and its epimers |
| US4898855A (en) * | 1987-09-14 | 1990-02-06 | Hoffman-La Roche Inc. | Deuterated analogs of 1,25-dihydroxycholecalciferol |
| US4804502A (en) * | 1988-01-20 | 1989-02-14 | Hoffmann-La Roche Inc. | Vitamin D compounds |
| DK0398217T3 (en) * | 1989-05-18 | 1994-02-14 | Hoffmann La Roche | Dehydrocholecalciferol derivatives |
-
1989
- 1989-01-03 ZA ZA8923A patent/ZA8923B/en unknown
- 1989-01-17 CA CA000588384A patent/CA1337529C/en not_active Expired - Fee Related
- 1989-01-17 PH PH38057A patent/PH25605A/en unknown
- 1989-01-17 NZ NZ227641A patent/NZ227641A/en unknown
- 1989-01-17 DK DK019789A patent/DK169945B1/en not_active IP Right Cessation
- 1989-01-18 AR AR89313011A patent/AR247551A1/en active
- 1989-01-18 IL IL88989A patent/IL88989A/en not_active IP Right Cessation
- 1989-01-18 HU HU89175A patent/HU201007B/en not_active IP Right Cessation
- 1989-01-19 YU YU11789A patent/YU47298B/en unknown
- 1989-01-19 AU AU28644/89A patent/AU622139B2/en not_active Ceased
- 1989-01-19 MC MC902029A patent/MC1998A1/en unknown
- 1989-01-19 KR KR89000514A patent/KR960009119B1/en not_active IP Right Cessation
- 1989-01-19 JP JP1008782A patent/JPH0764806B2/en not_active Expired - Fee Related
- 1989-01-19 FI FI890283A patent/FI90764C/en not_active IP Right Cessation
- 1989-01-19 NO NO890239A patent/NO175429C/en unknown
- 1989-01-19 PT PT89486A patent/PT89486B/en not_active IP Right Cessation
- 1989-01-19 IE IE15789A patent/IE60921B1/en not_active IP Right Cessation
- 1989-01-20 AT AT89100974T patent/ATE74350T1/en not_active IP Right Cessation
- 1989-01-20 DE DE8989100974T patent/DE58901056D1/en not_active Expired - Fee Related
- 1989-01-20 EP EP89100974A patent/EP0325279B1/en not_active Expired - Lifetime
- 1989-01-20 ES ES198989100974T patent/ES2033467T3/en not_active Expired - Lifetime
-
1992
- 1992-06-03 GR GR920401138T patent/GR3004786T3/el unknown
-
1994
- 1994-02-24 BG BG98544A patent/BG60530B2/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1337529C (en) | 16-dehydro-vitamin d -derivatives | |
| US5145846A (en) | Vitamin D3 analogs | |
| US5087619A (en) | Vitamin D3 analogs | |
| EP0654467B1 (en) | Vitamin D3 analogs | |
| CA2096105A1 (en) | Vitamin d3 fluorinated analogs | |
| HU201736B (en) | Process for producing didehydro-d3-vitamin derivatives and pharmaceutical preparations containing same | |
| EP0580968A2 (en) | Vitamin D3 fluorinated analogs | |
| US5919986A (en) | D-homo vitamin D3 derivatives | |
| AU669222B2 (en) | Vitamin D3 analogs | |
| EP0180399B1 (en) | Anti-tumor 4-hydroxy-2-cyclopentenones | |
| EP0796843B1 (en) | 1,25-dihydroxy-16,22,23-trisdehydro-cholecalciferol derivatives | |
| EP0977734A2 (en) | Arylsecocholadiene derivatives | |
| Enrico et al. | Vitamin D 3 analogs | |
| WO1997016423A1 (en) | 24-homo-26,27-hexafluoro-cholecalciferols | |
| SI8910117A (en) | 16-dehydro-d3 vitamin derivatives | |
| Barbier et al. | D-homo vitamin D 3 derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |