CA2222785C

CA2222785C - Vitamin d analogues

Info

Publication number: CA2222785C
Application number: CA002222785A
Authority: CA
Inventors: Martin John Calverley
Original assignee: Leo Pharmaceutical Products Ltd AS
Current assignee: Leo Pharma AS
Priority date: 1995-12-05
Filing date: 1996-12-02
Publication date: 2006-04-04
Anticipated expiration: 2016-12-02
Also published as: CA2222785A1

Abstract

The present invention relates to compounds of formula (I) in which formula X is hydrogen or hydroxy; R1 and R2 stand for methyl or ethyl, or, when taken together with the carbon atom bearing the group X, can form a C3-C5 carbocyclic ring; Q is either a single bond or a C1-C8 hydrocarbylene in which one of any methylene groups not directly bonded to the carbonyl group may optionally be replaced by an oxygen atom (or methyl by hydroxy); Y is either a single bond or C1-C8 hydrocarbylene; and derivatives of (I) in which one or more of the hydroxy groups are masked as groups which can be reconverted to hydroxy groups in vivo. The compounds show antiinflammatory and immunomodulating effects as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells.

Description

VITAMIN D ANALOGUES
' This invention relates to a hitherto unknown class of compounds which shows strong activity in inducing differentiation and inhibiting undesirable proliferation of l0 certain cells, including skin cells and cancer cells, as well as immunomodulating and antiinflammatory effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and/or prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation such as e.g. psoriasis and other disturbances of keratinization, HIV-associated dermatoses, wound healing, cancer, including skin cancer, and of diseases of, or imbalance in, the immune system, such as host versus graft and graft versus host reaction and transplant rejection, and autoimmune diseases, such as discoid and systemic lupus erythematosus, diabetes mellitus and chronic dermatoses of autoimmune type, e.g. scleroderma and pemphigus vulgaris, and inflammatory diseases, such as rheumatoid arthritis and asthma, as well as a number of other disease states includ-ing hyperparathyroidism, particularly secondary hyperpara-thyroidism associated with renal failure, cognitive impair-ment or senile dementia (Alzheimers disease) and other neu-rodegenerative diseases, hypertension, acne, alopecia, skin atrophy, e.g. steroid induced skin atrophy, skin ageing, including photo-ageing, and to their use for promoting osteogenesis and treating/preventing osteoporosis and osteomalacia.
The compounds of the invention constitute a novel class of vitamin D analogues represented by the general formula I:

WO 97/20811 PCT/DK9b/00502 ~J

Ha''' in which formula X is hydrogen or hydroxy; R3 and R2 stand for methyl or ethyl, or, when taken together with the carbon atom bearing the group X, can form a C3-C5 carbo-cyclic ring; Q is either a single bond or a Cl-C$
hydrocarbylene in which one of any methylene groups not directly bonded to the carbonyl group may optionally be replaced by an oxygen atom (or methyl byhydroxy); Y is either a single bond or CI-C$ hydrocarbylene.
In the context of this invention, the expression hydrocarbylene indicates the diradical obtained after removal of 2 hydrogen atoms from a straight, branched or cyclic, saturated or unsaturated hydrocarbon.
Examples of Q and Y (when not a single bond) include, but are not limited to, methylene, ethylene, CH=CH, C-C, trimethylene, CH=CHCH2, CH2CH=CH, C=CCH2, CH2-C--__C, analog-ously derived C4- (tetramethylene) and C5-diradicals, and additionally, for Q: O-CH2, O-CH2CH2, CH2-O-CH2CH2, CH2CH2-O-CH2, CH(OEt) -C=CH, CH(OH) -CH2, CH(OEt) -C=C, and for Y:
phenylene (o-, m-, p-). , The compounds of the invention can comprise more than one diastereoisomeric form (e.g. E or Z configurations when ' a double bond is present in the group Q or Y; R and S con-figurations when a branching carbon is present}. The inven-tion covers all these diastereoisomers in pure form and also mixtures thereof. In addition, prodrugs of I in which one or more of the hydroxy groups are masked as groups which can be reconverted to hydroxy groups in vivo are also within the scope of the invention.
The compounds I may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or recrystallisation from an organic solvent or mixture of said solvent and a cosolvent which may be organic or inorganic, such as water. The crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all cry-stalline modifications and forms and also mixtures thereof.
A number of vitamin D analogues have recently been described that show some degree of selectivity in favour of the cell differentiation inducing/cell proliferation in-hibiting activity in vitro as compared with the effects on calcium metabolism in vivo (as measured in increased serum calcium concentration and/or increased urinary calcium excretion), which adversely limit the dosage that can safe-ly be administered. One of the first of these to appear, calcipotriol (INN) or calcipotriene (USAN), has been devel-oped on the basis of this selectivity and is now recognized worldwide as an effective and safe drug for the topical treatment of psoriasis.
A study with another analogue (EB 1089) selected on this basis supports the concept that systemically adminis-tered vitamin D analogues may inhibit breast cancer cell proliferation in vivo at sub-toxic doses (Colston, K.W. et al., Biochem. Pharmacol. 44, 2273-2280 (1992)).
Promising immunosuppressive activities of vitamin D
analogues have been reviewed (Binderup, L., Biochem. Phar-' macol. 43, 1885-1892 (1992)). Thus, a series of 20-epi-vitamin D analogues has been identified as potent " inhibitors of T-lymphocyte activation in vitro (Binderup, L. et al, Biochem. Pharmacol. 42, 1569-1575 (1991)). Two of these analogues, MC 1288 and KH 1060, systemically ad ministered, have shown immunosuppressive activities in vivo in experimental animal models. Additive or synergistic effects were observed in combination with low-dose cyclosporin A. KH 1060, alone or in combination with cyclosporin A, has also been shown to prevent autoimmune destruction of transplanted islets in diabetic NOD mice (Bouillon, R. et al. In: Vitamin D, Proceedings of the Ninth Workshop on Vitamin D, Orlando, Florida, Walter de Gruyter, Berlin, 1994, pp 551-552). MC 1288 was able to prolong survival of cardiac and small bowel grafts in rats (Johnsson, C. et al. In: Vitamin D, Proceedings of the Ninth Workshop on Vitamin D, Orlando, Florida, Walter de Gruyter, Berlin, 1994, pp 549-550). However, in all these studies, the dosages of the analogues that produced sig-nificant immunosuppression also induced increases in serum calcium levels. There is therefore a continuing need for new analogues with high potency showing an acceptable com-bination of prolonged therapeutic activity and minimum toxic effects.
The present invention provides a hitherto undisclosed series of 20-epicholecalciferol analogues which are characterised by the presence of a keto function in the side chain. Analogues of vitamin D with a keto moiety (a carbonyl group bonded to two carbon atoms) in the side chain are not new: For example, Kureha Chemical Industries KK in Japanese Patent Application No. 210016/1983 disclose the use of 23-oxo-1,25,26-trihydroxycholecalciferol as an antitumour drug. Norman, A.W. and Mayer, E. of the Univer-sity of California describe the synthesis of 1,25--dihydroxy-24-oxo-vitamin D3 and 1,23,25-trihydroxy-24-oxo--vitamin D3 (US 4,495,181, 1985). The Teijin Company dis-closes 24-oxo-vitamin D3 derivatives as neoplasm inhibitors in Japanese Patent Application No. 067,423/1985. Hamma, N. ' et al. describe fluorine derivatives of vitamin D3 and process for producing the same (EP 250,755, 1988). McLane, J.A. et al. disclose stable and active metabolites of 1,25--dihydroxy-16-ene-cholecalciferol (US 5,401,733, 1995). An example of a 22-oxa-24-ketone with cell differentiating activity is described by the Chugai Pharmaceutical Company in Japanese Patent Application No. 8,113,559/1995. How-ever, it should be noted that these and other prior art side chain keto compounds that have been exemplified are 5 characterised by the presence of the natural vitamin D
configuration of the C-20 methyl group. Furthermore, these compounds contain the keto function located at either the second or the third atom away from C-20 (position 23 or position 24).
The compounds of the present invention differ from the prior art side chain keto compounds in the configur-ation of the C-20 methyl group; this has the ,(3-projection as shown in the conventional representation used in formula I. In addition, the skeleton of the other C-20 substituent (the rest of the side chain) is not restricted to being either aliphatic or six-carbon, nor is the location of the keto group limited to either the second or the third atom away from C-20. These compounds have been discovered to possess exceptionally high immunosuppressive activities together with high tumour cell proliferation inhibiting activities. For example, the compound of Example 4 (Compound 104) was found to be more potent than the ana-logues MC 1288 and KH 1060 (the hitherto most potent compound tested) tablified in the above mentioned review (Binderup, 1992) in inhibiting allogeneic T-lymphocyte activation (mixed lymphocyte reaction) in vitro while it was less calcemic in vivo. Furthermore compound 104 was found to be at least ten times more potent than its corre-sponding 20-normal-configurated (20R) isomer in this immu-nological test system. The same orders of activity were observed in other in vitro immunological test systems such as the inhibition of the proliferative response of human lymphocytes induced by phytohemagglutinin (using the method described in Piekoszewski, W. et al., Immunopharmacology and Immunotoxicology, 16, 389-401 (1994)). The compounds of Examples 1 and 2 (Compounds 101 and 102) were also found to be over ten times more potent than their 20-isomers which had been synthesised for comparison purposes. The compounds were additionally highly active in the U937 cancer cell differentiation test, also referred to in the same review (Binderup, 1992), with the compounds of the present inven-tion being approximately ten-fold more potent than their 20-isomers.

Scheme 1 I I ( R= CHO ) IIa (R= H) (~-c-t~~-z III IV

cc~-c-cv~-z V I

S
A compound of formula I may be prepared by the general method of Scheme 1. In this Scheme, the vitamin D nucleus building block aldehyde II, in which the aldehyde carbon is .
positioned appropriately to become the side chain keto carbon in the target compound I, is the starting material.
This aldehyde II is either the simple compound in which Qa represents a single bond or a known derivative, or a new derivative prepared by a standard sequence of reactions. In the following, the symbol Qa in II indicates that this linking group may either be identical to Q in the compound I, or alternatively may be a group which can be converted to Q at any subsequent stage in the synthesis. Furthermore, the identity of Qa may change from intermediate to inter-mediate along the reaction sequence. However the actual identity will be apparent from the particular context.
Following the synthetic scheme as depicted:-1 II is reacted with an organometallic reagent of formula Z-(Ya)-M (wherein the metal radical M
represents optionally Li or Mg-Hal; Hal= C1, Br, or I), derived from a side chain building block of formula Z- (Ya) -H or Z- (Ya) -Hal, to establish the remainder of the carbon side chain skeleton in the intermediate III. The side chain alcohol configuration may be R or S
or a mixture and is irrelevant to the syn-thesis. Again, the symbol Ya is used to indi-cate optional identity with or convertibility to Y (see above far analogous use of Qa), and the symbol Z bears an analogous relationship to the group C(RI)(R2)(X). In a complementary approach to the intermediate III, the metal radical (-M) replaces the aldehyde (-CHO) func-tion in starting material II which is reacted with an aldehyde side chain building block of formula Z-(Ya)-CHO. The precursor IIa to the metallated derivative II (R= M) is prepared by a standard reaction sequence from an aldehyde of type II.
The remaining steps in the synthesis involve:-2 Oxidation of the alcohol to the ketone;
3 Optional conversion of the group Q to Q;
a 4 Optional conversion of the group Ya to Y;
5 Optional conversion of the group Z to C (Rl) (R2) (X) ;
6 Triplet-sensitised photoisomerisation of the vitamin D triene (5E to 5Z); and 7 Removal of the vitamin D nucleus silyl protective groups;
The sequence of steps 1 through 7 may be altered (e. g. the photoisomerisation step (6) may precede the reac-tion (step 1) with the side chain building block), and several steps may be combined (e.g. the conditions of the desilylation step (7) may also effect a deprotection of the alcohol group X (step 5). Examples of conditions and reagents for the specified reactions (i.e. for steps 2, 6, and 7) are well known in the prior art of vitamin D ana-logue synthesis. Alternative routes to any one of the intermediates II through v or the compound I are available and will be obvious to the man skilled in the art.
The present compounds are intended for use in pharma-ceutical compositions which are useful in the treatment of human and veterinary disorders as described above.
The amount required of a compound of formula I
(hereinafter referred to as the active ingredient) for - therapeutic effect will, of course, vary both with the particular compound, the route of administration and the - mammal under treatment. The compounds of the invention can be administered by the parenteral, intra-articular, enteral or topical routes. They are well absorbed when given enterally and this is the preferred route of administration in the treatment of systemic disorders. In the treatment of dermatological disorders like psoriasis or eye diseases topical or enteral forms are preferred.
In the treatment of respiratory diseases like asthma 5 an aerosol is preferred.
While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. Conveniently, the active ingredient comprises from 0.1 ppm to 0.2o by 10 weight of the formulation.
By the term "dosage unit" is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, re-maining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
The formulations, both for veterinary and for human medical use, of the present invention comprise an active ingredient in association with a pharmaceutically accept-able carrier therefore and optionally other therapeutic ingredient(s). The carriers) must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
The formulations include e.g. those in a form suit-able for oral, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra-articular and topical administration.
The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
_ Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus, electuary or paste.
A tablet may be made by compressing or moulding the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by com-pressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by mould-ing, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent.
Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.
Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
Formulations suitable for intra-articular administra tion may be in the form of a sterile aqueous preparation of ' the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous micro-crystalline suspension. Liposomal formulations or biode-gradable polymer systems may also be used to present the active ingredient for both intra articular and ophthalmic administration.

Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
For asthma treatment inhalation of powder, self--propelling or spray formulations, dispensed with a spray can, a nebulizer or an atomizer can be used. The formula-dons, when dispensed, preferably have a particle size in the range of 10 to 100 ~..
Such formulations are most preferably in the form of a finely comminuted powder for pulmonary administration from a powder inhalation device or self-propelling powder--dispensing formulations. In the case of self-propelling solution and spray formulations, the effect may be achieved either by choice of a valve having the desired spray characteristics (i.e. being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled par-ticle size. These self-propelling formulations may be either powder-dispensing formulations or formulations dispensing the active ingredient as droplets of a solution or suspension.
Self-propelling powder-dispensing formulations pref-erably comprise dispersed particles of solid active ingre-dients, and a liquid propellant having a boiling point below 18°C at atmospheric pressure. Generally, the propel-lant constitutes 45 to 99.9% w/w of the formulation whilst the active ingredient constitutes 0.1 ppm to 0.1% w/w, of the formulation.
In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients such as diluents, buffers, ' flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxy-benzoate (including anti-oxidants), emulsifying agents and the like. The compositions may further contain other thera-peutically active compounds usually applied in the treat-ment of the above mentioned pathological conditions.
The present invention further concerns a method for treating patients suffering from one of the above patho-logical conditions, said method consisting of administering to a patient in need of treatment an effective amount of one or more compounds of formula I, alone or in combination with one or more other therapeutically active compounds usually applied in the treatment of said pathological con-ditions. The treatment with the present compounds and/or with further therapeutically active compounds may be simul-taneous or with intervals.
In the treatment of systemic disorders daily doses of from 0.1-100 E.cg, preferably from 0.2-25 ~Cg, of a compound of formula I are administered. In the topical treatment of dermatological disorders, ointments,' creams or lotions containing from 0.1-500 ~Cg/g, and preferably from 0.1-100 ~.g/g, of a compound of formula I are administered. For topical use in ophthalmology ointments, drops or gels con-taining from 0.1-500 ~tg/g, and preferably from 0.1-100 ~.g/g, of a compound of formula I are administered. The oral compositions are formulated, preferably as tablets, cap-sules, or drops, containing from 0.05-50 E,r.g, preferably from 0.1-25 ~.g, of a compound of formula I, per dosage unit.
The invention is further illustrated by the following non-limiting Preparations and Examples:
Preparations and Examples The exemplified compounds I are listed in Table 1, whereas the starting materials and intermediates of general formulae II, III, IV and V are listed in Table 2.
The following standard abbreviations are used throughout this disclosure: Me = methyl; Et = ethyl; TBS =
t-butyldimethylsilyl; THP = tetra-hydro-4H-pyran-2-yl; THF
- tetrahydrofuran.

General:
Ether refers to diethyl ether. Tetrahydrofuran (THF) was dried over sodium/benzophenone. Reactions were routine- -ly run under an argon atmosphere unless otherwise noted.
In the standard work-up procedure, the organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, and concentrated in vacuo to give the product.
For fH nuclear magnetic resonance spectra (300 MHz) chemical shift values (b) (in ppm) are quoted, unless oth-erwise specified, for deuteriochloroform solutions relative to internal tetramethylsilane (b - 0.00) or chloroform (b =
7.25). The value for a multiplet, either defined (doublet (d), triplet (t), quartet (q)) or not (m) at the approximate mid point is given unless a range is quoted (s - ringlet, b = broad).

WO 97/20811 PCTlDK96/00502 Table 1: Exemplified I (Details t~ro-Compounds are vided for comp ounds ExampleNumber where an is given; the other may pre-compounds be y pared using reaction analogous sequences from the appro priate II or IIa) Comt~ound Compound Example Y R1 R2 X
Q

No. No.

101 1 (CH2)2 single bond Me Me H

102 2 single bond (CH2)4 Me Me OH

103 3 single bond C-C-~CH 2 Et Et OH

104 4 (CH2)2 single bond Me Me OH

15 105 5 (CH2)2 single bond -(CH2 )4- OH

106 6 *CH=CH single bond Me Me H

107 *CH=CH single bond Me Me OH

108 7 O-(CH2)2 single bond Et Et H

109 8 O-(CH2)2 single bond Et Et OH

110 CH2-O-(CH2)2 single bond Me Me OH

111 *CH=CH single bond -(CH2)2- H

112 cCH(OEt)-C=CH* single bond Et Et OH

113 #CH(OH)-CH2 single bond Me Me OH

114 cCH(OEt)-C=C single bond Et Et OH

115 CH2 (CH2)2 Me Me OH

116 (CH2)3 single bond Et Et OH

117 CH2 CH2 Me Me OH

* E-Configuration of this double bond.
# R-Configuration at this carbon.
' a S-Configuration at this carbon.

N N

N

M .IJ M

W N N N N N ' M V M

x a~~ a~ ~ x a~

N U N ~ ~ W N ~ W N N U N

~ ~ ~ ~ ~

_ _ _ _ U _ _ U U _ U _ U U U U U U U U U

d ~ ~ .

R

N N N

~r a~x ~rx a~~r x a~ a~ a _ U _ U _ W

N L7~ N X31N 57 tTl~7 t51N

x ~ U x U ~ x U ~ ~ ~ ~ x " - " _ " ~ a _ _ _ i m m m a U ~ r n b b .

W O Ot Q? N N N N N ~ * ~ O N N N N N
OctSO v b1 N b1N tJ1tT1CnU b1l71N N N N bl ~ x ~ x ~ ~ ~ n ~ ~ x x x x Us~ ccf -.-IU -r-tU ~ -~-tr1x -r1-~ U U U U -fi a~s~ ~ ~ -- m -- ~ a~ cnU r~v~

*
HHHHHHH,'~','>,'~,'~,'~* ,'~~Jv' øa H H H H H H H H H H H H -k H
O ?, U E-~
cLS
O UJ rl N M d~ Ln l0 t~ ~0 01 O ri rl N N M d' O O O O O O O O O ri rl rl rt c-i rl c-i O O O O O O O O O O O O O O O O
O O O O O O O O O O O O O O O O
U~
N ~-i ~-i id N
rl Q O
,~.t ~r-! '~ * v-1 N M di !11 l0 C~ CO a1 O ri ~ N M
((j p., .~ 'z, -k -k O O O O o O O o O ri r-i r1 c-1 v-!
H

N N N

W W

- M M M

N ~ .-. --~

~ 1J.i.1 M M M

W U N N U N U

N -- ~ f.~.~G~

-r1 .1.1 .I~ -rlJ-1r1 W w W

O O O O U U U
C

U U U

U U U U U U U
C

~t ..CZ ~ .L7..Q.~ .CZ ~ .Ct .~

N

x a~ a~ a~ as a~ a~ a~ a~a~
a flj U ~-I rl rl rl r-Ir-I r-! r-Ir-1 r-~t t7~b~ b'~ ~ tJtb~
b U

'r'~ 'r~ r~ W-~-r'~-r'~ r-~ r~'r~
r U rn ca m U1 cn m ~n u~m cr.

N

N

U

O --,.Q N N N N N N s *

O

M N
C

x x '.~',x ~ ~ _ t~ N U U U U U U N N U U N
C

x x N x !Ill x x U ~

O O O O O O ~ U U

* *
O * H -x * H H H * H H H H H H H H
U Ea ~ ~-I ra td O N Lf1 l0[~(~ DD01 O O r1N M tipO1 O rI
d~ N

r-I rirlv-Ir-Ic-1N N N N N N N M M
N M

O O O O O O O O O O O O O O O
O O

O o o O o 0 0 0 0 0 0 0 0 0 0 .r., U i rti N ~-I ~-1 c~ N

N

r-I N O E (LS.~ c S-1 -ri d~ tnl0l0 C~QO 0101 O ri * -k N
;~

L3~ J-1 -I rlrlri rir-irlu-1N N * * * N
,"y N H O

x x o U

M '~

ro ~a .~

M O

rl ~-I -~-i ~

N U N ~ fd w ~ ~ ~ N

a~

~

x 'Tj O N

U U Z ._ ' x N ~ N

ro ro ro o ~ m o . . ro ,-~
c~ ~

o ~ b a i~ ~ ri ri , a ~

, cn m ~ U

lDto d~ .~''.l~

~ o ~

x - O 't3~

~

~

x a iia ~ o U i U U N N

~ W -~-t._ cd * cJ~-QI * N .l,~1 l-1.4~ (d.t'', S-1ftSN J...l x -- w H w w U -~ . a~ v o 4.., c o 0 0 0 ~ ~ ~ ~

~ x ; ~

a U ~ ~ v ~

~ N ~ U o 0 ' N o o ~

~ ro ~ o ,.Q.i.~~ .c~

3 ~ O ~ ~ ~ ~ _ ~ rt ~

H

,7 H H H H ~ ~ ro-rl ~ roO C~!U U

H H H H rfO N ~-Ir-'I~ -~i E ~ ~ ~ o Ul.l-1 U H N

N U

O

rn~ H ~ ~ ~

O =~ -~ N O ~

~ N N J-3~1 h i-1.t~, O -=-IO O O

4-a O c1J M W W ~ t~co N N ~ ~ -rl , -ri-rl ~ M M M M M M U ~i.1.~~ ~ H O ~ O
5~

, O O O O O O rl N (0 t1S U (l~t~ O ft$f0 0 0 0 0 0 0 ~ E ~--~ ~ O ~

~ v ~ ~ -H i~tn N tn a~ M tnro ~ tntn ~ ~ b i ~ ~

O rn- ~ - 7 ro~ ~+-~~

O ~ ~ ~ O ~ O N ~ O O

~ ! r- t -1 -a I 'tf ca -~r~ r-trt!n'f U .u N U U

O ~ .~ ni.u ~
J~ Cl~U U1 tCjN W H E-~~' N ~I ~-1 ~

~.' ~I

r-t Qy O ~ .t~ U

~ -r-t ~ M d m uo~ O U1 * *

pa ~..1 N N N N N O N
'Z, * * * ~ LT

f~ G1*

General Procedure 1 (Preparations OZ 02 17) To a solution, maintained at about 5°C, of the Grig-. nard reagent prepared from magnesium (3.3 mmol) and the Side chain buildinct block (3 mmol) in dry THF (3 ml) was added via a syringe the Aldehyde (ca. 1 mmol) in dry THF (5 ml). After stirring at the same temperature for 30 min, the reaction mixture was partitioned between ether and satu-rated ammonium chloride solution. Standard work-up gave the oily Product.
Preparation O1: Compound 0003 (This preparation is a modification without separ-ation of isomers of the synthesis described in Calverley, M.J. and Binderup, E.T. Novel vitamin D analogues. Interna-tional Patent Application WO 9,100,271-A: (1991), Prepara-tion 32:) Szde chain building block: 6-bromo-2-methyl--2(trimethylsilyloxy)hexane (0.80 g); Aldehvde: Compound 0001 (0.55 g, 0.96 mmol); Without further purification, the Product containing the Title Compound was used in the next step.
Preparation 02: Compound 0004 fide chain building block: 2-bromopropane (0.37 g);
Aldehyde: Compound 0002 (0.60 g); Purification of the Prod-uct by chromatography on silica gel (50 g) (eluant: 1.5~
ether in petroleum ether) gave the Title Compound. Oil; b 0.05 (12H, m), 0.54 (3H, s), 0.75 to 1.0 (9H, m), 0.85 (9H, s), 0.9 (9H, s), 1.05 to 2.1 (20H, m), 2.3 (1H, bd), 2.55 (1H, dd). 2.87 (1H, bd), 3.31 (1H, m), 4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, m), 4.98 (1H, m), 5.81 (1H, d), 6.45 ( 1H, d) .
Preparation 03: Compound 0005 (This preparation is a modification without separ-ation of isomers of the synthesis described in Bretting, C.A.S. and Grue-Smrensen, G., International Patent Applica-tion WO 9,319,044-A1 (1993), Preparation 13:) To a solu-tion, maintained at about -70°C, of the lithio-derivative prepared from n-butyl-lithium (1.6 M in hexanes; 3 mmol) and the side chain building block 4-ethyl-4-(tetrahydro- , pyranyloxy)-hex-1-yne (0.65 g, 3.1 mmol) in dry THF (5 ml) 5 was added via a syringe Compound 0001 {0.575 g, 1 mmol) in , dry THF (2 ml). After stirring at the same temperature for 10 min and thereafter at 0°C for 45 min, the reaction mixture was partitioned between ether and water. Standard work-up gave the oily Product. Purification by chromatogra-10 phy on silica gel (50 g) (eluant: 30% ether in petroleum ether) gave the Title Compound as an oil.
General Procedure 2 (Preparatior~.s 04, 05) To a solution, maintained at about 25°C, of the Tri-15 methylsilyl ether (0.96 mmol} or the THP ether (0.22 mmol) in THF (2 ml) was added pyridinium p-toluenesulphonate (0.010 g, 0.04 mmol, for trimethylsilyl ether; 0.150 g, 0.6 mmol, for THP ether) in ethanol (10 ml}. After stirring at the same temperature for 15 min {trimethylsilyl ether) or 2 20 h {THP ether), the reaction mixture was partitioned between ethyl acetate and 5% sodium hydrogen carbonate solution.
Standard work-up gave the oily Product.
Preparation 04: Compound 0006 Trimethylsil~l ether: Compound 0003, the crude prod-uct from Compound 0001, (0.96 mmol}; Purification of the Product by chromatography on silica gel (50 g) (eluant: 40%
ethyl acetate in petroleum ether) gave the Title Compound.
Oil; S 0.06 {12H, m}. 0.54 (3H, s), 0.83 (3H, d), 0.86 (9H, s), 0.89 {9H, s), 1.01 to 2.15 (24H, m), 1.2 (6H, s), 2.31 {1H, bd), 2.55 (1H, dd), 2.88 (1H, bd}, 3.85 (IH, m), 4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, m), 4.98 (1H, m), 5.83 -( 1H, d} , 6 . 45 { 1H, d) .
Preparation 05: Compound 0007 THP ether: Compound 0005 (0.170 g, 0.217 mmol); With-out further purification, the Product Containing the Title Compound was used in the next step. 8 0.05 {12H, m), 0.55 (3H, s) , 0.85 (9H, s) , 0.88 (6H, t) , 0.89 (9H, s) , 1.03 (3H, d) , 1.15 to 2.1 (20H, m) , 2.31 -(1H, bd) , 2.37 (2H, m) , 2.54 (1H, dd), 2.87 (1H, m), 4.21 (1H, m), 4.52 (1H, m), 4.61 (1H, m), 4.93 (1H, m), 4.98 (1H, m), 5.82 (IH, d), 6.44 (1H, d).
Preparation 06: Compound 0008 To a solution, maintained at about 25°C, of Compound 0001 (0.481 g, 0.84 mmol) in dry toluene (3 ml) was added the side chain building block 2-propylcarbonylmethylenetri-phenylphosphorane (0.60 g, 1.72 mmol). After stirring at the same temperature for 10 min and thereafter at 110°C for 5 h, the reaction mixture was partially concentrated in vacuo and diluted with ether. The solution was set aside to crystallise and filtered. The filtrate was concentrated in vacuo to give an oil. Purification by chromatography on silica gel (50 g) (eluant: loo ether in petroleum ether) gave the Title Compound. Needles {from methanol); m.p. 123-124°C; b 0.05 (12H, m), 0.5 (3H, s}, 0.85 (9H, s), 0.89 (9H, s), 1 (3H, d), 1 to 1.82 (lOH, m), 1.09 {6H, d), 1.95 ( 3H, m) , 2 . 25 ( IH, m) , 2 . 3 ( IH, bd) , 2 . 54 ( 1H, dd) , 2 . 81 (1H, m), 2.84 (IH, bd), 4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, m), 4.97 {1H, m), 5.81 (1H, d), 6.1 (1H, d), 6.43 (IH, d}, 6.77 (1H, dd).
Preparation 07: Compound 0009 To a solution, maintained at about 25°C, of Compound 0006 (0.69 g, 0.1 mmol) in dry dichloromethane (2 ml) was added solid pyridinium chlorochromate (0.04 g, 0.19 mmol).
After stirring at the same temperature for 1 h, the reac-tion mixture was extracted with ether. The organic layer was separated and filtered and concentrated in vacuo to ' give an oil. Purification by chromatography on silica gel (15 g) (eluant: 20% ethyl acetate in petroleum ether) gave the Title Compound. Oil; b 0.06 (12H, m), 0.51 (3H, s}, 0.85 (9H, s), 0.88 (9H, s), 1.02 (3H, d}, 1.1 to 2.1 (20H, WO 97/20811 ~'CT/DK96/00502 m) , 1.2 (6H, s) , 2.31 (1H, bd) , 2.5 (4H, m) , 2.85 (1H, m) , 4.21 (1H, m), 4.51 (1H, m), 4.93 (1H, m), 4.97 (1H, m), 5.81 (1H, d) , 6.43 (1H, d) .
General Qrocedure 3 (Preparations 08. 09. I8) .
To a solution, maintained at about 25°C, of the Alco-ho, (0.2 to 0.5 mmol) in dry dichloromethane (10 ml) was added portionwise 1,1,1-triacetoxy-1,1-dihydro-1,2-benz-iodoxol-3(1H)-one (1.2 mol equiv.). After stirring at the same temperature for I5 min, the reaction mixture was par-titioned between ether and 5~ aqueous sodium bicarbonate solution also containing excess sodium thiosulphate. Stan-dard work-up gave the oily Product.
I5 Preparation 08: Compound 0010 Alcohol: Compound 0007, the crude product from Compound 0005, (0.217 mmol); The Product was purified by chromatography on silica gel (30 g) (eluant: 40o ether in petroleum ether) gave the Title Compound. Oil; b 0.05 (12H, m) , 0.54 (3H, s) , 0.85 (9H, s) , 0.88 (9H, s) , 0.92 (6H, t) , 1.1 to 2.1 {14H, m) . 1.14 (3H, d) , 2.3 (1H, bd) , 2.52 (2H, m), 2.56 (2H, s), 2.86 (1H, m), 4.2I (1H, m), 4.51 (1H, m), 4.93 (1H, m), 4.97 (1H, m), 5.81 {1H, d), 6.43 (1H, d).
Preparation 09: Compound OOI1 Alcohol: Compound 0004 (0.322 g, 0.5 mmol); The Prod-uct was purified by chromatography on silica gel (30 g) (eluant: 5~ ether in petroleum ether) gave the Title Compound. Needles (from methanol); m.p. 95-96°C; b 0.05 (12H, m) , 0.55 (3H, s) , 0.83 (3H, d) , 0.85 (9H, s) , 0.89 (9H, s), 1.08 (6H, d), 1.2 to 2.1 (16H, m), 2.25 to 2.7 (5H, m), 2.86 {1H, bd), 4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, m) , 4.98 (1H, m) , 5.81 (1H, d) , 6.45 {1H, d) .

Preparation 10: Compound 0011 (Alternative s~n-thesis) . To a solution, maintained at about 25°C, of Compound 0008 (1.15 g, 1.79 mmol) in toluene (50 ml) was added an . 5 aqueous solution of sodium dithionite (5.45 g, 31 mmol) containing sodium hydrogen carbonate {5.5 g) and methyltri-decylammonium chloride (0.55 g). After vigorous stirring at the same temperature for 5 min and thereafter at 80°C for 3 h, the reaction mixture was partitioned between ether and l0 water. Standard work-up gave the oily Product. Purification by chromatography on silica gel (30 g) (eluant: 30~ ether in petroleum ether) gave the Title Compound. Needles {from methanol); m.p. 95-96°C; b 0.05 (12H, m), 0.55 (3H, s), 0.83 (3H, d) , 0.85 (9H, s) , 0.89 {9H, s) , 1.08 (6H, d) , 1.2 15 to 2.1 (16H, m) , 2.25 to 2.7 (5H; m)', 2.86 (1H, bd) , 4.21 (1H, m), 4.52 (1H, m). 4.93 (1H, m), 4.98 (1H, m), 5.81 (IH, d) , 6.45 {1H, d) .
General Procedure 4 preparations 11a, 19a 20 To a solution, maintained at about 5°C, of the Ketone (ca. 0.5 mmol) in dry dichloromethane (3 ml) was added hexamethyldisilazane (2 molar equiv.) and then iodotri-methylsilane {0.6 molar equiv.). After stirring at the same temperature for 1 h and thereafter at -20°C overnight, the 25 reaction mixture was partitioned between ether and 5~
sodium hydrogen carbonate solution. Standard work-up gave the oily Product.
reparation lla: 24-Trimethvlsilvloxv-1(S),3(R)-bis-30 (TBS-oxy)-20~(S)-9.10-seco-cholesta--5 (E) , 7 (E) , 10 (19) . 24-tetraene (Compound 0012a) Ketone: Compound 0011 (0.395 g, 0.61 mmol); Purifica-tion of the Product by chromatography on silica gel {30 g) 35 (eluant: 1 ~ ether in petroleum ether) gave the Title Compound. Needles (from methanol); m.p. 69-71°C; b 0.05 (12H, m) , 0.15 (9H, s) , 0.53 {3H, s) , 0.86 {3H, d) , 0.86 (9H, s), 0.89 (9H. s), 1 to 2.08 (17H, m), 1.56 (3H, s), 1.59 (3H, s), 2.16 (1H, m), 2.3 (1H, bd), 2.55 {1H, dd), 2.86 (1H, bd), 4.21 (1H, m), 4.52 {1H, m), 4.93 (1H, m), 4.98 (1H, m) , 5.81 (1H, d) , 6.45 (1H, d) .
General Procedure 5 (Preparations llb, 19b) To a solution, maintained at about 5°C, of the Enol ether (ca. 0.2 mmol) in dry dichloromethane (5 ml) was added solid m-chloroperbenzoic acid (85-°s) (1.1 molar equiv.). After stirring at the same temperature for 15 min, the reaction mixture was partitioned between ether and 5%
sodium hydrogen carbonate solution. Standard work-up gave the oily Product.
Preparatior~ llb: Comgound 0012 Enol-ether: Compound 0012a (0.152 g, 0.21 mmol);
Purification of the Product by chromatography on silica gel (15 g} (eluant: 5 % ether in petroleum ether) gave the Title Compound. Needles (from methanol); m.p. 82-84°C; b 0.05 (12H, m), 0.15 (9H, s), 0.55 (3H, s), 0.84 (3H, d), 0.85 (9H, s) , 0.89 (9H, s) , 1.15 to 2.08 (16H, m) , 1.32 (6H, s), 2.3 (1H, bd), 2.56 (1H, dd), 2.62 (2H, m), 2.86 (1H, m), 4.21 (1H, m), 4.52 {1H, m), 4.93 (1H, m), 4.98 ( 1H, m) , 5 . 81 { 1H, d) , 6 . 45 ( 1H, d) .
General Procedure 6 (Preparations 12 through 15, 20, 21, 23) To a solution of the 5E-Vitamin D compound (ca. 0.1 t mmol), anthracene (9-acetylanthracene in Preparations 20 and 21) (0.03 g) and triethylamine (0.1 ml) in toluene or ~d.ichloromethane (5 ml) in a Pyrex flask was irradiated with light from a high pressure ultraviolet lamp, type TQ718Z2 ' (Hanau) at about 10°C for 30 minutes. The reaction mixture was partially concentrated in vacuo to give the oily Prod- ' uct.

WO 97/20811 PCTlDK96/00502 Preparation 12 Compound 0013 5E-Vitamin D compound: Compound 0011 (0.067 g, 0.104 . mmol) (in toluene); Purification of the Product by chro-matography on silica gel (15 g) (eluant: 5 % ether in pet-', 5 roleum ether) gave the Title Compound. Oil; 6 0.05 (12H, m) , 0.53 (3H, s) , 0.82 (3H, d) , 0.87 (18H, s) , 1.05 to 2.05 (16H, m), 1.08 (6H, d), 2.2 (1H, dd), 2.3 to 2.67 (4H, m), 2.81 (1H, m), 4.I8 (1H, m), 4.36 (1H, m), 4.85 (1H, m), 5 .17 (1H, m) , 6.00 (IH, d) , 6.22 (1H, d) .
Preparation 13: Compound 0014 5E-Vitamin D compound: Compound 0009 (0.080 g, 0.116 mmol) (in dichloromethane); Purification of the Product by chromatography on silica gel (15 g) (eluant: 30 ~ ethyl acetate in petroleum ether) gave the Title Compound. Oil; 8 0.05 (12H, m), 0.49 (3H, s), 0.87 (9H, s), 0.87 (9H, s), 1 (3H, d) , 1.19 (3H, s) , 1.19 (3H, s) , 2.2 {1H, dd) , 2.3 to 2.7 (4H, m), 2.81 (1H, m), 4.18 (1H, m), 4.36 (1H, m), 4.85 ( 1H, m) , 5 . 17 ( 1H, m) , 6 ( 1H, d) , 6 . 22 ( 1H, d) .
Preparation 14: Compound 0015 5E-Vitamin D compound: Compound 0010 (0.076 g, 0.109 mmol) (in dichloromethane): Purification of the Product by chromatography on silica gel (15 g} (eluant: 50o ether in petroleum ether) gave the Title Compound. Oil; b 0.05 (12H, m) , 0.53 (3H, s) , 0.87 (18H, s) , 0.92 (6H, t} , 1.14 (3H, d) , 2.2 (1H, dd) , 2.4 (1H, dd) , 2.53' (1H, m) , 2.57 (2H, s) , 2.81 (1H, m), 4.18 {1H, m), 4.36 (1H, m), 4.85 (1H, m), 5.17 {1H, m) , 6 (1H, d) , 6.22 (1H, d) .
Preparation 15: Compound 0016 5E-Vitamin D compound: Compound 0012 (0.062 g, 0.085 mmol) (in toluene); Purification of the Product by chroma-tography on silica gel (15 g) (eluant: 2 o ether in pet-roleum ether) gave the Title Compound. Oil; b 0.05 (12H, m) , 0.15 (9H, s) , 0.53 (3H, s) , 0.84 (3H, d) , 0.87 (18H, s) , 1.32 (3H, s) , 1.32 (3H, s) , 2.2 (1H, dd) , 2.4 (1H, m} , 2.62 (2H, m), 2.81 (1H, m), 4.18 (1H, m), 4.36 (1H, m), 4. 85 (IH, m} , 5.17 (1H, m) , 6 (1H, d} , 6.22 (IH, d) .
Preparation 16a: (2-Cyanoethoxv-1 (S) , 3 (R) -bis (TBS-oxy) -9. 10-20 (R) -seco-prec~na-5 (E) . -7(E),I0(19),24-triene (Compound 0017a To a solution, maintained at about 25°C, of 20(R)-hydroxy-1(S),3(R)-bis-(TBS-oxy)-9,10-20(R)-seco-pregna--5(E),7(E),10(19),24-triene (1.3 g, 2.32 mmol} in dichloromethane (40 ml) was added a 40% aqueous solution of tetrabutylammonium hydroxide (20 ml, 15 mmol) followed by acrylonitrile (4.84 g, 91 mmol). After vigorous stirring at the same temperature overnight, the reaction mixture was partitioned between ether and water. Standard work-up gave the oily Product. Purification by chromatography on silica gel (80 g) (eluant: 20o ether in petroleum ether) gave the Title Compound; b = 0.05 (m, I2H), 0.56 (s, 3H), 0.86 (s, 9H), 0.88 (s, 9H), 1.10 (d, 3H), 1.10-2.20 (m, I3H}, 2.30 {bd, 1H}, 2.55 (dd, 1H), 2.56 (t, 2H), 2.87 (bd, iH), 3.34 (m, 1H), 3.44 (m, 1H), 3.75 (m, 1H), 4.20 (m, 1H), 4.52 (dd, 1H), 4.92 (bt, 1H), 4.98 (bs, 1H), 5.79 (d, 1H), 6.45 (d, 1H) .
Preparation 16b: Compound 0017 To a solution, maintained at about -70°C, of compound 0017a (0.9 g, 1.46 mmol) in dry ether {45 ml) was added via a syringe diisobutylaluminium hydride (1 M in hexanes; 2 mmol). After stirring at the same temperature for 1 h, the reaction mixture was partitioned between ether and satu-rated ammonium chloride solution. After standard work-up, the oily Product was purified by chromatography on silica °
gel (50 g) (eluant: 30o ether in petroleum ether) to give the Title Compound as an oil; 8 = 0.05 (m, 12H), 0.53 (s, 3H), 0.86 (s, 9H), 0.88 (s, 9H), 1.09 (d, 3H), 1.05-2.10 (m, 13H) , 2.30 (bd, 1H) , 2.54 (dd, 1H) , 2.62 (dt, 2H) , 2.86 {bd, 1H), 3.30 (m, 1H), 3.55 (m, 1H), 3.88 (m, 1H), 4.20 (m, 1H), 4.52 (dd, 1H), 4.93 (bt, 1H), 4.98 (bt, 1H), 5.79 (d, 1H) , 6.44 (d, 1H) , 9. 78 {t, 1H) .
Preparation 17: Compound 0018 (General Procedure 1) Side chain building block: 3-bromopentane (0.45 g);
Aldehvde: Compound 0017 (0.49 g, 0.8 mmol); Purification of the Product by chromatography on silica gel (50 g) (eluant:
20% ether in petroleum ether) gave the Titie Compound as separate isomers which were recombined for use in the next step. First eluted isomer: Oil; b = 0.05 (m, 12H), 0.54 (s, 3H), 1.85 {m, 6H), 0.86 (s, 9H), 0.88 (s, 9H), l.ll {d, 3H), 1.10-2.15 (m, 20H), 2.30 (bd, 1H), 2.54 (dd, 1H), 2.86 (bd, 1H), 3.18 (bs, 1H), 3.26 (m, 1H), 3.49 (m, 1H), 3.75 (m, 2H), 4.21 (m, 1H), 4.52 (dd, 1H), 4.93 (bt, 1H), 4.98 (bs, 1H), 5.79 (d, 1H), 6.45 {d, 1H); Second eluted isomer:
Oil; b = 0.05 (m, 12H), 0.55 (s, 3H), 0.87 (m, 6H), 0.86 (s, 9H), 0.88 (s, 9H), 1.09 (d, 3H), 1.10-2.15 (m, 21H), 2.30 (bd, 1H) , 2.54 (dd, 1H) , 2.86 (bd, 1H) , 3 .29 (m, 1H) , 3.44 (m, 1H), 3.72 (m, 2H), 4.21 (m, 1H), 4.52 (dd, 1H), 4.93 (bs, 1H), 4.98 (bs, IH), 5.79 (d, 1H), 6.45 {d, 1H).
Preparation 18: Compound 0019 (General Procedure 3) Alcohol: Compound 0018 (0.22 g,, 0.32 mmol); The Prod-uct was purified by chromatography on silica gel (30 g) (eluant: 10~ ether in petroleum ether) gave the Title Compound; 8 = 0.05 (m, 12H), 0.54 (s, 3H), 0.83 (t, 3H), 0.84 (t, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 1.07 (d, 3H), 1.05-1.80 (m, 16H), 1.85-2.07 (m, 3H), 2.25-2.35 (m, 2H), 2.55 (m, 1H), 2.86 {bd, 1H), 3.29 (m, 1H), 3.46 (m, 1H), 3.79 (m, 1H), 4.21 (m, 1H), 4.51 (dd, 1H), 4.93 (m, 1H), 4. 97 (m, 1H) , 5.79 (d, 1H) , 6.45 (d, 1H) .

Preparation 19a: (3-Trimethylsilyloxy-4-ethyl-hex-3-en~rloxy) -1 (S) , 3 (R) -bis (TBS-oxv) --20 (R) -9 10-seco-preana-5 (E) . 7 (E) . -10(19)-triene (Compound 0020a) (General Procedure 4) Ketone: Compound (0.178 g, 0.25 mmol);
Purifica-tion of the by chromatography on silica gel (30 g) Product (eluant: in petroleum ether) gave the Title 1 %
ether Compound; 0.06 (m, 12H), 0.55 (s, 3H), 0.86 (s, 9H), b =

0.90 (s, 9H), 0.92 (t, 3H), 0.93 (t, 3H), 1.08 (d, 3H), 1.16 (s, 9H), 1.00-2.25 (m, 17H), 2.31 (bd, 1H), 2.37 (m, 2H), 2.55 (dd, 1H), 2.86 (bd, 1H), 3.3I (m, 2H), 3.63 (m, 1H), 4.21 (m, 1H), 4.53 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H) , 5 .79 (d, 1H) 6.46 (d, 1H) .
, Preparation 19b: Compound 0020 (General Procedure 5) F'nol-ether: Compound 0012a (0.1 g, 0.13 mmol); Puri-fication of the Product by chromatography on silica gel (15 g) (eluant: 5 % ether in petroleum ether) gave the Title Compound; b = 0.06 (m, 12H), 0.17 (s, 9H), 0.55 (s, 3H}, 0.77 (t, 3H), 0.78 (t, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 1. 08 (d, 3H) , 1. 00-2.15 (m, 17H) , 2.29 (bd, 1H) , 2.55 (dd, 1H), 2.70-2.92 (m, 3H), 3.30 (m, 1H), 4.45 (m, 1H), 3.78 (m, 1H) , 4.21 (m, 1H) , 4.53 (m, 1H) , 4.93 (m, 1H) , 4. 98 (m, 1H), 5.79 (d, 1H), 6.45 (d, 1H}.
Preparation 20: Compound 0021 (General Procedure 6) 5E-Vitamin D compound: Compound 0019 (0.06 g, 0.87 mmol) (in toluene); Without further purification, the Prod-uct containing the Title Compound was used in the next step. b in agreement with structure.
Preparation 21: Compound 0022 (General Procedure 6) ~F-yitamin D compound: Compound 0020 (0.07 g, 0.09 mmol) (in toluene); Without further purification, the Pr -uct containing the Title Compound was used in the next step. The following signals for the Title Compound could be discerned: b = 0.06(m, 12H), 0.17 {s, 9H), 0.56 (s, 3H), 0.78 (t, 3 H) 0.79 (t, 3H) , 0.88 (s, 18H) , 1.08 3H) , (d, , 1.00-2.15 (m,17H), 2.2 2 (dd, 1H), 2.45 (dd, 1H), 80 a 2. (m, 3H), 3.30 (m,1H), 3.45(m, 1H), 3.79 (m, 1H), 4.19 (m, S 1H) , 4 .38 {m,1H) 4. (m, 1H) , 5.18 (m, 1H) , 6.00{d, , 87 IH) , 6 .25 (d,1H) .

Preparations 22: Compound 0030 By replacing the side chain building block cyclopentylcarbonylmethylenetriphenylphosphorane for 2-propylcarbonylmethylenetriphenylphosphorane in Prepara-tion 06, the Title compound was prepared.
Pre aration 23: Compound 0033 I5 5E-Vitamin D compound: Compound 0008 (0.09 g, 0.14 mmol) {in dichloromethane); Purification of the Product by chromatography on silica gel (15 g) (eluant: 30a ether in petroleum ether) gave the Title Compound; b in agreement with structure.
Preparation 24: Compound 0035 The compound was prepared from Compound 0001 by the sequence: 1. CH2=CH-MgBr; 2. separation of isomers by chro-matography; 3. EtBr, KH; 4. S02; 5. 03; 6. PPh3; 7. heat, NaHC03; 8. Ph3PCHC02Me; 9. di-isobutylaluminium hydride;
10. L,Z,I-triacetoxy-l,l-dihydro-1,2-benziodoxol-3(1H)-- one ) .
Preparation 25: Compound 0036 The compound was prepared from Compound 0001 by the sequence: 1. CH3C02Et, LiN(SiMe3)2; 2. TBS-trifluoro-methanesulphonate, 2,6-lutidine; 3. di-isobutylaluminium hydride.

Preparation 26: Compound 0037 The compound was prepared from Compound 0001 by the sequence: 1. Me3SiCzCH, n-butyl-lithium; 2. EtBr, KH; 3.
tetrabutylammonium fluoride.

Preparation 27: Compound 0038 To a solution, maintained at about -70°C, of the lithio-derivative prepared from n-butyl-lithium (1.6 M in hexanes; 1 mmol) and Compound 0037 {1 mmol) in dry THF (5 10 ml) was added via a syringe 2-ethylbutanal (1 mmol) in dry THF (2 ml). After stirring at the same temperature for l0 min and thereafter at 0°C for 45 min, the reaction mixture was partitioned between ether and water. Standard work-up gave the oily Product. Purification by chromatography on 15 silica gel {50 g) (eluant: 30~ ether in petroleum ether) gave the Title Compound as an oil.
General Procedure 7 (Examples) To a mixture, maintained at about 25°C, of an ethyl 20 acetate solution (about 0.3 ml} of the TBS-ether (ca. 0.1 mmol} in acetonitrile (5 ml) was added 48% aqueous hydrofluoric acid (0.5 g, 12 mmol). After stirring at the same temperature for 1 h, the reaction mixture was parti-tioned between ethyl acetate and 1N sodium hydroxide sol-25 ution. After standard work-up gave the oily product was purified by chromatography on silica gel {15 g) (eluant:
ethyl acetate) to give the Title Compound.
Example 1 : 24-Oxo-1(S), 3 (R) -dihvdroxy-20 (S) -9 . 10-30 -seco-cholesta-5 (Z) , 7 (E) , 10 (19) -triene (Compound 101) TBS-ether: Compound 0013 (0.050 g, 0.078 mmol); Title Compound: Oil; S 0.56 (3H, s) , 0.83 (3H, d) , 1.09 {6H, d) , 1.15 to 2.1 (18H, m), 2.31 (1H, dd), 2.4 (1H, ddd), 2.5 (1H, m), 2.59 (IH, dd), 2.61 {1H, m), 2.82 (1H, dd), 4.23 (1H, m) , 4.43 (1H, m) , 5 (1H, m) , 5.32 (1H, m) , 6.02 (1H, d) , 6.37 (1H, d) .

Example 2: 1(S),3(R)-Dihydroxy-20(R)-(6-hvdroxy-6--methyl-1-heptanovl)-9,10-seco-preana--5(Z),7(E),10(19)-triene (Compound 102) TBS-ether: Compound 0014 (0.065 g, 0.095 mmol); Title Compound: Oil; b 0.52 (3H, s), 1.02 (3H, d), 1.1 to 2.05 (22H, m), 1.21 (6H, s), 2.3 (1H, s), 2.37 to 2.65 (4H, m), 2.81 (1H, m), 4.22 (1H, m), 4.42 (1H, m), 4.99 (1H, m), 5.33 (1H, m) , 6.01 (1H, d) , 6.35 (1H, d) .
Example 3: 1(S),3(R)-Dihydroxv-20(R)-(5-hydroxy-5--ethyl-2-hept5m-1-byl)-9,10-seco-preana--5 (Z) , 7 (E) , 10 (19) -triene (Compound 103) TBS-ether: Compound 0015 (0.07 g, 0.1 mmol); Title Compound: Oil; b 0.55 (3H, s), 0.93 (6H, t), 1.1 to 2.1 (20H, m) , 1.14 (3H, d) , 2.31 (1H, dd) , 2.53 (1H, m) , 2.57 (2H, s) , 2.59 (1H, m) , 2.82 (1H, dd) , 4.23 (1H, m) , 4.42 (1H, m), 4.99 (1H, m), 5.33 (1H, m), 6.01 (1H, d), 6.36 ( 1H, d) .
Example 4 : 24-Oxo-1 (S) , 3 (R) , 25-Trihydrox~r-20 (S) --9.10-seco-cholesta-S(Z),7(E),10(19)-tri-ene (Compound 104) TBS-ether: Compound 0016 (0.053 g, 0.073 mmol); Title Compound: Oil; b 0.57 (3H, s), 0.85 (3H, d), 1.2 to 2.1 (18H, m), 1.39 (6H, s), 2.31 (1H, dd), 2.55 (3H, m), 2.83 (1H, m) , 3.83 (IH, s) , 4.23 (1H, m) ,' 4.43 (1H, m) , 5 (1H, m) , 5.33 (1H, m) , 6.02 (1H, d) , 6.38 (1H, d) .
Example 5: 24-(1-Hydroxy-cyclopentyl)-24-oxo--1(S),3(R)-dihydroxy-20(S)-9,10-seco--chola-5 (Z) , 7 (E) , l0 (19) -triene (Compound ' 105 TBS-ether: Compound 0034 (0.05 g, 0.066 mmol); Titie Compound: Oil; b 0.57 (3H, s), 0.85 (3H, d), 1.2 to 2.1 (26H, m), 2.31 (1H, dd), 2.55 (3H, m), 2.83 (1H, m), 3.83 (1H, s) , 4.23 (1H, m) , 4.43 (1H, m) , 5 (1H, m) , 5.33 (IH, m) , 6.02 (1H, d) , 6.38 (1H, d) .

Example 6 : 24-Oxo-1 (S), 3 (R) -dihydroxv-20 (R) -.9, 10--seco-cholesta-5 (Z) , 7 (E) , 10 (19) , 22 (E) --tetraene (Compound 106) _ , TBS-ether: Compound 0033 (0.050 g, 0.078 mmol); Title Compound: Oil; 8 0.56 (3H, s} , I (3H, d) , 1.09 (6H, d) , 1.I5 to 2.1 (16H, m), 2,25 (1H, m), 2.31 (1H, dd), 2.59 (1H, dd), 2.81 (1H, m), 2.82 (1H, dd}, 4.23 (1H, m), 4.43 (1H, m) , 5 (1H, m) , 5.32 (IH, m} , 6.02 (1H, d) , 6.1 (1H, d) , 6 .37 (1H, d) , 6.77 (1H, dd) .
Example 7 : 1 (S) , 3 (R) -Dihydroxy-20 (R) - (3-oxo-4--ethyl-1-hexyloxy)-9,10-seco-preana--5 (Z) 7 (E) . 10 (19) -triene (Compound 108) TBS-ether: Compound 0021, the crude product from Preparation 20}; Title Compound: Oil; a 0.55 (s, 3H), 0.84 (t, 3H), 0.85 (t, 3H), 1.08 (d, 3H), 1.10-1.80 (m, 15H), 1.90-2.07 (m, 4H}, 2.25-2.35 (m, 2H), 2.60 (bd, IH), 2.75 (bq, 2H), 2.82 (bd, IH), 3.29 (m, 1H), 3.47 (m, 1H}, 3.79 (m, 1H), 4.23 (m, 1H), 4.42 (m, 1H), 5.00 (bs, 1H), 5.33 (bs, 1H}, 5.99 (d, 1H), 6.38 (d, 1H).
Example 8 : 1 (S) , 3 (R) -Dihydroxy-20 (R) - (3-oxo-4-hvdroxy-4-ethyl-1-hexyloxy)-9,10-seco--preana-5 (Z) 7 (E) , 10 (19) -triene (Compound TBS-ether: Compound 0022, the crude product from Preparation 21); Title Compound: Oil; b 0.54 (s, 3H), 0.77 (t, 3H), 0.79 (t, 3H), I.07 (d, 3H), 1.05-2.10 (m, I9H}, 2.30 (dd, 1H), 2.58 (m, 2H), 2.81 (m, 2H), 3.28 (m, 1H), 3.50 (m, 1H), 3.83 (s, 1H), 3.85 (m, 1H), 4.22 (m, IH), 4.41 (m, 1H}, 4.98 (m, 1H), 5.3I (m, 1H), 5.98 (d, 1H), 6.37 (d, 1H) .
Example 7: Capsules containina Compound 104 Compound 104 was dissolved in arachis oil to a final concentration of 1 ~.g/ml oil. Ten parts by weight of gela-tine, 5 parts by weight of glycerin, 0.08 parts by weight potassium sorbate, and 14 parts by weight distilled water were mixed together with heating and formed into soft gela-tine capsules. These were then filled each with 100 E.~.1 of the oily solution of Compound 104.
Example 8: Dermatological Cream containin Compound Compound 104 (0.05 mg) was dissolved in almond oil (1 to g). To this solution was added mineral oil (40 g) and self-emulsifying beeswax (20 g). The mixture was heated to liguifidation. After the addition of hot water (40 ml), the mixture was mixed well. The resulting cream contains ap-proximately 0.5 ~.g of compound 104 per gram of cream.

Claims

CLAIMS:

1. A compound of formula I

in which formula X is hydrogen or hydroxy; R1 and R2 stand for methyl or ethyl, or, when taken together with the carbon atom bearing the group X, can form a C3-C5 carbocyclic ring;
Q is either a single bond or a C1-C8 hydrocarbylene in which one of any methylene groups not directly bonded to the carbonyl group may optionally be replaced by an oxygen atom, or methyl replaced by hydroxy; Y is either a single bond or C1-C8 hydrocarbylene; and derivatives of formula I in which one or more of the hydroxy groups are masked as groups which can be reconverted to hydroxy groups in vivo.

2. A compound of formula I according to claim 1 in which Q
is selected from the group consisting of methylene, ethylene, CH=CH, C-C, trimethylene, CH=CHCH2, CH2CH=CH, C.ident.CCH2, CH2-C.ident.C, analogously derived C4-tetramethylene, C5-diradicals, O-CH2, O-CH2CH2, CH2-O-CH2CH2, CH2CH2-O-CH2, CH (OEt) -C=CH, CH (OH) -CH2, and CH (OEt) -C.ident.C and in which Y is selected from the group consisting methylene, ethylene, CH=CH, C.ident.C, trimethylene, CH=CHCH2, CH2CH=CH, C.ident.CCH2, CH2-C.ident.C, analogously derived C4-tetramethylene, C5-diradicals, and phenylene of o-, m-, or p-.

3. A compound of formula I according to claim 1 in which X
is hydroxy and Y is a single bond.

4. A diastereoisomer of a compound according to any one of claims 1 to 3, in pure form; or a mixture of such diasteroisomers.

5. A compound according to claim 3 which is 24-oxo-1(S), 3(R),25-Trihydroxy-20(S)-9,10-seco-cholesta-5(Z),7(E),10(19)-triene.

6. A compound according to claim 3 which is 1(S), 3(R)dihydroxy-20(R)-(3-oxo-4-hydroxy-4-ethyl-1-hexyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene.

7. A pharmaceutical composition containing one or more of the compounds of any one of claims 1 to 5, together with pharmaceutically acceptable, non-toxic carriers and/or auxiliary agents.

8. A pharmaceutical composition according to claim 7 in dosage unit form containing from 0.1 ppm to 0.1% by weight of the dosage unit of a compound of formula I.

9. A use for the treatment and/or prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation of a pharmaceutically effective amount of a pharmaceutical composition according to claim 7 or 8.

10. The use of a compound of any one of claims 1 to 5 in the manufacture of a medicament for the treatment and/or prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation.