HK1086817B - 2- propylidene-19-nor-vitamin d compounds - Google Patents

Description

2-propylene-19-nor-vitamin D compounds

Technical Field

The present invention relates to vitamin D compounds, and more particularly, to 2-alkylene-19-nor vitamin D analogs having a substituted propylene moiety at the 2-position of the carbon, pharmaceutical uses of the analogs, and general methods for the chemical synthesis of such analogs.

Background

The known natural hormone 1 alpha, 25-dihydroxyvitamin D₃And analogs of the ergosterol series, 1 alpha, 25-dihydroxyvitamin D₂Is a highly effective regulator of calcium homeostasis in animals and humans, and more recently Ostrem et al, Proc. Natl. Acad. Sci. USA,84its activity in cell differentiation was determined in 2610 (1987). Many structural analogs of these metabolites have been prepared and tested, including 1 alpha-hydroxy vitamin D₃1 alpha-hydroxy vitamin D₂Various side chain homologated (homologated) vitamins and fluorinated analogs. Several of these compounds show interesting differences in their activity in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of various diseases such as renal osteodystrophy, vitamin D resistant rickets, osteoporosis, psoriasis and several malignancies.

In 1990 a new vitamin D analogue was discovered, the so-called 19-nor vitamin D compound, characterised by the replacement of the exocyclic methylene group (carbon 19) of the A-ring of the typical vitamin D system by two hydrogen atoms. The 19-nor analog (e.g., 1 alpha, 25-dihydroxy-19-nor vitamin D)₃) The biological test shows that the compound has selective activity, high cell differentiation inducing activity and low calcium mobilization activity. Thus, these compounds may have potential as therapeutic agents for the treatment of malignant tumors, or for the treatment of various skin diseases. Two different methods for the synthesis of such 19-nor-vitamin D analogues have been described (Perlman et al, Tetrahedron Letters)311823 (1990); perlman et al Tetrahedron Letters327663(1991), and DeLuca et al, U.S. patent No.5,086,191). Several years later, 1 alpha, 25-dihydroxy-19-nor-vitamin D, in which the 2-position of the A ring is substituted by a hydroxyl or alkoxy group, was synthesized₃Analogs of (D) 5 (DeLuca et al, U.S. Pat. No.5,536,713). They have been determined to exhibit interesting selective activity. All these studies show that the binding site of the vitamin D receptor can be adapted to different substituents at the C-2 position of the synthetic vitamin D analogues.

In an ongoing effort to explore 19-nor retinoid D compounds of pharmacological significance, analogs characterized by the transfer of the exocyclic methylene group of the a ring from carbon 10(C-10) to carbon 2(C-2), i.e., 2-methylene-19-nor retinoid D compounds (Sicinski et al, j.med.chem.,414662 (1998); sicinski et al, Steroids 67, 247 (2002); DeLuca et al, U.S. Pat. Nos. 5,843,928, 5,936,133, and 6,382,071). Molecular mechanics studies performed on these analogs have shown that conformational changes in the a ring can lead to "flattening" (flattening) of the cyclohexanediol ring. According to the calculation of molecular mechanics and NMR research, the conformation equilibrium of the A ring is determined to be about 6: 4, and the conformation with the equatorial 1 alpha-OH is dominant. 2-methylene is introduced into the carbon skeleton of 19-nor-vitamin D so as to change the properties of the (1 alpha-and 3 beta-) A ring hydroxyl; with natural hormone 1 alpha, 25- (OH)₂D₃The 1 α -hydroxy groups in the molecule are similar and are now all allylic (critical for biological activity). It has been found that 1 α, 25-dihydroxy-2-methylene-19-nor vitamin D analogs are characterized by significant biological potency and are significantly enhanced in compounds having an "unnatural" (20s) -conformation.

More recently, 1 α, 25-dihydroxy-19-nor-vitamin D₃The 2-ethylene analog of (a) was synthesized. Such modification of the a ring provides the compound with significant biological potency, particularly greater activity in the E-type geometric isomer, Sicinski et al, j.med.chem.,45,3366(2002). Interestingly, it has been determined that the conformational equilibrium of the A ring of the E-isomer shifts considerably to a particular chair with the 1 α -hydroxy group in the equatorial position.

Disclosure of Invention

As a continuation of the research on biologically active 2-alkylene-19-nor retinoid compounds, analogs characterized by the presence of a substituted propylene moiety at the C-2 position have been synthesized and tested. The vitamin D analogues appear to be interesting targets since it can be expected that a bulky substitution in the C-2 position may cause a more pronounced tendency towards a particular a-ring chair conformation than 2-ethylene. On the other hand, the presence of an oxygen function at the end of the propylene segment may cause other interactions with vitamin D receptors.

A class of 1 α -hydroxylated vitamin D compounds heretofore unknown is the vitamin D isomer having the exocyclic methylene moiety at the C-10 position of the a-ring removed and the other fragment attached to the carbon-2 position by a substituted propylene group. Accordingly, the present invention is directed to 2-alkylene-19-nor vitamin D analogs containing a substituted propylene moiety at the 2-position of the carbon, various pharmaceutical applications of these analogs, and general methods for the chemical synthesis of these analogs. More specifically, the present invention is directed to (20R) -1 α, 25-dihydroxy-2- [ 3' -hydroxypropylene]-19-nor vitamin D₃E-and Z-isomers of (A), (B) and (20S) -1 alpha, 25-dihydroxy-2- [ 3' -hydroxypropylene]-19-nor vitamin D₃The E-isomer and the Z-isomer of (A). The invention also discloses 2- [ (3' -methoxy) propylene]-19-nor-1 α, 25- (OH)₂D₃。

The structural features of these novel analogs are shown in formula I below:

wherein Y is₁And Y₂Which may be the same or different, are each selected from the group consisting of hydrogen and hydroxy protecting groups, wherein X may be alkyl, hydrogen, hydroxy protecting groups, hydroxyalkyl, alkoxyalkyl and aryloxyalkyl, and wherein R represents any of the typical side chains known for vitamin D compounds.

More particularly, R may represent a saturated or unsaturated hydrocarbon group of 1 to 35 carbons, which may be linear, branched or cyclic, and may contain one or more other substituents, such as hydroxyl or protected hydroxyl, fluoro, carbonyl, ester, epoxy, amino or other heteroatom groups. Preferred side chains of this type are represented by the following structures:

wherein the stereochemical center (corresponding to C-20 of the steroid numbering) may beROrSConfiguration, (i.e., carbon 20 is either the natural configuration or the 20-epi configuration), and wherein Z is selected from the group consisting of Y, -OY, -CH₂OY, -C ≡ CY and-CH ═ CHY, wherein the double bond may be in cis or trans geometry, wherein Y is selected from hydrogen, methyl, -COR⁵And groups of the following structure:

wherein m and n, independently, represent an integer from 0 to 5, wherein R¹Selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl and C which is linear or branched and may optionally contain hydroxy or protected hydroxy substituents_1-5Alkyl, and wherein R²、R³、R⁴Each independently selected from deuterium, deuterated alkyl, hydrogen, fluorine, trifluoromethyl and C which is linear or branched and which may optionally have hydroxyl or protected hydroxyl substituents_1-5Alkyl radical, wherein R¹And R²Together represent oxo, or alkylene, ═ CR²R³Or- (CH) wherein p is an integer from 2 to 5₂)_p-, wherein R³And R⁴Taken together represent oxo, or- (CH) wherein q is an integer from 2 to 5₂)_q-, and wherein R⁵Represents hydrogen, hydroxy, protected hydroxy, or C_1-5Alkyl radicalAnd wherein any CH-group in position 20, 22 or 23 of the side chain may be replaced by a nitrogen atom, or wherein any-CH (CH) in position 20, 22 or 23₃)-，-(CH₂)_m-，(CH₂)_nor-CR¹R²The groups may be replaced by oxygen or sulfur atoms, respectively.

The wavy line attached to the methyl substituent at the carbon 20 position indicates that the carbon 20 may have either the R configuration or the S configuration, i.e., the native configuration (20R) or the non-native 20-mer configuration (20S).

The wavy line attached to the 1' position of the carbon indicates that the 2-propylene unit may have two geometric isomers (different orientations of substituents on the terminal carbon atom in the 1, 4-dimethylenecyclohexane segment of the A ring).

Particularly important examples of side chains having the natural 20R-configuration are structures represented by the following formulae (a), (b), (c), (d), and (e). I.e. occurs in 25-hydroxy vitamin D₃The side chain of (a); vitamin D₃The side chain of (a); 25-hydroxy vitamin D₂The side chain of (1) (c); vitamin D₂The side chain of (1) (d); and 25-hydroxyvitamin D₂The side chain (e) in the C-24 epimer of (1).

Suitably, the side chain may also be:

the novel 2-propylene-19-nor-vitamin D compounds of structure I above exhibit a desirable highly advantageous pattern of biological activity. These compounds are characterized by relatively high intestinal calcium transport activity, i.e., similar to 1 alpha, 25-dihydroxy vitamin D₃In the ability to mobilize calcium from the bone, with1 alpha, 25-dihydroxyvitamin D₃The comparison also shows a relatively high activity. Thus, these compounds are highly specific in calcemic activity. Their preferential activity in intestinal calcium transport and calcium mobilization activities allows the in vivo administration of these compounds for the treatment and prevention of metabolic bone diseases where maintenance or increase of bone content is required. Due to their preferential calcemic activity in intestinal calcium transport and bone, these compounds will be the preferred therapeutic agents for the treatment and prevention of diseases in which osteogenesis is desired, such as osteoporosis, especially low bone turnover (bone turnover) osteoporosis, steroid induced osteoporosis, senile osteoporosis or postmenopausal osteoporosis, as well as osteomalacia and renal osteodystrophy. The compounds may be formulated for topical, transdermal, oral or parenteral administration in a dosage form for topical, transdermal, oral or parenteral administration. The compound may be present in the pharmaceutical composition in an amount of from about 0.01 μ g/gm to about 100 μ g/gm of the composition, preferably from 0.1 μ g/gm to about 50 μ g/gm of the composition, and may be administered at a dosage of from about 0.01 μ g/day to about 100 μ g/day, preferably from 0.1 μ g/day to about 50 μ g/day.

The compounds of the invention are also particularly suitable for the treatment and prevention of human diseases characterized by a dysregulated immune system, such as autoimmune diseases, including multiple sclerosis, diabetes, lupus, host versus graft reactions, and transplant rejection; in addition, it can be used for treating and preventing inflammatory diseases such as rheumatoid arthritis and asthma, and inflammatory bowel diseases such as Crohn's disease or ulcerative colitis, and promoting fracture healing and improving bone transplantation. These compounds have also been found to increase bone strength, and in particular, to increase the fracture strength (cortical strength) and fracture strength (trabecular strength) of bone. Thus, these compounds may be used in conjunction with bone replacement procedures such as hip replacement, knee replacement, and the like. Other conditions that may be treated using the compounds of the present invention are acne, alopecia, skin disorders such as dry skin (lack of skin hydration), excessive skin laxity (insufficient skin firmness), insufficient sebum secretion and wrinkles, and hypertension.

The above compounds are also characterized by high cell differentiation activity. These compounds therefore also provide therapeutic agents useful in the treatment of psoriasis, or as anti-cancer agents, especially against leukaemia, colon cancer, breast cancer, skin cancer and prostate cancer. The compound may be present in the composition for treating psoriasis in an amount of from about 0.01 μ g/gm to about 100 μ g/gm of the composition, preferably from 0.1 μ g/gm to about 50 μ g/gm of the composition, and may be administered topically, transdermally, orally or parenterally at a dose of from about 0.01 μ g/day to about 100 μ g/day, preferably from 0.1 μ g/day to about 50 μ g/day.

In particular, 1 alpha, 25-dihydroxy-2- [ 3' -hydroxypropylene]-19-nor vitamin D₃The E-isomer and Z-isomer of (20R) and (20S) isomers of (E-isomer and Z-isomer of (E-isomer) have been synthesized, and their binding activity, transcription activity, calcemic activity (both intestinal calcium transport and bone calcium mobilization) and differentiation activity have been determined. The structural features of the E-isomer of this (20R) analog are shown in the following general formula Ia, and are referred to herein as "1 AGR";

the Z-isomer of this (20R) analog has structural characteristics shown in the following formula Ib, and is referred to herein as "2 AGR".

The structural features of the E-isomer of this (20S) analog are shown in the following general formula Ic and are referred to herein as "1 AGS";

the structural features of the Z-isomer of this (20S) analog are shown below by the general formula Id and are referred to herein as "2 AGS";

another 2-propylene compound which has been synthesized is 2- [ (3' -methoxymethoxy) propylene]-19-nor-1 α, 25-dihydroxyvitamin D₃And measured for binding activity, transcriptional activity, calcemic activity (both intestinal calcium transport and bone calcium mobilization), and differentiation activity. The structural features of the analogs are shown in the following general formula and are referred to herein as "F-Wit":

the invention also provides a novel synthesis for the preparation of the final products of formula I, in particular of formulae Ia to Id. Furthermore, the present invention provides novel intermediates generated during the synthesis of the final product. The structural features of these novel intermediates are shown in the following general formulas V, VI, VII, VIII, IX and X, wherein Y is₁、Y₂、Y₃And Y₄May be the same or different and each is selected from hydrogen and a hydroxyl protecting group, and X may be alkyl, hydrogen, a hydroxyl protecting group, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl.

Drawings

FIG. 1 is a drawing illustrating 1 α, 25-dihydroxy vitamin D₃2- [ (3' -methoxymethoxy) propylene radical as described and claimed herein]-19-nor-1 α, 25- (OH)₂D₃(F-Wit) a graph of relative activity of binding to 1 α, 25-dihydroxyvitamin D porcine nuclear receptor;

FIG. 2 is a graph illustrating 1 α, 25-dihydroxy vitamin D₃2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH) as described and claimed herein₂D₃E-isomer of (1AGR), 2- (3' -hydroxypropyl) -19-nor- (20S) -1 alpha, 25- (OH)₂D₃E-isomer of (1AGS), 2- (3' -hydroxypropyl) -19-nor-1 alpha, 25- (OH)₂D₃And 2- (3' -hydroxypropyl) -19-nor-1 alpha, 25- (OH)₂D₃A graph of the relative activity of the Z-isomer of (2 AGS);

FIG. 3 is a schematic representation of vitamin D as 1 alpha, 25-dihydroxy₃(20S) -2-methylene-19-nor-1 alpha, 25-dihydroxyvitamin D₃(2MD) and 2- [ (3' -methoxymethoxy) propylidene group as described and claimed herein]-19-nor-1 α, 25- (OH)₂D₃(F-Wit), 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃E-isomer of (1AGR), and 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃A plot of the percentage of HL-60 cell differentiation as a function of E-isomer (1AGS) concentration of (b);

FIG. 4 is a drawing illustrating the use of (20S) -2-methylene-19-nor-1 α, 25-dihydroxyvitamin D as a 1 α, 25-dihydroxyvitamin₃(2MD) and 2- [ (3' -methoxymethoxy) propylidene group as described and claimed herein]-19-nor-1 α, 25- (OH)₂D₃(F-Wit), 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃E-isomer of (1AGR), and 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃A plot of transcriptional activity as a function of E-isomer (1AGS) concentration of (A);

FIG. 5 is a graph illustrating the comparison of the control (vehicle) with various doses) And (20S) -2-methylene-19-nor-1 alpha, 25-dihydroxyvitamin D₃(2MD) comparative 2- [ (3' -methoxymethoxy) propylidene group]-19-nor-1 α, 25- (OH)₂D₃(F-Wit), 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃E-isomer of (1AGR), and 2- (3' -hydroxypropyl) -19-nor- (20S) -1 alpha, 25- (OH)₂D₃A histogram of the intestinal calcium transport activity of the E-isomer of (1 AGS);

FIG. 6 is a graph illustrating the comparison of (vehicle) and (20S) -2-methylene-19-nor-1 α, 25-dihydroxyvitamin D at various doses₃(2MD) comparative 2- [ (3' -methoxymethoxy) propylidene group]-19-nor-1 α, 25- (OH)₂D₃(F-Wit), 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃E-isomer of (1AGR), and 2- (3' -hydroxypropyl) -19-nor- (20S) -1 alpha, 25- (OH)₂D₃Histogram of bone calcium mobilization activity of the E-isomer of (1 AGS).

Detailed Description

The term "hydroxy protecting group" as used in the specification and claims denotes any group commonly used to temporarily protect a hydroxy function, such as alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl (hereinafter simply referred to as "silyl"), and alkoxyalkyl. Alkoxycarbonyl protecting groups are alkyl-O-CO-groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl. The term "acyl" denotes alkanoyl of 1 to 6 carbons, including all isomeric forms thereof, or carboxyalkanoyl of 1 to 6 carbons, such as oxalyl, malonyl, succinyl, glutaryl, or aromatic acyl such as benzoyl, or halogen, nitro or alkyl substituted benzoyl. The word "alkyl" as used in the specification and claims denotes straight or branched chain alkyl groups of 1 to 10 carbons, including all isomeric forms thereof. Alkoxyalkyl protecting groups are groups such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl. Preferred silyl protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl, and similar alkylated silyl groups. The term "aryl" refers to phenyl, or alkyl, nitro or halogen substituted phenyl.

As defined above, "protected hydroxy" refers to a hydroxy group derived from or protected by any of the above groups commonly used to protect hydroxy functionality, such as silyl, alkoxyalkyl, acyl, or alkoxycarbonyl groups, either temporarily or permanently. The terms "hydroxyalkyl", "deuterated alkyl", "fluoroalkyl" refer to alkyl groups substituted with one or more hydroxyl, deuterium or fluorine, respectively.

It should be noted in this specification that the term "24-high" refers to the addition of one methylene group at the carbon 24 position of the side chain, while the term "24-double high" refers to the addition of two methylene groups at the carbon 24 position of the side chain. Likewise, the term "thd" refers to the addition of three methylene groups. Similarly, the term "26, 27-dimethyl" refers to an addition of one methyl group at each of carbons 26 and 27 such that, for example, R³And R⁴Is ethyl. Similarly, the term "26, 27-diethyl" means that one ethyl group is added to each of the 26 and 27 carbon positions so that R is³And R⁴Is propyl.

In the following list of unsaturated side chain and saturated side chain compounds, the term "20 (S)" or "20-table" shall be included in each of the compounds listed below if the methyl group attached to carbon 20 is in an epitope or unnatural configuration. Likewise, if the side chain includes an oxygen atom substitution at any of positions 20, 22 or 23, the terms "20-oxa", "22-oxa" or "23-oxa" should be added to the enumerated compounds, respectively. If desired, the compounds listed may also be vitamin D₂Type (b).

Specific and preferred examples of 2-propylene-19-nor-vitamin D compounds of structural formula I when the side chain is unsaturated are:

2- (3' -hydroxypropyl) -19-nor-1 alpha-hydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-25-hydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-1 alpha, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-24-homo-1, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-24-bishomo-1, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-24-homo-1, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dimethyl-24-homo-1, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dimethyl-24-bishomo-1, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dimethyl-24-thhomo-1, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-diethyl-24-homo-1, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-diethyl-24-bishomo-1, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-diethyl-24-thgao-1, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dipropyl-24-homo-1, 25-dihydroxy-22-dehydrovitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dipropyl-24-bishomo-1, 25-dihydroxy-22-dehydrovitamin D₃(ii) a And

2- (3' -hydroxypropyl) -19-nor-26, 27-dipropyl-24-trihexo-1, 25-dihydroxy-22-dehydrovitamin D₃。

For the above unsaturated compounds, it is noted that the double bond between the carbon atoms at positions 22 and 23 of the side chain may be in the (E) configuration or the (Z) configuration. Thus, depending on its configuration, the terms "22, 23 (E)" or "22, 23 (Z)" may be included in each of the compounds listed above. Likewise, the double bond between the carbon atoms at positions 22 and 23 is often labeled as "Δ²²". Thus, for example, the fourth compound listed above can be written as 2- (3' -hydroxypropyl) -19-nor-24-homo-22, 23(E) - Δ²²-1，25-(OH)₂D₃Wherein the double bond is in the (E) configuration. Similarly, if the methyl group attached to carbon 20 is in a non-natural configuration, the compound can be written as 2- (3' -hydroxypropyl) -19-nor-20 (S) -24-homo-22, 23(E) - Δ²²-1，25-(OH)₂D₃。

Specific and preferred examples of 2-propylene-19-nor-vitamin D compounds of structural formula I, when the side chain is saturated, are:

2- (3' -hydroxypropyl) -19-nor-1 alpha-hydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-25-hydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-1 alpha, 25-dihydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-24-homo-1, 25-dihydroxyvitamin D₃；

2-(3′-hydroxypropyl) -19-nor-24-bishomo-1, 25-dihydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-24-thgao-1, 25-dihydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dimethyl-24-homo-1, 25-dihydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dimethyl-24-bishomo-1, 25-dihydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dimethyl-24-thgao-1, 25-dihydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-diethyl-24-homo-1, 25-dihydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-diethyl-24-bishomo-1, 25-dihydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-diethyl-24-thgao-1, 25-dihydroxyvitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dipropyl-24-homo-1, 25-dihydroxy vitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dipropyl-24-bishomo-1, 25-dihydroxy vitamin D₃；

2- (3' -hydroxypropyl) -19-nor-26, 27-dipropyl-24-trihexo-1, 25-dihydroxy vitamin D₃；

The preparation of 1 α -hydroxy-19-nor-vitamin D compounds of the basic formula I containing a substituted propylene moiety in the C-2 position can be carried out by the usual conventional method, i.e. the condensation of a bicyclic Windaus-Grundmann ketone II with an allylic phosphine oxide III to form the corresponding hydroxy-protected vitamin D analogue IV followed by deprotection in the C-1 and C-3 positions.

In structures II and III, the group Y₁、Y₂X and R represent the radicals defined above; y is₁、Y₂And X is preferably a hydroxyl protecting group, it being understood that any functional group on R that may be susceptible to, or interfere with, a condensation reaction is suitably protected as is well known in the art. The above procedure represents the application of a convergent synthetic concept which has been used effectively in the preparation of vitamin D compounds (e.g., Lythgoe et al, J.chem.Soc.Perkin Trans.I, 590 (1978); Lythgoe, chem.Soc.Rev).9449 (1983); toh et al, J.org.chem.481414 (1983); baggiolini et al, j.513098 (1986); sardina et al, j.51，1264(1986)；J.Org.Chem.511269 (1986); DeLuca et al, U.S. patent No.5,086,191; DeLuca et al, U.S. patent No.5,536,713).

The indandiones of the formula II (Hydridanone) are known or can be prepared by known methods. Particularly important specific examples of such known bicyclic ketones are structures containing the above side chains (a), (b), (c) and (d), i.e. 25-hydroxy Grundmann's ketone (e) [ Baggiolini et al, J.org.chem,51，3098(1986)](ii) a Grundmann's ketone (f) [ Inhoffen et al, chem.90，664(1957)](ii) a 25-hydroxy Windaus ketone (g) [ Baggiolini et al, J.org.chem.,51，3098(1986)]and Windaus ketones (h) [ Windaus et al, Ann.,524，297(1936)]：

as previously mentioned, a new synthetic route has been developed for the preparation of the desired phosphine oxides of the general formula III starting from the bicyclic lactone 1 obtained under the trade name (1R, 3R, 4S, 5R) - (-) -quinic acid [ Hanessian et al, J.org.chem.62，465(1997)]. Scheme 1 outlines the overall conversion process for the conversion of the starting lactone 1 to the desired a-ring synthon. Thus, one of the two secondary hydroxyl groups of 1 (the equatorial hydroxyl group at the C-3 position) was selectively protected with tert-butyldimethylsilyl ether (TBDMS), after which the other hydroxyl group was oxidized with Dess-Martin periodinane (periodinane) reagent to form 4-keto 3. The tertiary-1-hydroxy group is acetylated and the resulting acetoxy ketone 4 is subjected to a Wittig reaction with an internal onium salt formed from the appropriate phosphonium salt. The phosphonium salt used for this purpose should be selected taking into account the structure of the final 19-nor vitamin D. If an attempt is made to synthesize 19-nor vitamin D analogs with a 2-propylene moiety substituted on the terminal carbon atom with some functional group other than a hydroxyl group, it may be desirable to incorporate the propylene moiety at the carbon 4 position of the ketone compound 4. This is illustrated in the experimental section as example I, which describes 1 α, 25-dihydroxy-2- [ 3' - (methoxymethyloxy) -propylidene]-19-nor vitamin D₃(21) And (4) synthesizing. In the case of an attempt to synthesize a 1 α, 25-dihydroxy-2- (3' -hydroxymethylene) -19-nor-vitamin D analog, it may be desirable to attach the protected 3-hydroxypropylene moiety to compound 4 at the 4-carbon position. This is exemplified in the experimental part as in example II, which describes 1 α, 25-dihydroxy-2- [ 3' -hydroxypropylene]-19-nor vitamin D₃Synthesis of the E and Z geometric isomers of (24a, b) and their corresponding E and Z geometric isomers of the 20S-enantiomer (25a, b). Phosphonium salts a and B used in these processes are prepared from 3-bromo-1-propanol. Thus, in the first synthesis step, Wittig reaction of ketolide 4 with an internal onium salt formed from phosphonium bromide and n-butyllithium produces two isomeric olefinic compounds 5a and 5b in a ratio of about 5: 1. Simultaneous reduction of the lactone ring and acetoxy group of the main compound 5a with sodium borohydride or other suitable reducing agent (e.g., lithium aluminum hydride) to form the triol 7 (scheme II)The alcohol is then oxidized with sodium periodate to form cyclohexanone derivative 9. The next step of the process involves protection of the secondary hydroxyl group as TBDMS ether and subsequent Peterson reaction of ketone 11 with methyl (trimethylsilyl) acetate. The resulting mixture of allyl esters 13a and 13b (isomer ratio about 7: 1) is treated with DIBALH or other suitable reducing agent, such as lithium aluminum hydride, and the resulting allyl alcohols 15a and 15b are subsequently converted to the desired A-epoxyphosphines 17a and 17 b. The final conversion involved 3 steps, i.e., tosylation in situ with n-butyllithium and p-toluenesulfonyl chloride, followed by reaction with diphenylphosphine lithium salt and oxidation with hydrogen peroxide. Alternatively, in the second synthesis step ketolide 4 undergoes a Wittig reaction with the internal onium salt produced by the phosphonium bromide and produces the isomeric olefins 6a and 6b in a ratio of about 3: 2. Reduction and periodate oxidation followed by silylation yield the corresponding ketone compound 12. The subsequent Peterson reaction produces a mixture of allyl esters 14a and 14b (with an isomer ratio of about 6: 1) which are converted to phosphine oxides 18a and 18b, respectively.

Several 2-methylene-19-nor vitamin D compounds can be synthesized using the A ring synthons 17a, 17b and 18a, 18b and the appropriate Windaus-Grundmann ketone containing the desired side chain structure. Thus, a phosphonooxy lithium carbanion (lithermphosphinothyloxy carbanion) as generated from 17a with phenyl lithium and according to the published procedure [ Sicinski et al, j.37，3730(1994)]The prepared 25-hydroxy protected Grundmann's ketone 19a is subjected to a Wittig-Horner coupling (scheme III) to afford the desired protected vitamin compound 20. Deprotection of the compound with tetrabutylammonium fluoride affords 1 α, 25-dihydroxy-2- [ 3' - (methoxymethoxy) -propylidene]-19-nor vitamin D₃(21). Alternatively, the anion generated from 18a, 18b and phenyllithium is subjected to a Wittig-Horner reaction with 25-hydroxy protected Grundmann's ketone 19a to yield the desired 1 α, 25-dihydroxy-2- (3' -hydroxypropyl) -19-nor-vitamin D after deprotection of the hydroxy group₃E-and Z-isomers (24a, b) of (a) and the coupling reaction of the phosphine oxides 18a, 18b with (20S) -Grundmann 'S ketone derivatives 19b followed by hydrolysis results in the formation of the corresponding (20S) -1 α, 25-dihydroxy-2- (3' -hydroxy-l-2)Propylene) -19-nor-vitamin D₃The E-and Z-isomers of (25a, b).

As described above, other 19-nor vitamin D analogs can be synthesized according to the methods disclosed herein.

The invention is described by the following illustrative examples. In these examples, specific products identified by an arabic number (e.g., 1, 2, 3, etc.) refer to specific structures identified in the foregoing description and in scheme I, scheme II, and scheme III.

Examples

Melting point (uncorrected) was determined by a Thomas-Hoover capillary melting point apparatus. The UV absorption spectra were recorded by a Perkin-Elmer Lambda 3B UV-VIS spectrophotometer in ethanol.¹H Nuclear Magnetic Resonance (NMR) spectra were recorded using Bruker Instruments DMX-400 and DMX-500Avance console spectrometers in deuterated chloroform (deteriochloroform) at 400 and 500 MHz.¹³C Nuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker instruments DMX-500Avance console spectrometer in deuterated chloroform at 125 MHz. Chemical shifts (. delta.) from internal standard Me₄Si (. delta.0.00) is recorded to low field. Electron Impact (EI) mass spectra were obtained using a Micromass AutoSpec (Beverly, Mass.) instrument. High Performance Liquid Chromatography (HPLC) was performed on Waters Associates liquid phase equipped with 6000A solvent delivery system, U6K Universal syringe and 486 tunable absorption detector. THF was freshly distilled from sodium benzophenone ketyl under argon before use.

Example 1

1 alpha, 25-dihydroxy-2- [ (3' -methoxymethoxy) propylidene group]-19-nor vitamin D₃Preparation of

As previously described, referring first to scheme I, the starting bicyclic lactone 1 is available from commercial (-) -quinic acid [ Hanessian et al, j.62，465(1997)]。

(a) Protection of the 3-hydroxy group in lactone 1

(1R，3R，4S, 5R) -1, 4-dihydroxy-3- [ (tert-butyldimethylsilyl) oxy]-6-oxa-bicyclo [3.2.1]Octane-7-one (2). To a stirred solution of lactone 1(1.80g, 10.34mmol) and imidazole (2.63g, 38.2mmol) in anhydrous DMF at 0 deg.C was added tert-butyldimethylsilyl chloride (1.80g, 11.9 mmol). The mixture was stirred at 0 ℃ for 30 minutes, at room temperature for 1h, poured into water and extracted with ethyl acetate and diethyl ether. The organic layer was washed several times with water and dried (MgSO)₄) Evaporation gave a colorless crystalline residue which was recrystallized from hexane/ethyl acetate to give 2.12g of pure 2. The mother liquor was evaporated and purified by flash chromatography. Elution with hexane/ethyl acetate (8: 2) gave an additional amount of crystalline monoether 2(0.14g, 76% overall yield) and an amount of crystalline isomeric (3-OH, 4-OTBDMS) ether (0.10g, 3%). 2: melting point 90-94 deg.C (hexane); [ alpha ] to]²⁴ _D-44°(c 1.00CHCl₃)；¹H NMR(500MHz，CDCl₃)δ0.095(6H，s，2×SiCH₃) 0.901(9H, s, Si-t-Bu), ca.2.0(2H, br m, 2 α -and 2 β -H), 2.29(1H, ddd, J ═ 11.6, 6.0, 2.6Hz, 8 β -H), 2.63(1H, d, J ═ 11.6Hz, 8 α -H), 3.89(1H, ddd, J ═ 10.4, 7.0, 4.5Hz, 3 β -H), 3.98(1H, t, J ═ 4.6Hz, 4 β -H), 4.88(1H, dd, J ═ 6.0, 4.8Hz, 5 α -H);¹³C NMR(125MHz)δ-5.0(Si-CH₃)，-4.7(Si-CH₃)，17.9[C(CH₃)₃]，25.6[C(CH₃)₃]，36.4(C₈)，40.2(C₂)，65.8(C₄)，67.0(C₃)，71.9(C₁)，76.3(C₅) 177.9(C ═ O), ms (ei) M/z (relative abundance) 288 (M)⁺1, 231(41), 213(21), 185(85), 75 (100); HRMS (ESI), exact mass calculated as C₁₃H₂₄O₅SiNa(M⁺+ Na)311.1291, measurement 311.1287; c₁₃H₂₄O₅Calculated Si elemental analysis: c, 54.14, H, 8.39. measured value: c, 53.94, H, 8.36.

(b) Oxidation of the 4-hydroxy group in dihydroxylactone 2.

(1R, 3R, 5R) -3- [ (tert-butyl) 3Butyldimethylsilyl) oxy]-1-hydroxy-6-oxa-bicyclo [3.2.1]Octane-4, 7-dione (3). To a stirred Dess-Martin periodinane reagent (6.60g, 15.5mmol) in anhydrous CH₂Cl₂(100mL) to the suspension was added Compound 2(3.86g, 13.4 mmol). The mixture was stirred at room temperature for 18h, poured into water and extracted with ethyl acetate. The organic layer was washed several times with water and dried (MgSO)₄) Evaporation gave an oily residue which slowly crystallized upon cooling (3.67g, 95%). TLC showed high purity of ketone 3, which was used in the next step without further purification. The analytical sample was obtained by recrystallization from hexane. 3: the melting point is 92-95 ℃;¹H NMR(400MHz，CDCl₃) δ 0.040 and 0.133(3H and 3H, each being s, 2 × SiCH)₃)，0.895(9H，s，Si-t-Bu)，2.15(1H，dd，J＝12.4，10，4Hz，2α-H)，2.42(1H，d，J＝12.5Hz，8α-H)，2.54(1H，ddd，J＝12.4，9.0，3.9Hz，2β-H)，2.86(1H，ddd，J＝12.5，6.7，3.9Hz，8β-H)，4.54(1H，dd，J＝10.4，9.0Hz，3β-H)，4.73(1H，d，J＝6.7Hz，5α-H)；¹³CNMR(125MHz)δ.-5.6(Si-CH₃)，-4.8(Si-CH₃)，18.2[C(CH₃)₃]，25.6[C(CH₃)₃]，42.3(C₈)，43.0(C₂)，70.3(C₃)，71.8(C₁)，78.7(C₅)，177.1(C＝O)，202.4(C₄) (ii) a MS (EI) M/z (relative abundance) M-free⁺，271(M⁺-CH₃，4)，229(92)，201(28)，157(100)；HRMS(ESI)C₉H₁₃O₅Si(M⁺t-Bu) exact mass calculation value 229.0532, measured value 229.0539; c₁₃H₂₂O₅Si x H₂Calculated value of O element analysis: c, 51.29, H, 7.95. measured values: c, 51.09, H, 7.90.

(c) Acetylation of 1-hydroxy group in hydroxyketone 3

(1R, 3R, 5R) -1-acetoxy-3- [ (tert-butyldimethylsilyl) oxy]-6-oxa-bicyclo [3.2.1]Octane-4, 7-dione (4). A solution of hydroxyketone 3(1.64g, 5.8mmol) in anhydrous pyridine (12mL) and acetic anhydride (5.5mL) was added at room temperatureStirred for 3 h. Then poured into water and extracted with ethyl acetate. The organic layer was saturated NaHCO₃Saturated CuSO₄And washed with water and dried (MgSO)₄) Evaporation gave an oily residue which was dissolved in hexane/ethyl acetate (8: 2) and filtered through short silica gel. Evaporation of the solvent gave pure crystalline acetate 4(1.51g, 81%). Analytical samples were obtained by recrystallization from hexane/ethyl acetate. 4: the melting point is 134-7 ℃; [ alpha ] to]²⁴ _D-78°(c 1.00CHCl₃)；¹H NMR(400MHz，CDCl₃) δ 0.046 and 0.141(3H and 3H, s, 2 × SiCH each)₃)，0.901(9H，s，Si-t-Bu)，2.17(3H，s，CH₃CO)，2.28(1H，dd，J＝12.2，10.4Hz，2α-H)，2.32(1H，d，J＝12.1Hz，8α-H)，2.65(1H，ddd，J＝12.2，8.8，3.9Hz，2β-H)，3.56(1H，ddd，J＝12.1，6.9，3.9Hz，8β-H)，4.58(1H，dd，J＝10.4，8.8Hz，3β-H)，4.80(1H，d，J＝6.9Hz，5α-H)；¹³C NMR(125MHz)δ-5.8(Si-CH₃)，-4.9(Si-CH₃)，18.2[C(CH₃)₃]，20.9(CH₃-C＝O)，25.6[C(CH₃)₃]，38.3(C₈)，40.3(C₂)，70.4(C₃)，75.3(C₁)，78.4(C₅)，169.1(CH₃-C＝O)，171.5(C＝O)，201.8(C₄) (ii) a MS (EI) M/z (relative abundance) 328 (M)⁺，6)，271(100)，256(38)，229(54)，211(53)；HRMS(ESI)C₁₁H₁₅O₆Si(M⁺t-Bu) exact mass calculation value 271.0638, measured value: 271.0646, respectively; c₁₅H₂₄O₆Calculated Si elemental analysis: c, 54.86, H, 7.37. measured values: c, 54.88, H, 7.37.

(d) Preparation of phosphonium bromide A

[3- (methoxymethoxy) propyl group]Triphenylphosphonium bromide (A). To a solution of bromomethyl ether (1.3mL, 16mmol) and N, N-diisopropylethylamine (4.5mL, 27.7mmol) in anhydrous CH at 0 deg.C₂Cl₂(50mL) to the solution was added 3-bromo-1-propanol (1.0mL, 11mmol) and the mixture was stirred at 0 deg.C for 1h, at room temperatureAnd (5) 20 h. The reaction mixture was poured into 1N HCl (150mL), the organic phase was separated and the aqueous phase was washed with CH₂Cl₂And (4) extracting. The combined organic phases were washed with water and NaHCO₃Diluting and drying (MgSO)₄) And evaporated to give a pale yellow oil. The residue was purified by flash chromatography. Elution with hexane/ethyl acetate (95: 5) gave pure 1-bromo-3- (methoxymethoxy) propane (1.12g, 55%) as an oil.¹H NMR(400MHz，CDCl₃)δ2.13(2H，m，CH₂-CH ₂-CH₂)，3.37(3H，s，O-CH₃)，3.53(2H，br t，J＝6.5Hz，Br-CH₂)，3.67(2H，brt，J＝5.8Hz，CH₂-CH ₂-O)，4.63(2H，s，O-CH₂-O).

Triphenylphosphine (0.71g, 2.7mmol) was added to a solution of 1-bromo-3- (methoxymethyloxy) propane (0.46g, 2.5mmol) in dry toluene (1.5mL) under argon with stirring. The mixture was heated at 100 ℃ for 20h and then cooled to room temperature. After pouring off the liquid, the solid residue is scraped off with a spatula (ground), filtered and washed several times with diethyl ether. After drying overnight in a vacuum desiccator, colorless phosphonium salt crystals A (0.98g, 88%) were obtained which were used for the Wittig reaction without further purification. A:¹H NMR(500MHz，CDCl₃)δ1.96(2H，m，CH₂-CH ₂-CH₂)，3.31(3H，s，O-CH₃)，3.85(2H，br t，J＝5.6Hz，CH₂-CH ₂-O)，4.00(2H，m，P-CH₂)，4.60(2H，s，O-CH₂-O), 7.70, 7.79 and 7.86(6H, 3H and 6H, each m, Ar-H); c₂₃H₂₆O₂Calculated value of PBr elemental analysis: c, 62.03, H, 5.88, Br, 17.94, found: c, 61.87, H, 5.77, Br, 17.89.

(e) Wittig reaction of 4-keto-4 with an ylium salt derived from A

[ (E) -and (Z) - (1R, 3R, 5R) -1-acetoxy-3- [ (tert-butyldimethylsilyl) oxy ] oxy]-6-oxa-4- [ 3' - (methoxymethyloxy) propylidene]Bicyclo [3.2.1]Octane-7-one (5a and 5 b). Under argon at 0 ℃ under argonTo a solution of phosphonium bromide A (420mg, 0.94mmol) in anhydrous THF (5mL) was added n-BuLi (1.6M in hexane, 1.12mL, 1.8mmol) dropwise with stirring. After 5 min another portion of A (420mg, 0.94mmol) was added and the solution was stirred at 0 ℃ for 10 min and then at room temperature for 20 min. The red-orange mixture was cooled to-78 ℃ and then was siphoned into 2 equal portions (30 min apart) into a solution of lactone ketone 4(300mg, 0.91mmol) in dry THF (8 mL). The reaction mixture was stirred at-78 ℃ and quenched by addition of 1% HCl in brine (3h after addition of the first Wittig reagent). Ethyl acetate (9mL), benzene (6mL), diethyl ether (3mL), saturated NaHCO was added₃(3mL) and water (3mL), and the mixture was stirred vigorously at room temperature for 18 h. The organic phase was then separated, washed with brine and dried (MgSO)₄) And evaporated. The oily residue (comprising mainly isomers 5a and 5b in a ratio of 5: 1) was separated by flash chromatography on silica gel. The product fractions were separated by elution with hexane/ethyl acetate (85: 15): 29mg of 5b, a mixture of 5a and 5b (85mg) and pure 5a (176 mg; total yield 77%). The combined fractions were subjected to secondary chromatographic separation to give an almost completely separated product. 5 a: [ alpha ] to]²⁴ _D-63°(c 0.60CHCl₃)；¹H NMR(500MHz，CDCl₃)δ0.074(6H，s，2x SiCH₃)，0.914(9H，s，Si-t-Bu)，2.13(3H，s，OCH₃) 2.00(1H, br t, J ═ 11.2, Hz, 2 α -H), 2.10(1H, d, J ═ 10.8Hz, 8 α -H), 2.34(1H, ddd, J ═ 11.7, 7.0, 2.9Hz, 2 β -H), 2.38, and 2.43(1H and 1H, each m ═ C — CH)₂)，3.31(1H，ddd，J＝10.8，6.5，2.9Hz，8β-H)，3.35(3H，s，O-CH₃) 3.54 and 3.60(1H and 1H, each being m, CH)₂-CH ₂-O)，4.41(1H，t，J＝8.2Hz，3-H)，4.60(2H，s，O-CH₂-O)，5.52(1H，d，J＝6.5Hz，5-H)，5.71(1H，br t，J＝7.1Hz，＝CH)；¹³C NMR(125MHz)δ.-5.1(Si-CH₃)，-4.9(Si-CH₃)，18.1[C(CH₃)₃]，21.1CH₃-C＝O)，25.7[C(CH₃)₃]，27.5(CH₂-CH ₂-C＝)，40.5(C₈)，41.5(C₂)，55.2(O-CH₃)，66.7(O-CH₂-CH₂)，66.8(C₃)，77.1(C₁)，73.9(C₅)，96.3(O-CH₂-O)，121.9(＝C-CH₂)，136.8(C₄)，169.1(CH₃-CO), 172.9(C ═ O); MS (EI) M/z (relative abundance) without M⁺，383(M⁺-OCH₃，3)，357(10)，325(44)，297(12)，267(15)，265(40)，237(89)，75(100)；HRMS(ESI)C₂₀H₃₄O₇SiNa(M⁺+ Na) exact mass calculation value 437.1972, measured value: 437.1975.

5b：¹H NMR(500MHz，CDCl₃) δ 0.108 and 0.125(3H and 3H, s, 2 × SiCH each)₃)，0.912(9H，s，Si-t-Bu)，2.13(3H，s，OCH₃) 2.15(1H, dd, J ═ 12.6, 8.3Hz, 2 α -H), 2.31(1H, d, J ═ 10.8Hz, 8 α -H), 2.33(1H, 2-H and 8 α -H overlap), 2.67 and 2.73(1H and 1H, each m ═ C-CH ═ C-H)₂)，3.25(1H，ddd，J＝10.8，6.3，2.8Hz，8β-H)，3.36(3H，s，O-CH₃)，3.55(2H，m，CH₂-CH ₂-O)，4.61(2H，s，O-CH₂-O)，4.71(1H，br t，J～7Hz，3β-H)，4.94(1H，d，J＝6.3Hz，5α-H)，5.64(1H，dt，J＝1.7，7.1Hz，＝CH)；¹³C NMR(125MHz)δ-4.6(Si-CH₃)，-4.5(Si-CH₃)，17.9[C(CH₃)₃]，21.1(CH₃-C＝O)，25.7[C(CH₃)₃]，27.8(CH₂-CH ₂-C＝)，38.9(C₈)，41.2(C₂)，55.3(O-CH₃)，67.1(O-CH₂-CH₂)，67.2(C₃)，77.1(C₁)，81.8(C₅)，96.4(O-CH₂-O)，128.9(＝C-CH₂)，134.8(C₄)，169.1(CH₃-CO), 173.0(C ═ O); MS (EI) M/z (relative abundance) without M⁺，383(M⁺-OCH₃，2)，357(2)，325(22)，297(17)，267(35)，265(14)，237(96)，75(100)；HRMS(ESI)C₂₀H₃₄O₇SiNa(M⁺+ Na) exact mass calculation value: 437.1972 measured value：437.1974.

(f) Reduction of acetoxylactone 5a (scheme II)

[ (E) - (1 ' R, 3 ' R, 5 ' R) -3- [ (tert-butyldimethylsilyl) oxy ] oxy]-1 ', 5-dihydroxy-4 ' - [3 ' - (methoxymethoxy) propylene]Cyclohexyl radical]Methanol (7). (a) To a stirred solution of compound 5a (165mg, 0.40mmol) in absolute ethanol (5mL) at 0 deg.C was added NaBH₄(151mg, 4.0mmol) and the mixture was stirred at 0 ℃ for 1h, then at 6 ℃ for 10h and at room temperature for 2 h. Adding saturated NH₄Cl, the mixture was poured into brine and extracted several times with ether and dichloromethane. The extracts were washed with brine, combined and dried (MgSO)₄) And evaporated. The oily residue was purified by flash chromatography. Elution with hexane/ethyl acetate (2: 8) gave triol 7(115mg, 79%) as a pure colorless oil. 7: [ alpha ] to]²⁴ _D-59°(c 1.40CHCl₃)；¹H NMR(400MHz，CDCl₃) δ 0.087 and 0.110(3H and 3H, s, 2 × SiCH each)₃)，0.895(9H，s，Si-t-Bu)，1.66(1H，dd，J＝13.0，9.1Hz，6β-H)，1.69(1H，dd，J＝13.8，3.1Hz，2β-H)，1.84(1H，s，OH)，1.96(1H，ddd，J＝13.8，5.0，1.7Hz，2α-H)，2.04(1H，ddd，J＝13.0，4.6，1.7Hz，6α-H)，2.54(1H，s，OH)，2.63(2H，m，＝C-CH₂)，3.34(3H，s，O-CH₃) 3.39 and 3.50(1H and 1H, D)₂After O: each d, J ═ 11.0Hz, CH ₂-OH)，3.50(1H，s，OH)，3.58(2H，m，CH₂-CH ₂-O)，4.19(1H，s，OH)，4.47(1H，m，w/2＝10Hz，3β-H)，4.63(2H，s，-O-CH₂-O)，4.89(1H，m；D₂After O: dd, J ═ 9.1, 4.6Hz, 5 α -H), 5.51(1H, t, J ═ 8.3Hz, ═ CH);¹³C NMR(125MHz)δ-5.2(Si-CH₃)，-4.7(Si-CH₃)，18.0[C(CH₃)₃]，25.7[C(CH₃)₃]，27.2(CH₂-CH ₂-C＝)，41.3(C₂)，44.1(C₆)，55.4(O-CH₃)，66.4(C₅)，66.7(O-CH₂-CH₂)，70.3(CH₂-OH)，73.7(C₁)，75.9(C₃)，96.4(O-CH₂-O)，122.0(＝C-CH₂)，144.2(C₄) (ii) a MS (EI) M/z (relative abundance) without M⁺，358(M⁺-H₂O，2)，327(3)，297(3)，239(17)，75(100)；HRMS(ESI)C₁₈H₃₆O₆SiNa(M⁺+ Na) exact mass calculation value: 399.2179, measurement: 399.2198.

(b) to a solution of compound 5a (186mg, 0.45mmol) in dry THF (17mL) at 0 deg.C was added LiAlH₄(128mg, 3.42mmol) and the mixture was stirred at 0 ℃ for 1h, room temperature for 3 h. The mixture was carefully poured into saturated Na₂SO₄The solution was extracted several times with ethyl acetate and diethyl ether. The organic layer was washed with brine and dried (MgSO₄) And evaporated. The oily residue was purified by flash chromatography. Elution with hexane/ethyl acetate (2: 8) gave triol 8(100mg, 59%) as a pure colorless oil.

(g) Cleavage of vicinal diols 7

[ (E) - (3R, 5R) -3- [ (tert-butyldimethylsilyl) oxy ] oxy]-5-hydroxy-4- [ 3' - (methoxymethyloxy) propylidene]]Cyclohexanone (9). Water (1.2mL) saturated with sodium periodate was added to a solution of triol 7(79mg, 0.21mmol) in methanol (5mL) at 0 ℃. The solution was stirred at 0 ℃ for 1h, poured into brine and extracted with ethyl acetate and ether. The extract was washed with brine and dried (MgSO)₄) And (5) evaporating. The oily residue was taken up in hexane/CH₂Cl₂Redissolved and passed through a Sep-Pak cartridge. Elution with hexane/ethyl acetate (7: 3) gave pure hydroxyketone 9(64mg, 88%) as an oil which crystallized slowly in the refrigerator. 9: [ alpha ] to]²⁴ _D+41°(c 1.45CHCl₃)；¹H NMR(500MHz，CDCl₃) δ 0.048 and 0.076(3H and 3H, s, 2 × SiCH each)₃)，0.863(9H，s，Si-t-Bu)，2.34(1H，m，＝C-CH₂One), 2.50(1H, dd, J ═ 16.0, 6.0Hz, 2 α -H), 2.62(1H, m, dd, J ═ one of 16.1, 3.2Hz, 6-H), 2.65(1H, m ═ C-CH)₂)，2.70(1H，dd，J＝16.0，3.4Hz2 β -H), 2.75(1H, dd, J ═ one of 16.1, 3.4Hz, 6-H), 3.33(3H, s, O-CH)₃) 3.53 and 3.74(1H and 1H, each m, CH)₂-CH ₂-O), 4.62(3H, br m, 3-H and O-CH₂-O)，4.95(1H，t，J～3.3Hz，5α-H)，5.73(1H，dd，J＝10.2，6.3Hz，＝CH)；¹³C NMR(125MHz)δ-4.9(Si-CH₃)，-4.7(Si-CH₃)，18.0[C(CH₃)₃]，25.6[C(CH₃)₃]，28.0(CH₂-CH ₂-C＝)，45.3(C₂)，48.3(C₆)，55.4(O-CH₃)，63.1(C₅)，65.7(O-CH₂-CH₂)，70.3(C₃)，96.3(O-CH₂-O)，126.7(＝C-CH₂)，142.5(C₄)，208.7(C₁) (ii) a MS M/z (relative abundance) without M⁺，313(M⁺-OCH₃，3)，287(15)，269(7)，255(21)，237(11)，227(68)，225(91)，213(17)，195(57)，75(100)；HRMS(ESI)C₁₃H₂₁O₅Si(M⁺-t-Bu) the exact mass is calculated as: 287.1315, measurement: 287.1312.

(h) protection of the 5-hydroxy group in hydroxyketone 9.

[ (3R, 5R) -3, 5-bis [ (tert-butyldimethylsilyl) oxy ] oxy]-4- [ 3' - (methoxymethyloxy) propylidene]Cyclohexanone (11). To anhydrous CH of hydroxyketone 9(40mg, 117. mu. mol) at 50 ℃ C₂Cl₂To a solution (0.4mL) was added 2, 6-lutidine (32. mu.l, 274. mu. mol) and t-butyldimethylsilyl triflate (56. mu.L, 240. mu. mol). The mixture was stirred at-50 ℃ for 5 minutes, then warmed to-15 ℃ and stirred at this temperature for a further 30 minutes. Benzene and water were added and the mixture was poured into water and extracted with benzene. Extracting with saturated CuSO₄And washed with water and dried (MgSO)₄) And evaporated. The oily residue was redissolved in hexane and purified by flash chromatography on silica gel. Elution with hexane/ethyl acetate (95: 5) gave pure protected ketone 11(30mg, 57%; 66% based on recovered substrate) and unreacted 9(6mg) as a colorless oil. 11：[α]²⁴ _D-26°(c0.30CHCl₃)；¹H NMR(400MHz，CDCl₃) δ 0.019 and 0.065(3H and 9H, each s, 4 × SiCH)₃) 0.838 and 0.912(9H and 9H, each s, 2x Si-t-Bu), 2.32(1H, dd, J ═ 14.1, 10.4Hz, 2 α -H), 2.45(3H, br m ═ C-CH₂And 6 α -H), 2.53(1H, ddd, J ═ 14.4, 3.2, 2.1Hz, 6 β -H), 2.75(1H, ddd, J ═ 14.1, 5.6, 2.1Hz, 2 β -H), 3.36(3H, s, O — CH), 2.3, 2.7 (1H, ddd, J ═ 14.1, 5.6, 2.1Hz, 2 β -H), 3.36(3H, s, O — CH)₃)，3.58(2H，m，CH₂-CH ₂-O)，4.62(2H，s，O-CH₂-O)，4.75(1H，ddd，J＝10.4，5.6，1.4Hz，3β-H)，5.01(1H，t，J～3.2Hz，5α-H)，5.70(1H，dt，J＝1.7，7.8Hz，＝CH)；¹³C NMR(125MHz)δ-5.08(Si-CH₃)，-5.06(Si-CH₃)，-5.05(Si-CH₃)，-5.00(Si-CH₃)，17.9[C(CH₃)₃]，25.5[C(CH₃)₃]，27.7(CH₂-CH ₂-C＝)，50.2(C₆)，52.4(C₂)，55.2(O-CH₃)，65.8(C₃)，67.1(O-CH₂-CH₂)，67.8(C₅)，96.4(O-CH₂-O)，118.5(＝C-CH₂)，141.5(C₄)，207.5(C₁) (ii) a MS (EI) M/z (relative abundance) 443 (M)⁺+H，2)，427(M⁺-CH₃，5)，401(55)，371(15)，339(20)，75(100)；C₁₂H₄₃O₄Si₂(M⁺-CH₃) Accurate mass calculated value: 427.2700, measurement: 427.2701. preparation of allyl esters 13a and 13b

[ (E) -and (Z) - (3 'R, 5' R) -3 ', 5' -bis [ (tert-butyldimethylsilyl) oxy ] oxy]-4' - [3 "- (methoxymethoxy) propylene]Cyclohexylidene radical]Methyl acetate (13a and 13 b). To a solution of diisopropylamine (25. mu.L, 0.18mmol) in dry THF (0.15mL) under stirring at argon-78 ℃ was added n-BuLi (2.5M in hexane, 72. mu.L, 0.18mmol) followed by methyl (trimethylsilyl) acetate (30. mu.L, 0.18 mmol). After 15 minutes, a solution of ketone 11(38.4mg, 84. mu. mol) in dry THF (0.2mL) was added. The solution was stirred at-78 ℃ for an additional 2h,the reaction mixture was quenched with wet ether, poured into brine, and extracted with ether and benzene. The combined extracts were washed with brine and dried (MgSO)₄) And (5) evaporating. The oily residue was redissolved in hexane and passed through a Sep-Pak cartridge. Elution with hexane/ethyl acetate (97: 3) gave the pure allyl esters 13a and 13b (37.2mg, 86%; isomer ratio 13 a: 13b ═ 7: 1). Isolation of the product was achieved by HPLC (10mm X25cm Zorbax-Sil column, 4mL/min) using a hexane/ethyl acetate (95: 5) solvent system. Pure compounds 13a and 13b eluted as colorless oils at retention volumes of 41mL and 44mL, respectively. 13 a:¹H NMR(500MHz，CDCl₃) Delta-0.006, 0.056, 0.078, 0.107 (3H each, s, 4x SiCH each)₃) 0.832 and 0.923(9H and 9H, each s, 2x Si-t-Bu), 1.87(1H, t, J ═ 11.8Hz, 2 α -H), 2.28(1H, br d, J ═ 13.2Hz, 6 α -H), 2.34(1H, br d, J ═ 13.2Hz,β-H)，2.42(2H，q，J～7Hz，＝C-CH₂)，3.36(3H，s，CH₂-O-CH ₃)，3.55(2H，m，CH₂-CH ₂-O)，3.70(3H，s，CO-O-CH₃)，4.14(1H，dd，J＝12.8，3.8Hz，2β-H)，4.45(1H，br m，3β-H)，4.62(2H，s，O-CH₂-O)，4.88(1H，narr m，5α-H)，5.55(1H，brt，J＝7.5Hz，＝CH-CH₂) 5.65(1H, br, ═ CH-CO); MS (EI) M/z (relative abundance) M-free⁺，499(M⁺-CH₃，2)，482(11)，469(31)，457(65)，425(63)，351(70)，293(76)，89(100)；HRMS(ESI)C₂₆H₅₀O₆Si₂Na exact mass calculated value: 537.3044, measurement: 537.3018.

13b：¹H NMR(500MHz，CDCl₃) Delta-0.008, 0.048, 0.057 and 0.063 (3H each, s, 4x SiCH each)₃) 0.804 and 0.915(9H and 9H, s, 2x Si-t-Bu, respectively), 1.95(1H, br d, J ═ 13.8Hz, 2 β -H), 2.17(1H, t, J to 11.6Hz,β-H)，2.42(2H，m，＝C-CH₂)，2.55(1H，ddd，J～12.4，～5.0，～1.2Hz，6α-H)，3.36(3H，s，CH₂-O-CH ₃)，3.55(2H，m，CH₂-CH₂-O)，3.67(3H，s，CO-O-CH₃)，3.96(1H，br d，J＝13.8Hz，2α-H)，4.51(1H，br m，5α-H)，4.62(2H，s，O-CH₂-O)，4.89(1H，narr m，3β-H)，5.50(1H，br t，J＝7.5Hz，＝CH-CH₂) 5.80(1H, br, ═ CH-CO); MS m/z (relative abundance): without M⁺，499(M⁺-CH₃，4)，482(14)，469(34)，457(82)，425(69)，351(58)，293(59)，89(100)；HRMS(ESI)C₂₆H₅₀O₆Si₂Na exact mass calculated value: 537.3044, measurement: 537.3053.

(j) reduction of allyl esters 13a and 13b

2- [ (E) -and (Z) - (3 'R, 5' R) -3 ', 5' -bis [ (tert-butyldimethylsilyl) oxy ] oxy]-4' - [3 "- (methoxymethoxy) propylene]Cyclohexylidene radical]Ethanol (15a and 15 b). Diisobutylaluminum hydride (1.0M in toluene, 0.35mL, 0.35mmol) was added slowly to a stirred solution of allyl esters 13a and 13b (37.2mg, 74. mu. mol) in toluene/dichloromethane (2: 1, 1.5mL) under argon-78 ℃. Stirring was continued at-78 deg.C for 1H and the mixture was purified by the addition of potassium sodium tartrate (2N, 2mL), HCl (2N, 2mL) and H₂Quenched with O (24mL) and then diluted with ether and benzene. Organic layer diluted NaHCO₃And washed with brine, dried (MgSO)₄) And (5) evaporating. The residue was purified by flash chromatography. The product fraction was isolated by eluting with hexane/ethyl acetate (95: 5): 16mg of a mixture of 15a, 15a and 15b (15mg) and pure 15b (3 mg; total yield 97%). The mixture fraction was subjected to secondary chromatography to give an almost completely separated product.

15a (main product):¹H NMR(500MHz，CDCl₃) Delta-0.007, 0.057, and 0.067(3H, 6H and 3H, each s, 4x SiCH)₃) 0.839 and 0.916(9H and 9H, each s, 2xSi-t-Bu), 1.81(1H，t，J＝11.7Hz，2α-H)，2.17(1H，d，J＝13.4Hz，6α-H)，2.26(1H，br d，J＝13.4Hz，6β-H)，2.41(2H，q，J＝7Hz，＝C-CH ₂-CH₂)，2.86(1H，dd，J＝12.5，3.8Hz，2β-H)，3.36(3H，s，O-CH₃)，3.54(2H，m，CH₂-CH ₂-O)，4.38(1H，dd，J＝10.6，3.8Hz，3β-H)，4.17(2H，t，J～6Hz；D₂After O: d, J ═ 6.9Hz, CH ₂-OH)，4.62(2H，s，O-CH₂-O)，4.81(1H，narr m，5α-H)，5.48(2H，m，2x＝CH) (ii) a MS (EI) M/z (relative abundance) 486 (M)⁺，3)，468(30)，454(17)，441(32)，429(24)，423(34)，89(100)；HRMS(ESI)C₂₅H₅₀O₅Si₂Na exact mass calculated value: 509.3095, measurement: 509.3111.

15b (trace):¹H NMR(500MHz，CDCl₃) δ 0.011, 0.054, 0.069(3H, 3H and 6H, each s, 4 × SiCH)₃) 0.850 and 0.917(9H and 9H, each s, 2xSi-t-Bu), 1.88(1H, br d, J ═ 13.4Hz, 2 β -H), 2.03(1H, t, J ═ 11.4Hz, 6 β -H), 2.42(2H, m ═ C-CH)₂)，2.51(1H，ddd，J＝12.0，4.8，1.2Hz，6α-H)，2.75(1H，br d，J＝13.4Hz，2α-H)，3.36(3H，s，O-CH₃)，3.55(2H，m，CH₂-CH ₂-O), 4.02 and 4.15(1H and 1H, each being m; d₂After O: each dd, J ═ 11.8, 7.2Hz, CH ₂-OH)，4.40(1H，br m，5α-H)，4.62(2H，s，O-CH₂-O)，4.90(1H，narr m，3β-H)，5.53(1H，br t，J＝7.4Hz，＝CH-CH₂)，5.71(1H，t，J＝7.2Hz，＝CH-CH₂-OH); MS (EI) M/z (relative abundance) 486 (M)⁺，5)，468(27)，454(11)，441(22)，429(30)，423(29)，89(100)；HRMS(ESI)C₂₅H₅₀O₅Si₂Na exact mass calculated value: 509.3095, measurement: 509.3108.

(k) conversion of allyl alcohols 15a and 15b to phosphine oxides 17a and 17b

[2- [ (E) -and (Z) - (3 'R, 5' R)) -3 ', 5' -bis [ (tert-butyldimethylsilyl) oxy)]-4' - [3 "- (methoxymethoxy) propylene]Cyclohexylidene radical]Ethyl radical]Diphenylphosphine oxides (17a and 17 b). To a solution of allylic alcohols 15a and 15b (about 7: 1, 34mg, 70. mu. mol) in anhydrous THF (0.8mL) was added n-BuLi (2.5M in hexane, 28. mu.L, 70. mu. mol) with stirring under argon at 0 ℃. The newly recrystallized tosyl chloride (14.0mg, 73. mu. mol) was dissolved in anhydrous THF (190. mu.L) and then added to the allylic alcohol-BuLi solution. The mixture was stirred at 0 ℃ for 5 minutes and then left at 0 ℃. In another dry flask, which was purged with air with argon, n-BuLi (2.5M in hexane, 140. mu.L, 0.35mmol) was added to Ph with stirring at 0 deg.C₂pH (62. mu.L, 0.34mmol) in dry THF (420. mu.L). The red solution was siphoned into a solution of p-toluenesulfonate (tosylate) under argon pressure until the orange color persisted (ca. solution of 1/4 was added). The resulting mixture was stirred at 0 ℃ for a further 40 minutes by addition of H₂The reaction was quenched with O (40. mu.l). The solvent was evaporated under reduced pressure and the residue redissolved in dichloromethane (1.0mL) with 10% H₂O₂(0.5mL) was stirred at 0 ℃ for 1 h. The organic layer was separated, washed with cold aqueous sodium sulfite solution and H₂O washing and drying (MgSO)₄) And (5) evaporating. The residue was purified by flash chromatography. Elution with hexane/ethyl acetate (85: 15) gave unreacted allyl alcohol (3.9 mg). The product fraction was subsequently isolated by elution with benzene/ethyl acetate (7: 3): 27.6mg of 17a, a mixture of 17a and 17b (2mg) and pure 17b (2 mg; overall yield 68%). Purification by HPLC (10mm X25cm Zorbax-Sil column, 4mL/min) using a hexane/2-propanol (9: 1) solvent system gave samples for analysis of both isomers. Pure oily compounds 17a and 17b eluted at retention volumes of 41mL and 44mL, respectively. 17 a:¹H NMR(500MHz，CDCl₃) Delta-0.031, -0.013, 0.017, and 0.024 (3H each, s, 4xSiCH each)₃) 0.795 and 0.899(9H and 9H, s, 2x Si-t-Bu each), 1.47(1H, br t, J-11 Hz, 2 α -H), 2.06(1H, br m, 6 α -H), 2.23(1H, d, J ═ 13.5Hz, 6 β -H), 2.37(2H, q, J ═ 7.0 ═ C-C ═ H)H ₂-CH₂)，2.62(1H，dd，J＝12.8，4.5Hz，2β-H)，3.34(3H，s，O-CH₃)，3.51(2H，m，CH₂-CH ₂-O)，4.33(1H，dd，J＝10.6，4.5Hz，3β-H)，3.15(2H，dd，J＝15.2，7.6Hz，CH₂-PO)，4.60(2H，s，O-CH₂-O)，4.74(1H，narr m，5α-H)，5.28(1H，m，＝CH-CH₂-PO)，5.44(1H，t，J～7Hz，＝CH-CH₂-CH₂) 7.45, 7.52 and 7.73(4H, 2H and 4H, each m, Ar-H); MS (EI) M/z (relative abundance) M-free⁺，613(100)，538(9)，481(31)，449(22)；HRMS(ESI)C₃₇H₅₉O₅Si₂PNa exact mass calculated value: 693.3536, measurement: 693.3506.

17b：¹H NMR(500MHz，CDCl₃) Delta-0.035, 0.018, 0.022, and 0.030 (3H each, s, 4x SiCH each)₃) 0.822 and 0.885(9H and 9H, each s, 2xSi-t-Bu), 1.47(1H, br d, J ═ 12.9Hz, 2 α -H), 1.93(1H, m, 6 β -H), 2.36(2H, q, J ═ 7.2Hz, ═ C-CH ═ C-H)₂) 2.46(2H, br m, 2 α -and 6 α -H), 3.03 and 3.17(1H and 1H, each m, CH)₂-PO)，3.35(3H，s，O-CH₃)，3.50(2H，m，CH₂-CH ₂-O)，4.36(1H，dd，J＝10.6，4.0Hz，5α-H)，4.60(2H，s，O-CH₂-O)，4.75(1H，narr m，3β-H)，5.39(1H，m，＝CH-CH₂-PO)，5.44(1H，br t，J＝7.3Hz，＝CH-CH₂) 7.4-7.75(10H, br m, Ar-H); MS (EI) M/z (relative abundance) M-free⁺，613(100)，538(28)，481(90)，449(80)；HRMS(ESI)C₃₇H₅₉O₅Si₂PNa exact mass calculated value: 693.3536, measurement: 693.3538.

(l) Wittig-Horner coupling of protected 25-hydroxy Grundmann' s

1 alpha- [ (tert-butyldimethylsilyl) oxy group]-2- [ 3' - (methoxymethoxy) propylidene]-25- [ (triethylsilyl) oxy]-19-nor vitamin D₃Tert-butyldimethylsilyl ether (20). To a solution of phosphine oxide 17a (15.5mg, 23. mu. mol) in anhydrous THF (0.25mL) at-78 ℃ was slowly added with stirring under argonPhenyllithium (1.8M cyclohexane/diethyl ether solution, 13. mu.L, 23. mu. mol) was added. The solution turned dark orange. The mixture was stirred at-78 ℃ for 20 minutes and then slowly added [ Sicinski et al, J.Med.Chem.37, 3730(1994) ]prepared according to the published procedure]Is pre-frozen (-78 deg.C) with a solution of protected hydroxyketone 19a (19mg, 48. mu. mol) in anhydrous THF (0.25 mL). The mixture was stirred at-78 ℃ for 3 hours and 6 ℃ for 16 hours under argon. Ethyl acetate and water were added, and the organic layer was washed with brine and dried (MgSO)₄) And evaporated. The residue was dissolved in hexane and eluted with hexane/ethyl acetate (98: 2, 10mL) using a Sep-Pak silica gel cartridge to give 19-nor vitamin derivative 20(9.5mg, 48%). The Sep-Pak column was then washed with hexane/ethyl acetate (96: 4, 10m) to recover the non-exchanged C, D-cyclic ketone 19a (10mg), followed by ethyl acetate (10mL) to recover the diphenylphosphine oxide 17a (1 mg). 20: UV (Hexane)_max 244.0，252.5，262.5nm；¹H NMR(500MHz，CDCl₃) Delta-0.015, 0.056, 0.061, and 0.069(3H each, s, 4x SiCH each)₃)，0.556(3H，s，18-H₃)，0.565(6H，q，J＝7.9Hz，3x SiCH₂) 0.821 and 0.921(9H and 9H, each s, 2xSi-t-Bu), 0.930(3H, d, J. about.7 Hz, 21-H)₃)，0.947(9H，t，J＝7.9Hz，3x SiCH₂CH ₃) 1.191(6H, s, 26-and 27-H)₃)，1.79(1H，t，J＝12.2Hz，10α-H)，1.90(1H，m)，2.00(2H，m)，2.20(1H，br d，J＝13.2Hz，4β-H)，2.29(1H，br d，J＝13.2Hz，4α-H)，2.41(2H，q，J～7Hz，＝CH-CH ₂)2.79(1H，br d，J＝12.6Hz，9β-H)，3.04(1H，dd，J＝12.4，4.5Hz，10β-H)，3.36(3H，s，O-CH₃)，3.54(2H，m，CH₂-CH ₂-O)，4.35(1H，m，w/2＝21Hz，1β-H)，4.62(2H，s，O-CH₂-O)，4.81(1H，t，J～2.7Hz，3α-H)，5.47(1H，dt，J＝1.5，7.6Hz，HC＝C-CH₂) 5.87 and 6.12(1H and 1H, each d, J ═ 11.0Hz, 7-and 6-H).

(m) 19-nor-vitamin D₃Hydrolysis of the silyl protecting group of derivative 20.

1 alpha, 25-dihydroxy-2- [ 3' - (methoxymethyloxy) propylidene]-19-nor vitamin D₃(21). Protected 19-nor vitamin D₃To a solution of 20(3.0mg, 3.5. mu. mol) in anhydrous THF (200L) was added tert-butylammonium fluoride (1.0M in THF, 210. mu.L, 210. mu. mol). The mixture was stirred at room temperature under argon for 18 hours, then poured into brine and extracted with ethyl acetate. The organic extracts were washed with brine and dried (MgSO)₄) And evaporated. The residue was purified by HPLC (10mmx25cm Zorbax-Sil column, 4mL/min) using a hexane/2-propanol (75: 25) solvent system. Analytically pure 19-nor vitamin 21(1.27mg, 71%) was collected at a retention volume of 26 mL. This compound also gave a single peak on reverse phase HPLC (6.2 mm. times.25 cm Zorbax-ODS column, 2mL/min) using a methanol/water (8: 2) solvent system; it was concentrated at a retention volume of 35 mL. 21: UV (ethanol)_max243.5，252.0，262.0nm；¹H NMR(500MHz，CDCl₃)δ0.549(3H，s，18-H₃)，0.940(3H，d，J＝6.4Hz，21-H₃) 1.220(6H, s, 26-and 27-H)₃)，2.38(1H，m，＝CH-CH ₂One), 2.47(2H, narr m, 4 α -and 4 β -H), 2.59(1H, m, ═ CH-C)H ₂One), 2.82(1H, br d, J ═ 12.8Hz, 9 β -H), 3.14(1H, dd, J ═ 13.1, 4.9Hz, 10 β -H), 3.34(3H, s, O — CH)₃) 3.55 and 3.63(1H and 1H, each m, CH)₂-CH ₂-O)，4.44(1H，m，w/2＝20Hz，1β-H)，4.62(2H，s，O-CH₂-O)，4.84(1H，m，w/2＝10Hz，3-H)，5.68(1H，t，J＝7.4Hz，HC＝C-CH₂) 5.88 and 6.31(1H and 1H, each d, J ═ 11.2Hz, 7-and 6-H); HRMS (ESI) C₃₁H₅₂O₅Na exact mass calculated value: 527.3712, measurement 527.3702.

Example II

1 alpha, 25-dihydroxy-2- (3' -hydroxypropyl) -19-nor-vitamin D₃Preparation of the Compounds

As described in examples I (a-c), and with initial reference to scheme 1, the ketolide 4 is obtained from commercial (-) -quinic acid.

(a) Preparation of phosphonium bromide B.

[3- [ (tert-butyldimethylsilyl) oxy ] oxy]Propyl radical]Triphenylphosphonium bromide (B). To 1-bromo-3- [ (tert-butyldimethylsilyl) oxy) was added under stirring under argon]To a solution of propane (2.18g, 8.56mmol) in dry benzene (1.6mL) was added triphenylphosphine (2.64g, 10.2 mmol). The mixture was heated at 85 ℃ for 18 hours and cooled to room temperature. The liquid was decanted and the solid residue was taken out with a spatula, filtered and washed several times with ether. Colorless crystalline phosphonium salt B (3.7g) was obtained by purification through silica gel column chromatography. Elution with chloroform/methanol (96: 4) gave pure salt B (3.04g, 69%). B:¹H NMR(500MHz，CDCl₃)δ0.039(6H，s，2×SiCH₃)，0.857(9H，s，Si-t-Bu)，1.93(2H，m，CH₂-CH ₂-CH₂)，3.86-3.94(4H，br m，CH₂-CH ₂-O and P-CH₂) 7.70, 7.79 and 7.85(6H, 3H and 6H, each m, Ar-H).

(b) Wittig reaction of 4-keto-4 with the ylium salt formed from B

[ (E) -and (Z) - (1R, 3R, 5R) -1-acetoxy-3- [ (tert-butyldimethylsilyl) oxy ] oxy]-6-oxa-4- [ 3' - ((tert-butyldimethylsilyl) oxy) propylene]Bicyclo [3.2.1]Octane-7-one (6a and 6 b). To a solution of phosphonium bromide B (1.55g, 3.04mmol) in dry THF (42mL) at-20 deg.C under stirring under argon was added n-BuLi (2.0M in cyclohexane, 1.50mL, 3.00mmol) dropwise. The solution was stirred at-20 ℃ for 15 minutes. The orange-red mixture was cooled to-45 ℃ and siphoned into a solution of ketone acetate 4(700mg, 2.13mmol) in dry THF (24mL) over 15 minutes. The reaction mixture was stirred at-40 ℃ for 2 hours and stopped by adding 1% HCl in brine. Ethyl acetate (30mL), benzene (20mL), diethyl ether (10mL), saturated NaHCO was then added₃(10mL) and water (10mL) and the mixture was stirred vigorously at room temperature for 18 h. The organic phase was then separated, washed with brine and dried (MgSO)₄) And evaporated. The residue (comprising mainly 6a and 6b isomers in a ratio of about 3: 2) was purified by flash chromatography on silica gel. With hexane/ethyl acetate (9:)1) Elution yielded a mixture of 6a and 6b products (905mg, 87%). Analytical samples of the two isomers were separated by HPLC (10 mm. times.25 cm Zorbax-Sil column, 4mL/min) using a hexane/ethyl acetate (9: 1) solvent system. Pure oily compounds 6a and 6b were eluted at retention volumes of 28mL and 29mL, respectively.

6a：¹H NMR (500MHz, CDCl3) delta 0.049 and 0.073(6H and 6H, s, 4x SiCH respectively₃) 0.889 and 0.914(9H and 9H, each s, 2x Si-t-Bu), 2.01(1H, br t, J ═ 11.0Hz, 2 α -H), 2.07(1H, d, J ═ 10.5Hz, 8 α -H), 2.13(3H, s, OAc), 2.26-2.36(3H, m, 2-H overlaid with ═ C-CH)₂)，3.29(1H，ddd，J＝10.5，6.4，2.8Hz，8β-H)，3.65(2H，m，CH₂-CH ₂-O), 4.40(1H, -t, J-8.5 Hz, 3 β -H), 5.50(1H, d, J-6.4 Hz, 5 α -H), 5.71(1H, t, J-7.3 Hz, CH), ms (ei) m/z (relative abundance): without M⁺，469(M⁺-Me，1)，427(64)，367(13)，337(26)，73(100)；HRMS(ESI)C₂₄H₄₄O₆Si₂Na(M⁺+ Na) exact mass calculation value: 507.2574, measurement: 507.2575.

6b：¹H NMR(500MHz，CDCl3)δ0.042(6H，s，2x SiCH₃) 0.098 and 0.117(3H and 3H, s, 2x SiCH respectively)₃) 0.885 and 0.907(9H and 9H, each s, 2x Si-t-Bu), 2.13(3H, s, OAc), 2.14(1H, m, 2 α -H), 2.31(1H, 2-Hoverlapped with 8 α -H), 2.32(1H, d, J ═ 11.0Hz, 8 α -H), 2.51 and 2.64(1H and 1H, each m ═ C-CH-Bu), 2.13(3H, s, OAc), 2.14(1H, m, 2 α -H), 2.51 and 2.64(1H and 1H, each m ═ C-CH₂)，3.24(1H，m，8β-H)，3.62(2H，m，CH₂-CH ₂-O), 4.69(1H, -t, J-7.2 Hz, 3 β -H), 4.93(1H, d, J-6.3 Hz, 5 α -H), 5.63(1H, t, J-7.0 Hz, CH), ms (ei) M/z (relative abundance) M-free⁺，469(M⁺-Me，1)，427(32)，367(13)，337(40)，73(100)；HRMS(ESI)C₂₄H₄₄O₆Si₂Na(M⁺+ Na) exact mass calculation value: 507.2574, measurement: 507.2560.

(c) reduction of acetoxylactones 6a with 6b (scheme 2).

[ (E) -and (Z) - (1 ' R, 3 ' R, 5 ' R) -3- [ (tert-butyldimethylsilyl) oxy]-1 ', 5-dihydroxy-4' - [3 "- [ ((tert-butyldimethylsilyl) oxy) propylene]Cyclohexyl radical]Methanol (8a and 8 b). To a stirred solution of compounds 6a and 6b (150mg, 0.309mmol) in absolute ethanol (4mL) at 0 deg.C was added NaBH₄(116mg, 3.09mmol) and the mixture was stirred at room temperature for 21 h. The mixture was poured into saturated NH₄Cl and extracted several times with ethyl acetate. The organic layer was washed with brine and dried (MgSO₄) And evaporated. The oily residue was purified by silica gel chromatography. Elution with hexane/ethyl acetate (4: 6) gave a semi-crystalline mixture of triols 8a and 8b (136mg, 98%).

8a (main product): [ alpha ] to]²⁴ _D-53°(c 1.00CHCl₃)；¹H NMR(500MHz，CDCl₃) δ 0.077, 0.082, 0.084 and 0.110(4 × 3H, s, 4 × SiCH each)₃) 0.887 and 0.902(9H and 9H, 2x s, 2x Si-t-Bu), 1.58(1H, dd, J ═ 12.8, 10.2Hz, 6 ' β -H), 1.62(1H, dd, J ═ 14.0, 2.8Hz, 2 ' β -H), 2.03(1H, ddd, J ═ 14.0, 3.9, 1.9Hz, 2 ' α -H), 2.11(1H, ddd, J ═ 12.8, 4.5, 1.9Hz, 6 ' α -H), 2.46 and 2.66(1H and 1H, each m ═ C-CH ═ H), 1.58(1H, dd, J ═ 12.8, 4.5, 1.9Hz, 6 ' α -H), 2.46 and 2.66(1H and 1H₂) 3.35 and 3.47(1H and 1H, D)₂After O: 2x d, J ═ 10.8Hz, 1-H₂)，3.68(2H，m，CH₂-CH ₂-O)，4.46(1H，～t，J＝3.3Hz，3’β-H)，4.88(1H，D₂After O: dd, J ═ 10.2, 4.5Hz, 5' α -H), 5.45(1H, t, J ═ 8.6Hz, ═ CH);¹³C NMR(125MHz)δ-5.6(Si-CH₃)，-5.38(Si-CH₃)，-5.36(Si-CH₃)，-4.5(Si-CH₃)，17.9[C(CH₃)₃]，18.4[C(CH₃)₃]，25.7[C(CH₃)₃]，26.0[C(CH₃)₃]，29.2(CH₂-CH ₂-C＝)，40.4(C_2’)，44.1(C_6’)，62.2(O-CH₂-CH₂)，66.2(C_5’)，70.3(C₁)，73.8(C_1’)，74.1(C_3’)，121.9(＝C-CH₂)，145.0(C_4’)，HRMS(ESI)C₂₂H₄₆O₅Si₂Na(M⁺+ Na) exact mass calculation value: 469.2824, measurement 469.2781.

(d) Cleavage of vicinal diols 8a and 8 b.

[ (E) -and (Z) - (3R, 5R) -3- [ (tert-butyldimethylsilyl) oxy]-5-hydroxy-4- [ 3' - [ ((tert-butyldimethylsilyl) oxy) propylidene]]Cyclohexanone (10a and 10 b). Sodium periodate-saturated water (1.6mL) was added to a solution of triols 8a and 8b (104mg, 0.233mmol) in methanol (8mL) at 0 ℃. The solution was stirred at 0 ℃ for 1h, poured into brine and extracted with ethyl acetate and ether. The extract was washed with brine and dried (MgSO)₄) And (5) evaporating. The oily residue was dissolved in hexane/CH₂Cl₂And (4) passing through a Sep-Pak small column. The hydroxyketones 10a and 10b (85mg, 88%) slowly crystallized in the refrigerator as an oil eluted with hexane/ethyl acetate (8: 2).

10a (main product): [ alpha ] to]²⁴ _D+55°(c 1.17CHCl₃)；¹H NMR (400MHz, CDCl3) delta 0.042, 0.065 and 0.074(3H, 6H and 3H, s, 4x SiCH respectively₃) 0.849 and 0.880(9H and 9H, each s, 2x Si-t-Bu), 2.28(1H, m, ═ C-CH)₂One), 2.50(1H, dd, J ═ 16.2, 5.4Hz, 2 α -H), 2.55-2.70(3H, m, 2-H with 6-H and ═ C-CH)₂One overlap), 2.77(1H, dd, J ═ 16.2, 2.5Hz, one of 6-H), 3.62(1H, dt, J ═ 2.6, 10.2Hz, CH)₂-CH ₂One of-O), 3.85(1H, m, CH)₂-CH ₂One of-O), 4.60(1H, m, 3 β -H), 4.90(1H, narr m, 5 α -H), 5.66(1H, dd, J ═ 10.5, 6.0Hz, ═ CH);¹³C NMR(125MHz)δ-5.6(Si-CH₃)，-5.4(Si-CH₃)，-4.9(Si-CH₃)，-4.6(Si-CH₃)，18.0[C(CH₃)₃]，18.5[C(CH₃)₃]，25.7[C(CH₃)₃]，26.0[C(CH₃)₃]，30.7(CH₂-CH ₂-C＝)，45.1(C₂)，47.9(C₆)，63.0(C₅)，61.8(O-CH₂-CH₂)，70.8(C₃)，127.5(＝C-CH₂)，142.9(C₄)，208.9(C₁) (ii) a MS M/z (relative abundance) M-free⁺，399(M⁺-Me，2)，357(69)，339(12)，327(41)，299(9)，265(10)，225(81)，73(100)；HRMS(ESI)C₂₁H₄₂O₄Si₂Na(M⁺+ Na) exact mass calculation value: 437.2519, measurement 437.2537.

(e) Protection of the 5-hydroxy group in hydroxyketones 10a and 10b

[ (3R, 5R) -3, 5-bis [ (tert-butyldimethylsilyl) oxy ] oxy]-4- [ 3' - [ ((tert-butyldimethylsilyl) oxy) propylene]Cyclohexanone (12). Anhydrous CH to hydroxyketones 10a and 10b (22mg, 53. mu. mol) at-50 deg.C₂Cl₂To the solution (0.2mL) was added 2, 6-lutidine (14.5. mu.L, 124. mu. mol) and tert-butyldimethylsilyltrifluoromethanesulfonic acid (25. mu.L, 106. mu. mol). The mixture was stirred at-50 ℃ for 50 minutes. Adding ice-cold moist CH₂CH₂And the mixture was poured into water and then treated with CH₂CH₂And (4) extracting. The extract is saturated with CuSO₄And washed with water and dried (MgSO)₄) And evaporated. The oily residue was redissolved in hexane and purified by flash chromatography on silica gel. Elution with hexane/ethyl acetate (95: 5) gave pure protected ketone 12(18mg, 64%; 74% based on recovered substrate) as a colorless oil, and a mixture of unreacted 10a and 10b (3 mg).

12：[α]²⁴ _D-17°(c 1.35CHCl₃)；¹H NMR(500MHz，CDCl3)δ0.008(3H，s，SiCH₃)，0.061(15H，s，5×SiCH₃) 0.833, 0.900 and 0.910(3 × 9H, s, 3 × Si-t-Bu each), 2.32(1H, dd, J ═ 14.2, 10.4Hz, 2 α -H), 2.32-2.43(2H, br m ═ C-CH₂)，2.43(1H，dd，J＝14.4，2.8Hz，6α-H)，2.52(1H，ddd，J＝14.4，3.4，2.2Hz，6β-H)，2.75(1H，ddd，J＝142, 5.6, 2.2Hz, 2. beta. -H), 3.65 and 3.71 (1H each, m, CH each)₂-CH ₂-O)，4.76(1H，ddd，J＝10.4，5.6，1.7Hz，3β-H)，5.01(1H，～t，J＝3.2Hz，5α-H)，5.70(1H，dt，J＝1.7，7.6Hz，＝CH)；¹³C NMR(125MHz)δ-5.27(Si-CH₃)，-5.25(Si-CH₃)，-5.01(Si-CH₃)，-5.00(Si-CH₃)，-4.95(Si-CH₃)，-4.89(Si-CH₃)，17.9[C(CH₃)₃]，18.3[C(CH₃)₃]，18.4[C(CH₃)₃]，25.6[C(CH₃)₃]，25.8[C(CH₃)₃]，26.0[C(CH₃)₃]，29.7(CH₂-CH ₂-C＝)，50.4(C₆)，52.5(C₂)，62.8(O-CH₂-CH₂)，65.9(C₃)，67.9(C₅)，119.1(＝C-CH₂)，141.1(C₄)，207.5(C₁) (ii) a MS (EI) M/z (relative abundance) M-free⁺，513(M⁺-Me，2)，471(74)，381(5)，339(63)，73(100)；C₂₇H₅₆O₄Si₃(M⁺-C₄H₉) Accurate mass calculated value: 471.2782, measurement: 471.2796.

(f) preparation of allyl esters 14a and 14 b.

[ (E) -and (Z) - (3 'R, 5' R) -3 ', 5' -bis [ (tert-butyldimethylsilyl) oxy ] oxy]-4' - [3 "- [ ((tert-butyldimethylsilyl) oxy) propylene]Cyclohexylidene radical]Methyl acetate (14a and 14 b). To a solution of diisopropylamine (49 μ L, 0.363mmol) in dry THF (0.37mL) under argon at-78 deg.C with stirring was added n-BuLi (2.5M in hexane, 146 μ L, 0.365mmol) followed by methyl (trimethylsilyl) acetate (60.5 μ L, 0.366 mmol). After 15 minutes, a solution of ketone 12(76.5mg, 0.145mol) in dry THF (0.45mL) was added. The solution was stirred at-78 ℃ for an additional 70 minutes then quenched with wet ether, poured into brine and extracted with ether and benzene. The combined extracts were washed with brine and dried (MgSO)₄) And evaporated. The oily residue is removedRedissolved in hexane and passed through a Sep-Pak cartridge. Elution with hexane/ethyl acetate (98.5: 1.5) gave the pure allyl esters 14a and 14b (60mg, 68%; isomer ratio 14 a: 14b ═ about 6: 1)

14a (main product): [ alpha ] to]²⁴ _D：-33(c 0.48CHCl₃)；¹H NMR(500MHz，CDCl₃) Delta-0.014, 0.054, 0.059, 0.070, 0.080 and 0.109 (3H each, s, 6 × SiCH each)₃) 0.830, 0.845 and 0.926 (9H each, s, 3 × Si-t-Bu each), 1.87(1H, t, J ═ 12Hz, 2 ' α -H), 2.26(1H, br d, J ═ 13.2Hz, 6 ' α -H), 2.33(1H, br d, J ═ 13.2Hz, 6 ' β -H), 2.3-2.4(2H, m, ═ C-CH-H)₂)，3.6-3.7(2H，m，CH₂-CH ₂-O)，3.71(3H，s，COOCH₃)，4.15(1H，ddd，J＝12.7，4.9，1.5Hz，2’β-H)，4.46(1H，dd，J＝10.7，4.9Hz，3’β-H)，4.88(1H，～t，J＝3Hz，5’α-H)，5.54(1H，dt，J＝1.5，7.3Hz，＝CH)，5.65(1H，br s，2-H)；¹³CNMR(125MHz)δ-5.26(Si-CH₃)，-5.22(Si-CH₃)，-5.14(Si-CH₃)，-4.92(Si-CH₃)，-4.87(Si-CH₃)，-4.77(Si-CH₃)，17.95[C(CH₃)₃]，18.38[C(CH₃)₃]，18.41[C(CH₃)₃]，25.6[C(CH₃)₃]，25.9[C(CH₃)₃]，26.0[C(CH₃)₃]，30.8(CH₂-CH ₂-C＝)，40.7(C_6’)，46.5(C_2’)，50.9(CH₃CO)，63.1(O-CH₂-CH₂)，66.5(C_5’)，69.6(C_3’)，117.0(＝C-CH₂)，116.9(C₂)，142.7(C_4’)，156.0(C_1’)，166.6(C₁) (ii) a Selected minor isomer (Z): 5.50(1H, dt, J ═ 1.5, 7.3Hz, ═ CH), 5.80(1H, br s, 2-H).

(g) Reduction of allyl esters 14a and 14b

2- [ (E) -and (Z) - (3 'R, 5' R) -3 ', 5' -bis [ (tert-butyldimethylsilyl) oxy]-4' - [3 "- [ ((tert-butyldimethylsilyl) oxy) propylene]Cyclohexylidene radical]Ethanol (16a and 16 b). Diisobutylaluminum hydride (1.0M in hexane, 616. mu.L, 616. mu. mol) was added slowly to a stirred solution of allyl esters 14a and 14b (6: 1, 60mg, 103. mu. mol) in toluene/dichloromethane (2: 1, 2.25mL) at-78 ℃ under argon. Stirring was continued at-78 deg.C for 1 hour and the mixture was purified by adding potassium sodium tartrate (2N, 2mL), HCl (2N, 2mL) and H₂O (24mL) was quenched and then diluted with ether and benzene. The organic layer was diluted NaHCO₃And washed with brine and dried (MgSO)₄) And evaporated. The residue was purified by flash chromatography. Elution with hexane/ethyl acetate (95: 5) gave 49mg of a mixture of product 16a and 16b in 86% yield. Samples for analysis of both isomers were obtained by HPLC (10 mm. times.25 cm Zorbax-Sil column, 4mL/min) using a hexane/ethyl acetate (9: 1) solvent system. Pure oily compounds 16a and 16b eluted at retention volumes of 28mL and 29mL, respectively.

16a (main product):¹H NMR(500MHz，CDCl₃) Delta-0.016, 0.055, 0.059, and 0.068(3H, 6H, 6H and 3H, each being s, 6x SiCH)₃) 0.831, 0.888 and 0.911 (9H each, s, 3x Si-t-Bu each), 1.80(1H, t, J ═ 11.8Hz, 2 ' α -H), 2.16(1H, br d, J ═ 13.2Hz, 6 ' α -H), 2.26(1H, br d, J ═ 13.2Hz, 6 ' β -H), 2.34(2H, m, ═ C-t-Bu each), 1.80(1H, t, J ═ 13.8Hz, 2 ' α -H), 2.26(1H, br d, J ═ 13.2Hz, 6 ' β -H), 2H ₂-CH₂)，2.86(1H，ddd，J＝12.4，4.4，1.5Hz，2’β-H)，3.62(2H，m，CH₂-CH ₂-O)，4.19(2H，t，J～6Hz；D₂After O: d, J ═ 7.0Hz, 1-H), 4.37(1H, D)₂After O: dm, J ═ 10.4Hz, 3 'β -H), 4.80(1H,. about.t, J ═ 3Hz, 5' α -H), 5.47(2H, m, 2x ═ C)H)；¹³C NMR(125MHz)δ-5.28(2x Si-CH₃)，-5.06(Si-CH₃)，-5.00(Si-CH₃)，-4.85(Si-CH₃)，-4.79(Si-CH₃)，18.0[C(CH₃)₃]，18.4[2xC(CH₃)₃]，25.6[C(CH₃)₃]，25.9[C(CH₃)₃]，26.0[C(CH₃)₃]，30.8(CH₂-CH ₂-C＝)，40.0(C_2’)，45.5(C_6’)，58.7(C₁)，63.2(O-CH₂-CH₂)，66.5(C_5’)，70.0(C_3’)，116.6(＝C-CH₂)，125.4(C₂)，137.2(C_1’)，143.4(C_4’) (ii) a MS (EI) M/z (relative abundance) M-free⁺，538(M⁺-H₂O，9)，499(12)，471(7)，424(39)，407(11)，349(23)，73(100)，HRMS(ESI)C₂₉H₆₀O₄Si₃Na(M⁺+ Na) exact mass calculation value: 579.3697, measurement: 579.3704.

16b (trace):¹h NMR (500MHz, CDCl3) delta 0.029, 0.055, 0.060, 0.064 and 0.069(3H, 6H, 3H, 3H and 3H, each s, 6x SiCH₃) 0.849, 0.898 and 0.918 (9H each, s, 3x Si-t-Bu each), 1.87(1H, br d, J ═ 13.8Hz, 2 'β -H), 2.03(1H, br t, J ═ 11.5Hz, 6' β -H), 2.34(2H, m, ═ C-CH₂)，2.51(1H，ddd，J＝12.0，5.0，1.6Hz，6’α-H)，2.76(1H，br d，J＝13.8Hz，2’α-H)，3.64(2H，m，CH₂-CH ₂-O), 4.02 and 4.13(1H and 1H, each being m; d₂After O: each dd, J ═ 11.8, 7.2Hz, CH ₂-OH)，4.39(1H，dm，J＝10.6Hz，5’α-H)，4.89(1H，brs，3β-H)，5.52(1H，dt，J＝1.3，7.5Hz，＝CH-CH₂)，5.71(1H，t，J＝7.2Hz，＝CH-CH₂-OH); MS (EI) m/z (relative abundance): without M⁺，538(M⁺-H₂O，4)，499(6)，471(4)，424(12)，407(6)，349(11)，73(100)；HRMS(ESI)C₂₉H₆₀O₄Si₃(M⁺-H₂O) exact mass calculated value: 538.3694, measurement: 538.3689.

(h) conversion of the allyl alcohols 16a and 16b to the phosphine oxides 18a and 18 b.

[2- [ (E) -and (Z) - (3 'R, 5' R) -3 ', 5' -bis [ (tert-butyldimethylsilyl) oxy ] oxy]-4' - [3 "- [ ((tert-butyldimethylsilyl) oxy) propylene]Cyclohexylidene radical]Ethyl radical]Diphenylphosphine oxides (18a and 18 b). To a solution of allylic alcohols 16a and 16b (5.5: 1, 40.5mg, 70.2. mu. mol) in anhydrous THF (0.8mL) was added n-BuLi (2.5M in hexane, 35. mu.L, 87.5. mu. mol) with stirring under argon at 0 ℃. Freshly recrystallized tosyl chloride (14.0mg, 73. mu. mol) was dissolved in anhydrous THF (190. mu.L) and added to the allyl alcohol-BuLi solution. The mixture was stirred at 0 ℃ for 5 minutes and left at 0 ℃. In another dry flask with air replaced by argon, n-BuLi (2.5M in hexane, 140. mu.L, 0.35mmol) was added to Ph with stirring at 0 deg.C₂pH (62. mu.L, 0.34mmol) in dry THF (420. mu.L). The red solution was siphoned into a solution of p-toluenesulfonate under argon pressure until the orange color persisted (about 1/4 solution was added). The resulting mixture was stirred at 0 ℃ for a further 40 minutes and then purified by addition of H₂O (40. mu.l) quench. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (1.0mL) and reacted with 10% H₂O₂(0.5mL) was stirred at 0 ℃ for 1 hour. The organic layer was separated, washed with cold aqueous sodium sulfite solution and H₂O washing and drying (MgSO)₄) And evaporated. The residue was subjected to flash chromatography. Elution with hexane/ethyl acetate (95: 5) gave unchanged allyl alcohol (16.3 mg). Then eluted with hexane/ethyl acetate (7: 3) to obtain a mixed product: 18a and 18b (25mg, 49%; 81% calculated on the recovered substrate 16a, b).

18a (major isomer):¹h NMR (500MHz, CDCl3) delta-0.044, -0.022, 0.011, 0.020, 0.030, and 0.035 (3H each, s, 6x SiCH each)₃) 0.787, 0.878 and 0.894 (9H each, s, 3x Si-t-Bu each), 1.47(1H, br t, J-11 Hz, 2 ' α -H), 2.04(1H, m, 6 ' α -H), 2.22(1H, d, J ═ 13.7Hz, 6 ' β -H), 2.28(2H, m ═ C-H), 2.7 (C-H, C-H ₂-CH₂)，2.62(1H，dd，J＝12.8，4.2Hz，2’β-H)，3.58(2H，m，CH₂-CH ₂-O)，4.32(1H，dm，J～10Hz，3’β-H)，3.17(2H，dd，J＝15.2，7.6Hz，CH₂-PO)，4.73(1H，br s，5’α-H)，5.27(1H，m，＝CH-CH₂-CH₂)，5.43(1H，brt，J～7Hz，＝CH-CH₂-PO), 7.46, 7.51 and 7.72(4H, 2H and 4H, each m, Ar-H); HRMS (ESI) C₄₁H₆₉O₄Si₃PNa(M⁺+ Na) exact mass calculation value: 763.4139, measurement: 763.4157.

Wittig-Horner coupling of protected 25-hydroxy Grundmann's ketone 19a with phosphine oxides 18a and 18b (scheme III).

1 alpha- [ (tert-butyldimethylsilyl) oxy group]-2- [ 3' - [ ((tert-butyldimethylsilyl) oxy) propylene]-25- [ (triethylsilyl) oxy]-19-nor vitamin D₃Tert-butyldimethylsilyl ether (22a and 22 b). To a solution of phosphine oxides 18a and 18b (6: 1, 20.3mg, 27.6. mu. mol) in anhydrous THF (0.3mL) was added phenyl lithium (1.56M cyclohexane solution, 19. mu.L, 30. mu. mol) slowly with stirring under argon-78 ℃. The solution turned dark orange. The mixture was stirred at-78 ℃ for 20 minutes and then slowly added according to the published procedure [ Sicinski et al j.37，3730(1994)]A prefreezed (-78 ℃) solution of the protected hydroxyketone 19a (15.4mg, 39. mu. mol) in dry THF (80. mu.L) was prepared. The mixture was stirred at argon-78 ℃ for 3 hours and at 6 ℃ for 19 hours. Then ethyl acetate, benzene and water were added and the organic phase was washed with brine and dried (MgSO)₄) And evaporated. The residue was redissolved in hexane and passed through a silica gel column. Elution with hexane/ethyl acetate (99.5: 0.5) gave 19-nor vitamin derivatives 22a and 22b (8.6mg, 47% based on recovered substrate). The column was then washed with hexane/ethyl acetate (96: 4) to recover some unconverted C, D-cyclic ketone 19a (7mg), and then with ethyl acetate to recover unreacted diphenylphosphine oxide (5.5 mg). Purification by HPLC (10 mm. times.25 cm Zorbax-Sil column, 4mL/min) using a hexane/ethyl acetate (99.8: 0.2) solvent system gave an analytical sample of the main product 22 a. Pure compound 22a eluted at a retention volume of 28mL to a colorless oil.

22 a: UV (ethanol)_max 244.0，252.5，262.5nm；¹H NMR(500MHz，CDCl₃) Delta-0.023, 0.052, 0.056, 0.061, 0.063 and 0.070 (3H each, each)Is s, 6x SiCH₃)，0.555(3H，s，18-H₃)，0.565(6H，q，J＝7.9Hz，3x SiCH₂) 0.819, 0.897 and 0.923(9H and 9H, each s, 3 xsi-t-Bu), 0.878(3H, d, J ═ 7.1Hz, 21-H)₃)，0.947(9H，t，J＝7.9Hz，3x SiCH₂CH ₃) 1.190 and 1.191(3H and 3H, s, 26-and 27-H, respectively)₃)，1.79(1H，t，J＝11.6Hz，10α-H)，1.90(1H，m)，2.00(2H，m)，2.19(1H，br d，J～14Hz，4β-H)，2.27(1H，br d，J～14Hz，4α-H)，2.33(2H，m，＝CH-CH ₂)，2.79(1H，br d，J～13Hz，9β-H)，3.05(1H，dd，J＝12.0，4.0Hz，10β-H)，3.62(2H，m，CH₂-CH ₂-O)，4.34(1H，m，w/2＝20Hz，1β-H)，4.81(1H，t，J～2.8Hz，3α-H)，5.47(1H，dt，J～1.5，～7.5Hz，HC＝C-CH₂) 5.88 and 6.12(1H and 1H, each d, J ═ 11.0Hz, 7-and 6-H); HRMS (ESI) C₅₃H₁₀₄O₄Si₄Na(M⁺+ Na) exact mass calculation value: 939.6909, measurement: 939.6900.

(j) (20S) -1- [ (tert-butyldimethylsilyl) oxy group]-2- [ 3' - [ ((tert-butyldimethylsilyl) oxy) propylene]-25- [ (triethylsilyl) oxy]-19-nor vitamin D₃Tert-butyldimethylsilyl ether (23a and 23 b).

Protected 19-nor vitamin D₃Compounds 23a and 23b were obtained by a process analogous to the preparation of (20R) -isomers 22a and 22b as described above, by a Wittig-Horner coupling reaction of protected 25-hydroxy Grundmann's ketone 19b with phosphine oxides 18a and 18 b. The protected vitamin was purified by column chromatography on silica gel using a hexane/ethyl acetate (99.5: 0.5) solvent system to give a yield of about 47%. Purification by HPLC (10 mm. times.25 cm Zorbax-Sil column, 4mL/min) using a hexane/ethyl acetate (99.7: 0.3) solvent system gave a sample of protected vitamin 23a for analysis. Pure compound 23a eluted at a retention volume of 25mL to a colorless oil. 23 a: UV (ethanol)_max 243.5，252.5，262.5nm；¹HNMR (500MHz, CDCl3) delta-0.024, 0.057, 0.059 and0.069(3H, 3H, 6H, and 6H, each s, 6x SiCH)₃)，0.550(3H，s，18-H₃)，0.560(6H，q，J＝7.5Hz，3x SiCH₂) 0.818, 0.895 and 0.923(9H each, s, 3x Si-t-Bu each), 0.867(3H, d, J ═ 7.0Hz, 21-H₃)，0.943(9H，t，J＝7.5Hz，3x SiCH₂CH ₃) 1.191(6H, s, 26-and 27-H)₃)，1.79(1H，t，J～12Hz，10α-H)，1.90(1H，m)，2.00(2H，m)，2.19(1H，br d，J～13Hz，4β-H)，2.27(1H，br d，J～13Hz，4α-H)，2.33(2H，m，＝CH-CH ₂)，2.79(1H，br d，J～11.5Hz，9β-H)，3.05(1H，dm，J～12Hz，10β-H)，3.62(2H，m，CH₂-CH ₂-O)，4.34(1H，m，w/2＝20Hz，1β-H)，4.80(1H，br s，3α-H)，5.47(1H，t，J＝7.0Hz，HC＝C-CH₂) 5.88 and 6.11(1H and 1H, each d, J ═ 11.2Hz, 7-and 6-H); HRMS (ESI) C₅₃H₁₀₄O₄Si₄Na(M⁺+ Na) exact mass calculation value: 939.6909, measurement: 939.6907.

(k) 19-nor-vitamin D₃Hydrolysis of the silyl protecting groups in derivatives 22a and 22 b.

1 alpha, 25-dihydroxy-2- [ 3' -hydroxymethylene]-19-nor vitamin D₃(24a and 24 b). To a solution of protected vitamins 22a and 22b (5.7mg, 6.2. mu. mol) in dry THF (4.3mL) was added tetrabutylammonium fluoride (1.0M in THF, 372. mu.L, 372. mu. mol). The mixture was stirred under argon at room temperature for 18 hours, poured into brine and extracted with ethyl acetate and ether. The organic extracts were washed with brine and dried (MgSO)₄) And evaporated. The residue was purified by HPLC (10 mm. times.25 cm Zorbax-Sil column, 4mL/min) using a hexane/2-propanol (8: 2) solvent system. The pure mixture of 19-nor vitamins 24a and 24b was collected at a retention volume of 37.5 mL. Separation of the two isomers was readily achieved by reverse phase HPLC (6.2 mm. times.25 cm Zorbax-ODS column, 2mL/min) using a methanol/water (8: 2) solvent system. Analytically pure E-isomer 24a (2.8mg, 97%) was collected at a retention volume of 23mL and Z-isomer 24b (11. mu.g) was collected at a retention volume of 29 mL.

24 a: UV (ethanol)_max243.0，251.0，261.5nm；¹H NMR(500MHz，CDCl3)δ0.549(3H，s，18-H₃)，0.940(3H，d，J＝6.3Hz，21-H₃) 1.22(6H, s, 26-and 27-H)₃) 2.33 and 2.55(1H and 1H, each m, ═ CH-CH)₂) 2.47(2H, narr m, 4 α -and 4 β -H), 2.82(1H, br d, J-13 Hz, 9 β -H), 3.16(1H, dd, J ═ 13.0, 4.8Hz, 10 β -H), 3.66 and 3.76(1H and 1H, each m, CH, respectively)₂-CH ₂-O)，4.45(1H，m，w/2＝20Hz，1β-H)，4.85(1H，narr m，3α-H)，5.66(1H，t，J＝7.3Hz，HC＝C-CH₂) 5.88 and 6.31(1H and 1H, each d, J ═ 11.2Hz, 7-and 6-H); HRMS (ESI) C₂₉H₄₈O₄Na(M⁺+ Na) exact mass calculation value: 483.3450, measurement: 483.3461.

24 b: UV (ethanol)_max 243.0，251.5，262.0nm；¹H NMR(800MHz，CDCl3)δ0.553(3H，s，18-H₃)，0.939(3H，d，J＝6.6Hz，21-H₃) 1.22(6H, s, 26-and 27-H)₃) 2.19(1H, t, J ═ 11.0Hz, 4 β -H), 2.25(1H, br d, J ═ 14.6Hz, 10 β -H), 2.40 and 2.56(1H and 1H, each m ═ CH-C)H ₂) 2.74(1H, dd, J ═ 13.0, 4.8Hz, 4 α -H), 2.81(1H, br d, J ═ 12.5Hz, 9 β -H), 2.93(1H, dd, J ═ 14.6, 3.8Hz, 10 α -H), 3.67 and 3.76(1H and 1H, each m, CH, and g — H)₂-CH ₂-O)，4.48(1H，m，w/2＝19Hz，3α-H)，4.89(1H，narr m，1-H)，5.65(1H，t，J＝8.1Hz，HC＝C-CH₂) 5.85 and 6.40(1H and 1H, each d, J ═ 11.0Hz, 7-and 6-H).

(l) 19-nor-vitamin D₃Hydrolysis of the silyl protecting groups in derivatives 22a and 22 b.

(20S) -1 alpha, 25-dihydroxy-2- [ 3' -hydroxymethylene]-19-nor vitamin D₃(24a and 24 b). Vitamins 25a and 25b are prepared by hydrolysis of 19-nor vitamin derivatives 23a and 23b by procedures similar to those described above for the preparation of (20R) -isomers 24a and 24bTo obtain the silyl protecting group of (1). The residue was purified by HPLC (10 mm. times.25 cm Zorbax-Sil column, 4mL/min) using a hexane/2-propanol (8: 2) solvent system. A pure mixture of 19-nor vitamins 25a and 25b was collected at a retention volume of 36.5mL (95% yield). Separation of the two isomers was readily achieved by reverse phase HPLC (6.2mmx25cm Zorbax-ODS column, 2mL/min) using a methanol/water (8: 2) solvent system. Analytically pure E-isomer 25a was collected at a retention volume of 18mL and Z-isomer 25b was collected at a retention volume of 28mL (ratio 25 a: 25b 160: 1).

25 a: UV (ethanol)_max 243.0，251.5，261.0nm；¹H NMR(500MHz，CDCl₃)δ0.548(3H，s，18-H₃)，0.858(3H，d，J＝6.4Hz，21-H₃) 1.21(6H, s, 26-and 27-H)₃) 2.35 and 2.54(1H and 1H, each m, ═ CH-CH ₂) 2.47(2H, narr m, 4 α -and 4 β -H), 2.82(1H, br d, J ═ 12.7Hz, 9 β -H), 3.16(1H, dd, J ═ 13.1, 4.9Hz, 10 β -H), 3.65 and 3.76(1H and 1H, each m, CH, and g-₂-CH ₂-O)，4.45(1H，m，w/2＝25Hz，1β-H)，4.85(1H，narr m，3α-H)，5.66(1H，t，J＝7.4Hz，HC＝C-CH₂) 5.88 and 6.31(1H and 1H, each d, J ═ 11.4Hz, 7-and 6-H); HRMS (ESI) C₂₉H₄₈O₄Na(M⁺+ Na) exact mass calculation value: 483.3450, measurement: 483.3427.

25 b: UV (ethanol)_max 243.0，251.5，262.0nm；¹H NMR(800MHz，CDCl₃)δ0.550(3H，s，18-H₃)，0.854(3H，d，J＝6.6Hz，21-H₃) 1.21(6H, s, 26-and 27-H)₃) 2.19(1H, t, J-12 Hz, 4 β -H), 2.24(1H, br d, J ═ 14.6Hz, 10 β -H), 2.40 and 2.56(1H and 1H, each m ═ CH-C)H ₂) 2.74(1H, dd, J ═ 13.2, 4.4Hz, 4 α -H), 2.82(1H, br d, J ═ 12.4Hz, 9 β -H), 2.92(1H, dd, J ═ 14.6, 3.7Hz, 10 α -H), 3.61 and 3.72(1H and 1H, each m, CH, and H, respectively)₂-CH ₂-O)，4.47(1H，m，w/2＝18Hz，3α-H)，4.88(1H，narr m，1β-H)，5.65(1H，t，J～7.5Hz，HC＝C-CH₂) 5.85 and 6.40(1H and 1H, each d, J ═ 11.0Hz, 7-and 6-H).

Route I

MOM＝-CH₂OCH₃

TBDMS＝-Sit-BuMe₂

Route II

Route III

For therapeutic purposes, the novel compounds of the invention defined by general formula I may be formulated for pharmaceutical use in the following dosage forms according to conventional methods well known in the art: solutions in non-toxic solvents, or emulsions, suspensions or dispersions in suitable solvents or carriers, or pills, tablets or capsules containing a solid carrier. Any of these dosage forms may also contain other pharmaceutically acceptable and non-toxic excipients such as stabilizers, antioxidants, binders, colorants or emulsifiers or flavoring agents.

The compounds can be administered orally, topically, parenterally or transdermally. The compounds may advantageously be administered by injection or intravenous infusion or in a suitable sterile solution, or in liquid or solid dosage form through the alimentary canal, or in the form of a cream, ointment, patch, or similar vehicle suitable for transdermal application. The compound is 0.01-100 μ g/day, preferablyThe dosage selected from about 0.1 μ g/day to about 50 μ g/day is suitable for therapeutic purposes and may be adjusted depending on the condition to be treated, its severity and the patient's response, as is well known in the art. Since the novel compounds exhibit specificity of activity, each of them may suitably be administered alone or in fractionated doses of other active vitamin D compounds such as 1 alpha-hydroxyvitamin D when different levels of bone mineral mobilization and calcium transport stimulation are found to be beneficial₂Or D₃Or 1 alpha, 25-dihydroxyvitamin D₃Are administered together.

Compositions for treating psoriasis and other malignancies described above comprise as an active ingredient an effective amount of one or more 2-propylene-19-nor-vitamin D compounds as defined above in formula I, together with a suitable carrier. An effective amount of the compound for use in the present invention is from about 0.01 μ g to about 100 μ g per gram of the composition, preferably from about 0.1 μ g to about 50 μ g per gram of the composition, and may be administered at a dosage of from about 0.01 μ g/day to about 100 μ g/day, preferably from about 0.1 μ g/day to about 50 μ g/day, topically, transdermally, orally or parenterally.

The compounds may be formulated as creams, lotions, ointments, topical patches, pills, capsules or tablets, or in liquid form such as solutions, emulsions, dispersions or suspensions in pharmaceutically non-toxic and acceptable solvents or oils, and these formulations may additionally contain other pharmaceutically non-toxic or beneficial ingredients such as stabilisers, antioxidants, emulsifiers, colourants, binders or flavourings.

The compound may advantageously be administered in an amount sufficient to affect differentiation of promyelocytes to normal macrophages. As is well understood in the art, the above dosages are appropriate, and it is understood that the dosages administered may be adjusted depending on the severity of the disease and the condition and response of the patient.

The dosage form of the present invention comprises the active ingredient together with a pharmaceutically acceptable carrier for the active ingredient and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the dosage form and not deleterious to the recipient thereof.

Dosage forms of the invention suitable for oral administration may take the form of discrete units each containing a predetermined amount of the active ingredient, e.g. in the form of capsules, sachets, tablets or lozenges; in the form of powder or granules; in the form of a solution or suspension in an aqueous or anhydrous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.

Formulations for rectal administration may take the form of suppositories with the active ingredient combined with a carrier, for example, cocoa butter, or as enemas.

Dosage forms suitable for parenteral administration may conveniently comprise a sterile oily or aqueous preparation of the active ingredient, and are preferably isotonic with the blood of the recipient.

Dosage forms suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, applications, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops; or a spray.

For the treatment of asthma, powdered inhalants, self-propelled or nebulized compositions dispensed using a spray can (spray can), nebulizer or atomizer may be used. When dispensed, these compositions preferably have a particle size of 10 to 100 μ.

The compositions may conveniently be presented in dosage unit form and may be prepared according to any of the methods well known in the pharmaceutical art. The term "dosage unit" refers to a unit, i.e., a single dose capable of being administered to a patient as a physiologically and chemically stable unit dose comprising the active ingredient or a mixture thereof in solid or liquid pharmaceutical diluent or carrier.

2-propylidene-19-nor sustained-release compound

Modified vitamin D compounds that exhibit a desirable and highly advantageous pattern of biological activity in vivo, i.e., a more soothing onset and longer duration of activity, may also be used herein.

Structurally, a key feature of modified vitamin D compounds having desirable biological attributes is that they are derivatives of 2-propylene-19-norvitamin analogs in which a hydrolyzable group is attached to the hydroxyl group at the 25-position of the carbon, and optionally to any other hydroxyl group in the molecule. Depending on the different structural factors of the attached group- -such as type, size, structural complexity, these derivatives hydrolyze at different rates in vivo to the active 2-propylene-19-nor vitamin D analog, thereby providing a "sustained release" effect of the biologically active vitamin D compound in vivo.

Of course, the "sustained release" activity profile of these compounds in vivo can be further adjusted by using a mixture of derivatives or by using a mixture consisting of one or more vitamin D derivatives and underivatized vitamin D compounds.

It is important to stress that the key structural feature of the above identified vitamin derivatives is the presence of a hydrolysable group attached to the hydroxyl group at the 25-position of the molecular carbon. The presence of a hydrolysable group at this position allows the resulting derivative to have the desired "sustained release" biological activity profile described above. Other hydroxyl functional groups present in the molecule (e.g., hydroxyl functional groups on carbon 1 or 3) may be present as free hydroxyl groups, or one or more of them can also be derivatized with a hydrolyzable group.

The "hydrolyzable group" present in the above derivatives is preferably an acyl group, i.e. Q¹A group of the CO-type, wherein Q¹Represents hydrogen or a linear, cyclic, branched, saturated or unsaturated hydrocarbon group which may be of 1 to 18 carbon atoms. Thus, for example, the hydrocarbyl group may be a linear or branched alkyl group, or a linear or branched alkenoyl group containing one or more double bonds, or may be an optionally substituted cycloalkyl or cycloalkenyl group, or an aryl group such as a substituted or unsubstituted phenyl, benzyl or naphthyl group. Particularly preferred acyl groups are alkanoyl or alkenoyl groups, of which some representative examples are formyl, acetyl, propionyl, hexanoyl, isobutyryl,2-butenoyl, palmitoyl, or oleoyl. Another suitable class of hydrolyzable groups is hydrocarbyloxycarbonyl, i.e., Q²A radical of the type-O-CO-, in which Q²Is C as defined above₁-C₁₈A hydrocarbyl group. Examples of such hydrocarbon radicals are methyl, ethyl, propyl and higher straight-chain or branched alkyl and alkenoyl radicals, and also aromatic hydrocarbon radicals such as phenyl or benzoyl.

These modified vitamin D compounds are hydrolyzable to the active analog in vivo for a period of time after administration, and thus can modulate the in vivo bioavailability of the active analog, thereby modulating its in vivo activity profile. The term "activity profile" refers to the biological response of a vitamin D compound over time. Individual modified compounds, or mixtures of such compounds, can be administered to fine tune the desired response time course.

The term "modified vitamin D compound" as used herein encompasses any vitamin D compound in which one or more of the hydroxyl functional groups present in the compound is derivatized with a hydrolyzable group so as to be modified. A "hydrolyzable group" is a hydroxyl modifying group that can be hydrolyzed in vivo to regenerate the free hydroxyl functionality.

In the context of the present disclosure, the term hydrolyzable group preferably includes acyl and hydrocarbyloxycarbonyl groups, i.e. Q respectively¹CO-and Q²A radical of the O-CO class, in which Q¹And Q²Are defined as before.

Structurally, contemplated modified vitamin D compounds can be represented by the following general formula XI:

wherein Y is₁，Y₂And R is as previously defined for formula I, wherein as previously defined, except for R in the side chain⁵is-OY₃And Y is₃Is acylOr a hydrocarbyloxycarbonyl group.

Some specific examples of such modified vitamin D compounds include 2-propylene-19-nor vitamin D derivatives such as:

2- (3' -hydroxypropyl) -19-nor-1 α, 25(OH)₂-D₃-1, 3, 25-triacetate, wherein Y₁＝Y₂＝Y₃And is CH₃CO；

2- (3' -hydroxypropyl) -19-nor-1 α, 25(OH)₂-D₃1, 3, 25-trihexanoate, in which Y is₁＝Y₂＝Y₃And is CH₃(CH₂)₄CO；

2- (3' -hydroxypropyl) -19-nor-1 α, 25(OH)₂-D₃-1, 3, 25-trinononanoate, wherein Y₁＝Y₂＝Y₃And is CH₃(CH₂)₇CO；

2- (3' -hydroxypropyl) -19-nor-1 α, 25(OH)₂-D₃-25-acetate, wherein Y₁＝Y₂And is H, and Y₃Is CH₃CO。

These compounds can be prepared according to known methods. See, for example, U.S. Pat. No.5,843,927.

Biological activity of 2-propylene-19-nor vitamin D compounds

FIGS. 1 and 2- -competitive VDR binding

Competitive binding of the analogs to porcine intestinal receptors was performed by the method described by Dame et al (Biochemistry 25, 4523-.

FIG. 3- -HL-60 cell differentiation

Differentiation of HL-60 promyelocytes into monocytes was determined as described by Ostrem et al (J.biol.chem.262, 14164-14171, 1987).

FIG. 4- -transcriptional activation

Transcriptional activity was measured in ROS 17/2.8 (bone) cells stably transfected upstream of the 24-hydroxylase (24OHAse) gene promoter of the luciferase receptor gene (Arbour et al, 1998). Cells were given a series of doses. Cells were harvested 16 hours after dosing and luciferase activity was measured by luminometer.

In FIG. 4, "RLU" refers to relative luciferase units.

FIGS. 5 and 6- -intestinal calcium transport and bone calcium mobilization

Male freshly weaned Sprague-Dawley rats were given a Diet of Diet 11 (0.47% Ca) for + AEK for one week, followed by administration of Diet 11 (0.02% Ca) + AEK 3 for 3 weeks. The rats were then switched to a diet containing 0.47% Ca for 1 week, followed by two weeks of a diet containing 0.02% Ca. Dosing was started during the last week of the 0.02% calcium diet. 4 consecutive ip doses were administered approximately 24 hours apart. 24 hours after the last dose, blood was collected from the severed neck and serum calcium concentration was determined as a measure of bone calcium mobilization. The first 10cm of intestine was also collected and analyzed for intestinal calcium transport by the intestinal tube eversion method (everted gut sac method).

Description of biological data

FIG. 1 illustrates 2- [ (3' -methoxymethoxy) propylidene group]-19-nor-1 α, 25- (OH)₂D₃(also referred to herein as "F-Wit") with 1 alpha, 25-dihydroxyvitamin D₃Relative activity in binding to 1 alpha, 25-dihydroxyvitamin D porcine nuclear receptor. FIG. 2 illustrates 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃E-isomer of (1AGR), 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃Z-isomer of (2AGR), 2- (3' -hydroxypropyl) -19-nor- (20S) -1 alpha, 25- (OH)₂D₃E-isomer of (1AGS) (also referred to herein as "1 AGS"), 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The Z-isomer of (a) (also referred to herein as "2 AGS") and 1 alpha, 25-dihydroxy vitamin D₃Relative activity in binding to 1 alpha, 25-dihydroxyvitamin D porcine nuclear receptor. FIGS. 1 and 2 show that F-Wit, 1AGR, 2AGR, 1AGS and 2AGS are related to 1 alpha, 25-hydroxyvitamin D₃Rat receptor binding was active.

The 2-propylene-19-nor compound of the present invention shows a biological activity pattern having high efficacy in promoting differentiation of malignant cells, relatively high intestinal calcium transport activity, and relatively high activity of mobilizing calcium from bones. This is illustrated by the biological assay results obtained from F-Wit, 1AGR, 2AGR, 1AGS and 2AGS, which are summarized in FIGS. 3-6. FIG. 3 shows the known active metabolite 1 alpha, 25-dihydroxyvitamin D₃With 2-methylene-19-nor- (20S) -1, 25(OH)₂D₃Comparison of the activity of the analogs (also referred to herein as "2 MD") and the presently claimed F-Wit, 1AGR and 1AGS in inducing the differentiation of human leukemia cells (HL-60 cells) into monocytes in culture. Differentiation activity was assessed by standard differentiation assays, abbreviated as NBT reduction (nitro blue tetrazolium reduction). The assay is carried out according to known procedures as given by Deluca et al, U.S. Pat. No.4,717,721 and Ostrem et al, J.biol.chem.262, 14164, 1987. For this assay, the differentiation activity of a test compound is expressed as the percentage of HL-60 cells that differentiate into normal cells under the influence of a given concentration of the test compound.

The results summarized in FIG. 3 clearly show that these analogs F-Wit, 1AGR and 1AGS are all related to 1 α, 25-dihydroxy vitamin D₃And 2MD are equally effective in promoting leukemia cell differentiation. Thus, in the NBT assay, nearly 90% of the cells are covered with 1 α, 25-dihydroxyvitamin D₃At 1x10^-7M concentration induced differentiation, while F-Wit, 1AGR and 1AGS analogs were at 1X10^-7The same level of differentiation was induced at M.

FIG. 4 illustrates that F-Wit, 1AGR and 1AGS all have significant transcriptional activity in skeletal cells. This result, together with the cell differentiation activity of figure 3, indicates that the presently claimed 2-propylene compounds of structure I, especially F-Wit, 1AGR and 1AGS, would be very effective against psoriasis, since they have direct cellular activity to promote cell differentiation and inhibit cell growth. These data also show that the presently claimed 2-propylene compounds of structure I, especially F-Wit, 1AGR and 1AGS, have significant activity as anti-cancer drugs, especially drugs against leukemia, colon, breast, skin and prostate cancer.

FIGS. 5 and 6 show a comparison of calcemic activity of the known active 19-nor analog, 2MD, and the presently claimed F-Wit, 1AGR, and 1AGS analogs. FIG. 5 shows that F-Wit, 1AGR and 1AGS all have relatively high intestinal calcium transport activity and have stronger intestinal calcium transport activity than 2 MD. Also, fig. 6 shows that F-Wit, 1AGR, and 1AGS have significant activity in mobilizing calcium from bone, and activity in this respect is weaker than 2 MD. Thus, in summary, the 2-propylene-19-nor-analogs of structure I, particularly F-Wit, 1AGR, and 1AGS, exhibit selective activity profiles with high potency in inducing differentiation of malignant cells, relatively high intestinal calcium transport activity, and moderate bone calcium mobilization activity.

Claims (94)

1. A compound of the formula:

wherein Y is₁And Y₂Identical or different, are each selected from hydrogen and hydroxy protecting groups, where X is C_1-10Alkyl, hydrogen, and a hydroxyl protecting group, and wherein R is selected from the following structures:

2. the compound of claim 1, wherein X is alkoxy C_1-10An alkyl group.

3. The compound of claim 1 which is 2- [ (3' -methoxymethoxy) propylidene having the general formula]-19-nor-1 α, 25- (OH)₂D₃：

4. The compound of claim 1 which is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH) having the formula₂D₃E-isomer of (a):

5. the compound of claim 1 which is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH) having the formula₂D₃The Z-isomer of (A):

6. a compound according to claim 1, wherein,which is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 alpha, 25- (OH) having the following formula₂D₃E-isomer of (a):

7. the compound of claim 1 which is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH) having the formula₂D₃The Z-isomer of (A):

8. a pharmaceutical composition comprising an effective amount of at least one compound of claim 1 and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition according to claim 8, wherein the effective amount is from 0.01 μ g to 100 μ g of the at least one compound according to claim 1 per gram of the composition.

10. The pharmaceutical composition of claim 8, wherein the effective amount is from 0.1 μ g to 50 μ g of the at least one compound of claim 1 per gram of composition.

11. The pharmaceutical composition according to claim 8, wherein the composition comprises 2- [ (3' -methoxymethoxy) propylidene in an amount of 0.01 μ g to 100 μ g per gram of the composition]-19-nor-1 α, 25- (OH)₂D₃。

12. The pharmaceutical composition according to claim 8, wherein the composition comprises 2- [ (3' -methoxymethoxy) propylidene in an amount of 0.1 μ g to 50 μ g per gram of the composition]-19-nor-1 α, 25- (OH)₂D₃。

13. The pharmaceutical composition of claim 8, wherein each gram of the composition comprises 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH) in an amount of 0.01 μ g to 100 μ g₂D₃The E-isomer of (1).

14. The pharmaceutical composition of claim 8, wherein each gram of the composition comprises 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH) in an amount of 0.1 μ g to 50 μ g₂D₃The E-isomer of (1).

15. The pharmaceutical composition of claim 8, wherein each gram of the composition comprises 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH) in an amount of 0.01 μ g to 100 μ g₂D₃The Z-isomer of (1).

16. The pharmaceutical composition of claim 8, wherein each gram of the composition comprises 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH) in an amount of 0.1 μ g to 50 μ g₂D₃The Z-isomer of (1).

17. The pharmaceutical composition of claim 8 wherein each gram of the composition comprises 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH) in an amount of 0.01 μ g to 100 μ g₂D₃The E-isomer of (1).

18. The pharmaceutical composition of claim 8 wherein each gram of the composition comprises 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH) in an amount of 0.1 μ g to 50 μ g₂D₃The E-isomer of (1).

19. The pharmaceutical composition of claim 8 wherein each gram of the composition comprises 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH) in an amount of 0.01 μ g to 100 μ g₂D₃The Z-isomer of (1).

20. The pharmaceutical composition of claim 8 wherein each gram of the composition comprises 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH) in an amount of 0.1 μ g to 50 μ g₂D₃The Z-isomer of (1).

21. Use of a compound of the formula:

wherein Y is₁And Y₂Identical or different, are each selected from hydrogen and hydroxy protecting groups, where X is C_1-10Alkyl, hydrogen, and a hydroxyl protecting group, and wherein R is selected from the following structures:

22. the method of claim 21, wherein X is alkoxy C_1-10An alkyl group.

23. The use of claim 21, wherein the disease is senile osteoporosis.

24. The use according to claim 21, wherein the disease is postmenopausal osteoporosis.

25. The use according to claim 21, wherein the disease is steroid-induced osteoporosis.

26. The use of claim 21, wherein the disease is osteoporosis with low bone turnover.

27. The use of claim 21, wherein the disease is osteomalacia.

28. The use according to claim 21, wherein the disease is renal osteodystrophy.

29. The use of claim 21, wherein the medicament is formulated for oral administration.

30. The use according to claim 21, wherein the medicament is formulated for parenteral administration.

31. The use of claim 21, wherein the medicament is formulated for transdermal administration.

32. The use of claim 21, wherein the compound is 2- (3' -methoxymethyloxy) propylidene) -19-nor-1 α, 25- (OH)₂D₃。

33. The use of claim 21, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The E-isomer of (1).

34. The use of claim 21, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The Z-isomer of (1).

35. The use of claim 21, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The E-isomer of (1).

36. The use of claim 21, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The Z-isomer of (1).

37. Use of a compound of the formula:

wherein Y is₁And Y₂Identical or different, are each selected from hydrogen and hydroxy protecting groups, where X is C_1-10Alkyl, hydrogen, and a hydroxyl protecting group, and wherein R is selected from the following structures:

38. the method of claim 37, wherein X is alkoxy C_1-10An alkyl group.

39. The use of claim 37, wherein the medicament is formulated for oral administration.

40. The use according to claim 37, wherein the medicament is formulated for parenteral administration.

41. The use of claim 37, wherein the medicament is formulated for transdermal administration.

42. The use of claim 37, wherein the medicament is formulated for topical administration.

43. The use of claim 37, wherein the compound is 2- (3' -methoxymethyloxy) propylidene) -19-nor-1 α, 25- (OH)₂D₃。

44. The use of claim 37, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The E-isomer of (1).

45. The use of claim 37, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The Z-isomer of (1).

46. The use of claim 37, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The E-isomer of (1).

47. The use of claim 37, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The Z-isomer of (1).

48. Use of a compound of the formula:

wherein Y is₁And Y₂Identical or different, are each selected from hydrogen and hydroxy protecting groups, where X is C_1-10Alkyl, hydrogen, and a hydroxyl protecting group, and wherein R is selected from the following structures:

49. the method of claim 48, wherein X is alkoxy C_1-10An alkyl group.

50. The use of claim 48, wherein the medicament is formulated for oral administration.

51. The use according to claim 48, wherein the medicament is formulated for parenteral administration.

52. The use of claim 48, wherein the medicament is formulated for transdermal administration.

53. The use of claim 48, wherein the compound is 2- (3' -methoxymethyloxy) propylidene) -19-nor-1 α, 25- (OH)₂D₃。

54. The use of claim 48, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The E-isomer of (1).

55. The use of claim 48, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The Z-isomer of (1).

56. The use of claim 48, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The E-isomer of (1).

57. The use of claim 48, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃Z-isomer of (A)

58. Use of a compound of the formula:

wherein Y is₁And Y₂Identical or different, are each selected from hydrogen and hydroxy protecting groups, where X is C_1-10Alkyl, hydrogen, and a hydroxyl protecting group, and wherein R is selected from the following structures:

59. the method of claim 58, wherein X is alkoxy C_1-10An alkyl group.

60. The use of claim 58, wherein the bone strength is cortical strength.

61. The use of claim 58, wherein the bone strength is trabecular strength.

62. The use of claim 58, wherein the medicament is formulated for oral administration.

63. The use of claim 58, wherein the medicament is formulated for parenteral administration.

64. The use of claim 58, wherein the medicament is formulated for transdermal administration.

65. The use of claim 58, wherein the compound is 2- (3' -methoxymethyloxy) methoxy) Propylene) -19-nor-1 α, 25- (OH)₂D₃。

66. The use of claim 58, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The E-isomer of (1).

67. The use of claim 58, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The Z-isomer of (1).

68. The use of claim 58, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The E-isomer of (1).

69. The use of claim 58, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The Z-isomer of (1).

70. Use of a compound of the general formula:

wherein Y is₁And Y₂Identical or different, are each selected from hydrogen and hydroxy protecting groups, where X is C_1-10Alkyl, hydrogen, and a hydroxyl protecting group, and wherein R is represented by the following structure:

71. the method of claim 70, wherein X is alkoxy C_1-10An alkyl group.

72. The use of claim 70, wherein the disease is multiple sclerosis.

73. The use of claim 70, wherein the disease is diabetes.

74. The use of claim 70, wherein the disease is lupus.

75. The use of claim 70, wherein the medicament is formulated for oral administration.

76. The use of claim 70, wherein the medicament is formulated for parenteral administration.

77. The use of claim 70, wherein the medicament is formulated for transdermal administration.

78. The use of claim 70, wherein the compound is 2- (3' -methoxymethyloxy) propylidene) -19-nor-1 α, 25- (OH)₂D₃。

79. The use of claim 70, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The E-isomer of (1).

80. The use of claim 70, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The Z-isomer of (1).

81. The use of claim 70, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The E-isomer of (1).

82. The use of claim 70, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The Z-isomer of (1).

83. Use of a compound of the formula:

wherein Y is₁And Y₂Identical or different, are each selected from hydrogen and hydroxy protecting groups, where X is C_1-10Alkyl, hydrogen, and a hydroxyl protecting group, and wherein R is selected from the following structures:

84. the method of claim 83, wherein X is alkoxy C_1-10An alkyl group.

85. The use according to claim 83, wherein the disease is Crohn's disease.

86. The use of claim 83, wherein the disease is ulcerative colitis.

87. The use of claim 83, wherein the medicament is formulated for oral administration.

88. The use according to claim 83, wherein the medicament is formulated for parenteral administration.

89. The use of claim 83, wherein the medicament is formulated for transdermal administration.

90. The use of claim 83, wherein the compound is 2- (3' -methoxymethyloxy) propylidene) -19-nor-1 α, 25- (OH)₂D₃。

91. The use of claim 83, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The E-isomer of (1).

92. The use of claim 83, wherein the compound is 2- (3' -hydroxypropyl) -19-nor-1 α, 25- (OH)₂D₃The Z-isomer of (1).

93. The use of claim 83, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The E-isomer of (1).

94. The use of claim 83, wherein the compound is 2- (3' -hydroxypropyl) -19-nor- (20S) -1 α, 25- (OH)₂D₃The Z-isomer of (1).