This invention was made with United States government support awarded by the Department of Health and Human Services ( IH), Grant number: DK-14881. The United States Government has certain rights in this invention.

This invention relates to biologically active vitamin D compounds. More specifically, the invention relates to 19-nor-analogs of lα-hydroxylated vitamin D compounds and to a general process for their preparation.

Background The lα-hydroxylated metabolites of vitamin

D — most importantly lα, 25-dihydroxyvitamin D3 and lα, 25-dihydroxyvitaπin D ₂ — are known as highly potent regulators of calcium homeostasis in animals and humans, and more recently their activity in cellular differentiation has also been established. As a consequence, many structural analogs of these metabolites, such as compounds with different side chain structures, different hydroxylation patterns, or different stereochemistry, have been prepared and tested. Important examples of such analogs are lα

-hydroxyvitamin D3 , la-hydroxyvita in D2, various side chain fluorinated derivatives of la, 25-cihydroxyvi amin

D3 , and side chain homologated analogs. Several of these known compounds exhibit highly potent activity in vito or in vitro, and possess advantageous activity profiles anc thus are in use, or have been proposed for use, in the treatment of a variety of diseases such as renal osteocystrophy , vitamin D-resistant rickets, osteoporosis, psoriasis, and certain aliαnancies .

-2- Disclosure and Description of the Invention A class of lα-hydroxylated vitamin D compounds not known heretofore are the 19-nor-analogs, i.e. compounds in which the ring A exocyclic methylene group (carbon 19) typical of all vitamin D system has been removed and replaced by two hydrogen atoms. Structurally these novel analogs are characterized by the general formula I

where X ¹ and X^ are each selected from the group consisting of hydrogen and acyl, and where the group R represents any of the typical side chains known for vitamin D type compounds. Thus, R may be an alkyl, hydrogen, hydroxyalkyl or fluoroalkyl group, or R may represent the following side chain:

wherein R 1 represents hydrogen, hydroxy or O-acyl, R9 and R are each selected from the group consisting of alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group — ( ^CH 2^m — where is an integer having a value of from 2 to 5, R^ is selected from the group consisting of hydrogen, hydroxy, fluorine, O-acyl, alkyl, hydroxyalkyl and fluoroalkyl, R5 is selected from the group consisting of hydrogen,

-3- fluorine, alkyl, hydroxyalkyl and fluoroalkyl, or, R and R^ taken together represent double-bonded oxygen, R° and R' are each selected from the group consisting of hydrogen, hydroxy, O-acyl, fluorine and alkyl, or, R" and R ⁷ taken together form a carbon-carbon double bond, and wherein n is an integer having a value of from 1 to 5, and wherein the carbon at any one of positions 20, 22, or 23 in the side chain may be replaced by an 0, S, or N atom. Specific important examples of side chains are the structures represented by formulas (a), (b), (c), (d) and (e) below, i.e. the side chain as it occurs in 25-hydroxyvitamin D3 (a); vitamin D (b); 25- hydroxyvitamin D ₂ (c); vitamin D ₂ (d); and the C-24- e

In this specification and the claims, the term 'alkyl' signifies an alkyl radical of 1 to 5 carbons in all isomeric forms, such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, pentyl, etc., and the terms 'hydroxyalkyl' and 'fluoroalkyl* refer to such an alkyl radical substituted by one or more hydroxy or fluoro groups respectively, and the term 'acyl' means an aliphatic acyl group of 1 to 5 carbons, such as formyl, acetyl, propionyl, etc. or an aromatic acyl group such as benzoyl, nitrobenzoyl or halobenzoyl. The term

'aryl ¹ signifies a phenyl-, or an alkyl-, nitro- or halo-substituted phenyl group.

The preparation of lα-hydroxy-19-nor-vitamin D compounds having the basic structure shown above can be accomplished by a common general method, using known vitamin D compounds as starting materials. Suitable starting materials are, for example, the vitamin D compounds of the general structure II:

where R is any of the side chains as defined above. These vitamin D starting materials are known compounds, or compounds that can be prepared by known methods.

Using the procedure of DeLuca _et_ _al_. (U.S. Patent 4,195,027), the starting material is converted to the corresponding lα-hydroxy-3 ,5-cyclovitamin D derivative, having the general structure III below, where X represents hydrogen and Q represents an alkyl, preferably methyl:

O

So as to preclude undesired reaction of the lα-hydroxy group in subsequent steps, the hydroxy group is converted to the corresponding acyl derivative, i.e. the compound III shown above, where X represents an acyl group, using standard acylation procedures, such as treatment with an acyl anhydride or acyl halide in pyridine at room temperature or slightly elevated temperature (30-70 C). It should be understood also that whereas the process of this invention is illustrated here with acyl protection of hydroxy functions, alternative standard hydroxy-pro ec ing groups can also be used, such as, for example, alk lsilyl or alkoxyalkyl groups. Such protecting groups are well-known in the art (e.g. trime h lsilyl, triethylsilyl, t.-butyldimethylsilyl, or tetrahydrofuranyl, methoxyταethyl) , and their use is considered a routine modification of experimental detail within the scope of the process of this invention.

The derivative as obtained above is then reacted with oamium tetroxide, to produce the 10,19-dihydroxy analog, IV (where X is acyl), which is subjected to diol cleavage using sodium πetaperiodate or similar vicinal diol cleavage reagents (e.g. lead tetraacetate) to obtain the 10-oxo-intermediate, having the structure V below (where X is acyl) :

w

These two consecutive steps can be carried out according to the procedures given by Paaren _e _ JL [J. Org. Chem. _i_, 3819 ^• (1983)]. If the side chain unit, R, carries vicinal diols (e.g. 2 ,25-dihydroxy- or 25,26-dihydroxy, etc _* ) , these, of course, also need to be protected, e.g. via acylation, silylation, or as the isopropylidene derivative prior to the periodate cleavage reactions.

In most cases, the acylation of the lα-hydroxy group as mentioned above will simultaneously effect the acylation of side chain hydroxy functions, and these acylation conditions can, of course, be appropriately adjusted (e.g. elevated temperatures, longer reaction times) so as to assure complete protection of side chain vicinal diol groupings.

The next step of the process comprises the reduction of the 10-oxo-group to the corresponding 10-alcohol having the structure VI shown below (where X is acyl and Y represents hydroxy). When X is acyl, this reduction is carried out conveniently in an organic solvent at from about 0 C to about room temperature, using NaBH, or equivalent hydride reducing agents, selective for the reduction of carbonyl groups without cleaving ester functions. Obviously, when X is a hydroxy- protecting group that is stable to reducing agents, any of the other hydride reducing agents (e.g. LiAlH, , or analogous reagents) may be employed also.

VI

-1-

The 10-hydroxy intermediate is then treated with an alkyl- or arylsulfonylhalide (e.g. mathanesulfonylchloride) in a suitable solvent (e.g. pyridine) to obtain the corresponding 10-0-alkyl- or arylsulfonyl derivative (the compound having the structure shown VI above, where Y is alkyl-SO 0-, or aryl-S0_0-, and this εulfonate intermediate is then directly reduced, with li hiun aluminum hydride, or the analogous known lithium aluminum alkyl hydride reagents in an ether solvent, at a temperature ranging from 0 C to the boiling temperature of the solvent, thereby displacing the sulfonate group and obtaining the 10-deoxy derivative, represented by the structure VI above, where X and Y are both hydrogen. As shown by the above structure, a 1-0-acyl function in the precursor compound V is also cleaved in this reduction step to produce the free lα-hydroxy function, and any O-acyl protecting group in the side chain would, of course, likewise be reduced to the corresponding free alcohol function, as is well understood in the art. If desired, the hydroxy groups at C-1 (or hydroxy groups in the side chain) can be reprotected by acylation or silylation or ether formation to the corresponding acyl, alkylsilyl or alkoxyalkyl derivative, but such protection is not required. Alternative hydroxy-protecting groups, such as alkylsilyl or alkoxyalkyl groups would be retained in this reduction step, but can be removed, as desired, at this or later stages in the process by standard methods known in the art.

The above lα-hydroxy-10-deoxy cyclov tamin D intermediate is next solvolyzed in the presence of a low-molecular weight organic acid, using the conditions of DeLuca ez_ a . (U.S. Patents 4,195,027 and 4,260,549). When the solvolysis is carried out in acetic acid, for example, there is obtained a

ixture of lα-hydroxy-19-nor-vitamin D 3-acetate and lα- hydroxy-19-nor-vitamin D 1-acetate (compounds VII and VIII, below) , and the analogous 1- and 3-acylates are produced , when alternative acids are used for solvolysis .

fl l\

Y *\

Direct basic hydrolysis of this mixture under standard conditions then produces the desired lα-hydroxy-19-nor-vitamin

1 2 D compounds of structure I above (where X and X are hydrogen). Alternatively, the above mixture of monacetates may also be separated (e.g. by high pressure liquid chroma ography) and the resulting 1-acetate and 3-acetate iso ers may be subjected separately to hydrolysis to obtain the same final product from each, namely the lα-hydroxy-19-nor-vitamin D compounds of structure I. Also the separated monoacetates of structure VII or VIII or the free 1,3-dihydroxy compound can, of course, be reacylated according to standard procedures with any desired acyl group, so as to produce the product of

1 2 structure I above, where X and X represent acyl groups which may be the same or different.

Biological Activity of lα-Hydroxy-19-Nor-Vitamin D Compounds

The novel compounds of this invention exhibit an unexpected pattern of biological activity, namely high potency in promoting the differentiation of malignant cells and little or no activity in calcifying bone tissue. This is illustrated by the biological assay results obtained for lα,25-dihydroxy-19- nor-vitamin D_ (compounds Ia) , which are summarized in Tables 1 and 2, respectively. Table 1 shows a comparison of the activity of the known active metabolite lα,25-dihydroxyvitamin D and the 19-nor analog (Ia) in inducing the dif erentiation of human leukemia cells (HL-60 cells) in culture to normal cells ( onocytes). Differentiation activity was assessed by three standard differentiation assays, abbreviated in Table 1 as NBT (nitroblue tetrazolium reduction) , NSE (non-specific esterase activity), and PHAGO (phagocytosis activity). The assays were conducted according to known procedures, as given, for example, by DeLuca _et_ a _. (U.S. Patent 4,717,721) and Ostrem __t al. , J. Biol. Chem. 262, 14164, 1987). For each assay, the differentiation activity of the test compounds is expressed in terms of the percent of HL-60 cells having differentiated to normal cells in response to a given concentration of test compound.

The results summarized in Table 1 clearly show that the new analog, lα,25-dihydroxy-19-nor-vitamin D (Ia) is as potent as lα,25-dihydroxyvitamin D. in promoting the differentiation of leukemia cells. Thus in all three assays close to 90% of the cells are induced to differentiate by lα,25-dihdyroxy- vitanin D_ at a concentration of 1 x 10 molar, and the same degree of differentiation (i.e. 90, 84 and 90%) is achieved by the 19-nor analog (Ia) .

Table 1 Differentiation of HL-60 Cells lα,25-dihydroxyvitaπin D X Differentiated Cells (moles/liter) (mean _+ SEM)

lα,25-Dihydroxy-19-nor- vit

In contrast to the preceding results, the new 19-nor analog (Ia) exhibits no activity in an assay measuring the calcification of bone, a typical response elicited by vitamin D compounds. Relevant data, representing the results of an assay comparing the bone calcification activity in rats of lα,25-dihydroxyvitamin D_ and lα,25-dihydroxy-19-nor--vitarair. D. (Ia), are summarized in Table 2. This assay was conducted according to the procedure described by Tanaka _et_ al. , Endocrinology 92, 417 (1973).

The results presented in Table 2 show the expected bone calcification activity of lα,25-dihydroxyvitamin D as reflected by the increase in percent bone ash, and in total ash at all dose levels. In contrast, the 19-nor analog Ia exhibits no activity at all three dose levels, when compared to the vitamin D-deficient (-D) control group.

Table 2 Calcification Activity

Compound Amount Administered % Ash Total Ash (mg)

(pmoles/day/7 days) (mean _+ SEM) (mean _+ SEM)

-D (control) 19 + 0.8 23 + 1.2

lα,25-dihydroxy- 32.5 23 0.5 34 +_ 1.6 vita in D_ 65.0 26 _+ 0.7 36 +_ 1.1

325.0 28 + 0.9 40 + 1.9

lα,25-dihydroxy-19- 32.5 22 +_ 0.9 28 ^ 1.6 nor-vitamin D, (Ia) 65.0 19 + 1.5 28 _+ 3.4

325.0 19 + 1.2 30 + 2.4

Each assay group comprised 6 rats, receiving the indicated amount of test compound by intraperitoneal injection daily for a period of seven days.

Thus the new 19-nor analog shows a selective activity profile combining high potency in inducing the

differentiation of malignant cells with very low or no bone calcification activity. The compounds of this novel structural class, therefore, can be useful as therapeutic agents for the treatment of malignancies. Because the differentiative activity of vitamin D compounds on keratinocytes of skin (Smith _et_ ^., J. Invest. Dermatol. 6_, 709, 1986; Smith _et_ _al_. , J. Am. Acad. Dermatol. JL9, 516, 1988) is believed to be an indication of successful treatment of psoriasis (Takamoto et al., Calc. Tissue Int. 39_, 360, 1986), these compounds should prove useful in treating this and other skin disorders characterized by proliferation of undifferentiated skin cells. These compounds should also find use in the suppression of parathyroid tissue, as for example, in cases of secondary hyperparathyroidism found in renal disease (Slatopolsky et al., J. Clin. Invest. V_, 2136, 1984).

For treatment purposes, the novel compounds of this invention can be formulated as solutions in innocuous solvents, or as emulsions, suspensions or dispersions in suitable innocuous solvents or carriers, or as pills, tablets or capsules, containing solid carriers according to conventional methods known in the art. For topical applications the compounds are advantageously formulated as creams or ointments or similar vehicle suitable for topical applications. Any such formulations may also contain other pharmaceutically-accep able and non-toxic excipients such as stabilizers, anti-oxidants, binders, coloring agents or emulsifying or taste-modifying agents.

The compounds are advantageously administered by injection, or by intravenous infusion of suitable sterile

solutions, or in the form of oral doses via the alimentary canal, or topically in the form of ointments, lotions, o -in suitable transdermal patches. For the treatment of malignant diseases, the 19-nor-vitamin D compounds of this invention are administered to subjects in dosages sufficient to inhibit the proliferation of malignant cells and induce their differentiation into normal monocyte-macrophages. Similarly, for the treatment of psoriasis, the compounds may be administered orally or topically in amounts sufficient to arrest the proliferation of undifferentiated keratinocytes, and in the treatment of hyperparathyroidism, the compounds are administered in dosages sufficient to suppress parathyroid activity, so as to achieve parathyroid hormone levels in the- normal range. Suitable dosage amounts are from 1 to 500 μg of compound per day, such dosages being adjusted, depending on diseases to be treated, its severity and the response or condition of the subject as well-understood in the art.

This invention is more specifically described by the following illustrative examples. In these examples specific products identified by Roman numerals and letters, i.e. Ia, lb,

..., Ila, lib, ..., etc. refer to the specific structures and side chain combinations identified in the preceding description.

Example 1

Preparation of lα,25-dihydroxy-19-nor-vitamin D, (Ia) (a) lα,25-Dihydroxy-3,5-cyclovitamin D. 1-acetate, 6-methyl ether: Using 25-hydroxyvitamin D_ (Ila) as starting material, the known lα,25-dihydroxy-3,5-cyclovitarain D derivative Ilia

(X=H) was prepared according to published procedures (DeLuca _et_ al. , U.S. Patent 4, 195,027 and Paaren et_ a_l. , J. Or . Chem. 45, 3252 (1980)). This product was then acetylated under standard conditions to obtain the corresponding 1-acetate derivative Ilia (X-Ac).

(b) 10,19-Dihydro-lα,10,19,25-tetrahydroxy-3,5-cyclovitamin D _; 1-acetate, 6-methyl ether (IVa) : Intermediate Ilia (X=Ac) was treated with a slight molar excess of osmium tetroxide in pyridine according to the general procedure described by Paaren et_ al. (J. Org. Chem. ^+8_, 3819 (1983)) to obtain the 10,19-dihydroxylated derivative IVa. Mass spectrum m/z (relative intensity), 506 (M ⁺ , 1), 488 (2), 474 (40), 425 (45), 396 (15), 285 (5), 229 (30), 133 (45), 59 (80), 43 (100). ^λ R . NMR (CDC1 ₃ ) 5 0.52 (3H, s, 18-CH ₃ , 0.58 (IH, , 3-H) , 0.93 (3H, d, J=6.1 Hz, 21-CH ), 1.22 (6H, s, 26-CH arid 27-CH ₃ , 2,10 (3H, s, C0CH ₃ ), 3.25 (3H, s, 6-OCH ₃ , 3.63 (2H, m, 19-CH ₂ ), 4.60 (IH, d, J=9.2 Hz, δ-H), 4.63 (IH, dd, IfJ-H) , 4.78 (IH, d, J=9.2 Hz, 7-H).

(c) lα,25-Dihydroxy-10-oxo-3,5-cyclo-19-nor-vitamin 1-acetate, 6-methyl ether (Va) : The 10,19-dihydroxylated intermediate IVa was treated with a solution of sodium metaperiodate according to the procedure given by Paaren al. (J. Org. Chem. __ , 3819, 1983) to produce the 10-oxo- cyclovitamin D derivative (Va, X=Ac). Mass spectrum uι/_ (relative intensity) 442 (M ⁺ -MeOH) (18), 424 (8), 382 (15), 364 (35), 253 (55), 225 (25), 197 (53), 155 (85), 137 (100). ¹ H NMR (CDC1 δ 0.58 (3H, s, 18-CH ₃ ) , 0.93 (3H, d, J=6.6 Hz, 21-CH ₃ ), 1.22 (6H, s, 26-CH and 27-CH. _j ) , 2.15 (s, 3-OCOCH. ,

3.30 (3H, s, 6-0CH ₃ ), 4.61 (IH, d, J=9.1 Hz, 6-H) , 4.71 (IH, d, J=9.6 Hz, 7-H), 5.18 (IH, , lβ-H) .

It has been found also that this diol cleavage reaction does not require elevated temperatures, and it is, indeed, generally prefereable to conduct the reaction at approximately room temperature.

(d) lα-Acetoxy-10,25-dihydroxy-3,5-cyclo-19-nor-vitamin D_ 6-methyl ether (Via, X-Ac, Y _° 0H): The 10-oxo derivative Va (X-Ac) (2.2 mg, 4.6 μmol) was dissolved in 0.5 ml of ethanol and to this solution 50 μl (5.3 μmol) of a NaBH, solution

(prepared from 20 mg of NaBH,, 4.5 ml water and 0.5 ml of 0.01 H NaOH solution) was added and the mixture stirred at 0 C for ca. 1.5 h, and then kept at 0°C for 16 h. To the mixture ether was added and the organic phase washed with brine, dried over MgSO, , filtered and evaporated. The crude product was purified by column chromatography on a 15 x 1 cm silica gel column and the alcohol Via (X=Ac, Y=0H) was eluted with ethyl acetate hexane mixtures to give 1.4 mg (3 μmol) of product. Mass spectrum m/z (relative intensity) 476 (M ) (1), 444 (85), 426 (18), 384 (30), 366 (48), 351 (21), 255 (35), 237 (48), 199 (100), 139 (51),"59 (58).

(e) lα,25-Dihydroxy-19-nor-vitamin D„ (Ia, X ¹ =X ² =H): The 10- alcohol (Via, X=Ac, Y=0H) (1.4 mg) was dissolved in 100 μl anhydrous CH_C1_ and 10 μl (14 μmol) triethylamine solution [prepared from 12 mg (16 μl) triethylamine in 100 μl anhydrous CH Cl_], followed by 7 μl (5.6 μmol) mesyl chloride solution (9 ng mesyl chloride, 6.1 μl, in 100 μl anhydrous CH-C1„) added at 0 C. The mixture was stirred at 0 C for 2 h. The solvents were removed with a stream of argon and the residue (comprising compound Via, X=Ac, Y=CH ₃ S00-) dissolved in 0.5 ml of

anhydrous tetrahydrofuran; 5 mg of LiAlH, was added at 0 C and the mixture kept at 0 C for 16 h. Excess LiAlH, was decomposed with wet ether, the ether phase was washed with water and dried over MgSO,, filtered and evaporated to give the 19-nor product

Via (X=Y-H).

This product was dissolved in 0.5 ml of acetic acid and stirred at 55 C for 20 min. The mixture was cooled, ice water added and extracted with ether. The other phase was washed with cold 10% sodium bicarbonate solution, brine, dried over

MgSO,, filtered and evaporated to give the expected mixture of

3-acetoxy-lα-hydroxy- and lα-acetoxy-3-hydroxy isomers, which were separated and purified by HPLC (Zorbax Sil column, 6.4 x

25 cm, 2-propanol in hexane) to give about 70 μg each of compounds Vila and XHIa. UV (in EtOH) λ 242.5 (OD 0.72), ^r max 251.5 (OD 0.86), 260 (OD 0.57).

Both 19-nor-l,25-dihydroxyvitamin D. acetates Vila and Villa were hydrolyzed in the same manner. Each of the monoacetates was dissolved in 0.5 ml of ether and 0.5 ml 0.1 N KOH in methanol was added. The mixture was stirred under argon atmosphere for 2 h'. More ether was added and the organic phase washed with brine, dried over anhydrous MgSO, , filtered and evaporated. The residue was dissolved in a 1:1 mixture of 2-propanol and hexane and passed through a Sep Pak column and washed with the same solvent. The solvents were evaporated and the residue purified by HPLC (Zorbax Sil, 6.4 x 25 cm, 10%

2-propanol in hexane). The hydrolysis products of Vila and

1 2 Villa were identical and gave 66 μg of la (X =X =H). Mass spectrum (m/z relative intensity) 404 (M ) (100), 386 (41), 371

(20), 275 (53), 245 (51), 180 (43), 135 (72), 133 (72), 95

(82), 59 (18), exact mass calcd. for C^H^O 404.3290, found

404.3272. ^X H NMR (CDC1 ₃ ) δ 0.52 (3H, s, 18-CH. _j ) , 0.92 (3H, d,

J=6.9 Hz, 21-CH ₃ ), 1.21 (6H, s, 26-CH and 27-Cli ) , 4.02 (IH, m, 3α-H), 4.06 (IH, m, lβ-H) , 5.83 (IH, d, J-11.6 Hz, 7-11),

6.29 (IH, d, J-10.7 Hz, 6-H). UV (in EtOH) , λ 243 (OD max 0.725), 251.5 (OD 0.823), 261 (OD 0.598).

Example 2

Preparation of lα-hydroxy-19-nor-vitamin D- (lb)

(a) With vitamin D_ (lib) as starting material, and utilizing the conditions of Example la, there is obtained known lα-hydroxy-3,5-cyclovitamin D_ 1-acetate, 6-methyl ether, compound Ilib (X=»Ac).

(b) By ^' subjecting intermediate Illb (X=Ac) , as obtained in Example 2a above to the conditions of Example lb, there is obtained 10,19-dihydro-lα,10,19-trihydroxy-3,5-cyclovitamin D,. 1-acetate, 6-methyl ether IVb (X=Ac).

(c) By treatment of intermediate IVb (X=Ac) with sodium πetaperiodate according to Example lc above, there is obtained lα-hydroxy-10-oxo-3,5-cyclo-19-nor-vitamin D 1-acetate, 6-methyl ether Vb (X=»Ac).

(d) Upon reduction of the 10-oxo-intermedIate Vb (X=Ac) under the conditions of Example Id above, there is obtained lα-acetoxy-10-hydroxy-3,5-cyclo-19-nor-vitaroin n 6-methyl ether VIb (X=Ac, Y=0H).

(e) Upon processing intermediate VIb (X ^« =Ac, Y-OH) through the procedure given in Example le above, there is obtained lα-hydroxy-19-nor-vitamin D (lb, X^X^H) .

Example 3

Preparation of lα,25-dihydroxy-19-nor-vitamin D_

(a) Utilizing 25-hydroxyvitamin D_ (lie) as starting material and experimental conditions analogous to those of Example la, there is obtained lα,25-dihydroxy-3,5-cyclovitamin D„ 1-acetate, 6-methyl ether, compound IIIc (X=Ac) .

(b) Subjecting intermediate Hid (X=Ac) , as obtained in Example 3a above, to the reaction conditions of Example lb, provides 10,19-dihydro-lα,10,1 ,25-tetrahydroxy-3,5-cyclo- vitamin D_ 1-acetate, 6-methyl ether, IVc (X-=Λc) .

(c) By treatment of intermediate IVc (X=__c) with sodium aetaperiodate according to general procedures of Example lc above, there is obtained lα,25-dihydroxy-10-oxo-3,5-cyclo-19- nor-vitamin D_ 1-acetate, 6-methyl ether Vc (X»Ac) . (d) Upon reduction of the 10-oxo-intermediate Vc (X-Ac) under conditions analogous to those of Example Id above, there is obtained lα-acetoxy-10,25-dihydroxy-3,5-cyclo-19-nor-vitamin D„ 6-methyl ether Vic (X=Ac, Y=0H). (e) Upon processing intermediate Vic (X=Ac, Y=0H) through the procedural steps given in Example le above , there is obtained lα,25-dihydroxy-19-nor-vitamin D (lc, X =X ² -=H) .

Example 4

Preparation of lα-hydroxy-19-nor-vitamin D„

(a) With vitamin D„ (lid) as starting material, and utilizing the conditions of Example la, there is obtained known lα-hydroxy-3,5-cyclovitamin D_ 1-acetate, 6-methyl ether, compound Hid (X=Ac).

(b) By subjecting intermediate Hid (X=Ac) , as obtained in Example 4a above to the conditions of Example lb, there is

obtained 10,19-dihydro-lα,10,19-trihydroκy-3,5-cyclovitarain ϋ 1-acetate, 6-mechyl ether, IVd (X=Ac).

(c) By treatment of intermediate IVb (X=Ac) with sodium metaperiodate according to Example lc above, there is obtained lα-hydroxy-10-oxo-3,5-cyclo-19-nor-vitamin D- 1-acetate, 6-methyl ether, Vd (X=Ac).

(d) Upon reduction of the 10-oxo-intermediate Vd (X=Ac) under the conditions of Example Id above, there is obtained lα-acetoxy-10-hydroxy-3,5-cyclo-19-nor-vitarain D„ 6-raethyl ether, VId (X»Ac, Y=0H).

(e) Upon processing intermediate VId (X=Ac, Y«=0H) through the procedure given in Example le above, there is obtained lα-hydroxy-19-nor-vitamin D (Id, X =X ² =H) .