HYDROXYVITAMIN D2 COMPOUNDS AND PROCESS FOR PREPARING THEM

Abstract: Hydroxylated derivatives of vitamin D2., processes for preparing such compounds, intermediates utilized in such processes and certain isotopically labelled vitamin D2 compounds. The vitamin D2 derivatives would find application in the treatment of or prophylaxsis for various disease states characterized by calcium and phosphorous imbalances and as a substitute for vitamin D3 and its metabolites in their various applications.

Description: Description Hydr-oxyvi * t * -amin D ? Compounds Process for Prep-aring Them Technical Field * This invention relates to biologically active vitamin D compounds. More specifically, this invention relates to a process for the preparation of hydroxylated derivatives of vit-amin D_, and to novel intermediates used in this process. Still more specifically, this invention relates to the synthesis of 25-hydroxyvi * i^min D„ and the 24-epimer thereof, to certain alkyl and aryl-analogs and to 5,6-trans-, and the acyl derivatives of these coπpounds. Background The D vitamins are very iinportant agents for the control of calcium and phosphate metabolism in animals and humans, -and have long been used as dietary supplements and in clinical practice to assure proper bone growth and development. It is now known that the in vivo activity of these vitamins, specifically of vitamin D~ and D_, is dependent on metabolism to hydroxylated forms. Thus, vitamin D-. undergoes two successive hydroxylation reactions in vivo, leading first to 25-hydroxyvitaιtιin D^ and then to 1,25-dihydroxyvitamin D_ and the latter is indeed thought to be the cαt ound responsible for the well-known beneficial effects of vitamin D_. Likewise, vitamin D_, which is commonly used as a dietary supplement, undergoes an analogous hydroxylation sequence to its active forms, being first converted to 25-hydroxyvitamin D 2 (25-OH-D-.) and then to 1,25-dihydroxyvitamin D„ (l,25-(OH) 2 D_) . These facts are well established and well known in the- art [see, for example, Suda et al. Biochemistry 8_, 3515 (1969) and Jones et al. Biochemistry 14, 1250 (1975)]. OMH Like the metabolites of the vitamin D., series, the ^ hydroxylated forms of vitamin D 2 named above are, because of their potency and other beneficial properties, highly desirable dietary supplements, or pharmaceutical agents, for the cure or prevention of bone or related diseases, and their value and possible use is recognized in patents relating to these corripounds [U.S. Letters Patents 3,585,221 and 3,880,894]. ltfhereas all metabolites of vitamin D-, have been prepared by chemical synthesis, there has been but little work on the preparation of vitamin D 2 metabolites. The known synthetic processes for the metabolites of the D^-series (especially as far as they relate to the preparation of side chain " hydroxylated compounds) are, of course, in general not suitable for the preparation of the αsrresponding vitamin D_ metabolites, since the latter are characterized by a side chain structure (i.e. presence of a double bond and an extra methyl group) which requires a different synthetic approach from that applicable to side chain hydroxylated D_ compounds. Two -ompovinds structurally related to 25-OH----D,, have been prepared, namely 22-dehydro-25-hydroxycholecalciferol, which may be considered a 24-desmethyl analog of 25-OH-D 2 (see U.S. Patent 3,786,062), and 24,25-dihydroxyvitamin D , the 24-hydrαxy-analog of 25-OH-D 2 [Jones et al. Biochemistry 18_, 1094 (1979)] . Hσwev-er, the synthetic methods proposed in these reports are not applicable to the preparation of 25-OH-D 2 itself. No synthesis of the latter compound has appeared in the literature, and although there is the mention in the paper by Salmond et al. (Tetrahedron Letters, 1695-1698 (1977) , see p. 1697 and footnote 11) of the successful preparation of 25-OH-D 2 , no information on the overall process has been published to date. OMPI Disclosure of Invention A novel and convenient synthesis of 25-hydroxylated vitamin D_ -compounds has now been developed and is fully described herein. This synthesis provides 25-hydroxyvitamin D 2 (25-CΗ-D 2 ) and its 24-epimer, 25-h.ydroxy-24-epi-vit.3min D 2 (25-0iϊ-24-epi D 2 ) , characterized by the structures shown below (where X. and X ? are hydrogen and Y is methyl) , as well as the corresponding alkyl or aryl analogs, characterized by the structures above where Y is alkyl or aryl, and the hydroxy-protected derivatives-of these compounds characterized by the structures above, where either of X- and X 2 , or both of and X_ are acyl. In addition, the present process provides the 5,6-trans-isomers of the -above compounds, and novel intermediates that are of utility for the preparation of 25-OH-D -.analogs and/or isotopically-labeled products. The term "acyl", as used in this specification or in the claims, signifies an aliphatic acyl group of from 1 to about 6 carbons, in all possible iso eric forms (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, etc.), or an aromatic acyl group (aroyl group) such as benzoyl, the isomeric methyl-benzoyls, the isomeric nitro- or halo-benzoyIs, etc., or a dicarbox lic acyl group of from 2 to 6 atoms chain length, i.e. acyl groups of the type R00C(CH 2 ) CO-, or R00CCH 2 * )-CH-.CO-, where n has values between 0 and 4 inclusive and R is hydrogen or an alkyl radical, such as oxalyl, malonyl, succinoyl, glutaryl, adipyl, diglycolyl. The term "alkyl" refers to a lower alkyl group of 1 to 6 carbons in all ≠ possible isomeric forms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, pentyl, etc., and the word "aryl" signifies a phenyl or substituted phenyl group, e.g. alylphenyl, methoxyphenyl, etc. 'The overall process developed for the preparation of the above cαipounds may be divided into two general phases, namely (a) addition of a side chain fragment to a suitable steroidal precursor to produce a 5,7-diene steroid as the central intermediate, and (b) conversion of this 5,7-diene to the vitamin D structure with, as required, further modification of the side chain to produce the desired 25-hydroxylated coπpounds. This general scheme allows for sore flexibility in the choice of specific starting material and in the exact order of individual process steps, two features that are of considerable practical advantage and convenience. The reaction sequence illustrated by Process Scheme I presents an embodiment of the overall process, whereas Process Scheme II illustrates sane of the options available for executing the last four steps of the synthesis. Starting materials for the present process are steroidal 22-aldehydes in which the ring B double bond(s) is(are) protected in an appropriate manner. As shown in Process Scheme I, suitable compounds are for example, the PTAD-diene-protected-22-aldehyde (1) (where PTAD refers to the phenyltriazoline-3,5-dione-protecting group shewn) or the 3,5-cyclo-22-aldehyde (4) wherein the A -double bond is protected via i-ether formation. Both of these compounds are known products (see for example Barton et al. J. Chem. See. (C) 1968 (1971); and Heyl et al. U.S. Patent 2,623,052) and both can be carried through the steps of the present process in a basically analogous fashion. The first step of this process comprises the addition of a suitable side chain fragment. Thus, condensation of aldehyde (1) with a sulfonyl-side chain fragment as shown in Process Scheme I the Scheme (sulfone A, further described below) present in the form of its anion, in an ether or hydrocarbon solvent, provides the hydroxy-sulfone intermediate (2) . The anion of the sulfone A side chain fragment is generated by treatment of the sulfone with a strong base, such as lithium diethylamide, .n-butyl lithium or ethyl magnesium bromide (or similar Grignard reagent) in an ether or hydrocarbon solvent, and to this solution of sulfone -anion the steroid aldehyde (compound _1) as an ether or hydrocarbon solution is then added. The reaction may be conducted advantageously at about room temperature, and is best effected under an inert atmosphere. The analogous addition of sulfone A to aldehyde (4) provides the hydroxy-.sulfone intermediate characterized by -structure (5) in Process Scheme I. The next step comprises the removal of the hydroxy- and phenylsulfonyl groups in the side chain with formation of the 22(23)-trans-double bond. Thus, treatment of compound (2) , in methanol solution saturated with NaHPO., with sodium amalgam under an inert atmosphere, gives cαnpound (3) featuring the desired trans-22-double bond in the side chain. The analogous treatment of cαπpound (5_) gives the 22-olefinic ccmpound (6) . If desired, the 22-hydroxy group in coπpounds (2) or (5) can also be acylated or sulfonylated (e.g. mesylated) prior to the Na/Hg-reduction step, but this is not gener-ally required. It is to be noted that, as shown in Process Scheme I, addition of the side chain fragment, sulfone A, to the aldehydes (1) or (4) , does not cause epimerization at the asymetric center of carbon 20, i.e. the stereochemistry at that center is retained, as is required. If desired, retention of stereochemistry at carbon 20 may be checked at this stage of the synthesis by the conversion of intermediates of type (3_) or (6_) back to the original aldehyde starting materials. For example, subjecting ccπpound (6) to ozonolysis with reductive work-up, using fully conventional and standard conditions, yields the corresponding C-22-aldehyde, i.e. the υ REA OMPI aldehyde of structure (4_) . Spectroscopic and chrcmatographic •comparison of the aldehyde obtained from ozonolysis with the original starting material confirms retention of C-20 stereochemistry. The third operation of the process involves conversion of these'ring B-protected steroids to the desired 5,7-diene intermediate (7) . In the case of the PTAD-diene-protected compound (_3) , this conversion is accomplished in a single step, namely treatment of (3) with a strong hydride reducing agent (e.g. LiAlH in an ether solvent at reflux temperature gives the diene [1) . This same material, compound (1) , is produced from the i-ether derivative [6) , in several steps, all of which -are conventional and well-known in the art. The - i-ether (6) is first solvolyzed in glacial acetic acid at reflux for ca. 2 hours to yield the corresponding 5-ene-3-acetate derivative (6a) . This compound, in a hydrocarbon solution (e.g. hexane) at reflux temperature preferably under an inert atmosphere, is then treated with a brominating reagent (e.g. l,3-dibroπ -5,5-dimet ιylhydantoin) over a period of about 20 minutes, and the resulting C-7-bromo-intermediate is directly dehydrobrcminated by dis-solution in xylene and treatment with a base (e.g. s-collidine) at reflux temperatures under an inert atmosphere for about 90 minutes. The resulting product, the 5,7-diene-3-acetate is then isolated in the usual way and purified by high performance liquid chromatography or thin layer chromatography on silica gel plates. Simple hydrolysis of the acetate (5% KOH in MeOH) then provides 5,7-diene (7) . This hydrolysis step may, however, also be αnitted since both the 5,7-diene-3-ol (7) or the corresponding 3-O-acylates can be used for the subsequent steps of the process. Any such 3-O-acylates are, of course, also readily accessible by sirrple acylation of (7_) according to conventional procedures. Conversion of 5,7-diene (7_) to the final vitamin D products cαηprises a sequence of four steps, the precise order of which may be altered as convenient. The sequence shown in -Process Scheme I involves first the irradiation of an ether or hydrocarbon solution of the 5,7-diene (7) with ultraviolet light to yield the previtamin analog (8) which by warming (50-90°C) in a suitable solvent (e.g. ethanol, hexane) undergoes iscmerization to the vitamin D 2 -analog (9) . The next step, -removal of the ketal protecting group, is a critical one, since ketal removal by hydrolysis to give the corresponding keto-derivative (10) must be accomplished without iscmerization of the 22(23)-double bond to the conjugated 23(24)-position. Isomerization of a β, S-unsaturated ketone to the conjugated β-unsaturated ketone can readily occur under conditions of ketal hydrolysis, but must be avoided in this case, since it would defeat the purpose of the entire synthetic sequence. In the present process, ketal removal is achieved by heating ketal (9) in hydroxylic solvent under acid catalysis for 1-2 hours. (It is desirable to monitor the progress of reaction by periodic chromatographic analysis of the crude reaction mixture. Analysis by HPLC is suitable and convenient.) The product, ketone (10) thereby -obtained, is then alkylated in the final step by means of a Grignard reagent (an alkyl—, or aryl-magnesium halide, e.g. methyl magnesium branide in this case) to give the 25-hydroxyvitamin D_ compound (11) . Alkylation via an alkyllithium reagent, e.g. methyl lithium, is also effective and convenient. If the side chain fragment, sulfone A, as used in the first step, is racemic, i.e. exists as a mixture of its (R) and (S_)-enantiαners, then compound (11) will be obtained as a mixture of two C-24-epimers, i.e. (24Σ3)-epimer (11a) which corresponds to the natural product, and the (24R)-epimer (lb) which is 25-OH-24-epi-D 2 . These C-24-epimers are conveniently separated by high performance liquid chromatography (HPLC) on an efficient microparticulate silica gel column to obtain 25-OH-D 2 (11a) and 25-OH-24-epi-D 2 (lib) in pure form. ■ ^13R£Λ OMPI It is to be noted that with racemic sulfone A as the side Chain starting material, the early synthetic intermediates, e.g. (3) [or (6), and (6a)] as well as the 5,7-diene (7_) and subsequent intermediates ( ) , (9) , and (10) also occur as the two C-24-ep±mers. If desired and convenient, separation of epimers can be conducted at any of these intermediate stages, and the (24R) and (24S_) epi ers may then be processed separately through the remaining steps to yield 25-OH-D 2 (11a) or 25-OH-24-epi-D (lib) as desired. It is generally convenient to effect separation at the stage of the final products. Since the mixtures of (24R)- and (24SJ-epimers arise when the side chain fragment, sulfone A, as used in the above process is itself a racemic compound, i.e. is present as an enantiomeric mixture of the (R) and (S_) forms, it is also possible, if desired, to circumvent the need for epimer separation by the use of optically active sulfone A. Thus, use of the (R)-epimer of sulfone A in the present process yields specifically 25-OH-D- (11a) , while use of the corresponding (S_)-epimer of sulfone A provides 25-OH-24-epi-D 2 (lib) as well as, of course, the respective intermediates in the pure (24R) or (24S_) forms; the use of such optically pure sulfone starting material requires no other modification of the process steps described. It is also important to note that the exact sequence of steps between the 5,7-diene (7) and the final products may be altered. Indeed, there are three convenient synthetic sequences, all involving the s-ame steps, but in different order. These alternate sequences are shown in Process Scheme II, where X, .-and X ? in the structural drawings signify hydrogen or an acyl group such as for example acetyl, propionyl, butyryl, benzoyl or substituted benzoyl. The first sequence (identified by the letter A in Process Scheme II) , leading from diene (7A) (which, when X,=H, corresponds to diene (7) of Process Scheme I) to intermediates (8A) , (9A) , -and to the final product (11) presents the order of reactions as discussed above. Alternatively, the ketal in diene (7A) may be hydrolyzed first (see sequence B in Process Scheme II) , to yield the diene-ketone identified as (7B) in the scheme, which after irradiation gives the previtamin ketone (8B) , and thermal iscmerization then leads to vitamin D^-ketone (10) , which via a final Grignard reaction yields the 25-OH-D_-epimers (11) . In the third sequence (C) , the 5,7-diene-ketone (7B) is first reacted with Grignard reagent to yield the 25-hydroxy intermediate (7C) , which after irradiation gives the corresponding 25-OH-^>revitamin D (8C) , and a final thermal iscmerization provides the 25-OH-D 2 products (11) . Thus, these three sequences differ only in the exact order in which specific steps -are carried out, but the experimental conditions for the individual steps are analogous to the procedures described earlier, and as described in detail by the Examples. Among the three alternate sequences, sequence A is generally preferred, because of the utility of intermediates such as (9A) and (10) for the preparation of other vitamin D 2 —analogs and/or labeled derivatives (see also below) . For any of these sequences, the 5,7-diene (7_) may be used as the free hydroxy cαπpound or as its C-3-acylate. Depending on the sub.sequent reaction sequence, the final 25-OH- 2 products will be obtained as the free hydroxy coirpounds or, if desired, as the C-3-, or C-25-acylates, or 3,25-diacylates. Thus, synthesis according to sequence A or B would normally provide the 25-OH-D products as the free hydroxy compounds since the final Grignard reaction coπmon to both sequences removes any acyl groups. Sequence C can be used to produce the 25-OH-D_ epimers (11) as the free hydroxy compounds, or as the 3- or 25-monoacylate, or 3,25-diacylate, depending on the intermediate used. For example, the 5,7-diene intermediate (7C) shown in Process Scheme II, may be us-ed as the 3-acyl, or OM Process Scheme II Process Scheme IE sulfone A OMPI 25-acyl, or 3,25-diacyl derivatives, which are available from the 3,25-diol by reaction with acyl chloride or acid anhydride reagents according to conventional procedures. Thus, reaction of 3,25-diol intermediate (7C) with acetic anhydride is pyridine at room temperature gives the 3-acetate, and the corresponding 3,25-diacεtate is obtained by further acylation at elevated teπperature; the latter may be selectively hydrolyzed with dilute KOH/MeOH at room temperature to give the 25-mono-acetate. Further conversion of any of such acyl intermediates through the remaining steps [to (8C) and (11)] in Process Scheme II, then yields the 25-OH-D„-epimers (11) in any desired acylated form. The individual 25-OH-D 2 -epimers, 25-OH-D 2 (11a) or ~25-OH-24-epi-D-. (lb) when obtained in the free hydroxy forms, are also conveniently acylated at the C-3 or C-25, or at both positions, by reaction with acid anhydrides or acyl chlorides using conventional conditions. Thus, 25-OH-D 2 (11a) nay be acylated to yield, for exartple, the 25-OH-D 2 * -3--acetate, or the corresponding 3,25-diacetate. The 3-moncacetate, in a like fashion, may be further acylated at C-25 by treatment with a different acylating reagent, or, alternatively, the 3,25-diacetate may be selectively hydrolyzed by mild base (KOH/MeOH) to give the 25-monoacetate, which if desired can be reacylated with a different acyl group at C-3. In addition to acetic anhydride, suitable acylating agents are propionic, butyric, pentanoic or hexanoic anhydrides or the corresponding acid chlorides, or aromatic acylating agents such as the acid chlorides of benzoic or substituted benzoic acids, or the anhydrides of dicarboxylic acids, such as succinic, glutaric, adipic, diglycolic anhydrides, or the acyl chlorides of these dicarboxylic acid monoesters. In addition to the acylates, the 5,6-trans-isαrers of 25-OH-D 2 and 25-OH-24-epi-D_ are compounds of potential utility in medical applications because of their considerable vitamin D-like activity. These 5,6-trans-cαrpounds are OMPI 13 prepared from the 5,6-cis-iscmers (i.e. 11a or lib) by iodine catalyzed iscmerization according to the procedures of Verlcop et al. Rec. Trav. Chim. Pays Bas 7j8, 1004 (1969) , and the corresponding 3- and/or 25-acylates are likewise obtained by analogous iscmerization of the corresponding 5,6-cis-acylates, or by acylation of the 5,6-trans-25-OH-D compounds. It is to be noted also that the 25-keto-intermediate (i.e. compound (10) in Process Scheme I) can serve as a substrate for the convenient preparation of 25-OH-D 2 or its 24-epimer in isotopically labeled form, namely by reaction of the ketone with commercially available isotopically labeled Grignard or methyl lithium reagents to provide 25-OH-D-, 13 14 2 3 compounds 1-abeled at carbon 26 with C, C, H or H. Furthermore, the keto-vitamin D compound (10) also serves as a convenient intermediate for the synthesis of 25- H-D 2 -analogs, of the formula (12) shown below. where X, and X„ are selected from hydrogen and acyl, and where Y is an alkyl group other than methyl or an aryl group. These coπpounds are prepared by reaction of ketone (10) with the appropriate alkyl- or aryl- Grignard or alkyl- or aryl-lithium reagent. For example, treatment of ketone (10) with ethyl magnesium iodide yields product (12) above, where X-=X 2 =H, and Y=ethyl; likewise treatment of ketone (10) with isopropyl magnesium bromide, or phenyl magnesium bromide yields the corresponding 25-OH-D 2 ~congeners of structure (12) above, where Y=isopropyl, or phenyl, respectively, and other alkyl analogs of structure (12) , e.g. where Y is propyl, butyl, sec.-butyl, isobutyl, pentyl, are prepared by analogous reactions. Acylation of these products by the procedures discussed above provides the C-3-, or C-25-O-acylates, or OMPI 3,25-di-O-acylates, and isomerization of the 5,6-double bond according to the procedure of Verloop et al. cited above yields the 5,6-trans-isαners of the compounds of structure (12) and/or the acylates thereof. Since the coπpounds, " where Y is a higher hcmolog of methyl, are generally more lipophilic, the alkyl- or aryl-analogues represented by structure (12) above or their 5,6-trans-iscroers, are expected to have utility in applications where a greater degree of lipcphilicity is desired. The required side chain fragment, sulfone A, is itself prepared according to the process shown in Process Scheme III. This synthesis is straightforward and involves as a first step the reaction of commercially available 4-hydrx>xy-3-methyl- butan-2-one with p-toluenesulfonylchloride to form the corresponding toluenesulfonyl ester. This product is then treated with thioph-enol in the presence of base (e.g. potassium t-butylate) whereby the toluenesulfonyl group is displaced and the corresponding phenyltliioether is formed. In the next step, the ketone group is protected as the ethylene ketal by reaction with ethyl-ene glycol under acid catalysis, using conventional conditions well established in the art. Oxidation of this product with a peracid (e.g. perbenzoic acid, or m-chloroperbenzoic acid) in halocarbon solution (e.g. CH 2 C1 2 ) then provides the desired sulfone, labeled sulfone A, as shown in Process Scheme III. If sulfone A is desired in optically active form, i.e. as the pure (R) or (SJ-epimer, it is appropriate to use optically active starting materials , for example, the ethylene ketal of (3R)-4-hydroxy-3-methylbutan-2-one or the ethylene ketal of (3 )-4-hydroxy-3-methylbutan-2-one. Each of these ethylene ketals is then processed through the appropriate steps of Process Scherre III, namely a) tosylation, b) phenylsulfide formation, and c) peracid oxidation, to yield from the (R) ketal starting material the (S_)-enantiomer of sulfone A, and vju "- -.- O ΓI from the (S_)-ketal the (R)-enantiαner of sulfone A. The (R) ■and (S) ketal starting materials are themselves conveniently obtained from commercially available recemic α-methylaceto- acetate ethyl ester (ethyl 2-methyl-3-oxo-butonate) as follows: The keto ester is converted to the ethylene ketal > ester by reaction with ethylene glycol under acid catalysis using conventional procedures, -and the ester function is then reduced (LiAlH. in ether) to yield the racemic ketal-alcohol (2,2-e * t±ylenedioxy-3-methylbutan-4-ol) . Resolution of the racemic mixture is accomplished by conversion to a mixture of " diastereomers (by reaction of the alcohol f * unction with an optically active acylating agent) which are then separated. For exartple, the alcohol can be converted to the corresponding αr-n^thoxy-α-trifluoromethylphenylacetyl derivative (or si-mil-ar optically active acylate) by reaction in pyridine solution with the chloride of optically active (+) α-methoxy-T*- trifluorcmethyl-phenylacetic acid (according to the procedures of, for example, Dale et al. , J. Org. Che . 34, 2543 (1961); Eguchi et al. , Proc. Natl. Acad. Sci. USA 78, 6579 (1981)) ; this disastereαrteric acyl-derivative mixture is now separable by HPLC or similar chromatographic πethods into its two components, namely the acylate of the (R)-enantiσmer and the acylate of the (S -en-antio er. Removal of the a-cyl group in each compound by base hydrolysis under standard conditions then provides the ethylene ketal of (3R)-4-hydroxy-3-methylbutan-2-one, and the ethylene ketal of (3S_)-4-hydroxy-3-methylbutan-2-one, which are then separately processed to the respective sulfone A enantiomer as described above. If desired,, optically active hydroxybutanone intermediates, i.e. (3R)-4-hydroxy-3-methylbutan-2-one and (3S_)-4-hydroxy-3-methylbutaan-2-one, can also be prepared from naturally occurring optically active substrates. Thus, by reaction of the known (S_)-3-hydroxy-2-methylpropanoic acid ( β-hydroxyisobutyric acid) with methyl lithium there is obtained (3S)-4-hydroxy-3-methylbutan-2-one; and the OMPI corresponding (3R)-hydroxybutanone can be prepared from the -sane (S_)-hydroxy-iisobutyric acid, by transposition of functionalities, i.e. elaboration of the hydroxymethyl group to a methyl ketone function, and reduction of the acid to alcohol, according to obvious and conventional procedures. The present invention is further described by means of the following illustrative examples. In these examples, numerals designating specific products (e.g. cαrpσunds (1) , (2) , (3) , etc. in Examples 1 through 12, or cαtpounds (7A) , (8B) , (8C) , etc. in Examples 13 and 14) refer to the structures so numbered in Process Schemes I or II. Example 1 The C-22 aldehyde (1) is -obtained by degradation of ergosterol acetate (in -which the ring B diene system has been protected by Diels-Alder addition of 4-phenyl-l,2,4- triazoline-3,5-dione) according to the procedure of Barton et al. (supra) . The i-ether aldehyde (4) is obtained from stig asterol by the method of U.S. Patent 2,623,052. Example 2 Synthesis of the Side Chain Fragment (Sulfone A) To a stirred solution of 4-hydroxy-3-^nethylbut.an-2--one (12.75 g; 0.125 ol) in pyridine (100 ml) is added p-toluenesulfonyl chloride (p-TsCl) (33.25 g, 0.175 mol) in portions, and after standing for 14 h at room temperature, the reaction mixture is poured into water and extracted with OLC—. The extract is washed several times with aqueous CuSO. solution and water and then dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gives the crude tosylate which is used directly for the next reaction. Thiophenol (14 g) dissolved in DMF (100 ml) is treated with t-BuOK (14 g) . To this reagent, the tosylate is added and after 12 h at room temperature, the reaction mixture is poured into water and extracted with CH_C1 2 . The extract is washed with-aqueous Na 2 CO_ solution and water, then dried. Evaporation of solvent gives an oily residue which is purified by silica gel column chromatography. Pure phenyl sulfide is ^ eluted with benzene (yield 15 g) . To this phenyl sulfide derivative (15 g) , in benzene (100 ml) , ethylene glycol (6 g) and p-TsOH (20 mg) is added and the reaction mixture is heated under a Dean-Stark trap for 3 h. After cooling, it is extracted with Na ), solution and water, then dried and the solvent is evaporated. The product, the desired ketal, is chrαnatographically homogenous and can be used in the next step without further purification. Crude ketal in dichloromethane (250 ml) solution is treated with m-chloroperbenzoic acid (m-CPBA) (80-85%, 27 g, added in portions) while maintaining the temperature of the reaction mixture below 30°C. After the addition of reagent, * the reaction is allowed to stand at room temperature with occasional shaking. When the reaction reaches completion (about 1.5 h) , the aromatic acids are removed by extraction with aqueous MH_, and the organic layer is washed with water and dried. Evaporation of solvent gives the oily sulfone (sulfone A) in essentially qu-antitative yield (19 g) . The product is substantially pure (homogenous by TIC) and can be used without any further purification; " Ή-NMR; S; 1.18 (d, J = 7 Hz, 3H, CH--CH-), 1.19 (s, 3H, CH_-C-) , 3.84 (m, 4H, —V5 —J ketal-H) , 7.3-7.6 and 7.6-7.9 (m, 3H + 2H, aromatic protons); KBr —1 IR, V • 1305,1147,1082 cm ; mass spectrum, m/z_ (rel. intensity): 255 (M + -Me, 21), 184 (66), 87 (92), 43 (100). Example 3 Coupling of Sulfone A to Aldehyde (1) : Hydroxysulfone (2) and Olefin (3) . Grignard reagent is prepared from Mg (535 mg; 22.22 mmol) -and ethyl brcmide in ether (10 ml) , and the vigorously stirred solution is treated with sulfone A (6 g; 2.22 irtnol) in benzene (6 ml) . The precipitate formed is ground with a spatula, stirring is continued, and after 15 min the aldehyde (1) (2.0 g) is added in benzene (10 ml). The reaction mixture is stirred at room temperature for 24 h, then poured into aqueous (NH.) 2 SO. solution and extracted with OMPI 18 benzene. The org-anic lay-er, after washing with water, drying and evaporation gives an oily residue which is chromatographed on silica gel. In the benzene-ether fractions (8:2) , excess sulfone is recovered (4.5 g); elution with benzene-ether (3:1) affords unreacted aldehyde (1) (1.0 g) ? the reaction products » (2) are eluted with ethyl acetate. The crude mixture of steroidal α-hydroxysulfones (2) is dissolved in methanol (200 ml) saturated with Na 2 H 0 4 . Sodium amalgam (5.65%, 15 g) is added and the reaction mixture is stirred at 4°C for 15 h. After completion of the Na/Hg reduction, mercury is removed by filtration, and methanol by evaporation under reduced pressure, water is added and the organic material is ' extracted with benzene. After drying and evaporation of solvent, the oily residue is chromatographed on a silica gel column. Elution with benzene-ether (1:4) gives compound (3_) a colorless foam; -NMR, £ : 0.80 (s, 18-H) , 0.97 (s, 19-H) , 1.22 (s, 26-H), 3.93 (m, 4H, ketal-H) , 4.44 (m, 1H, 3 -H) , 5.25-5.45 (m, 2H, 22-H and 23-H) , 6.23 and 6.39 (doublets, J = 8 Hz, 2 x 1H, 7-H and 6-H) , 7.25-7.45 (m, 5H, -C.H ; - - 6-5 , IR, i mCHaxC13: 3603 (0-H) , 1 + 749, 1692 (C=0) , 1406,1038 on ; mass spectrum, m/z: 440 (M - triazoline, 24) , 87 (100) . (To increase yield, unreacted aldehyde (1) , as recovered above, can be recycled through the sulfone addition, and the resulting α-hydrσxy sulfcnes (2) are then, as above, traεated with sodium .amalgam in buffered methanol to provide additional olefin (3_) . The above reactions are preferably conducted under an inert atmosphere, such as argon.) Example 4 Coupling of Sulfone A to Aldehyde (4) Hydroxysulfone (5) and Olefin (6) . Grignard reagent is prepared from Mg (75 mg, 3.1 rtmol) and ethyl bromide in ether (10 ml) . To the stirred solution of ethyl magnesium bromide, sulfone A (891 mg; 3.3 rtmol) in benzene (5 ml) is added. After stirring the resulting suspension at room temperature for 15 min, a solution of aldehyde (4) (290 mg) in benzene (5 ml) is added. The reaction is continued for 2.5 h, then quenched with saturated (NH.) 3 S0 4 solution (5 ml) and diluted with ether. The separated organic layer is washed with water, dried, and evaporated. The oily residue containing (5_) is treated with acetic anhydride (2 ml) and pyridine (2 ml) . The reaction mixture is allowed to stand for 24 h, poured into water and extracted with benzene. The benzene extract is washed with an aqueous solution of CuSO., water, dried, and evaporated. The crude product [the acetate of (5)] is dissolved in meth-anol saturated with Na 2 HPO. and sodium amalgam (5.65%, 8 g) is added. The reaction mixture is stirred at 4°C for 16 h. After the reaction, mercury is removed by filtration, methanol is evaporated, and water and benzene are added to dissolve the residue. The benzene layer is dried and evaporated. The oily residue is chromatographed over silica gel. Elution with benzene-ether mixture (93:7) affords compound (6) (206 mg; 54%), -^-NMR, S: 0.74 (s, 18-H) , 1.04 (s, 19-H) , 1.25 (s, 26-H), 2.78 (m, 1H, 6 -H) , 3.34 (s, 3H, -COy , 3.97 (m, 4H, ketal-H), 5.25-5.45 (m, 2H, 22-H and 23-H) , IR, V ?J: 3470 (O-H) , 1095 cm " ; mass spectrum, m/z (rel. intensity) : 456 (M + , 1) , 441 (M + -Me, 45) , 87 (100) . It should be noted that the acetylation step described above is not essential and may be omitted if desired; i.e. the hydroxysulfone (5_) may be submitted directly to Na/Hg-reduction, as in Ex-ample 3. The above reactions are preferably conducted under an inert atmosphere, e.g. argon. Example 5 Removal of PTAD-protecting Group: 5,7-Diene (7). A mixture of the -compound (3_) (1 g) and lithium aluminum hydride (1.8 g) in THF (120 ml) is heated under reflux for 10 h. After cooling, excess reagent is destroyed with a few drops of water, and the mixture is dried over anhydrous MgSO., filtered, and solvent is evaporated to give colorless crystalline material. Crude diene 7_ is repeatedly crystallized from ethanol; first and second crops ccmbined give 415 mg of (7) . The mother liquor is chromatographed on silica, gel column, to give with benzene-ether (7:3) , an ' additional 120 mg of ( ) total yield 535 mg (79%) ; m.p. 132-134°C (from ethanol) , " h-I-NMR, S:0.63 (s, 18-H) , 0.95 (s, 19-H) , 1.23 (s, 26-H) , 3.63 ( , IH, 3 -H) , 3.95 ( , 4H, ketal-H), 5.20-5.50 (m, 3H, 22-H, 23-H and 7-H) , 5.57 (m, IH, T RT —1 6-H); IR, Y : 3430 (0-H) , 1063, 1038 cm ; -mass spectrum, — max . . m/ (rel. int.): 440 (M , 50), 407 (M -H-O-Me, 11), 87 (100); OT, '.Amax i 282 n (£= 11, r 000). Example 6 Irra-diation of Cotpound (7) : Previtamin Analog (8) . A solution of diene (7) (50 nrg) in 150 ml of benzene-ether (1:4) is cooled on ice and deoxygenated with argon for 20 min. The reaction mixture is irradiated under argon atπo-sphere for 18 min with a mercury arc lartp (Hanovia SA-1) fitted with a Vycor filter. The solvent is evaporated and the residue is ctocimatographed on HPLC (6.2 mm x 25 cm microparticulate silica gel, 4 rol/min, 1400 psi) -and eluted with 2% 2-propanol in hexane to yield 22 mg (44%) of previtamin (8); " ϊ-NMR; S: 0.73 (s, 18-H) , 1.24 (s, 26-H) , 1.64 (s, 19-H) , 3.96 (m, 5H, ketal-H and 3 -H) , 5.35 (m, 2H, 22-H and 23-H) , 5.50 (m, IH, 9-H) , 5.69 and 5.94 (doublets, J = 11.5 Hz, 2 x IH, 6-H and 7-H) ; UV, A Et0H : 263 nm ' — — max (£= 8,900). Example 7 Iscmerization of (8) to the Vitamin-Analog (9) . Previtamin 8_ (22 mg) is dissolved in ethanol (40 ml) and heated under reflux for 150 min (argon atmosphere) . The product is purified by HPLC to yield 18 mg (82%) of the pure vitamin (9) ; " ^Ϊ-NMR, 6: 0.75 (s, 18-H) , 1.24 (s, 26-H) , 3.94 (m, 5H, ketal-H and 3 -H) , 4.81 and 5.04 (2 narrow m, 2 x IH, 19(Z)- and 19(E)-H), 5.33 (m, 2H, 22-H and 23-H) , 6.03 (d, J = 21 - 11 Hz, IH, 7-H) , 6.22 (d, J = 11 Hz, IH, 6-H) ; mass spectrum, m/z_ (rel. int.): 440 (M + , 17), 87 (100), UV, Λ ^ H : 265 nm (&= 17,000). Exaπple 8 Hydrolysis of the ketal: Keto-Vitamin D p -Analog (10) . To the solution of compound (9) (18 mg) in ethanol (35 ml) , p-toluenesulfonic acid (7.5 mg) in water (1 ml) is added and the reaction mixture is heated under reflux for 90 min (the reaction course is monitored by HPLC) . The solvent is evaporated, the residue is dissolved in benzene and extracted with water. The benzene solution is dried (anhydrous MgSO.) , and evaporated to yield product (10) (16 mg; 99%). Tϊ-NMR, <$ * : 0.57 (s, 18-H) , 1.04 (d, J = 7 Hz, 21-H) , 1.13 (d, J = 7 Hz, 28-H) , 2.12 (s, 3H, 26-H) , 3.10 (m, IH, 24-H) , 3.96 (m, IH, 3 -H) , 4.82 and 5.05 (2 narrow , 2 x 1 H, 19(Z)- and 19(E)-H) , 5.2-5.5 (m, 2H, 22-H and 23-H) , 6.03 (d, J = 11.5 Hz, IH, 7-H) , 6.22 (d, J = 11.5 Hz, IH, 6-H) , IR, V C ?? 1 3: 3596 (0-H) , 1709 cm (C=0) ; mass spectrum, m z (rel. int.): 396 (M , 41), 363 (M + -H 2 0-Me, 13) , 271 (M + -side chain, 16) , 253 (m + -side chain-H0, 23), 136 (100), 118 (95); UV, A?ma°x H : 265 nm (ε = 17,900). Example 9 Reaction of Ketone (10) with Methyl agnesium Iodide: 25-0H-D 2 , (11a) , and its Epimer (lb) . Grignard reagent is prepared from magnesium (240 mg) and methyl iodide in anhydrous ether (20 ml) . To one-tenth of this solution (2 ml; 0.5 M -solution of CH^Mgl) ketone (10) (16 mg; 0.04 mmol) in ether (2 ml) is added. The reaction mixture is stirred at room temperature for 2 h under an in-ert atmosphere, then quenched with squeous solution of NH.C1, diluted with benzene and washed with water. The organic layer is separated, dried and evaporated. The crude product is first purified by silica gel column chromatography (elution with 20% ether in benzene) and the mixture of (11a) and (lib) OMPI (16 mg; 96%) thereby obtained is then repeatedly Chrαratographed on HPLC column using 2% 2-ρropanol in hexane as an eluent to separate the 24-stereoisomers, 24-epi-25-0H-D 2 (lib) and 25-0H-D 2 (11a) . Chrαnatography and rec ro atography of each stereoisomer yields 4 mg of (lib) (collected at 68 ml) , 4 mg of (11a) (collected at 74 ml) and 7 mg of the mixture of both epimers. Treatment of 2 mg of the epimer mixture with excess acetic anhydride in pyridine solution at room temperature overnight followed by standard work-up yields the corresponding 3-0-acetates. 25-OH-D 2 (11a) : b]i? 5 + 56.8° (C = 0.2 in EtOH); ^H-NMR, Si 0.57 (s, 18-H) , 1.00 (d, J * = 7 Hz, 28-H) , 1.04 (d, J = 7 Hz, 21-H), 1.15 and 1.17 (2 singlets, 26-H and 27-H) , 3.95 ( , IH, 3 -H) , 4.82 and 5.05 (2 narrow m, 2 x IH, 19(Z)- and 19(E)-H), 5.23-5.43 (m, 2H, 22-H and 23-H) , 6.05 and 6.22 (2 T * doublets, J = 11 Hz, 2 x IH, 7- —H " ■ • * and 6- * ™H ■ ) ; IR, V i ~rcix~: 3401 (O-H) , 1645, 1631 (C=C) , 971 c (trans C=C) ; mass spectrum, m/z (rel. int. ) : 412 (M + , 63) , 394 (M + -H 2 0, iθ) , 379 (M + -H 2 0-I%, 23) , 271 (M + -side chain, 37) , 253 (M + -side chain-H- -m»O, 43) , 136 (100) , 118 (86) , 59 (99) , UV, Λ l E uc t u? H : 265 nm ( £ = 17,950) . 24-epi-25-0H-D 2 (l b) : \ l^+ 50.7° (C = 0.2 in EtOH) , ■ ^-NM , S: 0.57 (s, 18-H) , 0.99 (d, J = 7 Hz, 28-H) , 1.03 (d, J = 7 Hz, 21-H) , -1.14 and 1.16 (2 singlets, 26-H and 27-H) , 3.94 (m, IH, 3 -H) , 4.82 and 5.03 (2 narrow m, 2 x IH, 19 (Z) - and 19 (E) -H) , 5.20-5.40 ( , 2H, 22-H and 23-H) , 6.04 and 6.22 KBr p (2 doublets, J = 11 Hz, 2 x IH, 7-H and 6-H) , IR, V 3401 max * (OH), 1643, 1630 (C=C) , 971 on "1 (trans C=C) ; mass spectrum, m/ (rel. int.): 412 (M + , 62) 394 (M + -H 2 0; 12), 379 (M^^O-Me, 31) , 271 (M + -side chain, 44) , 253 (M + -side chain-H 9 0, 55), 136 (100), 118 (67), 59 (38); UV, Λ Et0H : 265 nm (£= 17,300). It should be noted that from pure provitamin (7_) further synthesis (i.e. the irradiation, isomerization, deketalization and Grignard reaction steps) may be accomplished without chr-aOmatographic purification of any intermediate. Careful ■ column chrcmatography on silica gel before the final separation on HPLC removes all by-products. By reaction of 25-OH-D 2 (11a) with each of the following acylating reagents, acetic anhydride propionic anhydride, benzoyl chloride and .succinic anhydride, under conventional conditions there is obtained, respectively: 25-OH-D 2 -3-acetate 25-OH-D 2 -3,25-diacetate 25-OH-D 2 -3-propionate 25-OH-D 2 -3,25-diprcpionate 25-OH-D 2 ~3-benzoate 25-OH-D -3,25-dibenzoate 25-OH-D_-3-hemisuccinate. By reaction of 25-OH-24-epi-D 2 (lb) with, respectively, -acetic anhydride, benzoyl chloride and diglycolic anhydride, tender conventional conditions, there is obtained, respectively: 25-OH-24-epi-D 2 -3,25-diacetate 25-OH-24-epi-D 2 -3-benzoate 25-OH-24-epi-D 2 -3-hemidiglycolate. Example 10 By coupling of aldehyde (1) with optically active (R)-sulfone A having the structure and subsequent Na/Hg reduction of the product according to the conditions of the experiment described in Example 3, there is obtained cc pound (3_) having the (2 S) configuration in the side ch-ain as shown by the structure. OMPI and treatment of this product with LiAlH. according to the -conditions of Example 5 provides the 5,7-diene (7) having the (24S_)-side chain configuration; by irradiation of this product and subsequent thermal iscmerization according to the conditions of -Examples 6 and 7 there are -obtained, successively, the previtamin D -compound (8) and vitamin D ■compound (9) having the (24S_) configuration. Hydrolysis of compound (9_) thus obtained, according to the conditions of Exartple 8, provides the (24S)-ketcvitamin D compound (10) and from this product, by a Grign-ard reaction, according to Example 9 there is obtained 25-OH-D 2 (structure (11a) in Process Scheme I) . Example 11 Using optically active (S)-isulfone A, having the structure 0 O O L_J in the reactions described in Example 3, there is obtained compound (3) , having the (24R)-side chain structure as shown below and reduction of this product according to the conditions of Exartple 5 provides the 5,7-diene (7_) having the (24R) configuration. Irradiation of (24R)-(_7) according to Example 6 gives the previtamin D analog (8) with the (24R) configuration, and by subsequent thermal iscmerization, according to the conditions of Example 7, there is obtained the vitamin D compound (9) having the (24R)-side chain configuration. Ketal hydrolysis, according to the conditions of Exarrple 8, then yields the (24R)-25-ketovitamin D (10) , and by a reaction of this product with a methyl Grignard reagent ^ ' ilEΛ 25 according to the conditions of Exarrple 9, there is obtained -25-hydroxy-24-epi-vitamin D~ (structure lib, in Process Scheme I). Example 12 Preparations of 5,6-trans-Cαπpounds 25-OH-D 2 (compound 11a) is dissolved in ether containing a drop of pyridine and treated with a solution of iodine in hexane (ca. 0.5 mg/ml) for 15 min. Addition of an aqueous solution of sodium thiosulfate, separation of the organic phase, and evaporation of solvents yields a residue, from which the desired 25-hydroxy-5,6-trans_-vitamin D 2 is isolated by HPLC using a microparticulate silica gel column and 2% of 2-ρropanol in hexane as eluent. By the same procedure, there is obtained from 25-hydroxy-24-epi-D 2 the corresponding trans-isomer, namely 25-hydroxy-5,6-trans-24-epi-D 2 . From 25-OH-D 2 3-acetate, there is obtained 25-OH-5,6-trans-D 3-acetate, and from 25-OH-24-epi-D 2 3-acetate there is obtained 25- H-5,6-trans-24-epi-D 3-acetate by the application of the above isorrerization procedure. Acylation of 25-OH-5,6-trans-D 2 or 25-OH-5,6-trans-24-epi-D > under conventional conditions provides the respective acylates, such as: 25-OH-5,6-trans-D 2 -3-acetate 25-OH-5,6-trans-D 2 -3,25-diacetate 25-OH-5,δ-trans-D^-S-benzoate 25-OH-5,6-trans-D -3-acetate-25-benzoate 25-OH-5,6-trans-24-epi-D 2 -3-acetate 25-OH-5 , 6-trans-24-epi-D-,-3 , 25-dibenzoate . Example 13 Hydrolysis of 5,7-diene-25-ketal (ccmpound (7A) , where X,=H) using the conditions described in Example 8 gives 3β -hydroxy-24-methyl 27-norcholesta-5 , 7 , 22-trien-25-one {compound 7B, where X,=H) . Irradiation of this product under conditions analogous to those of Example 6 gives the 25-keto previtamin D„ analog characterized by structure (8B) , where X =H. Heating of (8B) in an ethanol .solution according to the conditions of Exarrple 7 provides the 25-keto vitamin D 2 product (compound 10, where X=H). > —~ 1 Example 14 Reaction of 3β-hydroxy-24~-methyl-27-nor-ctølesta-5,7,22- trien-25-one (compound (7B) , "where X,=H) as -obtained in Exarrple 13 with methyl magnesium bromide in accordance with the conditions of Example 9 gives 24-methylcholesta-5,7,22- triene-3β,25-diol (compound (7C) , where X- X-^H) . Irradiation of this product, according to the conditiαs of Exarrple 6, gives 25-hydroxy previtamin D_ product characterized by structure (8C, where X,=X 2 =H) . Thermal isαnzerlation of this previtamin using the conditions of Example 7 provides the 25-hydroxyvitamin D_ compound (11; where X =X =H) . Processing of 24-methylcholesta-5,7,22-triene-3β,25-diol 3,25-diacetate (cαipound 7C, X =X 2 =acetyl) through the reaction steps involving irradiation and thermal iscmerization according to the conditions of Examples 6 and 7 respectively gives the 25-OH-D- 3,25-diacetate epimers (compound (11) , where X =X =acetyl) . Exarrple 15 Using the conditions analogous to those of Example 9, Mg is r-eacted with the following halides, ethyl iodide; propyl iodide; isopropyl bromide; butyl bromide; sec.-butyl iodide; isobutyl iodide; pentyl iodide; and phenyl bromide, to obtain the corresponding Grign.ard reagents. By reaction of each of these reagents with ketone (10) by procedures analogous to that of Example 9, there are obtained, respectively, the following products: compound (12) where X^X^H, Y=ethyl compound (12) where X =X 2 =H, Y=propyl compound (12) where X,=X 2 =H, Y=isopropyl compound (12) where X-.=X 2 =H, Y=butyl compound (12) where X =X 2 =H, Y=sec.-butyl compound (12) where X =X 2 =H, compound (12) where X =X_=H, Y=pentyl compound (12) where X =X =H, Y=phenyl > — X - * . By reaction of ketone (10) with i-sotopically labeled 13 14 2 methyl Grign-ard reagents, namely CHJMgl, OLMgl, C E j Mgl, C H_MgI, under conditions analogous to those of Example 9, there are obtained, respectively, the following products: compound (12) where cαrpound (12) where compound (12) -where compound (12) where characterized by isotopic substitution in the methyl group of carbon 26 of the molecule. -$υ E OMPI

Claims: Claims i. A process for preparing a compounds having the formula wherein X.. and X- are each selected from hydrogen or acyl, and Y is an alkyl or aryl group, which comprises, irradiating a 5,7-diene steroid of the formula wherein X.. is hydrogen or acyl, with ultraviolet light to obtain the corresponding previtamin D product, iso erizing s^d previtamin D •compound in an inert solvent at a temperature fro about room temperature to about 100°C for a time sufficient to reach equilibrium, thereby obtaining a vitamin D compound of the formula ■ where X.. is hydrog-en or acyl, subjecting s.aid vitamin D compound to acid catalyzed hydrolysis to remove the ketal protecting group thereby ■obtaining the corresponding ketone, subjecting said ketone to alkylation with a reagent of the formula YMg- halide or YLi, where Y is an alkyl or aryl group and the halide is chloride, bromide or iodine, and, optionally, OMPI acylating one or both free hydroxy groups. 2. The process of Claim 1 wherein X, and 2 are hydrogen and Y is methyl. The process according to Claims 1 or 2, wherein the ketal hydrolysis step precedes the irradiation step, and where the resulting 25-ketone is then subjected sequentially to the irradiation, isomerization and alkylation steps. The process according to Claim 3, wherein the alkylation reaction precedes the irradiation step, and where the resulting 25-hydroxy-5,7-diene resulting frcm the alkylation is subjected sequentially to the irradiation and isomerization reactions. 5. The process of Claims 1 or 2 wherein the 5,7-diene steroid has the 24(R) configuration. 6. The process of Claims 1 or 2 wherein the 5,7-diene steroid has the 24(S) configuration. 7. The process of Claims 3 or 4, wherein the 5,7-diene steroid has the (24R) or the (24S) configuration. 8. Coπpounds having the where N is a steroid nucleus selected from the group wherein X.. is hydrogen or acyl. 9. The compounds of Claim 8 wherein the asymetric center at carbon 24 has the (R) configuration. 10. The compounds of Claim 8 wherein the asymetric center at carbon 24 has the (S) configuration. 11. Compounds having the wϊjerein X, is hydrogen or acyl, and R is selected from the group consisting of wherein X~ is hydrogen or acyl, and Y is an alkyl or aryl group. 12. The compounds of Claim 11 wherein X, and X~ are hydrogen or acetyl and Y is methyl. 13. The compounds of Claims 11 or 12 wherein the asymetric center at carbon 24 has the (R) configuration. 14. The cαrpounds of Claims 11 or 12 wherein the asymetric center at carbon 24 has the (S) configuration. 15. Coπpounds having the formula wherein X-. is hydrogen or acyl, and where R is selected from the group consisting of wherein X~ is hydrogen or acyl and Y is an alkyl or aryl group. 16. The compounds of Claim 15 wherein X, and X_ are hydrogen or acetyl and Y is methyl. 17. The -compounds of Claims 15 or 16 wherein the asymetric center at carbon 24 has the (R) configuration. OMPI 18. The compounds of Claims 15 or 16 wherein the asymetric center at carbon 24 has the (£>) configuration. 19. Compounds having the wherein X, is hydrogen or acyl, and where R is selected from the group consisting of wherein X~ is hydrogen or acyl and Y is alkyl or aryl, with the proviso that when Y is methyl, X.. and X_ cannot both be hydrogen. 20. The coπpounds of Claim 19, wherein R is ' the group • and X, is hydrogen, acetyl or benzoyl. 21. The compounds of Claim 20 wherein the asymetric center at carbon 24 has the (R) configuration. 22. The cαrpounds of Claim 20 wherein the asymetric center at carbon 24 has the (S_) configuration. 23. The compounds of Claim 19 wherein R is the group and X.. is hydrogen, acetyl or benzoyl. ^ 24. The -compounds of Claim 23 wherein the asymetric center at carbon 24 has the (R) configuration. 25. The compounds of Claim 23 wherein the asyπetric center at carbon 24 has the (S) configuration. 26. The compounds of Claim 19 wherein R is the group 27. The ccttpounds of Clam 26 ■ where n X, is selected frαn the group consisting of acetyl, benzoyl, succinyl, and diglycolyl, and 2 is selected from the group consisting of hydK5gen, acetyl, benzoyl, -succinyl .and diglycolyl * and Y is methyl. 28. The cαrpounds of Claims 26 or 27 wherein the asymetric center at carbon 24 has the (R) configuration. 29. The cαrpounds of Claims 26 or 27 wherein the asymetric center at carbon 24 has the (S) configuration. 30. Cαrpounds having the formula ^ different, are hydrogen or acyl and Y is an alkyl or aryl group. 31. The coπpounds of Claim 30 wherein the asymetric center at carbon 24 has the (R) configuration. 32. The compounds of Claim 30 wherein the asymetric center at carbon 24 has the (S) configuration. 33. The compound of Claim 31 wherein X. and X 2 are hydrogen and Y is methyl. 34. The cαrpound of Claim 32 wherein X, and X 2 are hydrogen and Y is methyl. 35. The cαrpounds of Claim 26 wherein X. and X_ are hydrogen and Y is an isotopically labelled methyl group. 36. The cαrpounds of Claim 35 wherein Y is selected from 13 14 2 3 CH 3 , CH 3 , CH. and CH..

Inventors: DELUCA HECTOR F, MORZYCKI JACEK W, SCHNOES HEINRICH K, DELUCA, HECTOR, F., MORZYCKI, JACEK, W., SCHNOES, HEINRICH, K.
Applicants: WISCONSIN ALUMNI RES FOUND, WISCONSIN ALUMNI RESEARCH FOUNDATION
Application year: 1983
Main classification: C07J9
IPC codes: A61K31, A61P3, A61P43, C07C67, C07C401, C07D317, C07J1, C07J9, C07J17, C07J43, C07J53, C07J71