CH667087A5 - UNSATURATED 1-HYDROXYVITAMIN D-LINKS IN THE SIDE CHAIN. - Google Patents

Description

The invention relates to 1-hydroxyvitamin D compounds which contain a 22, 23-cis double bond in the side chain.

10 State of the art

Because of the well-known and clearly identified activity of la-hydroxyvitamin D compounds in regulating calcium and phosphate homeostasis in animals or humans, there has been an interest in the production of the 15 natural metabolites and in the research of analog compounds with valuable medicinal properties. This has resulted in the production of a variety of compounds (see, e.g., DeLuca et al, Topics in Current Chemistry, Volume 83, page 1 (1979); Ann. 20 Rev. Biochem. 52, 411 (1983); Yakhimovich, Russian Chem. Rev. 49, 371 (1980), some of which, for example la-hydroxy-vitamin D3 (US Pat. No. 3,741,996) or la, 25-dihydroxy-vitamin D3 (US Pat. No. 3,697,559), are already used in the Interest in such compounds continues, in particular after it has now been recognized that, in addition to their classic function as regulators of calcium homeostasis, la, 25-dihydroxyvitamin D3 and its analogue compound la-hydroxy vitamin D3 are also cell differentiation methods 30 and are able to inhibit the growth and proliferation of certain malignant cells [Suda et al, U.S. Patent 4,391,802; Suda et al., Proc. Nati. Acad. Sci. USA 80, 201 (1983) ; Reitsma et al, Nature, Volume 306, pages 492-494 (1983)]. There are growing indications hen, who show, 35 that the expression of the biological activity of vitamin D metabolites and analogue compounds includes the binding to an intracellular receptor protein in one stage of the overall process (cf. DeLuca et al, as indicated above). The high affinity for this receptor protein is therefore a prerequisite for high efficacy, and the desirable vitamin D analogue compounds are those which effectively compete with the natural hormone 1,25- (OH) 2D3 for the receptor binding site.

Known side chain unsaturated vitamin D-compound 45 fertilizers include the hydroxy derivatives of vitamin D2, namely 25-hydroxyvitamin D2 (US Pat. No. 3,585,221), la, 25-dihydroxyvitamin I> 2 (US Pat. No. 3,880,894), 24 -Hydroxy- and 24,25-dihydroxyvitamin D2 (Jones et al, Arch. Biochem. Biophys. 202, 450 (1980)), la-Hydroxy vitamin D2 (US Pat. No. 3,907,843) and certain 24-demethylvitamin D2 compound -dungen (U.S. Patent 3,782,062; Bogoslovskii et al, J. Gen. Chem. USSR 48 (4), 828, (1978); Chem. Abstr. 89, 163848j and 89, 209016s). An example of a compound having a cis-double bond in the side chain is also known (Bogos-55 lovskii et al, location given above).

Presentation of the invention

The new compounds according to the invention are characterized by the following structures A and B:

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wherein the hydroxyl group (or protected hydroxyl group) on carbon atom 1 may have the stereochemical a or β orientation, and wherein X, and X2 represent hydrogen atoms or a hydroxyl protecting group, e.g. Acyl, alkylsilyl, methoxymethyl or tetrahydropyranyl).

These compounds are thus characterized by a 22.23-cis double bond (22Z double bond) in the side chain.

Preferred hydroxyl protecting groups are acyl (alkano-yl) radicals with 1 to 6 carbon atoms (e.g. formyl, acetyl, propionyl, butyryl, etc.) or aroyl radicals, such as benzoyl, halogen or nitrobenzoyl or carboxyalkanoyl radicals with 2 to 6 carbon atoms, such as oxalyl, malonyl, succinyl, glutaryl or adipyl.

The compounds of the above-mentioned type A with an la-hydroxyl group are particularly preferred because these compounds have an unexpectedly high affinity for the receptor protein. These compounds, like the 1-hydroxyvitamin D analogue compounds, are related to the known 1-hydroxylated vitamin D compounds, but it was believed that due to the presence of a 22Z double bond, they would have low receptor affinity or no affinity at all , since this 22.23-cis double bond forces the side chain into a quite different geometry than that which is assumed for the fully saturated side chain, as is the case in la-hydroxy vitamin D3 or in the natural hormone l, 25- (OH) 2D3 occurs, where both compounds are known to have a high affinity for the receptor protein (DeLuca et al, location specified above). Surprisingly and unexpectedly, however, it was found that the 1 a-hydroxy-22Z-dehydro compounds actually have a higher affinity for the receptor than the la-hydroxy vitamin D3.

The synthesis of the new compounds according to the invention is summarized in process scheme I. In the following description of this process and in the examples, the connection details by numbers (e.g. (X), (2), (3), .. etc.) refer to the structures numbered in this way in process scheme I or in the description.

The starting material for the synthesis process is the diene-protected aldehyde of structure (1), in which R is a methoxymethyl radical. This starting material is made from ergosterol by the method of Morris et al. (J. Org. Chem. 46, 3422 (1981)). The reaction of a compound (1) with a Wittig reagent of the structure given below

(CH3) 2CHCH2CH2-PPh3Br

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in an organic solvent and in the presence of a strong base gives the product (2) which has the desired 22Z-olefinic side chain.

By removing the hydroxy protecting group under acidic conditions, the product (2) is converted into the compound (3), which is subjected to reduction with a strong hydride reducing agent in an organic solvent to give the 5,7-diene sterol, compound (4 ), to obtain.

Irradiation of this material, which is dissolved in an organic solvent, with ultraviolet light converts the 5,7-diene into the corresponding pre-vitamin transition compound, which after isolation and purification leads to the 22Z-dehydro-vitamin D3 analogue compound of the structure (5 ) (R = H) isomerized by careful heating in an organic solvent at a temperature in the range from room temperature to reflux temperature.

The transition compound of structure (5) is a known vitamin D analogue compound that was recently described by Bo-goslovskii et al. (J. Gen. Chem. USSR, 48 (4), 828 (1978))

was made using a less convenient process.

The transition compound (5) is then converted to the desired end products by 1-hydroxylation using the general procedure of DeLuca et al. (U.S. Patents 4,195,027, 4,260,549). Compound (5) is first tosylated to give the 3β-tosylate of structure (6), which is then solvolyzed in buffered methanol to give the new 3,5-cyclovitamin D intermediate of structure (7) (R = H). This product is then treated with selenium dioxide and tert-butylhydroxy oxide in an organic solvent to obtain as the main product the la-hydroxycyclovitamin D analogue compound of structure (8), wherein R is a hydroxyl group. It is noteworthy that this allyl hydroxylation at carbon atom 1 proceeds without complications with respect to a compound, such as intermediate (7), which has the unusual cis double bond in the side chain with two allyl positions.

The 1-hydroxycy-clovitamin D product obtained as a transition compound is then solvolysed in glacial acetic acid in order to combine the 5,6-cis and 5,6-trans-vitamin D compounds of structures (9) and (10) obtained, which have a 3ß-acetoxy function. These acetate derivatives 0 and (10) are then separated and individually hydrolyzed in a mild base to produce the desired free diol products, which are characterized by structures (11) and (12), wherein X represents hydrogen.

3rd

5

10th

15

20th

25th

30th

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40

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Jferfahrmschem I

CM0

(1) RÏCHjOCHJ

«£.} R ° CM.OCMj. tlIR.K

W

15) R »H (S) R» Ts

(7J R «M Î @ J R» OI

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It was found that the 1-hydro-xylated cyclovitamin D product described above, of which the compound la-hydroxy-3,5-cyclo vitamin D of structure (8) is the main component. also contains a small amount of the corresponding 1β-hydroxy-3,5-cyclovitamin D epimer, i.e. of the product of the structure given below (13). After solvolysis in glacial acetic acid, this 1β-hydroxy epimer leads to the corresponding 5,6-cis and 5,6-trans-β-hydro-

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xy-3ß-acetoxy-vitamin D analogue compounds, which are indicated by structures (14) and (_15) below, which, if desired, can also be isolated from the solvolysis mixture by chromatography and then in a weak one Base can be hydrolyzed separately as described above to give the β, 3β-diol epimers which are characterized by structures (16) and (j / 7).

• do »

HjO'4'w © M CU} X, "Ae (Ifi) X.-M

caî Ks ° âs «US K," H

In practice, it has been found that the 5,6-trans-β-hydroxy derivative of the above structure (] _5) often represents such a small component of the solvolysis mixture that its direct isolation is unsuitable

65 is expensive. In such cases, it is generally more convenient to prepare the 5,6-trans-β-hydroxy analog compounds by the known isomerization process catalyzed by iodine according to Verloop et al. (Ree. Trav. Chim. Pays-

Bas 78, 1004 (1969)) from the corresponding 5,6-cis compounds. Such treatment of product (14) with a catalytic amount of iodine in a hydrocarbon or ether solvent gives the 5,6-trans product (15), and the analogous isomerization of (16) provides the corresponding trans compound of structure ( 17).

Acylated derivatives of the products according to the invention are easily produced by conventional processes. The monoacylates of structures (9), (10) or (14) and (15) result directly from solvolysis; such monoacylates can also be acylated to the corresponding 1,3-diacylates or desired acylates can be prepared after conventional acylation of the free diols of structures (11), (12) or (16) and (17). It should also be noted that the 1-hysroxycyclovitamin D intermediates of structure (8) or (13) can be acylated to the corresponding 1-O-acyl derivatives. Subsequent solvolysis of such acyl derivatives in glacial acetic acid or in an acidic aqueous medium (for example by the method of DeLuca et al, US Pat. No. 4,195,027) gives the 5,6-cis and 5,6-trans-1-hydroxyvitamin D analog compounds than their 1,3-di-O-acyl or lO-acyl derivatives.

A remarkable property of the new compounds according to the invention is their high affinity for the protein receptor, as expressed by the high binding affinity. It was believed that the change in side chain geometry dictated by the presence of a 22.23-cis double bond (22Z double bond) would abolish binding affinity, or at least lead to a significant decrease in binding affinity, it is known (e.g. see DeLuca et al, Topics in Curr. Chem., literature cited above) that even minor changes in stereochemistry (e.g. the change from 24R-hydroxy to 24S-hydroxy) lead to significant differences in the binding properties and the connections were made for the purpose of confirming this assumption. Surprisingly, it was found through competitive binding experiments (carried out according to the protocol of Shepard et al, Biochem. J. 182, 55 (1979)) that the la-hydroxy-22Z-dehydro-analogue compound of structure (11) is a 3 to 5 fold has a higher affinity for the receptor protein than la-hydro-xyvitamin D3, a well-known and very effective vitamin D3 derivative. The other products according to the invention show a lower, but still substantial, binding affinity, which is in any case higher than that of the corresponding compound, which contains a saturated side chain, as occurs in natural metabolites or other known analogue compounds.

Because of their high binding affinity, the compounds according to the invention can be highly suitable substitutes for the known metabolites in the therapy or prophylaxis of irregularities in the calcium balance, such as in rickets, hypoparathyroidism, bone dystrophy, bone softening or osteoporosis in humans or in related calcium deficiency diseases (e.g. milk fever) Animals. Accordingly, these compounds can be used in the treatment of certain malignant diseases, e.g. in human leukemia. The analog compound which is indicated by the structure (U) in process scheme I or the corresponding 5,6-trans compound of structure (12) or its acylated derivatives is particularly preferred for the applications indicated above. Appropriate mixtures of the above products can also be used in human or veterinary medicine, e.g. the combination of the products represented by structures (11) and (12).

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For therapeutic purposes, the compounds can be used by any conventional route of administration and in any suitable form for the selected mode of administration. The compounds can be formulated with any compatible and harmless pharmaceutical carrier in the form of pills, tablets, gelatin capsules or suppositories or as solutions, emulsions, dispersions or suspensions in harmless solvents or oils, and such a formulation can also have other therapeutically effective effects and contain advantageous components that are appropriate for the specific application forms. For human applications, the compounds are advantageously administered in amounts of from about 0.5 to about 10% per day 15, the specific dose being determined according to the compound specifically administered, the disease to be treated and the disease development, the condition and the Patient response behavior, as is familiar to those skilled in the art.

20th

The present connection is further described in the following detailed description, which description is only illustrative and does not limit the appended claims. In this description, the 25 physico-chemical information was obtained using the methods and apparatus described. High pressure liquid chromatography (HPLC) was performed on a model ALC / GPC 204 from Waters Associates using a Zorbax-Sil column (DuPont) 30 (6.2 mm x 25 cm, flow rate 4 ml / min, 1500 psi).

Column chromatography was performed on silica gel 60, 70-230 mesh ASTM (Merck). Preparative thin layer chromatography (TLC) was carried out using Sili-35 ka 60 PF-254 (20 x 20 cm plates, 1 mm silica gel). Irradiations were performed using a Hanovia 608A36 mercury arc lamp equipped with a Vycor filter. All reactions are preferably carried out under an inert gas atmosphere (e.g. 40 argon).

(22Z7 -iß- (methoxymethoxy) -5a, 8a- (4-phenyl-l, 2, -arazole) -cholesta-6,22-diene (2)

Isopentylphosphonium bromide 45 [(CH3) 2CHCH2CH2PPh3Br] (1.67 g, 4.04 mmol) in anhydrous tetrahydrofuran (73 ml) was treated with n-butyllithium (1.7 M solution in hexane, 2.42 ml, 4.11 mmol). treated at 3-5 ° C with stirring. After stirring at room temperature for 1 hour, the orange-red colored solution was cooled to 50 ° C. and aldehyde (V) (1.84 g, 3.36 mmol) in anhydrous tetrahydrofuran (24 ml) was added. The colorless reaction mixture was stirred at room temperature overnight and then poured into water and extracted with benzene. The organic extract was washed with 5% 55 HCl, saturated sodium bicarbonate and water, dried (Na2S04) and concentrated under reduced pressure to an oil which was purified on a column with silica gel. Elution with a mixture of benzene ether (94: 6) provided the adduct (2) (1.38 g, 68%) as a 60 foam: NMR § 0.83 (3H, s, 18-H3), 0 , 89 and 0.91 (6H, each d, J = 6.8 Hz, 26-H3 and 27-H3), 0.97 (3H, d, J = 6.8 Hz, 21-H3), 0, 98 (3H, s, 19-H3), 3.30 (IH, dd, J] = 4.4 Hz, J2 = 14 Hz, 9-H), 3.38 (3H, s, OCH3), 4, 33 (1H, m, 3-H), 4.70 and 4.81 (2H, ABq, J = 6.8 FIz, 0CH, 0), 5.21 (2H, br 65 m, 22-H and 23 -H), 6.23 and 6.39 (2H, ABq, J = 8.5 Hz, 6-H and 7-H), 7.41 (5H, br m, Ar-H); IR: 1756, 1703, 1601, 1397, 1046 cm-1; Mass spectrum m / z 601 (M +, <1%, 426 (4), 364 (61), 349 (16), 253 (18), 251 (18), 119 (PhNCO, 100).

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6

(22Z) -5a, 8a- (4-phenyl-1,2-urazole) cholesta-6,22-diene-3 $ -ol (3).

A solution of the adduct (2) (601 mg, 1 mmol) and p-toluenesulfonic acid (523 mg, 2.75 mmol) in a mixture of methanol (20 ml) -THF (12 ml) was stirred at room temperature for 2 days. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted a few times with benzene. The extracts were washed with water, dried (Na2S04) and evaporated under reduced pressure. Purification of the crude product by column chromatography (benzene ether 70:30 as eluent) gave the hydroxy adduct (3) (550 mg, 99%, in the form of a foam: NMR 5 0.83 (3H, s, 18-H3) , 0.89 and 0.91 (6H, each d, J = 6.8 Hz, 26-H3 and 27-H3), 0.95 (3H, s, 19-H,). 0.98 (3H, d, J = 6.8 Hz, 21-H3), 3.16 (1H, dd, J, = 4.4 Hz, J2 = 14 Hz, 9-H), 4.44 (1H, m, 3- H), 5.22 (2H, br m, 22-H and 23-H), 6.22 and 6.39 (2H, ABq, J = 8.5 Hz, 6-H and 7-H), 7 , 40 (5H, br m, Ar-H); IR: 3447, 1754, 1700, 1600. 1397 cm ~ '; mass spectrum, m / z (557 (M +, <1%), 382 (35), 349 ( 33), 253 (20), 251 (33), 119 (100), 55 (82).

(22Z) -Cholesta-5,7,22-trien-3ß-ol (4)

The adduct (3) (530 mg, 0.96 mmol) was added to the diene

(4) transferred by reduction with lithium aluminum hydride (1 g) in tetrahydrofuran (60 ml) under reflux temperature for a period of 18 hours. After the conventional work-up, the product was purified by chromatography on silica (benzene ether 94: 6 as eluent) to give the pure diene (4) (290 mg, 76%) after recrystallization from ethanol: melting point 148-151 ° C. ; Md24 = - 132 (c = 0.9, CHC13); NMR S 0.66 (3H, s, 18-H3), 0.90 and 0.91 (6H, each d, J = 6.8 Hz, 26-H3 and 27-H3), 0.96 (3H, s, 19-Hj), 0.98 (3H, d, J = 6.9 Hz, 21-H3), 3.64 (1H, m, 3-H), 5.20 (2H, br m, 22 -H and 23-H), 5.39 and 5.57 (2H, ABq, J = 6 Hz, 7-H and 6-H); W \ m.M 281 nm, IR: 3346, 1463, 1375, 1364, 1067, 1040, 831 cm- ', mass spectrum. m.z 382 (M +, 100), 349 (65), 323 (32), 271 (15), 253 (30).

(5Z, 7E, 22Z) -9,10-secocholesta-5,7,10 (19), 22-tetraen-3ß-ol d)

Irradiation of the 5,7-diene (4) (150 mg, 0.39 mmol), which was dissolved in ether (120 ml) and benzene (30 ml) (degassed with argon for 40 minutes), was at 0 ° C for 13 minutes using a UV lamp and a Vycor filter. HPLC (1% 2-propanol in hexane) of the mixture obtained gave the pro vitamin (56.9 mg, 38%) as a colorless oil: NMR 5 0.75 (3H, s, 18-CH3), 0.90 and 0.91 (6H, each d, J = 6.7 Hz, 26-H3 and 27-H3), 0.99 (3H, d, J = 6.8 Hz, 21-H3), 1.64 ( 3H, s, 19-H3), 3.90 (1H, m, 3-H), 5.20 (2H, br m, 22-H and 23-H), 5.69 and 5.95 (2H, ABq, J = 12 Hz, 7-H and 6-H); UVX.max 261 nm, Xmm 234 nm.

Thermal isomerization of the provitamin intermediate (56 mg, 0.15 mmol) in refluxing ethanol (3 hours) gave the oily vitamin analog compound (5) (43 mg, 77%) after separation by HPLC. NMR 5 0.60 (3H, s, 18-H3), 0.89 and 0.90 (6H, each d, J = 6.7 Hz, 26-H3 and 27-H3), 0.97 (3H, d, J = 6.6 Hz, 21-H3), 3.96 (1H, s, 3-H), 4.82 and 5.05 (2H, each narrow multiplets, 19-H2), 5.20 ( 2H, br m, 22-H and 23-H), 6.04 and 6.24 (2H, ABq, J = 11.4 Hz, 7-H and 6-H); mamax 265.5 nm, Xmin 228 nm; IR: 3427, 1458, 1379, 1048, 966, 943, 892 cm-1; Mass spectrum, m / z 382 (M +, 21), 349

(5), 271 (8), 253 (14), 136 (100), 118 (82).

1-hydroxylation of compound (5)

Freshly recrystallized p-toluenesulfonyl chloride (50 mg,

0.26 mmol) was added to a solution of the vitamin (5) (50 mg, 0.13 mmol) in anhydrous pyridine (300 fj.1). After 30 hours at 4 C, the reaction mixture was poured into ice-saturated NaHC03 with stirring . The mixture 5 was stirred for 15 minutes and then extracted with benzene. The organic extract was washed with NaH-CO 3, saturated copper sulfate and water, dried (Na-2 SO 4) and concentrated under reduced pressure to obtain the oily tosylate (6). The crude tosylate (6) was treated with 10 NaHCO 3 (150 mg) in anhydrous methanol (10 ml) and the mixture was stirred at 55 ° C for 8.5 hours. After cooling and concentrating to about 2 ml, the mixture was diluted with benzene (80 ml), washed with water, dried (Na2S04) and evaporated under reduced pressure. The oily 3,5-cyclovitamin D compound (7) thus obtained was sufficiently pure to be used for the subsequent oxidation step without any purification. To a vigorously stirred suspension of Se02 (5.1 mg, 0.046 mmol) in anhydrous CH2C12 (5 ml) 20 was added tert-butyl hydroperoxide (16.5 ml.1, 0.118 mmol). After 30 minutes, anhydrous pyridine (50 ml) was added and the mixture was stirred for a further 25 minutes at room temperature, diluted with CH2C12 (3 ml) and cooled to 0 ° C. The crude 3,5-cyclovitamin product (7) in 25 CH2C12 (4.5 ml) was then added. The reaction proceeded at 0 ° C for 15 minutes and the mixture was then allowed to warm slowly (30 minutes) to room temperature. The mixture was transferred to a separatory funnel and shaken with 30 ml of 10% NaOH. Ether (150 ml) 30 was added and the separated organic phase was washed with 10% NaOH, water and dried over Na2SO4. Concentration to dryness under reduced pressure gave a yellow oily residue, which was purified over a silica gel TLC plate by development in a 7: 3 mixture of hexane-ethyl acetate to give the 1-hydroxycyclovitamin product (20 mg , 37%): NMR 6 0.59 (3H, s, 18-H3), 0.63 (1H, m, 3-H), 0.89 and 0.90 (6H, each d, J = 6, 9 Hz, 26-H3 and 27-Hj), 0.96 (3H, d, J = 6.9 Hz, 21-H3), 3.25 (3H, s, 40 -OCH3), 4.17 (2H , m, 1-H and 6-H), 4.96 (1H, d, J = 9.3 Hz, 7-H), 5.1-5.4 (4H, br m, 19-H2, 22 -H and 23-H); Mass spectrum, m / z 412 (M +, 26), 380 (48), 339 (22), 269 (28), 245 (20), 135 (100).

This product is composed predominantly of the 45 la-hydroxycyclovitamin D compound of structure (8) and a small amount of the corresponding beta-hydroxy epimer (13). These components can be separated at this stage if desired, but such separation is not required.

50 The 1-hydroxycyclovitamin product (18 mg) obtained according to the above instructions was heated in glacial acetic acid (0.8 ml) (55 ° C./15 minutes), the mixture was neutralized (ice / saturated NaHC03) and extracted with benzene and ether in order to after HPLC (1.5% of 2-propanol in hexane as the 55 eluent) separation, give the pure 3β-acetoxy vitamins (9) (6.60 mg, 34%, elution at 42 ml), (10) (4.20 mg, 22%, elution at 50 ml) and (14) (1.44 mg, 7%, elution at 36 ml).

Compound (9): NMR 6 0.60 (3H, s, 18-H3), 0.90 and 60 0.92 (6H, each d, J = 7.0 Hz, 26-H3 and 27-H3), 0.97 (3H, d, J = 6.8 Hz, 21-H3), 2.04 (3H, s, -OCOCH3), 4.41 (1H, m, 1-H), 5.02 (1H , narrow multiplets, 19-H), 5.1-5.4 (4H, br m, 3-, 19-, 22- and 23-H), 6.03 and 6.35 (2H, ABq, J = 11.4 Hz, 7-H and 6-H); UVA, max 254.5 nm, Xmin 227.5 nm; Mas-65 spectrum, m / z 440 (M +, 10), 380 (72), 362 (7), 269 (31), 251 (12), 135 (100), 134 (99).

Compound (10): NMR S 0.60 (3H, s, 18-H3), 0.90 and 0.91 (6H, each d, J = 7.0 Hz, 26-H3 and 27-H3), 0 , 97 (3H,

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d, J = 6.9 Hz, 21-H3), 2.05 (3H, s, -OCOCH3), 4.49 (1H, m, d, J = 6.8 Hz, 21-H3), 4, 23 (1H, m, 3-H), 4.43 (1H, m, 1-H),

1-H), 5.00 and 5.14 (2H, each narrow multiplets, 19-H->), 5.00 (IH, narrow multiplets, 19-H), 5.1-5.4 (3H, br m, 19—,

5.20 (3H, br m, 3-, 22- and 23-H), 5.82 and 6.59 (2H, ABq, 22- and 23-H), 6.02 and 6.39 (2H, ABq, J = 11.4 Hz, 7-H

J = 12.0 Hz, 7-H and 6-H); U VXmax 270 nm, amine 228 nm; and 6-H); UV Xm.dK 264.5 nm, Xmin 227.5 nm, mass spec

Mass spectrum, m / z 440 (M +, 4), 380 (30), 269 (10), 135 5 truniî m / z 393 (M +, 21), 380 (8), 287 (6), 269 (7), 251 (5), 152

(100), 134 (52). (36), 134 (100). Elution volume 39 ml).

Compound (14): NMR 5 0.58 (3H, s, I8-H3), 0.89 and Compound (12): NMR S 0.61 (3H, s, I8-H3), 0.89 and

0.90 (6H, each d, J = 6.9 Hz, 26-H, and 27-H,), 0.96 (3H, 0.91 (6H, each d, J = 7.0 Hz, 26 -H3 and 27-H3), 0.97 (3H,

d, J = 6.9 Hz, 21-Hj), 2.06 (3H, s, -ÖCOCH3), 4.16 (1H, m, d, J = 6.9 Hz, 21-H3), 4, 25 (1H, m, 3-H), 4.51 (1H, m, 1-H),

1-H), 4.98 (2H, m, 3-H and 19-H), 5.1-5.4 (3H, br m, 19-, 10 4.98 and 5.13 (2H, each narrow multiplets, 19-H2), 5, 21

22- and 23-H); UV Ä, m.lx 263 nm, Xm-m 227 nm; Mass Spec- (2H, br m, 22-H and 23-H), 5.89 and 6.59 (2H, ABq,

tram m / z 440 (M +, 32), 380 (78), 362 (21), 269 (28), 251 (19), J = 11.5 Hz, 7-H and 6-H); UV 273 nm , lmin 229.5 nm;

135 (100), 134 (82). Mass spectrum, m / z 398 (M +, 17), 380 (4), 287 (5), 269 (5),

251 (4), 152 (29), 134 (100). (Elution volume 38 ml).

Hydrolysis of the 3β-acetoxy group in compounds (9), 15 compound (16): NMR 5 0.60 (3H, s, I8-H3), 0.89 and

(10) and (14) 0.91 (6H, each d, J = 7.0 Hz, 26-H3 and 27-Hj), 0.97 (3H,

Each of the 3β-acetoxy derivatives (9), (10) and (14) was d, J = 6.9 Hz, 21-H3), 4.10 (1H, m, 3-H), 4.36 ( 1H, m, 1-H),

separates hydrolyzed using the same procedure 5.01 (1H, d, J = 2 Hz, 19-H), 5.1-5.4 (3H, br m, 19-, 22-

has been. A solution of 3β-acetoxy vitamin (0.7-6 mg) in and 23-H), 6.06 and 6.45 (2H, ABq, J = 11.3 Hz, 7-H and

Ethanol (0.1 ml) was washed with 10% KOH in methanol (20 6-H); UVA, max 262.5 nm, A, min 226.5 nm; Mass spectrum,

(0.8 ml) was treated and the mixture was applied to m / z 398 (M +, 20), 380 (19), 269 (11), 251 (10), 152 (100), 134 for 1 hour

50 C heated. After the usual workup and the ab- (60). (Elution volume 32 ml).

subsequent HPLC purification (8% of 2-propanol in He- If desired, the inventive

xan as eluent) the corresponding 1-hysenic compounds were easily recrystallized from

droxyvitamine obtained, namely: 25 neten solvents such as ether, hexane, alcohols and

Compound (JJ_): NMR 5 0.59 (3H, s, I8-H3), 0.89 and mixtures thereof can be obtained as known to those skilled in the art

0.90 (6H, each d, J = 7.0 Hz, 26-H3 and 27-H3), 0.96 (3H, this area is clear.

Claims (5)

667 087 2. Compounds according to claim 1, wherein X) and X2 are hydrogen atoms. 2nd PATENT CLAIMS 1. Compounds of formula IA or IB (IA) or (IB), wherein X and X2 are hydrogen atoms or a hydroxy protecting group, and wherein the substituent on carbon atom 1 may have the stereochemical a or β orientation. 3. Compounds according to claim 1, characterized in that X) and / or X2 means acyl. 4. Compounds according to claim 3, wherein at least one of the radicals Xi and X2 is acetyl. 5. Compounds according to any one of claims 1 to 4 of the formula • «ö 6. A compound according to claim 5, wherein X! and X2 are hydrogen atoms. 7. Compounds according to claim 1 of the formula A ^ 8. A compound according to claim 7, wherein X] and X2 are hydrogen atoms. 9. A pharmaceutical composition which contains at least one of the compounds according to any one of claims 1 to 8 or a mixture thereof together with a pharmaceutically acceptable excipient. 10. A cyclovitamine of the formula wherein Z is a lower alkyl radical and R is hydrogen or hydroxy for the preparation of a compound according to any one of claims 1 to 8. 5 DESCRIPTION