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    • 专利摘要:
    1. A process for the preparation of 4-pregnane derivatives of formula 1 is reacted with an aldehyde of formula A-CHO or its acetals Br-C-Ox. A, O) BZ-S-A A or B B.J Bz / C-0. A CFI R Od A O) where A is n-propyl or n-butyl; Z is hydroxyl or hydroxyl esterified with a fatty acid with a straight or branched hydrocarbon chain having 1-5 carbon atoms, or a mixture of them with tereoisomers or their 22-epimers a. - or 5-type, characterized in that the oxycortisol of the formula AND where A has the indicated meanings; is the same or different and each represents a hydrogen or alkyl group with a straight or branched hydrocarbon chain having 1-4 carbon atoms in the presence of an acid catalyst and, if necessary, the 21-hydroxy group is esterified with a fatty acid with a straight or branched hydrocarbon chain with
    公开号:SU1156600A3
    申请号:SU813362002
    申请日:1981-12-03
    公开日:1985-05-15
    发明作者:Арне Тален Брор；Леннарт Браттсанд Ральф
    申请人:Актиеболагет Драко (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new 4-pregnene derivatives of formula 1
    0 ^ V H where A is n-propyl or n-butyl;
    - hydroxyl or hydroxyl esterified with a straight or branched chain hydrocarbon fatty acid having 1-5 carbon atoms, or a mixture of their stereoisomers or their R- or S-type 22 epimers with valuable pharmacological properties - high local anti-inflammatory activity and one at the same time low glucocorticoid systemic effect.
    Known glucocorticoids of General formula 1
    CH t Z co
    -0 r ^ H
    Z is a free or esterified hydroxyl group;
    R is alkyl C 2 -C 1o ;
    with local anti-inflammatory effect [1].
    Compounds of the general formula 1 cx are obtained by reacting the corresponding 16с /, 17 </ - diol with aldehydes ί0 of the formula 0 = С (£, where R has the indicated meanings, in the presence of an acidic catalyst, for example perchloric acid in dioxane, the resulting acetal derivative of the formula 1 "is subjected to purification by gel filtration on cross-linked dextran gels, for example hydroxypropylated [1J.
    The purpose of the invention is the preparation of novel 2Q steroid compounds having improved phramacological properties.
    The goal is achieved according to the method for producing 4-pregnene derivatives of the general formula J or a mixture of their stereoisomers or their 22-epimers, based on the known method [1] and consisting in the fact that oxycortisol of formula P
    where X is a hydrogen or fluorine atom in the case when Y is a hydrogen atom, and X is a fluorine atom in interact with the aldehyde, when Y is fluorine; House of Formula A - CHO or its acetals, or where. A has in <in 6 to 20 cross-linked binder using -35 solvent to the indicated values; the same or different, and each represents hydrogen or an alkyl group with a straight or branched hydrocarbon chain having
    1-4 carbon atoms, in the presence of an acid catalyst and, if necessary, the 21-hydroxy group is esterified with a straight or branched chain hydrocarbon fatty acid with
    1-5 carbon atoms, and, if necessary, the target compounds are subjected before or after etherification of chromatography on organic dextran volume of the eluent.
    As the crosslinked dextran gel, hydroxypropylated is preferably used; a ball-shaped dextran gel in which dextran chains are connected transversely and create a three-dimensional polysaccharide framework, and as an organic solvent, a mixture of n-hep-45 tan, chloroform and ethanol in a ratio of 0.5: (50-100) :( 10- one).
    The reaction between 16d-hydroxycortisole and the aldehyde or acetal is preferably carried out by adding 1 steroid to the solution of the aldehyde or acetal together with an acid * catalyst, for example perchloric, p-toluenesulfonic acid, hydrochloric and others, in dioxane or equivalent solvents, and the reaction mixture is then neutralized with methylene chloride. The resulting crude steroid ace
    1156600 The 4-derivative, which consists of a mixture of 22R and 225 epimers, is purified after isolation by chromatography on a suitable material, for example cross-linked dextran gels of Sephadex LH resin with suitable solvents as eluents, for example <halogenated hydrocarbons, ethers, complex esters esters such as ethyl acetate or acetonitrile.
    Example 1. 16 o /, 17oi- (22R5jProcylmethylenedioxy-4-pregnen-11/5, 21-diol-3,20-dione.
    To a solution of 125 mg of freshly distilled n-butanal and 0.1 ml of 72% perchloric acid in 20 ml of carefully purified and dried dioxane was added portionwise 500 mg of 16 ° (-oxycortisol for 15 minutes with stirring. The reaction mixture was then allowed to stand for 5 hours at stirring at room temperature.Then the mixture was diluted with 100 ml of methylene chloride.The solution was washed with 10% potassium carbonate solution and water, then dried and evaporated in vacuo.The residue was chromatographed on a column with an inner diameter of 77 6.3 cm, filled with Sephadex LH-20, using chlorophore m as an eluent. The 1995-2235 ml fraction was collected and evaporated. The residue was dissolved in methylene chloride and precipitated with petroleum ether. '446 mg (89%) of 1604, 17o2, (22 RS) of propylmethylenedioxy-4-pregnen-1 1/3 were obtained, 21-diol-3,20-dione, HPLC analysis showed 99.2% purity and the ratio between the 22S and 22K epimers was 47:53. The product had a melting point of 175-203 ° C, [>} 2i = + 138.0 ° (c = 0.198; CH g C1 g ); molecular weight 432 (calculated 432.6).
    Example 2. 16 ά, 17 </ - [22RS] Propylmethylenedioxy-4-pregnen-11/5, 21-diode-3,20-dione.
    To a solution of 118 mg of n-butanal of 6-diethylacetal and 0.1 ml of 72% perchloric acid in 25 ml of carefully purified and dried dioxane, 200 mg of 16s (-oxycortieol is added in portions for 15 minutes. The reaction mixture is allowed to stand at room temperature in 5 hours. Analogously to example 1. get 214 mg of the crude product. The product is chromatographed on a column with an inner diameter of 83 2.5 cm, filled with Sephadex LH-20, using
    156600 using chloroform as an eluent. The 365-356 ml fraction is collected • and evaporated. The residue was further purified by chromatography on a Sephadex LH-20 column (85 × 2.5 cm) using n-heptane-chloroform-ethanol mixture (20:20: 1) as eluent. Collect and evaporate, fraction 8551010 ml. The residue was dissolved in methylene chloride and precipitated with petroleum ether. 152 mg (67%) of 16 ° (, 17c (- [22 p5] propylmethylenedioxy-4-pregnen-11/3, 21-diol ~ 3.20-dione) are obtained, HPlC analysis showed 98.2% purity and a ratio of 43 : 57 between 225 and 22K epimers Molecular Weight of 432 (calculated 432.6).
    Example Z. 1bo £, 17s / - [22 { 5] ~ Propylmethylenedioxy-11 / J -oxy-21acetoxy-4-pregnen-3, 20-dione.
    To a solution of 918 mg of 16oi, 17 / - [22 R5jpropylmethylene dioxy-4-pregnen-11/3, 21-diol-3,20-dione in 60 ml of pyridine was added dropwise with stirring a solution of 460 mg of acetyl chloride in 30 ml of dioxane. The reaction mixture was allowed to stand overnight at room temperature, and then diluted with 500 ml of methylene chloride, washed with 5% aqueous sodium carbonate solution, water and dried. After evaporation in vacuo, the residue is chromatographed on a column with an inner diameter of 72 6.3 cm, filled with Safadex LH-20, using chloro-form as eluent. The 1275-1695 ml fraction was collected, evaporated and precipitated with a mixture of methylene chloride and petroleum ether. 671 mg (67%) of 16 ° /, 1 7a / - [22H53 ~ propylmethylene-dioxo-11/3-hydroxy-21-acetoxy-4-pregnen-3,20-dione are obtained, HPlC analysis showed 99% purity and the ratio between the 225- and 22K epimers is 53:47. The product has a melting point of 118-137 ° C; [oi] 2 ^ = + 125.0 ° (c = 0.200, CH 2 Cl 2 ); molecular weight 474 (calculated ^ 474.6).
    PRI me R 4. 16ci, 17c / - [22SJ- and 16 ίί, 17d - [22 R] -Propylmethylene indioci11 / 3-Rxi-21-acetoxy-4-pregnen-3,20dione.
    </, 17s / - [22 R5] - For example, go oxy- 11 / z-oxy-21-acetoxy-4-pregnen 3,20-dione (40 mg) are chromatographed on a column with an inner diameter of 75-6.3 cm filled with Sephadex LH-20, using n-heptai-chloroform-ethanol (20: 20: 1) as an eluent. The fractions of 1530-1680 ml and 1681-1860 ml were collected and evaporated. Both products are precipitated from a mixture of methylene chloride and petroleum ether. The product from the first fraction (16.5 mg) was identified by 1 H-NMR and mass spectrometry as the 228 epimer, and the product from the subsequent fraction (13 mg) in the same way as the 228 epimer. Epimer S has a melting point of '1 76-179 ° C; = + 107.3 ° (s = 0.262,
    CH 2 Cl 2 ); molecular weight 474 (calculated 474.6). Epimer 8-melting point 112-117 ° C; [F] p 5 = + 132.2 ° (c = 0.152; CH 2 Cl 2 ); molecular weight 474 (calculated 474.6). The purity of epimers is defined as 99.7% for
    5-epimer and 95.0% for the R-epimer, 4% of the impurities of the R-epimer is epi .. measure 5.
    PRI me R 5. 16cZ, 17 <e / - [225 rJPropylmethylenedioxy-11/3 -oxy-21-butyryl c-4-pregnen-3,20-dione.
    To a solution of 100 mg of 16oi, 17c / - [22RS9Propylmethylenedioxy-4-pregnen-11/1, 21-diol-3,20-dione in 5 ml of pyridine was added dropwise 70 mg of butyryl chloride in 3 ml of dioxane. The reaction and isolation of the crude product is carried out analogously to example 2. The crude product is chromatographed on a column with an internal diameter of 80-2.5 cm, filled with Sephadex LH-20, using chloroform as an eluent. A 200-250 ml fraction was collected, evaporated and precipitated from a mixture of methylene chloride and petroleum ether. 70 mg (60%) of 16pi, 17c £ - [22RSj-nponHnmethylenedioxy-11 /} -oxy-21-butyryloxy-4-pregnen-3,20-dione are obtained. HP LC analysis showed 99.7% purity and a ratio of 22S and 22 ( - epimers 44:56. The product has a melting point of 64-75 ° C; [<| 2 / = + 121.0 ° (c = 0.218 , CH 2 Cl 2 ); molecular weight 502 (calculated 502.6).
    PRI me R 6. 16A /, 1 7U- [22 RS] Propylmethylenedioxy-11 /} - hydroxy-21-pivalyloxy-4-pregnen-3, 20-dione.
    To a solution of 100 mg of 16 a /, 17ph- [22 R5JPropylmethylenedioxy-4-pregnen-11/3, 21-diol-3,20-dione in 5 ml of pyridine was added dropwise a solution of 65 mg of trimethylacetyl chloride in 3 ml of dioxaia. The reaction and isolation of the crude product is carried out analogously to example 2. The crude product is chromatographed on a column with an inner diameter of 73 * * 6.3 cm, filled with Sephadex LH ^ ZO,. 1 156600 using chloroform as eluent.
    The 1245–1485 ml fraction was collected, evaporated, and precipitated from a mixture of methylene chloride and petroleum ether. 74 mg (61%) of 16 </, 17i / - [22RSjpropylmethylenedioxy-11d-hydroxy-21-pivalyloxy-4-pregnen-3, 20-dione are obtained. The analysis showed a purity of 98.7% and a ratio between the 22S and 228 epimers of 46:54. The product has a melting point of 95-105 ° C; (cG 2 / = + 115.5 ° (c = 0.110, .CH 2 Cl 2 ); molecular weight 516 (calculated 516.7).
    PRI me R 7. 16ol, 17 "i-f22RS Butylmethylenedioxy-4-pregnen-11p, 21-diol-3,20-dione.
    To a solution of 170 mg of n-pentanal and 0.3 ml of perchloric acid (72%) in thoroughly purified and dried dioxane was added 500 mg of 16 </ - hydroxycortisol in portions over 15 minutes. Then the reaction mixture was allowed to stand for 5 hours at room temperature. Analogously to example 1 receive 1590 mg of crude product, which is chromatographed on a column with an inner diameter of 73-6.3 cm, filled with Sephadex LH-20, using chloroform as eluent. The 1860-2400 ml fraction was collected and evaporated. The residue was dissolved in methylene chloride and precipitated from petroleum ether. 513 mg (87%) of 16οό, 17oi-f22RSl-butylmethylenedioxy-4-pregnen-11 p, 21-diol-3,20-dione are obtained. The analysis shows a purity of 98.9% and a ratio of 50:50 between 225 and 22K epimers. The product has a melting point of 154-160 ° C; [oiJ 25 = + 129.6 ° (c = O, 3O8, CH 2 Cl 3 ); molecular weight 446 (calculated 446.6).
    An example. 16o (, 17ot- (22RS] Butylmethylenedioxy-4-pregnen-11p, 21-diol-3,2 0-dione.
    To a solution of 53 mg of n-pentanal-6-propylene acetal and 0.1 ml of 72% perchloric acid in 25 ml of thoroughly purified and dried dioxane was added 100 mg of 16 ° (-oxycortisol in portions for 15 minutes. The reaction mixture was allowed to stand for 5 hours at room temperature and processing is carried out analogously to example 1. The crude product is chromatographed on a column with an internal diameter of 83-2.5 cm, filled with Sephadex LH-20, using chloroform as an eluent. A fraction of 285-380 ml is collected and evaporated.
    This product is further purified by chromatography on Sephadex LH-20 (column with an inner diameter of 85 <2.5 cm) using a mixture of n-heptane-chloroform-ethanol (20: 20: 1) as an eluent. The 735-915 ml fraction was collected and evaporated. The residue was dissolved in methylene chloride and precipitated with petroleum ether. 77 mg (64%) of 16c /, 17 ° C- [22 of RSj-butylmethylenedioxy-4-pregnen-11β, 21gdiol-3.20dione are obtained. The analysis showed 96.8% purity and the ratio of 22 S and 221 -Epimers 46:54; molecular weight 446 (calculated 446.6),
    PRI me R 9. 16cL, 17 <£ - [22Sj and 16с /, 1 7с / - [22 Rj-Butylmethylenedioxy-
    4-pregnen-11 b, 21-diol-3,20-dione.
    16c4, 1 7 </ - [22 R9 J-Butylmethylenedioxy-4-pregnen-11/3, 21-diol-3,20-dione (500 mg) are chromatographed on a column with an internal diameter of 76-6.3 cm, filled with Sephadex LH-20, using a mixture of n-heptane-chloroform-ethanol (20: 20: 1) as an eluent. Fractions 4050-4395 and 4771-4950 ml were collected, evaporated and precipitated from a mixture of methylene chloride and petroleum ether. Products are identified by Ή-NMR and mass spectrometry as
    5-epimer (79 mg) and R-epimer (127 mg), respectively. The epimer purity is 97.3% (8-epimer content 2.1% for the S-epimer) and 97.9% (S-epimer content 0.5% for the R-epimer. In addition, the S epimer has a melting point of 165-71 ° С; Lot] 2 / = + 119.9 ° (с = 0.382, СН 2 С1 2 ); molecular weight 446 (calculated 446.6), and epimer R - melting point 154-62 ° С; = + 148, 3 ° (c = 0.302, CH 2 Cl 2 ); molecular weight 446 (calculated 446.6).
    Example. 16 <17 </ - [22RS] * Butylmethylenediocide si-11β-ok si-21-ace-toxi-4-pregnen-Z, 20-dione.
    16οί, 17s / - [22 RSJ-Butylmethylenedioxy-4-pregnen-11/3, 21-diol-3,20-dione. (658 mg) and acetic anhydride (5 ml) are dissolved in 5 ml of pyridine and left overnight at room temperature. The resulting mixture was then poured into ice water and extracted several times with methylene chloride. The mixed extracts are washed with diluted 1% hydrochloric acid, sodium carbonate (5% in water), saturated sodium chloride solution, dried and evaporated in vacuo. The remainder of the chromium 9 is graphed on a column with an inner diameter of 73-6.3 cm, filled with Sephadex LH-20, using chloroform as an element. A fraction of 12151455 ml was collected and evaporated. Residue 5 is dissolved in methylene chloride and precipitated from petroleum ether. 507 mg (71%) of 16> 17o4- [22RSj-butylmethylenedioxy-11 / s-ox-21-acetoxy-4-pregnen-3, 20-dione are obtained. HPLC-ana , 0 lys showed 98.5% purity and the ratio of 22R and 225 epimers was 51:49. The product has a melting point of about 10825 C; 5 = Il + 126.5 (c = 0.238, CH 2 C1 2); molecular weight 488 (calculated '5,488.6).
    PRI me R 11. 16oi, 17ci ~ C22Sj and 16οέ, 17 </ - C22K] -Butylmethylenedioxy11 p-si-21-ace-current si-4-pren-3,20dion. twenty
    16o (, 17oi- [2 2RS J-Butylmele diode επί 1β-oxy-21-acetoxy-4-pregnen-3.20 dione (485 mg) are chromatographed analogously to Example 3. Fractions 1275-1425 and 1486-1590 ml are collected and 25 The products are precipitated from a mixture of methylene chloride and petroleum ether and identified by 1 H-NMR and mass spectrometry, respectively, as 5-epimer (140 mg) and R-epimer (2Q4 mg), 3 ^ Epimer purity according to HPLC analysis 97 , 5% for the 5-epimer (with 1.3% R-epimer) and 97.1% for the R-epimer (with 1.2% 5-epimer). Epimer 5 has a melting point of 152-57 ° C; 35
    W ^ = + 104 ', 4 ° (c = 0.226, CH 2 c 1 z ), molecular weight 488 (calculated 488.6), and epimer R - melting point 75-77 ° С; &] ^ = 140.4 e (c = 0.228, CH 2 Cl 2 ); molecular weight 488 (calculated 488.6) .40 Example 12 ,. 16ol, 17o (- [22SjBuylmethylenedioxy-4-pregnen-11/3, 21-diol-3,20-dione.
    To a solution of 16 </, 17о (- [22 5} -butylmethylenedioxy-11/3-hydroxy-21-acetoxy-4S 4-pregnen-3,2-dione (53 mg) in 10 ml of methanol was added 1.5 ml of carbonate potassium (10% in water) After 10 minutes stirring at room temperature in a nitrogen atmosphere, mixture 50 was neutralized with acetic acid, diluted with 25 ml of water and extracted with methylene chloride. The combined extracts were dried and evaporated in vacuo. The residue was chromatographed on an S3 column with an inner diameter of 83 2.5 cm filled with Sephadex LH-20 using chloroform as eluent. Collect and evaporate the fraction. 285-330 ml 35 mg (73%) of 16 ° (, 17 ° / -C22 $ 7-butylmethylenedioxy ~ 4preney-11 p, 21-diol-3,20-dione are obtained after precipitation from a mixture of methylene chloride and petroleum ether. The product is identified by mass spectrometry and its purity, as shown by HPL.C analysis, is 98.8% (it contained 0.8% R-epimer), its melting point is 160-67 ° C; And 2 / = + 115.0 ° (s = 0.322; CH 2 Cl 2 ); molecular weight 446 (calculated 446.6) ..
    Example 13 ‘. 16oi, 17c / - [22KjButylmethylenedioxy-4-pregnen-11β, 21-diol-3,20-dione.
    To a solution of 16οζ 1 7оС-С22Ч] -butylmethylenedioxy-11β, hydroxy-21-acetoxy4-pregnen-З, 20-dione (58 mg) in 10 ml of methanol was added 1.5 ml of potassium carbonate (10% in water). The reaction mixture is treated as in Example 10. The crude product is chromatographed on a column with an internal diameter of 83-2.5 cm, filled with Sephadex LH-20, using chloroform as the eluent. A 305-360 ml fraction was collected and evaporated. 43 mg (81%) of 16c4, MoL- [22K] butylmethylenedioxy-4-pregnen-11/3, 21-diol-3,20-dione are obtained after precipitation from a mixture of methylene chloride and petroleum ether. The product was identified by mass spectrometry, and its purity, as shown by HPLC analysis, was 95.4% (containing 2.5% S-epimer). Melting point 152-62 ° C25 = + 149.0 th (s = 0.312, CH 2 Cl 2 ); molecular weight 446 (calculated 446.6).
    Pharmacological tests.
    All steroids provided in the invention are physiologically active compounds. Their glucocorticoid properties were compared with those of budesonide (general formula Ια), 16οί, 17c6 ~ C22RSj-nponiin ~ methylenedioxypregna-1,4-diene-11 / j, 21-diol-3,20-dione, since this compound is one of glucocorticoids, which has achieved most in the direction of the required combination of local and systemic action; anti-inflammatory effect was evaluated by the ability to prevent ear swelling in rats according to the procedure described below.
    Ear edema was induced in male rats weighing about 90 g using 20 μl per
    I
    156600
    I 2 the edge of the ear of 5% ethylphenippropiolate (Aldrich KO), dissolved in acetone. After 2 hours, ear edema was measured with a special micrometer (Auditest, HCKroplinl. Glucocorticoids were used 5 hours later. Induction of edema was 20 μl to the ear edge in the form of solutions in acetone (0.08-50 μg) of the steroid (ml per 0.0064 μg rat). for each dose tested 6 ears. 10 relative inflammatory activity of test compounds on preventing ear edema was calculated according to the linear regression analysis as compared to the reference compound (budesonide). 15
    The activity of the compounds to ensure systemic glucocorticoid action was investigated by subcutaneous injections, since at the dose levels used in the aforementioned test 20 for topical application, no systemic effect was achieved.
    0.5 ml of the steroid preparation was injected to rats of the same weight and gender as already described. At least 5 25 doses of each of the test compounds were administered in the range of 20-1280 μg per rat, 4 animals per dose. In the first two days after the injection, an increase in body weight of animals was recorded, and after the next two days, the weight of the thymus gland was recorded, since these time intervals are optimal for determining the corresponding systemic effect. The relative activity of the compounds was calculated according to the analysis of linear regression compared with the control substance (budesonide). The test results of the glucocorticoids of the invention in accordance with the procedure carried out are shown in the table. It is known that the introduction of a double bond at position 1.2 of cortisol increases its glucocorticoid activity. The table shows that the new compounds (derivatives of 4-pregnene) have approximately the same high anti-inflammatory activity as budesonide (derivatives of 1, 4-pregnadiene).
    The table also shows that the new compounds are 3-20 times less active than budesonide in the manifestation of undesirable systemic glucocorticoid effects. The new compounds also have 5-10 times higher anti-inflammatory activity than previously known 1bF, 17o6- [22K] methylmethylenedioxy-4-pregnen-11/3, 21-dzol- '3,20-dione, with the same systemic glucocorticoid activity.
    Thus, the new compounds of the invention satisfy the requirement of combining high local anti-inflammatory activity and relatively low system action.
    权利要求:
    Claims (3)
    [1]
    1-5 carbon atoms, and if necessary, the target compounds are subjected before or after the etherification of chromatography on a cross-linked dexTRan gel using an organic solvent as eluent.
    [2]
    2. The method according to claim 1, about tl and h and rent and with the fact that as a cross-linked dextran gel
     use is made of spherical hydroxypropylated dextran gel, in which the dextran chains are crosslinked and create a three-dimensional polysaccharide framework, and as an organic solvent - a mixture of n-heptane, chloroform and ethanol in a ratio of 0.5: (50-100):: (10 -one).
    This invention relates to a process for the preparation of new 4-pregnane derivatives of the formula 1 CH, Z where A is n-propyl or n-butyl; 2 - hydroxyl or hydroxyl esterified with a fatty acid with a straight or branched hydrocarbon chain having 1-5 carbon atoms, or mixtures of their stereoisomers or their R or 5 type epimers with valuable pharmacological properties — high local about tissue inflammatory activity and temporarily low glucocorticoid systemic action. Glucocorticoids of total 1 CHtZ with m., -, X are a hydrogen or fluorine atom in the case when Y is a hydrogen atom, and X is a fluorine atom in the case when Y is fluorine; Z is a free or esterified hydroxyl group; R is alkyl Cj - € ,,; with local anti-inflammatory effects. Compounds of general formula 1a are prepared by reacting the corresponding 16 °, 17 ° -diol with an aldehyde of the formula, where R has the indicated values, in the presence of an acidic catalyst, for example perchloric acid in a dioxane medium, the resulting acetal derivative of formula 1 is purified by gel filtration on cross-linked dextran gels, for example hydroxypropylated lj. The purpose of the invention is to obtain new steroid compounds possessing improved framacological properties. The objective is achieved according to the method for producing 4-pregnane derivatives of general formula J or a mixture of their stereoisomers or their 22-epimers, based on the well-known method tl and the conclusion that oxycortisol formum in P CH2OH is reacted with an aldehyde of formula A-CHO or its acetals B2 -Cili Bj-C4 where. A has the indicated meanings; i (, identical or different and each represents a hydrogen or an alkyl group with a straight or branched hydrocarbon chain having 1-4 carbon in the presence of an acid catalyst and, if necessary, esterifying with the resulting compound with oxyhydrogen my or a branched hydrocarbon chain with 1-5 carbon atoms, and if necessary, the target compounds are subjected before or after esterification of the chromatography on a transverse bound dextran gel with the use of an organic solvent in each as an eluent. As a cross-linked dextran gel, an oxypropylated gram-shaped dextran gel is preferably used crosslinked to form dextran chains and create a three-dimensional poly saccharide framework, and an organic solvent is a mixture of n-tane, chloroform and ethanol a ratio of 0.5: (50-100) :( 10-1). The reaction between 16 ° C-oxycortisol and aldehyde or acetal is preferably carried out by adding a steroid to an aldehyde or acetal solution together with an acid catalyst oh, p-toluene acid, hydrochloric and others, in dioxane or equivalent solutions, the reaction mixture then being neutralized with methylene chloride. The resulting crude steroid acetal derivative, which consists of a mixture of 22R and 225 epimers, is purified after separation by chromatography on a suitable material, for example transversely coupled dextran gels of a Sephadex LH resin with suitable solvents as eluents, for example halogenated hydrocarbons, ethers, esters such as ethyl acetate or acetonitrile. Example 1. 1bo 17 - 22R Procylmethylenedioxy-4-pregnen-11 /, 21-diol-3,20-dione. To a solution of 125 mg of advanced distilled n-butanal and 0.1 ml of 72% perchloric acid in 20 ml of thoroughly purified and dried dioxane, 500 mg of 16 ° (oxycortisol) are added in portions over 15 minutes with stirring. The reaction mixture is then allowed to stand 5 hours while stirring at room temperature. The mixture is then diluted with 100 ml of methylene chloride. The solution is washed with a 10% potassium carbonate solution and water, then dried and evaporated in vacuo. The residue is chromatographed on a column with an inner diameter of 77 6.3 cm, filled with Sephadex LH-20 using chlorine as eluent. The fraction of 1995-2235 ml is collected and evaporated. The residue is dissolved in methylene chloride and precipitated with petroleum ether. 446 mg of (89;) 6oL, 17b, (22 RS) propylmethylenedioxy-4-pregnan-11p, 21-diol is obtained. -3.20-dione, HPLC analysis showed 99.2% purity and a ratio between 22S and 22P epimers 47:53. The product has a melting point of 175-203 ° C, i -1-138.0 (, 198; CHjCl j); molecular weight 432 (calculated 432.6). Example 2 16ci, 17 ° - 22R5 Propylmethylenedioxy-4-pregnen-11/3, 21-diode-3, 20-dione. To a solution of 118 mg of n-butanal 6-diethyl acetal and O, 1 ml of 72% perchloric acid in 25 ml of thoroughly purified and dried dioxane, 200 mg of 16 ° -oxycortisol are added in portions over 15 minutes. The reaction mixture was allowed to stand at room temperature at 5 pm. Similarly to Example 1, 214 mg of crude product was obtained. The product is chromatographed in a column with an internal diameter of 83-2.5 cm, filled with Sephadex LH-20, using chloroform as eluent. The fraction of 365-356 ml is collected and evaporated. The residue is further purified by chromatography on a Sephadex 1K-20 column (85-2.5 cm) using n-heptane-chloroform-ethanol (20: 20: 1) as eluent. Collect and evaporate, a fraction of 8551010 ml. The residue is dissolved in methylene chloride and precipitated with petroleum ether. 152 mg (67%) 16 ° (, p53-propylmethylenedioxy-4pregnen-11/5, 21-diol-3,20-dione, HP1. C-analysis showed 98.2% purity and a 43:57 ratio between 225 - and 22R epimers. Molecular weight 432 (calculated 432.6) .Template 16c, 17-22R5 Propylmethyndioxy-11 / J-hydroxy-21 acetoxy-4-pregnen-3, 20-dione. To a solution of 918 mg of 16 ° C, 17c (R5 proxy methylenedioxy-4-pregnen-11/5, 21-diol-3,20-dione in 60 ml of pyridine) a solution of 460 mg of acetyl chloride in 30 ml of dioxane is added dropwise with stirring. The reaction mixture is allowed to stand overnight at room temperature, and then diluted with 500 ml of methylene chloride The residue was washed with a 5% aqueous solution of sodium carbonate and water, and dried. After evaporation in vacuo, the residue was chromatographed on a column with an internal diameter of 72–6.3 cm, filled with Safadex LH-20, using chloroform as eluent The fraction 1275-1695 ml is collected, evaporated and precipitated with a mixture of methylene chloride and petrol ether. 671 mg (67%) 16B /, 17Y-C22X51-propylmethylenedioxy-11 /) - hydroxy-21-acetoxy-4-progen-3, 20-dione, HPLC analysis showed 99% purity and a ratio between 225- and 22H-epimerms 53:47. The product has a melting point of 118-137 ° C; ,, 200, CHjClp; molecular weight 474 (calculated 474.6). EXAMPLE 4: 16ci, 17oi-i22Sj- and 16oi; 17o-C22Kz-Propylmethylenedioxy 11/5-pxy-21-acetoxy-4-pregnen-3, 20 dione. 16o, Propylmethylenedio-1/11-oxy-21-acetoxy-4-pregnen3, 20-dione (40 mg) are chromatographed on a column with an internal diameter of 75-6.3 cm, filled with Sephadex LH-20, using as eluek n-heptane-chloroform-et nol mixtures (20: 20: 1). The 1530-1680 ml and 1681-1860 ml fractions are collected and evaporated. Both products are precipitated from a mixture of methylene chloride and petroleum ether. The product from the first fraction (16.5 mg) is identified by H-NMR and mass spectrometry as 22Y-epimer, and the product from the subsequent fraction (13 mg) is in the same way as 22R epimer. Epimer 5 has a melting point of 176-179 ° C; Gy: d +107.3 (, 262, CH2Cl2); molecular weight 474 (calculated 474.6). Epimer P melting point: 112-117 ° C; M25 + 132.2 "(, 152;); molecular weight 474 (calculated 474.6). The purity of the epimers is defined as 99.7% for the 5-epimer and 95.0% for the R-epimer, 4% of the impurities for the R-epimer is epi meter S. EXAMPLE 5: 16oi, 17u / -C225R Propylmethylenedioxy-11-hydroxy-21-butyryloxy-4-pregnen-3, 20-dione. To a solution of 100 mg of 16of, propylmethylenedioxy-4-pregen-11/1, 21-diol-3,20-dione in 5 ml of pyridine, 70 mg of butyryl chloride in 3 ml of dioxane are added dropwise. The reaction and isolation of the crude product is carried out analogously to example 2. The crude product is chromatographed on a column with an internal diameter of 80-2.5 cm, filled with Sephadex LH-20, using chloroform as eluent. The fraction 200-250 ml is collected, evaporated and precipitated from a mixture of methylene chloride and petroleum ether. 70 mg (60%) of 16od, 17o - 221 5 propylmethylenedioxy-11 /} - hydroxy-21-butyryloxy-4-pregnen-3, 20-dione are obtained. HPLC analysis showed 99.7% purity and a ratio of 225 and 22 / epimers 44:56. The product has a melting point of 64-75 ° C; ,, 218,); molecular weight 502 (calculated 502.6). PRI me R 6. 16a, 17o -f22RS Propylmethylenedioxy-11 /} - hydroxy-21-pivalshloxy-4-pregnen-3, 20-dione. A solution of 65 mg of trimethylacetyl chloride in 3 ml of dioxane is added dropwise to a solution of 100 mg of 16 °, 17 (Propylmetstendioxy-4-pregnen-11/3, 21-diol-3, 20-dione in 5 ml of pyridine). Raw product is carried out analogously to example 2. The crude product is chromatographed on a column with an inner diameter of 73.3 cm, filled with Sephadex 1.H-20, using chloroform as eluent. The fraction 1245-1485 ml is collected, evaporated and precipitated from a mixture of methylene chloride and petroleum ether. Get 74 mg (61%) 16 17 / -i; 22R5j propylmethylenedioxy-1 1 | 9-hydroxy-21 pivalloxy-4-pre Gnen-3, 20-dione. The analysis showed a purity of 98.7% and a ratio between 225 and 22P-epimers 46:54. The product has a melting point of 95-05C; ci-Ш5.5 (110,.) molecular weight 516 (calculated 516.7). EXAMPLE 7: 16oi, 17 ° -G22I5 Butylmethylenedioxy-4-pregnan-11p, 21-diol-3,20-dione. To a solution of 170 mg n-pentanal and 0.3 ml of perchloric acid (72%) in thoroughly purified and dried dioxane do not add 500 mg of 16 ° -oxicortisol in portions over 15 minutes. The reaction mixture is then allowed to stand at room temperature for 5 hours. Analogously to example 1, 1590 mg of crude product is obtained, which is chromatographed on a column with an inner diameter of 73-6.3 cm, filled with Sephadex LH-20, using chloroform as eluent. A fraction of 1860-2400 ml is collected and evaporated. The residue is dissolved in methylene chloride and precipitated from petroleum ether. 513 mg (87%) of 16ci, 17oi are obtained: -C22ReJbutylmethylenedioxy-4-pregnen-11e, 21-diol-3,20-dione. The analysis shows a purity of 98.9% and a ratio of 50:50 between 225 and 22K epimers. The product has a melting point of 154-160 ° C; ,, 308, SNGSGs); Molecules of weight 446 (immiscible 446,6). EXAMPLE 8. 16c /, 17oi-f22RS Butylmethylenedioxy-4-pregnen-1IP, 21-diol-3,20-dione. To a solution of 53 mg of n-pentanal-6-propylene acetal and 0.1 ml of 72% perchloric acid in 25 ml of thoroughly purified and dried dioxane, 100 mg of 16-oxycortisol are added in portions over 15 minutes. The reaction mixture was allowed to stand at room temperature for 5 hours and was treated in the same manner as Example 1. A crude chromate product was recorded on a column with an internal diameter of 83-2.5 cm, filled with Sephadex LH-20, using chloroform as eluent. The fraction 285-380 ml is collected and evaporated. This product is further purified by chromatography on Sephadex LH-20 (column with an inner diameter of 85-2.5 cm) using a mixture of H2 heptan-chloroform-ethanol (20: 20: 1) as eluent. A fraction of 735–915 ml is collected and evaporated. The residue is dissolved in methylene chloride and precipitated with petroleum ether. 77 mg (64%) of 16 °, 176-622P5 -but1 methylenedioxy-4-pregnen-11, 21 di-3,20 dione are obtained. The analysis showed a 96.8% purity and a ratio of 22S and 22P epimers 46:54; molecular weight 446 (calculated 446.6). Example9. 16c (17 ° (. And 16c), 1 Rj-Butylmethylenedioxy4-pregnen-11b, 21-diol-3,20-dione. 16ot, 1 7) J-Butylmethylenedioxy-4-pregnen-11/3, 21-diol-3 , 20-dione (500 mg) are chromatographed on a column with an internal diameter of 76-6.3 cm, filled with Sephadex L, H-20, using n-heptane-chloroform-ethanol (20: 20: 1) as eluent. Fractions 4050-4395 and 4771-4950 ml are collected, evaporated and precipitated from a mixture of methylene chloride and petroleum ether. Products are identified by H-NMR and mass spectrometry as Z-epimer (79 mg) and R-epimer (127 mg), respectively. Purity epimer 97.3% (the content of R-epimera 2, 1% for S-epimer) and 97, (5-epimera content of 0.5% for R-epimer. In addition, epimer S has a melting point of 165-71 ° C, -W2 + P9.9 ° (, 382, CHjCI ); molecular weight is 446 (calculated 446.6), and epimer R is the melting point of 154-62 ° C; 0 - 148.3 (, 302,); molecular weight is 446 (calculated 446.6). 17c; - 22RSjButylmethylenedioxy-1 /--hydroxy-21-acetoxy-4-pregnen-3, 20-dione. 16o, 1 K5-Butylmethienedioxy-4-pregnen-11 /}, 21-diol-3,20-dione. (658 mg) and acetic anhydride (5 ml) are dissolved in 5 ml of pyridine and left overnight at room temperature. The mixture was then poured into ice water and extracted several times with methylene chloride. The combined extracts are washed with dilute 1% hydrochloric acid, sodium carbonate (5% in water), with a valuable solution of sodium chloride, dried and evaporated in vacuo. The residue is chromatographed on a column with an inner diameter of 73-6.3 cm, filled with Sephadex LH-20, using chloroform as an element. A fraction of 12151455 ml is collected and evaporated. The residue is dissolved in methylene chloride and precipitated from petroleum ether. 507 mg (71%) of 16, 17, -C22RS, butylmethylenedioxy-1 1 /} - hydroxy-21-acetoxy-4-pregnen-3, 20-dione are obtained. HPLC analysis showed a 98.5% purity and a ratio of 22P and 225 epimers 51:49. The product has a melting point of 10825 ° C; Wy +126.5 (; 238, CHjClj); molecular weight 488 (calculated 488.6). PRI me R 11. 16oi, 17o-C22Sj and 16o, 17s1-C22H-Butylmethylenedioxy 11 / -oxy-21-acetoxy-4-pregnen-3,20 dione. 16oi, 17Y- 2 K53-Butsh1methylenedioxy 11 -oxy-21-acetoxy-4-pregnen-3, 20dione (485 mg) are chromatographed analogously to an example
    [3]
    3. Fractions 1275-1425 and 1486-1590 ml are collected and evaporated. The products are precipitated from a mixture of methylene chloride and petroleum ether and identified by H-NMR and mass spectrometry, respectively, as 5-epimer (140 mg) and R-epimer (204 mg Purity of epimers according to HPLC analysis 97, .5% for 3-zpimer (with a content of 1.3% R-epimer) and 97.1% for (-zpimer (with 1.2% 5-epimer). Epimer 5, melting point 152-57 ° C; WI + 104.4 ° (, 226 , CH2Cl2); molecular weight 488 (calculated 488.6) and epimer R, melting point 75-77 ° C, 4 (, 228, CHjCl), molecular weight 488 (calculated 488.6) Example 12,. 16ot, 17 ° -G225 Butylmethylenedioxy-4-pregnen-11/3, 21-diol-3,20-dione. To a solution of 16 (, 17 ° / -C22 5 -buty lmethylenedioxy-11p-hydroxy-21-acetoxy4-pregnen-3, 20-dione (53 mg) in 10 ml of methanol was added 1.5 ml of potassium carbonate (10% in water). After 10 minutes of stirring at room temperature in an atmosphere the mixture is neutralized with acetic acid, diluted with 25 ml of water and extracted with methylene chloride. The combined extracts are dried and evaporated in vacuo. The residue is chromatographed on a 2.5 cm inner diameter of 83.5 cm filled with Sephadex 1, H-20, using chloroform as the solvent. . The fraction 285-330 ml is collected and evaporated. 35 mg (73%) of 16oi, 17oi- (22S of 1-boot 4-dylenedioxy-4 preg-11, 3, 21-diol-3,20-dione after precipitation from a mixture of methylene chloride and petroleum ether are obtained. The product is identified by mass spectrometry and its purity, as shown by HPLC analysis, is 98.8% (it contained 0.8% R-epimer), its melting point is 160-67 ° C; M + 115, OCh 0.322;); molecular weight is 446 (446.6 injected). Example 13. 16oi, 17s - 22K Butylmethylenedioxy-4-pregnan-11, 21-diol-3,20-dione. 1.5 ml of potassium carbonate (10% in water) are added to a solution of 16 (3, 17- 6-G22NAZ-butylmethylenedioxy-11, hydroxy-21-acetoxy-4-pregnen-3, 20-dione (58 mg) in 10 ml of methanol. The reaction mixture is treated as in Example 10. The crude product is chromatographed on a column with an internal diameter of 83-2.5 cm, filled with Sephadex L, H-20, using chloroform as eluent. A fraction of 305-360 ml is collected and evaporated. 43 mg ( 81%) 16oi, 17 ° - 22 P -butylmethylenedioxy-4pregnen-11p, 21-diol-3,20-dione, after precipitation from a mixture of methylene chloride and petroleum ether. c using mass spectrometry, and its purity, as HPLC analysis showed, was 95.4% (contained 2.5% of 5-zimer). Melting point 152-62C; a; j2j + 149,, 312,)} molecular weight 446 (calculated 446.6). Pharmacological testing. All steroids of the invention are physiologically active compounds. Their glucocorticoid properties were compared with those of budesonide (formula 1), 16 °, 17 ° C-22Ha-1-4-1H-methylenedioxypregna-1, 4-diene-11/3, 21-diol-3,20-dione, since this compound is one of the glucocorticoids which has achieved the most towards the desired combination of local and systemic action; anti-inflammatory effect was evaluated by the ability to prevent ear edema in rats according to the procedure described below. Ear edema was found in male rats weighing about 90 g using 20 µl per 1 edge of the ear of 5% ethylphenylpropiolate (Aldrich KO) dissolved in acetone. After 2 hours, the ear edema was measured with a special micrometer (Oditest, HCKroplinl Glucocorticoids were used 16 hours prior to induction of edema 20 µl per ear edge as solutions in acetone (0.08-50 µg) of steroid (ml per 0.0064 µg per rat). For each dose, 6 ears were tested. The relative activity of the test compounds was to prevent ear edema was calculated by linear regression analysis versus control compound (budesonide). The activity of the compounds to ensure the systemic glucocorticoid effect was investigated by subcutaneous injections, since at the dose levels used in the above local application experience no systemic effect was achieved. 0.5 ml of the steroid preparation was injected into the same rats weight and sex, as already described. At least. 5 doses of each of the test compounds were administered in the range of up to 20–1280 microns per rat, 4 animals for each dose. In the first two days after the injection, an increase in the body weight of the animals was recorded, and after the next two days, the weight of the thymus gland was recorded, since these time intervals are optimal for determining the corresponding systemic effect. The relative activity of the compounds was calculated from linear regression analysis versus control substance (budesonide). The test results of the glucocorticoids of the invention in accordance with the procedure performed are shown in the table. It is known that the introduction of a double bond at the 1.2 position of cortisol increases its glucocorticone activity. The table shows that the new compounds (derivatives of 4-pregnene) have approximately the same high anti-inflammatory activity as budesonide (derivatives of 1,4-pregnadiene). The table also shows that new compounds are 3–20 times less active than budesonide in the development of undesirable systemic glucocorticoid effects. The new compounds also have 5–10 times higher anti-inflammatory activity than the previously known 16B, 17 ° - 22K -methylmethylenedioxy-4-pregnan-11/3, 2 1 -diol 3, 20-dione, with the same systemic cranocorticoid activity. Thus, the novel compounds of the invention satisfy the requirement of a combination of high local anti-inflammatory activity and a relatively low system of action.
    3115660014
    Pharmacological action of the tested compounds
    -he
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    SE8008524A|SE8008524L|1980-12-04|1980-12-04|4-PREGNEN DERIVATIVES, A PROCEDURE FOR THEIR PREPARATION, PREPARATION AND METHOD OF TREATMENT OF INFLAMMATORY CONDITIONS|
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