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    NEW MATERIAL:Compounds of formula I (R1 is 1-10C alkyl, monohydroxy- 2-10C-alkyl; R2 is 1-10C alkyl, 3-8C cycloalkyl; R3 is H, alpha-OH, d-methyl; R4 is H, F, Cl; R5 is H, F, Cl; X is O, S; Z is carbonyl, beta-hydroxymethylene; the dotted line in ring A is single or double bond) and their quaternary ammonium salts where at least one of R1 and R2 are haloalkyl. EXAMPLE:11beta - Hydroxyl - 17alpha - methylcarbonyloxyandrost - 4 - ene - 3- 17beta - carboxylic chloromethyl ester. USE:Anti-inflammatory. PREPARATION:The reaction between a compound of formula II (R3' is H, alpha- methyl) and another compound of R2OCOCl is conducted in a solvent of THF under anhydrous conditions to produce a novel compound of formula III (R3'' is H, alpha-methyl). The product is converted to a metal salt, which is made to react with a compound of R1-W (W is halogen) to give the compound of formula I.
    公开号:SU1318169A3
    申请号:SU813306552
    申请日:1981-07-09
    公开日:1987-06-15
    发明作者:Стивен Бодор Николас
    申请人:Оцука Фармасьютикал Ко, Лтд (Фирма)；
    IPC主号:
    专利说明:

    The invention of OTFIOCHTCH to a method of producing steroid compounds of the general formula
    ORi
     about II
    ,
    where R, is lower haloalkyl;
    R is lower alkyl;
    R is hydrogen, "; or / 3-methyl;
    R is hydrogen or fluorine;
    R is hydrogen, fluorine or methyl;
    Z - carbonyl or -oxymethylene dashed line means a possible carbon-carbon bond, or their quaternary ammonium salts with a number of valuable pharmacological properties.
    The purpose of the invention is to obtain new steroid compounds with high anti-inflammatory activity with minimal systemic activity.
    Example. 1. 1 1 | 6-hydroxy-1 7cx-me-Eoxycarbonyloxyandrost-en-3-one- 1 7 /} - carboxylic acid is combined with an equivalent amount of sodium hydroxide IN in methanol and this solution is diluted 100 times from the initial volume of ethyl ether. The resulting suspension is frozen for 1 hour. Then, the resulting crystals are removed by filtration, dried in a desiccator, which is pumped out, and dissolved in hexamethylphosphoride (10% w / v). Part of the resulting solution containing 1 mole of the acid salt, t ..e. 1 I / J-hydroxy-1 7 ° (, - methoxycarbonyloxyandrost-4-ene-3-one-17p-sodium carboxylate, combined with 4 mol of chloromethyl iodide. The reaction mixture is maintained at room temperature for 3 hours, then diluted to 10 the original volume is washed with ethyl acetate. The diluted reaction mixture is washed successively with 5% sodium thiosulfate, 3% sodium bicarbonate and water. The organic layer is separated, dried with magnesium sulfate and filtered. The filtrate is concentrated under vacuum until a foam forms.
    81692
    by crystallization from a suitable solvent (ethyl ether or tetrahydrofuran / hexane). Chloromethyl-1 1/3-hydroxy-1 7og.-meth-5 oxycarbonyl-oxyandrost-4-en-3-one-17-carboxylate is obtained in this way. 171-173 ° C after crystallization.
    IR (KBr) 3000-2800 (C-H), 1760, 1748 (CsD), 1650 (). , o NMR (CdCl,) S 5.67 (s, 1,), 5.82, 5.62, (ABq, J 5.5 Hz2,), 4.47 (v, 1, CHOH).
    Calculated,%:
    C, 60.72; H 6.87; C1 7.79.
    15
    five
    five
    C ,, H ,, C10.
    Found,%: C 60.50; H 7.06; C1 7.06; C1 7.50.
    Replacing the steroid acid with an equivalent amount of 17-ethoxycarbo-niloxy-1 1/3-from: siandroth-4-en-3-one-1 7/3-carboxylic acid and repeating this procedure gives the intermediate salt 1 7-ethoxycarbonyl-ca - si-1 1p-oxyandrost-4-en-3-one-1 7 / -carb-sodium oxylate, and chloromethyl-1 7oi- ethoxycarboxynelyloxy- 11 is obtained as the final product 11 | α-oxyandrost-4-en-3-one-17p-carboxylate, m.p. 197-200.C after crystallization.
    0 IR (KVG) 3600-3200 (0-H), 3000-2800 (C-H), 1763., 1740 (), 1650 () cm -. NMR (CDC1 ,,)
    5.7 (s, 1,),. 5.81, 5.62 (ABq, J 5HZ, 2, -ОСН ,, С1, Calculated,%: C 61.46; H 7.09. N., CU,
    C, 61.58; H 7.08.
    ..1.i7
    Found
    In the same way, by replacing steroid acid with an equivalent amount of 1 76-butoxycarbonyloxy-1 1-hydroxy-androst-4-en-3-one-17-carboxylic acid and by repeating the procedure described, the intermediate salt 1 7 "4-butoxycarbonyloxy- 1 1-oxyandrast-4-en-3-one-1 7/3-sodium carboxylate, and chloromethyl-1 7o | 1-butoxycarbonyloxy-11-oxyandrost-4-en-3- on-17p-carboxylate with so pl. 98-100 ° C after crystallization.
    IR (KBG) 3600-3300 (0-H), 3000-2800 (C-H), 1765 (), 1735 (), 1650 () see
    NMR (CDC1) S 5.80.8 5.60 (2, Bq, J 4.5 HZ-QCHjCl), 5.67 (s, I,), 4.45 (v, 1, SNON), 4, 08 (t, 2, J bnK, O COCHi-Clp.
    Calculated,%: C, 62.77; H 7.44; C1 7.14. C ,, H „C10 ,.
    Found,%: C 62.88; H 7.23; C1 7.30.
    When replacing a steroid acid with an equivalent amount of 11p-hydroxy-17p-isopropoxycarbonyl oxyandrost-proct-en-3-one-17p-carboxylic acid and repeating the procedure described, an intermediate salt of 1 lp-oxy-17oi-isoproproxycarbonylsoxoacetate is obtained by means of an intermediate 17oi-isopropoxo-parabolic compound. - 3-o-l 7y-sodium carboxylate; as the final product, chloromethyl-1 1-hydroxy-17-6-isopropoxycarbonyloxyandrost-4-en-3-one-17-carboxy-xylate is obtained, m.p. 183.5-184, after recrystallization from tetrahydrofuran-hexane.
    The steroid acid is also replaced by an equivalent amount of 17a; -ethoxycarbonne-1-1 | 3-hydroxyandrost-4-ene-3-one-17-carboxylic acid, chloromethyl iodide is replaced by an equivalent amount of butyl chloride, and the procedure is repeated with the exception of washing steps with 5% sodium thiosulfate.
    In the same way, the intermediate salt 1 7.l is obtained:; - ethoxycarbonyloxy- 1 Sh-hydroxyandrost-4-en-3-one-1 7 / sodium carboxylate and the final product butyl-7ob-ethoxycarbonyloxy-11-hydroxy-androst -4-en-3-one-1 7 / -carboxylate with so pl. 148-149 ° C after crystallization from acetone.
    After chromatography and crystallization of IR (KBG) 3600-3200 (p-H), 3000-2800 (C-H), 1750 (), Gb70 ().
    NMR (CDC1,) S 5.64 (s, 1,) 4.46 (v, 1, CHOH), 4.32–4.95 (m, 4, pines jCH,, COOCHjCHj-).
    Calculated,%: C, 67.99; H 8.39.
    With OY
    Found,%: C 67.76; H 7.74.
    Example 2. Following the procedure of Example 1 and replacing the corresponding reagents, the following compounds are prepared:
    2A-1: chloromethyl-1 7cg, -ethoxycarbonyloxy-9ob-fluoro-1 1 A-hydroxyandrost-4-en-3-one-17 | 3-carboxylate, m.p. 228-229 C (THF / hexane);
    2A-2: chloromethyl-7e-ethoxycarbonyloxy-9o (.-Fluoro-1-hydroxy-16-methyl-androst-, 4-diene-3-one-1 7 /} - carboxylate, m.p. 220-22 ° C (THF / hexane);
    five
    - O - t S -
    20 - -30 35
    -
    , 40
    50
     ,four
    2A-3: chloromethyl-7ob-ethoxycarbonyloxy-9 |) b-fluor-1Y-OXI-1 6l-methyl-androst-1, 4-diene-3-one-1 7 / -carboxylate, t. square 230-235 ° C (THF / hexane); 52A-4: chloromethyl-1 7 () - ethoxycarbonyloxy-1 1 | -oxyandrost-1,4-diene-3-one-7 / -carboxylate, mp, 220.5-223.5 ° C (THF / hexane);
    2A-5: chloromethyl-1 1 -oxy-1 7a; -isopropoxycarbonyloxyandrost-1,4-di- 3-one-17 3-carboxylate, m.p. 197-98 ° C (THF / hexane);
    2A-6: chloromethyl 17 ° (, - ethoxycarbonyloxy-9c6-fluoro-1p-oxyandrost-1, 4-diene-3-one-17 -carboxylate, mp.245-248 ° C (THF / hexane);
    2A-7: chloromethyl-9o-phto p-1 1 / -oxy-1 7c6-isopropoxycarbonyloxy-1 6ob-methylandrost, 4-diene-3-one-17ft-carboxylate, m.p. 84.5-186 ° C (THF / hexane);
    2A-8: chloromethyl-9 ":, - fluoro- / 3-hydroxy- 1 7 | -isopropoxycarbonyloxy-6p-methylandrost-, 4-diene-3-one-1 7 -carboxylate, m.p. 174-175.5 ° C (THF);
    2A-9: chloromethyl-1 1Y-OXY- 7 |; -iso-butoxycarbonyloxyandrost-4-en-3-one-17 -carboxylate, m.p. 140-141 ° C (THF / isopropyl ether);
    2A-10: chloromethyl-17 ° C-cyclohexyl-hydroxycarbonyloxy-1 1 -oxandrost-4-en-3-one-17 -carboxylate, m.p. 148-50 ° C (isopropyl ether / hexane);
     chloromethyl-1 1 -oxy-1 7ot-propoxycarbonyloxyandrost-4-ene-3-one-17 (3-carboxylate, mp 181-182 ° C (THF / hexane);
    2A-1 2: chloromethyl-9-fluoro-If) -oxy- 1 6 (-methyl-1 7 °;, - propoxycarbonyloxy-androst-1, 4-diene-3-on-1 7/3-carboxylate, mp 176-176.5 ° C (THF / hexane);
    2A-13: methyl-1 1 -oxy-1 7 (-isopropoxycarbonyloxyandrost-4-en-3-on-7p-carboxylate, mp 21 1.5-213.5 s (THF / hexane);
    2A-14: ethoxymethyl-1 1/3-OXY-1 7bb-isopropoxycarbonyloxyandrost-4-en-3-OH-7p-carboxylic silate, m.p. 137-38 ° C (THF / hexane);
    2A-15: chloromethyl-1 7o6-benzyloxycarbonyloxy-11-oxyandrost-4-ene-3-one-17-carboxylate, mp. 82-183-C (ethanol);
     1-chloroethyl-1 l | 3-oxy-17a6-isopropoxycarbonyloxide-4-he-3-on-l 7 -carboxylate, so pl. 181-182, THF / hexane, m.p. 199-200 s (THF / hexane);
    45
    51з
    2A-17: ethoxycarbonylmethyl-I 1/3 hydroxy-1 7y, -isopropoxycarbonyloxyand-growth 4-en-3-one-17p-carboxylate, mp; 73-7 / 4 C (isopropyl ether);
    2A-18: 1-chloroethyl-9c-fluoro-P / 5-ox-1 7 (x; -isopropoxycarbor {iloxy-1 6/3-methylandrost-G, 4-diene-3-on-1 7 | -carb-oxylate, mp, 67.5-169 ° C (THF / hexane), mp 163-164 ° C (THF / hexane);
    2A-1 9: chloromethyl-9 | x; -fluoro-1 7c-isopropoxy of rbonyloxy-6 methyland-growth-1,4-diene-3,11-dione-17-carboxylate, m.p. 200-20 s (THF / isopropyl ether);
    2A-20: chloromethyl-9c C-fluoro-1 7o-iso-propoxycarbonyloxy-1 bo-methylen-growth-1, 4-diene-3, 1 i -dione-7-carboxylate, m.p. 138-140 ° C (THF / isopropyl ether);
    2A-2 1: chloromethyl-9o6-fluoro-1 1 | 3-oxy-1 7oi-meth-carboxylic-1 bob-methyl-androst-1,4-diene-3-one-17 / e-carboxylate, t. square 260-263 ° C (THF / hexane);
    2A-22: fluoromethyl-1 1 -oxy-1 7if, -ii30-propoxycarbonyloxyandrost-4-en-3 it-17/3-carboxylate, m.p. 207.5-210 ° C (THF / hexane);
    2A-23: chloromethyl-9og, -fluoro-1 1/5-hydroxy-16 (y; -methyl-1 7o, -pyentyloxycarbonyloxy-androst-1,4-diene-3-one-17p-carboxylate, t mp 176-177 ° C (THF / hexane);
    2A-24: chloromethyl-1 6ci., 1 (ethoxycarbonyloxy) -6 (li-fluor-1/3-hydroxyand-growth-154 diene-3-one-17 p-carboxylate, mp 153-154 ° C (THF / Hexane);
    2A-25: fluoromethyl-1 7 |) -ethoxycarbonyloxy-9sL-fluoro-1 1 -oxy-16o6-methyl-androst-1, 4-diene-3-one-1 7 / -carboxy lat, m.p. . 239-240, (TGO / hexane);
    2A-26 acetoxymethyl-1 7 (ethoxycarbonyloxy-1 1B-hydroxyandrost-4 - en-3-one-17/3-carboxylate NMR (CDCl) 5.76 (s., 2, OCH, 0) , 2.01 (s., 3, SSh,)
    2A-27: chloromethyl-1 7ob-ethoxycarbonyloxy-6o, 9c1C-difluoro-1 1 -oxy-1 6 (i.-Me-tylandrost-1,4-diene-3-one-7-carboxylate, mp 195-197 s (THF / hexane);
    2A-28; 2-CHLORETHYL-1 7sb-ethoxycarbonyloxy-9o6-fluoro-1 1/5-hydroxy-6l-metsh1-androst-1, 4-diene-3-one-7/3-carboxydate, so pl. 243-245 ° C (THF / hexane);
    2A-29: methyl-17ob-ethoxycarbonyl-hydroxy-9l-fluoro-1 5 -o xi-6 ″ -methyland growth-1,4-diene-3-one-1 7/3-carboxylate, mp. 258.5-262.5 C (THF / hexane);
    2A-30: 2-chlorometsh1-1 7ob-isopropoxycarbonyloxy-11-oxyandrost-4-en9 6
    H-one-17-carboxylate, m.p. 188.8-189, (THF / hexane).
    Compounds 2A-16 and 2A-18 are diastereomers.
    Example 3. The starting material 1 1p-oxy-1 7 {1,; - the methoxycarbonyloxyando-growth-4-en-3-one-1 7/3-carboxylic acid used in example 1 is replaced by an equivalent amount of 11 /,
    1 71x; -dioxyandrost-4-en-3-one-1 7 / i -carboxylic acid and repeat the procedure of Example I. Thus, as the intermediate salt I, I 1 / 5-1 7e.-dioxyandrost-4 -en-3-one-1 7/3-sodium carboxylate, and as the final product - chloromethyl-1 1 / J, 1 7 b-dioxy-androst-4-en-3-one-1 7/5-carboxylate from m.p. 184-186 ° C (recrystallization from tetrahydrofuran / ether-hexane).
    Example 4, Chloromethyl- 7 (b-ethoxycarbonyl.oxy-9sb-fluoro-1/3-hydroxy-16ob-methylandrost-1, 4-diene-3-one-7/3-carboxylate (2 g) is dissolved in anhydrous dichloromethane (200 ml) and pyridine chloroformate (3.5 g) is added at room temperature with stirring. The resulting mixture is stirred for 24 hours, then the solvent
    concentrated under reduced pressure at 10-20 ° C, the residue is subjected
    chromatography on a silica gel column (Kiesel gel 60) using chloroform as a solvent, followed by recrystallization from a mixture of tetrahydrofuran and isopropyl ether to obtain chloromethyl 1 7 () b-ethoxycarbonyloxy-9o | 1-fluoro-1 bob methyl androst-1, 4-diene-3, 1 1-dione-1 7p-carboxylate with a yield of 1.7 g, mp 38-140 ° C.
    Example 5 In Example 4, chloromethyl 9o-fluoro-1 7c6-isoproxy-hydroxycarbonyloxy-1 6/3-methylandrost 1, 4-diene-3, 1 1 -dione-1 Jj carboxylate is obtained,
    m.p. 200-201 s.

    Example 6. Using the general procedure of Example I, but replacing the appropriate reagents, methyl-1 7oi- (2-chlorophoxy) carbonyloxy- -9 | ; -fluoro-1 l / i-hydroxy-1 bob-methyl androst-1,4-diene-3-one-1 7/1-carboxylate. After recrystallization from isopropanol, the product has m „PL. 223-227 C.
    Example 7 According to Example I, 2-chloroethyl-7o-ethoxycarbonyloxy-9o-fluoro-1/5-hydroxy-1 boC-methylandroth-1,4-diene-3-one-1 7 / -carboxylate is obtained. Product
    after recrystallization from rofuran-hexane tetrahydride, m.p. 243-.
    Example 8, Kpormethyl-17a; .- ethoxycarbonyloxy-11-oxyandrost-4-en-3-one-17p-carboxylate (0.01 mol and I, 2-dimethylpyrrolidine (0.01 mol. Dissolved in acetonitrile. (80 ml and heated to reflux. The reaction mixture was kept at that temperature with stirring for 4 hours. Approximately 65 ml of acetonitrile was separated, then the mixture was cooled to room temperature and excess ethyl ether was added to precipitate. are filtered, washed and dried in vacuo, thus obtaining the corresponding quarters common ammonium salt.
    Example 9. Following the general procedure described in Example 1 and using the appropriate reagents, the following new intermediate products are obtained:
    9C-1: 1 7ob-allyloxycarbonyloxy-9c6-fluoro-1 1 -oxy-1b9, -methyandrost-1,4-diene-3-one-17 -carboxylic acid
    9C-2: 11 -n-propoxycarbonyloxy- bob, 9k, -difluoro-1 1p-hydroxy-1 bob-methyl and-growth-1,4-diene-3-one-17p-carboxylic acid;
    9C-3: 1 7o-isopropoxycarbonyloxy-6o, 9 (y1-difluoro-1 1p-hydroxy-1 6 -methyl-androst-1,4-diene-3-one-17-carboxylic acid;
    9C-4: 1 7o-ethoxycarbonyloxy-6o-fluoro-1 1 -oxy-1 6o6-methylandrost-1, 4-diene-3-one-1 7 -carboxylic acid;
    9C-5: 1 7o.-n-propoxycarbonyloxy - 6 () (, - fluoro-1 lp-hydroxy-16o6-methylandrost-1,4-diene-3-one-17 -carboxylic acid
    9C-6: 1 7-isopropoxycarbonyloxy bs-fluoro-1 1p-hydroxy-1 6l-methylandrost-1,4-diene-3-one-1 7 | 5-carboxylic acid
    9C-7: 1 7-methoxycarbonyloxy-1 1/3 oxyandrost-1, 4-diene-3-one-1 7 /} - carboxylic acid;
    9C-8: 1 7ob-methoxycarbonyloxy-6 (1bfluoro-1 1 | 5-hydroxy-16ob-methylandrost-1,4-diene-3-one-1 7/5-carboxylic acid;
    9C-9: I 7ob-ethoxycarbonyloxy-1 1/3-hydroxyandrost, 4-diene-3-one-17-carboxylic acid;
    9C-10: 17 (s-metoxycarbonyl-9-fluoro-1 1 -oxy-16-methylandrost-1,4-diene-3-one-1 7/5-carboxylic acid;

    98
    9C-11: 1 7o -n-propoxycarbonyloxy-9o: -fluoro-1 jb-OKCH-16 -methyandrost-1, 4-diene-3-one-1 7/3-carboxylic acid.
    Intermediate products are presented in table. one ,
    Example 10 Following the procedure described in Example 1 and using the appropriate reagents, the following compounds are prepared:
    10C-1: chloromethyl-1 7o: -isopropoxy-carbonyloxy-bos, 9a; -difluoro-1 1 -oxy-1 bob-methyl androst-1, 4-diene-3-one-1 carboxylate;
    10C-2: chloromethyl-1 7o-n-propoxy-carbonyloxy-bs, 9c, -difluoro-1 1 -oxy-16o (.-Methylandrost-1, 4-diene-3-one-1 carboxylate;
    1OC-3: fluoromethyl-1 7c-n-propoxy-carbonyloxy-91ch1-fluoro-1 1 -oxy-1 bl, - methylandrost-1,4-diene-3-one-1 7/3-carboxyl oxylate;
    1 OC-4: 2-chloroethyl-1 7ei-isopropoxy carbopyloxy-1 1 -oxandrost-1, 4-diene-3-one-1 7-carboxylate;
    10C-5: methyl-1 7 (b- (2-chloroethoxy) carbonyloxy-9 | X-fluoro-1 1/3-hydroxy-16ot-methylandrost-1,4-diene-3-one-17 -carb- oxylate;
    10C-6: chloromethyl-1 7cc-ethoxycarbonyloxy-6c gfluoro-1 p-oKCH-bs (.-Methyl-androst-1, 4-diene-3-one-1 7/3-carboxylate;
    1 OC-7: chloromethyl-1 7og, -n-propoxy-carbonyloxy-bss-fluoro-1-oxy-16 (- methylandrost-1, 4-diene-3-one-1 7 3 -carboxylate;
    10C-8: XJ-termethyl-l 7th; - isopropoxy-carbonyloxy-bl-fluoro-1 1 | 3-hydroxy-1 6ct-methylandrost-1, 4-diene-3-one-1 7/3-carboxyoxylate;
    10C-9: chloromethyl-1 7o6-n-propoxy-carbonyloxy-11p-oxyandrost-1,4-diene-3-on-1 7 | 3-carboxylate;
    1OC-1 0: chloromethyl-1 7-methoxycarbonyloxy-1-oxyandrost-1,4-diene-3-one-17p-carboxylate;
    1 OS-1 1: chloromethyl- 1 7CC-methoxycarbonyloxy-b (L-fluoro-1 1 -oxy-1 bo-methyl androst-1,4-diene-3-one-17-carboxylate;
    JUS-12: chloromethyl-1 7yb-methoxycarbonyloxy-9o.-fluoro-1 1 -oxy-16p-methyl androst-1, 4-diene-3-one-1 7 / -carboxylate;
    JUS-13: chloromethyl-I 7c1-n-propoxy-carbonyl-hydroxy-9ob-fluoro-1 1p-hydroxy-1b - methylandrost-1, 4-diene-3-one-1 7/3-carboxylate.
    913
    The compounds obtained are presented in Table. 2
    Example 1 1 To a solution of 3 g of chloromethyl-1 Ip-OKCH-l 7-isopropoxycarbonyloxy-aa-dyrost-4-en-3-one-1 7/3-carboxylate in 10.0 ml of O-acetonitrile was added 7.9 g (10 mol) of AgF and the mixture was stirred at room temperature for 12 days, shielding the reaction system from light. The reaction mixture is then filtered and the filter cake is washed completely with ethyl acetate. The filtrate and ethyl acetate solution are combined and the mixture is washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulphate. The solvents were distilled off to give 2 g of crude crystalline product. The product is subjected to preparative thin layer chromatography (silica gel 60F 254, Merck) using a mixture of chloroform and methanol (15: 1) as eluent. The product is then recrystallized from a mixture of tetrahydrofuran and n-hexane to obtain 180 mg of fluoromethyl-1 p-hydroxy-1 7ob-isopropoxy-carbonyloxyandrost-4-en-3-one-1 7/5-carboxylate in the form of colorless needles, melting at 207.5-210 C.
    Example 12. In Example 11, replacing the reagents, the following compounds are obtained:
    12-1: fluoromethyl-1;
    12-2: fluoromethyl-1 7 ln-propoxy and carbonyloxy-9o1-fluoro-11 p -oxy-16c 5-methylandrost-1, 4-diene-3-he-1 7y-carboxyl oxylate.
    Example 13. According to the procedure described in examples 1 or 12, with the replacement of the corresponding reagents, the compounds shown in Table 2 were obtained. 3
    Mild steroids of the formula I and quaternary ammonium salts are strong local anti-inflammatory agents. However, due to the fact that their easy destruction in vivo only leads to an inactive steroid metabolite, the compounds have much less systemic activity than the known glucocorticosteroids, from whose inactive metabolites 910
    the tone they occur. Many of the compounds are completely devoid of systemic activity.
    The results of studies of the activity of the proposed compounds indicate a strong anti-inflammatory activity and minimal systemic activity (toxicity) of soft steroids of formula I. Because of this, soicinines can be used in the treatment of topical or other localized inflammatory processes without causing serious systemic side effects commonly manifested by known natural and synthetic glucocorticosteroids, such as cortisone, hydrocortisone, hydrocortisone-1 7a1-butyrate, betamethasone-17-va- lerat, triamcinolone, betamethasone dipropionate, etc.
    Thymus involution test. The test animals were female Spague-Dawley rats weighing approximately 40-45 g. One side of each ear of each rat was treated with 25 μl of a solution (ethanol / isopropyl-myristate or acetone / isopropyl myristate 90:10) containing the test compound. Control animals were treated in the same way, but without the test compound. After 24 hours, all rats were sacrificed and weighed, their thymuses (thymus g) were removed and weighed.
    In tab. Figure 4 shows the effect of topical steroids on thymus weight, where SD is the standard (rms) deviation.
    Thymus weight change is
    a measure of systemic activity, and therefore toxicity. The lower the weight of thymus, the higher the systemic activity.
    As can be seen from the above data,
    even hydrocortisone, a natural glucocorticoid, causes a significant reduction in the weight of the thymus compared with the control. Reduced weight of the thymus caused by equal doses of the proposed
    compounds, much less significantly, therefore, these compounds have much less systemic activity than hydrocortisone.
    55
    Examination of blanching.
    Studies on the blanching of people of the Mekenzie type were undertaken to study the effects of blanching caused by the test compounds in particular 1113
    Chloromethyl-1 7c, -ethoxycarbonyl-hydroxy-1 1-oxyandrost-4-en-3-one-1 7 | J-carboxylate. The ability of compounds to cause blanching in humans has been found to be related to their anti-inflammatory activity.
    The test compound was dissolved in ethanol / isopropyl pyristate (90:10 or 70:30) in concentrations of 0.03; 0.01; 0.003; 0.001 and 0.0003 m. Pieces of a gauze bandage were soaked in a solution of 50 µl each and the patch applied to the forearm. After a 6-hour exposure, the dressing was removed. After 1-5 hours after removal of the dressing, fading was observed even at the lowest concentrations of the test compound.
    When testing hydrocortisone, blanching was not observed at concentrations of hydrocortisone below 0.03 M. In addition, it was observed that hydrocortisone at a concentration of 0.03 M caused approximately the same degree of blanching as chloromethyl-7od-3TOKCHKap-bonyloxy-1 1 | 5 -oxyandrost-4-ene-1 carboxylate at a concentration of 0.001 M.
    Test with ear edema.
    Experimental animals were Sprague-Dawley rats weighing approximately 150 g. The test compound was dissolved in acetone containing 5% croton oil, and 50 µl of the solution was applied to the inner surface of the rat's right ear. The control group was treated identically only by the carrier, i.e. 5% solution of croton oil in acetone. After 6 h
    after applying croton oil, the same area of each ear was removed by incision under anesthesia. 48 hours after the steroid treatment, the animals were killed and the thymuses and adrenal glands were removed and weighed. The test results, showing the inhibitory effect of topically applied steroids. On the ear tumor caused by croton oil are summarized in Table. five.
    As can be seen from the table. 5, chloromethyl-1 7-ethoxycarbonyloxy-11-oxyand-growth-4-ene-3-one-17th-carboxylate substantially inhibits the formation of a tumor (and therefore weight gain) of the ear caused by croton oil, i.e. the compound exhibits significant anti-inflammatory activity. On the other hand, in contrast to the action caused.
    6912
    betamethasone-17-valerate, the proposed compound did not cause a significant decrease in the weight of the thymus compared with the control, i.e. it did not detect a significant degree (systemic activity.
    Test with the formation of granulomas.
    The test compound was dissolved in acetone and certain doses with various concentrations were injected into cotton ball pills. The pills were dried, and then one pill was implanted under the skin of each experimental Sprague-Dawley male rat weighing 152-189 g. After six days the animals died and the granulation tissue (granuloma), which was formed inside the ball and around the implanted ball, was removed , dried and weighed. In addition, thymuses and adrenal glands were removed and weighed. The ability of a compound to inhibit granuloma formation in this experiment indicates a local anti-inflammatory activity: the lower the weight of the granulation tissue, the higher the anti-inflammatory activity. On the other hand, a significant reduction in the weight of the thymus is evidence of high systemic activity; and vice versa, a slight decrease in the weight of the thymus with the tested compound as compared with the control indicates the absence (or the presence of minimal) systemic side effects.
    The effect of steroids in local administration on body weight, thymus weight and the formation of tissue granulation caused by implantation of cotton balls into rats is shown in Tables 6–9.
    Given in Table. 6–9, data suggest that the proposed compounds show significant anti-inflammatory activity at lower doses than the known steroids (hydrocortisone-17-butyrate and beta-metazon-17-valerate). On the other hand, all known steroids dramatically reduce the weight of thymus and, thus, show a very high systemic activity, while the proposed compounds almost do not reduce the weight of thymus. Thus, the proposed compounds have a much higher therapeutic ratio, i.e. local demarcation
    1313
    anti-inflammatory and systemic activity than the known steroid anti-inflammatory agents.
    According to the test results, it was calculated. the magnitude, EDU and ED and the relative strength of action (relative activity) of the proposed compounds, which are shown in Table 10. The strength of the action of chloromorbyl-1 1p-hydroxy-1 7oi- isopropoxycarbonyloxyandrost-4-ene-one-17r-carboxylate 1 for each level of AU, and the forces of other compounds are expressed relative to a given value. The values of AU, and AU are the doses required to achieve respectively a 40, 50 and 60% reduction in the weight of the granulation tissue.
    Thymus Inhibition Test
    Determine the effect of individual compounds on the weight of thymus in rats with the systematic administration of the drug (subcutaneously). Male Sprague-Dawley rats were used in each study. Test compounds were suspended in 0.5% carboxymethylcellulose and injected subcutaneously with one. once a day for three days. On the fifth day (cherbz 48 h after the last treatment), the animals were euthanized and thymus weight was recorded. The increase (increase) in body weight was measured 24 h after the last treatment.
    The results of the experiments are presented in table. 11-13.
    The TED45, TED values (the thymolytic effective doses required to achieve 40 and 50% inhibition of thymus weight, respectively) and the relative strength of the proposed compounds and known steroids administered subcutaneously are shown in Table. 14, with the relative strength of the known steroid betamethasone-17-vaperta taken as 1, while the strength of the other compounds is expressed relative to a given value. Obviously, the greater the inhibition of thymus activity at a given dose, the more toxic the compound is.
    The thymolytic activity of the proposed compounds was determined in comparison with betamethasone-17-valerate. The drug was administered intravenously to rats using a blind analysis for the granuloma in a cotton ball. Used male rats Spra914
    gue-dawley weighing 1 85 grams (166-196 g). Two cotton balls of 30 mg each, not containing test compounds, were sterilized and implanted.
    subcutaneously in the back of each experimental animal. This day was considered the day of zero implantation. Test compounds suspended in 0.8% polysorbate-80 were administered intravenously once daily for three days, beginning on the first day. On the 5th day, the animals were sacrificed and two balls with the corresponding granulomas were removed, dried in an oven overnight at 58 ° C and weighed (dry weight of the granulomas). Thymus weight and final body weight were also recorded. The results are given in table. 15.
    In previous experiments, the deactivation of soft steroids administered intravenously in a rat was determined. The ratio between the strength of the test
    steroids and betamethasone-17-vaperate versus local inflammation were 283: 0.7 (Table 11). This means that the test compounds exhibit local anti-inflammatory activity that is approximately 400 times higher than that of betamethasone-17-valerate. Test compounds were administered intravenously to rats for testing for systemic anti-inflammatory activity compared to betamethasone-1 7-valerate. The test compounds have a lower activity in inhibiting the formation of granulation tissue, as well as in relation to the activity of the reverse development of the thymus, than betamethasone-17-valyrate. From the results of experiments, it can be assumed that compounds that are not easily subjected to metabolism (deactivation) have systemic anti-inflammatory activity, as is the case with betamethasone-i7-valerate.
    The values of ED calculated by analysis of a local granuloma in a cotton ball and the values calculated on the basis of experiments on thymus inhibition were used to determine the relative potency and therapeutic coefficient (index) of the proposed compounds compared to the known steroids (Table 16).
    15
    The data table. 16 show strong anti-inflammatory activity and minimal systemic toxicity of the proposed compounds.
    Toxicity was determined by subcutaneously administering the compound to mice devoid of food for 12 hours prior to testing.
    The following LD values of 5 mg / kg were obtained:
    2D-2More than 5000
    2A-3
    2A-5
    2 A-7
    2A-8- -
    2A-12-2A-19More than 5000
    2A-20-2A-21-2A-23
    2 A-2 7

    II 11 It
    T |
    It
    9
    sixteen
    R,. Is hydrogen, about - or -methyl;
    R, is hydrogen or fluorine;
    Rj is hydrogen, fluorine or methyl;
    Zg - carbonyl or, y-hydroxymethylene, dotted line means a potential carbon-carbon bond, or their quaternary ammonium salts characterized in that the compound of the general formula I
    HE
    about
    .-- VTR-20
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    ; The method of obtaining steroid compounds of General formula I
     about
    3
    where RI is lower haloalkyl; R is lower alkyl;
    five
    0
    five
    where Rj, R, R, Ry and dashed line
    have the indicated meanings;
    M is an alkali metal, is subjected to interaction with the compound of the formula
    R, W, where R has the indicated meanings;
    W - helogen,
    and, if necessary, the obtained compounds of the formula I, where R (the lower halogen-substituted group, is reacted with a tertiary amine or with a nonsaturated amine, followed by isolation of the target products in free form or as quaternary
    ammonium salts. I
    ; Table 1
    9C-1-CHjCH CHj et-CH, F N
    9C-2 -CH CHjCHj-CH, F F
    CH,
    9C-3-CH
    - CH,
    ct-CH, F F
    sh
    n
    1.4 227-229
    (THF / Hexane)
      148-155
    (ethanol / water decomposition)
    1,4 157-159 (ethanol / water)
    1 OS-1
    -sn, C1, SNS
    IOC-2, -CH
    10C-3-CHjF-CH, CH, jCH, .o6-CH,
    / SNZ
    10C-4 -CH, CH, C1-CHvH
    SNS
    Continued tabl, 1
    .HE
    JUS-I
    -CHj, Cl
    -en.
    oi-CH,
    Continuation of table 2
    (THF / n-hexane)
     /HE
    F X.
    .he
    1.4
    244.5-245.5 (THF / n-hexane)
    0, 75
    0.75 0.75
    364 + 29 274145
    347if3I
    309t4
    Control Chloromethyl-0.3 I 7 "-ethiCi-carbonyl-I-I-1lp-hydroxy-aid-3 growth-4-ene-3-one-7) 5-carboxylate
    75, 546.611.4 61.4t8.9-333 1523.3ii, 7
    62, at3.050, at2.4 23.3t7,262,129042526.042.5
    55, Ota, 648.4t, 0, I4.06t6.577.2293i2iI8.7 ±, 4
    52.6tl, 83I, 6t3.2 3.7t8, J9 (, 028812120.3 + 0.8
    48.44 61.42 27 + 6
    49.44 61.15 24 ± 7
    48.06 62.10 29 + 5
    45.57 60,60 33 + 6
    Table 5
    Hydrocortical eo11-17butnrat15
    Betameeon17-iperate I5
    50.0 + 2.3 52.012.5-3, 5 106.0 303i2l 20.2 ± 0.7 55, 2 50.4 ± 2.0 10, 3 82.2 I8.9tt, 9
    Table 6
    Table 7
    Control
    Chloromethyl17-ethoxycarbonyl-
    C-9A-fluoro1 ljj-hydro
    si-6-methylandrost 1, 4-da1en-3on-17 -carboxylate
    Hlrrmethyl-9Y.- fluoro-P) -hydroxy-16 C-me — type-1Uy-propoxycarbonyl-oxyandrost-1, D-diene-3-one-17p-carboxyl
    Betameson-57-valerate
    Clobetasol-17-propionate
    Control Chloromethyl-9bofluoro-1 7oi-H3o-propoxycarbonyloxy-16 methylandroth-1,4-diene-3,11-dione-I7 -carboxylate
     Table 8
    307
    238-394
    47
    15-85
    6.5
    653
    0.47 0.23-0.75
    0.25
    0,004-0,886
    1228
    Table 10
    460
    690
    360-623
    523-1023
    301
    2., 3
    178-627
    2.44
    . 283
    1.65-3.86
    0.97
    3.75
    474
    184
    0.08-2.31
    1.25-7.68
    2,316.45
    13371
    1, 07-6,38 2,96-44,58
    - - - -
     Clobetasol-17-propyrnate - - 3
    Chlormetsh1-9eb- 0,581,20
    fluoro-1 l 5-hydroxy-16oi-methyl-17oi.-529383 propoxycarbonyl
    Oxyandrost-1,4- (0.20-1.01) (0.67-2.88) (1.37-13.32) Dien-3-one-17r-carboxylate
    10 2, -49
    Note, numbers in parentheses are 95% guaranteed limits.
    Control
    Chloromethyl-1 1 -
    HYDROXI-1 7 (| 6-Isopropoxycarbonyl-oxyandrost-4-en-3-one-17th-carboxylate
    Chloromethyl-hydroxy-17H -iso-propoxycarbonyl-oxyandrost1,4-diene-3-one-17 - carboxylate
    18.01
    38
    6.47-393.8
    1015 0.7
    (72426866)
    10 2, -49
    277
    Table 1 1
    Control
    Chloromethyl-1 7os-ethoxycarbonyloxy-9ob-fluoro-1 1 | 3-hydroxy-G6l-methylandrost-1,4-diene-3-one-1 7/5-carboxylate
    Chloromethyl-9vb fluoro-1 1 3-hydroxy-1 7rb-isopropoxycarbonyloxy-16 "b-meth1andro st-1 4-da1en-3-one-1 7 -carboxylate
    Chloromethyl-9 "b-fluoro-11/1-gid-. Roxy-1 7-isopropoxy-1-sarbonyloxy-6 5-met1shandrost-1,4-diene-3-one-17-carboxylate
    Table 12
    18.9 ± 0.6 550 + 24
    14.2 + 1.9 533 ± -31
    3.1
    2.7 + 1.9 234t31
    57.5
    5.3il, 4 260t26
    52.7
    Note. The weight of rats is 91-112 g.
    31.0
    0, 01
    (23 9-41-9)
    16.2
    0, 02
    (11.2-2.2)
    51.5
    0, 0058
    (26.5-29.0)
    1,3
    0.23
    Even with a dosage level of 100 mg / kg / day, it cannot reach 50%
    decrease in thymus weight.
    Table 5
    58.5
    (33 -87.1) 35.3
    (24.6-57.5)
    51.5
    0.01
    0.02
    0.011
    2.0
    0.29
    17-.
    0.1 0.3 I 3
    Chloromethyl-1 1p-hydro-
    Roxy-1 7 "b-isopropoxycarbonyloxyand-growth-4-ene-3-one-17 - carboxylate
    Chloromethyl-1lp-hydro
    Roxy-1 7ob-isopropoxycarbonyloxyand-growth-I, 4-diene-3-one-17th-carboxylate
    Chloromethyl-17sb-ztok-
    Sicarbonyloxy-9 | 1b-fluoro-11 | hydroxy-
    1bl-methylandrost1, 4-dien-3-one-1
    carboxylate
    Chloromethyl-9c-fluoro-1 Li-hydroxymethyl-androst-1,4-diene-3-one-17b carboxylate
    Hydrocortisone-17-butyrate
    Vetameson-17-valerat
    The anti-inflammatory effect of the granuloma caused by cotton balls (µg / ball).
      For a delaying effect on thymus growth with subcutaneous administration (mg / kg. The ratio between the relative strength with ED, and the relative strength with
     .
    VNIIPI Order 2441/58 Circulation 347 Subscription
    Random polygons pr-tie, Uzhgorod, st. Project, 4
    21.4 305 1427.7 29.2288i2731.8
    26.5233tl544,8
    24.6I67t2260,4
    Table
    sixteen
    1/24
    24
    1/12
    48
    1/40
    18,000
    1/36
    one
    four
    7270 1
    one
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4607028A|1983-08-18|1986-08-19|Ciba-Geigy Corporation|Novel carboxylic acid esters|
    SE8501693D0|1985-04-04|1985-04-04|Draco Ab|NOVEL 16,17-ACETALSUBSTITUTED ANDROSTANE-17BETA-CARBOXYLIC ACID ESTERS|
    IL78144D0|1985-04-04|1986-07-31|Draco Ab|Novel androstane-17beta-carboxylic acid esters|
    DE19947235A1|1999-09-30|2001-04-05|Asta Medica Ag|New combination of loteprednol and beta¶2¶ adrenoreceptor agonists|
    US6858596B2|2000-08-05|2005-02-22|Smithkline Beecham Corporation|Formulation containing anti-inflammatory androstane derivative|
    GB0019172D0|2000-08-05|2000-09-27|Glaxo Group Ltd|Novel compounds|
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    BRPI0113042B8|2000-08-05|2021-05-25|Glaxo Group Ltd|compound of the formula or a physiologically acceptable solvate thereof, use thereof, pharmaceutical composition, pharmaceutical formulation, method of treating a human or animal subject with an inflammatory and/or allergic condition, and, process for preparing a compound or a solvate thereof|
    CA2445839A1|2001-04-30|2002-11-07|Glaxo Group Limited|Anti-inflammatory 17.beta.-carbothioate ester derivatives of androstane with a cyclic ester group in position 17.alpha|
    GB2389530B|2002-06-14|2007-01-10|Cipla Ltd|Pharmaceutical compositions|
    MXPA05013898A|2003-06-19|2006-05-25|Nicholas S Bodor|Enhancement of activity and/or duration of action of soft anti-inflammatory steroids for topical or other local application.|
    GB0523251D0|2005-11-15|2005-12-21|Glaxo Group Ltd|Novel compounds|
    TWI374147B|2006-01-27|2012-10-11|Sun Pharma Advance Res Company Ltd|Novel 11β-hydroxyandrosta-4-ene-3-ones|
    US7687484B2|2006-05-25|2010-03-30|Bodor Nicholas S|Transporter enhanced corticosteroid activity|
    WO2018232007A1|2017-06-13|2018-12-20|Bodor Laboratories, Inc.|Potent soft anti-inflammatory corticosteroid compounds and uses therof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US16845380A| true| 1980-07-10|1980-07-10|
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