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United States Patent O?ice 3,®@9,4Z€l Patented Dec. 18, 19532 1 3,069,420 16¢,1'7a-‘(IYQLQCARBONATE ESTERS 0F 160:,17a l6a-hydroxycortisone 16a,17u-carbonate, l6a-hydroxycortisone 16a,17a-carbonate 21-acetate, 2ot-methyl- l 6a-hydroxyeortisone 16a,17ot-C?11‘bOna’[e, 9a-?uoro-l6a-hydroxycortisone 16a,l7a-carbonate, DEHYBROXY STEROIDS Josef Fried, Princeton, Ni, assignor to @lin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed July 17, 1961, Ser. No. 124,383 7 Claims. ((11. 269-43955) 12a-?uoro- l 6a-hydroxycortisone 16a, Hot-carbonate, 6a-methyl-1 6OL~i1ydfOXYCOIlIlSO116 16cc, 17OL-CEUE‘bODatG, 6a-chloro-16a-hydroxycortisone 16a,17a-carbonate, 6:1,9ot-di?l10f0-16ot-hYd1‘OXYCOItiSOI16 16a,17a-carbonate, This invention relates to 16a,17a-cyclocarbonate esters of 160:,170t-dii1Ydf0XY steroids of C-ring substituted preg 90:,21-di?uoro-A4-pregnene-16a, 17a.-diol-3 ,11,.20~trione 16a,17ot-carbonate. nenes, that is steroids having a pregnene, pregnadiene or pregnatriene nucleus. More particularly, the invention relates to compounds represented by the formula 15 16a-hydroxyprednisolone l6tt,l7u-carbonate, 9a-?uoro-1oa-hydroxyprednisolone 16a,17ot-carbonate, lla-chloro-l6a-hydroxyprednisolone 16a,17a-carbonate, éa-methyl-l6ot-hydroxyprednisolone IMAM-carbonate, 6ot~fluoro-l6ahydroxyprednisolone 16a, 17a-c arbonate, 6a.,9a-di?uoro-l6a~hydroxyprednisolone 1604,17» carbonate, 9a,21sdi?uoro-alA-pregnadiene-1 lp,16cx,17a—triol-3,20 dione 16u,l7ot-carbonate. loct-hydroxyprednisone 160:,170t-C31‘i30115t6, 25 loa-hydroxyprednisone 16m, Nit-carbonate 2.1~acetate, 9oc-?llO1'O- l 6m-hydroxyprednisone 1606,17Ct-C8Ib0l'1?i6, i2a-?uoro-l6a-iiydroxyprednisone 16cc, 170t-C21fb0l13t6, 6a.-rnethyl- 1 ?a-hydroxyprednisone l6a,17v.-carbonate, In Formula I, the 1,2- and/or 6,7—positions may be satu rated or double bonded so that A4-, A1143 A‘LB- and AL“ 30 pregnanes are included within the scope of this invention. 6a-chloro~l6a-hydroxyprednisone l6cz,17ot-CarbOnate, 6a,9a-di?uoro-l6a-hydroxyprednisone 16ot,170t.-C21Ib0l'13i6. The symbols in Formula I have the following meanings: R represents hydrogen, R’ represnts fi-hydroxy or to gether R and R’ are keto (C20); R" represents hydro gen, halogen or lower alkyl; X and X’ each represents 35 hydrogen or halogen, but at least one of these two sym bols represents hydrogen; Y represents hydrogen or lower alkyl, preferably methyl; and Z represents hydrogen, halogen, hydroxy or the acyloXy radical of a hydrocarbon carboxylic acid of less than 10 carbon atoms. The symbols R”, X, X" and Z represent all four halo gens but chlorine and ?uorine are preferred in this group. The same or different halogens may appear in a given compound. Lower alkyl groups represented by Y and R" include straight and branched chain saturated hydro carbon radicals such as methyl, ethyl, propyl, isopropyl, butyl, t~butyl, amyl and the like. The compounds of this invention can be prepared by Carboxylic acids from which the acyloxy radical Z may reacting a compound of the formula be derived to produce ZI-esters include, for example, alkanoic acids, preferably lower alkanoic acids such as (II) acetic, propionic, butyric, heXanoic acids and the like, 50 (ll-I22’ lower alkenoic acids such as acrylic acid, monocyclic aromatic carboxylic acids such as benzoic and o~, m- and C=Q p-toluic acids, cycloalkanoic acids such as cyclohexanoic acid, cycloalkenoic acids such as cyclohexenoic acid, and monocyclic aryl-lower alkanoic acids such as phenylacetic 55 and B-phenylpropionic acids. The following 16a,17a-cyclocarb0nate esters of C-ring substituted-16a,l7a-dihydroxypregnenes are compounds of this invention. They and the working examples which follow serve to illustrate the class of esters included. l6a-hydroxyhydrocortisone 16a,17a-carbonate 21-acetate, 90c.—?tl0l‘0— l 6a-hydroxyhydrocortisone 16cc, 1 Wat-carbonate, IZa-chloro-l 6a-hydroxyhydrocortisone 16ot,17ot— carbonate, 6a.-methyl-16ot-hydroxyhydrocortisone 16c<,17a carbonate, 6a-?uoro-16ot-hydroxyhydrocortisone 16a,17a-carbonate, 6a,9<x-di?uoro-16u-hydroxyhydrocortisone 16a, 1 70¢ carbonate, |_ .. — _ __ ea - - tit-H 60 RE! wherein the 1,2- and/0r 6,7-positions are saturated or double bonded, R, R’, R", X, X’, and Y have the same meaning as before and Z’ represents hydrogen, halogen or the acyloxy radical of a hydrocarbon carboxylic acid of less than 10 carbon atoms, with phosgene to produce the cyclic carbonate. The reaction is carried out in the presence of an organic nitrogen base such as pyridine, col lidine, triethanolamine, quinoline or the like and the prod uct is recovered from the solution by conventional pro cedures. Preferably the compound of Formula II is dis solved or suspended in the basic medium and then treated 3,069,420 4 3 with an equimolecular proportion or excess of the phos hydroxyprednisolone, 6a,9a-di?uoro—l6a-hydroxypredni gene at a temperature below about 0° C. The starting materials of Formula I are known sub solone. The 2l-esters of l6a-hydroxyprednisones such as the stances or are readily obtained from known compounds. 21-acetates of l6ot-hyo‘roxyprednisone, 9ot-fluoro-l6a-hy Thus 16a,17u-dihydroxy compounds may be obtained from their known 17or~hydroxy analogs by enzymatic hy droxylation at the 16-positi0n by means of the micro methyl-l6a hydroxyprednisone, 6a—chloro-16u-hydroxy prednisone, 6e,9a-di?uoro-16tx-hydroxyprednisone. droxyprednisone, 12a-?uoro-l6a-hydroxyprednisone, 6a organism Streptomyces roseochromogenus according to ll-hydroxy- or 1l-keto-At-pregnene-l6a,l7a»di0l~3,20~ the method described in US. Patent No. 2,855,343. diones such as Similarly, compounds saturated in the l,2~position may 10 be convered to the corresponding 1,2-unsaturated com pound by the action of Bacterium cyclooxydans according to the method described in Example 1 of US. Patent No. 2,822,318. Compounds of Formula 11 bearing l2a-halo and/or 6cx-rnethyl substituents may be produced as described in my copending application Serial No. 677,205, ?led August 9, 1957, now abandoned. The 21-acyloxy-l6ot,17a-diol starting materials for the compounds of this invention can be obtained by treating the corresponding 16a,l7c¢,2l-triols with an acid anhy dride in pyridine and separating the resulting mixture by fractional crystallization. An alternate, more lengthy trione. but more general procedure involves the treatment of the The compounds of this invention are physiologically ac 25 l6a,l7u,2l-triol with a ketone (e.g. acetone) or the alde< tive substances which possess glucocorticoid and anti-in hyde in the presence of an acid catalyst, (e.g. perchloric ?ammatory activities and hence can be used in lieu of acid) to yield the corresponding 16L¥,17®-'l(€t21l or acctal known glucocorticoids such as hydrocortisone and corti which is then treated with an acyl chloride (e.g. acetyl sone in the treatment of rheumatoid arthritis for which chloride) or an acid anhydride (e.g. acetic anhydride) purpose they can be administered in the same manner 30 in a basic organic medium (e.g. pyridine) to form the as, for example, hydrocortisone, the dosage being adjusted corresponding 2l-acyloxy-l6a,-17a-ketal or acetal. The latter is converted by hydrolysis with aqueous formic acid to the desired 2l-acyloxy-16a,l7ot-diol by the proce dure described in my copending application Serial No. 84,989, ?led January 26, 1961. The 21-halo~16ot,17wdiol starting materials for the compounds of this invention are prepared by converting for the relative potency of the particular steroid. They may be administered orally, for example, in the form of tablets or capsules by incorporating a therapeutic 35 dosage with a carrier according to conventional practice. The following examples are presented to more fully illustrate the present invention (all temperatures being ex pressed in degrees centigrade). the corresponding 16u,17u,21-triol to its 16a,17u-ketal or acetal as described above, treating the latter with an organic sulfonyl chloride (e.g. tosyl chloride or rnesyl 40 chloride) to prepare the 2l-sulfonyloxy derivative which is then 2l-halogenated by treatment with an alkali metal (A) PREPARATION OF TRIAMCINOLONE 2l-ACETATE A solution of 500 mg. of triamcinolone and .195 ml. halide (e.g. potassium bi?uoride, lithium chloride, lithium (1.6 moles) of acetic anhydride in 8 ml. of pyridine is bromide and sodium iodide). The latter is converted to the desired 2l-halO-l6oz,l7oc-dl0l compound by hydrolyz EXAMPLE 1 Triamcinolone Z 604,17ot-Cdl‘b0?dt8 21-Acetate 45 allowed to stand at room temperature for 20 hours. After removal of the reagents in vacuo, the residue is triturated ing oil‘ tie 16a,l7ot-acetal or ketal grouping with formic acid. When a 6,7~saturated steroid is used as the starting material and a 6-dehydro ?nal product is desired, the washed with chloroform. The crystalline precipitate after in ethyl acetate and acetic acid. Among the starting materials of Formula II which may be used to produce the products of Formula I are the 5.75, 5.82, 6.04, 6.20 and 625a Analysis.—Calc’d for C23H29OqF (436.46): C, 63.29; with chloroform, the resulting crystals ?ltered, and recrystallization from acetone furnishes about 130 mg. latter may be obtained by treating the 6,7-saturated 50 of pure triamcinolone 21-monoacetate having the follow ing properties: M.P. 2l8~220° and 227~229°; l6u,l7a-cyclic esters of this invention with a dehydro [a]D23—|-57° (c. .37 in acetone); genating agent capable of selectively dehydrogenating this postiion. A suitable dehydrogenating agent is chloranil Hit}. 238 mu (E=13,600); Milli?‘ 2.88 (shoulder), 2.98, following: H, 6.69. Found: C, 63.21; H, 6.81. The 21-esters of l6u-hydroxyhydrocortisones, such as (B) PREPARATION OF TRIAMCINOLONE 160.,17a the 2l-acetates of 16u-hydroxyhydrocortisone, Zea-methyl 16a-hydroxyhydrocortisone, 9ct—?ll01"0—l6oz-hYClI'0XYhYdI'O CARBONATE 21-ACETATE 60 cortisone, 12a-chloro - 16a - hydroxyhydrocortisone, 6a - To a solution of 200 mg. of triamcinolone 2l-mono methyl- 1 6a-hydroxyhydrocortisone, 6a-?1lO1'O-16ot-hyClI‘OX yhydrocortisone, and 6a,9a-di?uoro-l6a-hydroxyhydro acetate in 6, ml. of anhydrous pyridine is added with tisone, 9ot-iluoro-l6ot-hydroxycortisone, 120L-?llOI'0-16ot water, dilute sodium bicarbonate solution and again with stirring at 0°, 2.5 ml. of a 10% solution of phosgene in toluene. The reaction is allowed to proceed at 0° for cortisone. 20 minutes after which timeice and water are added. 65 The ill-esters of hydroxycortisones such as the 21-ace~ The mixture is extracted with chloroform. The chloro tates of 16a-hydroxycortisone, 2a-methyl-16oz-hydroxycor form extract is washed with water, dilute sulfuric acid, hydroxycortisone, Got-methyl - 160a - hydroxycortisone, 6a chloro-l6whydroxycortisone, 6ot~?uoro-l6a-hydroxycorti sone, and éa-?a-di?uoro-l6ot-hydroxycortisone. The 2l-esters of l6u-hydroxyprednisolones such as the ZI-acetates of 1éa-hydroxyprednisolone, 9a-?uoro-16u Water, died over sodium sulfate and the solvent removed in vacuo. The crystalline residue (about 224 mg.) is recrystallized from 95% alcohol (with the aid of car bon) and has the following properties: M.P. 267—278°; ];23 +69° (c. .47 in chlf.); hydroxyprednisolone, 12a-chloro ~ 16oz - hydroxypredniso lone, 6a-methyl-16a-hydroxyprednisolone, 6a-?uoro-16u 75 A333?‘ 2.95, 5.50, 5.72, 5.75, 6.03, 6.18, and 6.23;; 3,069,420 .yields Analysis.—Calc’d for CHI-127081? (462.45): C, 62.33; H, 5.88. Found: C, 62.60; H, 5.16. 6 2l-chloro-9a-fluoro-A1-4-pregnadiene-1l?,16a,17oc triol-3,20-dione 16,17-acetonide which melts at about 310° after recrystallization from acetone-ethanol. By further processing the above product as described in EXAMPLE 2 Triamcinolone 1 601,1 7a-Carb0nate Example 4, 21 - chloro - 9a - ?uoro - A1,‘! - pregnadiene 1l?,l6ot,l70c-tfiOl-3,20-Cli0l1€ IMAM-carbonate is ob To a solution of 100 mg. of triamcinolone 16a,l7¢x tained. carbonate 21-acetate in 10 ml. of methanol is added EXAMPLE 6 under nitrogen 1 ml. of a 10% solution potassium car 6 a-F luorotriam cinolone 1 6 “,1 7 tit-Carbonate 21~Pr0pi0nate bonate in water. The mixture is allowed to stand at 10 room temperature for 1/2 hour after which the mixture is (A) PREPARATION OF GwFLUOROTRIAMCINOLONE acidi?ed with 0.1 ml. of glacial acetic acid, 2 ml. Water \21-PROPIONATE are added and the methanol removed in vacuo. The resulting crystalline precipitate is ?ltered off, washed with , water and dried to yield the product triamcinolone IMAM-carbonate. EXAMPLE 3 A solution of 200 mg. of 6a-?uorotriamcinolone ace tonide in 1 ml. of pyridine and 0.5 ml. of propionic an hydride is allowed to remain at room temperature for twenty hours. After removal of the reagents in vacuo the residue l60t,170¢~aC€tOIllde of 6a-?uorotriamcinolone 2l-propionate is deacetonated with 60% formic acid at 100° according to the procedure described in Example A solution of 250 mg. of the product of Example 113 20 .4, thereby yielding 6ot~?uorotriamcinolone 2l-propionate. and 1.250 g. of recrystallized chloranil in 15 ml. of tert. (B) PREPARATION OF ?a-FLUOROTRIAMCINOLONE butanol is heated under re?ux for three hours. The mix 16a,17a~CARBONATE ZI-PROPIONATE ture is cooled, ?ltered, the ?ltrate poured into water and the layers separated. After an additional extraction of To a solution of 1 g. of the product of part A in 30 the aqueous layer with ethyl acetate, the ethyl acetate ml. of pyridine is added, with stirring, at 0°, 10 ml. of extract is washed with a 1 N sodium hydroxide solution a 10% solution of phosgene in toluene. The reaction until the aqueous layer becomes colorless. The washed mixture is treated as in Example 18 to yield the product 6-Dehydrotriamcinolone 16a,17a-Carb0nate 21-Acetate 6ot-?uorotriamcinolone IMAM-carbonate ZI-propionate. extract is dried over sodium sulfate and evaporated to dryness in vacuo leaving as residue the product 6-dchy 30 drotriamcinolone 16a,17ot-carbonate 21-acetate. EXAMPLE 7 2-Methyltriamciiz0lone 1 6a,] 7ot—Carb0naz‘e 21 -Acetate EXAMPLE 4 200 mg. of Za-methyl-triamcinolone 2l-acetate (pre pared by sequentially acetonating, acctylating and deacetonating 2tx-methyl triamcinolone in accordance with the procedure of Example 6A) is dissolved in 3 ml. of pyridine and treated at 0° with stirring with 2.5 ml. To a solution of 1 g. of triamcinolone acetonide in 10 ml. of anhydrous pyridine is added at 0° 1 ml. of meth anesulfonyl chloride. After two hours at 0° ice Water of a 10% solution of phosgene in toluene in accordance is added and the precipitated mesylate is removed by ?l 40 with the procedure of Example 113 thereby ielding the tration. The precipitate is washed thoroughly with Wa product 2 ~ methyltriamcinolone - l6CL,17OL ~ carbonate~2l acetate. ter and dried in vacuo, then recrystallized from acetone hexane. The triamcinolone acetonide 21-mesylate melts at about 248—250° (dec.) or 286-287° (dec.) (poly morphic forms). EXAMPLE 8 45 A mixture containing 1 g. of triamcinolone acetonide 21-mesylate, 1 g. of potassium ?uoride and 25 ml. of Zoe-Methy l~16a-Hydr0xyhydrocortisone 1 6 [1,] 706 Carbonat'e 21 -A aerate 2ot-methyl-l6ot—hydroxyhydrocortisone ZI-acetate (pre pared by sequentially acetonating, acylating and deace ethylene glycol is re?uxed (180°) for 19 hours. The dark solution is poured into ice water and extracted with tonating 2ct-methyl-1éot-hydroxyhydrocortisone in ac chloroform. The chloroform extract is washed with wa 50 cordance with the procedure in Example 6A) is treated ter, dried over sodium sulfate and evaporated to dryness in a solution of pyridine with phosgene as described in in vacuo. The residue, 16a,l7a-isopropylidene-9a,2l-di Example 1B thereby yielding the product 2ut-rnethyl-16tt hydroxyhydrocortisone léocl'lu-carbonate ZI-acetate. ?uoro-AlA-pregnadiene-11,6-16u,17a-triol - 3,20 - dione, is recrystallized from acetone with the aid of charcoal and melts at about 310°. 55 The above product is deacetonated by treatment with formic acid by the procedure of Example 7 of my co pending application Serial No. 84,989, ?led January 26, 1961, to obtain 9,21 - di?uoro - A114 - pregnadiene 11/3,16a,17ot-triol-3,20—dione. Treatment of the above products with phosgene in pyridine at 0° for 20 minutes in accordance with the 16a,l7a-Carb0nate 21 -A cetate The product of the preceding example is treated with recrystallized chloranil in accordance with the procedure 60 of Example 3 yielding the product 2ot-rnethyl-6-dehydro l6a-hydroxyhydrocortisone 160:,17u-C2l1‘b0112l't6 21~acetate. EXAMPLE 10 12a-Chl0ro-1 6 OL-Hydroxycortisone-I 6a,] hit-Carbonate procedure of Example 1B yields the ?nal product 904,21 di?uoro-AlA-pregnadiene-1l/3,16a,17a-triol - 3,20 - dione 16a,17a-carbonate. 65 EXAMPLE 5 ZI-ChZora-9a-?uoro-AlA-Pregnadiene-J16,16a,17ot-Triol— Sid-Dione 16a,17ot-Carb0nate EXAMPLE 9 2oc-Methyl-6-D ehydro-I doc-Hydroxyhydromrtisone 21 -A cetale Substitution of 1 g. of 12a-chloro~l6u-hydroxycor tisone-Zl-acetate (prepared by sequentially treating 12a chloro-l6a-hydroxycortisone with acetone and perchloric acid, acetic anhydride and pyridine and 60% formic acid A solution of 200 mg. of triamcinolone acetonide 21 70 in accordance with the procedure of Example 6A) is meeylate and 900 mg. of lithium chloride in 25 ml. of treated with phosgene in accordance with the procedure dimethylformamide is kept at 100° for 24 hours. The mixture is poured on ice, extracted with chloroform and of Example 13 thereby yielding the product IZwChlOI‘O l6a-hydroxycortisone 16a,17ot-carbouate ZI-acetate. the chloroform extract washed with Water and dried over This invention may be variously otherwise embodied sodium sulfate. Evaporation of the solvent in vacuo 75 within the scope of the appended claims. 3,069,420 What is claimed is: wherein the acyloxy group is the acyloxy radical of a hy a 1. A compound selected from the group consisting of steroids of the formula drocarbon carboxylic acid of less than ten carbon atoms and the halo group is a member of the group consisting of chlorine and ?uorine. 3. A compound of the formula 10 15 and the 1,2- and 6,7-unsaturates thereof, wherein R rep resents hydrogen, R’ represents B-hydroxy and together R and R’ are keto; R" represents a member of the group consisting of hydrogen, chlorine, ?uorine and lower alkyl; X and X’ each represents a member of the group consist 20 wherein the acyloxy group is the acyloxy radical of a hy drocarbon carboxylic acid of less than ten carbon atoms ing of hydrogen chlorine and ?uorine, at least one rep and the halo group is a member of the group consisting resenting hydrogen; Y represents a member of the group of chlorine and fluorine‘ consisting of hydrogen and lower alkyl; and Z represents 4. Triarncinolone 1606,1704-C3fb01’13te 21-acetate. a member of the group consisting of hydrogen, chlorine, 5. 9a-?u01‘O-l6o: - hydroxyhydrocortisone 1604,1706 - car ?uorine, hydroxy and the acyloxy radical of a hydrocar 25 bonate 21—acetate. bon carboxylic acid of less than 10 carbon atoms. 2. A compound of the formula 7. 6ot-?uorotriarncinolone - 16%1711 - carbonate 21-pro 30 pionate. References Qited in the file of this patent 35 Noller Chemistry of Organic Compounds, W. B. Saun ders Co., Philadelphia, Pa. (1957) , p. 741.