SE440656B - SET TO PREPARE 16-METHYL-9ALFA-HALOGEN-PREDNISOLONESTERS AND EETERS - Google Patents

Abstract

1510617 21 - Deoxy - 16 - methyl corticosteroid derivatives PLURICHEMIE ANSTALT 26 March 1975 [27 March 1974 (2) 10 May 1975] 12608/75 Heading C2U The invention comprises compounds of formula wherein X is Cl or F, and either (i) R 1 is OH or C 1-16 acyloxy and R 2 is tetrahydropyran-2-yloxy, or (ii) R 1 is C 6-16 acyloxy and R 2 is OH, or (iii) R 1 and R 2 are each C 1-16 acyloxy. Preparation of I is from the corresponding 11, 17-diols by conversion to their 11-(tetrahydropyran-2-yl) ethers or 11-(di- or tri-chloro- or fluoro-acetates), followed as appropriate by 17-esterification, selective 11-hydrolysis (or solvolysis in the presence of silica gel) and 11- esterification. 21 - Deoxybeclomethasone and its 16α- epimer are prepared from their 9,11-epoxy analogues by reaction with HCl. 21 - Deoxybeclomethasone 11 - propionate is prepared from its 11-(tetrahydropyran-2-yloxy) analogue by reaction with EtCO 2 H. Anti-inflammatory compositions for oral, topical and parenteral administration comprise a compound I and a carrier.

Description

'78030M-8 2 can lead to a monoiodine derivative - on a product with esterified 17d hydroxy group; it is surprising that during the iodination there is no hydrolysis of the l7a ester group, and that during the later acylation of the iodine derivative with an acid other than that corresponding to the l7d ester group there is no partial acyl migration from l7d to 21. An important feature of the process according to the invention is that the 11β-hydroxy group in the starting material is protected as described in claim 1; in this case, it becomes possible to prepare 118-hydroxy compounds of the specified type when removing the protecting group; or 11β-esters by replacing a tetrahydropyran-2'-yloxy protecting group with the desired ester function; or a llß ether by leaving said ether protecting group in the molecule. The present production method is thus very flexible compared to the known method.

Preparation of the above-mentioned starting compounds a and g has been described in Swedish patent 418 294.

A particular advantage of the present method of preparation is that it allows the preparation of certain hitherto unknown compounds. Examples of these include the above-mentioned 11β-tetrahydropyran-2'-yloxide derivatives, compounds which have high topical (local) activity; 17d monoesters having up to 16 carbon atoms in the ester group, it has hitherto only been possible to prepare such esters having up to 6 carbon atoms in the 17d ester group; and a series of llß, l7d- and lld, 2l-diesters and llß, 17d, 21-triesters. Some such compounds have been included in a table at the end of the description in connection with the indication of their anti-inflammatory efficacy.

In this context, it is pointed out that topical application of a number, especially anti-inflammatory steroids, is nowadays of great importance and that extensive work has been done to explore potent anti-inflammatory steroids for topical use. The novel compounds of the present invention have a higher ratio of topical anti-inflammatory potency to systemic activity than any topical anti-inflammatory steroid so far described.

It has been found that 11β, 17d, 21l triesters having a total number of carbon atoms in the three ester functions of 6-11 exert a high anti-inflammatory potency and have a very low systemic activity upon topical administration, especially those compounds containing a chlorine atom. , and when the total number of carbon atoms in the ester groups is more than 11, these hitherto unknown triesters show long-term activity in parenteral administration, especially those compounds which contain a fluorine atom.

Among the compounds prepared by the process of the invention, the following are preferred, inter alia: A. Topical use: 16β-methyl-9-chloro- and 9-fluoroprednisolone-11β, 211-diacetate-17d--propionate, 16β-methyl-9-chloro- and 9d-fluoroprednisolone- 11β, 17β-dipropionate-21-acetate, 16β-methyl-9-chloro- and 9-fluoro-prednisolone-11β, 17α, 21-tripropionate, and 1,6-methyl-9-chloro- and 9-fluoroprednisolone-11β-propionate-17α-valate acetate.

All of these preferred compounds have high anti-inflammatory potency and very low systematic activity upon topical application, and the relationship between these two properties is more favorable than in any hitherto known, anti-inflammatory, topical steroid.

B. For prolonged activity on intramuscular administration: 16β-methyl-9-fluorofrednisolone-11β-propionate-17α-heptanoate, 16β-methyl-9d-fluoropridnisolone-11β, 21β-dipropionate-17α-valerate, and 16β-methylprol-β-ethylene-9drfluorone l7a, 2l-tripropionate.

These preferred compounds are characterized by a depot effect on intramuscular administration and provide clinically valuable storage levels over long periods of time, 2-12 days after the administered 7803M14 dose and the carrier for the administered dose, in patients where long-acting cortisone interval is indicated. Thus, the frequency of administration is reduced and side effects, such as stomach bleeding, which may occur with prolonged oral therapy, are avoided.

Of course, the preferred compounds include the equivalent 16u-methyl analogs.

The common starting compound for the preparation of compounds belonging to the 16β-methyl-9u-fluorine series is 16B-methyl-9a- -fluoro-11β, 1,7-dihydroxy-1,4-pregnadiene-3,20-dione, the synthesis of which was first described in U.S. Patent 3,792,046. The chloro analog can be readily obtained from 16B-methyl-9 (11) -epoxy-17u-hydroxy-1,4-pregnadiene-3,20-dione, a compound described in the same patent specification, by contacting it with aqueous concentrated hydrochloric acid.

The analog starting compounds in the 16d methyl series are described in British Patent Specification 934 701.

According to the present invention, a 21-esterified hydroxy group can be introduced into a 17d monoester with protected 11B hydroxy group. It has been found that the per se known Z1 hydroxylation via 211-mono- or 21,21-diiodine derivatives can be successfully carried out without hydrolysis of the ester groups in the 17α or 11β position. 21l-mono- or 21-diiodo derivatives are prepared, in a manner known per se, by reacting llß, 17u-mono- or -diesters (or certain llß-ether-17d- -monoesters of 21-deoxysteroids in methanol, optionally mixed with tetrahydrofuran, in the presence of alkali, such as calcium oxide, and in the absence of water, to give the Z1 monoiodinated derivative, if the reaction mixture contains calcium chloride, respectively, 2l-diiodo derivatives are formed. reacting with an alkali metal salt or with an amine salt of a carboxylic acid or of phosphoric acid or sulfuric acid to give the respective 21-hydroxylated derivative in esterified form.

If the compound to be iodinated has an β1-di- or -trichloro- or -fluoroacetoxy group, the conditions of iodination and subsequent acyloxylation can be selected so that this protecting group remains in the molecule, and it is also possible to select the conditions so , that it is eliminated; If the precipitation is effected by adding the reaction mixture for these reaction steps very slowly to ice water, which has a volume of about 10 times the volume of the reaction mixture, no substantial hydrolysis occurs in the IIl position; however, if the precipitated water is added slowly to the reaction mixture, within 1-4 hours, the 118-protecting group becomes completely hydrolyzed without hydrolysis of the 17d- and 21-ester groups. The 21-acyloxylation thus gives 17d, 211-diesters and 11β, 17d, 211-triesters of 16α- or 16β-methyl-9d-fluoro- or 9d-chloro-prednisolone high and constant yields, whereby all ester groups can be mutual various. In addition, 118-di-, trichloro- or -fluoroacetoxy-17α, 21-triesters are also obtained according to the special conditions indicated above. In accordance with what is known from DK patent 117 350 it has been found that these 116-di-, -trichloro- or -fluoro esters can be selectively hydrolysed in the 21-position with the aid of perchloric acid (60-70%) in methanol to give 116-di-, -trichloro- or -fluoro-17a-acetoxy esters. The reaction temperature is between 0 ° C and room temperature, and the reaction time is 12-24 hours. However, if a slightly alkaline hydrolysis is used, the 118-di-, -trichloro- or -fluoroacetyl group can be selectively disposed of without affecting the 17d and 21-ester functions. Such selective hydrolysis is carried out by adding 0.35-1.0 moles of dilute aqueous sodium bicarbonate solution per mole of the triesters in methanol with stirring for 30-90 minutes at room temperature. After acidification with 0.5N acetic acid and precipitation with water, the 17α, 21l diesters are obtained in almost quantitative yield.

In contrast to the above observation, treatment of 11B-tetrahydropyranyloxy-17u, 21-diester with perchloric acid in methanol, as above, followed by slow addition of water, leads to precipitation of the respective 17d monoester, when the 11B-tetrahydropyranyloxy group is much more sensitive to acidic conditions than the llß-trifluoroacetate. However, the 11β-tetrahydropyranyloxy group does not undergo cleavage into lower carboxylic acids, such as acetic acid and propionic acid, at room temperature. In analogy to what is known from DE-OS 2 144 408, the llß-di-, -trichloro- or -fluoroacetoxy group can be selectively solvolysed starting from the respective llß, l7a diesters as well as from the respective llß, l7d , 2l-triesters, without solvolysis of the other ester functions present. The solvolysis is carried out in suitable organic solvents, such as di-, tri- or tetrachloromethane, tetrahydrofuran, dioxane, benzene, ethyl acetate or mixtures thereof, by catalytic action of activated silicic acid, ie 1 silica gel. However, to ensure good yields, a few conditions must be met, thus the silica gel should preferably be activated at 110 ° C. A preferred method of carrying out this activation is as follows: a water-saturated silica gel is dried by heating to 110 ° C for 1-2 hours. The solvolysis yield can vary as much as from 3% to 100% depending on the origin and quality of the silica gel as well as on its activation. Good yields can be obtained with "Silica Gel for TLC" from "Camag", Muttern, Switzerland - a grade containing 20% water - after activation for 1h at 110 ° C. The silica gel is present in a significant excess and is brought into contact with the solution of the compound to be solvolyzed for 1 to 12 hours. The solvolysis can be carried out either by slowly passing the organic solution through a chromatography column or by simply stirring the organic solution with silica, followed by filtration. The optimum time for solvolysis should be determined by thin layer chromatography during the course of the reaction, as it can vary considerably depending on the quality and degree of activation of the silica gel used and of the compound to be solvolysed. optimal is harmful and leads to lower yields.The silica gel, which completely absorbs the steroid, is then dried at low temperature, between 25 ° C and 45 ° C, and eluted with a suitable solvent mixture, such as a mixture of equal parts chloroform and methanol. Other solvent mixtures may also be useful depending on the substituents present in the molecule. The eluate is then evaporated under reduced pressure and recrystallized. The silica gel-catalyzed solvolysis can also be used to solvolyze the 11β-tetrahydropyran-2'-yloxy group under the same conditions as for the 11β-di-, -trichloro- and fluoroacetates, the yield being over 90%. 7803041-8 7 Trityl ether solvolysis, which is catalyzed with activated silica gel, is described by J. Lehrfeld, Journ, Org. Chem. vol 32, pp. 2544-2546 (1967).

All mono-, di- and triesters described here are slightly soluble in water and can therefore be isolated by precipitation by adding water to the reaction mixture. The crude esters are then purified in a manner known per se. The following examples illustrate different ways of insulating and cleaning.

It is obvious that the method described here, in addition to obtaining said hitherto unknown compounds, also makes it possible to recover in higher yields and in a simple manner the known ururmonoesters and l1a, 2l-diesters of l6df and l6ß-methyl- -9d-fluorine. or chlorprednisolone. The preparation of these esters is described in British Patents 996,080, 1,043,518 and 1047,519 and in U.S. Patent 3,529,060. All of these patents use the esterification via 17d, 211- (11-alkoxy) -11-substituted methylenedioxisteroids (17a, 21l). cyclic orthoesters), which are then hydrolyzed under acidic conditions to give the corresponding 17c-acylates. British Patent Specification 1,047,519 relates to the preparation of 17α, 211-diesters by acylation of the 21--hydroxy-17D-monoesters under alkaline conditions in a manner known per se. It should be noted that this patent also relates to the direct esterification of the 17-hydroxy group of the 21-esters of 11β, 17d, 21-trihydroxysteroid compounds. The only example, Example 25, shows that this process is of no practical interest due to the generation of mixtures of 11β, 17d, 211-triacetate, 11B, 211-diacetate and 17α, 211-diacetate. The desired 17d, 21l diacetate was not obtained in pure form even after preparative chromatography column separation, and the presence of the compound could only be detected by thin layer chromatography.

Accordingly, in all known, practically useful processes, a cyclic orthoester is first prepared, which uses as reagents the respective orthoesters, which are not commercially available and whose preparation is complicated and limited to lower alkyl chains having up to 9 carbon atoms.

The present pharmaceutically useful novel compounds can be mixed with suitable carriers for the preparation of lotions, ointments, creams and other preparations for topical or topical use, including inhalation sprays and injection preparations for intraparticular and intramuscular administration.

EXAMPLE 1 IVGJ1 Diesters 812-16 * ° <= h 16ß-meëxlzâstlslsnêlærsëaisslsas; Step a) 21.3 g of 16B-methyl-9d-chloro-21-deoxyprednisolone-11B-trifluoroacetate-17a-valerate are added to a mixture of 56 ml of absolute methanol and 14 ml of 10% methanolic solution of calcium chloride.

After stirring for 5 minutes, 7 g of calcium oxide powder are added, and stirring is continued for 15 minutes at room temperature. Then a solution of 18.8 g of resublimated iodine in 42 ml of 10% methanolic solution of anhydrous calcium chloride and 28 ml of absolute methanol is added to the reaction mixture of the steroid under a nitrogen atmosphere and with the exclusion of direct light at 25-28 ° C on such way that a constant coloring is maintained, the addition taking about 40-60 minutes. After stirring for a further 20 minutes, the reaction mixture is cooled to -15 ° C and poured into 2000 ml of water containing 500 g of ice and 25 ml of acetic acid. The mixture is stirred for 30 minutes, filtered, washed with water and dried at 30-35 ° C. The 21,21-diiodine derivative thus obtained (iodine content 38.7%) is sufficiently pure to be used in subsequent reaction steps.

Step b) 27.5 g of the 21,21-diiodide derivative obtained in step a) are dissolved in dimethylformamide, and the solution is added to a mixture of 210 ml of acetone and 2.1 ml of acetic acid containing 21 g of anhydrous potassium acetate. The mixture is refluxed for 1.5 hours in the dark and under a nitrogen atmosphere. Then the mixture is cooled to + 10 ° C, and 1200 ml of water containing 300 g of ice and 20 ml of acetic acid are added. After filtration and drying, 20.1 g of the desired 165-methyl-9G-chloro-11β, 17α, 211-trihydroxy-1,4-pregnadiene-3,20-dione-11β-trifluoroacetate-17α-valerate are obtained. -21-acetate. The main peaks in the IR spectrum of mineral oil are at 5.59 μm, 5.19-5.24 μm, (double), 5.99 μm, 6.1 μm, 6.18 μm, 8.1 μm, 8.5 pm, 8.7 pm, 11.28 pm. Within the range 2.5-3.0 pm no peak appears. Step c) 1 g of the product obtained in the previous step is dissolved in 10 ml of methanol, and 1 ml of a 5% aqueous solution of sodium hydrogencarbonate is added at room temperature. After stirring for 1 h, the mixture is acidified to pH 5 with 0.5N acetic acid and precipitated with 200 ml of water, whereby 168-methyl-hydrochloro-11β, 17d, 21-trihydroxy-1,4-pregnadiene-3,20-dione 17d-valerate-21-acetate (amp 199-20100) is recovered. By repeating the same procedure but using 1 g of 16β-methyl-9α-chloroprednisolone-11β-trifluoroacetate-17d, 21-dipropionate and 2.5 ml of a 5% sodium hydrogencarbonate solution, 16β-methyl-9d-chlorine is obtained. -prednisolone-17d, 21-dipropionene 1 a yield of 96.2% <[e] š2 = + a9 °; e = o, s 1 diexen).

In an analogous manner, the following 17α, 2,1-diesters are prepared by the respective 11β-trifluoroacetate: 16β-methyl-9d-chloroprednisolones: 17α, 21-dibutyrate; IR (nujol) 2.92; 3.38; 3.50; 5.80; 6.05; 6.26; 6.90; 7.30; 8.13; 11.20; 14.20 pm. 17a, 21-aiveleree; emp 215-216 ° c. 17u-propionate-21-acetate; [α] D 25 = + 91 ° C (c = 1 in dioxane) 16α-methyl-9d-chloroprednisolones: 17e, 21; aiprepienet; E1% = 209 at 237-238 nm (1 methanol) 1 c 17 d-valerate-21-acetate; El gm = 286 at 238 nm (in methanol).

EXAMPLE 2 129121 Diesters of 169: And láß-me§2l: 2§: äl9;: 2l: 9§sš9i§elsesë Step b) in Example 1 is repeated but with carrying out the precipitation in a reverse manner as follows: When When the reflux is complete, the reaction mixture is cooled to 50 ° C, and 80 ml of water are added thereto to dissolve the inorganic salts. Then 1300 ml of water are added dropwise with stirring, which takes about 4 hours. The precipitate is filtered and dried, leaving 17.4 g of 166-methyl-9-chloro-11β, 17α, 211-trihydroxy-1,4-pregnadiene-3,20-dione 17-valerated-21-acetate is obtained. The 21-acetate thus obtained is recrystallized from acetone. Mp 200-20500. Eα: m = 288 at 234 nm 1 methanol. ušz = + 75 ° (c = 1 1 aiexen). The compound is soluble in methanol and chloroform, relatively soluble in acetone and insoluble in water. The main peaks in the IR spectrum of mineral oil are at 2.95 μm, 5.7 μm, 5.8 μm, 6.02 μm, 6.2 μm, 6.24 μm, 8.0 μm, 8.12 μm, 11 .9 pm, 11.32 pm. 78030111-8 10 EXAMPLE 3 l7 @, 2l-diestëar av l fifl f Och 16ß-meëzlzâ9: šl29§: êl: §§§9ë; 2; §êai§919nez Step a) _- 21 g av 11B-trif1uoracetat-l7orva1eratet av l6orva1eratet -methyl-9uf-fluoro-21-deoxyprednisolone is deiodinated according to step a) in Example 1 and acetoxylated according to step b) in Example 1, whereby 20.8 g of 165-methyl-9a-fluoro-11β, 17a, 21-trihydroxy-1 , 4-pregnadiene-3,20-dione-11B-trifluoroacetate-17-valerate-21-acetate is obtained. Mp 135-138 ° C.

Ea: m = 223 at 237 nm in methanol. The main peaks in the IR spectrum of mineral oil are at 5.59 μm, 5.69-5.75 μm (double), 5.98 μm, 6.1 μm, 6.15 μm, 8.1 μm, 10.25 μm , 11.0 Pm, 11.27 pm.

Step b) 1 g of the product obtained in the previous step is solvolyzed with silica gel, whereby 0.77 g of 166-methyl-9-fluoro-11β, 17d, 21- -trihydroxy-1,4-pregnadiene-3,20-dione -17a-valerate-21-acetate is obtained.

Mp 196-202 ° C. Ea: m = 302 at 239 nm in methanol. The main peaks in the IR spectrum of mineral oil are at 2.92 μm, 5.69-5.78 μm (doublet), 6.0 μm, 6.15-6.21 μm, 8.1 μm, 9.4 μm. 11.06 pm, 11.2 pm.

In an analogous manner, the following 17α, 21-diesters are prepared from 16β-methyl-9α-fluoroprednisolone from the respective 11β-trifluoroacetate: 17α, 21-diacetate; [α] D = + 68 ° C (c = 1 in dioxane) 17α, 21-dipropionate; mp 168-170 ° C 17a, 21-aivalrate, [u] š5 = + sz ° (C = o, s in aioxane) 17u-propionate-21-acetate; mp 158-159 ° C 17u-valerate-21-acetate; Ea im = 302 at 239 nm (in methanol) the 17d-propionate-21-trimethylacetate; [α] D 5 = + 61 ° (c = 0.5 in dioxane); and of 16α-methyl-9u-fluoroprednisolone: 17α, 21-aalketate; [α] D 25 = + 34 ° (c = 1 1 aioxane) 17a, 21l-dipropionate, mp 203-204 ° C 17a, 21-aivalrate, mp 158-16o ° c 17®, 21-aikaprylate, Eâ: m = 231 at 237-239 nm (1 methanol) 17u-propionate-21-acetate, mp 196 ~ 200 ° C 17u-valerate-21-acetate, mp 159-161 ° C 17Q-propionate-21-trimethyl-acetate, mp 221-223 ° C 78030411 ll EXAMPLE 4 Allowance 505091118 of Recirculation-Lylericylic acid Step a) _ Add 20 g of 166-methyl-9c-fluoro-11β, 17a, 21-trihydroxy-1,4-pregna-diene-3,20 -11β-Trifluoroacetate-17d-valerate-21-acetate, obtained in step a) of Example 3, in 3500 ml of methanol is added 140 ml of 70% perchloric acid. After standing overnight at room temperature, the mixture is precipitated by adding 14 liters of water to give 14.1 g of crude 115-trifluoroacetate-17d-valerate of betamethasone. Mp 135 ~ 388 ° C. Ei: m = 247 at 237 nm in methanol. The main peaks in the IR spectrum of mineral oil are at 2.9 μm, 5.58 μm, 5.77 μm, 5.98 μm, ε, 1-6.2 μm, 8.55 μm, 11, 0 μm, 11, 24 pm.

Step b) 1 g of the product obtained in the previous step was dissolved in 220 ml of chloroform, mixed with silica gel (Silica Gel "Camag" containing 20% water) which silica gel is activated at 110 ° C for 1 h, and stirred. The sample, which is filtered, is washed with a small amount of chloroform and eluted with 1 ml of a mixture of equal parts of chloroform and methanol. The eluate is checked by thin layer chromatography. After 10 hours the diester spot is no longer visible on the thin layer chromatography plate. draw silica gel Merck 254; mobile phase 95 parts dichloroethane, 5 parts methanol and 0.2 parts water; the stains are developed by spraying with 50% orthophosphoric acid and heating to 180 ° C for 5 minutes).

After filtering the reaction mixture, it is washed with chloroform. The silica gel is extracted with 120, 60 and 60 ml of a mixture of equal parts of chloroform and methanol. The eluate is concentrated to dryness, dissolved in 10 ml of acetone, precipitated by adding 200 ml of water and ice, filtered, washed and dried. Betamethasone-17C-valerate is obtained. After recrystallization from acetone and hexane, the analytical values of the product are the same as in the literature. Yield 93%. 7eo3o41-a 12 EXAMPLES 5 l1B, l7a, 2l-triesters and llßL2l-diestr§§_§v löar och_l6B-mgtyl:: 29: ël9r2: eêai§9l92 Step a) 2l g 165-methyl-9a-chloro-llß, 14-urdihydroxy-1,4-pregnadiene-3,20- -dione-11B-propionate-15-valvalated, iodinated and 21-acetoxylated according to step a) and b) in Example 1, wherein 11B-propionate-17a-valerate -21 -acetate is obtained; IR (nujol): 3.40; 5.75, 5.80; 6.04; 6.20; 6.95; 7.33; 8.60 pm. In an analogous manner, the following triesters of 16β-methyl-9u- -chloroprednisolonez11, 21-diacetate-170-propionate are obtained; mp 195-197 ° C 116.170-dipropionate-21-acetate; mp 195-196 ° C 116, 170,21-tripropionate; mp 200-20400, and of 16α-methyl-90-chloroprednisolone: 11β, 17α-dipropionate-211-acetate; Ei% = 270 at 236-237 nm cm (in methanol) Step b) Example 5 is repeated but using the triesters obtained in the previous step instead of the 11β-trifluoroacetate-17α-valerate-21-acetate.

Solvolysis gives the 11β, 17α-diesters of 16β-methyl-9α-chloro-prednisolone, respectively: 11β, 170-aypropionate; IR and 11.20 μm 11β, 17α-divalerate; E n \ ° å = 269 at 235-237 nm (in methanol) O m EXAMPLE 6 llëllZ @; 2l-frieSfrar_99h llßr2l ~ dieSt§a§_§y_l§9: _99ë_l§ê: m§: yl: â9: zšlseëeäsëeiäelsa Examples 1 (steps a) and b)) are repeated but starting from 11B, 17α-diesters of 16 or 166-methyl-9α-fluoro-21-deoxyprednisolone, obtained according to step d) in Example 3 of the Swedish patent 418,294 to give the following esters of 16β-methyl-9u-fluoroprednisolone: the 11β, 17U-divalerate; El 78030141-8. 13β, 21-diacetate-17β-propionate; mp 201-2O4OC 11β, 17α-dipropionate-21β-acetate; [α] D 3 = + 910 (c = 0.5 in dioxane) 11β, 17β, 21-tripropionate; mp 182-15 ° C 11β-propionate-17α-valerate-21-acetate, mp 162-164 ° C 11β, 17α-divalerate-21-acetate; Ema in = 250 at 235-236 nm (in methanol) 11β, 17U-dipropionate; IR (nujol) 2.90; 3.45; 5.75; 6.00; 6.85, 3.50 μm (1 μm = 283 at 235-231 nm (1 methanol) and of 16-methyl-9α-fluoroprednisolone: 11β, 21-diacetate-17α-propionate; mp 119-123 ° C 11β, 17H-dipropionate-21-acetate; El% = 292 at 235-237 nm 1 cm (in methanol) 11β, 173,21-tripropionate; mp 179-1s2 ° c 11B-propionate-17α-valerate-21-acetate; Ema = 271 at 235-237 nm (in methanol) 11b, 17u-dipropionate; Ea: m = 310 at 236-237 nm (in methanol). Biological Experiments The compounds obtained by the present invention were tested according to McKenzie's vasoconstriction test (AW McKenzie and RM Atkinson, Arch. Derma, vol. 80, pp. 741-746, (1964). 34 healthy persons participated in the main experiment. the doses were 0,025, 0,025, 0,05 and 0,1 pg. These doses were chosen for each compound (0,025-0,05 or 0,1 pg) according to calculations based on preliminary results. at least 6 times, i.e. at least 18 additions per compound were made, while the betamethasone-17-valerate administration, which was used as standard, was repeated 68 times at 4 different doses.

To facilitate comparison with McKenzie's results, the value of betamethasone valerate was set to 360, i.e., the strength was expressed relative to fluocinolone acetonide, which was set to 100, and the results are given in the following table. 78030414 Compound '16B-methyl-90-chloro-prednisolone-17α--valerate 16β-methyl-9α-fluoroprednisolone-17α--valerated lauromethyl-9uffluoroprednisolone-17α--valerate 16β-methyl-9α-chloro-prednisolone -valerate-21-acetate 16B-methyl-9a-fluoroprednisolone-17ur -valerate-21-acetate A 16a-methyl-9-fluorofrednisolone-17a--valerate-21-acetate 16B-methyl-9arfluoroprednisclon-11β, 17a-21-dipropionate Acetate 16β-methyl-9α-chloro-11- (tetrahydropyran-2'-yloxy) -prednisolone-17α, 21-divalated 16β-methyl-9α-fluoro-11B- (tetrahydropyran-2'--yloxy) -prednisolone -17a, 21-dipropionate 16B-methyl-9a-fluoroprednisolone-17arheptanoate 16a-methyl-9a-fluoroprednisolone-17a, 21l-dipropionate "':' = '' '' 'íFIuoci Relative strength nolone acetonide = 100) 90 360 280 450 186 <5O 470 640 760 80 1145 1aozoa1-a 16 Any clearly visible white aureola or spot was considered positive.After 15 hours the occlusive polyethylene tube was removed and the observations were made after 15 min, 1, 2, 3, 4 and 5 h. It is remarkable that in all cases the maximum visibility The intensity of the positive reaction was between 15 minutes and 3 hours, while for the Triester all spots appeared after only 3 hours or their intensity increased until the fourth hour. K.

The compounds of the 1-methylmethyl series are clearly inferior to the 166-methyl isomers in this test, indicating that the steric configuration of the 16-methyl group plays a significant role in the mechanism of action of the steroids in this test.

To demonstrate this prolonged activity, paw edema tests were performed on rats (J. Hillbrecht, Arzneim. Forsch., Å, 607, 1954 and L. Chevillard, H. Giono, "Rhumatisme" - Paris, l2: te December 1952). 2 mg / kg intramuscularly (i.m.) of each compound to be tested was loosely injected into propylene glycol in a group of 6 rats, and 8, 14, 21 and 28 days thereafter the hind paw volume was measured. Then a 0.05 ml kaolin suspension was injected into the plantar region and the swelling of the paw was measured after 1.5 and 3 hours, after which the swelling was compared with the group of 6 rats that did not initially receive any corticosteroid administration but only kaolin injection in the plantar region. For the 8 and 14 day tests, the same group of rats was used, the swelling being achieved by injecting kaolin once in the left hind paw and the second time in the right hind paw, and for 21 and 28 days other groups of 6 rats were used. The tests in which the average reduction in swelling was 30% or more, compared with the control group, were considered to be positive.

Thus, depot activity was determined with the following results: 7803041-8 Compound Duration of anti-inflammatory activity after im, administration (day fi _ 166-methyl-9a-fluoroprednisolone-17a-heptanoate 16ß ~ methyl-9a-fluoroprednisolone-17a-caprylate 16β-methyl-9-fluorofrednisolone-11β, 17α--divalate-21-acetate 163-methyl-9α-fluoropridnisolone-11β, 17α--divalated-21-propionate 21 21 21 28 2 É a780301 + 1 ~ 8 Reaction Scheme I It should be noted that compounds d and f are both included in the definition of formula I in claim 1. 7soso41-8 Reaction Scheme II Compounds i, j, k and l are all included in the definition of formula I in claim l.

Claims (6)

78030111-8 20 PATENT CLAIMS A process for preparing esters and ethers of 16u- or 168-methyl-9a-chloro- or 9a-fluoro-prednisolone having the following formula: in which X is chlorine or fluorine, R 1 is an esterified hydroxy group having 1 to 16 carbon atoms, R 2 is a tetrahydropyran-2'-yloxy group, a hydroxy group or an esterified hydroxy group having 1-16 carbon atoms, R 3 is a hydroxy group or an esterified hydroxy group having 1 to 16 carbon atoms, and the 16-methyl group is either in the d- or β-st characterized in that a 16d- or 16B-methyl-9a-chloro- or -fluoro-21-deoxyprednisolone-17a-monoester having the 11β-hydroxy group protected with a di- or trichloro- or -fluoroacetyl group or with a tetrahydropyran- - (2'-yl) -ether group, is iodinated in the 21-position, after which the mono- or di-iodo derivative thus obtained is reacted with a potassium or sodium salt of a carboxylic acid having 1-16 carbon atoms and optionally a tetrahydropyran (2'-yl) protecting group is removed or a di- or tri-chloro- or fluoro-acetyl group is removed to form a 17u, 2l-diester, or optionally an 11β-tetrahydropyran- (2'-yl) -ether group is replaced directly with an ester function to form a 118,21-diester or a 11b, 17m, 2l-triester , optionally, the 21-ester group is selectively hydrolyzed to form a 17α-monoester or 11β, 17α-diester of 16α- or 16β-methyl-9α-chloro- or fluoro-prednisolone. 7803041-3 21 2. A process according to claim 1, characterized in that the 21-hydroxylation is carried out by leaving 11β-hydroxy group-protected solder or 16β-methyl-9d-chloro- or -fluoro-21-deoxy-prednisolone-17d-monoesters reacted with elemental iodine in the presence of calcium oxide in methanol and tetrahydrofuran to give the 21-mono-iodine derivative, or in the presence of calcium chloride and calcium oxide in methanol to give the 21-di-iodine derivative, and that mono- or di-iodine derivative the iodine derivative is then reacted with a salt of a carboxylic acid to introduce a 21-esterified hydroxy group, to give 11β-hydroxy-protected 17d, 21-diesters, when the precipitation of the 21-substituted derivatives is carried out by rapidly pouring the reaction mixture into ice water, or to obtain 11β-hydroxy-17d, 211-diesters, when the protection is 1,1B-di- or trichloro or fluoroacetyl, the precipitation of the 2I-substituted derivatives being carried out by slow addition of water to the reaction mixture. 3. A method according to claim 1, characterized in that selective removal of the 11β-di- or tri-chloro- or fluoroacetyl group is carried out by an 11β-di- or tri-chloro- or fluoro-acetoxy-17α-monoester or 17d, 21l-diester is selectively hydrolyzed at the 11β position with dilute aqueous sodium bicarbonate, or selectively solvolysed with activated silica gel, to give the 17d monoesters and the 17a, 21l diesters, respectively. 4. A method according to claim 1, characterized in that selective removal of the 11β-tetrahydropyran- (2'-yloxy) group from 17α-monoesters or from 17D, 211-diesters is carried out by the 118-protected 21- the hydroxy-17a-esters or the 17d, 211-diesters are selectively solvolyzed at 11β- with activated silica gel in an organic solvent system to give the respective 11β-hydroxy-17α-mono- or 171,2-diesters. 5. A process according to claim 1, characterized in that for simultaneous hydrolysis at 21- and cleavage at 11β- a 11β-tetrahydropyran- (2'-yloxy) -17α, 21l-diester is reacted with perchloric acid in methanol and precipitated by slowly adding water to obtain the 11β, 21-dihydroxy-17d-monoesters. 6. A process according to claim 1, characterized in that the direct exchange of a 11β-tetrahydropyran- (2'-yl) -ether group with an ester function to form a 1,16,17a diester or vaozou1-a 22 l1ß, 17a, 21l -triester is carried out by heating the 11β-tetrahydropyran (2'-yl) -ether-17α-monoester or the 17α, 21-diester in one. pharmaceutically acceptable carboxylic acid having 1-8 carbon atoms.