FI58645B - SAETT ATT FRAMSTAELLA TERAPEUTISKT ANVAENDBARA 9-CHLORPREDNISOLONDERIVAT - Google Patents

Description

ΓβΊ «« ADVERTISEMENT γ β / i ρ '11 * UTLÄGGNINGSSKRIFT ί> Ö Ο 4 5 • JäAjS C ^ Pa ton Iti issued 10 03 1031 ^^ (51) Kv ^ liwXI ^ C ^ "J? / 00 FINLAND—« FINLAND (21) P «* nttlhik * mu * - Pat« nun * öknln | TT2922 (22) HtkamtopAJvi — An * eknlnpd »g 0U.10.T7 (I * ^^ (23) AlkupiM — Glltif h« t * dif 0U .10.77 (41) Became Public - Bllvlt offantllf 05. OU. 78

National Board of Examiners and Registers (44) Date of issue and publication

Patent · och registerstyralsen AnaBkan utlagd och utl.skrlftan publkarad 28.ll. 80 (32) (33) (31) Privilege requested — Begird priorltet 0U. 10.78 21.09 · 77 Federal Republic of Germany-Förbunds-republiken Tyskland (DE) P 26U5105.8 p 27U2982.9 (71) Schering Aktiengesellschaft, Berlin / Bergkamen, DE; Miillerstrasse 170-178, D-l Berlin 65, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Klaus Annen, Berlin, Henry Laurent, Berlin, Helmut Hoftoeister, Berlin,

Rudolf Wiechert, Berlin, Hans Wendt, Berlin, Joachim-Friedrich Kapp,

Berlin, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (7U) Oy Kolster Ab (5U) Method for the manufacture of therapeutically useful 9-chloroprednisolone derivatives - Sätt att framställa terapeutiskt användbara 9 ~ chloro-prednisolonderivat

The invention relates to a process for the preparation of new therapeutically useful derivatives of 9-chloroprednisolone.

The iso ion of 9-chloroprene (= 9 of chloro-1 / 3.17? (21-trihydroxy-1,4-pregnadiene-3,20-dione) has long been known (J.-Aeer. Chem.

Soc., 77, 1955, 4161). This corticoid is not suitable as an active ingredient in Pharmaceutical preparations used for the topical treatment of inflammatory diseases because of its very potent systemic effects.

It has now been found that the hitherto unknown 9-chloro-prednisolone derivatives are almost ineffective systemically, but in topical use they surprisingly have a good anti-lamination effect, which is often better than that of the most effective commercial corticoids.

The novel derivatives of 9-chloroprednisolone are known from the general formula I, 58645 2

CH0X

I 2 C = O H -ORR '(I) wherein R 1 is an alkanoyl group having 1 to 8 carbon atoms or a benzoyl group and X is a chlorine atom, a hydroxy group or an alkanoyloxy group having 1 to 8 carbon atoms.

By alkanoyl group having 1 to 8 carbon atoms and alkanoyloxy group having 1 to 8 carbon atoms X are meant groups derived from a straight-chain or branched fatty acid such as, for example, formic acid, acetic acid, propionic acid, trioic acid, butyric acid, isobutyric acid, valeric acid, valeric acid of caproic acid, tert. butyl acetic acid or caprylic acid.

Highly preferred alkanoyl groups and alkanoyloxy groups X are those derived from an alkanecarboxylic acid having 2 to 6 carbon atoms.

Highly preferred alkanoyl groups and alkanoyloxy groups X are those derived from an alkanecarboxylic acid having 2 to 6 carbon atoms.

These compounds are not only relevant as pharmacologically active substances. They can also be used as intermediates in the preparation of 9-chloroprednisolone derivatives of the general formula I in which X represents a chlorine atom or an alkanoyloxy group.

The 9-chloroprednisolone derivatives of the general formula I in which X represents an alkanoyloxy group are preferably those in which the radicals and X together contain 3 to 14 carbon atoms.

The novel 9-chloroprecmisolone derivatives can be prepared according to methods known from the process, in a manner known per se, 9 11 a) by coupling HOCl1 to the double bond of the compound of the general formula II Δ ', 3,58645 ch2x

C = G

Wherein U and R 1 are as defined above, or b) for the preparation of 9-chloroprednisolone derivatives of general formula I in which X represents a hydroxy group or chlorine atoms, a cleavable orthoester of general formula IV, CH 2 O c = o hard ^ kS ....... o / Χ "3 di uv) 5 864 5 wherein R3 is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms or a phenyl group and R3 is an alkyl group having 1 to 4 carbon atoms, hydrolytically or trimethylsilyl halide or triphenylmethyl halide, or c) for the preparation of 9-chloroprednisolone derivatives of general formula I in which X represents a chlorine atom or an alkanoyloxy group, a 9-chloro derivative of general formula Ia,

CH-OH

c = o L ....._ 0R-.

J1 1_1 (Ia), which is as defined above, is chlorinated or esterified at the 21-position.

The process of the invention according to process alternatives, a and c, can be carried out under the conditions described in U.S. Patent Nos. 3,678,034, 3,718,671 and 3,828,083. The process according to the invention according to process variant b can be carried out under the conditions described in U.S. Pat. No. 3,152,154 and German Application Publication Nos. 26 13 875 and 24 36 747.

It is known that the starting compounds for the process according to the invention can be prepared in a simple manner and in high yields from prednisolone, which in turn can be synthesized relatively simply from diosgenin. As a result, the compounds of the invention can be prepared from diosgenin at a relatively low cost with an overall yield of about 15%. In contrast, the syntheses of known highly effective corticoids from diosgenin are considerably more costly and the overall yields achieved are significantly lower (about 0.5-5%).

5,58645 This is important in view of the increasing difficulties in obtaining sufficient starting materials for corticoid syntheses and also in view of the high active ingredient costs which burden the preparation of corticoid-containing drugs.

The compounds according to the invention have, as already mentioned, a good anti-inflammatory effect in topical use, but only a very weak effect in systemic use. The pharmacological properties of the compounds were determined by the following test: A) Anti-inflammatory effect in topical use in the rat ear:

The test substance is dissolved in a stimulant consisting of 4 parts of pyridine, 1 part of distilled water, 5 parts of ether and 10 parts of a 4% ethereal croton oil solution. The test solution is soaked in felt strips attached to the inside of the target glass tweezers and lightly pressed for 15 seconds into the right ear of a male rat weighing 100 to 160 g. The left ear is not processed and serves as a reference. Three hours after placing the test substance in the ear, the animals are killed and 9 mm pieces are cut from their ears. The difference in weight between a piece taken from the right ear and a corresponding piece taken from the left ear is a measure of the edema (swelling) that has formed.

Determine the dose of test substance at which 50% inhibition of edema is observed after 3 hours.

B) Anti-inflammatory effect after subcutaneous (subcutaneous) use in the rat paw: SPF rats weighing 13Q to 150 g were injected with 0.1 ml of 0.5 l of Mycobacterium butyrieum suspension (available from the American company Difko) in the right hind paw to induce inflammation. Prior to injection, the paw extent of the rats is measured. Twenty-four hours after injection, paw area is remeasured to determine the extent of edema. Finally, rats are injected subcutaneously with varying amounts of test substance - dissolved in a mixture of 29% benzyl benzoate and 71% castor oil. After a further 24 hours, the size of the paw is measured again.

Control animals are treated in a similar manner, with the difference of 6,586,4 that they are injected with a benzyl benzoate-castor-oil mixture without the test substance.

Based on the paw sizes obtained, the amount of test substance required to achieve a 50% improvement in paw edema is determined in a conventional manner.

C) Thymolytic effect after oral administration: In SPF rats weighing 70-110 g, the adrenal gland is removed under ether anesthesia. 6 animals each form a test group, and the animals in the test group receive a predetermined amount of test substance orally for 3 days each.

On the fourth day, the animals are killed and the weight of their thymus is determined. Control animals are treated in a similar manner, but receive a benzyl benzoate-castor oil mixture without test substance. From the thymus weights obtained, the amount of test substance at which 50% thymolysis (thymus destruction) is observed is determined in the usual manner.

The reference substances used in these tests were 9-chloroprednisolone and its 21-acetate and beclomethasone 17,21-dipropionate (= 9β-chloro-11β-hydroxy-16, Α-methyl-17β, 2,1- dipropionyloxy-l, 4-pregnadiene-3,20-dione).

The results obtained in these tests are shown in the following table: T 58645

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B 58645

Similar results are obtained when determining the pharmacological activity of the 9-chloroprednisolone derivatives prepared according to the invention by means of a known vasoconstriction (vasoconstriction] test or a known sodium potassium retention test.

The following examples illustrate the invention.

I] Syntheses

Example 1 a] To 5.0 g of 9qf-chloro-11 / 3.17 / 3.21-trihydroxy-1,4-pregna-diene-3,20-dione is added 500 ml of benzene, 40 ml of dimethyl Iform-amide and 500 mg of absolute pyridine tosylate. The mixture is heated, distilled off at 50 [deg.] C. at a bath temperature of 50 ml of solvent, 50 ml of orthobenzoic acid triethyl ester are added and, within 2 1/2 hours, the residual benzene is distilled off. To the residue is added 2.4 ml of pyridine, concentrated in vacuo to give 17β, 21- (1-ethoxy-benzylidenedioxy] -90 (-chloro-11β-hydroxy-1,4-pregnadiene-3,20-dione as an oily crude product.

b) To the obtained crude product are added 150 ml of metabolism, 54 ml of 0.1 N aqueous acetic acid and 6 ml of 0.1 N aqueous sodium acetate solution and heated for 90 min. time to reflux. The reaction mixture is concentrated in vacuo, water is added to the residue and extracted with ethyl acetate. The organic phase is washed with water, concentrated in vacuo, the residue is purified by chromatography on a column of silica gel, recrystallized from acetone-hexane to give 3.7 g of 17α-benzoyloxy-9o6chloro-11β, 3,21-dihydroxy-1,4-pregnadiene. 3,20-dione, m.p. is 216 ° C (dec.).

Example 2 0.5 g of 17β-benzoyloxy-90,4-chloro-11β, 21-dihydroxy-1,4-pregnadiene-3,20-dione is stirred with 10 ml of formic acid for 24 hours at room temperature. The reaction mixture is then poured into ice water, extracted with dichloromethane, the organic phase is washed, dried over sodium sulphate and concentrated in vacuo to give 400 mg of 17α-benzoyloxy-9,4-chloro-21-formyloxy-1H-hydroxy-1,4-pregnadiene-3,20-dione as a glass as a solidified mass. Δ ^ -J-q ~ + 58 ° (chloroform).

g 58645

Example 3 To 1.5 g of 17β-benzoyloxy-9e4chloro-11β, 211-dihydroxy-1,4-pregnadiene-3,20-dione are added 17 ml of pyridine and 8.0 ml of acetic anhydride and stirred for 1 hour at 0 ° C. . The reaction mixture is then poured into ice water, the separated product is filtered off, dissolved in dichloromethane, the organic phase is washed, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed using a gradient of methylene chloride-acetone through a column of silica gel, recrystallized from acetone-hexane to give 1.2 g of 21-acetoxy-17α-benzoyloxy-9b-chloro-11β-hydroxy-1,4-pregnadiene. 3,20-dione, m.p. is 221 ° C (dec.).

Example 4 To 1.5 g of 17β-benzoyloxy-90,6-chloro-11β, 21-dihydroxy-1,4-pregnadiene-3,20-dione are added 17 ml of pyridine and 8.0 ml of propionic anhydride and stirred for 1 hour at 0 °. C. The reaction mixture is further treated as described in Example 3 to give 960 mg of 17α-benzoyloxy-90 ° -chloro-11H-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione, m.p. is 226 ° C (dec.). '·

Example 5 To 2.3 g of 17α-benzoyloxy-9α-chloro-1,1'-dihydroxy-1,1'-pregnadiene-3,20-dione are added 50 ml of pyridine and 25 ml of butyric anhydride and stirred for 16 hours at room temperature. The reaction mixture is further treated as described in Example 3 to give 2.0 g of 17β-benzoyloxy-21-butyryloxy-9β-chloro-1H-3-hydroxy-1,4-pregnadiene-3,20-dione, m.p. . is 226 ° C. (decomposing).

Example 6 To 2.3 g of 17α-benzoyloxy-9Cl (-chloro-11β, 3,21-dihydroxy-1,1-pregnadiene-3,20-dione) are added 50 ml of pyridine and 25 ml of valeric anhydride and stirred for 16 hours. The reaction mixture is further treated as described in Example 3 to give 1.63 g of 17,4-benzoyloxy-9α-chloro-β-hydroxy-21-valeryloxy-1,1'-pregnadiene-3,20-dione, m.p.

is 208 ° C.

Example 7 To 2.3 g of 17 ° (-benzoyloxy-90 ° (chloro-11β, 21-dihydroxy-1,3,4-pregnadiene-3,20-dione) are added 50 ml of pyridine and 25 ml of trimethylacetic anhydride and stirred for 16 hours. The reaction mixture is further treated as described in Example 3 to give 1.72 g of 17β-benzoyloxy-9,4-chloro-11β-10,58645 hydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione, which mp 236 ° C.

Example 8 To 2.3 g of 17α-benzoyloxy-9β-chloro-11,2,2-dihydroxy-1,4-pregnadiene-3,20-dione are added 50 ml of pyridine and 25 ml of isobutyric anhydride and stirred for 16 hours at room temperature. . The reaction mixture is further treated as described in Example 3 to give 2.1 g of 17β-benzoyloxy-90,4-chloro-11β-hydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione as a glassy mass. = +6 8 ° (chloroform).

Example 9 To 2.3 g of 17-O-benzoyloxy-90 (chloro-11H, 21-dihydroxy-1,4-pregnadiene-3,20-dione) are added 50 ml of pyridine and 20 ml of isovaleric acid chloride and stirred for 2 hours. ° C.

The reaction mixture is further treated as described in Example 3 to give 2.1 g of 17-benzoyloxy-9 c * -chloro-11/5-hydroxy-21-isovaleryloxy-1,4-pregnadiene-3,20-dione, which mp. is 197 C.

Example 10 To 2.3 g of 17α-benzoyloxy-9α <-chloro-11/3,21-dihydroxy-1,4-pregnadiene-3,20-dione are added 50 ml of pyridine and 30 ml of enanthic anhydride and stirred for 16 hours at room temperature. mode.

The reaction mixture is poured into ice water, heated and the excess enanthic acid is fried by steam distillation. It is then extracted with dichloromethane, the organic phase is further treated as described in Example 3 to give 2.03 g of 17β-benzoyloxy-90 (-chloro-21-heptanoyloxy-11γ% -hydroxy-1,4-pregnadiene-3), 20-dione as an oily product, = +64 (chloroform).

Example 11 a) 7.5 g of 9 <k-k laar - 11 / t>, 17 7 k k, 21 - trihydroxy - 1,4-p-reg nad i een i - 3,20-dione is reacted with orthoacetic acid triethyl ester under the conditions described in Example 1 and further treated.

17ck, 21- (1-ethoxy-ethylidenedioxy) -9β-chloro-11β-hydroxy-1,4-pregnadiene-3,20-dione is obtained as a crude product.

b) The crude product thus obtained is reacted under the conditions described in Example 1b, further treated to give 5.2 g of 17β-chloro-9cC-chloro-11,5,2-dihydroxy-1,4-pregnadiene-3,20 -di onia, m.p. is 205 ° C (decomposed).

Example 12 To 1.0 g of 17β-acetoxy-9β-chloro-11,3,2-hydroxy-1,4-pregnadiene-3,20-dione is added 20 ml of pyridine and 5 ml of acetic anhydride. X1 58645 and stirred for 1 hour at room temperature. The reaction mixture is then poured into ice water, the product separated is filtered off with suction, dissolved in dichloromethane, the organic phase is washed and concentrated in vacuo. The residue is recrystallized from acetone-hexane to give 860 mg of 1H-1,2-diacetoxy-9β-chloro-11β. -hydroxy-1,4-pregnadiene-3,20-dione, m.p. is 222 ° C (dec.).

Example 13

Under the conditions of Example 4, 1.0 g of 17β-acetoxy-9β-chloro-1β, 21-dihydroxy-1,4-pregnadiene-3,20-dione is reacted with propionic anhydride, further treated to give 940 mg of 17β-acetoxy anhydride. N-acetoxy-90-chloro-11β-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione, m.p. is 219 ° C (dec.).

Example 14

Under the conditions of Example 6, 1.0 g of 17β-acetoxy-9β-chloro-1,1 ', 21-dihydroxy-1,4-pregnadiene-3,20-dione is reacted with valeric anhydride, further treated to give 660 mg of 17 ° N-acetoxy-90,4-chloro-11β-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione, m.p. is 220 ° C (decomposed).

Example 15 a) Under the conditions of Example 1a, 7 g of 90 ° -chloro-17β-trihydroxy-1,4-pregnadiene-3,20-dione are reacted with orthopropionic acid triethyl ester, further treated to give 17? - (1-ethoxy-propylidenedioxy) -9? -Chloro-1β-hydroxy-1,4-pregnadiene-3,20-dione as a crude product.

b) The crude product obtained is reacted according to Example Ib. under further conditions, 2.9 g of 9β-chloro-11,2,2-dihydroxy-17β-propionyloxy-1,4-pregnadiene-3,20-dione are obtained, m.p. is 181 ° C, (dec.).

Example 16

Under the conditions described in Example 2, 1.2 g of S-chloro-11β, 21-dihydroxy-17o (-propionyloxy-1,4-pregnadiene-3,20-dione) is reacted with formic acid, further treated to give 400 mg of an oily substance. 9β-Chloro-21-formyloxy-11β-hydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione.

[α] D + 67 ° (chloroform).

12,58645

Example 17 700 mg of 9β-chloro-11β, 21-dihydroxy-17β-propionyloxy-1,4-pregnadiene-3,20-dione are reacted as described in Example 3 with acetic anhydride, further treated to give 320 mg of 21 -acetoxy-9-chloro-11β-hydroxy-17,4-propionyloxy-1H-pregnadiene-3,20-dione, m.p. is 210 ° C (decomposed).

Example 18 700 mg of 90β-chloro-11β, 21-dihydroxy-17β, propionyloxy-1,4-pregnadiene-3,20-dione is reacted with propionic anhydride under the conditions described in Example 4, further treated to give 420 mg of 9 * Ε-chloro-11β-hydroxy-11β-dipropynyloxy-1,4-pregnadiene-3,20-dione, m.p. is 215 ° C (dec.).

Example 1 650 mg of 9-chloro-11β (9,21-dihydroxy-17β-propionyloxy-1,4-pregnadiene-3,20-dione are reacted with butyric anhydride under the conditions described in Example 5, further treated to give 360 mg of 21- butyryloxy-9c4: chloro-11β-hydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione, mp 208 ° C (dec.).

Example 20

Under the conditions of Example 6, 700 mg of 9'b-chloro-11β, 5,21-dihydroxy-17β-propionyloxy-1,4-pregnadiene-3,20-dione is reacted with valeric anhydride, further treated to give 520 mg. 9β-chloro-1H-hydroxy-17,4'-propionyloxy-21-valeryloxy-1,4-pregnadiene-3,20-dione, m.p. is 210 ° C (decomposed).

Example 21 To 3.0 g of 9β-chloro-1 H, 21-dihydroxy-17β-propionyloxy-1,4-pregnadiene-3,20-dione are added 30 ml of pyridine and 15 ml of caproic anhydride and stirred for 90 min. time at room temperature.

The reaction mixture is further treated as described in Example 3 to give 2.6 g of N, N-chloro-21-hexanoyloxy-11β-hydroxy-17β-propionyloxy-1,4-pregnadiene-3,2-dione.

13 58645

Example 22 a) Under the conditions of Example 19, 25 g of 11 / 3,170 (-21-trilydroxy-1,4-propylene i-3,20-dione) are reacted with butyric anhydride, further treated to give 23.1 g. g of 21-butyryloxy-11 / 17,17 (-dihydroxy-1,4-pregnadiene-3,20-dione).

b) To a suspension of 24 g of copper (I) chloride in 4 to 0 ml of absolute tetrahydrofuran is added dropwise, under an argon atmosphere at 0 ° C, 100 ml of a 5% ethereal solution of methyl yttrium. The mixture is then cooled to -30 [deg.] C. and a solution of 22.3 g of 21-butyryloxy-11,17,17 (-dihydroxy-1,4-pregnadiene-3,20-dione) is added. stirred for 4 hours until the primary formed 11/9-hydroxy-17ci ', 21- (1-hydroxy-i-butyl-1-idioxy) -1,4-pregnadiene i-3.2 0 Aqueous ammonium chloride solution is added to the reaction mixture, extracted with methylene chloride, the organic phase is washed, concentrated in vacuo to give 20.3 g of 17 Cf-butyryloxy-11 / 3,21-dihydroxy-1,4-pregnadiene-3.20 -dione as a product.

c) Under the conditions of Example 3, 20 g of the crude product obtained are reacted with acetic anhydride, further treated to give 14.2 g of 2-acetoxy-170 (butyryloxy-11/3-hydroxy-1,4). -pregnadiene- 3,20-d ion ia.

d) 5.4 ml of methanesulphonic acid chloride are added dropwise at room temperature to a solution of 10 g of 2-acetoxy-176'-butyryloxy-11β-hydroxy-1,4-pregnadiene-3,20-dione in 50 ml. in dimethylformamide and in 11 ml of pyridine. The reaction mixture is stirred for 2 hours at 85 [deg.] C., then, after cooling, it is poured into ice water, worked up as described in Example 3 to give 6.5 g of 21-acetoxy-170 [epsilon] -1,4,9 - (II) -pregnatriene-3,20-dione as a crude product.

e) 6 g of the crude product thus obtained are suspended in 80 ml of dioxane and 5.6 g of N-chlorosuccinimide are added. Then instill for 10 min. at 20 ° C, 42 ml of a 10% aqueous perchloric acid solution are stirred in the mixture, stirred for 3 hours at 20 ° C and the mixture is poured into a solution of 2.5 g of sodium hydrogen sulphite in 400 ml of water. The separated product was filtered off with suction as described in Example 3, worked up to give 3.1 g of 21-aceto-i-17of-butyryl-io-i-9c <-chloro-ri-11/3-hydroxy-1.4 -pregnad ieen i -3,20-d ionia. Melting point 215 ° C.

Example 23 and 9.5 g of a crude product of 17o (butyryloxy-11 / 3,21-dihydroxy-1,4-impregnene-3,20-dione) prepared according to Example 22 are administered react with the conditions of Example 7 with trimethylacetic anhydride, δ 58645 is further treated to give 6.3 g of 17-t-butyryloxy-11/5-hydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione.

b) 5.0 g of 17 ° <- butyl 1 io ks i - 11 hydrohydro i - 21 -1 methyl ethoxy-14- □ regnadiene-3,20-dione are reacted under the conditions of Example 23d with methanesulfonic acid chloride, further treated to give 3.4 g of 17 * -butyryloxy-21-1-dimethylacetoxy-1,4,9 (11) -pregnatriene-3,20-dione as a crude product.

c) 3.0 g of the crude product obtained above are reacted under the conditions of Example 23, further treated to give 1.1 g of 17 <* - butyl solution - 9 «* - chloro-11H-hydroxy-21-trimethylacetoxy -1,4-pregnadiene-3,20-dione ia. Melting point 259 ° C.

Example 24 a) Under the conditions of Example 22b, 20 g of 11 / ®, 17 (* - dihydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione are reacted with lithium dimethyl copper para, further treated and 18.6 g of 11/3, 21-dihydroxy-17eC-Valyloxy-1,4-pregnadiene-3,20-dione are obtained as a crude product.

b) 18 g of the crude product obtained above are reacted with propionic anhydride under the conditions of Example 3, further treated to give 10.8 g of 11/8-hydroxy-21-propynyloxy-17e-valeryloxy-1,4-pregnadiene -3.20-dione.

c) 9 g of 11,3-hydroxy-21-p Ropyloxy-17 7-K-valeryloxy - 1,4-Dregnadiene-3,20-dione are reacted under the conditions of Example 22d with methanesulfonic acid chloride, is further treated to give 4.9 g of 21-propionyl-17,7x-valeryl-1,4,9 (11) -pregnatriene-3,20-dione as a crude product.

d) 4.0 g of the crude product obtained are reacted under the conditions of Example 22e, further treated to give 1.4 g of 9 <X-chloro-11 / S-hydroxy-21-propionyloxy-17c <-valeryloxy-1, 4-pregnadiene-3.20-dione. Melting point 242 ° C.

Example 25 a) 17.2 g of 1 L, 21-dihydroxy-17 <x-valyloxy-1,4-p Regna-diene-3,20-dione the crude product is reacted with valeric anhydride under the conditions of Example 6, further treated to give 9.7 g of 1 1 β-hydroxy-1 7 <*, 21 - di valery 1 i ox i - 1,4-pregnadiene - 3.20- dione.

is 5 8 6 4 5 b) 11 g of 11 / - - hydroxy - 1 7 <X, 21 - di valium 1 io ks i - 1,4-preg nad i ee ni - 3,20-dione reacted with methanesulfonic acid chloride under the conditions of Example 22d, further treated to give 4.6 g of 17 ', <, 21-divaleyloxy-1,4,9 (11) -pregnatriene-3,20-dione as a crude product.

c) 4.5 g of the crude product obtained are reacted under the conditions of Example 22e, further worked up to give 1.8 g of 9'-chloro-11β-hydroxy-17α, 21-divaleyloxy-1,4 -Pregnadien-3,20-dione.

Sp. 25 4 ° C.

Example 26

1.2 g of 90 ° -chloro-11/2>, 21-dihydroxy-17 * -propionyl-1-di-1,4-pregnadiene-3,20-dione are reacted with thionyl chloride, treated further and 860 mg of 9o <, 21-dichloro-11H-hydroxide *; -propionic acid i, 1,4-pregnadiene-3,20-dione are obtained, m.p. is 232 ° C.

Example 27

Under the conditions of Example 26, 8.5 g of 17β-benzoyloxy-9β-chloro-11β-21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted, further treated to give 4.1 g of 17,7-benzoyloxy-9 <*, 21-dichloro-1-hydroxy-1,4-pregnadiene-3,20-dione, m.p. is 220 ° C.

Example 28 5 g of crude according to Example 1a from 9 «> <- chloroprednisolone and orthoethyl ester is prepared from 1 7o <, 21- (1-ethoxyethylidenedioxy) -9e <-chloro -1 1/3-hydroxy 1,4-Pregadiene-3,20-dione is stirred (at reflux) in 30 ml of methylene chloride with 3 g of triphenylmethyl chloride for 1 hour under a nitrogen atmosphere.

The solvent is distilled off and the residue is purified on 350 g of silica gel using a gradient of methylene chloride-acetone (0-15% acetone).

Yield: 1.3 g of 17o-aceto-io-9o <, 2 1-dichloro-1 1/3-hydroxy-1,4-preg Nadiene - 3,20-Dione i a. Sp. 222 ° C (decomp.) + 1 24 ° (py ri d i i ni).

U \ /: 8 239 = 1 ^ 200 (methanol).

Example 29 2 g, crude according to Example 1a, prepared from 9'-chloro-predicone ion and orthropropionic acid triethyl ester 17,7 <, 2 1- (1-ethoxy-propylidenedioxy) -9o (-chloro-11 N-hydroxy-1,4-pregnadiene-3,20-dione is stirred in 50 ml of dimethylformamide with 5 ml of trimethylsilyl chloride for 2 hours at room temperature, and after precipitation with ice water and standard work-up, 1.4 g of 9oi, 21 - dichloro-1-hydroxy-17β-propyloxy-1,4-pregna-diene-3,20-dione, which is purified by recrystallization from acetone / hexane, mp 232 ° C: m.p. + 78 ° (chloroform) UV: 6 ^ 39-132Π0 (methanol).

Claims (1)

A process for the preparation of therapeutically useful 9-chloroprene-Solon derivatives of the general formula CH 2 X c = o - - □ R 1 (I) Cl wherein R 1 is an alkanoyl group having 1 to Θ carbon atoms or a benzoyl group and X is a chlorine atom, a hydroxy group or an α 1 canoyloxy group having 1 to 8 carbon atoms, characterized in that in a manner known per se a) H 2 Cl is attached to a double bond of a compound of general formula II, ch2x C = O / vlA- - ° «1 fjr— (where X and R 2 are as defined above, or 17 58645 b) for the preparation of 9-chloroprednisone ion derivatives of the general formula I in which X represents a hydroxy group "or a chlorine atom, a cleaved orthoester of the general formula (CH) is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms or a phenyl group and R2 is an alkyl group having 1 to 4 carbon atoms, hydrolytically or with trimethylsilyl halide or triphenylmethyl with a halide, or c) for the preparation of 9-chloroprodnisone ion derivatives of the general formula I in which X represents a chlorine atom or an alkanoyloxy group, a 9-chloro derivative of the general formula Ia, C H 2 OH 00 H 0 -R 0 (Ia) Cl j is as defined above, chlorinated or esterified at the 21-position. ie 58645 Patent patent: Sätt att framställa terapeutiskt användbara derivat av av-9-chlororededololone med denemänna formeln ch2x C = 0 - ° R1 | (i) Cl color is an alkanoyl group having 1-8 cholaters or a benzoyl group and X is a chlorine group, a hydroxyl group or an alkanoyloxy group having 1 to 8 cholaters, the first of which is a solution. 9 11 (a) H0C1 to A 'double bond in the form of all of the compounds of formula II CH? XL - ° R' (II) color X and in the form of an aliquot, or (b) for a mixture of 9-chloroprednisolone derivatives with all of the compounds of formula I, color X in which the hydroxyl group or chlorine, hydrolytic or of trimethylsilyl halides or triphenylmethyl-1-halides are attached to the orthoester of formula IV