PL71425B1 - - Google Patents

Description

The holder of the patent: Schering AG, West Berlin. The method of producing a new 6-fluoro-9,1l-dihalo-21-hydroxy-16 - "- methyl-1,4-pregnadiene-3,20-dione and its esters. a method for the preparation of the new 6-ifyluTO-9,11-dihalo-21-hydroxy-16α-methyl-1,4-pregnadien-3,20-dione and its esters of formula 1, in which R is a hydrogen atom or an acyl group, X and Y represent a halogen atom, the atomic weight of Y being equal to or greater than the atomic weight of X. Preparation of the new 6-fluoro-9,1l-dichloro-21-hydroxy-16a-methyl-1,4- pregnadien-3,20-dione and its esters of the formula I, in which all the symbols have the meaning given above, according to the invention is that ZJ9 (U) steroid of formula II, in which R has the above meaning , with a reagent of formula XY or with two reagents of formula XA and YB, where X and Y are halogen, A is hydrogen or alkali metal, B is N-acylamino or N- - acylimide and depending on the meaning of the symbol R in position 21 and in the molecule of the final product it eventually saponifies or esterifies the obtained steroid. The symbol R in position 21 in the molecule of the final product denotes groups derived from pharmacologically acceptable acids and steroids used in chemistry to esterify free hydroxyl groups. Preference is given to using acids with 15 carbon atoms, in particular lower and intermediate molecular weight aliphatic carboxylic acids. In addition, unsaturated, branched, polybasic, optionally substituted with hydroxyl or amino groups or halogen atoms are used. It is also possible to use cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids, which may contain suitable substituents. Examples of suitable acids are: formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enantic acid, n-undecyl acid. , trimethylacetic, diethylacetic, (1,1-dimethylethyl) -acetic, phenylacetic, cyclopentylpropionic, oily, lactic, mono-, di- and trichloroacetic, aminoacetic, amber, adipic, benzoic, nicotinic. It is also possible to use inorganic acids, for example sulfuric, nitric and phosphoric acid. (Ii) The steroids used as raw materials in the process according to the invention are obtained by dehydrating the corresponding compounds containing the hydroxyl group in the 11-position. -Hydroxy-21-acyloxy-steroid dehydrates by treatment with nano-methanesulfonic acid chloride in pyridine and dimethylformamide. 6α-Fluoro-21-hydroxy-16α-methyl-1,4,9 (11) -prognatrione-3,2 O-dione is obtained by saponification of an ester containing an ester linkage at the 21-position. for the double bond of Zl9 * 11), for example, a halogen atom can be directly attached to the double bond by the action of a free halogen such as 714253 71425 4 chlorine or bromine or a halogen-halogen compound such as chlorine fluoride or bromine chloride. or a polyhalide such as potassium triiodide or iodobenzene dichloride. The attachment of the halogens is most effective when the A * (n) - steroids are treated simultaneously with a compound containing a halogen in the cation or anion. Halogen-containing compounds in the anion or cation are, for example, halosuccinimide, haloacetic acid amide or aqueous halogens, and halogen-anion compounds are, for example, hydrogen halides or alkali metal halides. for the double bond of J9 (ii) steroids is always done in such a way that the positive charge halogen is attached in position 9, and with a negative charge in position 11. For this reason, the atomic weight of the halogen attached in the 9 position cannot be never less than the molecular weight of the halogen in position 11. Halogens are attached at a temperature from -75 ° C to + 50 ° C. The free hydroxide group or ester group in position 21 is esterified or saponified. However, in order to obtain good performance, these processes should be carried out with caution. As shown by the vasoconstrictor test performed on experimental males, the new compounds applied topically show an excellent anti-inflammatory effect. This is shown in the table below by an example of compounds II-IX prepared by the process of the invention compared to compound I, which is known as 6αH-fluoro-11,21-dihydroxy-16α-methyl-14 -pregnadiene-3. , 20-dione. The vasoconstrictor test was used to experimentally, clinically prove the superiority of the compounds according to the invention. This test was performed as described below. A Stratocorneum was placed on the backs of male subjects (18-38 years old) under the experiments by pressing and tearing off the 2 cm wide test strip 204 times, producing a marked congestion. Then, 50 mg of a water-oil ointment containing 0.01%, 0.001% and 0.0001%, respectively, was applied to the marked area of the hyperemic skin with an area of 4 cm2 with the same pressure.

Claims (2)

1. Claim A method for the preparation of a new 6-fluoro-9,1l-dihalo-21-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione and its esters of formula 1, wherein R is a hydrogen atom or an acyl group, X and Y represent a halogen atom, the atomic weight of Y being equal to or greater than the atomic weight of X, characterized in that, in Z19 / o, a steroid of formula II, wherein R has the above given meaning, using reagent XY or two reagents of formula XA and YB, where X and Y are halogen atom, A is hydrogen atom or alkali metal atom, B is N-acylamide group or N-acylimide group, and depending on the meaning of the symbol R at position 21 in the end product molecule, optionally additionally saponifies or esterifies the obtained steroid. CH20R C = 0 CH20R C = 0 <Formula 2., K.Z.Graf. No. 1, issue 389/74 Price PLN 10 53 U 3 s N o) ^ ^ £ 3 ° O 'w O 3 T3 w ^ ~ cd "* ¦ + ¦» S. ir «O) ¦" 3 si * o O) d OO • - 'W) o -ow) O CD * 1 Si o W) CD 8 Ó o 3 uv Q ooo i- co cp 3 S 8 as O) 3 2 ¦ O) ^ 5 CM -a ^ v ^? aoo M § <"11? a, £ 2 J «? - 2 •• • * 3 £ i = § «i PL