CH551399A - 2-Chloro-substd. pregnane steroids as anti-inflammatories - prepd. by alkaline hydrolysis of corresp. esterified pregnane derivs - Google Patents

Abstract

2-Chloro-substd. steroids of the pregnane series of formula (I): (where X is H or F; R1, R2 and R3 are free- or esterified hydroxy, of which 1 is in the free state; and R3 may also be H), are prepd. by alkaline hydrolysis of a cpd. (I) (where >=1 of R1, R2 and R3 has the esterified form). (I) have thymolytic- and adrenal-inhibitory activity and esp. anti-inflammatory activity. They may be used as cortico-steroid analogues are also used as inters. for other pharmacologically-active cpds.

Description

  

  
 



   The present invention relates to a process for the preparation of new steroids of the pregnane series of the formula which are substituted in the 2-position by chlorine
EMI1.1
 in which X is hydrogen or fluorine and R1, Re and R, are free or esterified hydroxyl groups, at least one of which is in free form, and R6 can also be hydrogen.



   The new compounds of the above formula (I) have valuable pharmacological properties. In addition to a thymolytic and adrenal inhibiting effect, they also have an anti-inflammatory effect, as shown in animal experiments, e.g. shows in the rat, in the foreign body granuloma test. The new compounds can therefore be used as corticosteroid analogs, in particular as anti-inflammatory agents. The new compounds are also valuable intermediates for the preparation of other useful substances, especially pharmacologically active compounds.



   Particularly noteworthy is the # 1,4-2-chloro-6α, 9α-difluoro-16α-methyl-11ss, 17α, 21-trihydroxy-3,20-dione, which has a very good anti-inflammatory effect Has relatively few side effects on adrenal glands.



   The process of the present invention is characterized in that in a compound of the formula
EMI1.2
 where X has the same meaning as for formula (I), R1, R2, R3 are free or esterified hydroxyl groups, at least one of which is in esterified form and R3 can also be hydrogen, converts at least one esterified hydroxyl group into a free hydroxyl group.



   The release of the esterified groups in accordance with the process can be carried out in a manner known per se, especially by alkaline hydrolysis, e.g. by the action of an alkali metal carbonate or hydrogen carbonate in an aqueous, aliphatic alcohol such as methanol or ethanol. The starting materials used are esters, which are e.g. derive from organic carboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series, in particular from those with 1-18 carbon atoms, e.g. formic acid, acetic acid, propionic acid, butyric acids, valeric acids, such as n-valeric acid, or

  Trimethylacetic acid, trifluoroacetic acid, caproic acids such as β-trimethylpropionic acid or diethyl acetic acid, enanthic, caprylic, pelargonic, capric, undecylic acids, e.g. of undecylenic acid, of lauric, myristic, palmitic or stearic acids, e.g. oleic acid, cyclopropane, butane, pentane and hexane carboxylic acid, cyclopropyl methane carboxylic acid, cyclobutyl methane carboxylic acid, cyclopentyl ethane carboxylic acid, cyclohexyl ethane carboxylic acid, cyclopentyl, cyclohexyl or cyclohexyl acetic acid, such as phenoxy acetic acid, phenoxy acetic acid, phenoxy acetic acid, such as phenoxy acetic acid, such as phenoxy acetic acid, phenoxy acetic acid, such as phenoxy acetic acid, such as phenoxy acetic acid or phenoxy acetic acid, such as phenoxy acetic acid, phenoxy methanecarboxylic acid, cyclobutyl methane carboxylic acid, phenoxy Phthalic acid, quinolinic acid, furan-2-carboxylic acid, 5-tert-butyl-furan-2-carboxylic acid, 5-bromo-furan-2-carboxylic acid, nicotinic acid or isonicotinic acid,

   or of sulfonic acids, such as benzenesulfonic acids, or of inorganic acids, such as e.g.



  Phosphoric or sulfuric acids.



   The ester groups can, however, also be derived from orthocarboxylic acids such as orthoformic acid, orthoacetic acid or orthopropionic acid, these acids and also the abovementioned dicarboxylic acids being able to give cyclic 17,21 esters.



   The compounds to be used as starting materials can e.g. by adding chlorine to the 1,2-double bond of corresponding compounds not chlorinated in the 2-position and splitting off hydrogen chloride from the 1,2-dichloro derivatives thus obtained. The addition of chlorine takes place e.g. with elemental chlorine, and before geous in a lower aliphatic carboxylic acid, such as propionic acid, instead; the elimination of hydrogen chloride can e.g. by means of a basic agent such as a tertiary organic base, e.g. Pyridine.

  Kollidine or triethyiamine, or an inorganic base such as sodium acetate, can be obtained.



  In this way, one can initially also prepare compounds of the formula (II) in which all three groups R1, R2 and Ra are free hydroxyl groups and one or more of these groups can subsequently be esterified, or such a subsequent esterification can be carried out in compounds in which one or two ester groups are already present.



  For the production of 21-monoester e.g. the 21-hydroxy compounds are treated in a manner known per se with reactive functional carboxylic acid derivatives, preferably with those of the acids mentioned above, e.g. with an acid anhydride or an acid halide, e.g. in a tertiary base such as pyridine. A free hydroxyl group in the 17α-position can be selectively esterified by methods known per se. E.g. by acylation with a cirboxylic acid anhydride, e.g.

  Acetic anhydride, with the addition of a strong acid, especially an aromatic sulfonic acid, e.g. p-Toluenesulfonic acid, as a catalyst, produces the 17a, 21-Dieiter and then saponifies the 21-EStar group under mild conditions. For this purpose, for example, solutions of an alkali methyl carbonate or hydrogen carbonate in an aqueous, aliphatic alcohol such as methanol or ethanol are used.



     17α-monoesters can also be obtained in the following manner known per se. Compounds of the formula (I) which have free hydroxyl groups in the 17α and 21-positions are obtained on reaction with an orthoester of the type R'-C (OR ") 3, where R 'is a hydrogen atom or an alkyl radical and R "is an alkyl radical, in the presence of a staric acid, such as p-toluenesulfonic acid, as a catalyst, in an inert solvent, such as Benzene cyclic 17α, 21-orthoesters. By hydrolysis with a weak organic acid such as e.g.

  Oxalic acid, then the 21 ester linkage is selectively hydrolyzed to give a 17? Monoester.



  illustrated in main patent no. 510 655.



   The new pharmacologically active substances described above can be used together with a pharmaceutical carrier material for the production of pharmaceutical preparations for use in human or veterinary medicine. The carrier used is organic or inorganic substances which are suitable for enteral, e.g. oral, parenteral or topical administration are suitable. Substances that do not react with the new compounds, e.g. Water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum, polyalkylene glycols, petrolatum, cholesterol and other known excipients.

  The pharmaceutical preparations can be in solid form, e.g. as tablets, dra gees or capsules, or in liquid or semi-liquid form as solutions, suspensions, emulsions, ointments or creams. If necessary, these pharmaceutical preparations are sterilized and / or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. The new compounds can also serve as starting materials for the production of other valuable compounds.



   The compounds prepared according to the invention can also be used as feed additives.



   The invention is described in more detail in the following examples. The temperatures are given in degrees Celsius.



   Example I.
9.0 g of # 1,4-6α, 9α-difluoro-16α-methyl-17α-hydroxy-11ss, 21- -diacetoxy-3,20-dioxo-pregnadiene are dissolved in 750 ml of pure dioxane with heating . After cooling until the dioxane starts to crystallize, it is poured all at once
66 ml of a solution consisting of 36 chlorine in 500 ml of pure
Add propionic acid and let it stand for 7 days at 0-5 in the dark. The reaction solution is poured onto 3 l of ice water. It is extracted three times with 500 ml of methylene chloride each time and the extracts are washed successively with water, saturated aqueous sodium bicarbonate solution and again with water.

  The washed, combined extracts are dried over sodium sulphate, filtered and completely evaporated in vacuo at a bath temperature of 30,350. The # 4-6α, 9α-difluoro-1,2-dichloro-16α-methyl-17α-hydroxy-11ss, 21-diacetoxy-3,20-dioxoprene is thus obtained. 12 g of this dichloride are dissolved in 150 ml of pure pyridine and the solution is left to stand at room temperature for 24 hours. The reaction solution is then poured onto 1 liter of ice-cold normal hydrochloric acid. It is extracted five times with 250 ml of methylene chloride each time and the extracts are washed successively several times with ice-cooled hydrochloric acid, water, ice-cooled and saturated sodium bicarbonate solution and again with water.

  The washed and then combined extracts are dried over sodium sulfate, filtered and completely evaporated in vacuo. The crude product obtained is chromatographed on 750 g of silica gel and eluted first with toluene 'ethyl acetate 95: 5, then at 90:10 and finally at 80:20. After concentration, the A1'4-6s a-di- fluoro-2-chloro-16α-methyl-17α-hydroxy-11ss, 21-diacetoxy-3,20-dioxo-pregnadiene of m.p. 240 (246-250) [α] 20 D = + 90 (c) = 1% dioxane) and #max (fine spirit) 245 m (# = 14600).



   15 g of # 1,4-6α, 9α-difluoro-2-chloro-16α-methyl-17α-hydroxy-11ss, 21-diacetoxy-3,20-dioxo-pregnadiene are added to 100 ml of methanol Warming to boiling and bubbling nitrogen through dissolved. The resulting solution is then cooled to room temperature under nitrogen and a solution of 11 g of potassium carbonate in 40 ml of water is then added dropwise over the course of about an hour. The reaction solution is stirred at room temperature, while nitrogen is passed through, until in a sample by thin-layer chromatographic control on silica gel with toluene-acetone 1: 1 as the mobile phase, essentially only the product saponified in the 11- and 21-positions is present.

  The reaction mixture is then first concentrated to 2-300 ml under reduced pressure at a bath temperature and then poured into 1500 ml of water. It is extracted several times with ethyl acetate, the extracts are washed successively repeatedly with water, dried over sodium sulphate, filtered and evaporated completely. # 1,4-6α, 9α-difluoro-2-chloro-16α-methyl-11ss, 17α, 21-trihydroxy-3,20-dioxopregnadiene of melting point 220.2220 (with decomposition ).



   Example 2
14.3 g # 1,4-6α, 9α-difluoro-2-chloro-16α-methyl-11ss, 17α-dihydroxy-21-acetoxy-3,20-dioxo-pregnadiene [2-chloro -flumethasone-21-acetate] are dissolved in 950 ml of methanol while heating to boiling and passing nitrogen through. The resulting solution is then cooled to 0-50 under nitrogen and a solution of 3.2 g of sodium bicarbonate in 38 ml of water is then added dropwise over the course of 10 minutes. The reaction solution is then stirred for a further 2-3 days at 0-50 under nitrogen, the reaction product gradually crystallizing out. The progress of the saponification is checked by means of thin-layer chromatography on silica gel with toluene-acetone 1: 1 as the mobile phase.

  At the moment when no starting material can be found in the reaction solution, the reaction mixture is first concentrated to 2-300 ml under reduced pressure at a bath temperature and then poured into 1500 ml of water. It is extracted several times with ethyl acetate, the extracts are washed successively repeatedly with water, dried over sodium sulphate, filtered and evaporated completely.

  The yield is 12.2 g of crystalline # 1,4-6α, 9α-difluoro-2-chloro-16α-methyl-11ss, 17α, 21- -trihydroxy-3,20-dioxopregnadiene [2-chloroflumethasone ], which melts with decomposition between 220-2220; the product is pure by thin layer chromatography (silica gel, toluene-acetone 1: 1), [α] D20 + 40 (= 0.97% in dioxane). ; imaX 245 m (15000) in fine fuel

 

Claims (1)

PATENT CLAIM Process for making steroids of the pregnancy series of the formula EMI2.1 in which X is hydrogen or fluorine and R ,, R2 and Rg are free or esterified hydroxyl groups, at least one of which is in free form and R3 can also be hydrogen, characterized in that compounds of the same formula in which X is the Same meaning skin, R1, R2, R3 are free or esterified hydroxyl groups, at least one of which is in esterified form and R3 can also be hydrogen, at least one esterified hydroxyl group is converted into a free hydroxyl group. SUBClaim Process according to patent claim, characterized in that the starting materials are treated with alkaline hydrolyzing agents to release the esterified hydroxyl groups.