CH619969A5 - Process for the preparation of new halogenated derivatives of the 16alpha-methylpregnane series - Google Patents

Abstract

Compounds of formula: <IMAGE> in which L represents hydrogen or a C1-C18 acyl and Y/X in the 11 beta /9 alpha position represent Cl/Cl, Cl/Br or F/Cl, are obtained by halogenation of 16 alpha -methyl-21-LO-pregna-1,4-diene-3,20-dione by means of agents capable of introducing X and Y into the positions mentioned, especially a mixture of N-X succinimide or N-X acetamide and an agent which donates the halide ion Y<->. The 21-acyloxy compounds may then be saponified or the 21-hydroxy compounds obtained acylated. The compounds have a remarkable anti-inflammatory activity when administered locally, but practically none when administered systemically. They may be used for the treatment of local inflammatory reactions without having to fear cortisone-type side effects.

Description

The present invention relates to processes for the preparation of new halogenated derivatives of the 16a-methyl pregnane series of formula:

in which L represents a hydrogen atom, or an acyl radical containing from 1 to 8 carbon atoms, and

- Or else Y in position 11ß represents a chlorine atom and X in position 9 a represents a chlorine atom or a bromine atom.

~ or else Y in position 11ß represents a fluorine atom and X in position 9a represents a chlorine atom.

When L represents an acyl radical, it is preferably the acyl residue of a saturated or unsaturated aliphatic or cycloaliphatic acid and, in particular, the remainder of an alkanoic acid such as acetic, propionic, butyric, isobutyric or valeric acid. or undecylic acid, of a cycloalkylcarboxylic acid, or cycloalkylalkanoic acid, such as for example cyclopropyl, cyclopentyl or cyclohexylcarboxylic acid, cyclopropyl, cyclopentyl or cyclohexylacetic or propionic acid, benzoic acid, optionally substituted by one or more atoms of halogen, one or more alkyl or alkoxy radicals, nicotinic or isonicotinic acid, diethylaminoacetic acid, aspartic acid or formic acid.

The invention relates in particular to a process for the preparation of products of formula I for which L represents an acyl radical containing from 1 to 18 carbon atoms, and more particularly of those for which L represents an acetyl radical, of those for which Y and X both represent

a chlorine atom, of those for which Y represents a chlorine atom and X a bromine atom, of those for s

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which Y represents a fluorine atom and X represents a chlorine atom.

The subject of the invention is also a process for preparing the products of formula I for which L is chosen from the group consisting of a hydrogen atom, a propa-nucleus radical, an isonicotinoyl radical, a formyl radical and a pentanoyl radical, and in particular of those for which X and Y represent a chlorine atom.

Among the products of formula I, mention may be made, in particular, of those described in the examples and, in particular, the product of example 1.

Already known derivatives of pregnane having a certain relationship with the compounds of formula I, in particular those of French patent 546 M; US Patent 3,049,554 describes compounds which do not carry a methyl group in position 16, while other related compounds described in French patent 2,115,437 have a methyl substituent in position 6.

The products of formula I have interesting pharmacological properties: they show in particular remarkable anti-inflammatory activity locally, and are practically devoid of anti-inflammatory activities generally. This dissociation of anti-inflammatory properties locally and generally is very interesting, because it allows the compounds of formula I to be used in doses where there is no need to fear the classic side effects of the cortisonic type.

These products can therefore be used to fight against local inflammatory reactions such as, for example, edema, dermatitis, pruritus, various forms of eczema and erythema solar.

Thus, the products of formula I can be used as medicaments.

Among these drugs, mention may be made in particular of the products described in the examples and in particular the product of Example 1.

The products of formula I can be used to prepare pharmaceutical compositions containing, as active principle, at least one of said products.

These pharmaceutical compositions can be administered topically by topical application to the skin and the mucous membranes.

These compositions can be solid or liquid and are presented in the pharmaceutical forms commonly used in human medicine, such as powders, ointments, creams, gels and aerosol preparations; they are prepared according to the usual methods. The active principle can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, starch, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting, dispersing, or emulsifying agents and preservatives.

The useful dosage varies in particular depending on the subject to be treated and the condition in question. It can be for example between 1 and 4 applications per day of an ointment containing 1.5% of active ingredient.

The process for preparing the products of formula I, which is the subject of the invention, is characterized in that a compound of formula is subjected:

in which L retains its previous meaning, to the action of halogenating agents capable of introducing a halogen atom X at 9a and another halogen atom Y at 11β, X and Y retaining their previous meaning, for obtain the corresponding formula I compound.

The subject of the invention is in particular a process characterized in that the halogenating agents consist of a mixture of succinimide NX or acetamide NX and of agent giving halide ions Y-, X and Y retaining the same meaning as previously.

As halogenating agents and in particular as agents which give halide ions, it is possible to use the acids HY, Y representing a halogen atom; it is also possible to use a lithium halide YLi in an acid medium.

In a preferred embodiment of the process of the invention, the lithium halide is used in acetic medium. The subject of the invention is also a process for preparing the products of formula I, which consists in first of all preparing a product of formula 1 according to the above process, then the product of formula I is subjected in which L represents an acyl radical containing from 1 to 18 carbon atoms, to a saponification agent to obtain the corresponding product of formula I, in which L represents a hydrogen atom, or the product of formula I is subjected, in which L represents a hydrogen atom to an esterifying agent.

In a preferred embodiment of this method of the invention:

the saponification agent used is preferably an alkaline base such as sodium hydroxide or potassium hydroxide, sodium amide, potassium terbutylate and the saponification reaction is preferably carried out in an alcohol such as methanol or l ethanol;

the esterification agent used is preferably an acid, or a functional acid derivative such as an acid anhydride, or an acid halide such as a chloride or a bromide;

- The esterification reaction is preferably carried out in the presence of a basic agent such as for example pyridine, collidine, or in the presence of a condensing agent such as the dineopentylacetal of dimethylformamide.

The products of formula II used as starting materials are generally known; they can be prepared, for example, according to the process indicated in French patents 1,296,544 and 1,461,655.

Examples of implementation of the invention will now be given.

Example 1

9a llß-dichloro 16a-methyl 21-acetoxy-pregna 1,4-dien 3,20-dione

5 g of 16 amethyl 21-acetoxy 1,4, 9 (ll) -triene 3,20-dione and 20 g of anhydrous lithium chloride in 200 cm3 of acetic acid are introduced with stirring and under a stream of nitrogen. The reaction mixture is cooled to 0 ° C. and 1.9 g of N-chlorosuccinimide are added, then a solution containing 520 mg of gaseous hydrochloric acid in 5 cm 3 of tetrahydrofuran. The reaction mixture is kept under stirring for three hours at 20 ° C., then it is placed in a cooler overnight. The reaction mixture is poured into a mixture of water and ice. It is filtered, washed with water and the precipitate obtained is dried. 5.7 g of a product are thus obtained which is purified by recrystallization from an isopropyl ether-methanol-methylene chloride mixture to obtain 2.4 g of 9a, 11ß-dichloro 16a-methyl 21-acetoxy-pregna 1 , 4-dien 3,20-dione melting at 214 ° C.

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Example 2

9a-bromo llßchloro 16 <x-methyl 21-acetoxy-pregna 1,4-dien 3,20-dione 3 g of 16a-methyl acetoxy 1,4, 9 (ll) -triene are introduced into 120 cm3 of acetic acid . 12 g of lithium chloride are added to the solution thus obtained. Stir until completely dissolved. It is brought to 0, + 5 ° C. and 1.32 g of N-bromoacetamide are added. 3 cm3 of a solution of anhydrous hydrochloric acid in tetrahydrofuran are then added (to 140 mg of gaseous hydrochloric acid per cm3 of tetrahydrofuran). The mixture is stirred at room temperature for two hours forty-five minutes. Poured into water, filtered the precipitate obtained, washed with water and dried under reduced pressure. This gives 3.76 g of 9a-bromo llß-chloro 16a-methyl 21-acetoxy-pregna 1,4-dien 3,20-dione melting at 190 ° C.

Example 3

9a-chloro llß-fluoro 16a-methyl 21-acetoxy-pregna 1,4-dien 3,20-dione 3 g of 16a-methyl 21-acetoxy-pregna 1,4, 9 (ll) -triene are introduced with stirring , 20-dione and 1.2 g of N-chlorosucci-nimide in a solution containing 23.7 g of anhydrous hydrofluoric acid in 50 cm3 of tetrahydrofuran. The reaction mixture is kept under stirring for four hours at 20 ° C. and again 0.2 g of N-chlorosuccinimide is added. Stirring is continued for thirty minutes. Ice is added, dry sodium bicarbonate is added, poured into an aqueous sodium bicarbonate solution and extracted with ether. A product is obtained which is subjected to 2 chromatographies on silica in the benzene-ethyl acetate mixture (8.2). After recrystallization from isopropyl ether, 1.167 g of 9a-chloro llßfluoro loamethyl 21-acetoxy-pregna 1,4-dien 3,20-dione, melting at 180 ° C., is obtained.

Example 4

9a-11ß-dichloro 16a-methyl 21-hydroxy pregna 1,4-dien 3,20-dione 19.45 g of 9a, llß-dichloro 16a-methyl 21-acetoxy-pregna 1,4-dien 3 are introduced, 20-dione (described in Example 1) in 156 cm3 of methanol. 78 cm3 of a 2.5% solution of potassium hydroxide in methanol are added to the solution thus obtained. It is left in contact for one hour, the reaction mixture is poured into ice water and neutralized with acetic acid. It is filtered, washed with water and the precipitate obtained is dried. 17.25 g of the desired product are thus obtained, melting at 215 ° C.

Example 5

9a, 11ß-dichloro 16a-methyl 21-propanoyloxy pregna 1,4-dien 3,20-dione 2.5 g of the product of Example 4 are dissolved in 20 cm3 of pyridine, 5 cm3 of propionic anhydride are added and leave in contact for one hour, pour into ice water,

leave to stand for 15 minutes, drain, wash with water, dry and obtain 2.9 g of crude product which is taken up in a methanol-chloroform mixture (15: 3).

Concentrate, spin-dry ice, dry, and obtain 2.6 g of product which is recrystallized from ethyl acetate; 2.4 g of expected product are obtained, melting at 200 ° C.

Example 6

9a, llß-dichloro 16a-methyl 21-isonicotinoyloxy pregna

1,4-dien 3,20-dione 2 g of product from Example 4, 50 cm3 of tetrahydrofuran, 1.6 g of isonicotinic acid and 2.8 cm3 of dineo-pentyl acetal of dimethylformamide are mixed , brings to reflux and maintains for 3 hours 15 minutes, then brings to dryness, purifies by passage over a silica column, eluting with a benzene-ethyl acetate mixture (1: 1) and obtains 2 g of crude product which is recrystallized in the ethyl acetate-methanol mixture (1: 1) and obtains 1.5 g of the expected product, melting at 160 ° C.

Example 7

9a, 11ß-dichloro 16a-methyl 21-formyloxy pregna 1,4-dien 3,20-dione Place in an ice bath 12.5 cm3 of pure acetic anhydride, drop by drop 6.25 cm3 of a 98% formic acid solution, stirred for 15 minutes at 50 ° C under a nitrogen atmosphere, cooled to 0 ° C, then added 18.75 cm3 of Pyridine and allowed to stand for 5 minutes at 0 ° C. 2.5 g of product from Example 1 are then added and the mixture is left for 1 hour at 0 ° C. Poured into 500 cm3 of ice water, allowed to stand for 15 minutes, drained, dried and obtained 2.6 g of crude product which is dissolved in a mixture of 26 cm3 of isopropyl ether and 20.8 cm3 of methanol . Concentrate, ice, drain, dry to obtain 2.3 g of product which is recrystallized from ethyl acetate and 2.1 g of the expected product is obtained, melting at 170 ° C.

Example 8

9a, 11ß-dichloro 16a-methyl 21-pentanoyloxy pregna 1,4-dien 3,20-dione 2.5 g of product from Example 4 are mixed, 7.5 cm3 of pyridine and 2.5 cm3 of anhydride pentanoic; after 3 hours, pour into 200 ml of ice water and then extract with chloroform, wash the organic extracts successively with an aqueous solution of hydrochloric acid N, a saturated solution of sodium bicarbonate, then twice with water.

Dried, brought to dry and obtained 3.9 g of crude product which is purified by passage over a column of silica eluting with ethyl ether-petroleum ether mixture Eb .: 60-80 ° C (2: 1) . 3.3 g of product are obtained which is dissolved in a mixture of 5 cm 3 of ethyl ether and 11.6 cm 3 of isopropyl ether.

Ice, drain, dry and obtained 2.6 g of the expected product which is recrystallized from a mixture of 3.9 cm3 of ethyl ether and 9 cm3 of isopropyl ether. 2.1 g of expected product, melting at 76 ° C., is then obtained.

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Claims (13)

619,969 2. Method according to claim 1, characterized in that the halogenating agents consist of a mixture of N — X succinimide or N— X acetamide and agent halide donor Y-. 2 CLAIMS 1. Process for the preparation of the compounds of formula: in which L represents a hydrogen atom or an acyl radical containing from 1 to 18 carbon atoms, and - or else Y in position 11ß represents a chlorine atom and X in position 9 a represents a chlorine or bromine atom, - or else Y in position 11ß represents a fluorine atom and X in position 9 a represents a chlorine atom, characterized in that a corresponding compound, of formula: 0 CH. to the action of halogenating agents capable of introducing a halogen atom X at 9a and another halogen atom Y at 11β, X and Y retaining their previous meaning. 3. Method according to claim 1, characterized in that compounds of formula I are prepared for which L represents an acyl radical containing from 1 to 18 carbon atoms. 4. Method according to claim 3, characterized in that compounds of formula I are prepared for which L represents an acetyl radical. 5. Method according to claim 3, characterized in that compounds of formula I are prepared for which L is a propanoyl radical, an isonicotinoyl radical, a for-myl radical or a pentanoyl radical. 6. Method according to one of claims 1, 3 and 4, characterized in that compounds of formula I are prepared for which Y and X both represent a chlorine atom. 7. Method according to one of claims 1, 3 and 4, characterized in that compounds of formula I are prepared for which Y represents a chlorine atom and X a bromine atom. 8. Method according to one of claims 1, 3 and 4, characterized in that compounds of formula I are prepared for which Y represents a fluorine atom and X represents a chlorine atom. 9. Method according to claim 5, characterized in that compounds of formula I are prepared for which X and Y both represent a chlorine atom. 10. Process for the preparation of the compounds of formula: CO-CÎTOH CH, in which X and Y, the meanings of which are mentioned in claim 1, characterized in that compounds of formula I are prepared by the process according to claim 1, in which L represents an acyl radical containing from 1 to 18 carbon atoms, and the compounds obtained are subjected to the action of a saponification agent. 11. Method according to claim 10, characterized in that compounds of formula I are prepared for which X and Y both represent a chlorine atom. 12. Process for the preparation of the compounds of formula: CH in which X and Y have the meanings indicated in claim 1 and L represents an acyl radical containing from 1 to 18 carbon atoms, characterized in that compounds of formula I are prepared by the method according to claim 1, in which L represents a hydrogen atom, and the compounds obtained are subjected to an esterification agent capable of introducing the radical L. 13. Method according to claim 12, characterized in that compounds of formula I are prepared for which X and Y both represent a chlorine atom.