DK156401B - ANALOGY PROCEDURE FOR PREPARING HALOGEN DERIVATIVES OF 16 ALPHA-METHYL PREGNANCY SERIES - Google Patents

Description

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DK 156401 B

The invention relates to an analogous process for the preparation of novel halogen derivatives of the 16 alpha-methylpreg nanowire having the general formula I as set forth in claim 1.

Similar 9 alpha, 11 beta-dihalogen-1,4-pregnadiene compounds with useful local anti-inflammatory action are known from French Patent No. 564 M and from U.S. Patent 3,049,554.

However, the compounds of the invention have greater local anti-inflammatory action on the skin than the known compounds.

In particular, the invention relates to a process for the preparation of the products of formula I wherein L represents an acyl group having from 1 to 18 carbon atoms, and in particular to the compounds wherein L represents acetyl.

The invention also relates in particular to a process for preparing the products of formula I wherein L is selected from a group consisting of hydrogen, propanoyl, isonicotinoyl, formyl and pentanoyl, and in particular such compounds wherein X and Y represent a chlorine atom.

Among the products of formula I, mention is particularly given to those described in the Examples, and in particular the product prepared according to Example 1.

The products of formula I have interesting pharmacological properties. In particular, they have a remarkable inflammatory inhibitory effect by local pathway and are practically without systemic anti-inflammatory effect. This separation of the anti-inflammatory properties by local pathway and the systemic is very interesting, because it makes it possible to use them in the process according to the invention.

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direct compounds at doses where there is no need to fear the classic cortisone type side effects.

These products can thus be used to combat local inflammatory reactions such as breath, dermatosis, pruritus 5 and various types of eczema and sunburn.

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

In particular, among these drugs are mentioned those containing the products described in the Examples and in particular the product prepared according to Example 1.

The products of formula I can be used for the preparation of pharmaceutical products containing as active ingredient at least one of said products I.

These pharmaceutical products can be administered topically in topical application to the skin and mucous membranes.

These products may be solid or liquid and may be present in the pharmaceutical forms commonly used in human medicine such as powders, pomades, creams, jellies and aerosol preparations. They are manufactured according to the usual methods. The active ingredient may be incorporated therein together with additives commonly used in these pharmaceutical products such as talc, starch, aqueous or non-aqueous carriers, animal or vegetable origin fats, paraffin derivatives, glycols, various humectants, dispersants. 25 or emulsifiers and preservatives.

In particular, the useful dose varies depending on the patient being treated and the disorder in question. Between 1 and 4 applications per application can be used. day of a pomade containing 1.5% active ingredient.

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The method according to the invention is peculiar to the characterizing part of claim 1.

In particular, the invention relates to a process which is characterized in that the halogenating agents are constituted by a mixture of N-X-succinimide or N-X-acetamide and a donor agent for halogen ions Y, X and Y having the same meaning as above.

As the halogenating agent and especially as the halogen ion donor substances, the acids HY where Y represents chlorine or fluorine can be used. A lithium halide YLi can also be used in an acidic environment.

In a preferred embodiment of the process according to the invention, the lithium halide is used in acetic acid environment.

A particular embodiment of the invention consists in first producing a product of formula I in the halogenation reaction and then hydrolyzing or esterifying this product as set forth in claim 1.

The hydrolyzing agent used is preferably an alkali metal base such as sodium or potassium hydroxide, sodium amide and potassium tert-butylate, and the hydrolysis reaction is preferably carried out in an alcohol such as methanol or ethanol.

The esterifying agent used is preferably an acid 25 or a functional acid derivative such as an acid anhydride or an acid halide such as an acid chloride or bromide.

The esterification reaction is preferably carried out in the presence of a base agent such as e.g. pyridine or collidine or in the presence of a condensing agent such as dimethyl - 4 -

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formamiJJineopentylacêtâl.

The soin starting products used products of formula II

are known. For example, they can are prepared according to the procedure set forth in French Patent Specification no.

5,296,544 and No. 1,461,655.

Examples 1-8 below illustrate the process of the invention while Examples 9-10 illustrate the preparation of pharmacological compositions containing the compound of formula I.

Example 1 9alpha, 11beta-dichloro-16alpha-methyl-21-acetoxypreqna-1,4-diene-3,20-dione

5 g of 16alpha-methyl-21-acetoxypregna-1,9,9 (11) -triene-3,20-dione 15 and 20 g of anhydrous lithium chloride are added in 200 ml of acetic acid during stirring and under nitrogen stream. The reaction mixture is cooled to 0 ° C and 1.9 g of N-chlorosuccinimide is added and then a solution containing 520 mg of gaseous hydrogen chloride in 5 ml of tetrahydrofuran.

The reaction mixture is kept under stirring for 3 hours 20 at 20 ° C and refrigerated overnight. The reaction mixture is poured into a mixture of water and ice.

You suck, wash with water and dry the obtained precipitate. There is thus obtained 5.7 g of a product which is purified by recrystallization of a mixture of 25 isopropyl ether, methanol and methylene chloride to give 2.4 g of 9alpha, 11beta-dichloro-16alpha-methyl-21-acetoxypregna-1,4 -diene-3,20-dione with m.p.

214 ° C.

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Example 2 9alpha-bromo-11beta-chloro-16alpha-methyl-21-acetoxypregna-1,4-diene-3,20-dione

3 g of 16 alpha-methyl-21-acetoxypregna-4,9 5 (11) -triene-3,20-dione are introduced into 120 ml of acetic acid. To the solution thus obtained is added 12 g of lithium chloride. Stir until complete dissolution. Bring to a temperature between 0 and 5 ° C and add 1.22 g of N-bromoacetamide. To this is added 3 ml of a solution 10 of anhydrous hydrogen chloride in tetrahydrofuran (140 mg of gaseous hydrogen chloride per ml of tetrahydrofuran). Stir at room temperature for 2 hours 45 minutes. It is poured into water, filtered out the precipitate obtained, washed with water and dried under reduced pressure. There was thus obtained 3.76 g of 9alpha-bromo-11beta-chloro-16alpha-methyl-21-acetoxypregna-1,4-diene-3,20-dione with m.p. 190 ° C.

Example 3 9alpha-chloro-11beta-fluoro-16alpha-methyl-21-acetoxypreqna-1,4-diene-3,20-dione

While stirring, 3 g of 16alpha-methyl-21-acetoxypregna-1,4,9 (11) -triene-3,20-dione and 1.2 g of N-chlorosuccinimide are introduced into a solution containing 23.7 g of anhydrous hydrofluoric acid in 50 ml. ml of tetrahydrofuran. The reaction mixture is stirred for 4 hours at 20 ° C and 0.2 g of N-chlorosuccinimide is added again. Stir under stirring for 30 minutes. One is cooled down, added with sodium bicarbonate, poured into aqueous sodium bicarbonate solution and extracted with ether. A product is obtained which is subjected to two chromatography on silica gel in a mixture of benzene and ethyl acetate in the ratio of 8: 2. After a recrystallization of isopropyl ether, 1,167 g of 9alpha-chloro-11beta-fluoro-16alpha-methyl-21-acetoxypregna-1,4-diene-3,20-dione are obtained with m.p. 180 ° C.

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Example 4 9alpha, 11beta-dichloro-16alpha-methyl-21-hydroxypregna-1,4-diene-3,20dione

19.45 g of 9alpha, 11beta-dichloro-16alpha-methyl-5 21-acetoxy-pregna-1,4-diene-3,20-dione (described in Example 1) are introduced into 156 ml of methanol. To the thus obtained solution is added 78 ml of 2.5% methanolic potassium hydroxide solution. Allow to stand for 1 hour, pour the reaction mixture into ice-cold water and neutralize with acetic acid. Filter, wash with water and dry the obtained precipitate. There was thus obtained 17.25 g of the expected product with m.p. 215 ° C.

Example 5 9alpha, 15lbeta-dichloro-16alpha-methyl-21-propanoyloxypregna-1,4-diene-3.20 dione

2.5 g of the product of Example 4 is dissolved in 20 ml of pyridine, added 5 ml of propionic anhydride and left in contact for 1 hour, poured into ice-cold water, left to stand for 15 minutes, suctioned, washed with water , terre and get 2.9 g of raw product which is taken up in a mixture of methanol and chloroform in a 15: 3 ratio.

Evaporate, cool down, suction, dry and get 2.6 g of product which is recrystallized from ethyl acetate. 25 2.4 g of the expected product are obtained with m.p. 200 ° C.

Example 6 9alpha, 1 ^ οίη-άΐοίι1οη-16η1ρ1 ^ -ιη6ίΐΊν1-21-Ϊ3οηίοοίίηον1οχν-preqna-1,4-diene-3,20-dione

Mix 2 g of the product of Example 4, 50 ml of tetrahydro-

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Drofuran, 1.6 g of isonicotinic acid and 2.8 ml of diumethylformamide-dinopentyl acetal, warms to reflux and maintains this state for 3 hours 15 minutes, evaporating to dryness, purifying by passage over a silica gel oil eluting with a mixture of benzene and ethyl acetate in the ratio of 1: 1 to obtain 2 g of crude product which is recrystallized from a mixture of ethyl acetate and methanol in the ratio of 1: 1 to give 1.5 g of the expected product, m.p. 160 ° C.

Example 7 9alpha, 11beta-dichloro-16alpha-methyl-21-formyloxypreqna-1,4-diene-3,20-dione In an ice bath, 12.5 ml of pure acetic anhydride is added and 6.25 ml of 98% is added dropwise. of formic acid solution 15 and stir for 15 minutes at 50 ° C under nitrogen atmosphere, then cool to 0 ° C, add 18.75 ml of pyridine and leave for 5 minutes at 0 ° C. Then 2.5 g of the product of Example 4 is added and allowed to stand for 1 hour at 0 ° C. It is poured into 500 ml of ice-cold water, allowed to stand for 15 minutes, suctioned, dried and obtained 2.6 g of crude product which are dissolved in a mixture of 26 ml of isopropyl ether and 20.8 ml of methanol. Evaporate, ice-cool, suction, dry and get 2.3 g of product which is recrystallized from ethyl acetate. 2.1 g of the expected product is obtained with 25 m.p. 170 ° C.

Example 8 9alpha, 11beta-dichloro-16alpha-methyl-21-pentanoyloxypreqna-1,4-diene-3,20-dione 2.5 g of the product of Example 4 is mixed with 7.5 ml of pyridine.

yours and 2.5 ml of pentanoic anhydride. After 3 hours, pour into 200 ml of ice-cold water. Extract with chloroform, the organic extracts are washed successively with 1 N

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hydrochloric acid, a saturated sodium bicarbonate solution and then twice with water.

Dry, evaporate to dryness and father 3.9 g of crude product which is purified by passage over a silica gel column eluting with a mixture of ether and petroleum ether (b.p.

60-80 ° C) in a 2: 1 ratio. 3.3 g of product are obtained which are dissolved in a mixture of 5 ml of ether and 11.6 ml of isopropyl ether.

Ice cools, sucks, teres and leaves 2.6 g of the expected product, which is recrystallized from a mixture of 3.9 ml of ether and 9 ml of isopropyl ether. 2.1 g of the expected product are obtained with m.p. 76 ° C.

Example 9

A pomade for topical application is prepared according to the recipe:

Product prepared according to Example 1 1.5 g additive per 100 g

Additive details: lanolin and vaseline

Example 10 A pomade for topical application according to the recipe is prepared: product prepared according to Example 4 1.5 g additive per 100 g

Additive details: lanolin and vaseline 25 Pharmacological examination 9alpha, 11beta-dichloro-16alpha-methyl-21-acetoxypregna-1,4-diene-3,20-dione (product A), 9alpha-bromo-11beta-chloro-16 alpha -methyl-21-acetoxypregna-1,4-diene-3,20-dione (product B) and - 9 -

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9alpha-chloro-11beta-fluoro-16alpha-methyl-21-acetoxy-pregna-1,4-diene-3,20-dione (product C), 9alpha, 11beta-di-chloro-16alpha-methyl-21-hydroxypregna- 1,4-diene-3,20-dione (product D), 9alpha, 11beta-dichloro-16alpha-methyl-21-propanoyloxypregna-1,4-diene-3,20-dione (product E), 9alpha , 11beta-dichloro-16alpha-methyl-21-formyloxypregna-1,4-diene-3,20-dione (product F) and 9alpha, 11beta-dichloro-16alpha-methyl-21-pentanoyl-oxypregna-1,4-diene -3,20-dione (product G) is compared with dexamethasone and 9alpha, 10lbeta-dichloro-16alpha-methyl-17alpha-hydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione (product X) .

The products are used in an aqueous dispersant containing 0.25% carboxymethyl cellulose and 0.20 polysorbate 80.

15 1) Examination of anti-inflammatory effects by oral route

This effect is determined by the classical granuloma test.

By the experimental technique used, which is a modification of the method according to R. Meier et al. (Experientia, 1950, 6, 469), conventional Wistar female rats weighing 100-110 g receive an implantation of two cotton balls each 10 mg under the thoracic skin. The oral treatment, which begins immediately after this implantation, lasts two days and consists of two surgeries per day. day. 16 hours after the last administration, ie the third day, the animals are killed.

25 The cotton balls, surrounded by granular tissue formed, are weighed in fresh condition and thereafter after storage for 18 hours at ~ 60 ° C. The weight of the granuloma is obtained by subtracting the original weight of the cotton.

Weighing of the thymus, taken simultaneously with the granuiomas, makes it possible to assess the thymolytic activity of the products.

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The results expressed in DA ^ -q, i.e. the dose which induces a 50% inhibition of granuloma and a dose which induces a thymus involution of 50% is as follows: - granuloma_ thymus product al inhalatively at 50 mg / kg 50 mg / kg 5 product B> 50 mg / kg '> 50 mg / kg product C> 50 mg / kg 30 mg / kg product D inactive at 50 mg / kg 20 mg / kg product E inactive at 50 mg / kg ^ 50 mg / kg product JP 50 mg / kg 35 mg / kg 10 product G inactive at 50 mg / kg 15 mg / kg dexamethasone, 0.045 mg / kg 0.035 mg / kg product X 9 ng / kg 6 mg / kg

Products A, B, E, and F are at least 1000 times less active than dexamethasone in granuloma inhibition and thymus evolution.

Products C, D and G are about 500 times less active than dexamethasone in thymus involution.

2) Examining the effect on the skin

Trials with croton oil edema 20 The pre-test technique used is inspired by the following

Tonelli et al. (Endocrinology 1965, 77, page 625): A mouse edema is induced by the application of croton oil to a sore.

a) Activity on local road 25 - on the mice in a first team, the croton oil solution is applied to the right vein.

- On the mice in another team, the right ear croton

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- the oil solution added to product A or product B, product C, product D, product E, product F or product G or added dexamethasone or product X.

- No product is left on the left side of the mice.

5 After 6 hours, cut off the ears and weigh them.

The difference in weight between right and left veins gives the degree of inflammation.

The results are expressed in CA the active concentration which reduces the odor induced by half on the control animals with croton oil 10.

0Λη0 in mg / ml of product Λ —------— product B 0, ° ^

product C

product D 0.25 product E 0.45 15 0 π product F 'Ό

0 1 R

product G * 0 dexamethasone ° '50 0.07

Conclusion 20 The activity of the skin of product A by local pathway is of the same magnitude as the activity of dexamethasone.

The activity on the skin of products B, C, B, E, F and G by local route is 2-6 times weaker than the activity of dexamethasone.

25 Activity on the skin of all products made according to - 12 -

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the invention by local means is greater than the activity of the known product X.

(b) Oral activity

Proceed as in (a), but products A, B, C and dexamethasone are administered by oral route, while at the same time inducing them with croton oil.

The results in DA.-n, ie. the active dose which decreases

YOU

the edema to half compared to the control animals is as follows: 10 EA50 in mg / kg product A Inatti vt 50 ~ product S ^ product C <MaV + ,. .

inactive at 50 d exaine thason ^^

The activity of products A, B and C is at least 360 times 15 weaker than the action of dexamethasone.

Claims (8)

An analogous process for the preparation of halo derivatives of the lOalpha-methylpregnan series of the general formula I-O-O-Cl 2 OL (I) ch K} rxi 3 wherein L represents a hydrogen atom or an acyl group having 5 to 18 carbon atoms, preferably isonicotinoyl and wherein either Y in the 11beta position represents a chlorine atom and X in the 9alpha position represents a chlorine or bromine atom, or - Y in the 11beta position represents a fluorine atom and X in the 9alpha position represents a chlorine atom, k characterized by subjecting a prodact of formula II 0 wherein L has the same meaning as above, effect of halogenating agents, preferably a mixture of NX-succinimide or of NX-acetamide and a donor agent for halide ions Y, especially the acids hydrogen chloride or> DK Fluoride or lithium halide in acidic environment which halogenating agents are capable of introducing a halogen atom X in the 9 alpha position and another halogen atom Y in the 11 beta position, X and Y having the same meaning as above, to obtain the corresponding product of formula 1, and then, if desired, subject the product of formula I wherein L represents an acyl group of 1 to 18 carbon atoms, effect of a hydrolyzing agent to obtain the corresponding product of formula I, wherein L 10 represents a hydrogen atom and / or subjecting the formed product of formula I wherein L represents a hydrogen atom, the action of an esterifying agent having 1-18 carbon atoms in the acyl moiety and in which the acyl group is different from the acyl group in a first formed 15 acyl compound of formula I to form the corresponding compound of formula I wherein L represents an acyl group of 1-18 carbon atoms. Process according to claim 1, characterized in that L represents an acyl group having 1-18 carbon atoms. Process according to claim 1, characterized in that L represents an acetyl group. Process according to claim 1, characterized in that L is selected from a group consisting of propanoyl, isonicotinoyl, formyl and pentanoyl. 5. A process according to claims 1, 2 or 3, characterized in that Y and X both represent a chlorine atom. 6. A process according to claims 1,2 or 3, characterized by Y denoting a chlorine atom and X denoting a bromine atom. A process according to claims 1, 2 or 3, characterized by Y denoting a fluorine atom and X denoting DK 156401 E-15 - a chlorine atom. Process according to claim 4, characterized in that X and Y both represent a chlorine atom.