IE44866B1 - New halogenated derivatives of the 16a-methylpregnane series,processes for preparing them and pharmaceutical compositions containing them - Google Patents

Abstract

1530975 9,11 - Dihalo - 16 - methyl steroids ROUSSEL UCLAF 2 March 1977 [2 March 1976] 08713/77 Heading C2U The invention comprises compounds of formula (wherein L is H or C 1-18 acyl, and either X is Cl or Br and Y is Cl, or X is Cl and Y is F); and their preparation from the corresponding 9(11)- enes by halogenation, e.g. with an N-X-succinimide or -acetamide in conjunction with HY or LiY, optionally followed by acylation/deacylation interconversions at C-21. Topical anti-inflammatory compositions comprise a compound I and a carrier.

Description

PATENT APPLICATION BY (71) ROUSSEL-UCLAF, A FRENCH BODY CORPORATE, OF 35 BOULEVARD DES INVALIDES, PARIS 7EME, FRANCE. 4 8.6 6 This invention relates to new halogenated derivatives of the 16a-methy1pregnane series, processes for preparing them and pharmaceutical compositions containing them.

Accordingly, in one of its aspects, this invention provides 5 certain halogenated 16a - methyl pregnane derivatives of general formula: II wherein L represents a hydrogen atom or an acyl radical having from 1 to 18 carbon atoms, X is in the a configuration and Y is in the β configuration, and either X represents a chlorine or bromine atom and Y represents a chlorine atom and Y represents a fluorine atom. 4486β Whan L is an acyl radical it is desirably derived from a saturated or unsaturated cycloaliphatic or aliphatic acid, an aromatic carboxylic acid or an amino acid, and is preferably the residue of an alkanoic acid such as formic, acetic, propionic, butyric, isobutyric, valeric or undecylic acid, of a cycloalkylcarboxyl ic acid such as cyclopropyl, cyclopentyl or cyclohexylcarboxylic acid, of a cycloalkylalkanoic acid such as cyclopropy!-, cyclopentyl- or cyclohexylacetic acid, or cyclopropyl-, cyclopentyl- or cyclohexyl-propionic acid, of benzoic acid, which may optionally be substituted by one or more halogen atoms, or by one or more alkyl or alkoxy radicals, of nicotinic or isonicotinic acid, of an amino acid, such as diethylamino - acetic acid or aspartic acid. One preferred group of compounds comprises the compounds of general formula I wherein L is the acetyl radical. A second preferred group comprises those compounds wherein L represents a hydrogen atom, a propanoyl radical, and isonicotinoyl radical, a formyl radical or a pentanoyl radical. Within that group the compounds wherein both X and Y represent a chlorine atom are especially preferred.

Specific preferred compounds include:9“,llS - dichloro - 16“ - methyl - 21'- acetoxypregna - 1,4 - diene - 3,20 - dione; 9a - bromo - Π β - chloro - 16a - methyl - 21 - acetoxypregna 1,4 - diene - 3,20 - dione; 9α - chloro - llg - fluoro - 16a - methyl - 21 - acetoxypregna - 1,4 - diene - 3,20 - dione; 9a,llg - dichloro - 16a - methyl - 21 -hydroxypregna - 1,4 diene - 3,20 - dione; 9a,llg - dichloro - 16a - methyl - 21 - propanoyloxypregna - 1,4 diene - 3,20 - dione; 9a,llg - dichloro - 16a - methyl - 21 - isonicotinoyloxypregna 1,4 - diene - 3,20 - dione; 9a, llg - dichloro - 16a - methyl - 21 - formyloxypregna - 1,4 10 diene - 3,20— dione; and 9a,llg - dichloro - 16a - methyl - 21 - pentanoyloxypregna 1,4 - diene- 3,20 - dione.

In another aspect, this invention provides a process for the preparation of a compound of general formula I, ‘in which an appropriate compound of general formula: (II) CH. '3 44β®6 (wherein L is as defined in relation to general formula I), is treated with halogenating agents capable of introducing the desired halogen atom X at 9a and the desired halogen atom Y at llg, (X and Y being as defined in relation to general formula I) thereby obtaining the coresponding halogenated compound of general formula I.

The halogenating agents employed preferably comprise a combination of the appropriate N - X - succinimide, or N - X - acetamide, with an agent capable of donating Y-halide ions, which latter agent is conveniently an acid (HY) or a lithium salt (Li Y) of the halogen Y. Lithium salts are preferably employed in an acidic medium, which preferably comprises acetic acid.

The halogenating agents may be employed together as a single halogenating mixture or introduced sequentially into the reaction mixture. The compounds of general formula II, used as starting products in this process, are generally known and may be prepared according to the process described in French Patent Specifications Nos. 1,296,544 and 1,461,655.

The compounds of general formula I wherein L represents an acyl radical may alternatively be prepared by treating an appropriate compound of general formula I wherein L represents a hydrogen atom with an appropriate esterifying agent to give the desired ester of general formula I.

The esterifying agent employed may of course be an appropriate acid, although it is more preferably an acid functional derivative such as an acid anhydride or an acid halide, for example an acid chloride or bromide.’ The reaction is preferably performed in the presence of a base such as pyridine or collidine, or with a condensation agent such as dimethylformamide dineopentyl acetal.

The compounds of general formula I wherein L represents a hydrogen atom may be prepared by treating an appropriate compound of general formula I wherein L represents an acyl radical having from 1 to 18 carbon atoms with a saponifying agent to obtain the desired alcohol of general formula I.

; The saponifying agent employed is preferably a mineral base such as sodium hydroxide, potassium hydroxide, or sodium amide or an organic base such as potassium t-butylate, and the saponifying reaction is preferably carried out in an alcohol, for example methanol or ethanol.

- The compounds of general formula I show interesting pharmacological properties; they display a remarkable anti-inflammatory activity when administered by the local route, but show very little antiinflammatory activity when administered by the general route. This difference in anti-inflammatory activity is important, for it enables the compounds of the invention to be administered in effective doses with little fear of causing standard secondary effects of the cortisone type. ' The products may therefore be useful as medicaments for controlling local inflammatory reactions such as, for example, oedema, dermatosis, pruritis, various forms of; eczema and solar erythema. 44836 However, before any of the compounds of this invention may be used in medicine, they should preferably be formed into pharmaceutical compositions by association with suitable pharmaceutical vehicles.

The term pharmaceutical is used herein to exclude any possibility that the nature of the vehicle, considered of course in relation to the route of administration to the patient, could be harmful. The choice of a suitable mode of presentation, together with an appropriate vehicle, is believed to be within the competence of those accustomed to the preparation of pharmaceutical, formulations.

Accordingly, in yet another aspect, this invention provides pharmaceutical compositions containing as active principle one or more of the compounds of general formula I, in association with a suitable pharmaceutical vehicle. The preferred active principles include the compounds described hereinafter in the Examples, and a particularly preferred active principle is the compound described in Example 1.

The compositions of this invention may be administered by local route, that is by topical application to the skin or mucous membranes, and in respect of this mode the pharmaceutical vehicle is preferably the solid or liquid excipient of a powder, paste, lotion, salve, cream, gel, ointment, ungeunt or aerosol. Whilst these preparations represent those most likely to be employed, they do not necessarily exhaust the possibilities.

The excipients used may be those usually employed in such pharmaceutical preparations; that is talc, starch, aqueous or nonaqueous liquid vehicles, fatty substances of animal or vegetable origin, paraffin derivatives and glycols, optionally compounded with various wetting, dispersing or emulsifying agents and preservatives.

Whilst the dosages of the pharmacologically active ingredient will, to a certain degree, depend upon the person to be treated and the nature of the complaint, it may be said by way of general indication, that for an adult the useful dose ranges from 1 to 4 applications per day of an ointment containing 1,5$ of active principle.

The following Examples and Formulations are given to show, by way of illustration, some preferred aspects of this invention.

Example 1 9a,lie -dichloro - 16a - methyl - 21 - acetoxy - pregna 1,4 - diene - 3,20 - dione g of 16a - methyl - 21 - acetoxy - pregna - 1,4,9(11) 15 triene - 3,20 - dione and 20 g of anhydrous lithium chloride were introduced, with agitation, into 200 cm of acetic acid under an atmosphere of nitrogen. The mixture was cooled to 0°C and 1.9g of N-chloro-succinimide, followed by a solution containing 520 mg of hydrochloric acid gas in 5 cm3 of tetrahydrofuran were further added. The resultant mixture was maintained under agitation at . 20°C for three hours, then put into an ice-box for one night, after which the reaction mixture was poured into a mixture of water and ice. The precipitate formed was separated by vacuum-filtration, washed with water and dried to give 5.7 g of crude product. This was purified by recrystallisation from an isopropyl ether/methanol/methylene chloride mixture to give 2.4 g of 9a,llg - dichloro- 16a - methyl - 21 acetoxypregna - 1,4 - diene - 3,20 - dione, melting at 214°C.

Example 2 9a - bromo - 11β - chloro - 16a - methyl - 21 - acetoxypregna 1,4 - diene - 3,20 - dione. 3 g of 16a - methyl - 21 - acetoxy - pregna - 1,4,9(11) 3 triene - 3,20 - dione were introduced into 120 cm of acetic acid; g of lithium chloride were added to the solution thus obtained, agitating until complete dissolution of the solid. The solution was brought to between 0° and +5°C, then 1.32 g of N - bromoacetamide were added, followed by 3 cm3 of a solution of anhydrous hydrochlroic acid in tetrahydrofuran (containing 140 mg of hydrochloric acid gas per cm3 of tetrahydrofuran). The mixture was agitated at ambient temperature for two hours forty-five minutes, after which it was poured into water. The precipitate obtained was separated by vacuum filtration, washed with water and dried under reduced pressure to give 3.76 g of 9a - bromo -lip- chloro - 16a - methyl - 21 - acetoxypregna - 1,4 - diene - 3,20 - dione, melting at 190°C.

Example 3 9a -chloro-llg - fluoro-16a -methyl-21-acetoxypregna-1,4-diene3,20-dione. g of 16a - methyl - 21 - acetoxypregna - 1,4,9(11) - triene - 3,20 - dione and 1,2 g of N-chlorosuccinimide were introduced, with agitation, into a solution of 23.7 g of anhydrous hydrofluoric acid in 50 cnT of tetrahydrofuran; the resultant mixture was maintained under agitation for four hours at 20°C before adding another 0.2 g of N - chloro-succinimide and agitating for a further thirty minutes. The mixture was chilled, dry sodium bicarbonate added, then poured into an aqueous solution of sodium bicarbonate. The product was extracted with ether, ’and twice chromatographed on silica in an 8 : 2 benzene/ethyl acetate mixture to obtain, after recrystallisation from isopropyl ether, 1,167 g of 9 a- chloro - lie - fluoro - 16« - methyl - 21 - acetoxypregna -.1,4 - diene - 3,20 - dione, melting at 180°C.

I ' Example 4 9a,llg-dichloro-16tt-methyl-21-hydroxypregna -1,4-diene-3,20-dione. 19.45 g of 9α,Πβ -dichloro - 16« - methyl - 21 - acetoxypregna - 1,4 - diene - 3,20 - dione (prepared in Example 1) were 3 3 introduced into 156 cm of methanol, ’and 78 cm of a solution of 2.5? of potassium hydroxide in methanol were added to the solution thus obtained. The mixture was left to stand for one hour, poured into iced water and then neutralized with acetic acid.

The precipitate formed was separated by vacuum filtration, washed with water and dried, to give 17.25 g of the desired compound, melting at 215°C.

Example 5 9a,Π β-di chloro-16a-methyl-21-propanoyloxypregna-1,4-diene-3,20-dione. o 2,5 g of the compound of Example 4 were dissolved in 20 cm 0 of pyridine; 5 cm of propionic anhydride were added to the solution formed, and the mixture was left to stand for one hour before being poured into iced water. The precipitate formed was, after fifteen minutes, recovered by vacuum filtration, washed with water and dried, to give 2.9 g of crude product. This product was taken up with a 15:3 methanol/chloroform mixture, the liquor was concentrated and chilled, and the precipitate so formed was vacuum-filtered and dried to give 2.6 g of product. This was recrystallized from ethyl acetate to give 2.4 g of the desired compound, melting at 200°C.

Example 6 9a,11β-dichloro-16a-methyl-21-isonicotinoyloxypregna-1,4-diene-3,20-dione. g of the compound of Example 4, 50 cm3 of tetrahydrofuran, 1.6 g of isonicotinic acid and 2.8 cm3 of dimethylformamide di neopentyl acetal were mixed together then refluxed for three hours fifteen minutes. The mixture was brought to dryness, then purified by passage over a column of silica (eluting with a 1:1 benzene/ ethyl/acetate mixture) to obtain 2 g of crude product. This was recrystallized from a 1:1 ethyl acetate/methanol mixture to give 1.5 g of the expected product, melting at 160°C.

Example 7 9a,llg -dichloro-16a-methyl-21-formyloxypregna-1 ,4-diene-3,20-dione. 12.5 cmJ of pure acetic anhydride were placed in an ice bath and, drop by drop, 6.25 cm of a 98# solution of formic acid were added. The mixture was agitated under an atmosphere of nitrogen at 50°C, for fifteen minutes, then cooled to 0°C. 18.75 cm3 of 44s f'6 pyridine were added, and the mixture was left to stand at 0°C for five minutes before the addition of 2.5 g of the compound of Example 4, whereupon it was left for a.further hour at 0°C. The mixture was then poured into 500 cm of iced water, and the formed precipitate was, after fifteen minutes, separated by vacuum-filtration and dried to give ο 2,6 g of crude product. ‘ This was dissolved in a mixture of 26 cm of isopropyl ether and 20.8 cm of methanol; the liquor was concentrated and chilled, and the precipitate was vacuum-filtered and dried to recover 2.3 g of product, which product was recrystallized from ethyl acetate to obtain 2.1 g of the desired pure compound, : melting at 170°C.

Example 8 9a,ng-dichloro-16a-methyl-21-pentanoyl. oxypregna-1,4-diene-3,20-dione. 2,5 g of the compound of Example 4, 7.5 cm of pyridine and 2.5 cm of pentanoic anhydride were mixed; after three hours the mixture was poured into 200 ml of iced water. The product was extracted with chloroform, and the organic extracts were washed successively with an aqueous solution of N hydrochloric acid, . a saturated solution of sodium bicarbonate, and finally twice with water. The extracts were then dehydrated and dried to give 3.9 g of a crude product that was purified by passing over a column of silica, eluting with a 2:1 ethyl ether/petroleum ether (B.Pt. 60 - 80°C) mixture. 3.3 g of product were recovered which product was dissolved in a mixture of . 5 cm of ethyl ether and 11.6 cm of isopropyl ether. The liquor 4 866 was chilled, and the precipitate obtained was vacuum-filtered and dried to give 2.6 g of product. This was finally recrystallized from a 3 3 mixture of 3.9 cm of ethyl ether and 9 cm of isopropyl ether to give 2.1 g of the expected pure compound, melting at 76°C.

Formulation 1 An ointment for topical application was prepared using the following formula: Product of Example 1 1.5 g Excipient q.s.v. 100 g The excipient was a mixture of lanolin and Vaseline (Trade Mark) Formulation 2 A second ointment for topical application was prepared using the following formula: Product of Example 4 1.5 g Excipient q.s.v. 100 g The excipient was again a mixture of lanolin and Vaseline.

Claims (32)

1. A halogenated 16u-methylpregnane derivative of general formula:(I) wherein L represents a hydrogen atom or an acyl radical having 5 from 1 to 18 carbon atoms, X is in the α configuration and Y is in the 8 configuration, and either X represents a chlorine or bromine atom and Y represents a chlorine atom, or X represents a chlorine atom and Y represents a fluorine atom.

2. A compound as claimed in claim 1, in which L represents 10 an acetyl radical. 14 8 6 6

3. A compound as claimed in claim 1, in which L represents a hydrogen atom, a propanoyl radical, an isonicotinoyl radical, a formyl radical or a pentanoyl radical.

4. A compound as claimed in claim 3, in which both X and Y represent a chlorine atom. 5. A compound as claimed in either claim 1 or claim 2, in which Y and X both represent a chlorine atom.

5. 9α,lie - Dichloro - 16a - methyl - 21 - acetoxypregna 1,4 - diene - 3,20 - dione.

6. 7. 9a - Bromo - Πβ ~ chloro - 16a - methyl - 21 - acetoxypregna - 1,4 - diene - 3,20 - dione.

7. 8. 9a - chloro - Πβ - fluoro - 16a - methyl - 21 - acetoxypregna - 1,4 - diene - 3,20 - dione.

8. 9. 9α,ΠΒ - Dichloro - 16a - methyl - 21 - hydroxypregna - 1,4 diene - 3,20 - dione.

9. 10. 9a, 11β - Dichloro - 16a - methyl - 21 - propanoyloxypregna 1,4 - diene - 3,20 - dione.

10. 11. 9α, 11β - Dichloro - 16a - methyl - 21 - isonicotinoyl oxypregna 1,4 - diene - 3,20 - dione.

11. 12. 9a,lie - Dichloro - 16a - methyl - 21 - formyloxypregna 1,4 - diene - 3,20 - dione.

12. 13. 9α,Πβ - Dichloro - 16o: - methyl - 21 - pentanoyloxy pregna - 1,4 - diene - 3,20 - dione.

13. 14. A process for the preparation of a compound of general formula I, in which an appropriate compound of general formula: A*® (wherein L is as defined in relation to general formula I), is treated with halogenating agents capable of introducing the desired halogen atom X at 9o and the desired halogen atom Y at lie, 5 . (X and Y being as defined in relation to general formula I) thereby obtaining the corresponding halogenated compound of general formula I.

14. 15. A process as claimed in claim 14, in which the halogenating agents employed comprise a combination of an appropriate 10 N - X - succinimide or N - X - acetamide, with an acid (HY) or a lithium salt (Li Y) of the halogen Y.

15. 16. .. A process as claimed in claim 15, in which the lithium salt is employed in an acidic medium.

16. 17. A process as claimed in claim 16, in which the acidic medium comprises acetic acid.

17. 18. A process for preparing a compound of general formula I wherein L represents an acyl radical having from 1 to 18 carbon 5 atoms, in which process an appropriate compound of general formula I wherein L represents a hydrogen atom is treated with an appropriate esterifying agent to give the desired ester of general formula I.

18. 19. A process as claimed in claim 18, in which the esterifying agent is an appropriate acid or a functional derivative thereof. 10 20. A process as claimed in claim 19, in which the functional derivative is an acid anhydride or an acid halide. 21. A process as claimed in any of claims 18 to 20, in which the reaction is performed in the presence of a base or a condensation agent. 15 22. A process as claimed in claim 21, in which the base is pyridine or collidine. 23. A process as claimed in claim 21, in which the condensation agent is dimethylformamide dineopentylacetal. 24. A process as claimed in any of claims 18 to 23, in which the

19. 20 compound of general formula I wherein L represents a hydrogen atom is prepared by treating an appropriate compound of general formula I wherein L represents an acyl radical having from 1 to 18 carbon atoms with a saponifying agent to obtain the desired alcohol of general formula I.

20. 25. A process as claimed in claim 24, in which the saponifying agent is a mineral or organic base.

21. 26. A process as claimed in claim 25, in which the mineral base is sodium hydroxide, potassium hydroxide, or sodium amide.

22. 27. A process as claimed in claim 25, in which the organic base is potassium t-butyTate.

23. 28. A process as claimed in any of claims 24 to 27, in which the saponifying reaction is carried out in an alcoholic medium. :

24. 29. A process fo,r preparing a compound of general formula I wherein L represents a hydrogen atom as defined in any of claims 24 to 28.

25. 30. A process for preparing a compound of general formula I substantially as described hereinbefore with reference to any one of the Examples.

26. 31. A compound of general formula I when prepared by a process claimed in any of claims 14 to 29.

27. 32. A pharmaceutical composition containing as active principle one dr more of the compounds of general formula Γ, in association with a suitable pharmaceutical vehicle.

28. 33. A composition as claimed in claim 32, in which the pharmaceutical vehicle is the solid or liquid excipient of a powder, paste, lotion, salve, cream, gel, ointment, unguent or aerosol.

29. 34. A composition as claimed in claim 32 or 33, in which the active principle is a compound claimed in claim 3 or claim 4.

30. 35. A composition as claimed in claim 32 or 33, in which the active principle is a compound as claimed in any of claims 6 to 8.

31. 36. A composition as claimed in claim 32 or 33, in which the 5 active principle is a compound as claimed in any of claims 9 to 13.

32. 37. A composition substantially as hereinbefore described with reference to either of the Formulations.