IE46955B1 - New pregn-4-ene derivatives processes for preparing them and pharmaceutical compositions containing them - Google Patents

Description

This invention relates to new pregn-4-ene derivatives, processes for preparing them and pharmaceutical compositions containing them.

In one aspect this invention provides the new pregn-4-ene derivatives of the general formula: wherein R, which as indicated hy the wavy line may be at position 16a or 16j3, represents a hydroxy group or a methyl group; R^ represents a hydrogen atom or an acyl radical containing from 1 to 18 carbon atoms; Xg represents a hydrogen atom or a hydroxy group; Y represents a hydrogen atom or a halogen atom; the dotted line in the A ring represents an. optional second carbon-carbon bond at the 1 (2) position; and either A and 3 each represent a hydrogen atom, at position 6 and at position 7 respectively; or A represents a methyl group or a chlorine or fluorine atom at position 6 and B represents a hydrogen atom; or A and B together form a second carbon-carbon bond at the 6 (7) position.

The compounds of formula I may exist in two diastereoisomeric forms - syn and anti isomers - with respect to the C=N double bond. It is to he understood that the invention extends to the syn compounds, to the anti compounds and to - 2 46955 mixtures of both syn and anti isomers, and unless otherwise indicated all references herein to compounds falling within general formula I are to be construed as referring to the individual isomers and all mixtures thereof.

When R^ represents an acyl radical this is preferably an acyl radical derived from a saturated or unsaturated, aliphatic or cycloaliphatic acid and in particular it may be the residue of an alkanoic acid such as acetic, propionic, butyric, isobutyric or undecylic acid, of a cycloalkylcarboxylic or cycloalkylalkanoic acid such as cyclopropyl-, cyclopentyl- or cyclohexyl-acetic or cyclopropyl-, cyclopentyl- or cyclohexyl- propionic acid, of benzoic acid, of a phenylalkanoic acid such as phenylacetic or phenyIpropionic acid, of an anino acid such as diethylaninoacetic or aspartic acid or of formic acid.

The compounds of general formula (I) may be ethylenically unsaturated at the 1 (2) position in the A ring, or alternatively the A ring may tiave no ethylenic unsaturation at the 1 (2) position.

Amongst the compounds of the invention there are a number of preferred groups of compounds - namely, those wherein A and P each represent a hydrogen atom; those wherein represents a hydroxy group; and those whe’ein X? represents a hydrogen atom. Further noteworthy groups cf compounds are those wherein H represents a methyl radical at position 16a; and those wherein Y represents a fluorine atom at the 9a position.

A specific preferred compound of the invention is - 3 46955 9a-fluoro-ΙΙβ, 17a, 21-trihydroxy-16a-methyl-pregna-1,4 -diene-3,20-dione 3-semicarbazone, as its syn or anti isomer.

The invention also provides a process for preparing the compounds of formula I, in which a compound of the general formula: (wherein R, R^, Xg, Y, A ar.dBare as defined hereinbefore), is reacted with senicarbazide or with an acid addition salt thereof, to obtain the desired compound of general formula I.

The syn and anti isomers of the formed compound of general formula I can be separated according to the usual methods of crystallisation or chromatography.

In a preferred method of carrying out the above process an acid.addition salt of semicarbazi-de, such as a hydrochloride salt, is employed rather than semicarbazide itself. The process is preferably carried out at or below ambient temperature.

When the formed compound of general formula I is a compound wherein R^ represents an acyl radical containing from 1 to 18 carbon atoms this may be reacted with a saponification agent to obtain the corresponding compound of general formula I wherein R^ represents a hydrogen atom. 4 6955 The saponification agent used in such a process is preferably sodium hydroxide or potassium hydroxide.

The compounds of general formula I have been found to show interesting pharmacological properties and in particular have exhibited very marked anti-allergic activity comparable to or even in some cases greater than that of known agents such as dexamethasone, whilst being much less anti-inflammatory than the latter compound. This dissociation of anti-inflammatory and anti-allergic properties is of great interest for it may enable the compounds of general formula I to be used at doses which display only the anti-allergic properties and at which there is little dangerof the standard side effects of anti-inflammatory steroids. These properties suggest that the compounds of general formula I are suitable for use in human or animal therapy as medicaments. In particular, they may be useful in the treatment of seasonal or aperiodic rhinitis, asthma and skin disorders of various origins such as urticaria.

However, before using the compounds of general formula I in medicine it is preferred to form them into pharmaceutical compositions by association with suitable pharmaceutical vehicles.

Accordingly, in a further aspect, this invention provides pharmaceutical compositions containing as active ingredient one or more compounds of general formula I in association with a pharmaceutically-acceptable vehicle.

The compositions of the invention preferably contain as active ingredient one or more of those compounds of - 5 4695» general formula I described, hereinbefore as being preferred.

A particularly preferred active ingredient is 9a~fluoro-Iip,l7a,2l-trihydroxy-l6a-methyl-pregna-1,4-diene-3,20-dione 3 -semicarbazone, as its syn or anti isomer.

The term pharmaceutically-acceptable is used herein to exclude, any possibility that the vehicle, considered of course in relation to the route by _ which the composition is to be administered, could be harmful to the patient being treated.

- The choice of a suitable vehicle is believed to be within the competence of those accustomed to the preparation, of pharmaceutical formulations. The compositions are preferably administered bucally, rectally, by a parenteral route, or locally by topical application to the skin or ' mucous membranes. In respect of these routes the pharmaceutical vehicle may be, for example :(a) the ingestible excipient of a tablet or pill, such as a plain or sugar-coated compressed tablet; the ingestible container of a capsule or cachet and particularly . a gelatin capsule; the ingestible pulverulent solid carrier of a powder or granules; or the ingestible liquid medium of a syrup, solution, suspension or elixir; (b) the solid or liquid medium of a paste, cream, ointment or gel, or the liauified propellant gas of an , aerosol; (c) a sterile injectable liquid solution or suspension medium; or (d) the base material of a suppository. - 6 ί 6855 Whilst the pharmaceutical forms just listed represent those most likely to be employed, they do not necessarily exhaust the possibilities.

The vehicles will generally be prepared from those 5 materials commonly employed in the formulation of pharma- : ceutical compositions. Such materials may be solid or liquid as appropriate to the pharmaceutical form chosen, and may include a wide range of organic and inorganic solids, and aqueous and non-aqueous liquids; examples include talc, gum arabic, starch, lactose, magnesium stearate or fatty substances of animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. These materials may be compounded with one or mo-e wetting, dispersing or emulsifying agents and/or one or more preservatives.

The dosage of the active ingredient to be administered to a patient will of course vary with the compound concerned, the complaint and the.patient being treated and the route of administration chosen. By way of illustration it may be said that a desirable dosage in an adult would be from 2θ 0.5 to 100 mg per day administered by the oral route.

The following Example is now given, though only by way of illustration, to show certain preferred aspects of the invention.

Example: gg-fluoro-l^S,17a,21-trihydroxy-16a-methyl-pregn3-5 4,Wier.e-3,20-dione ,3-gemicartazone, as its syn and anti isomer.

One dissolves 10 g of 9a-fluoro-l6a-methyl-113,17a, 21-trihydroxy-pregna-l,4-diene 3,20-dione and 3-412 g of - 7 46955 semicarbazide hydrochloride in 600 cnr of methanol. One maintains under agitation and under a current of nitrogen for 16 hours at 2O~22°G. One then adds 30.6 cm5 of a normal solution of sodium hydroxide. One brings to dryness under reduced pressure at 40°C. One triturates the dry extract in water, vaccum-fliters it, washes it and dries it. One obtains 10.6 g of a product which one chromatographs on silica, eluant: chloroform and methanol (9:1).

One isolates for the one part 5.3 g of a product of Sf = 0.18 which one triturates in dimethoxypropane. One thus obtains the product sought (syn isomer) melting at 300°C. [a]20 = +206° ί 4° (c = 0.5%, EtOH).

NMR Spectrum (DMSO) Ethylenic H^ at 6-75 p.p.m.

One isolates for the other part 3·8 g of a product of Rf = 0.1? which one purifies hy reerystallisation from isopropanol then from methylethylketone. One thus obtains the product sourht (anti isomer).

Ca)20 = +78.5° i 2-5° (c = 0.6,5, EtOH).

NMR Spectrum (DMSO) Ethylenic H^ at 5-93 p.p.m.

Claims (19)

1. CLAIMS: The pregn-4-ene derivatives of the general formula: OH C NH ? C0NHN A 'C-CK 2 ΟΒ χ (I) wherein R, which as indicated by the wavy line may be at 10 position 16a or 16β, represents a hydroxy group or a methyl group; R^ represents a hydrogen atom or an acyl radical containing from 1 to 18 carbon atoms; X-, represents a hydrogen atom or a hydroxy group; Y represents a hydrogen atom or a halogen atom; the dotted line in the A ring represents an optional second 15 carbon-carbon bond at the 1 (7) position; and either A and B each epresent a hydrogen atom; or A represents a methyl group or a chlorine or fluorine atom at position 6 and B represents a hydrogen atom; or A and B together form a second carbon-carbon bond at the 6 (7) position. 20 o. A compound as claimed in Claim 1, wherein the A ring has no ethylenic unsaturation at the 1 (7) position.
2. 2. 3. A compound as claimed in Claim 1 or Claim 2, wherein A and B each represent a hydrogen atom.
3. 3. 4. A compound as claimed in any of Claims 1 to ?, wherein 25 χ represents a hydroxy group.
4. 4. 5. A compound as claimed in any of Claims 1 to 3, wherein Χ., represents a hydrogen atom. - 9 46955
5. 5. 6. A compound as claimed in any of Claims 1 to 5, wherein H represents a methyl radical at position 16a.
6. 6. 7- A compound as claimed in any of Claims 1 to 6, wherein Y represents a fluorine atom at the 9a position. 5
7. 7. 8. A compound as claimed in any of Claims 1 to 7, wherein R-j represents a hydrogen atom or an acetyl radical.
8. 8. 9· 9a-Fluoro-ll3,l7a,2l-trihydroxy-l6a-methyl-pregna-1,4-diene-5,20-dione 3-semicarbazone, anti isomer.
9. 9. 10. 'ix-FluorO“ll3,l7a,?l-trihydroxy-l6a-methyl-pregns-1,410 -diene-3,20-dione 3-semicarhazone, svn isomer.
10. 10. 11. A process for preparing the compounds of formula 1, in which a compound of the general formula: 20 (wherein R, fi,, Y, A and Bare as defined in Claim 1) is reacted with oemicarbazide. or with an acid addition salt thereof, to obtain the desired compound of general formula I.
11. 11. 12. A process as claimed in Claim 11, in which the hydrochloride salt of seaicarbazide is employed. 25
12. 12. 13. A process as claimed in Claim 11 or Claim 12, which is carried out at or below ambient temperature.
13. 13. 14. A process as claimed in any of Claims 11 to 15, in ) which the formed compound of general formula I, when represents an acyl radical, containing from 1 to IP, carbon atoms, is reacted with a saponification agent to obtain the corresponding compound of general formula I wherein represents a hydrogen atom.
14. 14. 15. A process as claimed in Claim 14, in which the saponification a-ent is sodium hydroxide or potassium hydroxide.
15. 15. 16. A process as claimed in any of Claims 11 to 15, and substantially as described herein with reference to the Example.
16. 16. 17. A compound of general formula I as defined in Claim 1, whenever prepared by a process as claimed in any of Claims 11 to 16.
17. 17. 18. A pharmaceutical composition containing as active ingredient one or more compounds of general formula I as defined in Claim 1 in association with a pharmaceuticallyacceptable vehicle.
18. 18.
19. 19. A composition as claimed in Claim 18, in whicn the active ingredient is one or more compounds as claimed in any of Claims ?. to 8. -Ύ». A composition as cl ! -imed in Claim 19, in which the active ingredient is one or both of the compounds claimed in Claims 9 and 10.