CA1129407A - Antiinflammatory steroid of the androstane series - Google Patents
Antiinflammatory steroid of the androstane seriesInfo
- Publication number
- CA1129407A CA1129407A CA321,032A CA321032A CA1129407A CA 1129407 A CA1129407 A CA 1129407A CA 321032 A CA321032 A CA 321032A CA 1129407 A CA1129407 A CA 1129407A
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- Prior art keywords
- beta
- alpha
- methyl
- fluoro
- diene
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
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- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
The specification describes the new compound chloromethyl 17.alpha.-acetoxy-9.alpha.-fluoro-ll.beta.-hydroxy-16.beta.-methyl-3-oxo androsta -1, 4-diene-17.beta.-carboxylate which has useful anti-inflammatory properties.
The specification describes the new compound chloromethyl 17.alpha.-acetoxy-9.alpha.-fluoro-ll.beta.-hydroxy-16.beta.-methyl-3-oxo androsta -1, 4-diene-17.beta.-carboxylate which has useful anti-inflammatory properties.
Description
~L1299~
The present invention relates to an anti-inflamma-tory steroid of the androstane series.
In our British Patent Specification No. 1,438,940, we describe and claim anti-inflammatory steroids having the general formula ol-R4 Rl~~R2 ~ I
0~
wherein X`represents a hydrogen, chlorine or fluorine atom;
Rl represents a ~-hydroxy group, an oxo group or (when X
is a chlorine atom) a ~-chlorine atom;
R represents a hydrogen atom, a methylene group or an ~- or ~-methyl group;
R represents a hydrogen atom or a Cl 4 alkyl group;
R4 represents a fluoro-, chloro-, bromo-, or iodo-methyl group or a fluoroethyl group; and represents 11294~7 a single or double bond.
We have now discovered a new compovnd fal]ing within the broad scope of general formula I above and having particularly advantageous properties compared with close analogues thereof specifically described in our above-men-tioned Patent Specification.
The new compound is chloromethyl 17a-acetoxy-9~-fluoro-ll~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate. It has been found that this compound has a high topical anti-inflammatory activity in man, as measured by the McKenzie patch test, coupled with a relatively weak systemic activity, for example as measured by depression of the thymus weight in mice. Furthermore when the compound is applied locally to the skin of mice, it shows a good ratio of anti-inflammatory activity, as measured by the reduction of croton oil-induced oedema, to undesired systemic activity, as measured by the depression of the hypothalamo-pituitary-adrenal axis. These results indicate that the compound of the invention will be of value in the local treatment of inflammations in man and animals with minimal liability to cause undesired systemic side effects.
The new compound according to ~he present invention can be prepared, for example, according to the methods described in British Patent Specifications Nos 1,384,372 and 1,438,940.
Thus, according to a further feature of the present invention, we provide a process for the preparation of the :' :
1129~C~7 above mentioned compound according to the invention which comprises esterifying the corresponding 17a-acetoxy-andro-stane-17~-carboxylic acid (or functional equivalent thereof) or chloromethyl 17a-hydroxy-androstane-17~-carboxylate to produce the compound according to the invention.
Thus, for example, the compound of the invention may be prepared by reacting a salt of the parent 17~-acetoxy 17~-carboxylic acid with a compound of formula ClCH2Y
wherein Y is an appropriate displaceable substituent, e.g.
a halogen atom other than fluorine, preferably bromine or iodine. The preferred halo cGmpound is iodochloromethane.
The above-described reaction is advantageously effect-ed using as the salt of the parent 17~-carboxylic acid an alkali metal, e.g. lithium, sodium, potassium or caesium salt or an ammonium salt such as the triethylammonium salt or a quaternary ammonium salt such as the tetrabutylammonium salt, conveniently in a polar solvent, particularly a dipolar aprotic solvent such as an amide solvent such as dimethylformamide, dimethylacetamide or hexamethylphosphor-amide or a sulphoxide solvent such as dimethylsulphoxideconveniently at a temperature in the range 15-100C.
According to a further feature of the present invention we provide a further process for the preparation of the compound according to the invention which comprises subjecting a corresponding iodomethyl or bromomethyl 17~-carboxylate to a halogen exchange reaction serving to replace the halogen substituent in the halomethyl group by 1:~L294~
chlorine. Thus, the chloromethyl 17~-carboxylate compound may be prepared from the corresponding iodomethyl or bromo-methyl 17~-carboxylate compound by reaction with for example an alkali metal, alkaline earth metal or an ammonium chloride, e.g. lithium chloride. The reaction is advantageously effected in a solvent medium comprising for example acetone, methy] ethyl ketone, dimethylformamide, dimethylacetamide, hexamethylphosphoramide or ethanol.
The 17a-acetoxy-17~-carboxylic acid may be pre-pared according to the process described in our BritishPatent No. 1384372 as illustrated in the Preparation given hereinafter.
Alternatively, the parent 17-hydroxy-17~-carboxylate corresponding to the compound according to the invention may be sub3ected to esterification of the 17a-hydroxyl group, the 17a-hydroxy-17~-carboxylate being prepared for example by esterifying the corresponding 17a-hydroxy-17B-carboxylic acid by the methods described above.
The esterification of the 17a-hydroxy group in the preparation of the new androstane compound may, if desired, be effected by conventional techniques, e.g. by reacting ! the parent 17-hydroxy compound with a mixed anhydride of acetic acid, which may, for example, be generated in situ by reating acetic acid with an appropriate anhydride such as trifluoroacetic anhydride preferably in the presence of an acid catalyst, e.g. p-toluene-sulphonic acid or sulphosalicylic acid. Alternatively, the mixed anhydride .,~, llZ9~
may be generated ln situ by reacting acetic anhydride with an appropriate further acid, e.g. trifluoroacetic acid.
The esterification reaction is advantageously effect-ed in an organic solvent medium such as benzene, methylene chloride or an excess of the carboxylic acid employed in forming the mixed anhydride, the reaction being conveniently effected at a temperature of 20-100C.
Alternatively, the 17a-hydroxy group may be esterified by reaction of the parent 17a-hydroxy compound with acetic anhydride or acetyl chloride, if desired, in the presence of non-hydroxylic solvents, e.g. chloroform, methylene chloride or benzene, and preferably in the presence of a strong acid catalyst, e.g. perchloric acid, p-toluene sulphonic acid or a strongly acidic cation exchange resin, e.g. Amberlite IR 120, the reaction being conveniently effected at a temperature of 25 to 100C.
For the preparation of the 17a-ester of the 173-carboxylic acid which may be employed in the preparation of the compound of the invention, it is preferred to treat the parent 17-hydroxy-17~-carboxylic acid with acetic anhydride, if desired in the presence of a base such as potassium carbonate. This reaction is conveniently effected at an elevated temperature. Any mixed anhydride formed may be solvolysed under ac dic (e.g. aqueous acetic acid) or basic (e.g. aqueous pyridine or diethylamine/
acetone) conditions. Alternatively, the parent 17a-hydroxy-17~-carboxylic acid may be treated with acetyl 11~,9~7 chloride, preferably in a solvent such as a halogenated hydrocarbon e.g. methylene chloride, and advantageously in the presence of a base such as triethylamine, preferably at a low temperature e.g. 0C.
As is well known to those skilled in the art it may frequently be convenient to elaborate the desired substituents in the 17- and 17~-positions at an inter-mediate stage of the preparation of the compound of the invention, one or more other substituents (or unsaturation) being introduced at a later stage.
There are also provided pharmaceutical compositions (including veterinary compositions) for use in anti-inflammatory therapy, comprising the said compound accord-ing to the invention together with one or more pharmaceutical carriers or excipients. Compositions adapted for topical administration are particularly preferred in view of the high topical activity of the compound of the invention.
However since the compound has some systemic activity, following appropriate routes of administration, ~0 compositions adapted for internal use are also of value.
Thus the active androstane compound may advantageously be formulated into a preparation suitable for topical administration with the aid of a topical vehicle therefor.
By topical administration as used herein, we include administration by insufflation and inhalation. Examples of various types of preparation for topical administration, include ointments, lotions, creams, powders, drops, (e.g.
';~
~Z9~7 for the nose, throat, lung or skin), suppositories, retention enemas, chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers), capsules or cartridges, for use in an inhaler or insufflator, and aerosols, (e.g. for the nose, throat or lung).
Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Such base may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as a polyethylene glycol having an average molecular weight in the range 200-fj00 or a mono- or di-ethylene glycol monoethyl ether or propylene carbonate. Thickening agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols having an average molecular weight in the range 4,000-6,000, woolfat and beeswax and/or glyceryl mono-stearate and/or non-ionic emulsifying agents.
Lotions may be formulated with an aqueous or oily base and will in general also include one or more of the following namely, emulsifying agents, dispersing agents, thickening agents, solvents, colouring agents, suspending agents and perfumes.
Powders for application to the skin may be formed with the aid of any suitable powder base e.g. talc, lactose or starch. Drops may be formulated with an aqueous 1~294~
vehicle also comprising one or more dispersing agents, suspending agents or solubilising agents etc.
Spray compositions may for example be formulated as aqueous solutions or suspensions or as aerosols with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
Capsules and cartridges for use in an inhaler or insufflator, of e.g. gelatin, may be formulated containing a powder mix of the compound of the invention and a suitable powder base such as lactose or starch.
The proportion of the active androstane compound in the topical compositions according to the inven~L.jn depends on the precise type of formulations to be prepared but will generally be within the range of from 0.001 to 5.0%
weight. Generally however for most types of preparations advantageously the proportion used will be within the range of from 0.005 to 0.5% and preferably 0.01 to 0.25~.
However with powders for inhalation or insufflation the proportion used will be within the range of from 0.1 - 2%.
The forgoing formulations for topical application to the skin may be used for the treatment of inflammatory dermatoses of humans and animals, for example eczema, which are normally responsive to corticosteroid th~rapy, and also of less responsive conditions such as psoriasis in humans.
The formulations for administration by inhalation 94~7 or insufflation are intended for administration on a prcp-hylactic basis to humans suffering from allergic and/or inflammatory conditions of the nose, throat or lungs such as asthma and rhinitis, including hay fever. Aerosol formulations are preferably arranged so that each metered dose or 'puff' of aerosol contains 25-200 ,ug, preferably about 50 ~ug of the compound of the invention.
Administration may be several times daily, for example 2,3 or 4 times, giving for example 1,2 or 3 doses each time.
The overall daily dose with an aerosol will be within the range 100 ,ug - 2000 jug, preferably, 200-800 ~ug. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double those with aerosol formulations.
Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may often be used with advantage.
For internal admi~istration the new compound accord-ing to the invention may, for example, be formulated for oral, parenteral or rectal administration. For oral administration, syrups, elixirs, powders and granules may be used which may be formulated in conventional manner.
Dosage unit forms are however preferred as described below.
For parenteral administration the compounds may be presented in sterile aqueous or oily vehicles, suitable oily vehicles including arachis oil and olive oil.
Preferred forms of preparation for internal , llZ9~7 administration are dosage unit forms i.e. presentations in unitary form in which each unit contains a desired dose of the active steroid. Such dosage unit forms con-tain from lmg to 20mg preferably from 2.5 to 10 mg of the active steroid. For oral administration suitable dosage unit forms include tablets, coated tablets and capsules.
For parenteral administration dosage unit forms include sealed ampoules or vials each containing a desired dose of the steroid. Suppositories, which may be prepared for example with conventional commercial suppository bases, provide a dosage unit form for rectal administration.
The compound according to -the invention may in general be given by internal administration in cases where systemic adreno-cortical therapy is indicated.
In general terms preparations for internal adminis-tration may contain from 0.05 to 10% of the active ingred-ient dependent upon the type of preparation involved.
The daily dose may vary from 2.5 to 60mg. e.g. 5 - 30 mg, dependent on the condition being treated, the route of administration and the duration of treatment desired.
The compositions according to the invention may also include one or more preservatives or bacteriostatic agents e.g. methyl hydroxy benzoate, propyl hydroxy benzoate, thiomersa], chlorocresol or benzalkonium chloride. The compositions according to the invention may also contain other active ingredients such as antimicrobial agents, particularly antibiotics, such as neomycin, nystatin, '~
~129~7 gentamycin, tetracyclines and clioquinol.
The following examples illustrate the present invent-ion. All temperatures are in C., and organic extracts were dried over magnesium sulphate.
Preparation 1 17~-Acetoxy-9a-fluoro-11~-hydroxy-16~-methyl-3-oxoan-.
drosta-1,4-diene-17~-carboxylic acid A suspension of 9~-fluoro-11~, 17~-dihydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylic acid (5.0g) and potassium carbonate (2.11g.) in acetone (20ml.) was stirred and treated with acetic anhydride (19.4 ml.), then heated under reflux for 2 hours. After being cooled, the mixture was treated with water (63 ml), acidified with concentrated hydrochloric acid (3 ml.) whilst stirring at ca 0 for 1 hour. The solid was collected, washed with water and dried _ vacuo at 50 overnight and then suspended in acetone (114 ml.) and treated with diethyl-amine (4.8 ml).
After 30 minutes, volatile material was removed under reduced pressure and the residue was treated with water (107 ml); ethyl acetate (600 ml.) was added and the mixture was acidified to p~A 1 with 2N-hydrochloric acid.
The aqueous phase was separated and further extracted with ethyl acetate, the combined ethyl acetate phases were washed well with water, dried and concentrated to low volume. The solid product was collected, washed with ethyl acetate and dried ln vacuo at 60 for 2 days 11~294~7 to give the title compound as colourless crystals (4.916 g )~ ~max (ethanol) 239.5 nm (ElCm 337) A portion of the title acid (1.01 g.) in methanol (5 ml.) was converted with 2M methanolic sodium hydroxide (1.3 ml.) to the sodium salt (976 mg) which was precipitated with ether.
Preparation 2.
-Tetra-n-butylammonium and caesium salts of 17~-acetoxy-9~-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene--17~-carboxylic acids.
-a) Tetra-n-butylammonium salt.
A suspension of the title androstane-17~-carboxylic acid (2.102 g.) in chloroform (10 ml) was mixed with a solution of tetra-n-butylammonium hydrogen sulphate (1.702 g.) and sodium hydroxide (394 g.) in water (10 ml) and stirred for 30 minutes. The organic layer, containing the tetra-n-butylammonium androstane-17~-carboxylate, was separated and used directly.
b) _esium salt A solution of the androstane-17~-carboxylic acid (944 mg.) in methanol (20 ml) was stirred and treated with aqueous 20% caesium carbonate (3.7 ml), giving a slightly turbid solution of pH7. This was evaporated to dryness and the residue was re-evaporated twice from methanol, then dried overnight ln vacuo to give the caesium salt as a foam (1.592 g)~ ~max 241 nm (Elcm 196)-Preparation 3 llZ9~7 Chloromethyl 9a-fluoro-11~,17a-dihydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate.
A mixture of sodium 9a-fluoro-11~,-7a-dihydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17$-carboxylate (400 mg.) and chloroiodomethane (0.36 ml.) in hexamethylphosphor-amide (1.3 ml.) was stirred at room temperature for 3 1/3 hours. The solution was diluted with ethyl acetate and washed successively with water (3x), 5% sodium bicarbonate (lx), water (to pH 5-6), then dried and evaporated to a yellow solid t443 mg.). This was triturated with ethyl acetate-ether, then with ether (twice); the resulting liquors were evaporated to a foam (230 mg.) which was subjected to preparative layer chromatography on silica in chloroform-acetone (40:1, four runs) to give a colourless foam (162 mg). Two crystallizations from acetone-ether gave the title chloromethyl ester (37 mg.), mp. 174-178C (decomp., Kofler), ~max (ethanol) 237.5 nm (~ 15,400). The mother liquors were recovered, evaporated and the residue was crystallized twice from aqueous methanol to give a second crop (69 mg.), mp. 174-178C (decomp. Kofler).
_reparatio 4.
Iodomethyl 17a-Acetoxy-9a-fluoro-ll~-hyd_oxy-16~-methy 3-oxoandrosta-1,4-diene-17~-carboxylate.
A solution of chloromethyl 17a-acetoxy-9~-fluoro-ll~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (1.056 g) and sodium iodide (3.774 g) in 1 " ;':~
. .
99~(~7 acetone (30 ml) was stirred and heated at reflux for 1.5 hours. The mixture was evaporated, then dissolved in ethyl acetate and washed with water, aqueous lO~o sodium thiosulphate, water, aqueous 5% sodium bicarbonate, water and brine, dried and evaporated to a yellow foam (1.277 g).
The product was isolated after preparative layer chromatography (chloroform-acetone, 20:1, three runs) as a foam (951 m~) and this was crystallised twice from acetone to give the title iodomethyl ester as pale yellow crystals (677 mg), m.p. 174-176C, [~D + 18.6 (c 1.10, dioxan).
_eparation 5 Bromomethyl 17-Acetoxy-9-fluoro-11~-hydroxy-1 m _ hyl-3-oxoandrosta-1,4-diene-17~-carboxylate.
A suspension of sodium 17-acetoxy-9-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (250 mg.) in hexamethylphosphoramide (7.5 ml) was stirred with dibromomethane (4.0 ml.). Solid has dissolved after ca 15 minutes and reaction was almost complete after 5 hours as shown by t.l.c. (silica, chloroform-acetone 4:1) After 5.5 hours the mixture was diluted with 5~ sodium dicarbonate and extracted with ethyl acetate; the combined extracts were washed with water, dried and evaporated ln vacuo to a foam (291 mg.). Preparative layer chromato-graphy (silica, chloroform-acetone 4:1 three runs) gave the less polar minor product as crystals (70 mg.); two recrystallizations from acetone gave the title bromomethyl 1129~ 7 17a-acetoxyandrostane-17~-carboxylate as colourless crystals (42 mg.), mp. 199-200 (decomp., Kofler), [a]D + 25 (c 0.51, dioxan), shown by t.l.c. on silica (chlorofor~, eight runs), and by lH nmr. to be ca 90%
pure.
The following Examples 1-5 illustrate the preparation of the compound according to the present invention.
Example 1 10 (a) Sodium 17a-acetoxy-9a-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene 17~-carboxylate (976 mg.) was treated in hexamethyl phosphoramide (5 ml.) with chloroiodomethane (0.8 ml.) for 19 hours when the more reagent (0.8 ml.) for a further 4.5 hours. The mixture was diluted with ethyl acetate and ether was washed with water, 5% sodium bicarbonate solution, sodium thiosulphate and wa~er, dried and evaporated to give the non-acidic fraction (664 my.). Recrystallization from acetone gave colourless crystals of the desired chloromethyl ester 20 (472 mg). A portion (170 mg) recrystallized from acetone gave the analytical sample (144 mg), []D + 32.7 (dioxan c 0.308), ~ max (ethanol) 239 (~15,100).
(b) The sodium, caesium, and tetra-n-butylammonium salts of 17a-acetoxy--9a-fluoro-11~-hydroxy-16~-methyl 3-oxoandrosta-1,4-diene-17~-carboxylic acid were treated, following a similar procedure to that described in (a) above, with chloroiodomethane, the solvent and the period .~
of reaction being specified in the following Table. In the experiments employing the sodium salt, lithium chloride was added after the reaction. The amount of the desired chloromethyl ester present in the reaction mixture was estimated by HPLC or TLC as indicated.
~ABLE
17~ Carboxyl- Solvent ClC~l2I time ¦-iJiCl ~Cr~lc'e Product ate Salt used 1 ~e (hrs) ( ~ol Pro- ~ analysis as startiny mo . q. ccl) duct t ~-matcrial cclded yield ¦after (w/w)~ Product rcac- ~lCC. to ~ n i .-in~n~ic)n Sodium ! ~ 2 ) 3 2 . 0 1. 5I 3 1 10 5 ~0 " I~;e2sO 2.1 23.5I 3 I 91.5 68 .. ~e2~ .COCI13 2 .1 23 . 5 ! 3 ~ 61 .. Me2N.CIIO 2.1 23 . 5 I 3 I 88 60 Caesium (Mc2N) 3PO 2.0 5 ¦ _ ~G(th) ~~0 .. Me 2NC~IO 2 . 0 3 3 . 5 1 - 115 ~ 7 5 B U finN C I IC 13 2 . 7 6 9 ¦ _ 10 G -v 3 0 t w/w unless stated otherwise $ estimatc~l b~ h.p.l.c. or, where indica~ecl (~), by t.l.c.
(appro~imate),with respect to observable in~purities witl detcction bv ultraviolct absorption arcl ~luorcscencc -l~ quenchiny (2r,~nm) respectively.
9~7 Example 2 ~ mixture of iodomethyl 17ci-acetoxy-9c~-fluoro-11~-hydroxy-lG~-mcthyl-3-oxoandrosta-1,4-diene-'7~-carboxylate (50mg.) and lithium chloride (38mg.) in hexa~ethylphosphor-amide (0.5ml.) was stirred at room temperature ror 1 hour.
The resulting pale-yellow solution was shown to contain the desired chloromethyl ester by comparison ~lith an authentic specimen on -thin-layer chromatography on silica in chloro-form-acetone (10:1, two runs): no`startin~ iodom^thyl ester remained.
Exam~le 3 ., _ .
Chloromethyl 9c~-fluoro-11~, 17c~-dihydro~y-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (lmcJ.) was treated with a portion (O.lml.) of a mixture prepared from ~lacial acetic acld (lml.), trifluoroacetic anhyclride (0.2ml.) and a solution (0.025ml) of anhydrous toluene-p-sulphonic acid in chloroform (concentration ca 80mg/n~]); thc storoid ~ i il~9~7 1~
,,~
reaction mixture was then heated at 78-80C for 23 minutes.
The resulting solution was cooled and treated with 2N-sodium carbonate solution (0.5ml.), then extracted with ethyl acetate (3 x 0.3ml.); the combined extracts were evaporated under a stream of nitrogen and the residue was dissolved in chloroform for examination by thin-layer chromatography on silica. No starting steroid remained and the major product was shown to be identical to an authentic specimen of the desired chloromethyl 17~-acetoxyandrostane-17~-carboxylate by t.l.c. on silica in two solvent systems [chloroform-acetone (4:1) and ethyl acetate-petrol (bp 40-60C) (1:1)].
Example 4 A suspension of sodium 17~-acetoxy-9a-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (250mg.) in hexamethylphosphoramide (7.5ml) was stirred with chlorobromomethane (3.64ml.). Solid had dissolved after 15 minutes, an~ t.l.c. examination (silica, chloroform-acetone 4:1) after 1,5 hours showed almost complete reaction had occurred to give a sole major product, equipolar with an authentic sample of the desired chloromethyl ester. After 3.25 hours the reaction mixture was diluted with ethyl acetate (20ml) and 5% sodium bicarbonate solution (lOOml):
the aqueous phase was extracted further with ethyl acetate (2 x 20ml); and the combined extracts were washed with water (3 x 20ml), dried and evaporated in vacuo to a colourless crystalline solid (255mg.) which was shown by its proton magnetic resonance spectrum in deuteriochloro-form to be the desired chloromethyl ester solvated with hexamethylphosphoramide (ca. 1/3 mol).
Exam~le 5.
A suspension of sodium 17~-acetoxy-9~-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (250mg.) in hexamethylphosphoramide (7.5 ml) and dichloro-methane (3.59ml.) was stirred at room temperature. After 5 minutes a clear solution resulted: after 16 hours t.l.c.
on silica in chloroform-acetone (4:1) showed ca 50% con-11294~7-version to a mixture of two products in approximately equal amounts, one of which was identical to the desired chloro-methyl ester.
Example 6 Bromomethyl l~a-acetoxy-9a-fluoro~ -hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (5 mg ) and lithium chloride (4 mg ) in hexamethylphosphoramide (0,05 ml) were stirred together for 64 hours at room temperature. Thin-layer chromatography on silica in chloroform (five runs) showed that no starting bromomethyl ester remained and that it had all been converted to the desiredchloromethyl ester as indicated by comparison with an authentic specimen.
~9~(~7 ~D
_ ~q '~
The following Examples (A) - (D) illustrate topical formulations in accordance with the invention. In each Example the active ingredient is chloromethy 17~-acetoxy-9~-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-5 17~-carboxylate.
Example (A) Ointment Active Ingredient 0.1% w/w Liquid Paraffin B.P. 10% w/w 10 White soft paraffin to produce 100 parts by weight Ball-mill the active ingredient with a little of the liquid paraffin until the particle size is reduced to 95%
by number below 5~. Dilute the paste and rinse out the mill with the remaining liquid paraffin, mix and add the suspension to the melted white soft paraffin at 50C. Stir until cold to give a homogenous ointment.
Example (B) 20 Cream ~ w/w Active ingredient 0.1 Cetostearyl alcohol 10.0 Cetomacrogol 1,000 2.5 White soft paraffin 10.0 25 Liquid paraffin 10.0 Chlorocresol 0.1 Sodium acid phosphate 0.5 Purified water to 100.0 Method of Preparation The chlorocresol and sodium acid phosphate are dissolved in the water at about 70-75C. The waxes are melted together at about 65-70C and added with stirring to the aqueous phase when this has cooled to 65-70C.
The steroid is micronised (particle size as defined in BPC 1973 pg.911 for Ultra-Fine powder) and dispersed in a 1~294(~7 portion of liquid paraffin. The steroid suspension and the remainder of the liquid paraffin are added to the base with stirring at 60 to 65C. The preparation is cooled with stirring to ambient temperature.
5 Example (C) Metered dose_aerosol formulation per dose % w/w Active ingredient 0.05 mg 0.059 Fluorotrichloromethane 25.5 mg 30.0 Dichlorodifluoromethane to 85.0 mg to lO0.0 The active ingredient is micronized (particle size as defined in BPC 1973 pg. 911 for Ultra-Fine powder) and dispersed in the fluorotrichloromethane. This suspension is filled into aluminium aerosol containers, the headspace purged with gaseous dichlorodifluoromethane to exclude air, and a metered aerosol valve crimped into position on the container. Liquid dichlorodifluoromethane is pumped through the metering valve, under pressure, to weight.
_ample (D)_ 20 Inhalation capsul ~100 ~g/dose) per capsule ~_w/w Active ingredient 0.1 mg 0.4 Lactose to 25.0 mg to 100.0 The active ingredient is micronized (particle size as defined in BPC 1973 pg. 911 for Ultra-Fine powder) and blended with lactose in the proportions given in the above formula. The steroid lactose blend is filled into hard gelatin capsules to be administered with an inhalation device.
The present invention relates to an anti-inflamma-tory steroid of the androstane series.
In our British Patent Specification No. 1,438,940, we describe and claim anti-inflammatory steroids having the general formula ol-R4 Rl~~R2 ~ I
0~
wherein X`represents a hydrogen, chlorine or fluorine atom;
Rl represents a ~-hydroxy group, an oxo group or (when X
is a chlorine atom) a ~-chlorine atom;
R represents a hydrogen atom, a methylene group or an ~- or ~-methyl group;
R represents a hydrogen atom or a Cl 4 alkyl group;
R4 represents a fluoro-, chloro-, bromo-, or iodo-methyl group or a fluoroethyl group; and represents 11294~7 a single or double bond.
We have now discovered a new compovnd fal]ing within the broad scope of general formula I above and having particularly advantageous properties compared with close analogues thereof specifically described in our above-men-tioned Patent Specification.
The new compound is chloromethyl 17a-acetoxy-9~-fluoro-ll~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate. It has been found that this compound has a high topical anti-inflammatory activity in man, as measured by the McKenzie patch test, coupled with a relatively weak systemic activity, for example as measured by depression of the thymus weight in mice. Furthermore when the compound is applied locally to the skin of mice, it shows a good ratio of anti-inflammatory activity, as measured by the reduction of croton oil-induced oedema, to undesired systemic activity, as measured by the depression of the hypothalamo-pituitary-adrenal axis. These results indicate that the compound of the invention will be of value in the local treatment of inflammations in man and animals with minimal liability to cause undesired systemic side effects.
The new compound according to ~he present invention can be prepared, for example, according to the methods described in British Patent Specifications Nos 1,384,372 and 1,438,940.
Thus, according to a further feature of the present invention, we provide a process for the preparation of the :' :
1129~C~7 above mentioned compound according to the invention which comprises esterifying the corresponding 17a-acetoxy-andro-stane-17~-carboxylic acid (or functional equivalent thereof) or chloromethyl 17a-hydroxy-androstane-17~-carboxylate to produce the compound according to the invention.
Thus, for example, the compound of the invention may be prepared by reacting a salt of the parent 17~-acetoxy 17~-carboxylic acid with a compound of formula ClCH2Y
wherein Y is an appropriate displaceable substituent, e.g.
a halogen atom other than fluorine, preferably bromine or iodine. The preferred halo cGmpound is iodochloromethane.
The above-described reaction is advantageously effect-ed using as the salt of the parent 17~-carboxylic acid an alkali metal, e.g. lithium, sodium, potassium or caesium salt or an ammonium salt such as the triethylammonium salt or a quaternary ammonium salt such as the tetrabutylammonium salt, conveniently in a polar solvent, particularly a dipolar aprotic solvent such as an amide solvent such as dimethylformamide, dimethylacetamide or hexamethylphosphor-amide or a sulphoxide solvent such as dimethylsulphoxideconveniently at a temperature in the range 15-100C.
According to a further feature of the present invention we provide a further process for the preparation of the compound according to the invention which comprises subjecting a corresponding iodomethyl or bromomethyl 17~-carboxylate to a halogen exchange reaction serving to replace the halogen substituent in the halomethyl group by 1:~L294~
chlorine. Thus, the chloromethyl 17~-carboxylate compound may be prepared from the corresponding iodomethyl or bromo-methyl 17~-carboxylate compound by reaction with for example an alkali metal, alkaline earth metal or an ammonium chloride, e.g. lithium chloride. The reaction is advantageously effected in a solvent medium comprising for example acetone, methy] ethyl ketone, dimethylformamide, dimethylacetamide, hexamethylphosphoramide or ethanol.
The 17a-acetoxy-17~-carboxylic acid may be pre-pared according to the process described in our BritishPatent No. 1384372 as illustrated in the Preparation given hereinafter.
Alternatively, the parent 17-hydroxy-17~-carboxylate corresponding to the compound according to the invention may be sub3ected to esterification of the 17a-hydroxyl group, the 17a-hydroxy-17~-carboxylate being prepared for example by esterifying the corresponding 17a-hydroxy-17B-carboxylic acid by the methods described above.
The esterification of the 17a-hydroxy group in the preparation of the new androstane compound may, if desired, be effected by conventional techniques, e.g. by reacting ! the parent 17-hydroxy compound with a mixed anhydride of acetic acid, which may, for example, be generated in situ by reating acetic acid with an appropriate anhydride such as trifluoroacetic anhydride preferably in the presence of an acid catalyst, e.g. p-toluene-sulphonic acid or sulphosalicylic acid. Alternatively, the mixed anhydride .,~, llZ9~
may be generated ln situ by reacting acetic anhydride with an appropriate further acid, e.g. trifluoroacetic acid.
The esterification reaction is advantageously effect-ed in an organic solvent medium such as benzene, methylene chloride or an excess of the carboxylic acid employed in forming the mixed anhydride, the reaction being conveniently effected at a temperature of 20-100C.
Alternatively, the 17a-hydroxy group may be esterified by reaction of the parent 17a-hydroxy compound with acetic anhydride or acetyl chloride, if desired, in the presence of non-hydroxylic solvents, e.g. chloroform, methylene chloride or benzene, and preferably in the presence of a strong acid catalyst, e.g. perchloric acid, p-toluene sulphonic acid or a strongly acidic cation exchange resin, e.g. Amberlite IR 120, the reaction being conveniently effected at a temperature of 25 to 100C.
For the preparation of the 17a-ester of the 173-carboxylic acid which may be employed in the preparation of the compound of the invention, it is preferred to treat the parent 17-hydroxy-17~-carboxylic acid with acetic anhydride, if desired in the presence of a base such as potassium carbonate. This reaction is conveniently effected at an elevated temperature. Any mixed anhydride formed may be solvolysed under ac dic (e.g. aqueous acetic acid) or basic (e.g. aqueous pyridine or diethylamine/
acetone) conditions. Alternatively, the parent 17a-hydroxy-17~-carboxylic acid may be treated with acetyl 11~,9~7 chloride, preferably in a solvent such as a halogenated hydrocarbon e.g. methylene chloride, and advantageously in the presence of a base such as triethylamine, preferably at a low temperature e.g. 0C.
As is well known to those skilled in the art it may frequently be convenient to elaborate the desired substituents in the 17- and 17~-positions at an inter-mediate stage of the preparation of the compound of the invention, one or more other substituents (or unsaturation) being introduced at a later stage.
There are also provided pharmaceutical compositions (including veterinary compositions) for use in anti-inflammatory therapy, comprising the said compound accord-ing to the invention together with one or more pharmaceutical carriers or excipients. Compositions adapted for topical administration are particularly preferred in view of the high topical activity of the compound of the invention.
However since the compound has some systemic activity, following appropriate routes of administration, ~0 compositions adapted for internal use are also of value.
Thus the active androstane compound may advantageously be formulated into a preparation suitable for topical administration with the aid of a topical vehicle therefor.
By topical administration as used herein, we include administration by insufflation and inhalation. Examples of various types of preparation for topical administration, include ointments, lotions, creams, powders, drops, (e.g.
';~
~Z9~7 for the nose, throat, lung or skin), suppositories, retention enemas, chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers), capsules or cartridges, for use in an inhaler or insufflator, and aerosols, (e.g. for the nose, throat or lung).
Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Such base may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as a polyethylene glycol having an average molecular weight in the range 200-fj00 or a mono- or di-ethylene glycol monoethyl ether or propylene carbonate. Thickening agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols having an average molecular weight in the range 4,000-6,000, woolfat and beeswax and/or glyceryl mono-stearate and/or non-ionic emulsifying agents.
Lotions may be formulated with an aqueous or oily base and will in general also include one or more of the following namely, emulsifying agents, dispersing agents, thickening agents, solvents, colouring agents, suspending agents and perfumes.
Powders for application to the skin may be formed with the aid of any suitable powder base e.g. talc, lactose or starch. Drops may be formulated with an aqueous 1~294~
vehicle also comprising one or more dispersing agents, suspending agents or solubilising agents etc.
Spray compositions may for example be formulated as aqueous solutions or suspensions or as aerosols with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
Capsules and cartridges for use in an inhaler or insufflator, of e.g. gelatin, may be formulated containing a powder mix of the compound of the invention and a suitable powder base such as lactose or starch.
The proportion of the active androstane compound in the topical compositions according to the inven~L.jn depends on the precise type of formulations to be prepared but will generally be within the range of from 0.001 to 5.0%
weight. Generally however for most types of preparations advantageously the proportion used will be within the range of from 0.005 to 0.5% and preferably 0.01 to 0.25~.
However with powders for inhalation or insufflation the proportion used will be within the range of from 0.1 - 2%.
The forgoing formulations for topical application to the skin may be used for the treatment of inflammatory dermatoses of humans and animals, for example eczema, which are normally responsive to corticosteroid th~rapy, and also of less responsive conditions such as psoriasis in humans.
The formulations for administration by inhalation 94~7 or insufflation are intended for administration on a prcp-hylactic basis to humans suffering from allergic and/or inflammatory conditions of the nose, throat or lungs such as asthma and rhinitis, including hay fever. Aerosol formulations are preferably arranged so that each metered dose or 'puff' of aerosol contains 25-200 ,ug, preferably about 50 ~ug of the compound of the invention.
Administration may be several times daily, for example 2,3 or 4 times, giving for example 1,2 or 3 doses each time.
The overall daily dose with an aerosol will be within the range 100 ,ug - 2000 jug, preferably, 200-800 ~ug. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double those with aerosol formulations.
Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may often be used with advantage.
For internal admi~istration the new compound accord-ing to the invention may, for example, be formulated for oral, parenteral or rectal administration. For oral administration, syrups, elixirs, powders and granules may be used which may be formulated in conventional manner.
Dosage unit forms are however preferred as described below.
For parenteral administration the compounds may be presented in sterile aqueous or oily vehicles, suitable oily vehicles including arachis oil and olive oil.
Preferred forms of preparation for internal , llZ9~7 administration are dosage unit forms i.e. presentations in unitary form in which each unit contains a desired dose of the active steroid. Such dosage unit forms con-tain from lmg to 20mg preferably from 2.5 to 10 mg of the active steroid. For oral administration suitable dosage unit forms include tablets, coated tablets and capsules.
For parenteral administration dosage unit forms include sealed ampoules or vials each containing a desired dose of the steroid. Suppositories, which may be prepared for example with conventional commercial suppository bases, provide a dosage unit form for rectal administration.
The compound according to -the invention may in general be given by internal administration in cases where systemic adreno-cortical therapy is indicated.
In general terms preparations for internal adminis-tration may contain from 0.05 to 10% of the active ingred-ient dependent upon the type of preparation involved.
The daily dose may vary from 2.5 to 60mg. e.g. 5 - 30 mg, dependent on the condition being treated, the route of administration and the duration of treatment desired.
The compositions according to the invention may also include one or more preservatives or bacteriostatic agents e.g. methyl hydroxy benzoate, propyl hydroxy benzoate, thiomersa], chlorocresol or benzalkonium chloride. The compositions according to the invention may also contain other active ingredients such as antimicrobial agents, particularly antibiotics, such as neomycin, nystatin, '~
~129~7 gentamycin, tetracyclines and clioquinol.
The following examples illustrate the present invent-ion. All temperatures are in C., and organic extracts were dried over magnesium sulphate.
Preparation 1 17~-Acetoxy-9a-fluoro-11~-hydroxy-16~-methyl-3-oxoan-.
drosta-1,4-diene-17~-carboxylic acid A suspension of 9~-fluoro-11~, 17~-dihydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylic acid (5.0g) and potassium carbonate (2.11g.) in acetone (20ml.) was stirred and treated with acetic anhydride (19.4 ml.), then heated under reflux for 2 hours. After being cooled, the mixture was treated with water (63 ml), acidified with concentrated hydrochloric acid (3 ml.) whilst stirring at ca 0 for 1 hour. The solid was collected, washed with water and dried _ vacuo at 50 overnight and then suspended in acetone (114 ml.) and treated with diethyl-amine (4.8 ml).
After 30 minutes, volatile material was removed under reduced pressure and the residue was treated with water (107 ml); ethyl acetate (600 ml.) was added and the mixture was acidified to p~A 1 with 2N-hydrochloric acid.
The aqueous phase was separated and further extracted with ethyl acetate, the combined ethyl acetate phases were washed well with water, dried and concentrated to low volume. The solid product was collected, washed with ethyl acetate and dried ln vacuo at 60 for 2 days 11~294~7 to give the title compound as colourless crystals (4.916 g )~ ~max (ethanol) 239.5 nm (ElCm 337) A portion of the title acid (1.01 g.) in methanol (5 ml.) was converted with 2M methanolic sodium hydroxide (1.3 ml.) to the sodium salt (976 mg) which was precipitated with ether.
Preparation 2.
-Tetra-n-butylammonium and caesium salts of 17~-acetoxy-9~-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene--17~-carboxylic acids.
-a) Tetra-n-butylammonium salt.
A suspension of the title androstane-17~-carboxylic acid (2.102 g.) in chloroform (10 ml) was mixed with a solution of tetra-n-butylammonium hydrogen sulphate (1.702 g.) and sodium hydroxide (394 g.) in water (10 ml) and stirred for 30 minutes. The organic layer, containing the tetra-n-butylammonium androstane-17~-carboxylate, was separated and used directly.
b) _esium salt A solution of the androstane-17~-carboxylic acid (944 mg.) in methanol (20 ml) was stirred and treated with aqueous 20% caesium carbonate (3.7 ml), giving a slightly turbid solution of pH7. This was evaporated to dryness and the residue was re-evaporated twice from methanol, then dried overnight ln vacuo to give the caesium salt as a foam (1.592 g)~ ~max 241 nm (Elcm 196)-Preparation 3 llZ9~7 Chloromethyl 9a-fluoro-11~,17a-dihydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate.
A mixture of sodium 9a-fluoro-11~,-7a-dihydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17$-carboxylate (400 mg.) and chloroiodomethane (0.36 ml.) in hexamethylphosphor-amide (1.3 ml.) was stirred at room temperature for 3 1/3 hours. The solution was diluted with ethyl acetate and washed successively with water (3x), 5% sodium bicarbonate (lx), water (to pH 5-6), then dried and evaporated to a yellow solid t443 mg.). This was triturated with ethyl acetate-ether, then with ether (twice); the resulting liquors were evaporated to a foam (230 mg.) which was subjected to preparative layer chromatography on silica in chloroform-acetone (40:1, four runs) to give a colourless foam (162 mg). Two crystallizations from acetone-ether gave the title chloromethyl ester (37 mg.), mp. 174-178C (decomp., Kofler), ~max (ethanol) 237.5 nm (~ 15,400). The mother liquors were recovered, evaporated and the residue was crystallized twice from aqueous methanol to give a second crop (69 mg.), mp. 174-178C (decomp. Kofler).
_reparatio 4.
Iodomethyl 17a-Acetoxy-9a-fluoro-ll~-hyd_oxy-16~-methy 3-oxoandrosta-1,4-diene-17~-carboxylate.
A solution of chloromethyl 17a-acetoxy-9~-fluoro-ll~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (1.056 g) and sodium iodide (3.774 g) in 1 " ;':~
. .
99~(~7 acetone (30 ml) was stirred and heated at reflux for 1.5 hours. The mixture was evaporated, then dissolved in ethyl acetate and washed with water, aqueous lO~o sodium thiosulphate, water, aqueous 5% sodium bicarbonate, water and brine, dried and evaporated to a yellow foam (1.277 g).
The product was isolated after preparative layer chromatography (chloroform-acetone, 20:1, three runs) as a foam (951 m~) and this was crystallised twice from acetone to give the title iodomethyl ester as pale yellow crystals (677 mg), m.p. 174-176C, [~D + 18.6 (c 1.10, dioxan).
_eparation 5 Bromomethyl 17-Acetoxy-9-fluoro-11~-hydroxy-1 m _ hyl-3-oxoandrosta-1,4-diene-17~-carboxylate.
A suspension of sodium 17-acetoxy-9-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (250 mg.) in hexamethylphosphoramide (7.5 ml) was stirred with dibromomethane (4.0 ml.). Solid has dissolved after ca 15 minutes and reaction was almost complete after 5 hours as shown by t.l.c. (silica, chloroform-acetone 4:1) After 5.5 hours the mixture was diluted with 5~ sodium dicarbonate and extracted with ethyl acetate; the combined extracts were washed with water, dried and evaporated ln vacuo to a foam (291 mg.). Preparative layer chromato-graphy (silica, chloroform-acetone 4:1 three runs) gave the less polar minor product as crystals (70 mg.); two recrystallizations from acetone gave the title bromomethyl 1129~ 7 17a-acetoxyandrostane-17~-carboxylate as colourless crystals (42 mg.), mp. 199-200 (decomp., Kofler), [a]D + 25 (c 0.51, dioxan), shown by t.l.c. on silica (chlorofor~, eight runs), and by lH nmr. to be ca 90%
pure.
The following Examples 1-5 illustrate the preparation of the compound according to the present invention.
Example 1 10 (a) Sodium 17a-acetoxy-9a-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene 17~-carboxylate (976 mg.) was treated in hexamethyl phosphoramide (5 ml.) with chloroiodomethane (0.8 ml.) for 19 hours when the more reagent (0.8 ml.) for a further 4.5 hours. The mixture was diluted with ethyl acetate and ether was washed with water, 5% sodium bicarbonate solution, sodium thiosulphate and wa~er, dried and evaporated to give the non-acidic fraction (664 my.). Recrystallization from acetone gave colourless crystals of the desired chloromethyl ester 20 (472 mg). A portion (170 mg) recrystallized from acetone gave the analytical sample (144 mg), []D + 32.7 (dioxan c 0.308), ~ max (ethanol) 239 (~15,100).
(b) The sodium, caesium, and tetra-n-butylammonium salts of 17a-acetoxy--9a-fluoro-11~-hydroxy-16~-methyl 3-oxoandrosta-1,4-diene-17~-carboxylic acid were treated, following a similar procedure to that described in (a) above, with chloroiodomethane, the solvent and the period .~
of reaction being specified in the following Table. In the experiments employing the sodium salt, lithium chloride was added after the reaction. The amount of the desired chloromethyl ester present in the reaction mixture was estimated by HPLC or TLC as indicated.
~ABLE
17~ Carboxyl- Solvent ClC~l2I time ¦-iJiCl ~Cr~lc'e Product ate Salt used 1 ~e (hrs) ( ~ol Pro- ~ analysis as startiny mo . q. ccl) duct t ~-matcrial cclded yield ¦after (w/w)~ Product rcac- ~lCC. to ~ n i .-in~n~ic)n Sodium ! ~ 2 ) 3 2 . 0 1. 5I 3 1 10 5 ~0 " I~;e2sO 2.1 23.5I 3 I 91.5 68 .. ~e2~ .COCI13 2 .1 23 . 5 ! 3 ~ 61 .. Me2N.CIIO 2.1 23 . 5 I 3 I 88 60 Caesium (Mc2N) 3PO 2.0 5 ¦ _ ~G(th) ~~0 .. Me 2NC~IO 2 . 0 3 3 . 5 1 - 115 ~ 7 5 B U finN C I IC 13 2 . 7 6 9 ¦ _ 10 G -v 3 0 t w/w unless stated otherwise $ estimatc~l b~ h.p.l.c. or, where indica~ecl (~), by t.l.c.
(appro~imate),with respect to observable in~purities witl detcction bv ultraviolct absorption arcl ~luorcscencc -l~ quenchiny (2r,~nm) respectively.
9~7 Example 2 ~ mixture of iodomethyl 17ci-acetoxy-9c~-fluoro-11~-hydroxy-lG~-mcthyl-3-oxoandrosta-1,4-diene-'7~-carboxylate (50mg.) and lithium chloride (38mg.) in hexa~ethylphosphor-amide (0.5ml.) was stirred at room temperature ror 1 hour.
The resulting pale-yellow solution was shown to contain the desired chloromethyl ester by comparison ~lith an authentic specimen on -thin-layer chromatography on silica in chloro-form-acetone (10:1, two runs): no`startin~ iodom^thyl ester remained.
Exam~le 3 ., _ .
Chloromethyl 9c~-fluoro-11~, 17c~-dihydro~y-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (lmcJ.) was treated with a portion (O.lml.) of a mixture prepared from ~lacial acetic acld (lml.), trifluoroacetic anhyclride (0.2ml.) and a solution (0.025ml) of anhydrous toluene-p-sulphonic acid in chloroform (concentration ca 80mg/n~]); thc storoid ~ i il~9~7 1~
,,~
reaction mixture was then heated at 78-80C for 23 minutes.
The resulting solution was cooled and treated with 2N-sodium carbonate solution (0.5ml.), then extracted with ethyl acetate (3 x 0.3ml.); the combined extracts were evaporated under a stream of nitrogen and the residue was dissolved in chloroform for examination by thin-layer chromatography on silica. No starting steroid remained and the major product was shown to be identical to an authentic specimen of the desired chloromethyl 17~-acetoxyandrostane-17~-carboxylate by t.l.c. on silica in two solvent systems [chloroform-acetone (4:1) and ethyl acetate-petrol (bp 40-60C) (1:1)].
Example 4 A suspension of sodium 17~-acetoxy-9a-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (250mg.) in hexamethylphosphoramide (7.5ml) was stirred with chlorobromomethane (3.64ml.). Solid had dissolved after 15 minutes, an~ t.l.c. examination (silica, chloroform-acetone 4:1) after 1,5 hours showed almost complete reaction had occurred to give a sole major product, equipolar with an authentic sample of the desired chloromethyl ester. After 3.25 hours the reaction mixture was diluted with ethyl acetate (20ml) and 5% sodium bicarbonate solution (lOOml):
the aqueous phase was extracted further with ethyl acetate (2 x 20ml); and the combined extracts were washed with water (3 x 20ml), dried and evaporated in vacuo to a colourless crystalline solid (255mg.) which was shown by its proton magnetic resonance spectrum in deuteriochloro-form to be the desired chloromethyl ester solvated with hexamethylphosphoramide (ca. 1/3 mol).
Exam~le 5.
A suspension of sodium 17~-acetoxy-9~-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (250mg.) in hexamethylphosphoramide (7.5 ml) and dichloro-methane (3.59ml.) was stirred at room temperature. After 5 minutes a clear solution resulted: after 16 hours t.l.c.
on silica in chloroform-acetone (4:1) showed ca 50% con-11294~7-version to a mixture of two products in approximately equal amounts, one of which was identical to the desired chloro-methyl ester.
Example 6 Bromomethyl l~a-acetoxy-9a-fluoro~ -hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (5 mg ) and lithium chloride (4 mg ) in hexamethylphosphoramide (0,05 ml) were stirred together for 64 hours at room temperature. Thin-layer chromatography on silica in chloroform (five runs) showed that no starting bromomethyl ester remained and that it had all been converted to the desiredchloromethyl ester as indicated by comparison with an authentic specimen.
~9~(~7 ~D
_ ~q '~
The following Examples (A) - (D) illustrate topical formulations in accordance with the invention. In each Example the active ingredient is chloromethy 17~-acetoxy-9~-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-5 17~-carboxylate.
Example (A) Ointment Active Ingredient 0.1% w/w Liquid Paraffin B.P. 10% w/w 10 White soft paraffin to produce 100 parts by weight Ball-mill the active ingredient with a little of the liquid paraffin until the particle size is reduced to 95%
by number below 5~. Dilute the paste and rinse out the mill with the remaining liquid paraffin, mix and add the suspension to the melted white soft paraffin at 50C. Stir until cold to give a homogenous ointment.
Example (B) 20 Cream ~ w/w Active ingredient 0.1 Cetostearyl alcohol 10.0 Cetomacrogol 1,000 2.5 White soft paraffin 10.0 25 Liquid paraffin 10.0 Chlorocresol 0.1 Sodium acid phosphate 0.5 Purified water to 100.0 Method of Preparation The chlorocresol and sodium acid phosphate are dissolved in the water at about 70-75C. The waxes are melted together at about 65-70C and added with stirring to the aqueous phase when this has cooled to 65-70C.
The steroid is micronised (particle size as defined in BPC 1973 pg.911 for Ultra-Fine powder) and dispersed in a 1~294(~7 portion of liquid paraffin. The steroid suspension and the remainder of the liquid paraffin are added to the base with stirring at 60 to 65C. The preparation is cooled with stirring to ambient temperature.
5 Example (C) Metered dose_aerosol formulation per dose % w/w Active ingredient 0.05 mg 0.059 Fluorotrichloromethane 25.5 mg 30.0 Dichlorodifluoromethane to 85.0 mg to lO0.0 The active ingredient is micronized (particle size as defined in BPC 1973 pg. 911 for Ultra-Fine powder) and dispersed in the fluorotrichloromethane. This suspension is filled into aluminium aerosol containers, the headspace purged with gaseous dichlorodifluoromethane to exclude air, and a metered aerosol valve crimped into position on the container. Liquid dichlorodifluoromethane is pumped through the metering valve, under pressure, to weight.
_ample (D)_ 20 Inhalation capsul ~100 ~g/dose) per capsule ~_w/w Active ingredient 0.1 mg 0.4 Lactose to 25.0 mg to 100.0 The active ingredient is micronized (particle size as defined in BPC 1973 pg. 911 for Ultra-Fine powder) and blended with lactose in the proportions given in the above formula. The steroid lactose blend is filled into hard gelatin capsules to be administered with an inhalation device.
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of chloromethyl 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-16.beta. methyl-3-oxoandrosta-1,4-diene-17.beta.-carboxylate which comprises either (A) esterifying 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxoandrosta-1,4-diene-17.beta.-carboxylic acid (or a functional equivalent thereof) or chloro-methyl-9.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.beta.-methyl-3-oxoandrosta-1,4-diene-17.beta.-carboxylate to produce the desired compound; or (B) subjecting iodomethyl or bromomethyl 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-16 .beta.-methyl-3-oxoandrosta-1,4-diene-17.beta. carboxylate to a halogen exchange reaction serving to replace the halogen sub-stituent in the halomethyl group by chlorine.
2. A process as claimed in claim 1 wherein a salt of the said 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxoandrosta-1,4-diene-17.beta.-carboxylic acid is reacted with a compound of formula CICH2Y where Y is a halogen atom other than fluorine.
3. A process as claimed in claim 2 in which Y is an iodine or bromine atom.
4. A process as claimed in claim 1 wherein the said chloromethyl 9.alpha.-fluoro 11.beta.,17.alpha.,dihydroxy-16.beta.-methyl-3-oxoandrosta-1,4-diene-17.beta.-carboxylate is reacted with acetyl chloride or acetic anhydride or a mixed anhydride of acetic acid.
5. A process as claimed in claim 1 wherein iodomethyl or bromomethyl 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxoandrosta-1,4-diene-17.beta.-carboxylate is reacted with an alkali metal, alkaline earth metal or an ammonium or quaternary ammonium chloride.
6. Chloromethyl 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxoandrosta-1,4-diene-17.beta.-carboxylate, when prepared by the process of claim 1, 2 or 3, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB5131/78 | 1978-02-08 | ||
| GB513178 | 1978-02-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1129407A true CA1129407A (en) | 1982-08-10 |
Family
ID=9790294
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA321,032A Expired CA1129407A (en) | 1978-02-08 | 1979-02-07 | Antiinflammatory steroid of the androstane series |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS54145648A (en) |
| AT (1) | AT367771B (en) |
| AU (1) | AU520827B2 (en) |
| BE (1) | BE873996A (en) |
| CA (1) | CA1129407A (en) |
| CH (1) | CH639669A5 (en) |
| DE (1) | DE2904614A1 (en) |
| DK (1) | DK145578C (en) |
| ES (1) | ES477523A1 (en) |
| FI (1) | FI790403A (en) |
| FR (1) | FR2422688A1 (en) |
| IE (1) | IE47814B1 (en) |
| IL (1) | IL56613A (en) |
| IT (1) | IT1114534B (en) |
| NL (1) | NL7900967A (en) |
| NZ (1) | NZ189586A (en) |
| PT (1) | PT69192A (en) |
| SE (1) | SE435626B (en) |
| YU (1) | YU26779A (en) |
| ZA (1) | ZA79538B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE449106B (en) * | 1980-07-10 | 1987-04-06 | Otsuka Pharma Co Ltd | STEROID WITH ANTI-INFLAMMATORY EFFECT AND COMPOSITION CONTAINING THIS |
| US5237070A (en) * | 1985-07-22 | 1993-08-17 | Riker Laboratories, Inc. | Substituted DI-t-butylphenols |
| JP4847112B2 (en) * | 2005-11-29 | 2011-12-28 | 株式会社マキタ | Gardening hair clipper |
| EP2632896B1 (en) | 2010-10-27 | 2017-03-15 | Hovione Inter Limited | Electrophilic reagents for monohalomethylation,their preparation and their uses |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1384372A (en) * | 1971-01-20 | 1975-02-19 | Glaxo Lab Ltd | Dereivatives of 17alpha-hydroxyandrost-4-ene-17beta-carboxylic acids |
| GB1438940A (en) * | 1972-07-19 | 1976-06-09 | Glaxo Lab Ltd | 17beta-haloalkoxycarbonyl-17alpha-oxysteroids |
-
1979
- 1979-02-06 IT IT47909/79A patent/IT1114534B/en active
- 1979-02-07 ZA ZA79538A patent/ZA79538B/en unknown
- 1979-02-07 AT AT0092379A patent/AT367771B/en not_active IP Right Cessation
- 1979-02-07 NL NL7900967A patent/NL7900967A/en not_active Application Discontinuation
- 1979-02-07 DK DK50179A patent/DK145578C/en active
- 1979-02-07 BE BE0/193318A patent/BE873996A/en not_active IP Right Cessation
- 1979-02-07 JP JP1317379A patent/JPS54145648A/en active Pending
- 1979-02-07 FR FR7903085A patent/FR2422688A1/en active Granted
- 1979-02-07 SE SE7901100A patent/SE435626B/en unknown
- 1979-02-07 FI FI790403A patent/FI790403A/en unknown
- 1979-02-07 IE IE236/79A patent/IE47814B1/en unknown
- 1979-02-07 CA CA321,032A patent/CA1129407A/en not_active Expired
- 1979-02-07 PT PT7969192A patent/PT69192A/en unknown
- 1979-02-07 NZ NZ189586A patent/NZ189586A/en unknown
- 1979-02-07 ES ES477523A patent/ES477523A1/en not_active Expired
- 1979-02-07 YU YU00267/79A patent/YU26779A/en unknown
- 1979-02-07 DE DE19792904614 patent/DE2904614A1/en not_active Withdrawn
- 1979-02-07 CH CH121779A patent/CH639669A5/en not_active IP Right Cessation
- 1979-02-07 IL IL56613A patent/IL56613A/en unknown
- 1979-02-08 AU AU44084/79A patent/AU520827B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| ES477523A1 (en) | 1979-07-16 |
| IT7947909A0 (en) | 1979-02-06 |
| ZA79538B (en) | 1980-02-27 |
| DE2904614A1 (en) | 1979-08-09 |
| IE47814B1 (en) | 1984-06-27 |
| PT69192A (en) | 1979-03-01 |
| JPS54145648A (en) | 1979-11-14 |
| IL56613A (en) | 1982-12-31 |
| IT1114534B (en) | 1986-01-27 |
| BE873996A (en) | 1979-08-07 |
| AT367771B (en) | 1982-07-26 |
| DK50179A (en) | 1979-08-09 |
| FI790403A (en) | 1979-08-09 |
| FR2422688B1 (en) | 1982-07-16 |
| NL7900967A (en) | 1979-08-10 |
| FR2422688A1 (en) | 1979-11-09 |
| IL56613A0 (en) | 1979-05-31 |
| YU26779A (en) | 1983-01-21 |
| SE7901100L (en) | 1979-08-09 |
| ATA92379A (en) | 1981-12-15 |
| AU520827B2 (en) | 1982-03-04 |
| DK145578B (en) | 1982-12-13 |
| IE790236L (en) | 1979-08-08 |
| CH639669A5 (en) | 1983-11-30 |
| SE435626B (en) | 1984-10-08 |
| NZ189586A (en) | 1981-01-23 |
| AU4408479A (en) | 1979-08-16 |
| DK145578C (en) | 1983-05-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |