IE46047B1 - Polyhalogenated steroids - Google Patents
Polyhalogenated steroidsInfo
- Publication number
- IE46047B1 IE46047B1 IE1979/77A IE197977A IE46047B1 IE 46047 B1 IE46047 B1 IE 46047B1 IE 1979/77 A IE1979/77 A IE 1979/77A IE 197977 A IE197977 A IE 197977A IE 46047 B1 IE46047 B1 IE 46047B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- chlorine
- compound
- dione
- fluorine
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
-
- 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
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
Abstract
9 alpha ,21-Dihalo-11 beta ,17 alpha -dihydroxy-6 alpha -fluoro-16 alpha -methylpregna-1,4-diene -3,20-dione 17-esters of the formula in which X1 is chlorine or fluorine, X2 is bromine or chlorine, and Ac is an acyl group derived from a carboxylic acid, are distinguished by high local antiinflammatory activity with a reduced systemic effect, for which reason they can be used in medicine to alleviate and control inflammatory states. They are obtained by conventional replacement of an organic 21-sulphonyloxy group by halogen X2.
Description
The invention relates to the manufacture of new polyhalogenated steroids, especially 9a,21-dihalogeno-llp,l7adihydroxy-6a-fluoro-l6p-methyl-pregna-l,4-diene-3,20-dione compounds of the formula
F in which X-^ represents chlorine or fluorine, Xg represents bromine or chlorine, represents hydrogen or chlorine and R2 represents the acyl radical Ac of a carboxylic acid, or salts of such compounds having salt-forming properties, as well as to the new compounds themselves or salts of such compounds having salt-forming properties and also to pharmaceutical compositions which contain the new compounds, and the use thereof.
Carbon-containing compounds and radicals designated throughout this specification as lower contain not more than 7 carbon atoms.
An acyl group Ac is preferably derived from the carboxylic acids customary in steroid chemistry, for example those con, taiiring up to and including 18 carbon atoms, and is in particular derived from corresponding aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acids. The radical Ac is, in particular, lower alkanoyl, such as
- 2 4604 lower alkanoyl, which is substituted or unsubstituted, for example by free or etherified or esterified hydroxy, such as lower alkoxy, for example methoxy or ethoxy, or phenoxy, or halogen, for example chlorine, or carboxyl, i.e.
a straight-chain or branched lower alkanoyl, for example acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-ethyl-butyryl, 2,2- or 3,3-dimethylbutyryl, hexanoyl or heptanoyl, or hydroxy-lower alkanoyl, for example 3-hydroxypropionyl, phenoxy-lower alkanoyl, for example phenoxyacetyl, halogeno-lower alkanoyl, for example chloroacetyl, or carboxy-lower alkanoyl, for example 3-carboxypropionyl or 4-carboxy-butyryl, alkenoyl, for example undecylen oyl, cycloalkyl-lower alkanoyl, for example cyclopentylpropionyl or cyclohexylacetyl, substituted or unsubstituted benzoyl, for example benzoyl, or substituted or unsubstituted phenyl-lower alkanoyl or phenyl-lower alkenoyl, for example phenylacetyl.
Salts of compounds of the formula I having salt-forming groups are those of such compounds which contain corresponding
2u groups, which are optionally in the form of a salt, in an acyl radical Ac, above all the corresponding pharmaceutically useful non-toxic salts which are usually water-soluble. Compounds of the formula I having salt-forming properties are, in particular, those in which R2 represents a carboxy-lower alkanoyl radical Ac. Such compounds can in particular be in the form of a metal salt, for example in the
- 3 4 6 0 41?
-ijl form of an alkali metal salt, such as a sodium salt or potassium salt. The sodium salt of a compound of the formula I in which represents 3-carboxypropionyl, is particularly preferred.
The compounds of the present invention have valuable pharmacological properties. Thus they are distinguished by a pronounced anti-antiflammatory action, whilst having a reduced systemic action. Accordingly, for example, when applied locally in the raw cotton wool granuloma test on rats, inhibition lo of the inflammatory processes can be observed in the dosage range between about 0.001 and about 0.10 mg per cotton wool pellet. The first indications of a systemic action, however, are only apparent at, or even above, the upper limit of this dosage range, namely in the decrease in weight of the thymus at a dose above 0.03 mg per cotton wool pellet, of the adrenals at a dose above 0.1 mg per cotton wool pellet, and of the entire body only at a dose of 1 mg per cotton wool pellet. On topical administration (rat's ear test of Tonelli), ED^q is approx. 10 to 30 mcg/ml.
On account of these biological properties, the new .
compounds can be used in all indications for which glucocorticoid steroids with anti-inflammatory properties are suitable. In particular, they are suitable for use as anti-inflammatory glucocorticoids for topical application, for example for the treatment of inflammatory dermatoses,
- 4 46047 such as eczemas, or dermatides, or dermatoses which are partially corticoid-resistant, for example psoriasis.
They can also be used as useful intermediate products for obtaining other useful substances, especially other pharma5 cologically active steroids.
The invention preferably relates to those compounds of the formula I in which represents fluorine or chlorine, X2 represents chlorine, R^ represents hydrogen and R2 represents lower alkanoyl, for example propionyl.
The invention relates above all to compounds of the formula I in which represents fluorine or chlorine, X2 represents chlorine, represents chlorine and R2 represents lower alkanoyl, for example propionyl.
The invention above all relates most particularly to the compounds of the formula I mentioned in the examples.
The compounds according to the invention of the formula I can be manufactured in a manner which is known per se, for example by treating a compound of the formula
I
F with a hydrogen halide of the formula H-X^ (HI) and, if desired, converting a compound of the formula I, which is obtainable according to the process and has salt-forming properties, into a salt, and/or converting a salt, which is obtainable according to the process, of a salt-forming compound of the formula I into the free compound of the formula I or into another salt.
Cleavage of the 9p,lip-oxide group in a starting material of the formula II by treatment with a hydrogen halide • of the formula III, that is to say with hydrogen chloride or hydrogen fluoride, is carried out in a manner which is known per sg, advantageously using an anhydrous hydrogen halide, optionally in the presence of an inert solvent, such as chloroform, tetrahydrofurane or, in particular, dimethylformamide, or also hydrogen fluoride in aqueous solution.
In place of the hydrogen halide of the formula III, it is also possible to use an agent which releases hydrogen fluoride or hydrogen chloride, such as the salt of such an
- 6 46047 acid with a tertiary organic base, for example pyridine, or, especially if hydrogen fluoride is used, a similar suitable addition compound. A particularly advantageous process is described in U.S. patent 3,211,758, wherein hydrogen fluoride is used in the form of an adduct with a carbamic acid derivative or thiocarbamic acid derivative, especially with urea.
The starting materials of the formula II can be obtained in a manner which is known per se, for example by eliminating water from a 6a-fluoro-llp-hydroxy-l6β-methyl-2R-^-l7a-0R2-21-X2-pregn3-l ,4-diene-3,20-dione compound, for example by treatment with a suitable acid chloride, such as phosphorus oxychloride or methanesulphonyl chloride, in the presence of a base, for example pyridine, adding hypobromous acid (which, for example, is used in the form of Nhromoacetamide or N-bromosuccinimide) onto the 9,11-double bond of the 6a-fluoro-16 β-methy 1-2^-17 a-0R2-21-X2-pregna-l ,4,9 (11)-triene-3,20-dione compound which is thus obtainable and eliminating hydrogen bromide from the corresponding 9α,11βbromohydrin compound by treatment with a base, for example an alkali metal carbonate or alkali metal hydroxide, for example potassium carbonate or potassium hydroxide, with formation of the desired starting material of the formula II. In the above intermediate products, Rj, R2 and X2 have the abovementioned meanings.
746047
The new compounds of the formula I can also he obtained by converting the group Χθ in a compound of the general formula
I
F in which Χθ represents a group which can be converted into a halogen atom X2, into a halogen atom , and, if desired, carrying out the additional process steps.
A group Χθ which can be converted into a halogen atom X2 is the group -0-Ra, in which Ra represents the acyl radical of an organic sulphonic acid. The replacement of the sulph10 onyloxy group -0-Ra by the halogen atom X2 is effected in a manner which is known per se. The acyl radical Ra of an organic sulphonic acid is, in particular, the acyl radical of an aliphatic or carboxylic, optionally unsaturated sulphonic acid or of an aromatic sulphonic acid. Such acids are, inter alia, unsubstituted or substituted, for example halogenated,lower alkanesulphonic acids, cycloalkanesulphonic acids, in which the cycloalkyl radical can be monocyclic or polycyclic, or benzenesulphonic acids which are unsubstituted or substituted by lower alkyl, for example methyl, lower alkoxy, for example
2o methoxy, halogen, for example chlorine or bromine, and/or nitro.
Typical examples of such acids are trifluoromethanesulphonic acid, (+)-camphor-10-sulphonic acid, 4-bromobenzenesulphonic acid and 3-nitrobenzenesulphonic acid and especially g-toluenesulphonic acid and, in particular, methanesulphonic acid.
The substitution reaction is usually carried out by treating the starting material with an alkali metal halide of the formula M-X2 (V), in which 14 represents an alkali metal, in the presence of an aprotic organic solvent which has a dielectric constant of 29 or higher. An alkali metal M which can be used is, preferably, lithium. Aprotic organic solvents which can be used are, in particular, di~lower alkyl sulphoxides, for example dimethyl sulphoxide, N,N-di-lower alkylaniides of lower aliphatic carboxylic acids, for example Ν,Ν-dimethylformamide or Ν,Ν-dimethylacetamide, lower alkanenitriles or lower alkenenitriles, for example acetonitrile, hexa-lower alkylphosphoramides, for example hexamethylphosphortriamide, or, above all when using starting materials of the formula IV in which R2 represents hydrogen, also ketones, especially aliphatic or cycloaliphatic ketones containing up to and including 10carbon atoms such as corresponding alkanones, for example acetone, 2-butanone, 2- or 3-pentanone, 2-hexanone or 4-decanone, or cycloalkanones· containing up to and including 8ring carbon atoms, for example cyclopentanone or cyclohexanone, or mixtures of such solvents.
The reaction is appropriately carried out between room temperature and the boiling point of the reaction mixture and is effected with at least one equivalent of the alkali metal halide of the formula V.
A further group XQ which can he converted into a halogen atom X2 is hydroxyl and also a radical which, together with
-O-Rg, forms an etherified hydroxymethylenedioxy group of the formula
-O Rb (IVa)
.. .0/ ^O-R c
in which represents hydrogen or an organic radical, especially an aliphatic hydrocarbon radical, such as lower alkyl, for example methyl or ethyl, and Rc forms an organic radical, especially an aliphatic hydrocarbon radical, such as lower alkyl, for example methyl or ethyl.
The replacement of a hydroxyl group XQ by halogen X2 and also of the group of the formula IVa by X2 in the 2115 position with a simultaneous formation of an esterified hydroxyl in the
17«-position of the formula -O-CO-R^ can be carried out in a manner vhich is known per-se, for example by treatment with a phosphine, such as a tri-lower alkylphosphine, or preferably triphenylphosphins, and a carbon tetrahalide, preferably cartoon tetrachloride, and also bromotriehloromethane.
The reaction is preferably carried out in a dipolar aprotic medium, for example in the presence of a corresponding solvent of the amide type, such as dimethylformamide, dimethylacetamide,
- 10 46047 χ
l-mcthyl-2-pyrrolidone or hexamethylphosphortriamide, with cooling or warming, for example in a temperature range between about 10°C and about 125°C and, if necessary, in a closed vessel and/or in an inert gas atmosphere.
The starting materials of the formula IV are known or can be manufactured in a manner which is known per se . for example compounds of the formula IV, in which Χθ represents organic sulphonyloxy, can be manufactured by converting the 21-hydroxyl group in a 6a-fluoro-llp,21-dihydroxy-l6p-methyl-210 R-j_-9a-X^-17a-0R2-pregna-l,4-diene-3,20-dione compound into the desired organic sulphonyloxy group -0R_ by treatment with a a reactive derivative of an organic sulphonic acid of the formula R,-OH (VI), especially with a corresponding sulphonic acid chloride of the formula Ra-Cl (Via), in the presence of a base, for example pyridine; and compounds of the formula IV in which
XQ and -O-Rg together form a group of the formula IVa can be manufactured by treating a 6a-fluoro-lip,17a,21-trihydroxyl6p-methyl-2-R1-9a-X-L-pregna-l,4-diene-3,20-dione compound with a suitable orthocarboxylic acid ester, for example tri20 ethyl orthoformate or triethyl orthopropionate, in the presence of a strong acid, for example p-toluenesulphonic acid, and advantageously with removal of the alcohol which is set free, for example by azeotropic distillation.
The new compounds of the formula I in which X^ repres25 ents chlorine can also be obtained by adding hypochlorous acid onto the 9,11-double bond of a compound of the formula
and, if desired, carrying out the additional process steps.
According to the above reaction, the elements of hypochlorous acid are added onto the 9,11-double bond of the starting materials of the formula VII in a manner which is known per se. The reaction is carried out, for example, with aqueous hypochlorous acid, or a hypochlorous acid donor, such as a N-chlorocarboxylic acid amide or imide (cf. U.S. Patent Specification 3,057,886), can he used. The reaction is carried out in an inert solvent, such as a tertiary alcohol, for example tert, butanol, an ether, for example diethyl ether, methyl isopropyl ether, dioxane or tetrahydrofurane, or a ketone, for example acetone, in the presence of water and optionally of a strong acid.
The addition of hypochlorous acid to the 9,11-double bond of the starting material of the formula VII can also be carried out in a non-aqueous medium. A particularly advantageous embodiment of this modification is the use of lower alkyl hypochlorites, above all tert.-butyl hypochlorite, in an
- 12 46047 inert, water-immiscible solvent, for example a nitrohydrocarbon, usually in the presence of perchloric acid (cf. German Patent specification 2,011,559).
The starting materials of the formula VII can he manu5 factured in a mannei· which is known per se, for example by eliminating water from a 6a-fluoro-lip-hydroxy-l6p-methyl-2-R^17a-0R2-21-X2-pregna-l,4-diene-3,20-dione compound, for example by treatment with a suitable acid chloride, such as phosphorus oxychloride or methanesulphonyl chloride, in the presence of a base, for example pyridine.
The new compounds of the formula I in which R^ represents hydrogen can also be obtained by introducing the 1,2double bond into a compound of the formula
I
F and, if desired, carrying out the additional measures.
The introduction of the 1,2-double bond can be carried out by dehydrogenation, for example by treatment with a suitable dehydrogenating quinone, such as 2,3-dichloro-5,6-dicyano1,4-benzoquinone.
- 13 46047
The 1,2-dehydrogenation of starting materials of the formula VIII can also be effected by treatment with selenium dioxide or microbiologically, for example with suitable microorganisms, such as Corynebacterium simplex or Septomyxa affinis.
The starting materials of the formula VIII have valuable pharmaceutical properties analogous to those of end products of the formula I and can also be used in the same way as these latter. The compounds of the formula VIII, in which Xp X£ and R2 have the above meanings, also form an object of the present invention. They are obtained by means of the process described above, starting in each case from 1,2saturated, 2-unsubstituted compounds of the type of formula II, IV or VII, and carrying out the corresponding reaction. Thus they can be obtained for example by converting the 21-hydroxyl group of a 6K-fluoro-llp,21-dihydroxy-16p-methyl-9a-X^-17a-0R2pregn-4-ene-3,20-dione compound (i.e. a compound of the formula IV type) for example by treatment with a suitable sulphonic acid derivative, such as methanesulphonyl chloride, into a 21-organic sulphonyloxy group, and treating the intermediate with a lithium halide, for example lithium chloride. ,
A compound of the formula I which is obtainable according to the process can be converted into another compound of the formula I in a manner which is known per se.
- 14 46047
Thus, for example, in a compound of the formula I in which represents hydrogen,the latter can be replaced by chlorine. For this purpose it is possible to add one molecule of chlorine onto the 1,2-double bond in such a compound and to split off one mole of hydrogen chloride from the intermediate l,2-dichloro-pregn-4-ene-3,20-dione. The addition of chlorine to the 1,2-double bond can be effected by treatment with elementary chlorine or with a mixture of two different chlorine-containing compounds, one of which releases positive chlorine and the other releases negative chlorine.
The treatment with elementary chlorine can be carried out in an inert organic solvent, for example an ether, such as dioxane or tetrahydrofurane, a halogenated hydrocarbon, for example methylene chloride, or a carboxylic acid, especially a lower aliphatic carboxylic acid, such as acetic acid or propionic acid, or a derivative thereof, such as an acid amide, for example dimethylformamide, or a nitrile, such as a lower alkanenitrile, for example acetonitrile. Advantageously, it is also possible to use mixtures of such solvents, especially mixtures of an ether, such as dioxane, with one of the lower alkanecarboxylic acids mentioned. The chlorination is usually carried out using the stoichiometric amount of chlorine at low temperature, say between -50°C and + 3O°C, for example at between -2O°C and +10°C, and with the exclusion of light.
In a particularly preferred embodiment, the compound of the formula I in which R^ represents hydrogen,is dissolved in one of the above solvents, for example dioxane, and treated with a solution of chlorine in a lower aliphatic carboxylic acid, for example propionic acid, and this solution is then left to stand, for example at the indicated temperature.
In a mixture of two different chlorinating agents, reagents which can set free positive chlorine are chlorinated acid amides or acid imides, such as chlorosuccinimide or chloroacetamide, and reagents which yield negative chlorine are, for example, hydrogen chloride and also alkali metal chlorides.
The elimination of hydrogen chloride from the intermediate l,2-dichloro-pregn-4-ene-3,20-dione is advantageously effected by treatment with a base. Examples of suitable bases are tertiary organic nitrogen bases, such as lower aliphatic amines, for example a tri-lower alkylamine, such as triethylamine, hetero-aromatic bases, for example pyridine or collidine, or mixed aliphatic-aromatic bases, such as N,N-di-lower alkyl-aniline, for example N,Ndimethylaniline. The reaction is preferably carried out with an excess of the base, which at the same time can be used as solvent. However, it is also possible to use inorganic bases, such as, in particular, the alkali metal salts or alkaline earth metal salts which are also used for hydrolysis of the Ιΐβ-trifluoroacetate described below, for example potassium acetate or bicarbonate or sodium acetate or bicarbonate, in aqueous-alcoholic solution, as well as the corresponding hydroxides. The dehydrochlorination is preferably carried out in a temperature range between about 20°C and about 100°C.
16' 46047
Advantageously, those agents and reaction conditions are chosen which have no influence on the other functional groups, especially those in the 17-position and/or 21-position.
Before adding chlorine onto the 1,2-double bond in a compound of the formula I, in which represents hydrogen, the Ιΐβ-hydroxyl group is advantageaisly protected, for example by esterification, preferably in the form of a trifluoroacetoxy group, a compound of the formula I in which Rj represents hydrogen being reacted, in a manner which is known per se with a suitable reactive derivative of an acid, for example with trifluoroacetyl chloride or trifluoroacetic anhydride, it is known that the trifluoroacetyl group can be split off easily by solvolysis, for example by hydrolysis or alcoholysis, for example by treatment with alkali metal hydroxides, carbonates, bicarbonates or acetates or alkaline earth metal hjrdroxides, carbonates, bicarbonates or acetates, in a suitable medium, for example an alcoholic, such as methanolic, or aqueous-alcoholic medium. A particular method of carrying out the solvolysis of the 11-trifluoroaoetoxy group is described in German patent Spec20 ification 1,593,519. This procedure can be used mainly because it leaves intact any esterified hydroxyl group which may be present in the l7a-position and consists in treating the 11βtrifluoroacetoxy compound, in a lower alkanol, with the salt of an acid which has a pKa value in the range of from about 2.3 to about 7.3, for example with an alkali metal azide, for example sodium azide or potassium azide, or an alkali metal formate, for example sodium formate or potassium formate. If appropriate, this salt can also be used only in catalytic amounts. Furthermore, the Ιΐβ-trifluoroacetyl group can also be removed by treatment with other bases, for example with amines and especially with hetero-aromatic bases, such as pyridine or collidine. Finally, the cleavage of the trifluoroacetoxy group by treatment with silica gel according to the process described in German Offenlegungsschrift 2,144,405 is also possible.
Liberation of the Ιΐβ-hydroxyl group from the protected form can be effected immediately after the addition of chlorine to the 1,2-double bond or at the same time as the dehydrochlorination by means of a base, but if desired, it can also be effected only subsequently to this step as a separate operation.
Compounds of the formula I which are obtainable accord ing to the process and have salt-forming properties, that is to say which contain an acyl group R2 which is suitable for forming a salt, can be converted into their salts in a manner which is known per se. Accordingly those compounds in which R2 represents a carboxy-lower alkanoyl radical can be converted into their salts by treatment with a suitable base, such as a metal hydroxide, carbonate or bicarbonate, especially an alkali metal hydroxide, carbonate or bicarbonate, such as sodium hydroxide,carbonate or bicarbonate or potassium hydroxide, carbonate or bicarbonate (the equivalent amount of the base preferably being used), usually in an aqueous or aqueousalcohol medium.
Conversely, a salt, which is obtainable according to tne process, of a compound of the formula with saltforming properties can be converted into the free compound, the corresponding salt with a base, for example, by treatment with an acid, such as an inorganic acid (for example by acidifying a solution of the salt in an aqueous or aqueous-organic medium to a pH value of about 1-2).
The starting materials used in the above process steps are preferably those which result in the compounds described above as being particularly preferred.
The present invention also relates to pharmaceutical compositions which contain, as active ingredient, a compound according to the invention of the formula I, or a salt of such a compound with salt-forming properties, and to a process for the manufacture of such pharmaceutical compositions.
Suitable pharmaceutical compositions are in particular those for topical application, such as creams, ointments, pastes, foams, tinctures and solutions, which contain from about 0.005% to about 0.1% of the active compound, and also compositions for oral administration, for example tablets, coated tablets and capsules, and those for parenteral administration.
Creams are oil-in-water emulsions which contain more than 50% of water. Fatty alcohols are chiefly used as oleaginous base, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or bees-wax, and/or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances with primarily hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens-Registered Trade Mark); polyoxyethylene fatty alcohol ethers or esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alco.15 hoi sulphates, for example sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are customarily used in the presence of fatty alcohol, for example cetyl alcohol or stearyl alcohol.. Additives to the water phase include agents which reduce water loss through evapora20 tion, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, as well as preservatives, perfumes etc.
Ointments are water-in-oil emulsions which contain up to 70%, preferably however approx, 20% to about 50%, of water or aqueous phase. The oleaginous phase comprises chiefly hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which contain preferably hydroxy compounds suitable for improving the water-absorption, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans- Trade Mark), for example sorbitan oleate and/or sorbitan isostearate. Additives to the water phase include humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and preservatives, perfumes etc.
Greasy ointments are anhydrous and contain as base in particular hydrocarbons, for example paraffin, petroleum jelly and/or liquid paraffins, furthermore natural or partially synthetic fat, for example coconut fatty acid triglycerides, or preferably hardened oils, for example hydrated, ground nut or castor oil, and also fatty acid partial esters of glycerol, for example glycerol mono- and distearate, and, for example, the fatty alcohols, emulsifiers and/or additives for increasing the water-absorption mentioned in connection with the ointments.
460 47
Pastes are creams and ointments containing powdered ingredients which absorb secretions, such as metal oxides, for example titanium oxide or zinc oxide, and talc and/or aluminium silicates whose, purpose it is to bind moisture or secretion present.
Foams are administered from pressurised dispensers and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons, such as chlorofluoro-lower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoro10 ethane being used as propellants. For the oleaginous phase there are used, inter; alia, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropyl myristate, and/or other waxes.
As emulsifiers there are used, inter alia, mixtures of those emulsifiers with primarily hydrophilic properties, such as polyoxyethylene sorhitan fatty acid esters (Tweens—Registered Trade Mark), and those with primarily lipophilic properties, such as sorhitan fatty acid esters (Spans- Trade Mark). In addition, the conventional additives are used, such as preservatives etc.
Tinctures and solutions generally have an aqueous ethanolic base to which are added, inter alia. polyalcohols, for example glycerol, glycols, and/or polyethylene glycol, as humectants for reducing water loss, and fat-restoring substances, such as fatty acid esters with lower polyethylene
- 22 46047 glycols, I.e. lipophilic substances which are soluble in the aqueous mixture as substitute for fatty substances which are taken from the skin with the ethanol, and, if necessary, other assistants and additives.
The pharmaceutical compositions for topical application are obtained in known manner, for example by dissolving or suspending the active substance in the base or in a part thereof, if necessary. When processing the active substance in the form of a solution, it is usually dissolved in one of the two phases, before the emulsification, and when processing the active substance in the form of a suspension, it is mixed with a part of the base before the emulsification and then added to the remainder of the formulation.
In addition to the pharmaceutical compositions which can be applied topically, other suitable preparations are those for enteral, for example oral, and parenteral administration to warm-blooded animals and which contain the active substance as sole ingredient or together with a pharmaceutically acceptable carrier. These pharmaceutical composi20 tions contain about 0.01% to about 10% of active substance and are in dosage unit form, such as coated tablets, tablets, capsules, suppositories or ampoules. They are obtained in known manner, for example by conventional mixing, granulating, coating, dissolving or lyophilising methods.
460 47
The dosage of active substance depends on the species of warm-blooded animal, the age, and the individual condition as well as on the mode of application.
The new compounds of formula I and the salts of such 5 compounds with salt-forming properties are useful in medicine, preferably for treating inflammations, chiefly as antiinflammatory glucocorticoids for local application, normally in the form of pharmaceutical compositions, especially in the form of pharmaceutical composi tions for topical application.
The following Examples describe the invention in more detail, without in any way restricting the scope thereof.
- 24 46047
Example 1
230 mg of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) are added to a solution of 228 mg of 21-chloro-6«,9adifluoro-11β,17α-dihydroxy-16 β-methy1-pregn-4-ene-3,20-dione5 17-propionate in 11,4 ml of dioxane, which is then refluxed for 20 hours in a nitrogen atmosphere. The reaction mixture is concentrated in a water jet vacuum and the amorphous residue is chromatographed on 100 times its weight of silica gel (stepped column). The fractions eluted with a 99:1 mixture of methylene chloride/methanol yield the pure 21-chloro-6a,9adi fluoro-11β,17a-dihydroxy-16 β-methy1-pregna-1,4-diene-3,20dione-17-propionate which melts at 220°-221°C after recrystallisation from methylene chloride/ether.
The 17-monopropionate used as starting material is prepared as follows:
A suspension of 1 g of 21-chloro-9p,llp-epoxy-17ahydroxy-16p-methyl-pregn-4-ene-3,20-dione-17-propionate in
.4 ml of dioxane and 1.4 ml of triethyl orthoformate is treated with 0.9 ml of a solution consisting of 277 mg of
2o £-toluenesulphonic acid, 2.7 ml of dioxane and 0.55 ml of ethyl alcohol and stirred for 90 minutes at room temperature. After addition of 3.8 ml of pyridine, the reaction mixture is diluted with ethyl acetate, washed 3 times with a saturated solution of sodium chloride, dried and concentrated in a water jet vacuum. The crude 3-ethyl-enol ether (3-ethoxy-21-chloro- 25 46047 β,11β-epoxy-17α-hydroxy-16 β-methyl-pregna-3,5-di ene-2 0-one-17propionate) is dissolved in a mixture of 50 ml of tetrahydrofurane and 10 ml of water and the solution is treated for 40 minutes at room temperature with gaseous perchloroyl fluoride. After nitrogen has subsequently been introduced over the course of 10 minutes, the reaction solution is diluted with ethyl acetate, washed successively with 10% potassium iodide solution, 10% sodium thiosulphate solution and 3 times with a saturated solution of sodium chloride, then dried and concentrated in a water jet vacuum. The crude product is chromatographed on 100 times its weight of silica gel (stepped column).
The column is eluted with a 90:10 mixture of toluene/ ethyl acetate. Recrystallisation from methylene chloride/ether of the fractions obtained yields 21-chlorO“6a-fluoro-9P,11βepoxy-17a-hydroxy-16β-methyl-pregn-4-ene-3,20-dione-17propionate which melts at 174°-177°C.
14.5 ml of a reagent prepared by mixing 10 g of urea with 13.25 g of anhydrous liquid hydrogen fluoride are poured over 720 mg of the above compound in a plastic vessel. The reaction mixture is stirred for 3 hours with ice cooling, then poured onto 55 ml of an ice-cold saturated solution of ammonia, weakly acidified with acetic acid and extracted twice with chloroform. The organic phases are combined, washed with the ice-cold sodium hydroxide solution, dried and concentrated in
- 26 46047 a water jet vacuum. The crude product is chromatographed on 100 times its weight of silica gel (stepped column). The column is elute.d with 90:10 mixture of toluene/ethyl acetate. Recrystallisation from methylene chloride/ether of the fractions obtained yields 21-chloro-6a,9a-difluoro-llp,17a-dihydroxy-16pmethyl-pregn-4-ene-3,20-dione-17-propionate which melts at 212°-213°C.
Example 2
A solution of 3.7 g of 21-chloro-6a,9«-difluoro-llp,17a10 dihydroxy-16p-raethylpregna-l,4-diene-3,20-dione-17-propionate in 30 ml of dioxane is treated with 1.85 ml of a solution which is prepared by introducing 7.7 g of chlorine gas into 100 ml of propionic acid. The reaction mixture is allowed to stand for 5 days at 3-4°C. It is then diluted wish chloroform, washed successively with a 10% potassium iodide solution, a
% sodium thiosulphate solution, dilute sodium hydroxide solution and water, dried, and concentrated ii a water jet vacuum. The crude l^,2^,21-trichloro-6a,9a-difluoro-llp,17adihydroxy-16 p-methylpregn-4-ene-3,20-dione-17-propionate is dissolved in methylene chloride to remove HCl and filtered through a column of 37 g of basic alumina (activity 2). The eluted solution is concentrated and recrystallised from methylene chloride to yield 2,21-dichloro-6«,9a-difluoro-llp,
17a-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-1725 propionate which melts at 202°-204°C.
Example 3
A solution of 350 mg of 9a,21-dichloro-6a-fluorollp,17-dihydroxy-16p-methyl-pregn-4-ene-3,20-dione-17propionate and 525 mg of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone in 17.5 ml of dioxane is refluxed for 20 hours in an atmosphere of nitrogen. The cooled mixture is filtered and the filtrate is evaporated. The residue is dissolved in methylene chloride and filtered through 15 times its weight of neutral alumina (activity 2). The filtrate is concentrated and purified by preparative thin-layer chromatography (on silica gel, 3 developings by a 9:1 mixture of toluene/methanol as eluant).
The desired zone is localised by ultra-violet light having a wavelength of 254 nm, eluted from the adsorbent with ethyl acetate and recrystallised from methylene chloride/ether, affording the desired 9a,2l-dichloro-6a-fluoro-llp,17-dihydroxy16p- methyl-pregna-1,4-diene-3,20-dione-17-propionate which melts, with decomposition, at 212°-213°C.
The starting steroid is obtained as follows:
Hydrogen chloride gas is introduced at 0°C in the course of 30 minutes into a solution of 400 mg of 21-chloro-6a-fluoro9 p,11-epoxy-17-hydroxy-16 β-methyl-pregn-4-ene-3,20-dionepropionate in 20 ml of chloroform. The mixture is allowed to stand for a further 30 minutes at 0°C, diluted with chloroform, washed with an ice-cold saturated sodium hydrocarbonato solution dried and concentrated in vacuo. The crude 9a,21- 28 46047 dichloro-6a-fluoro-llp,17“dihydroxy-16p-methyl-pregn-4-ene3,20-dione-17-propionate can be used without purification for the dihydrogenation reaction.
Example 4
Hydrogen chloride gas is introduced at 0°C in the course of 30 minutes into a solution of 2.8 g of 21-chloro-δαfluoro- 9 rs, ll-epoxy-17-hydroxy-16p-methyl-pregna-l,4-diene-3,20 dione-propionate in 140 ml of chloroform. The mixture is allowed to stand for a further 30 minutes at 0°C, diluted with chloroform, washed with an ice-cold saturated sodium hydrocarbonate solution, dried and evaporated in vacuo. The crude product is chromatographed on 100 times its weight of silica gel (stepped column). The desired product is eluted with a 99:1 mixture of toluene/methanol. Crystallisation from methylene chloride/ether yields 9a,21-dichloro-6a-fluorollp,17-dihydroxy-Ιδβ-methyl-pregna-1,4-diene-3,20-dione-17propionate which melts, with decomposition, at 212°-213°C and is identical with the product of Example 3.
The starting steroid is obtained as follows:
A mixture of 3 g of 21-chloro-6a-fluoro-9p,ll-epoxy17-hydroxy-16p-methyl-pregn-4-ene-3,20-dione-propionate and 3 g of 2,3-diehloro~5,6-dicyano-l,4-ben2oquinone in 150 ml of dioxane is refluxed for 20 hours in an atmosphere of nitrogen. The cooled mixture is filtered, and the filtrate concentrated.
“ 29
0 47
The residue is dissolved in methylene chloride and filtered through 15 times its weight of neutral alumina (activity II). The filtrate is concentrated, affording the crude 21-chloro-6a-fluoro-9β-11-epoxy-17-hydroxy-16β-methyl5 pregna-l,4-diene-3,20-dione-propionate which can be treated with hydrogen chloride without further purification.
Example 5
An ointment containing 0.1% of 21-chloro-6a.9adifluoro-lip,17a-dihydroxy-16 p-methyl-ptegna-1,4~diene-3,2010 dione 17-propionate can be prepared as follows:
Composition
21-chloro-6a,9a-difluoro-11β,17a-dihydroxy- %
16p-methyl-pregna-l,4-diene-3,20-dione 17-propionate 0,1 white petroleum jelly 45.0 liquid paraffin 19.6 cetyl alcohol 5.0 beeswax 5.0 sorbitane sesquioleate 5.0 g-hydroxybenzoic acid ester 0.2 perfume . 0.1 water 20.0
- 30 46047
The fatty substances and emulsifiers are melted together. The preservative is dissolved in water and the solution is emulsified into the fatty melt at elevated temperature. After cooling, a suspension of the active compound in part of the fatty melt is incorporated into the emulsion and the perfume is then added.
Claims (24)
1. A process for the manufacture of a 9α,21-dihalogeno-lip, I7a-dihydroxy-6a-fluoro-l6p-methyl-pregna-l,4-diene-3,20-dione compound of the formula t F in which X^ represents chlorine or fluorine, Xg represents bromine or chlorine, represents hydrogen or chlorine and Rg represents the aeyl radical Ac of a carboxylic acid, or a salt of such a compound with salt-forming proper10 ties, which process comprises (a) treating a compound of the formula with a hydrogen halide of the formula H-X^ (III), or with an agent which donates the hydrogen halide HX, or (b) converting the group X Q in a compound of the general formula - 32 46047 in which X Q represents a group which can be converted into a halogen atom X 2 , into a halogen attan X 2 , or (c) in order to obtain a compound of the formula I in which X-, represents chlorine adding hypochlorous acid onto the 9,11-double bond of a compound of the formula F (VII) or (d) in order to obtain a compound of the formula X in which R^ is hydrogen, introducing the 1,2-double bond into a « F (VIII) - 33 4®0 47 and, if desired, converting a compound of the formula I, which is obtainable according to the process and has salt-forming properties, into a salt, and/or converting a salt, which is obtainable according to the process, of a salt-forming compound 5 of the formula I into the free compound of the formula I or into another salt.
2. A process according to process variant (b) of Claim 1 wherein Χθ in a compound of formula IV is a sulphonyloxy group -O-R in which R represents the acyl radical of an 9. a 10 organic sulphonic acid, and Χθ is replaced by chlorine.
3. A process according to process variant (c) of Claim 1, wherein a compound of the formula VII is treated with hypochlorous acid or a hypochlorous acid donor. 15
4. A process for the production of a compound of the formula I, in which R^ is chlorine, wherein chlorine is added onto the 1,2-double bond of a compound of formula I, in which r 3 represents hydrogen and hydrogen chloride is split off from the resulting intermediate of the formula F - 34 _ 4604? in which R2 represents the acyl radical Ac of a carboxylic acid, X^ represents chlor.ine or fluorine and represents bromine or chlorine, and in which process the 11-hydroxyl group is, if necessary, in a temporarily protected form, in 5. Which case the protective group is removed at any desired stage.
5. A process according to Claim 4, wherein the reaction is carried out while temporarily protecting the 118-hydroxyl group by conversion into the trifluoroacetate.
6. A process according to any one of Claims 1 to 3 for 10 the manufacture of a compound of the formula I in which X^ represents fluorine or chlorine, X 2 represents chlorine, R^ represents hydrogen and R 2 represents lower alkanoyl.
7. A process according to any one of Claims 1 to 5 for the manufacture of a compound of the formula I in which X^ 15 represents fluorine or chlorine, X 2 represents bromine or chlorine, and R^ represents chlorine.
8. A process according to any one of Claims 1 to 5 for the manufacture of a compound of the formula I in which represents fluorine or chlorine, X 2 represents chlorine, 20 represents hydrogen or chlorine and R 2 represents lower alkanoyl of 2 to 5 carbon atoms.
9. A process according to any one of Claims 1 to 5 for - 35 the manufacture of 2,21-dichloro-6a,9a-difluoro-llB, 17adihydroxy-16β-methyl-pregna-l,4-diene-3,20-dione-17-propionate
10. A process according to any one of Claims 1 to 3 for the manufacture of 9a,21-dichloro-6a-fluoro-llg,17a-dihydroxy5 16 β-methyl-pregna-l,4-diene-3,20-dione-17-propionate.
11. A process according to any one of Claims 1 to 3 for the manufacture of 21-chloro-6a,9a-difluoro-110,17a-dihydroxy16 β-methyl-pregna-l,4-diene-3,20-dione-17-propionate.
12. 9a,21-dihalogeno-118,17a-dihydroxy-6a-fluoro-16β10 methyl-pregna-l,4-diene-3,20-dione compounds of the formula ?2- Χ 2 wherein X^ represents chlorine or fluorine, X 2 represents bromine or chlorine, represents hydrogen or chlorine and R 2 represents the acyl radical Ac of a carboxylic acid, and 15 2-unsubstituted 1,2-dihydro derivatives thereof.
13. A compound of the formula Ϊ according to Claim 12 wherein X-^ represents fluorine, X 2 represents chlorine, R^ represents hydrogen and R 2 represents lower alkanoyl, and 1,2-dihydro derivatives thereof. - 36 46047
14. A compound of the formula I according to Claim 12, wherein X^ represents chlorine or fluorine, each of and represents chlorine and R^ represents lower alkanoyl.
15. A compound according to either of Claims 13 or 14, 5 wherein lower alkanoyl contains 2 to 5 carbon atoms.
16. 2,21-dichloro-6a,9a-difluoro-112,17a-dihydroxy-16 ¢methyl-pregna-1,4-diene-3,20-dione-17-propionate.
17. 21-chloro-6a,9a-difluoro-ΙΙβ,17«-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-17-propionate. 10
18. 21-chloro-6a,9tx-difluoro-112,17a-dihydroxy-16B-methylpregn - 4-ene-3,20-dione-17-propionate.
19. 9ct,21-dichloro-6a-fluoro-ΙΙβ,17a-dihydroxy-168-methylpregna-1,4-diene-3,20-dione-17-propionate.
20. 9a,21-dichloro-6a-fluoro-llB,17a-dihydroxy-16f3-methyl15 pregn - 4-ene-3,20-dione-17-propionate.
21. A pharmaceutical composition which contains at least one of the compounds described in Claims 16 to 24 and at least one pharmaceutical carrier.
22. A process for the manufacture of 9a,21-dihalogeno20 112,17a-dihydroxy-6a-fluoro-162-methyl-pregn-4-ene-3,20-dione 37 (VIII) compounds of the formula wherein X^ represents chlorine or fluorine, X 2 represents bromine or chlorine, and R 2 represents the acyl radical Ac of a carboxylic acid, which process comprises treating a (IIA) with a hydrogen halide of the formula Η-Χ τ (III) 10 in which X^ represents chlorine or fluorine, or with a corres ponding donor of H-X^, or (b) in a compound of the general formula (IVA) 38 ~ in which Χθ represents a yii.up which can be converted xtito the halogen atom X 2 , converting the group Χθ into the halogen atom X 2 , or (c) in order to obtain a compound of the formula VIII, in which X^ represents chlorine, adding hypochlorous 5 acid onto the 9,11-double bond of a compound of the formula F
23. A process according to process variant (b) of Claim 22 wherein a compound of the formula VIA, in Which Χθ is the group “O“R a i in which R fl is the acyl radical of an organic 10 sulphonic acid, the group -0-P. is replaced by chlorine. ci.
24. A process according to process variant (c) of Claim 22, wherein a compound of the formula VIIA is treated with hypochlorous acid or a donor thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU75903A LU75903A1 (en) | 1976-09-29 | 1976-09-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE46047L IE46047L (en) | 1978-03-29 |
| IE46047B1 true IE46047B1 (en) | 1983-02-09 |
Family
ID=19728370
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1979/77A IE46047B1 (en) | 1976-09-29 | 1977-09-28 | Polyhalogenated steroids |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS5356652A (en) |
| AT (3) | AT363197B (en) |
| AU (1) | AU514200B2 (en) |
| BE (1) | BE859120A (en) |
| CA (1) | CA1101410A (en) |
| CH (9) | CH624967A5 (en) |
| CY (1) | CY1178A (en) |
| DD (1) | DD133150A5 (en) |
| DE (1) | DE2743069A1 (en) |
| DK (1) | DK146017C (en) |
| ES (1) | ES462763A1 (en) |
| FR (1) | FR2366311A1 (en) |
| GB (1) | GB1563638A (en) |
| HK (1) | HK16683A (en) |
| HU (1) | HU175218B (en) |
| IE (1) | IE46047B1 (en) |
| IL (1) | IL53012A (en) |
| KE (1) | KE3258A (en) |
| LU (1) | LU75903A1 (en) |
| MY (1) | MY8400092A (en) |
| NL (1) | NL7710089A (en) |
| SE (1) | SE436751B (en) |
| SG (1) | SG3383G (en) |
| ZA (1) | ZA775800B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL187577C (en) * | 1978-04-05 | 1991-11-18 | Sibla Srl | 3-ACETOXY-9BETA, 11BETA-EPOXY-PREGNA-1,3,5-TRIEN, PROCESS FOR THE PREPARATION THEREOF, AND PROCESS FOR THE PREPARATION OF 6-alpha-halogen-1,4-diene-3-ones. |
| DE3227312A1 (en) * | 1982-07-19 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW 6.16 DIMETHYL CORTICOIDS, THEIR PRODUCTION AND USE |
| AU7556291A (en) * | 1990-03-27 | 1991-10-21 | Schering Corporation | Process for 9alpha-hydroxy steroid dehydration |
| US5972922A (en) * | 1990-06-11 | 1999-10-26 | Alcon Laboratories, Inc. | Steroids which inhibit angiogenesis |
| JP2005530679A (en) | 2001-11-29 | 2005-10-13 | ターロ ファーマシューティカルズ ユーエスエイ インコーポレイテッド | Method for preparing 6α-fluorocorticosteroid |
| US8809307B2 (en) | 2010-11-22 | 2014-08-19 | Dow Pharmaceutical Sciences, Inc. | Pharmaceutical formulations containing corticosteroids for topical administration |
| US11957753B2 (en) | 2010-11-22 | 2024-04-16 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
| RS60672B1 (en) | 2015-06-18 | 2020-09-30 | Bausch Health Ireland Ltd | Topical compositions comprising a corticosteroid and a retinoid for treating psoriasis |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB898292A (en) * | 1959-03-18 | 1962-06-06 | Upjohn Co | Improvements in or relating to steroids and the manufacture thereof |
| US3644340A (en) * | 1970-03-19 | 1972-02-22 | Syntex Corp | Preparation of 21-chloro steroids |
| US3992422A (en) * | 1975-08-14 | 1976-11-16 | Schering Corporation | Process for the preparation of 21-halogeno-21-desoxy-17α-acyloxy-20-keto-pregnenes |
-
1976
- 1976-09-29 LU LU75903A patent/LU75903A1/xx unknown
- 1976-12-09 CH CH1549976A patent/CH624967A5/en not_active IP Right Cessation
-
1977
- 1977-06-08 SE SE7706673A patent/SE436751B/en not_active IP Right Cessation
- 1977-06-09 DK DK256977A patent/DK146017C/en not_active IP Right Cessation
- 1977-09-14 NL NL7710089A patent/NL7710089A/en not_active Application Discontinuation
- 1977-09-24 DE DE19772743069 patent/DE2743069A1/en active Granted
- 1977-09-26 CH CH1172177A patent/CH632279A5/en not_active IP Right Cessation
- 1977-09-27 FR FR7729043A patent/FR2366311A1/en active Granted
- 1977-09-27 CA CA287,560A patent/CA1101410A/en not_active Expired
- 1977-09-27 GB GB40131/77A patent/GB1563638A/en not_active Expired
- 1977-09-27 CY CY1178A patent/CY1178A/en unknown
- 1977-09-27 DD DD7700201226A patent/DD133150A5/en unknown
- 1977-09-27 AU AU29148/77A patent/AU514200B2/en not_active Expired
- 1977-09-28 ZA ZA00775800A patent/ZA775800B/en unknown
- 1977-09-28 IE IE1979/77A patent/IE46047B1/en not_active IP Right Cessation
- 1977-09-28 IL IL53012A patent/IL53012A/en unknown
- 1977-09-28 HU HU77CI1774A patent/HU175218B/en unknown
- 1977-09-28 AT AT0691077A patent/AT363197B/en not_active IP Right Cessation
- 1977-09-28 BE BE181243A patent/BE859120A/en not_active IP Right Cessation
- 1977-09-29 JP JP11619377A patent/JPS5356652A/en active Granted
- 1977-09-29 ES ES462763A patent/ES462763A1/en not_active Expired
-
1979
- 1979-02-28 AT AT0151279A patent/AT363202B/en not_active IP Right Cessation
- 1979-02-28 AT AT0151379A patent/AT363203B/en not_active IP Right Cessation
-
1980
- 1980-11-18 CH CH853880A patent/CH625809A5/en not_active IP Right Cessation
- 1980-11-18 CH CH853980A patent/CH625810A5/en not_active IP Right Cessation
- 1980-11-18 CH CH853780A patent/CH625808A5/en not_active IP Right Cessation
-
1981
- 1981-10-26 CH CH683081A patent/CH631998A5/en not_active IP Right Cessation
- 1981-10-26 CH CH683181A patent/CH631999A5/en not_active IP Right Cessation
- 1981-10-26 CH CH683281A patent/CH632000A5/en not_active IP Right Cessation
-
1982
- 1982-01-06 CH CH4682A patent/CH632521A5/en not_active IP Right Cessation
-
1983
- 1983-01-20 SG SG33/83A patent/SG3383G/en unknown
- 1983-01-21 KE KE3258A patent/KE3258A/en unknown
- 1983-05-19 HK HK166/83A patent/HK16683A/en not_active IP Right Cessation
-
1984
- 1984-12-30 MY MY92/84A patent/MY8400092A/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4619921A (en) | Polyhalogeno-steroids | |
| US4124707A (en) | 7α-Halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor | |
| CA1234564A (en) | Carboxylic acid esters | |
| US4285937A (en) | Novel androstadiene-17-carboxylic acid esters | |
| US4267173A (en) | Use of 6β-fluoro-7α-halogenocorticoids as topical anti-inflammatories and pharmaceutical formulations useful therefor | |
| US4172132A (en) | 1,3,5(10),6,8,14-19-Nor-pregnahexaenes, their use as anti-psoriatic agents, and pharmaceutical formulations useful therefor | |
| BG60799B2 (en) | Aromatic, heterocylic steroid esters, their preparation and pharmaceutical compositions containing them | |
| US4226862A (en) | Steroids and process for preparing the same | |
| EP0029151B1 (en) | 6-alpha-fluoro-9-alpha-chloro-prednisolone-17,21 diesters, pharmaceutical compositions containing them and intermediates | |
| IE46047B1 (en) | Polyhalogenated steroids | |
| US4024131A (en) | 16-Methyl-9α-halo steroid esters, ethers and preparation thereof | |
| EP0001864A1 (en) | Novel 6-oxygenated-3,20-dioxo-pregnane derivatives, process for the preparation thereof, and pharmaceutical compositions containing them | |
| DE3102397A1 (en) | 17 (ALPHA) ACYLOXY-5 (BETA) CORTICOIDS AND 17 (ALPHA) ACYLOXY-5 (ALPHA) CORTICOIDS | |
| GB2105724A (en) | Corticoid 17-ester 21-thioesters | |
| US4185101A (en) | 1,3,5(10),6,8-19-Nor-pregnapentaenes, their use as anti-psoriatic agents, and pharmaceutical formulations useful therefor | |
| US4221786A (en) | Novel halogenopregnadienes and process for the manufacture thereof | |
| US3933799A (en) | 11β-Halo-9,12-unsubstituted-C19 -steroids | |
| DE2756550C2 (en) | Process for the preparation of 3,20-dioxo-7α-halo-4-pregnenen and 1,4-pregnadienes, 3,20-dioxo-7α-chloro and bromo-1,4-pregnadienes and drugs containing the latter | |
| EP0000609B1 (en) | Novel 19-nor-pregnahexaenes, process for the preparation thereof, and pharmaceutical compositions containing them | |
| CA1123337A (en) | Anti-mitotic pharmaceutical compositions | |
| KR840000154B1 (en) | Novel 6 -fluoro-prednisolone 17,21-diesters | |
| GB1563595A (en) | Halogenoprepnadienes and process for the manufacture thereof | |
| CH631185A5 (en) | Multiply halogenated steroids | |
| Phillipps et al. | 11β-Halo-9, 12-unsubstituted-C 19-steroids | |
| CH637406A5 (en) | Novel steroids of the pregnane series, process for their preparation and pharmaceutical products containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |