CA1101410A - Polyhalogenated steroids - Google Patents
Polyhalogenated steroidsInfo
- Publication number
- CA1101410A CA1101410A CA287,560A CA287560A CA1101410A CA 1101410 A CA1101410 A CA 1101410A CA 287560 A CA287560 A CA 287560A CA 1101410 A CA1101410 A CA 1101410A
- Authority
- CA
- Canada
- Prior art keywords
- alpha
- formula
- chlorine
- beta
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
Case 4-10717/+
Canada Polyhalogenated steroids Abstract of the Disclosure Novel 9.alpha.,21-dihalogeno-11.beta.,17.alpha.-dihydroxy-6.alpha.-fluoro-16.beta.-methyl-pregna-1,4-diene-3,2O-dione compounds of the formula
Canada Polyhalogenated steroids Abstract of the Disclosure Novel 9.alpha.,21-dihalogeno-11.beta.,17.alpha.-dihydroxy-6.alpha.-fluoro-16.beta.-methyl-pregna-1,4-diene-3,2O-dione compounds of the formula
Description
The invention relates to the manufacture of new polyhalogenated steroids, especially 9~,21-dihalogeno-11~,17~-dihydroxy-6~-fluoro-16~-methyl-pregna-1,4-diene-3,20-dione compounds of the formula l~2_x2 CH3 C=0 H0 ~ ~ 0-R ~I) 1 ~ H3 o F
in which Xl represents chlorine or fluorine, X2 represents bromine or chlorine, Rl represents hydrogen or chlorine and R2 represents a straight-chain lower alkanoyl group, as well as to 2-unsubstituted 1,2-dihydro derivatives of these compounds.
Carbon-containing compounds and radicals designated throughout this specification as "lower" preferably contain not more than 7 carbon atoms.
A straight-chain lower alkanoyl is~ for example, acetyl, propionyl, butyryl, valeryl, hexanoyl or heptanoyl.
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 of the inflammator~v 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 C ' ,~ --1--.. . . .
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), ED50 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-inflamma-tory 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) 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 pharmacologically active steroids.
The invention preferably relates to those compounds of the formula I
in which Xl represents fluorine or chlorine, X2 represents chlorine, R
represents hydrogen and R2 represents propionyl.
The invention above all relates st 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 CH3 C=O
~\ \ ~~ ~ O-R2 (II) 1 ~ CH3 O ~`
F
with a hydrogen halide of the formula H-Xl ~III).
Cleavage of the 9~ -oxido 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 se, advantageousl-y 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 "i ;, i . ,~ ,1 " .", :=:`, J
, 1 lQ 14 1 0 acid with a tertlary 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. paten~ 3,~11,758, 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 ob-tained in a manner which is known per se, for example by eliminating water from a 6a-fluoro-11~-hydroxy-16~-methyl-2-Rl-17a-GR2-21-X2-pregna-1,4-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 hypo-bromous acid (which, for example, is used in the form of N-bromoacetamide or N-bromosuccinimide) onto the 9,11-double bond of the 6a-fluoro-16~-methyl-2-Rl-17a-OR2-21-X2-pregna-1,4,9 (ll)-triene-3,20-dione compound which is thus obtainable and eliminating hydrogen bromide from the corresponding 9a,11~-bromohydrin 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 9 Rl, R2 and X2 have the above-` mentioned meanings.
_.
G~
~10~L4~ (~
The new compounds of the for~ula I can also be obtained by convert-ing the group XO in a compound of the general formula Cl H2-Xo CH, C=O
~ O R2 (IV~
o F
in which XO represents the group ~O~Ra, in which Ra represents the acyl radical of an organic sulphonic acid, (i.e. a sulphonyloxy group), is treated in a manner which is known per se with an alkaline salt of the halogen X2.
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 methoxy, halogen, for example chlorine or bromine, and/or nitro.
~ -5-Typical examples o~ such acids are trifluoromethanesulphonic acid, (~)-camphor-10-sulphonic acid, 4-bromob~nzenesulphonic acid and 3-nitrobenzenesulphonic acid and especially p-toluene-sulphonic 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 M represents an alkali metal, in the presence of an aprotic organic s~lvent which has a dielectric constant of 29 or higher. An alkali metal M
which can be used is, preferably, lithium. Aprotic organ-ic solvents which can be used are, in particular, di-lower alkyl sulphoxides, for example dimethyl sulphoxide, N,N-di-lower alkylamides of lower aliphatic carboxylic acids, for example .
N,N-dimethylformamide or N,N-dimethylacetamide, lower alkane-nitriles or lower alkenenitriles, for example acetonitrile, hexa-lower alkylphosphoramides, for example hexamethylphosphor-triamide, or, above all when using starting materials of the formula IV in which R2 represents hydrogen, also ketones, especially aliphatic or cycloaliphatic ketones conta~ng up to ~nd inclu~g lOcarbcn atoms such as corresponding alkanones, for example acetone, 2-butanone, 2- or 3-pentanone, 2-hexanone or 4-decanone, or cycloalkanones~contau~ngupto and inclu~ 8~gc~xn 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 11~141(;~
and is effected with at least one equivalent of the alkali metal halide of the formula V.
The starting materials of the formula IV are known or can be manufactured in a manner which is known per se, for example by converting the 2l-hydroxylgroup in a 6~-fluoro-ll~,2l-dihydroxy-l6~-methyl-2-Rl-9~-Xl-l7~-OR2-pregna-l,4-diene-3,20-dione compound into the desired organic sulphonyloxy group ~ORa by treatment with a reactive derivative of an organic sulphonic acid of the formula Ra-OH (VI), especially with a corresponding sulphonic acid chloride of the formula Ra-Cl (VIa), in the presence of a ; lO base, for example pyridine.
The new compounds of the formula I in which Xl represents chlorine can also be obtained by adding hypochlorous acid onto the 9,ll-double bond of a compound of the formula Cl13 C=O
21 ~ ~ -~2 (VII) O
F
in which Rl, R2 and X2 have the above meanings.
According to the above reaction, the elements of hypochlorous acid are added onto the 9,ll-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 ~ -7-.
.
~10~41(:~
specification 3,057,886), can be 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 tetra-hydrofurane, 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 -8_ , ~ :
11~141(~
inert, wa.ter-imm.iscible solvent, for example a nitro~
hydrocarbon, usually in the presence of perchloric acid (cf. ~erman patent specification 2,011,559).
The starting materials of the formula VII can be manu-factured in a manner which is known per se, for example by eliminating water from a 6a-fluoro-ll~-hydroxy-16~-methyl-2-Rl-17a-OR2-21-X2-pregna-1,4-diene-3,20-dione compound, for exarnple by treatment with a suitable acid chloride, such as phorphorus oxychloride or methanesulphonyl chloride, in the presence of a base, for example pyridine.
The new compounds of the formula I in which Rl repres-ents hydrogen can also be obtained by introducing the l,2-double bond into a compound of the formula .
fH2 -X2 CH ~=0 -0-R2 (VIII) l?
.
and, if desired, carrying out;the additional measures.
me introduction of the 1,2-double bond can be carried out by dehydrogenation, for example by treatment with a suit-able dehydrogenating quinone, such as 2,3-dichloro-5,6-dicyano-l,4-benzoquinone.
, I
.
.
., ~ .
11014~0 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 pharma-ceutical 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 Xl, X2 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 1,2-saturated, 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 6a-fluoro-11~,21-dihydroxy-16~-methyl-9a-Xl-17a-OR2-pregn-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, wherein Rl represents hydrogen, and which is obtainable according to the process can be converted into an analogous compound of the formula I, wherein Rl represents chlorine, in a manner which is known per se.
For this purpose it is possib]e 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 1,2-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 ~ ~ -10-.
. ~
~ .
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 tetrahydro-furane, 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 and +30, for example at between -20 and +10, and with the exclusion of light.
In a particularly preferred embodiment, the compound of the formula I in which Rl represents hydrogen, is dissolved in one of the above solvents, for example dioxane, ~ ..1;
~ 4 10 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 call set free positive chlorine are chlorinated acid amides or acid imides, such as chlorosuccinimide or chloro-acetamide, and reagents which yield negative chlorine are, for example, hydrogen chloride and also alkali metal chlorides.
The elimination of hydrogen chloride from the intermediate 1,2-dichloro-pregn~4-ene-3,20-dione is advantage-ously effected by treatment with a base. Ex-amples 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,N-dimethylaniline, The reaction is preferably carried out with an excess of the base, which at the same -time can be used as solvent. Howe~er, it is also possible to use in-organic bases, such as, in particular~ the alkali metal salts or alkaline ear-th metal salts which are also used for hydroly-sis of the ll~-trifluoroacetate described below, for example potassium acetate or bicarbonate or sodium acetate or bicarbon ate, in aqueous-alcoholic solution, as well as the corresponding hydroxides. The dehydrochlorination is preferably carried out in a temperature range between about 20Cand about 100C.
C i 1 ~
- ,~6 - , ~ 4 1~
Advantageouslys those agents and reaction conditions are chosen which have no influence on the other f~mctional 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 Rl represen-ts hydrogen, the ll~-hydroxyl group is advantagecusly protected, for example by esterification, preferably in the form of a trifluoroacetoxy group, a compound of the formula I in which Rl represents hydrogen being reacted in a manner which is kno~n per se with a suitable reactive derivative o~ 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 hydroxides, carbonates, bicarbonates or acetates, in a suitable medium, for example an alcoholic, such as methanolic, or aqueous-alcoholic medium. A particular method of carrymg out the solvolysis of the ll-tri~luoroacetoxy group is described in German patent spec-ification 1,593,519. This procedure can be used mainly because it leaves intact any esterified hydroxyl group which may be present in the 17a-position an~d consists in treating the 11~-trifluoroacetoxy 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 eæamp~ with an alkali metal azide, for example sodium aæide or potassium azide, or an alkali metal .
141~
formate, for example sodium formate or potassium formate. If appropriate, this salt can also be used only in catalytic amounts. Furthermore, the 11~-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 ll~-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.
- The starting materials used in the above process steps are prefer-ably those which result in the compounds described above as being particularly preferred.
The compounds of the present invention are especially useful for the manufacture of pharmaceutical compositions which contain, as active ingredient, a compound according to the invention of the formula I, or a
in which Xl represents chlorine or fluorine, X2 represents bromine or chlorine, Rl represents hydrogen or chlorine and R2 represents a straight-chain lower alkanoyl group, as well as to 2-unsubstituted 1,2-dihydro derivatives of these compounds.
Carbon-containing compounds and radicals designated throughout this specification as "lower" preferably contain not more than 7 carbon atoms.
A straight-chain lower alkanoyl is~ for example, acetyl, propionyl, butyryl, valeryl, hexanoyl or heptanoyl.
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 of the inflammator~v 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 C ' ,~ --1--.. . . .
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), ED50 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-inflamma-tory 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) 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 pharmacologically active steroids.
The invention preferably relates to those compounds of the formula I
in which Xl represents fluorine or chlorine, X2 represents chlorine, R
represents hydrogen and R2 represents propionyl.
The invention above all relates st 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 CH3 C=O
~\ \ ~~ ~ O-R2 (II) 1 ~ CH3 O ~`
F
with a hydrogen halide of the formula H-Xl ~III).
Cleavage of the 9~ -oxido 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 se, advantageousl-y 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 "i ;, i . ,~ ,1 " .", :=:`, J
, 1 lQ 14 1 0 acid with a tertlary 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. paten~ 3,~11,758, 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 ob-tained in a manner which is known per se, for example by eliminating water from a 6a-fluoro-11~-hydroxy-16~-methyl-2-Rl-17a-GR2-21-X2-pregna-1,4-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 hypo-bromous acid (which, for example, is used in the form of N-bromoacetamide or N-bromosuccinimide) onto the 9,11-double bond of the 6a-fluoro-16~-methyl-2-Rl-17a-OR2-21-X2-pregna-1,4,9 (ll)-triene-3,20-dione compound which is thus obtainable and eliminating hydrogen bromide from the corresponding 9a,11~-bromohydrin 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 9 Rl, R2 and X2 have the above-` mentioned meanings.
_.
G~
~10~L4~ (~
The new compounds of the for~ula I can also be obtained by convert-ing the group XO in a compound of the general formula Cl H2-Xo CH, C=O
~ O R2 (IV~
o F
in which XO represents the group ~O~Ra, in which Ra represents the acyl radical of an organic sulphonic acid, (i.e. a sulphonyloxy group), is treated in a manner which is known per se with an alkaline salt of the halogen X2.
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 methoxy, halogen, for example chlorine or bromine, and/or nitro.
~ -5-Typical examples o~ such acids are trifluoromethanesulphonic acid, (~)-camphor-10-sulphonic acid, 4-bromob~nzenesulphonic acid and 3-nitrobenzenesulphonic acid and especially p-toluene-sulphonic 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 M represents an alkali metal, in the presence of an aprotic organic s~lvent which has a dielectric constant of 29 or higher. An alkali metal M
which can be used is, preferably, lithium. Aprotic organ-ic solvents which can be used are, in particular, di-lower alkyl sulphoxides, for example dimethyl sulphoxide, N,N-di-lower alkylamides of lower aliphatic carboxylic acids, for example .
N,N-dimethylformamide or N,N-dimethylacetamide, lower alkane-nitriles or lower alkenenitriles, for example acetonitrile, hexa-lower alkylphosphoramides, for example hexamethylphosphor-triamide, or, above all when using starting materials of the formula IV in which R2 represents hydrogen, also ketones, especially aliphatic or cycloaliphatic ketones conta~ng up to ~nd inclu~g lOcarbcn atoms such as corresponding alkanones, for example acetone, 2-butanone, 2- or 3-pentanone, 2-hexanone or 4-decanone, or cycloalkanones~contau~ngupto and inclu~ 8~gc~xn 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 11~141(;~
and is effected with at least one equivalent of the alkali metal halide of the formula V.
The starting materials of the formula IV are known or can be manufactured in a manner which is known per se, for example by converting the 2l-hydroxylgroup in a 6~-fluoro-ll~,2l-dihydroxy-l6~-methyl-2-Rl-9~-Xl-l7~-OR2-pregna-l,4-diene-3,20-dione compound into the desired organic sulphonyloxy group ~ORa by treatment with a reactive derivative of an organic sulphonic acid of the formula Ra-OH (VI), especially with a corresponding sulphonic acid chloride of the formula Ra-Cl (VIa), in the presence of a ; lO base, for example pyridine.
The new compounds of the formula I in which Xl represents chlorine can also be obtained by adding hypochlorous acid onto the 9,ll-double bond of a compound of the formula Cl13 C=O
21 ~ ~ -~2 (VII) O
F
in which Rl, R2 and X2 have the above meanings.
According to the above reaction, the elements of hypochlorous acid are added onto the 9,ll-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 ~ -7-.
.
~10~41(:~
specification 3,057,886), can be 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 tetra-hydrofurane, 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 -8_ , ~ :
11~141(~
inert, wa.ter-imm.iscible solvent, for example a nitro~
hydrocarbon, usually in the presence of perchloric acid (cf. ~erman patent specification 2,011,559).
The starting materials of the formula VII can be manu-factured in a manner which is known per se, for example by eliminating water from a 6a-fluoro-ll~-hydroxy-16~-methyl-2-Rl-17a-OR2-21-X2-pregna-1,4-diene-3,20-dione compound, for exarnple by treatment with a suitable acid chloride, such as phorphorus oxychloride or methanesulphonyl chloride, in the presence of a base, for example pyridine.
The new compounds of the formula I in which Rl repres-ents hydrogen can also be obtained by introducing the l,2-double bond into a compound of the formula .
fH2 -X2 CH ~=0 -0-R2 (VIII) l?
.
and, if desired, carrying out;the additional measures.
me introduction of the 1,2-double bond can be carried out by dehydrogenation, for example by treatment with a suit-able dehydrogenating quinone, such as 2,3-dichloro-5,6-dicyano-l,4-benzoquinone.
, I
.
.
., ~ .
11014~0 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 pharma-ceutical 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 Xl, X2 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 1,2-saturated, 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 6a-fluoro-11~,21-dihydroxy-16~-methyl-9a-Xl-17a-OR2-pregn-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, wherein Rl represents hydrogen, and which is obtainable according to the process can be converted into an analogous compound of the formula I, wherein Rl represents chlorine, in a manner which is known per se.
For this purpose it is possib]e 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 1,2-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 ~ ~ -10-.
. ~
~ .
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 tetrahydro-furane, 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 and +30, for example at between -20 and +10, and with the exclusion of light.
In a particularly preferred embodiment, the compound of the formula I in which Rl represents hydrogen, is dissolved in one of the above solvents, for example dioxane, ~ ..1;
~ 4 10 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 call set free positive chlorine are chlorinated acid amides or acid imides, such as chlorosuccinimide or chloro-acetamide, and reagents which yield negative chlorine are, for example, hydrogen chloride and also alkali metal chlorides.
The elimination of hydrogen chloride from the intermediate 1,2-dichloro-pregn~4-ene-3,20-dione is advantage-ously effected by treatment with a base. Ex-amples 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,N-dimethylaniline, The reaction is preferably carried out with an excess of the base, which at the same -time can be used as solvent. Howe~er, it is also possible to use in-organic bases, such as, in particular~ the alkali metal salts or alkaline ear-th metal salts which are also used for hydroly-sis of the ll~-trifluoroacetate described below, for example potassium acetate or bicarbonate or sodium acetate or bicarbon ate, in aqueous-alcoholic solution, as well as the corresponding hydroxides. The dehydrochlorination is preferably carried out in a temperature range between about 20Cand about 100C.
C i 1 ~
- ,~6 - , ~ 4 1~
Advantageouslys those agents and reaction conditions are chosen which have no influence on the other f~mctional 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 Rl represen-ts hydrogen, the ll~-hydroxyl group is advantagecusly protected, for example by esterification, preferably in the form of a trifluoroacetoxy group, a compound of the formula I in which Rl represents hydrogen being reacted in a manner which is kno~n per se with a suitable reactive derivative o~ 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 hydroxides, carbonates, bicarbonates or acetates, in a suitable medium, for example an alcoholic, such as methanolic, or aqueous-alcoholic medium. A particular method of carrymg out the solvolysis of the ll-tri~luoroacetoxy group is described in German patent spec-ification 1,593,519. This procedure can be used mainly because it leaves intact any esterified hydroxyl group which may be present in the 17a-position an~d consists in treating the 11~-trifluoroacetoxy 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 eæamp~ with an alkali metal azide, for example sodium aæide or potassium azide, or an alkali metal .
141~
formate, for example sodium formate or potassium formate. If appropriate, this salt can also be used only in catalytic amounts. Furthermore, the 11~-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 ll~-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.
- The starting materials used in the above process steps are prefer-ably those which result in the compounds described above as being particularly preferred.
The compounds of the present invention are especially useful for the manufacture of pharmaceutical compositions which contain, as active ingredient, a compound according to the invention of the formula I, or a
2-unsubstituted 1,2-dehydro derivative thereof.
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.
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 O.i,. ~
~ ~ -14-- , .,. ' - ' ' .. , ~
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 compositions 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.
~ -15-., 141~
The dosage of active substance depends on the species of warm-blooded animal, the age, and the individual conditioll as well as on the mode of application.
The present invention also relates ~o the use of the new compounds the formula I and of the salts of such compounds with salt-forming properties, preferably for treating inflammations, chiefly as antiinfla~matory 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, - .. ~5 -4~.1) Example 1 230 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) are added to a solution oE 228 mg of 21-chloro-6~,9~-difluoro-ll,B~l7~-dihydroxy-l6~-methyl-pregn 4-ene-3,20-dione-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 i5 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,9a-difluoro-ll,B,170;-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione-17-propionate which melts at 220-221C after recrys-tallisation from methylene chloride/e~her.
The 17-monopropionate used as starting material is prepared as follows:
A suspension of 1 g of 21-chloro-9~ epoxy-17~-hydroxy-16~-methyl-pregn-4-ene-3,20-dione-17-propionate in 5.4 ml of dioxane and 1.4 ml of triethyl orthoformate is treated with 0.9 ml of a solution consisting of 277 mg of p-toluenesulphonic acid, 2.7 ml of dioxane and 0.55 ml of ethyl alcohol and stirred for` 90 minutes at room temperatureO
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-.~ /1 .~ - ~ _ llGl~O
9~ epoxy-17~-hydroxy-16~-methyl pregna-3~5-~iene-20-one-17-propionate) is dissolved in a mixture of 50 ml of tetrahydro-furane 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 colulnn is eluted with a 90:10 mixture of toluene/
ethyl acetate. Recrystallisation from methylene chloride/ether of the fractions obtained yield 21-chloro-6~-fluoro-9~
epoxy-17~-hydroxy-16~-methyl-pregn-4-ene-3,20-dione-17-propionate which melts at 174-177C.
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 à 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 acidiied 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 ~ 4 1~
a water je~ vacuum. The crude product is chromatograplled on 100 times its weight of silica gel (stepped column). The column is eluted with 90:10 mixture of toluene/ethyl acetate.
Recrystallisation from methylene chloride/ether of the fractions obtained yields 21~chloro-6a,9a-difluoro-11~,17a-dihydroxy-16~-methyl-pregn-4-ene-3~20-dione-17-propionate which melts at 212-213C.
Example 2 A solution of 370 g of 21-chloro-6a,9a-difluoro~ ,17a-dihydroxy-16~-methylpregna-1,4-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 3~4C. It is then diluted with chloroform, washed successively with a 10% potassium iodide solution, a 10% sodium thiosulphate solution, dilute sodium hydroxide solution and water, dried, and concentrated n a water jet vacuum~ The crude 1~,2~,21-trichloro-6a,9a-difluoro~ ,17a-dihydroxy-16~-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-6a,9a-difluoro-11~, 17a-dihydroxy-16~-methylpregna-1,4-diene-3,20-dione-17-propionatc which melts at 202-204C.
4~0 .
Example 3 A solution of 350 mg of 9a,21-dichloro-6~-fluoro-11~,17-dihydroxy-16,B-methyl-pregn-4-ene-3,20-dione-17-propionate and 525 mg o 2,3-dichloro-5,6-dicyano~1,4-benzo-quinone 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 lS 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,21-dichloro-6a-fluoro-11~,17-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione-17-propionate which melts, with decomposition, at 212-213C.
The starting steroid is obtained as follows:
Hydrogen chloride gas is introduced at 0C in the course of 30 minutes into a solution of 400 mg of 21-chloro-6~-fluoro-9,B,ll-epoxy-17-hydroxy-16~-me~thyl-pregn-4-ene-3,20-dione-propionate in 20 ml of chloroform. The mixture is allowed to stand for a further 30 minutes at 0C, diluted with chloroform, washed with an ice~cold saturated sodium hydrocarbonate solution dried and concentrated in vacuo. The crude 9c;,21-_~ _ ...,, .~
, 11~141~
dichloro-6~-fluoro-11~,17-dihydroxy-16~-methyl-pregn-4-ene
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.
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 O.i,. ~
~ ~ -14-- , .,. ' - ' ' .. , ~
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 compositions 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.
~ -15-., 141~
The dosage of active substance depends on the species of warm-blooded animal, the age, and the individual conditioll as well as on the mode of application.
The present invention also relates ~o the use of the new compounds the formula I and of the salts of such compounds with salt-forming properties, preferably for treating inflammations, chiefly as antiinfla~matory 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, - .. ~5 -4~.1) Example 1 230 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) are added to a solution oE 228 mg of 21-chloro-6~,9~-difluoro-ll,B~l7~-dihydroxy-l6~-methyl-pregn 4-ene-3,20-dione-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 i5 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,9a-difluoro-ll,B,170;-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione-17-propionate which melts at 220-221C after recrys-tallisation from methylene chloride/e~her.
The 17-monopropionate used as starting material is prepared as follows:
A suspension of 1 g of 21-chloro-9~ epoxy-17~-hydroxy-16~-methyl-pregn-4-ene-3,20-dione-17-propionate in 5.4 ml of dioxane and 1.4 ml of triethyl orthoformate is treated with 0.9 ml of a solution consisting of 277 mg of p-toluenesulphonic acid, 2.7 ml of dioxane and 0.55 ml of ethyl alcohol and stirred for` 90 minutes at room temperatureO
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-.~ /1 .~ - ~ _ llGl~O
9~ epoxy-17~-hydroxy-16~-methyl pregna-3~5-~iene-20-one-17-propionate) is dissolved in a mixture of 50 ml of tetrahydro-furane 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 colulnn is eluted with a 90:10 mixture of toluene/
ethyl acetate. Recrystallisation from methylene chloride/ether of the fractions obtained yield 21-chloro-6~-fluoro-9~
epoxy-17~-hydroxy-16~-methyl-pregn-4-ene-3,20-dione-17-propionate which melts at 174-177C.
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 à 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 acidiied 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 ~ 4 1~
a water je~ vacuum. The crude product is chromatograplled on 100 times its weight of silica gel (stepped column). The column is eluted with 90:10 mixture of toluene/ethyl acetate.
Recrystallisation from methylene chloride/ether of the fractions obtained yields 21~chloro-6a,9a-difluoro-11~,17a-dihydroxy-16~-methyl-pregn-4-ene-3~20-dione-17-propionate which melts at 212-213C.
Example 2 A solution of 370 g of 21-chloro-6a,9a-difluoro~ ,17a-dihydroxy-16~-methylpregna-1,4-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 3~4C. It is then diluted with chloroform, washed successively with a 10% potassium iodide solution, a 10% sodium thiosulphate solution, dilute sodium hydroxide solution and water, dried, and concentrated n a water jet vacuum~ The crude 1~,2~,21-trichloro-6a,9a-difluoro~ ,17a-dihydroxy-16~-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-6a,9a-difluoro-11~, 17a-dihydroxy-16~-methylpregna-1,4-diene-3,20-dione-17-propionatc which melts at 202-204C.
4~0 .
Example 3 A solution of 350 mg of 9a,21-dichloro-6~-fluoro-11~,17-dihydroxy-16,B-methyl-pregn-4-ene-3,20-dione-17-propionate and 525 mg o 2,3-dichloro-5,6-dicyano~1,4-benzo-quinone 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 lS 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,21-dichloro-6a-fluoro-11~,17-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione-17-propionate which melts, with decomposition, at 212-213C.
The starting steroid is obtained as follows:
Hydrogen chloride gas is introduced at 0C in the course of 30 minutes into a solution of 400 mg of 21-chloro-6~-fluoro-9,B,ll-epoxy-17-hydroxy-16~-me~thyl-pregn-4-ene-3,20-dione-propionate in 20 ml of chloroform. The mixture is allowed to stand for a further 30 minutes at 0C, diluted with chloroform, washed with an ice~cold saturated sodium hydrocarbonate solution dried and concentrated in vacuo. The crude 9c;,21-_~ _ ...,, .~
, 11~141~
dichloro-6~-fluoro-11~,17-dihydroxy-16~-methyl-pregn-4-ene
3,20-dione-17-propionate can be used without purification for the dihydrogenation reaction.
Example 4 Hydrogen chloride gas is introduced at 0C in the course of 30 minutes into a solution of 2.8 g of 21-chloro-6a-fluoro-9~ epoxy-17-hydroxy-16~-methyl pregna 1,4-diene~3,20-dione-propionate in 140 ml of chloroo~rm. The mixture is allowed to stand for a further 30 minutes at 0C, diluted with chloroform, washed with an ice-cold saturated sodium hydro-carbonate solution, dried and evapora~ed 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 9~,21-dichloro-6~-iluoro-11~,17-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione-17-propionate which melts, with decomposition, at 212-213C and is identical with the product of Example 3.
The starting steroid is obtained as ollows:
A mixture of 3 g of 21-chloro-6~-fluoro-9~,11-epoxy-17-hydroxy-16~-methyl-pregn-4-ene-3,20-dione-propionate and 3 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 150 ml of dioxane is reflu~ed for 20 hours in an atmosphere of nitrogen.
The cooled mixture is filtered, and the filtrate concentratedO
~f .
The resi.due is dissolved in methylene chloride and filtered through 15 times its weight of neutral alumina (activity II). The filtrate is concentrated, af:Eording the crude 21-chloro-6~-fluoro-9,B-ll-epoxy-17~hydroxy-16~-methyl-pregna-1,4-diene-3,2û-dione-propionate which can be treated with hydrogen chloride without further puri:Eication.
Example 5 An ointment containing 0.1% of 21-chloro-6c~,9~-difluoro~ll,3~17~-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione 17-propionate can be prepared as follows:
Composition 21-chloro-6a,9~x-difluoro~ ,17~-dihydroxy-16~-methyl-pregna-1,4 diene-3,20-dione 17-propionate0.1%
white petroleum jelly 45.0%
liquid paraf:Ein 19.6%
cetyl alcohol 5.0%
beeswax 5.0%
sorbitane sesquioleate 5.0%
p-hydroxybenzoic acid ester 0.2%
perfwne ~ 0.1%
water 20.0%
, llQ1410 The ~at-ty substances and emulsifiers are melted to-gether, The preserva-tive is dissolved in water and the solution is emulsi~ied into the fatty melt at elevated tempera-ture. 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.
~ ,;2 3 ,~.,.,i ~
Example 4 Hydrogen chloride gas is introduced at 0C in the course of 30 minutes into a solution of 2.8 g of 21-chloro-6a-fluoro-9~ epoxy-17-hydroxy-16~-methyl pregna 1,4-diene~3,20-dione-propionate in 140 ml of chloroo~rm. The mixture is allowed to stand for a further 30 minutes at 0C, diluted with chloroform, washed with an ice-cold saturated sodium hydro-carbonate solution, dried and evapora~ed 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 9~,21-dichloro-6~-iluoro-11~,17-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione-17-propionate which melts, with decomposition, at 212-213C and is identical with the product of Example 3.
The starting steroid is obtained as ollows:
A mixture of 3 g of 21-chloro-6~-fluoro-9~,11-epoxy-17-hydroxy-16~-methyl-pregn-4-ene-3,20-dione-propionate and 3 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 150 ml of dioxane is reflu~ed for 20 hours in an atmosphere of nitrogen.
The cooled mixture is filtered, and the filtrate concentratedO
~f .
The resi.due is dissolved in methylene chloride and filtered through 15 times its weight of neutral alumina (activity II). The filtrate is concentrated, af:Eording the crude 21-chloro-6~-fluoro-9,B-ll-epoxy-17~hydroxy-16~-methyl-pregna-1,4-diene-3,2û-dione-propionate which can be treated with hydrogen chloride without further puri:Eication.
Example 5 An ointment containing 0.1% of 21-chloro-6c~,9~-difluoro~ll,3~17~-dihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione 17-propionate can be prepared as follows:
Composition 21-chloro-6a,9~x-difluoro~ ,17~-dihydroxy-16~-methyl-pregna-1,4 diene-3,20-dione 17-propionate0.1%
white petroleum jelly 45.0%
liquid paraf:Ein 19.6%
cetyl alcohol 5.0%
beeswax 5.0%
sorbitane sesquioleate 5.0%
p-hydroxybenzoic acid ester 0.2%
perfwne ~ 0.1%
water 20.0%
, llQ1410 The ~at-ty substances and emulsifiers are melted to-gether, The preserva-tive is dissolved in water and the solution is emulsi~ied into the fatty melt at elevated tempera-ture. 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.
~ ,;2 3 ,~.,.,i ~
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a 9a,21-dihalogeno-11.beta.,17.alpha.-dihydroxy-6.alpha.-fluoro-16.beta.-methyl-pregna-1,4-diene-3,20-dione compound of the formula (I) in which X1 represents chlorine or fluorine, X2 represents bromine or chlorine, R1 represents hydrogen or chlorine and R2 represents a straight-chain lower alkanoyl, and of a corresponding 2-unsubstituted 1,2-dihydro derivative there-of of the formula VIII given hereinafter, wherein a) a compound of the formula (II) in which R1, R2 and X2 has the above meaning, or a 2-unsubstituted 1,2-dihydro derivative thereof, is treated with a hydrogen halide of the formula H-X1, in which X1 has the above meaning, or with an agent releasing HX1, or b) a compound of the general formula (IV) in which R1, R2 and X1 have the above meaning and Xo re-presents the group -ORa, in which Ra represents the acyl radical of an organic sulfonic acid, or a 2-unsubstituted 1,2-dihydroderivative thereof, is treated with an alkaline salt of the halogen X2, or c) hypochlorous acid is added onto the 9,11-double bond of a compound of the formula (VII) in which R1, R2 and X2 have the above meanings, or onto a 2-unsubstituted 1,2-dihydro derivative thereof, or d) if a compound of the formula I is required, in which R1 represents hydrogen the 1,2-double bond is introduced into a compound of the formula (VIII) in which R2, X1 and X2 have the above meaning, or e) if a compound of the formula I is required, in which R1 represents chlorine, a resulting compound of the formula I, in which R1 represents hydrogen, is treated with chlorine and hydrogen chloride is split off from the resulting intermediate compound of the formula in which R2, X1 and X2 have the above meanings and in which the 11-hydroxyl group is, if necessary, in a protected form, and the protective group which may be present is removed from 11-hydroxyl.
2. A process according to claim 1 , wherein a starting material is formed under the reaction conditions and/or is used in the form of a derivative.
3. A process according to claim 1, process variant c), wherein a compound of the formula VII is treated with hypochlorous acid or an agent which releases hypochlorous acid.
4. A process according to claim 1, wherein the reaction according to the process variant e) is carried out while temporarily protecting the 11.beta.-hydroxyl group by conversion into the trifluoroacetate.
5. A process according to any one of claims 1 to 3 for the manufacture of a compound of the formula I in which X
represents fluorine or chlorine, X2 represents chlorine, R1 represents hydrogen and R2 represents lower alkanoyl of 2 to 5 carbon atoms.
represents fluorine or chlorine, X2 represents chlorine, R1 represents hydrogen and R2 represents lower alkanoyl of 2 to 5 carbon atoms.
6. A process according to any one of claims 1 to 3 for the manufacture of a compound of the formula VIII in which X1 represents fluorine or chlorine, X2 represents chlorine, and R2 represents lower alkanoyl of 2 to 5 carbon atoms.
7. A process according to any one of claims 1 to 3 for the manufacture of a compound of the formula I in which X1 represents fluorine or chlorine, X2 represents chlorine, R1 represents chlorine and R2 represents lower alkanoyl of 2 to 5 carbon atoms.
8. A process according to any one of claim 1 to 3 for the manufacture of 2,21-dichloro-6.alpha.,9.alpha.-difluoro-11.beta.,17a-dihydroxy-16.beta.-methyl-pregna-1,4-diene-3,20-dione-17-propionate.
9. A process according to any one of claims 1 to 3 for the manufacture of 9.alpha.,21-dichloro-6.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.beta.-methyl-pregna-1,4-diene-3,20-dione-17-propionate.
10. A process according to any one of claims 1 to 3 for the manufacture of 21-chloro-6.alpha.,9.alpha.-difluoro-11.beta.,17.alpha.-di-hydroxy-16.beta.-methyl-pregna-1,4-diene-3,20-dione-17-propion-ate.
11. A process according to any one of claims 1 to 3 for the manufacture of 21-chloro-6.alpha.,9.alpha.-difluoro-11.beta.,17.alpha.-di-hydroxy-16.beta.-methyl-pregn-4-ene-3,20-dione-17-propionate.
12. A process according to any one of claims 1 to 3 for the manufacture of 9.alpha.,21-dichloro-6.alpha.-fluoro-11.beta.,17.alpha.-di-hydroxy-16.beta.-methyl-pregn-4-ene-3,20-dione-17-propionate.
13. A 9.alpha.,21-dihalogeno-11.beta.,17.alpha.-dihydroxy-6.alpha.-fluoro-16.beta.-methyl-pregna-1,4-diene-3,20-dione compound of the formula (I) wherein X1 represents chlorine or fluorine, X2 represents bromine or chlorine, R1 represents hydrogen or chlorine and R2 represents a straight-chain lower alkanoyl, or a 9.alpha.,21-dihalogeno-11.beta.,17.alpha.-dihydroxy-6.alpha.-fluoro-16.beta.-methyl-pregna-4-ene-3,20-dione compound of the formula (VIII) wherein X1 represents chlorine or fluorine, X2 represents bromine or chlorine, and R2 represents a straight-chain lower alkanoyl, whenever prepared according to claim 1 or a process which is an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU75903A LU75903A1 (en) | 1976-09-29 | 1976-09-29 | |
| LU75903 | 1976-09-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1101410A true CA1101410A (en) | 1981-05-19 |
Family
ID=19728370
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA287,560A Expired CA1101410A (en) | 1976-09-29 | 1977-09-27 | 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 |
| US7098328B2 (en) | 2001-11-29 | 2006-08-29 | Taro Pharmaceutical Industries Limited | Method for the preparation of 6α-fluoro corticosteroids |
| US11957753B2 (en) | 2010-11-22 | 2024-04-16 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
| US8809307B2 (en) | 2010-11-22 | 2014-08-19 | Dow Pharmaceutical Sciences, Inc. | Pharmaceutical formulations containing corticosteroids for topical administration |
| SI3310389T1 (en) | 2015-06-18 | 2020-11-30 | Bausch Health Ireland Limited | 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 AU AU29148/77A patent/AU514200B2/en not_active Expired
- 1977-09-27 CA CA287,560A patent/CA1101410A/en not_active Expired
- 1977-09-27 DD DD7700201226A patent/DD133150A5/en unknown
- 1977-09-27 CY CY1178A patent/CY1178A/en unknown
- 1977-09-27 GB GB40131/77A patent/GB1563638A/en not_active Expired
- 1977-09-27 FR FR7729043A patent/FR2366311A1/en active Granted
- 1977-09-28 IE IE1979/77A patent/IE46047B1/en not_active IP Right Cessation
- 1977-09-28 HU HU77CI1774A patent/HU175218B/en unknown
- 1977-09-28 ZA ZA00775800A patent/ZA775800B/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
- 1977-09-28 IL IL53012A patent/IL53012A/en unknown
- 1977-09-29 ES ES462763A patent/ES462763A1/en not_active Expired
- 1977-09-29 JP JP11619377A patent/JPS5356652A/en active Granted
-
1979
- 1979-02-28 AT AT0151379A patent/AT363203B/en not_active IP Right Cessation
- 1979-02-28 AT AT0151279A patent/AT363202B/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 CH683281A patent/CH632000A5/en not_active IP Right Cessation
- 1981-10-26 CH CH683181A patent/CH631999A5/en not_active IP Right Cessation
- 1981-10-26 CH CH683081A patent/CH631998A5/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
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