CA1078824A - Halogenopregnadienes and process for the manufacture thereof - Google Patents
Halogenopregnadienes and process for the manufacture thereofInfo
- Publication number
- CA1078824A CA1078824A CA267,597A CA267597A CA1078824A CA 1078824 A CA1078824 A CA 1078824A CA 267597 A CA267597 A CA 267597A CA 1078824 A CA1078824 A CA 1078824A
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- Prior art keywords
- acid
- process according
- alpha
- hydroxyl group
- lower aliphatic
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Classifications
-
- 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
-
- 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
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
Abstract of the Disclosure 2,9.alpha.-dichloro-paramethasone and its 21- or 17-monoesters or 17,2l-diesters possess a pronounced topical antiinflammatory action without concomitant actions on thymus, adrenals or body weight. They are prepared by conventional methods.
Description
32~
The invention provides 2,9~-dichloro-6a-fluoro-16~-methyl-11~,17,21-trihydroxy-pregna-1,4-diene-3,20-dione compounds of the formula CH3 P.2 GO~ C~l~Rl Cl ~ CH3 O \~ .
.
where;n each of Rl and R2 represents a free or esterified hydroxyl group, whilst Rl and R2 together can also represent a cyclic 17,21-diester g~oup e.g. which is derived from an ortho-carboxylic acid or from carbonic acid, and a ~rocess for the manufacture of these compounds~
The esterified hydroxyL groups menti~ned above are derived from acids which are customarily suitable as esteri-fication compounds in hydroxy~Steroids intended for therapeutic use, for example from unsubstituted or sub~tituted organic carboxylic acids containing 1 to 18 carbon atoms, from sulphonic acids or ~rom inorganic acids. Preferred carboxylic acids of the aliphatic series are in particular the lower aliphatic mono- or dicarboxylic acids contai~n~ 1 to 7 carbon atoms~ for exam~le acetic acid, propionic acid, the butyric acids, the valeric acids, the caproic acids, in particular .. . . . . ~ . ~.. .. . .. . . .
- ' -~ ~ 7 ~ ~ Z 4 trimethylacetic acid~ n7caproic acid, dimethylethylacetic acid, malonic acid,succinic acid, glutaric acid Suitable higher aliphatic carboxylic acids are, for example, capric or undecylenic acid, palmitic acid, oleic acid or stearic acid.
Examples of cycloaliphat;c or cycloaliphatic-aliphatic monocarboxylic acids are cyclopropane-, cycLobutane_,cyclo-pentane- and cyclohexanecarboxylic acid and cyclopropyl- or cyclobutyl-methanecarboxylic acidl or one of the cyclopentyl-or cyclohexyl-ethanecarboxylic acids. Preferred substituted carboxylic acids are in particular the hydroxylated carboxylic acids, for example the malic acids, the lactic acids3 the citric acids, glycollic or digLyco~ic acid, or aLkoxycarboxy~ic acids, in particular lower a~koxycarboxylic acids, such as methoxy- or ethoxyacetic acid or methoxy- or ethoxypropionic acid. Aromatic carboxylic acids which are particularly suitable as esterification components are the monocycLic acids, such as benzoic acid and the derivatives thereof, or phthalic acid, and araliphatic carboxylic acids are monocyclic-lower aliphatic carboxylic acids, such as phenylacetic or phenylpropionic acid~ The esterified hydroxyl groups can also however be derived from heterocyclic acids, for example from nicotinic or isonicotinic acid. Suitable sulphonic acids are chiefly methanesulphonic acid or monocyclic aromatic sulphonic acids, for example benzene- or toluenesulphonic acids, especially p-~oluenesulphonic acid. Finally, the esteri-fied group can be derived from inorganic acids, in particular sulphuric acid and ortho-, meta- or pyro-phosphoric acid.
. - , . ........ ,.:
, . : : , ~ .
., -, - ' ' . ~ ~` . ' ' ' ~
The esters of polybasic acids are generally in the form of the monoesters.
The es~er g~s can also be derived from ortho-carboxylic acids, in particular lower aliphatic ortho-carboxy-lic acids containing l to 7 carbon atoms, such as orthoformic acid, orthoacetic acid or orthopropionic acid, or from carbonic acid. The esters of such acids are in the form of cyclic 17,21-o~tho-carboxylic acid esters or cyclic 17,21-carbonates.
Water-sduble preparations.of formuLa (I) can be obtained by advantageously preparing hemiesters of polybasic acids, such as dicarboxylic acids, for example succinic or phthalic acid, or of sulphuric acids or of phosphoric acids, and then converting these into salts of organic bases, for example of simple aliphatic amines, such as trimethylamine, - diethylamine, ethylamine, propylamine or-isoprop~lamine, or~- -of cyclic bases, such as piperidine, morpholine or pyrrolidine, .
or the homologues thereo~. However, for the same purpose it is also possible to prepare esters which are derived from a carboxylic acid which contains amino groups, for ex~mple diethylamino-, piperidino- or morpholinoacetic acid, or any other known amino acid, and to quaternise the amino group in these esters, so. that the water-soluble quaternary ammonium salts are formed.
The novel compounds of the formula ~I) enc~mpass the free 2,9~-dichloro-6~-fluoro-16~-methyl-11~,17~,2'- ;
~- - 4 -~078B24 trihydroxy-pregna-1,4-diene-3,20-dione ~2, 9a - di chloropara-methasone), the 17a- and 21-monoester and the 17~,21-diPster thereof, in particular also the cyclic 17,21-diesters. These - compounds possess valuable pharmacological properti~s. By way of example, they have in particular a pronounced antiinflamma-tory action, as can be demonstrated in animal tests, for example on rats in the foreign body granuloma test. For example, when applied locally in the dosage range between 0.003 mg per cotton wool peLle~ and 0.03 mg per cotton wool pellet they exhibit a marked antiinflar~matory action. An action on the thymus is observed in this mode of administration only from 0.03 mg per cotton wool pellet and action on adrenals and body weight oco~s only at doses from 0.3 mg per cotton wool pellet.
For example, in the indicated mode of administration and in the above mentioned test on rats, both 2,9a-dichloroparam2thasone-21-pivalat~ and 2,9a-dichloroparamethaso~17,21-dipropionate exhibit an ED20-5o from ~.001 mg per co~Dn wool pellet.
The novel compounds can therefore be used as antiinflammatory agents, in particular in de~matology. However, they are also valuable intermediates for obtaining other useful substances, especially pharmacologically active compounds.
The compounds of the above formula (I) can be obtained in a manner known per se. In particular, they can be obtained by ~ _ - - , . . .
.
- ~ .
~.07~
(a) the addition of chlorine to the 1,2-double bond in a compound of the formula ~10 CU3 ~2 ~IrcO--~n2- R
~/` (Il) 0~
F
wherein Rl and R2 are as defined in formula (I), whilst optionally protecting the ll-hydroxy group temporarily beforehand, and the dehydrochlorination of the resultant 1,2-dichloro compound, or (b) treating a compound of the general formula .- - - ~ . - - .
~ . 1 3 CO~CH2 P~
Cl ~ ~ ~ CH3 (III) O ~ ~ :
F
wherein Rl and R2 are as defined in formula (I), with - . . . .
~ 0~88 ~ 4 .
hypochlorous acid or with a hypochlorous acid donor, or (c) treating a compound of the general formula C1~3 ~2 ~CO~ 2--R
O
- ' :'' ' '' ' wherein Rl and R2 are as defined in formula (I), with hydrogen chloride or a hydrogen chloride donor, and/or, if desired, in compounds o the formula (I), in which at least one of the~groups Rl and R~ is esterified, converting at least one esterified hydroxyl group into a free hydroxyl group, or in compounds of the formula (I), in which àt leas~ one of the groups Rl and R2 represents a free hydroxyl group, whilst optionally protecting the ll-hydroxyl group temporarily, esterifiying at least one free hydroxyl group, and/ora if desired, converting hemiesters of dicarboxy-lic acids or of polybasic inorganic acids into their metal salts or salts of organic bases.
According to method (a~, chlorine is added to the 1,2-double bond in a manner known per se, To this end, ~ 7 07&~3~ 4 preferably elementary chlorine is used and the chlorination is carried out in an inert solvent, for example an ether~ such as dioxane or tetrahydrofurane, a halogenated hydrocarbon, for example methylene chloride, or a carboxylic acid, in particular a lower aliphatic carboxylic acid, such as acetic acid or propionic acid. Instead of using carboxylic acids it is also possib~e to use derivatives thereof, such as acid amides 5 for example dimethyl ormamide, or nitriles, such as lower alkylnit riles, for example acetonitrile. Advantageously~ mixtures of these solvents can also be used, in particular a mixture of an ether, such as dioxane, with one of the above mentioned lower aliphatic carboxylic acids. The process can be carried out with chlorine in an amount substantially in excess of ~he theoretical amount; but preferably the stoichiometric amount of chlorine is used. The chlorination is advantageously carried out at low temperature, approx. between -50 and ~3Q~
for example between -20 and ~10C, and in the dark. The reaction time is normally sev~al hours or days, for example up to 7 days. In a particularly preferred embodiment of the process, the starting steroid is dissolved in one of the solvents mentioned above, for example dioxane, and treated with a solution of the chlorinating agent, for example chlorine, in a lower aliphatic carboxylic acid, for example propionic acid, and this solution is then allowed to stand at the given temperature for several days.
~ 8 -. . - . ~ , - - ~ , , . . ." . .....
~8824 However, the chlorination of the 1,2-double bond can also be effected with mLxtures of two different chlorine-containing compounds one of which yields positive and the other negative chlorine. Examples of suitable reagents which are able to 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 alkali metal chlorides. The above mentioned solvents can also be used for the addition of chlorine wi~h these reagents.
I~ desired, the ll-hydroxyl group can be protected before the chlorination, preferably by esterification with trifluoroacetic acid. The trifluoroacetates are obtai~ed by -reacting the starting materials with trifluoroacetic ch~oride or anhydride in a manner known per se. It is known that this ester can be easily split of again by hydrolysis or solvolysis, for example by treatment with hydroxides, carbonates, bicarbonates or acetates of alkali metals or alkaline earth metals, for example in alcoholic or aqueous-alcoholic solution, for example in methanolic solution, or with alcohols alone. A particular method of carrying out the solvolysis of the ll-trifluoroacetate group is that described in German patent speciication 1~593~519, which is chiefly suitable whenever it is a question of le~ving the ester groups in 17- and/or 21-position intact. This method comprises treating the ll-ester in a lower alcohol with a _ 9 _ ... . ...... ~ - . .. .
~ . . .
:- , . ;
.~-.. .. .
8~3Z~L
~alt of an acid whose pKa-value is in the range between about
The invention provides 2,9~-dichloro-6a-fluoro-16~-methyl-11~,17,21-trihydroxy-pregna-1,4-diene-3,20-dione compounds of the formula CH3 P.2 GO~ C~l~Rl Cl ~ CH3 O \~ .
.
where;n each of Rl and R2 represents a free or esterified hydroxyl group, whilst Rl and R2 together can also represent a cyclic 17,21-diester g~oup e.g. which is derived from an ortho-carboxylic acid or from carbonic acid, and a ~rocess for the manufacture of these compounds~
The esterified hydroxyL groups menti~ned above are derived from acids which are customarily suitable as esteri-fication compounds in hydroxy~Steroids intended for therapeutic use, for example from unsubstituted or sub~tituted organic carboxylic acids containing 1 to 18 carbon atoms, from sulphonic acids or ~rom inorganic acids. Preferred carboxylic acids of the aliphatic series are in particular the lower aliphatic mono- or dicarboxylic acids contai~n~ 1 to 7 carbon atoms~ for exam~le acetic acid, propionic acid, the butyric acids, the valeric acids, the caproic acids, in particular .. . . . . ~ . ~.. .. . .. . . .
- ' -~ ~ 7 ~ ~ Z 4 trimethylacetic acid~ n7caproic acid, dimethylethylacetic acid, malonic acid,succinic acid, glutaric acid Suitable higher aliphatic carboxylic acids are, for example, capric or undecylenic acid, palmitic acid, oleic acid or stearic acid.
Examples of cycloaliphat;c or cycloaliphatic-aliphatic monocarboxylic acids are cyclopropane-, cycLobutane_,cyclo-pentane- and cyclohexanecarboxylic acid and cyclopropyl- or cyclobutyl-methanecarboxylic acidl or one of the cyclopentyl-or cyclohexyl-ethanecarboxylic acids. Preferred substituted carboxylic acids are in particular the hydroxylated carboxylic acids, for example the malic acids, the lactic acids3 the citric acids, glycollic or digLyco~ic acid, or aLkoxycarboxy~ic acids, in particular lower a~koxycarboxylic acids, such as methoxy- or ethoxyacetic acid or methoxy- or ethoxypropionic acid. Aromatic carboxylic acids which are particularly suitable as esterification components are the monocycLic acids, such as benzoic acid and the derivatives thereof, or phthalic acid, and araliphatic carboxylic acids are monocyclic-lower aliphatic carboxylic acids, such as phenylacetic or phenylpropionic acid~ The esterified hydroxyl groups can also however be derived from heterocyclic acids, for example from nicotinic or isonicotinic acid. Suitable sulphonic acids are chiefly methanesulphonic acid or monocyclic aromatic sulphonic acids, for example benzene- or toluenesulphonic acids, especially p-~oluenesulphonic acid. Finally, the esteri-fied group can be derived from inorganic acids, in particular sulphuric acid and ortho-, meta- or pyro-phosphoric acid.
. - , . ........ ,.:
, . : : , ~ .
., -, - ' ' . ~ ~` . ' ' ' ~
The esters of polybasic acids are generally in the form of the monoesters.
The es~er g~s can also be derived from ortho-carboxylic acids, in particular lower aliphatic ortho-carboxy-lic acids containing l to 7 carbon atoms, such as orthoformic acid, orthoacetic acid or orthopropionic acid, or from carbonic acid. The esters of such acids are in the form of cyclic 17,21-o~tho-carboxylic acid esters or cyclic 17,21-carbonates.
Water-sduble preparations.of formuLa (I) can be obtained by advantageously preparing hemiesters of polybasic acids, such as dicarboxylic acids, for example succinic or phthalic acid, or of sulphuric acids or of phosphoric acids, and then converting these into salts of organic bases, for example of simple aliphatic amines, such as trimethylamine, - diethylamine, ethylamine, propylamine or-isoprop~lamine, or~- -of cyclic bases, such as piperidine, morpholine or pyrrolidine, .
or the homologues thereo~. However, for the same purpose it is also possible to prepare esters which are derived from a carboxylic acid which contains amino groups, for ex~mple diethylamino-, piperidino- or morpholinoacetic acid, or any other known amino acid, and to quaternise the amino group in these esters, so. that the water-soluble quaternary ammonium salts are formed.
The novel compounds of the formula ~I) enc~mpass the free 2,9~-dichloro-6~-fluoro-16~-methyl-11~,17~,2'- ;
~- - 4 -~078B24 trihydroxy-pregna-1,4-diene-3,20-dione ~2, 9a - di chloropara-methasone), the 17a- and 21-monoester and the 17~,21-diPster thereof, in particular also the cyclic 17,21-diesters. These - compounds possess valuable pharmacological properti~s. By way of example, they have in particular a pronounced antiinflamma-tory action, as can be demonstrated in animal tests, for example on rats in the foreign body granuloma test. For example, when applied locally in the dosage range between 0.003 mg per cotton wool peLle~ and 0.03 mg per cotton wool pellet they exhibit a marked antiinflar~matory action. An action on the thymus is observed in this mode of administration only from 0.03 mg per cotton wool pellet and action on adrenals and body weight oco~s only at doses from 0.3 mg per cotton wool pellet.
For example, in the indicated mode of administration and in the above mentioned test on rats, both 2,9a-dichloroparam2thasone-21-pivalat~ and 2,9a-dichloroparamethaso~17,21-dipropionate exhibit an ED20-5o from ~.001 mg per co~Dn wool pellet.
The novel compounds can therefore be used as antiinflammatory agents, in particular in de~matology. However, they are also valuable intermediates for obtaining other useful substances, especially pharmacologically active compounds.
The compounds of the above formula (I) can be obtained in a manner known per se. In particular, they can be obtained by ~ _ - - , . . .
.
- ~ .
~.07~
(a) the addition of chlorine to the 1,2-double bond in a compound of the formula ~10 CU3 ~2 ~IrcO--~n2- R
~/` (Il) 0~
F
wherein Rl and R2 are as defined in formula (I), whilst optionally protecting the ll-hydroxy group temporarily beforehand, and the dehydrochlorination of the resultant 1,2-dichloro compound, or (b) treating a compound of the general formula .- - - ~ . - - .
~ . 1 3 CO~CH2 P~
Cl ~ ~ ~ CH3 (III) O ~ ~ :
F
wherein Rl and R2 are as defined in formula (I), with - . . . .
~ 0~88 ~ 4 .
hypochlorous acid or with a hypochlorous acid donor, or (c) treating a compound of the general formula C1~3 ~2 ~CO~ 2--R
O
- ' :'' ' '' ' wherein Rl and R2 are as defined in formula (I), with hydrogen chloride or a hydrogen chloride donor, and/or, if desired, in compounds o the formula (I), in which at least one of the~groups Rl and R~ is esterified, converting at least one esterified hydroxyl group into a free hydroxyl group, or in compounds of the formula (I), in which àt leas~ one of the groups Rl and R2 represents a free hydroxyl group, whilst optionally protecting the ll-hydroxyl group temporarily, esterifiying at least one free hydroxyl group, and/ora if desired, converting hemiesters of dicarboxy-lic acids or of polybasic inorganic acids into their metal salts or salts of organic bases.
According to method (a~, chlorine is added to the 1,2-double bond in a manner known per se, To this end, ~ 7 07&~3~ 4 preferably elementary chlorine is used and the chlorination is carried out in an inert solvent, for example an ether~ such as dioxane or tetrahydrofurane, a halogenated hydrocarbon, for example methylene chloride, or a carboxylic acid, in particular a lower aliphatic carboxylic acid, such as acetic acid or propionic acid. Instead of using carboxylic acids it is also possib~e to use derivatives thereof, such as acid amides 5 for example dimethyl ormamide, or nitriles, such as lower alkylnit riles, for example acetonitrile. Advantageously~ mixtures of these solvents can also be used, in particular a mixture of an ether, such as dioxane, with one of the above mentioned lower aliphatic carboxylic acids. The process can be carried out with chlorine in an amount substantially in excess of ~he theoretical amount; but preferably the stoichiometric amount of chlorine is used. The chlorination is advantageously carried out at low temperature, approx. between -50 and ~3Q~
for example between -20 and ~10C, and in the dark. The reaction time is normally sev~al hours or days, for example up to 7 days. In a particularly preferred embodiment of the process, the starting steroid is dissolved in one of the solvents mentioned above, for example dioxane, and treated with a solution of the chlorinating agent, for example chlorine, in a lower aliphatic carboxylic acid, for example propionic acid, and this solution is then allowed to stand at the given temperature for several days.
~ 8 -. . - . ~ , - - ~ , , . . ." . .....
~8824 However, the chlorination of the 1,2-double bond can also be effected with mLxtures of two different chlorine-containing compounds one of which yields positive and the other negative chlorine. Examples of suitable reagents which are able to 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 alkali metal chlorides. The above mentioned solvents can also be used for the addition of chlorine wi~h these reagents.
I~ desired, the ll-hydroxyl group can be protected before the chlorination, preferably by esterification with trifluoroacetic acid. The trifluoroacetates are obtai~ed by -reacting the starting materials with trifluoroacetic ch~oride or anhydride in a manner known per se. It is known that this ester can be easily split of again by hydrolysis or solvolysis, for example by treatment with hydroxides, carbonates, bicarbonates or acetates of alkali metals or alkaline earth metals, for example in alcoholic or aqueous-alcoholic solution, for example in methanolic solution, or with alcohols alone. A particular method of carrying out the solvolysis of the ll-trifluoroacetate group is that described in German patent speciication 1~593~519, which is chiefly suitable whenever it is a question of le~ving the ester groups in 17- and/or 21-position intact. This method comprises treating the ll-ester in a lower alcohol with a _ 9 _ ... . ...... ~ - . .. .
~ . . .
:- , . ;
.~-.. .. .
8~3Z~L
~alt of an acid whose pKa-value is in the range between about
2 3 and abo-ut 7.3, such as sodium or po~assium azide or sodium or potassium formiate. If appropriate, this salt can also only be used in catalytic amounts Furthermore, the ~ydrolysis of the ll-trifluoroacetate group can also be effected by treatment wi~h other basic reagents, for example with amines3 in particular heterocyclic bases, such as pyridine or collidine. Finally, the saponification by treatment with silica gel according to the process described in DT-OS
2,144,405 is also possible.
The ll-hydroxyl protective group can be removed immediately after the addition of chlorine to the 1,2-double bond or, if appropriate, simultaneously~with dehydrochlorination -by treatment with a base to be carried out, according to the process, after the chlorination. However, if desired, the protective group can be removed not until after the removal of hydrogen chloride by treatment with a base.
The dehydrochlorinatio~ of the 1,2-dichloro compounds obtained by the addition of chlorine in the 1,2-double bond can advantageously be accomplished with a base. Suitable bases are, for example, tertiary organic nitrogen bases, such as the lower aliphatic amines, for example triethylamine, or heterocyclic bases, such as pyridine and homologues thereof, for example collidine, or aromatic bases, such as N,N-dialkyl-aniline, However, it is also possible to use inorganic bases, : ,, - : - . . : , -. ~ .
- . -. -- ~L0'7~2a~
such as in particular the alkali metal and alka~ine earth metal salts also used for removing the above mentioned ~ hydroxyl protective group, for example potassium or sodium acetate or potassium or sodium bicarbonate, in aque~us-alcoholic solution, and the corresponding hydroxides. The dehydrohalogenation is preferably carried out in the temperature range between approx 20 and 100C and over the course of half an hour up to approx. 30 hours, depending on whether the reaction is carried out at elevated or low temperature. Preferably, an excess of the dehydrohalogenating agent is used.
According to method (b), the elements of hypochlor-ous acid are added in a manner known peri se to the 9,11-double bond of the compounds of the formula (III) by, for example, treatment with aqueous hypochlorous acid or with hypochlorous acid donors, such as N-chlorocarboxamides or N-chlorocarboximides (cf. US patent specification 3,057,886), in the presence of water and/or an inert solven~ such as a tertiary alcohol, for axample butanol, an ether, for example diethyl ether, methyl isopropyl ether, dioxane, or a ketone, such as acetone~ optionally in the presence of a strong acid.
An advantageous method of carrying out this process is the reaction with tert.-butylhypochlorite in an inert water-immiscible solvent, for example a nitro-substituted hydro-carbon, in the presence of perchloric acid (cf. German patent specification 2,011,559).
.
- " ~
:~07~
According to method (c), the 9~ oxido group of the starting compounds of the formula (IV) is treated in a manner known per se with hydrogen chloride and the process can be carried out in aqueous medium or in an inert organic solvent.
According to the process, esterified hydroxyl groups in the 17- and/or 21-position can, if desired, be con-verted into free hydroxyl groups. This conversion can be accomplished in a manner known per se, for example preferably by alkaline saponification with the hydroxides, carbonates or bicarbonates o alkali metals, in particular of sodium or potassium, for example in aqueous or aqueous-alcoholic solution. The use of an aqueous solution of sodium bicarbonate in methanol ~ ethanol is preferred.
The selective saponification of the 21-ester group in 17,21-esters can be ~ffected in-a manner known per se by, ior example, treating these esters with a soLution of a strong acid, such as perchloric acid, in an alcohol, for example methanol, preferably at room temperature, to yield in this way the 17-monoesters. Another method of obtaining 17-mono-esters comprises treating the cyclic 17,21-orthoesters o~
a carboxylic acid with a weak organic acid, for example oxalic acid.
If desired, according to the process of this invention free hydroxyl groups can be esterified in the 17-- .. . .. - , .
. ~ ,,, , ... - ,., , , . :
~L0~18;Z4 andlor 21-position. The esterification is again carried out in a manner known per se, for example by treating the steroid alcohol with a reactive derivative of the acid in question, for example an organic acid, in particular a carboxylic acid.
In particular the chlorides or the anhydrides of these acids are used, preferably in the presence of a tertiary base, such as pyrldine or collidine. If it is desired to esterify both groups in 17,21-dihydroxy compounds, or also the 17a~
hydroxy group in 21-esters~ then acylation is carr~ out with the indicated reactive functional acid derivatives in the presence of a strong acid, in particular an aromatic sulphonic acid, for example p-toluenesulphonic acid, which ac~s as cataiyst~ It is advantageous to protect the ll-hydroxyl group temporarily before these esterification reactions, for example by conversion into the tri~oroacetate, because under the conditions in which the 17-hydroxy group is esteriEied, the ll-hydroxyl group is also easily acylated. As described above, the trifluoroacetoxy group can be selectively reconverted into the free hydroxyl group. It is known that ortho- -esters can be obtained advantageously by reacting a 17,21-steroid-diol with an orthoester of the R'-C(OR")3 type, wherein R' represents a hydrogen atom or an alkyl group, in the presence of a strong acid, for example p-toluenesulphonic acid, in an inert organic solvent, for example an aromatic hydrocarbon, such as benzene or homologues thereof. Chiefly .. .
:..
, . . .
or~hoacetates and orthopropionates are prepared.
The starting materials necessary for carrying out the above process methods are known or they can be obtained in a manner known per se.
The invention also relates to those embodiments of the process in which a compound obtainable in any stage of the process is used as starting material and the missing steps are carried out, or the process is in~errupted at any stage, or in which a starting material is formed under the reaction conditions.
The present invention also provides pharmaceutical preparations which contain as active ingredient a compound according to the invention of the formula (I) or a sa~Lt of such a compound with salt-forming properties, and a process for the manufacture of such pharmaceutical preparations.
Suitable pharmaceuticaL preparations are primarily ones for topical application, such as creams, ointments, pastes, foams, tinctures and solutions, which contain approx.
0.005% to approx. 0.1% of active compound, and also preparations 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 ~7882~
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 wlth 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-Trade-mark); polyoxyethylene fatty alcohol ethers or esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for example sodium lauryl suIphate ! sodium cetyl suIphate or sodium stearyl sulphate, which are customarily used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the water phase include agents which reduce water loss through evaporation, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, as well as preserva-tives, 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-absorp-tion, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax. Emulsi-fiers are corresponding lipophilic substances, such as .
-.
,~ . ;
- ' ' `' .. ~' .
-~L~78824 `sorbitan fatty acid esters (Spans-Trade-mark), ~or 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 anhydrou~ and contain as base in particular hydrocarbons, for example parafin, petroleum jelly and/or llquid paraffins, furthermore natural or par~ially synthetic fa~, for example coconut fatty acid triglycerides, or preferably hardened oils, or 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.
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 dichloro-tetrafluoroethane being used as propellants. For the oleaginous phase there are used, inter alia, hydrocarbons, ,, - ....... ,, ~ . ~, . : . - , ., .: ' : . . ~ . ' 1~7~8Z~
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 emuIsifiers with primarily hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters ~Tweens-Trade-mark), and those with primarily lipophilic properties, such as sorbitan fatty acid esters ~Spans-Trade-mark). In addition, the conven~ional additives are used, such as preservatives etc.
Tinctures and solutions generally have an aqueous ethanolic base to which are added, inter alia, poly-`
alcohols, or example glycerol, glycols, and/or poly-ethylene glycol, as humectants for reducin~ water loss, and fat-restoring substances, such as fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances which are soluble in the aqueous mixture as substitute for fatty substances which are taken from the skin wtth the ethanol, and if necessary, other assistants and additives.
The pharmaceutical preparations for topical applicat-ion 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 processlng the active substance in the form of a suspension, it is mixed with ':-. .
.
-7~
a part of the base before the emulsification and then added to the remainder of the formulation.
Besides the pharmaceutical preparations which can be applied topically, other suitable preparations are those for enteral, ~or example oral, and parenteral adminis~ration to warm-~oded animals and which contain the pharmacologically active substance as sole ingredient or together with a pharma~
ceutica~ly acceptable carrier. These pharmaceutical preparations 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 con~entional mixing, gran~ating, coating, dissolving or l~ophilising methods 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 present invention also relates to the use of the novel compounds of the formula I and of ~he salts of such compounds wlth salt-forming properties, preferably for treating inflammations, chiefly as an~.iinflammatory glucocorticoids for local application, normally in the form of pharmaceutical preparations, especially in the form of pharmaceutical preparations for topical application.
The compounds of the ~sent invention can also be used as additives to animal feeds.
The following Examples describe the invention in more detail. - 18 - ~
- .
, . : ,: , .
78~24 - xample 1 700 ml of tert.-butyl alcohol are poured over 34 57 g of 2-chloro-6~-fluoro-16~-methyl-17~,21-dihydroxy-pregna-1,4,9-triene-3,20-dione-21-acetate in a flask of 2000 ml capacity and, under nitrogen and with stirring, 35 ml of a 10% solu~ion of perchloric acid and finally 10 ml of tert.
butylhypochlor~e are added thereto. The steroid has completely dis~olved after stirring for a urther 2 hours; but after S hours, a crystalline material precipitates again Then 360 ml of water are added, stirring is continued for a time, and ~hen the precipitate is collected by filtration with suction~ The ~ilter cake is washed firstly w~th 200 ml of methanol water (1:1) and then thoroughly with water and dried in vacuo. The concentrated mother liquors are extracted with ethyl acetate and the extract is dried over sodium sulphate. The dry product is dissolved in acetone and tr~ated at elevated temperature with animal charcoal. Toluene is then added ~o the filtered solution and the ace~one is evaporated in vac~o. The precipi-tated crystals are collected with suction,washed with toleuene nnd dried in a vacuum exsiccator. The product is 2,9a-di-chloro~6a-fluoro-16~-methyl~ ,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (2~9~-dichloroparamethasone~
acetate), which melts at 124C. UV absorption spectrum 3~ maxO
249 nm (~ = 12952)o The starting material can be prepared as follows:
~ ~ 8 ~ ~ ~
35 g of 2-chloroparam~thason~21-acetate are dissolv-ed in 70 ml of pyridine and 210 ml of dimethyl formamide. The solution is cooled to -15 to -20 C and treated dropwise with stirring in the course of approx. 15 minutes, at a temperature of -10 to -15C, w;th 22 ml of a soLution prepared from 3 g of sulphur dioxide and 90.4 g of mesyl chloride (me~hanesulphonyl chloride). The mixture is stirred for a further 20 minutes a~ the same temperature and then water is added dropwise with caution (especially a~ the start), while the temperature is kept at 0 to -5C The mixture is then poured into 1500 ml o~ water and stirred for 30 minu~es.
After this time, the precipitate which has formed is collected with suction and washed with water. The filter cake is then dissolved in 700 ml of boiling methanol and, at boiling temperature, 210 ml of water are added5 whereupon a thick crystalline precipitate falls out o~ the solution. Ater cooling to 0C~ the precipitated crystals are collected with suction, washed with methanol/water (1:1) and dried in an exsiccator. The product is 2-chloro-6a-fluoro-16a-methyl-17a,21-dihydroxy-pregna-1,4,9-triene-3,20-dione 21-acetate, which melts at 130-148C .
Example 2 10 g of 2a9a-dichloro-paramethasone-21-acetate (2,9a-dichloro-6a-fluoro-16a-methyl-11~,17a-21-trihydroxy--". : ' : , . .;
;
~ll078824 pregnadiene-3,20-dione-21-acetate) are dissolved in 250 ml of me~anol and the solution is cooled to 0 C under nitrogen. To this solution is added dropwise at 0C and in the course of 15 minutes a solution prepared from 5 g of potassium carbonate, 70 ml of water and 70 ml of methanol and which has been freed from oxygen by introducing nitrogen. The mixture is then stirred for 45 minutes at 0 C. The solution is then adjusted with 10 ml oE 50% acetic acid to a slighly acid reaction.
The methanol is evaporated completelv in vacuo and the resultant suspension is filtered with suction. The filter cake is washed with water and then sharply filtered with suction.
The residue is dissolved in acetone and the solution is con centrated in vacuo and the res~ue dried to constant weight.
Crystallisation from acetone-toluene yields pure 2,~u-dichloro~
paramethasone, which melts at 240-250C ~with decomposition).
Example 3 With stirring, 2 g of 2j9a-dichloroparamethasone are d~olved in 10 ml of pyridine and the solution is treated with a solution obtained by mixing 4 ml of trimethylace~l-chloride and 10 ml of pyridine at 0C. The mixture is then allowed to stand for 1 hour at 20C. After addition of ice, the mixture is extracted with ethyl acetate and the extract is washed with 2N hydrochloric acid and then with water, dried and concentrated. The res~ue is filtered through a column of 30 g of aluminium oxide of activity II and the residue obtained : .
2 ~
from the filtrate is recrystallised ~rom methanol/water to yield 2~9a-dich~roparamethaso~21-pivalate (trime~hylacetate), which melts at 261 -262 C with decomposition.
Example 4 11,92 g of 2,9~-dichloroparamethasone ~e dissolved in 50 ml of tetrahydro~urane and the solution is treated at 20C with L2 ml of triethyl orthopropionate and 500 mg o p-toluenesulphonic acid and allowed to stand for 1 hour a~
20C. Then 4 ml of pyridine are added, the batch is slightly concentrated in vacuo and the reaction product is taken up in ethyl acetate. The ethyL acetate extract is washed 5 times w~h water, dried and concentrated. The re~due is then dissol~ed in approx. 150 ml of methylene chloride, freshly distilled isopropyl ether is added and the mixture is concentrated to some extent by heating. As the batdh cools, the ethyl-17~,21-ortho propionate of 2,9~-dichloroparame~hasoneprecipitates, is collected with suction, washed with isopropyl ether, and dried. Melting point: 223-237 C (with decomposition).
' Example 5 A solution of 1.5 g of 2,9~-dichloroparamethasone-17-propionate in 10 ml of pyridine is treated at 0C with 5 ml of propionic anhydride and the mixture is allowed to stand for 1 hour at 0C. After this time ice is added and the mixture is again allowed to stand for 1 hour and then extracted with .. .. . ~ . ~ . . . -- : -37~8~4 ethyl acetate. The extract is washed with 2N hydrochloric acid, water, potassium hydro~en carbonate and water, dried and concentrated.
The residue is crystallised from methanol to yield 2,9a-dichloroparamethasone-17~21-dipropionate, which is still further purified as follows:
The obtained amount of ester is chromatographed through a column of 50 g of silica gel wi~h methylene chloride as eluant, Fractions 4-13 are combined and recrys~allised from acetone-methanol~ The purified ester melts at 135 C.
The starting material can be prepared as follows:
A solution of 5 g of 2,9~-dichloro paramethason~l7,21-ethyl-ortho-propionate in 220 ml oE methanol and a solution of 1.4 g of oxalic acid (dihydrate) in 12 ml of water are stirred at 50C and after 5 minutes a clear solution results. After 1 hour water is added~ and the mixture is concentrated in vacuo and extracted with 500 ml of ethyl acetate. The extract is washed twice with 100 ml of 2N potassium hydrogen carbonate and three times with water, dried and concentr~ted. T~le residue is dissolved in acetone and ~oluene is added ~o the solution.
The mixture is heated, so that the acetone distiLls of, then cooled to yield 2,9a-dichloroparamethason~17-propionate, which melts at 239-248C (with decomposition).
~, .:
~, , . : .. . ..
78~324 Example 6 A solution, cooled to 0 C, of 1 g of 2,9~-dichloro-6a-fluoro-16a-methyl-11~,17a,21-trihydroxy-pregna-1,4-diene-
2,144,405 is also possible.
The ll-hydroxyl protective group can be removed immediately after the addition of chlorine to the 1,2-double bond or, if appropriate, simultaneously~with dehydrochlorination -by treatment with a base to be carried out, according to the process, after the chlorination. However, if desired, the protective group can be removed not until after the removal of hydrogen chloride by treatment with a base.
The dehydrochlorinatio~ of the 1,2-dichloro compounds obtained by the addition of chlorine in the 1,2-double bond can advantageously be accomplished with a base. Suitable bases are, for example, tertiary organic nitrogen bases, such as the lower aliphatic amines, for example triethylamine, or heterocyclic bases, such as pyridine and homologues thereof, for example collidine, or aromatic bases, such as N,N-dialkyl-aniline, However, it is also possible to use inorganic bases, : ,, - : - . . : , -. ~ .
- . -. -- ~L0'7~2a~
such as in particular the alkali metal and alka~ine earth metal salts also used for removing the above mentioned ~ hydroxyl protective group, for example potassium or sodium acetate or potassium or sodium bicarbonate, in aque~us-alcoholic solution, and the corresponding hydroxides. The dehydrohalogenation is preferably carried out in the temperature range between approx 20 and 100C and over the course of half an hour up to approx. 30 hours, depending on whether the reaction is carried out at elevated or low temperature. Preferably, an excess of the dehydrohalogenating agent is used.
According to method (b), the elements of hypochlor-ous acid are added in a manner known peri se to the 9,11-double bond of the compounds of the formula (III) by, for example, treatment with aqueous hypochlorous acid or with hypochlorous acid donors, such as N-chlorocarboxamides or N-chlorocarboximides (cf. US patent specification 3,057,886), in the presence of water and/or an inert solven~ such as a tertiary alcohol, for axample butanol, an ether, for example diethyl ether, methyl isopropyl ether, dioxane, or a ketone, such as acetone~ optionally in the presence of a strong acid.
An advantageous method of carrying out this process is the reaction with tert.-butylhypochlorite in an inert water-immiscible solvent, for example a nitro-substituted hydro-carbon, in the presence of perchloric acid (cf. German patent specification 2,011,559).
.
- " ~
:~07~
According to method (c), the 9~ oxido group of the starting compounds of the formula (IV) is treated in a manner known per se with hydrogen chloride and the process can be carried out in aqueous medium or in an inert organic solvent.
According to the process, esterified hydroxyl groups in the 17- and/or 21-position can, if desired, be con-verted into free hydroxyl groups. This conversion can be accomplished in a manner known per se, for example preferably by alkaline saponification with the hydroxides, carbonates or bicarbonates o alkali metals, in particular of sodium or potassium, for example in aqueous or aqueous-alcoholic solution. The use of an aqueous solution of sodium bicarbonate in methanol ~ ethanol is preferred.
The selective saponification of the 21-ester group in 17,21-esters can be ~ffected in-a manner known per se by, ior example, treating these esters with a soLution of a strong acid, such as perchloric acid, in an alcohol, for example methanol, preferably at room temperature, to yield in this way the 17-monoesters. Another method of obtaining 17-mono-esters comprises treating the cyclic 17,21-orthoesters o~
a carboxylic acid with a weak organic acid, for example oxalic acid.
If desired, according to the process of this invention free hydroxyl groups can be esterified in the 17-- .. . .. - , .
. ~ ,,, , ... - ,., , , . :
~L0~18;Z4 andlor 21-position. The esterification is again carried out in a manner known per se, for example by treating the steroid alcohol with a reactive derivative of the acid in question, for example an organic acid, in particular a carboxylic acid.
In particular the chlorides or the anhydrides of these acids are used, preferably in the presence of a tertiary base, such as pyrldine or collidine. If it is desired to esterify both groups in 17,21-dihydroxy compounds, or also the 17a~
hydroxy group in 21-esters~ then acylation is carr~ out with the indicated reactive functional acid derivatives in the presence of a strong acid, in particular an aromatic sulphonic acid, for example p-toluenesulphonic acid, which ac~s as cataiyst~ It is advantageous to protect the ll-hydroxyl group temporarily before these esterification reactions, for example by conversion into the tri~oroacetate, because under the conditions in which the 17-hydroxy group is esteriEied, the ll-hydroxyl group is also easily acylated. As described above, the trifluoroacetoxy group can be selectively reconverted into the free hydroxyl group. It is known that ortho- -esters can be obtained advantageously by reacting a 17,21-steroid-diol with an orthoester of the R'-C(OR")3 type, wherein R' represents a hydrogen atom or an alkyl group, in the presence of a strong acid, for example p-toluenesulphonic acid, in an inert organic solvent, for example an aromatic hydrocarbon, such as benzene or homologues thereof. Chiefly .. .
:..
, . . .
or~hoacetates and orthopropionates are prepared.
The starting materials necessary for carrying out the above process methods are known or they can be obtained in a manner known per se.
The invention also relates to those embodiments of the process in which a compound obtainable in any stage of the process is used as starting material and the missing steps are carried out, or the process is in~errupted at any stage, or in which a starting material is formed under the reaction conditions.
The present invention also provides pharmaceutical preparations which contain as active ingredient a compound according to the invention of the formula (I) or a sa~Lt of such a compound with salt-forming properties, and a process for the manufacture of such pharmaceutical preparations.
Suitable pharmaceuticaL preparations are primarily ones for topical application, such as creams, ointments, pastes, foams, tinctures and solutions, which contain approx.
0.005% to approx. 0.1% of active compound, and also preparations 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 ~7882~
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 wlth 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-Trade-mark); polyoxyethylene fatty alcohol ethers or esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for example sodium lauryl suIphate ! sodium cetyl suIphate or sodium stearyl sulphate, which are customarily used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the water phase include agents which reduce water loss through evaporation, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, as well as preserva-tives, 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-absorp-tion, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax. Emulsi-fiers are corresponding lipophilic substances, such as .
-.
,~ . ;
- ' ' `' .. ~' .
-~L~78824 `sorbitan fatty acid esters (Spans-Trade-mark), ~or 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 anhydrou~ and contain as base in particular hydrocarbons, for example parafin, petroleum jelly and/or llquid paraffins, furthermore natural or par~ially synthetic fa~, for example coconut fatty acid triglycerides, or preferably hardened oils, or 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.
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 dichloro-tetrafluoroethane being used as propellants. For the oleaginous phase there are used, inter alia, hydrocarbons, ,, - ....... ,, ~ . ~, . : . - , ., .: ' : . . ~ . ' 1~7~8Z~
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 emuIsifiers with primarily hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters ~Tweens-Trade-mark), and those with primarily lipophilic properties, such as sorbitan fatty acid esters ~Spans-Trade-mark). In addition, the conven~ional additives are used, such as preservatives etc.
Tinctures and solutions generally have an aqueous ethanolic base to which are added, inter alia, poly-`
alcohols, or example glycerol, glycols, and/or poly-ethylene glycol, as humectants for reducin~ water loss, and fat-restoring substances, such as fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances which are soluble in the aqueous mixture as substitute for fatty substances which are taken from the skin wtth the ethanol, and if necessary, other assistants and additives.
The pharmaceutical preparations for topical applicat-ion 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 processlng the active substance in the form of a suspension, it is mixed with ':-. .
.
-7~
a part of the base before the emulsification and then added to the remainder of the formulation.
Besides the pharmaceutical preparations which can be applied topically, other suitable preparations are those for enteral, ~or example oral, and parenteral adminis~ration to warm-~oded animals and which contain the pharmacologically active substance as sole ingredient or together with a pharma~
ceutica~ly acceptable carrier. These pharmaceutical preparations 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 con~entional mixing, gran~ating, coating, dissolving or l~ophilising methods 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 present invention also relates to the use of the novel compounds of the formula I and of ~he salts of such compounds wlth salt-forming properties, preferably for treating inflammations, chiefly as an~.iinflammatory glucocorticoids for local application, normally in the form of pharmaceutical preparations, especially in the form of pharmaceutical preparations for topical application.
The compounds of the ~sent invention can also be used as additives to animal feeds.
The following Examples describe the invention in more detail. - 18 - ~
- .
, . : ,: , .
78~24 - xample 1 700 ml of tert.-butyl alcohol are poured over 34 57 g of 2-chloro-6~-fluoro-16~-methyl-17~,21-dihydroxy-pregna-1,4,9-triene-3,20-dione-21-acetate in a flask of 2000 ml capacity and, under nitrogen and with stirring, 35 ml of a 10% solu~ion of perchloric acid and finally 10 ml of tert.
butylhypochlor~e are added thereto. The steroid has completely dis~olved after stirring for a urther 2 hours; but after S hours, a crystalline material precipitates again Then 360 ml of water are added, stirring is continued for a time, and ~hen the precipitate is collected by filtration with suction~ The ~ilter cake is washed firstly w~th 200 ml of methanol water (1:1) and then thoroughly with water and dried in vacuo. The concentrated mother liquors are extracted with ethyl acetate and the extract is dried over sodium sulphate. The dry product is dissolved in acetone and tr~ated at elevated temperature with animal charcoal. Toluene is then added ~o the filtered solution and the ace~one is evaporated in vac~o. The precipi-tated crystals are collected with suction,washed with toleuene nnd dried in a vacuum exsiccator. The product is 2,9a-di-chloro~6a-fluoro-16~-methyl~ ,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (2~9~-dichloroparamethasone~
acetate), which melts at 124C. UV absorption spectrum 3~ maxO
249 nm (~ = 12952)o The starting material can be prepared as follows:
~ ~ 8 ~ ~ ~
35 g of 2-chloroparam~thason~21-acetate are dissolv-ed in 70 ml of pyridine and 210 ml of dimethyl formamide. The solution is cooled to -15 to -20 C and treated dropwise with stirring in the course of approx. 15 minutes, at a temperature of -10 to -15C, w;th 22 ml of a soLution prepared from 3 g of sulphur dioxide and 90.4 g of mesyl chloride (me~hanesulphonyl chloride). The mixture is stirred for a further 20 minutes a~ the same temperature and then water is added dropwise with caution (especially a~ the start), while the temperature is kept at 0 to -5C The mixture is then poured into 1500 ml o~ water and stirred for 30 minu~es.
After this time, the precipitate which has formed is collected with suction and washed with water. The filter cake is then dissolved in 700 ml of boiling methanol and, at boiling temperature, 210 ml of water are added5 whereupon a thick crystalline precipitate falls out o~ the solution. Ater cooling to 0C~ the precipitated crystals are collected with suction, washed with methanol/water (1:1) and dried in an exsiccator. The product is 2-chloro-6a-fluoro-16a-methyl-17a,21-dihydroxy-pregna-1,4,9-triene-3,20-dione 21-acetate, which melts at 130-148C .
Example 2 10 g of 2a9a-dichloro-paramethasone-21-acetate (2,9a-dichloro-6a-fluoro-16a-methyl-11~,17a-21-trihydroxy--". : ' : , . .;
;
~ll078824 pregnadiene-3,20-dione-21-acetate) are dissolved in 250 ml of me~anol and the solution is cooled to 0 C under nitrogen. To this solution is added dropwise at 0C and in the course of 15 minutes a solution prepared from 5 g of potassium carbonate, 70 ml of water and 70 ml of methanol and which has been freed from oxygen by introducing nitrogen. The mixture is then stirred for 45 minutes at 0 C. The solution is then adjusted with 10 ml oE 50% acetic acid to a slighly acid reaction.
The methanol is evaporated completelv in vacuo and the resultant suspension is filtered with suction. The filter cake is washed with water and then sharply filtered with suction.
The residue is dissolved in acetone and the solution is con centrated in vacuo and the res~ue dried to constant weight.
Crystallisation from acetone-toluene yields pure 2,~u-dichloro~
paramethasone, which melts at 240-250C ~with decomposition).
Example 3 With stirring, 2 g of 2j9a-dichloroparamethasone are d~olved in 10 ml of pyridine and the solution is treated with a solution obtained by mixing 4 ml of trimethylace~l-chloride and 10 ml of pyridine at 0C. The mixture is then allowed to stand for 1 hour at 20C. After addition of ice, the mixture is extracted with ethyl acetate and the extract is washed with 2N hydrochloric acid and then with water, dried and concentrated. The res~ue is filtered through a column of 30 g of aluminium oxide of activity II and the residue obtained : .
2 ~
from the filtrate is recrystallised ~rom methanol/water to yield 2~9a-dich~roparamethaso~21-pivalate (trime~hylacetate), which melts at 261 -262 C with decomposition.
Example 4 11,92 g of 2,9~-dichloroparamethasone ~e dissolved in 50 ml of tetrahydro~urane and the solution is treated at 20C with L2 ml of triethyl orthopropionate and 500 mg o p-toluenesulphonic acid and allowed to stand for 1 hour a~
20C. Then 4 ml of pyridine are added, the batch is slightly concentrated in vacuo and the reaction product is taken up in ethyl acetate. The ethyL acetate extract is washed 5 times w~h water, dried and concentrated. The re~due is then dissol~ed in approx. 150 ml of methylene chloride, freshly distilled isopropyl ether is added and the mixture is concentrated to some extent by heating. As the batdh cools, the ethyl-17~,21-ortho propionate of 2,9~-dichloroparame~hasoneprecipitates, is collected with suction, washed with isopropyl ether, and dried. Melting point: 223-237 C (with decomposition).
' Example 5 A solution of 1.5 g of 2,9~-dichloroparamethasone-17-propionate in 10 ml of pyridine is treated at 0C with 5 ml of propionic anhydride and the mixture is allowed to stand for 1 hour at 0C. After this time ice is added and the mixture is again allowed to stand for 1 hour and then extracted with .. .. . ~ . ~ . . . -- : -37~8~4 ethyl acetate. The extract is washed with 2N hydrochloric acid, water, potassium hydro~en carbonate and water, dried and concentrated.
The residue is crystallised from methanol to yield 2,9a-dichloroparamethasone-17~21-dipropionate, which is still further purified as follows:
The obtained amount of ester is chromatographed through a column of 50 g of silica gel wi~h methylene chloride as eluant, Fractions 4-13 are combined and recrys~allised from acetone-methanol~ The purified ester melts at 135 C.
The starting material can be prepared as follows:
A solution of 5 g of 2,9~-dichloro paramethason~l7,21-ethyl-ortho-propionate in 220 ml oE methanol and a solution of 1.4 g of oxalic acid (dihydrate) in 12 ml of water are stirred at 50C and after 5 minutes a clear solution results. After 1 hour water is added~ and the mixture is concentrated in vacuo and extracted with 500 ml of ethyl acetate. The extract is washed twice with 100 ml of 2N potassium hydrogen carbonate and three times with water, dried and concentr~ted. T~le residue is dissolved in acetone and ~oluene is added ~o the solution.
The mixture is heated, so that the acetone distiLls of, then cooled to yield 2,9a-dichloroparamethason~17-propionate, which melts at 239-248C (with decomposition).
~, .:
~, , . : .. . ..
78~324 Example 6 A solution, cooled to 0 C, of 1 g of 2,9~-dichloro-6a-fluoro-16a-methyl-11~,17a,21-trihydroxy-pregna-1,4-diene-
3,20-dione in 5 ml of pyridine is treated with 2 ml of valeric anhydride and the reaction mixture is allowed to .
stand for 2 hours at 0C. After addition of ice, the mixture is s~ood for 15 minutes at 20 C and extracted with ethyl ace~ate. The combined ethyl acetate extracts are washed with 2N hydrochloric acid and water, dried, and filtered through a column of 30 g of aluminium oxide of activit~ II and washed.
The residue of the evapora~d filtrate is recrystallised from acetone-isopropyl ether to yield the 21-valerate of 2,9a-dichloro-6a-fluoro-16OE-methyl~ ,17a,21-trihydroxy-p~egna-1,4-diene-3,20-dione (2,9a-dichloroparamethasone~21-vale~ate), which melts at 188-191C.
... ~.: ....... . . . . . .. ... .. .
..
.. . . . . .
stand for 2 hours at 0C. After addition of ice, the mixture is s~ood for 15 minutes at 20 C and extracted with ethyl ace~ate. The combined ethyl acetate extracts are washed with 2N hydrochloric acid and water, dried, and filtered through a column of 30 g of aluminium oxide of activit~ II and washed.
The residue of the evapora~d filtrate is recrystallised from acetone-isopropyl ether to yield the 21-valerate of 2,9a-dichloro-6a-fluoro-16OE-methyl~ ,17a,21-trihydroxy-p~egna-1,4-diene-3,20-dione (2,9a-dichloroparamethasone~21-vale~ate), which melts at 188-191C.
... ~.: ....... . . . . . .. ... .. .
..
.. . . . . .
Claims (50)
1. A process for the manufacture of 2,9.alpha.-dichloro-6.alpha.
fluoro-16.alpha.-methyl-11.beta.,17,21-trihydroxy-pregna-1,4-diene-3,30-dione compounds of the formula (I) wherein each of R1 and R2 represents a free or esterified hydroxyl group, whilst R1 and R2 together can also repre-sent a cyclic 17,21-diester group which process comprises (a) the addition of chlorine to the 1,2-double bond in a compound of the formula (II) wherein R1 and R2 are as defined in formula (I), whilst optionally protecting the 11-hydroxyl group temporarily beforehand, and the dehydrochlorination of the resultant 1,2-dichloro compound, or (b) treating a compound of the general formula (III) wherein R1 and R2 are as defined in formula (I), with hypochlorous acid or with a hypochlorous acid donor, or (c) treating a compound of the general formula (IV) wherein R1 and R2 are as defined in formula (I), with hydrogen chloride or a hydrogen chloride donor, and/or, if desired, in compounds of the formula (I), in which at least one of the groups R1 and R2 is esterified, converting at least one esterified hydroxyl group into a free hydroxyl group, or in compounds of the formula (I), in which at least one of the groups R1 and R2 represents a free hydroxyl group, whilst optionally protecting the 11-hydroxyl group temporarily, esterifying at least one free hydroxyl group, and/or, if desired, converting hemi-esters of dicarboxylic acids or of polybasic inorganic acids into their metal salts or salts of organic bases.
fluoro-16.alpha.-methyl-11.beta.,17,21-trihydroxy-pregna-1,4-diene-3,30-dione compounds of the formula (I) wherein each of R1 and R2 represents a free or esterified hydroxyl group, whilst R1 and R2 together can also repre-sent a cyclic 17,21-diester group which process comprises (a) the addition of chlorine to the 1,2-double bond in a compound of the formula (II) wherein R1 and R2 are as defined in formula (I), whilst optionally protecting the 11-hydroxyl group temporarily beforehand, and the dehydrochlorination of the resultant 1,2-dichloro compound, or (b) treating a compound of the general formula (III) wherein R1 and R2 are as defined in formula (I), with hypochlorous acid or with a hypochlorous acid donor, or (c) treating a compound of the general formula (IV) wherein R1 and R2 are as defined in formula (I), with hydrogen chloride or a hydrogen chloride donor, and/or, if desired, in compounds of the formula (I), in which at least one of the groups R1 and R2 is esterified, converting at least one esterified hydroxyl group into a free hydroxyl group, or in compounds of the formula (I), in which at least one of the groups R1 and R2 represents a free hydroxyl group, whilst optionally protecting the 11-hydroxyl group temporarily, esterifying at least one free hydroxyl group, and/or, if desired, converting hemi-esters of dicarboxylic acids or of polybasic inorganic acids into their metal salts or salts of organic bases.
2. A process according to claim 1(a), wherein the star-ting material is treated in an inert organic solvent with elementary chlorine.
3. A process according to claim 2, wherein a lower ali-phatic or cyclic ether, a lower aliphatic halogenated hydrocarbon or a lower aliphatic carboxylic acid, or a mixture thereof, is used as inert organic solvent.
4. A process according to claim 3, wherein a solution of the starting material in dioxane is treated with a solu-tion of chlorine in propionic acid.
5. A process according to claim 2, wherein the reaction is carried out at low temperature and in the dark.
6. A process according to claim 1(a), wherein the star-ting material is treated with a mixture of two compounds one of which yields negative chlorine and the other positive chlorine.
7. A process according to claim 6, wherein a chlorinated carboxamide or carboximide is used in the presence of hydro-gen chloride or an alkali metal chloride.
8. A process according to claim 7, wherein the reaction is car-ried out in a lower aliphatic or cyclic ether, a lower aliphatic halogenated hydrocarbon or a lower aliphatic carboxylic aicd, or a mixture thereof.
9. A process according to claim 1a), wherein the 11.beta.-hydroxy group is protected by esterification with tri-fluoroacetic acid before the addition of chlorine to the 1,2-double bond.
10. A process according to claim 4, wherein the 11.beta.-hydro-xy group is protected by esterification with trifluoro-acetic acid before the addition of chlorine to the 1,2-double bond.
11. A process according to claim 1a), wherein hydrogen chloride is split off by treatment with a base from the 1,2-dichlorosteroids obtained by the addition of chlorine.
12. A process according to claim 11, wherein a 11.beta.-tri-fluoroacetoxy group formed before the addition of chlorine is reconverted by hydrolysis or solvolysis into the 11-hydroxyl group before, or simultaneously with the dehydro-chlorination.
13. A process according to claim 12, wherein the hydro-lysis is carried out with hydroxides, carbonates, bicar-bonates or acetates of alkali metals or alkaline earth metals in aqueous, alcoholic or aqueous-alcoholic solu-tion.
14. A process according to claim 11 wherein the starting material has been obtained by the addition of elementary chlorine in the dark at low temperature in a solvent selected from the group consisting of a lower aliphatic or cyclic ether, a lower aliphatic halogenated hydrocar-bon or a lower aliphatic carboxylic acid or a mixture thereof.
15. A process according to claim 11, wherein the starting material has been obtained by the addition of elementary chlorine in the dark at low temperature in dioxane, and chlorine is used as a solution in propionic acid.
16. A process according to claim 14, wherein the starting material is treated with a tertiary organic base.
17. A process according to claim 15, wherein the starting material is treated with an organic base.
18. A process according to claim 14, wherein the starting material is treated with pyridine or a homolog thereof or with an N, N-di - alkylaniline.
19. A process according to claim 15, wherein the starting material is treated with pyridine or a homolog thereof or with an N, N - dialkylaniline.
20. A process according to claim 14, wherein the starting material is treated with hydroxides, carbonates, bicarbo-nates or acetates of alkali metals or alkaline earth metals as bases.
21. A process according to claim 15, wherein the starting material is treated with hydroxides, carbonates, bicarbo-nates or acetates of alkali metals of alkaline earth metals as bases.
22. A process according to claim 1(b), wherein the star-ting materials are treated with N-chlorocarboxamides or N-chlorocarboximides in the presence of water and/or an inert solvent, optionally in the presence of a strong acid.
23. A process according to claim 1(b), wherein the star-ting materials are treated with tert.-butylhypochlorite in an inert solvent in the presence of perchloric acid.
24. A process according to claim 22, wherein water, a tertiary alcohol, an ether or a ketone is used as inert solvent.
25. A process according to claim 23, wherein a water im-miscible solvent is used as the inert solvent.
26. A process according to claim 22, wherein a nitro -substituted hydrocarbon is used as an inert solvent.
27. A process according to claim 23, wherein a lower aliphatic alcohol used as the inert solvent.
28. A process according to claim 1(c), wherein the star-ting materials are treated with hydrogen chloride in aqueous medium or in an organic solvent.
29. A process according to claim 1, wherein any esterified hydroxyl group in the 17 - position and/or 21 - position is hydrolysed with a metal carbonate or alkali metal bicarbo-nate in aqueous or aqueous - alcoholic solution to give the 2, 9.alpha. - dichloroparamethasone.
30. A process according to claim 1, wherein a 17, 21-diester or a cyclic 17, 21-orthoester is hydrolysed with a strong acid, or with a weak acid, to give a 17-monoester of the 2,9.alpha.-dichloroparamethasone.
31. A process according to claim 1, wherein the esterification of resultant compounds with at least one free hydroxyl group in the 17- and 21-position is carried out by treating said compounds with a reactive functional derivative of an acid.
32. A process according to claim 31, wherein the 11-hydro-xyl group is intermediately protected before the esteri-fication by converting it into the trifluoroacetoxy group.
33. Process as claimed in claim 1, wherein starting com-pounds are used wherein each of R1 and R2 represent hydro-gen.
34. Process as claimed in claim 1, wherein starting com-pounds are used wherein at least one of R1 and R2 repre-sents a hydroxyl group esterified with a lower aliphatic carboxylic acid having from 1 to 7 C atoms or R1 and R2 together represent a 17,21-orthoester group derived from a lower aliphatic ortho carboxylic acid having from 1 to 7 C atoms or from carbonic acid.
35. Process as claimed in claim 1, wherein any 2-chloro compound of formula (I) obtained which has one free hydro-xyl group R1, and R2 can be a free hydroxyl group or a hydroxyl group esterified with a lower aliphatic carboxylic acid having from 1 to 7 C atoms, is treated with a reactive acid derivative of a lower aliphatic carboxylic acid having from 1 to 7 C atoms, in the presence of a tertiary base, so as to give a corresponding 21 - ester, or a 2-chloro com-pound of formula (I) in which both R1 and R2 are free hydroxy groups, is treated with a lower aliphatic triester of a lower aliphatic ortho carboxylic acid having from 1 to 7 C atoms in the presence of a strong acid, or a 2-chloro compound of formula (I) in which R2 is a free hydroxyl group and R1 can be either a free hydroxyl group or a hydroxyl group esterified with a lower aliphatic car-boxylic acid having from 1 to 7 C atoms, is treated with a reactive acid derivative of a lower aliphatic acid having from 1 to 7 C atoms in the presence of a strong acid, optionally after having protected intermediately the 11 - hydroxyl group by esterification with trifluoroacetic acid.
36. Process as claimed in claim 35 wherein there are used acid chlorides or acid anhydrides as the reactive acid derivatives and p-toluene - sulphonic acid as the strong acid mentioned.
37. Process as claimed in claim 34, wherein a starting compound is used so as to produce the 2, 9.alpha.-dichloro-paramethasone 21- acetate.
38. Process as claimed in claim 34, wherein a starting compound is used so as to produce the 2, 9.alpha.-dichloro-paramethasone 21-pivalate.
39. Process as claimed in claim 35, wherein a starting compound is used so as to produce the 17, 21 - ethyl-ortho-propionate of 2, 9.alpha.-dichloroparamethasone.
40. Process as claimed in claim 35, wherein a starting compound is used so as to produce the 17.alpha.-monopropionate of 2, 9.alpha.-dichloroparamethasone.
41. Process as claimed in claim 35, wherein a starting compound is used so as to produce the 17.alpha., 21 - dipro-pionate of the 2, 9.alpha.-dichloroparamethasone.
42. Process as claimed in claim 34, wherein a starting compound is used so as to produce the 21-valerate of 2, 9.alpha.-dichloroparamethasone.
43. A compound of the formula (I) wherein each of R1 and R2 represents a free or esterified hydroxyl group, whilst R1 and R2 together can represent a cyclic 17,21-diester group and metal salts or salts of organic bases of hemiesters of dicarboxylic acids or of polybasic inorganic acids of these compounds, whenever pre-pared or produced according to the process as claimed in any one of claims 1, 34 or 35, or an obvious chemical equivalent thereof.
44. The 2, 9.alpha.dichloroparamethasone, whenever prepared or produced by a process as claimed in either of claims 29 or 33, or an obvious chemical equivalent thereof.
45. The 2, 9.alpha.-dichloroparamethasone 21 - acetate, whenever prepared or produced by a process as claimed in claim 37 or an obvious chemical equivalent thereof.
46. The 2, 9.alpha.-dichloroparamethasone 21 - pivalate, when-ever prepared or produced by the process as claimed in claim 38 or an obvious chemical equivalent thereof.
47. The 2, 9.alpha.dichloroparamethasone 21 - valerate, whenever prepared or produced by the process as claimed in claim 42 or by an obvious chemical equivalent thereof.
48. The 17, 21 -ethyl-ortho propionate of 2, 9.alpha.-dichloro-paramethasone, whenever prepared or produced by the pro-cess as claimed in claim 39 or an obvious chemical equivalent thereof.
49. The 17.alpha.-monopropionate of 2, 9.alpha.-dichloroparamethasone, whenever prepared or produced by the process as claimed in claim 40 or an obvious chemical equivalent thereof.
50. The 17.alpha., 21-dipropionate of 2, 9.alpha.-dichloroparametha-sone, whenever prepared or produced by the process as claimed in claim 41 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1615075A CH626632A5 (en) | 1975-12-12 | 1975-12-12 | Process for the preparation of halopregnadienes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1078824A true CA1078824A (en) | 1980-06-03 |
Family
ID=4414834
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA267,597A Expired CA1078824A (en) | 1975-12-12 | 1976-12-10 | Halogenopregnadienes and process for the manufacture thereof |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS5273852A (en) |
| AT (1) | AT353432B (en) |
| AU (1) | AU510864B2 (en) |
| BE (1) | BE849267A (en) |
| CA (1) | CA1078824A (en) |
| CH (2) | CH626632A5 (en) |
| DD (1) | DD128682A5 (en) |
| DE (1) | DE2655802A1 (en) |
| DK (1) | DK142326B (en) |
| ES (2) | ES454119A1 (en) |
| FR (1) | FR2358152A1 (en) |
| GB (1) | GB1563595A (en) |
| HU (1) | HU176936B (en) |
| IE (1) | IE44512B1 (en) |
| IL (1) | IL51085A (en) |
| NL (1) | NL7613711A (en) |
| NZ (1) | NZ182865A (en) |
| SE (1) | SE7613919L (en) |
| ZA (1) | ZA767381B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT78973A (en) * | 1984-07-25 | 1984-08-01 | Joao Emerico Villax | New preparation process of the 9alpha-fluoro 17,21-acylates or hidroxilades in 17 and 21 chloro-corticosteroid |
-
1975
- 1975-12-12 CH CH1615075A patent/CH626632A5/en not_active IP Right Cessation
-
1976
- 1976-12-09 DE DE19762655802 patent/DE2655802A1/en not_active Withdrawn
- 1976-12-09 FR FR7637093A patent/FR2358152A1/en active Granted
- 1976-12-09 NL NL7613711A patent/NL7613711A/en not_active Application Discontinuation
- 1976-12-10 AT AT914176A patent/AT353432B/en not_active IP Right Cessation
- 1976-12-10 ZA ZA767381A patent/ZA767381B/en unknown
- 1976-12-10 SE SE7613919A patent/SE7613919L/en unknown
- 1976-12-10 AU AU20471/76A patent/AU510864B2/en not_active Expired
- 1976-12-10 IE IE2699/76A patent/IE44512B1/en unknown
- 1976-12-10 CA CA267,597A patent/CA1078824A/en not_active Expired
- 1976-12-10 ES ES454119A patent/ES454119A1/en not_active Expired
- 1976-12-10 GB GB51695/76A patent/GB1563595A/en not_active Expired
- 1976-12-10 NZ NZ182865A patent/NZ182865A/en unknown
- 1976-12-10 DD DD7600196260A patent/DD128682A5/en unknown
- 1976-12-10 DK DK557576AA patent/DK142326B/en unknown
- 1976-12-10 HU HU76CI1703A patent/HU176936B/en unknown
- 1976-12-10 BE BE173137A patent/BE849267A/en unknown
- 1976-12-10 IL IL51085A patent/IL51085A/en unknown
- 1976-12-11 JP JP51149325A patent/JPS5273852A/en active Pending
-
1977
- 1977-12-29 ES ES465551A patent/ES465551A1/en not_active Expired
-
1980
- 1980-10-27 CH CH799480A patent/CH626094A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DE2655802A1 (en) | 1977-06-16 |
| DK142326B (en) | 1980-10-13 |
| IE44512L (en) | 1977-06-12 |
| ZA767381B (en) | 1977-11-30 |
| NL7613711A (en) | 1977-06-14 |
| IL51085A0 (en) | 1977-02-28 |
| ATA914176A (en) | 1979-04-15 |
| AT353432B (en) | 1979-11-12 |
| DD128682A5 (en) | 1977-12-07 |
| IL51085A (en) | 1980-09-16 |
| HU176936B (en) | 1981-06-28 |
| JPS5273852A (en) | 1977-06-21 |
| DK557576A (en) | 1977-06-13 |
| SE7613919L (en) | 1977-06-13 |
| BE849267A (en) | 1977-06-10 |
| NZ182865A (en) | 1979-06-08 |
| FR2358152A1 (en) | 1978-02-10 |
| GB1563595A (en) | 1980-03-26 |
| CH626632A5 (en) | 1981-11-30 |
| ES454119A1 (en) | 1978-03-01 |
| AU510864B2 (en) | 1980-07-17 |
| IE44512B1 (en) | 1981-12-30 |
| FR2358152B1 (en) | 1982-10-22 |
| CH626094A5 (en) | 1981-10-30 |
| ES465551A1 (en) | 1978-09-16 |
| AU2047176A (en) | 1978-06-15 |
| DK142326C (en) | 1981-03-09 |
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