CA1135253A - Hydrocortisone - 17, 21-diesters and method of the production of same - Google Patents
Hydrocortisone - 17, 21-diesters and method of the production of sameInfo
- Publication number
- CA1135253A CA1135253A CA000329780A CA329780A CA1135253A CA 1135253 A CA1135253 A CA 1135253A CA 000329780 A CA000329780 A CA 000329780A CA 329780 A CA329780 A CA 329780A CA 1135253 A CA1135253 A CA 1135253A
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- CA
- Canada
- Prior art keywords
- hydrocortisone
- propionate
- diesters
- production
- same
- 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
- 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
- C07J5/0053—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 not substituted in position 16
-
- 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]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The specification relates to hydrocortisone-17-21-diesters of general Formula (I) wherein R1 and R2 are the same or different and designate each a straight-chain or branched alkyl residue with 1-5 carbon atoms.
The specification also discloses the production of same and the use of same in pharmaceutical preparation. Furthermore, the specification relates to hydrocortisone-17-propionate, method of its production and also to its use as an intermediate product for the production of hydrocortisone-17-propionate-21-esters according to Formula 1. The above new 17,21-diesters possess considerable advantages over 21-monoesters and 17-monoesters of hydrocortisone, as well as over halogenized corticosteroids.
They possess good chemical stability and thus are particularly suitable for use in preparations for topical application when produced in a dissolved form. They possess valuable therapeutic proper.ties such as a good antiphlogistic effect combined with a low toxicity and thus do not produce certain undesired side effects typical in many corticosteroids.
The specification relates to hydrocortisone-17-21-diesters of general Formula (I) wherein R1 and R2 are the same or different and designate each a straight-chain or branched alkyl residue with 1-5 carbon atoms.
The specification also discloses the production of same and the use of same in pharmaceutical preparation. Furthermore, the specification relates to hydrocortisone-17-propionate, method of its production and also to its use as an intermediate product for the production of hydrocortisone-17-propionate-21-esters according to Formula 1. The above new 17,21-diesters possess considerable advantages over 21-monoesters and 17-monoesters of hydrocortisone, as well as over halogenized corticosteroids.
They possess good chemical stability and thus are particularly suitable for use in preparations for topical application when produced in a dissolved form. They possess valuable therapeutic proper.ties such as a good antiphlogistic effect combined with a low toxicity and thus do not produce certain undesired side effects typical in many corticosteroids.
Description
~35~
Belersdorf Aktiengesellschaft,~amburg HYDROCORTISONE-17,21-DIESTERS AND METHOD OF THE PRODUCTION DF Shi~
The present invention relates to hydrocortisone-17-21-diesters of ~eneral Formula C~O
~IO ~O-CO-R
~ (I) -0~ ,~ -, ~ , wherein R1 and R2 are the same or dlfferent and deslgnate each a straight-chain or branched alkyl residue wlth 1-5 carbon atoms. The invention also relates to the production of same and to the use of same ln pharmaceutical preparation.
Furthermore, the invention also relates to hydrocortisone-17-propionate, method of its production and also to its use as an intermediate product for the production of hydrocortisone-17-propionate-21-esters according to Formula I.
The above new 17,21-diesters possess considerable advan-tages over 21-monoesters and 17-monoesters of hydrocortisone, as well as o~er halogenated corticosteroids.
Hydrocortison-21-esters, whose best known representative is hydrocortisone-21-acetate, present compounds having a relati-vely good chemical stability. The drawback of the 21-esters resides in that, like the hydrocortisone itself, they possess only a relatively small efficacy. The reason for this disa~vantage is in their poor solubility both in water and ln lipold. In pharmaceutlc preparakions for the use ln topical applications, ~ i ~
~ 2 -~3L3~:53 they have to be contained in high concentration, usually 1~.
Even then, they are only moderately efflcient and are widely inferior to the more recently introduced corticosteroids.
Contrary to hydrocortisone-21~monoesters, certain hydro-cortisone derivatives esterified only in position 17, possess a strong topical efficacy. This is particularly so with 17-esters of hydrocortlsone with butyric and valeric acid. The great difference from the 21-esters in efficacy is due to the increased solubility of the compound in water and also due to significantly increased solubility in lip~. Yet, the 17~esters suffer from a drawback: their chemical stability ls reduced. It is further known to provide corticosteroid preparations for topical appllc-ations, contalning the acti~e substance in dissolved state, the preparations possessing a good efficacy. Preparations of this type with hydrocortisone-17-esters, however, rarely provide the storage stabllity requlred by law and must have an expiry date.
This applies, for lnstance, to creams and ointments containing hydrocortisone-17-valerate and to lotions with hydrocortisone-butyrate.
Certain chlorinated or fluorinated corticosteroids possess in their topically applicable forms a good degree o~ efficacy.
Their disad~antage is mainly in that they produce undeslred sids e~fects, particularly due to khe faet that they reach the blood c1rculation syætem of the patient.
Hydrocortisone-17,21-diesters accord1ng to the present invention do not suffer from the above drawbacks and eghibit a good degree of efficacy, corresponding to the degree of efficacy of hydrocortisone-17-butyrates and hydrocortisons-17-valerates.
Contrary to their monoesters, they possess a good chemical stability and thus are particularly suitable for use in prepar-ations for topical application when produced in a dissol~ed form.
They posse6s valuable therapeutlc properties such as a good . ~
~1~5~
antiphlogistic effect combined with a low toxicity and thus do not produce the undesired side effects typioal ~n many cortico-steroid6 .
Partlcularly favourable properties are present in those hydrocortisone-17,21-diesters which contain a total of 3 to 5 carbon atoms in both alkyl residues R1 R2 according to the Formula I. To these compounds belongs in particular the following selections hydrocortisone-17-propionate-21-acetate, hydrocortisone-17-butyrate-21-acetate, hydrocortisone-17-21_dipropionate, hydro-cortisone-17-propionate-21-butyrate and hydrocortisone-17-butyrate-21-propionate.
The literature on hydrocortisone-17-monoester explains that the optimum activity of hydrocortisone-17-butyrate and - vale-rate is coupled with the presence of a predetermlned "medium"
degree of affinity for lipids. Both compounds with a short-chain ester grouping, i.e. with less lipophilic derivatives, and those with long-chain ester groups, i.e. stronger lipophiles, show a reduced topical corticosteroid activity. On the other hand, it is due to the structure of the hydrocortison diesters, whose 20 hydrophilic free 21-OH group is absent, then one has to expect that these diesters possess an increased dissolvability of lipids in comparison with the 17-monoesters.
Pro¢eeding from the knowledge that the strong efflcacy of l~ydrocortisone-17-butyrate and -17-valerate corresponds to a predetermined associated "medium" degree of lipoph lic proper-ties, it was æurprising to f`ind out that the diesters which are very lipophilic due to the additional 21-ester group, possess a comparably strong topical efficacy.
Besides the production of topically administered application 30 forms such as creams, ointments, lotions, gels, powders and solutions, the compounds according to the invention can be mi~ced, if required, with suitable solld or liquid physiologically accept~
~
.. .
~5~3 able carriers and/or solvents of sultable typ~ for the production of solutlons for in~ection applicatlons, or can be proceæsed for peroral pharmaceutic preparatlons such as llquid medicatlons, dragees or tablets.
The portlon of hydrocortlsone dlesters ln such preparatlons depends on the particular type of preparation to be produced.
However, it generally is within the range of 0.001 to 0.5% and preferably withln the range of 0.01 to 0.25,'g.
The stabllity of the hydrocortlsone-17,21-diesters was establ~shed by comparlng their solutlons in ethanol and chloroform at an increased temperature, with the correspondlng properties OI the 17-monoesters. It was established that the diesters according to the present invention remain virtually or fully unchanged, while the concentration of monoesters was re-duced considerably (Table 1).
The stablllty of hydrocortlsone-17-21-diesters ln com-parison with hydrocort1 sone-17-monoesters in ethanol and chloro-form solutions. The table shows the percentage of unchanged stero1d after 5 day~ and 14 days in ethanol solution at 600C, as well as after 22 days, in a chloroform solution at 450C, in comparison with the starting, ori~;inal content (100,~) . _ ,~ unchanged steroid Substance Ethanol/60C Chloroform/45C
_ 5 days 14 days22 days Hydrocortisone-17-propionate-;~_sc~tate 100 97 95 Hydrocorti~one-17-butyrate-21-acetate 100 96 95 Compared withs EIydrocortisor~17-propionate 71 27 29 Hydrocortisor~17-butyrate83 51 57 Hydrocortlæone-17-valerate 89 59 62 ~L~IL;352~3 The method for the product1on of the ¢ompounds of Fo~mula I
ls characterlzed in that hydrocortisone, a corresponding hydro-cortlsone-monoester or a corresponding hydrocortisone-17-monoe~ter is treated with an acylating agent. The starting compounds are all descrlbed in the llter~ture, with the exception of hydrocort~-sone-17-propionate.
From hydrocrortisone or from the hydrocortisone-21-mono-esters can be obtained - if required, by protecting the ll-OH-group - for instance diesters with the same ester group ~n the 17- and 21-position, by treatment with a suitable carbonlc acld or its halogenide or anhydride.
In produclng mixed diesters, it is suitable to start from hydrocortisone-17-monoesters which can be obtained, for instance by known methods, through cyclic orthoesters or amidacetales. Hydro-cortisone-17-propionate can be obtained either by the treatment with an N,N-dialkyl propionic acid amide and an alkylation agent such as for instance dimethyl sulfate, or by treatment with a propionlc acid orthoester and subsequent hydrolysis of the reaction product. The esterification of the 21-hydro~y group is preferably carried out with the corresponding acid anhydride or acid halogeni-de under alkaline conditions. Most suitabl~, an excesæ of the alkalide, for instance pyridine, chinoline, N-methylpiperidine, N-methylmorpholine, 1,4-diazabicyclo-(2.2.2)-octane or dimethyl-aniline are used. Suitable solvents are benzol, toluol, dio~ane, tetrahydrofurane or dimethylformamide. The reaction can be carried out under cooling, at room temperature or under heat9ng.
The following examples will further describe the invention:
Hydrocortisone-17-propionate-21-acetate 3 g of hydrocortisone-17-prop~onate were dlssolved in 5 ml of absolute pyridine, cooled in an ice bath to 0C and ~ ~ 6 _ mixed with 5 ml of acetic acid anh~rdride. The mlxture was st~rred for 2 hrs under ice coollng and finally left standing aside a'c room temperature over night and then mlxed with 50 ml of ice.
The preclpitated oil was first dlgested three times with 50 ml of water, dissolved several times in 50 ml of methanol and the solvent withdrawn ln vacuum in order to remove pyridi~e residues.
The rest was fractionated with chloroform/3% methanol over a silica gel column. Following the crystallization from benzine (boiling range 60 - 800C), 1.78 g of pure hydrocortisone-17-propionate-21-acetate was obtalned.
Melting point: 144 - 450C
Hydrocortlsone-17-butyrate-acetate 3 g of hydrocortisone-17-butyrate was . treated in 5 ml of absolute pyridine with ~ ml of acetic acid anhydride according to Example 1 and purified. 1.67 g of hydrocortisone-17~Tbutyrate-acetate was obtained.
Melting point: 122 _ 430C
Hydrocortisone-17,21-dipropionate 6 g of hydrocortisone-17-propionate was treated in 39 ml of absolute pyridine with 3.48 ml of propionic acid anhydride according to Example 1. The diester crystallized without chroma-tographlc purification from petroleum ether. After crystalli~ation from a small volume of methanol/petroleum ether, 6.o g o~ pure hydrocortisone-17,21-dipropionate was obtained.
Melting point: 110 - 13C
~nalysis: found C68.89%; theoretical 68.83%
found H 8.37%; theoretlcal 8.07j~
~L35Z~3 Hydrocortisone-17-proplonate-21-butyrate
Belersdorf Aktiengesellschaft,~amburg HYDROCORTISONE-17,21-DIESTERS AND METHOD OF THE PRODUCTION DF Shi~
The present invention relates to hydrocortisone-17-21-diesters of ~eneral Formula C~O
~IO ~O-CO-R
~ (I) -0~ ,~ -, ~ , wherein R1 and R2 are the same or dlfferent and deslgnate each a straight-chain or branched alkyl residue wlth 1-5 carbon atoms. The invention also relates to the production of same and to the use of same ln pharmaceutical preparation.
Furthermore, the invention also relates to hydrocortisone-17-propionate, method of its production and also to its use as an intermediate product for the production of hydrocortisone-17-propionate-21-esters according to Formula I.
The above new 17,21-diesters possess considerable advan-tages over 21-monoesters and 17-monoesters of hydrocortisone, as well as o~er halogenated corticosteroids.
Hydrocortison-21-esters, whose best known representative is hydrocortisone-21-acetate, present compounds having a relati-vely good chemical stability. The drawback of the 21-esters resides in that, like the hydrocortisone itself, they possess only a relatively small efficacy. The reason for this disa~vantage is in their poor solubility both in water and ln lipold. In pharmaceutlc preparakions for the use ln topical applications, ~ i ~
~ 2 -~3L3~:53 they have to be contained in high concentration, usually 1~.
Even then, they are only moderately efflcient and are widely inferior to the more recently introduced corticosteroids.
Contrary to hydrocortisone-21~monoesters, certain hydro-cortisone derivatives esterified only in position 17, possess a strong topical efficacy. This is particularly so with 17-esters of hydrocortlsone with butyric and valeric acid. The great difference from the 21-esters in efficacy is due to the increased solubility of the compound in water and also due to significantly increased solubility in lip~. Yet, the 17~esters suffer from a drawback: their chemical stability ls reduced. It is further known to provide corticosteroid preparations for topical appllc-ations, contalning the acti~e substance in dissolved state, the preparations possessing a good efficacy. Preparations of this type with hydrocortisone-17-esters, however, rarely provide the storage stabllity requlred by law and must have an expiry date.
This applies, for lnstance, to creams and ointments containing hydrocortisone-17-valerate and to lotions with hydrocortisone-butyrate.
Certain chlorinated or fluorinated corticosteroids possess in their topically applicable forms a good degree o~ efficacy.
Their disad~antage is mainly in that they produce undeslred sids e~fects, particularly due to khe faet that they reach the blood c1rculation syætem of the patient.
Hydrocortisone-17,21-diesters accord1ng to the present invention do not suffer from the above drawbacks and eghibit a good degree of efficacy, corresponding to the degree of efficacy of hydrocortisone-17-butyrates and hydrocortisons-17-valerates.
Contrary to their monoesters, they possess a good chemical stability and thus are particularly suitable for use in prepar-ations for topical application when produced in a dissol~ed form.
They posse6s valuable therapeutlc properties such as a good . ~
~1~5~
antiphlogistic effect combined with a low toxicity and thus do not produce the undesired side effects typioal ~n many cortico-steroid6 .
Partlcularly favourable properties are present in those hydrocortisone-17,21-diesters which contain a total of 3 to 5 carbon atoms in both alkyl residues R1 R2 according to the Formula I. To these compounds belongs in particular the following selections hydrocortisone-17-propionate-21-acetate, hydrocortisone-17-butyrate-21-acetate, hydrocortisone-17-21_dipropionate, hydro-cortisone-17-propionate-21-butyrate and hydrocortisone-17-butyrate-21-propionate.
The literature on hydrocortisone-17-monoester explains that the optimum activity of hydrocortisone-17-butyrate and - vale-rate is coupled with the presence of a predetermlned "medium"
degree of affinity for lipids. Both compounds with a short-chain ester grouping, i.e. with less lipophilic derivatives, and those with long-chain ester groups, i.e. stronger lipophiles, show a reduced topical corticosteroid activity. On the other hand, it is due to the structure of the hydrocortison diesters, whose 20 hydrophilic free 21-OH group is absent, then one has to expect that these diesters possess an increased dissolvability of lipids in comparison with the 17-monoesters.
Pro¢eeding from the knowledge that the strong efflcacy of l~ydrocortisone-17-butyrate and -17-valerate corresponds to a predetermined associated "medium" degree of lipoph lic proper-ties, it was æurprising to f`ind out that the diesters which are very lipophilic due to the additional 21-ester group, possess a comparably strong topical efficacy.
Besides the production of topically administered application 30 forms such as creams, ointments, lotions, gels, powders and solutions, the compounds according to the invention can be mi~ced, if required, with suitable solld or liquid physiologically accept~
~
.. .
~5~3 able carriers and/or solvents of sultable typ~ for the production of solutlons for in~ection applicatlons, or can be proceæsed for peroral pharmaceutic preparatlons such as llquid medicatlons, dragees or tablets.
The portlon of hydrocortlsone dlesters ln such preparatlons depends on the particular type of preparation to be produced.
However, it generally is within the range of 0.001 to 0.5% and preferably withln the range of 0.01 to 0.25,'g.
The stabllity of the hydrocortlsone-17,21-diesters was establ~shed by comparlng their solutlons in ethanol and chloroform at an increased temperature, with the correspondlng properties OI the 17-monoesters. It was established that the diesters according to the present invention remain virtually or fully unchanged, while the concentration of monoesters was re-duced considerably (Table 1).
The stablllty of hydrocortlsone-17-21-diesters ln com-parison with hydrocort1 sone-17-monoesters in ethanol and chloro-form solutions. The table shows the percentage of unchanged stero1d after 5 day~ and 14 days in ethanol solution at 600C, as well as after 22 days, in a chloroform solution at 450C, in comparison with the starting, ori~;inal content (100,~) . _ ,~ unchanged steroid Substance Ethanol/60C Chloroform/45C
_ 5 days 14 days22 days Hydrocortisone-17-propionate-;~_sc~tate 100 97 95 Hydrocorti~one-17-butyrate-21-acetate 100 96 95 Compared withs EIydrocortisor~17-propionate 71 27 29 Hydrocortisor~17-butyrate83 51 57 Hydrocortlæone-17-valerate 89 59 62 ~L~IL;352~3 The method for the product1on of the ¢ompounds of Fo~mula I
ls characterlzed in that hydrocortisone, a corresponding hydro-cortlsone-monoester or a corresponding hydrocortisone-17-monoe~ter is treated with an acylating agent. The starting compounds are all descrlbed in the llter~ture, with the exception of hydrocort~-sone-17-propionate.
From hydrocrortisone or from the hydrocortisone-21-mono-esters can be obtained - if required, by protecting the ll-OH-group - for instance diesters with the same ester group ~n the 17- and 21-position, by treatment with a suitable carbonlc acld or its halogenide or anhydride.
In produclng mixed diesters, it is suitable to start from hydrocortisone-17-monoesters which can be obtained, for instance by known methods, through cyclic orthoesters or amidacetales. Hydro-cortisone-17-propionate can be obtained either by the treatment with an N,N-dialkyl propionic acid amide and an alkylation agent such as for instance dimethyl sulfate, or by treatment with a propionlc acid orthoester and subsequent hydrolysis of the reaction product. The esterification of the 21-hydro~y group is preferably carried out with the corresponding acid anhydride or acid halogeni-de under alkaline conditions. Most suitabl~, an excesæ of the alkalide, for instance pyridine, chinoline, N-methylpiperidine, N-methylmorpholine, 1,4-diazabicyclo-(2.2.2)-octane or dimethyl-aniline are used. Suitable solvents are benzol, toluol, dio~ane, tetrahydrofurane or dimethylformamide. The reaction can be carried out under cooling, at room temperature or under heat9ng.
The following examples will further describe the invention:
Hydrocortisone-17-propionate-21-acetate 3 g of hydrocortisone-17-prop~onate were dlssolved in 5 ml of absolute pyridine, cooled in an ice bath to 0C and ~ ~ 6 _ mixed with 5 ml of acetic acid anh~rdride. The mlxture was st~rred for 2 hrs under ice coollng and finally left standing aside a'c room temperature over night and then mlxed with 50 ml of ice.
The preclpitated oil was first dlgested three times with 50 ml of water, dissolved several times in 50 ml of methanol and the solvent withdrawn ln vacuum in order to remove pyridi~e residues.
The rest was fractionated with chloroform/3% methanol over a silica gel column. Following the crystallization from benzine (boiling range 60 - 800C), 1.78 g of pure hydrocortisone-17-propionate-21-acetate was obtalned.
Melting point: 144 - 450C
Hydrocortlsone-17-butyrate-acetate 3 g of hydrocortisone-17-butyrate was . treated in 5 ml of absolute pyridine with ~ ml of acetic acid anhydride according to Example 1 and purified. 1.67 g of hydrocortisone-17~Tbutyrate-acetate was obtained.
Melting point: 122 _ 430C
Hydrocortisone-17,21-dipropionate 6 g of hydrocortisone-17-propionate was treated in 39 ml of absolute pyridine with 3.48 ml of propionic acid anhydride according to Example 1. The diester crystallized without chroma-tographlc purification from petroleum ether. After crystalli~ation from a small volume of methanol/petroleum ether, 6.o g o~ pure hydrocortisone-17,21-dipropionate was obtained.
Melting point: 110 - 13C
~nalysis: found C68.89%; theoretical 68.83%
found H 8.37%; theoretlcal 8.07j~
~L35Z~3 Hydrocortisone-17-proplonate-21-butyrate
2.5 g of hydrocortisone-17-propionate was treated in 16 ml of absolute pyridine with 1.76 g of butyric acld anhydride according to Example 1. The raw diester crystallized from petrole-um ether on addition of few drops of methanol. 1.7 g of pure hydrocortisone-17-propionate-21~butyrate was obtained.
Melting point: 102 _ 40C
Hydrocortisone 17-butyrate-21-propionate
Melting point: 102 _ 40C
Hydrocortisone 17-butyrate-21-propionate
3 g of hydrocortisone-17-butyrate was treated in 7.5 ml Or absolute pyridine with 7.5 ml of propionic acid anhydride according to Example 1 and purified. 2.7 g of pure hydrocortisone-17-~butyrate-21-propionate were obtained.
Meltlng point: 75 - 77C
The hydrocortisone-17-propionate used as a starting compound was obtained from hydrocortisone as described in the following- example:
Hydrocortisone-17-propionate 18 g of hydrocortisone were dissolved in 18 ml of an absolute dimethylformamide and mi~ced with 16 ml of orthopropionic acid triethylester.Followlng an addition of 60 mg of p-toluol-sulfonic acid 1 ~I20, the reaction mixture was stirred for 6 hrs at about 110C. Following the cooling at room temperature, 0.~ ml of pyridine was added and eventually the mi~l:ture was reduced ln volume in vacuum. To the viscous residue dissolved in 1.2 l of methanol was added a buffer mlxture of 121.6 ml 0.1 m Trisodium-citrate solution and 24~ ml OI 0.1 n-hydrochloric acid and the 8 _ ., ,. ~
, ... . .
boiled under reflu~. After the cooling of the solution, the methanol was withdrawn to a conslderable degree under reduced pressure and the remaining suspension mixed with an equal volume of water. The crystalline raw product obtained by cooling, was fractionized with chloroform/3% methanol over silica gel. 9.5 g of pure hydrocortisone-17-propionate was obtained.
Melting pointt 192 - 930C.
~ 9 _
Meltlng point: 75 - 77C
The hydrocortisone-17-propionate used as a starting compound was obtained from hydrocortisone as described in the following- example:
Hydrocortisone-17-propionate 18 g of hydrocortisone were dissolved in 18 ml of an absolute dimethylformamide and mi~ced with 16 ml of orthopropionic acid triethylester.Followlng an addition of 60 mg of p-toluol-sulfonic acid 1 ~I20, the reaction mixture was stirred for 6 hrs at about 110C. Following the cooling at room temperature, 0.~ ml of pyridine was added and eventually the mi~l:ture was reduced ln volume in vacuum. To the viscous residue dissolved in 1.2 l of methanol was added a buffer mlxture of 121.6 ml 0.1 m Trisodium-citrate solution and 24~ ml OI 0.1 n-hydrochloric acid and the 8 _ ., ,. ~
, ... . .
boiled under reflu~. After the cooling of the solution, the methanol was withdrawn to a conslderable degree under reduced pressure and the remaining suspension mixed with an equal volume of water. The crystalline raw product obtained by cooling, was fractionized with chloroform/3% methanol over silica gel. 9.5 g of pure hydrocortisone-17-propionate was obtained.
Melting pointt 192 - 930C.
~ 9 _
Claims (2)
1. A process for the preparation of hydrocortisone-17-propionate-21-acetate of formula (I) characterized in that hydrocortisone is treated with N,N-dialkylpropionic acid amide and an alkylating agent, or, with a propionic acid orthoester to form cyclic hydro-cortisone-17,21-propionic acid orthoester, the orthoester is partially hydrolyzed; and the hydrocortisone-17-propionate thus obtained is treated with an acetylating agent.
2. Hydrocortisone-17-propionate-21-acetate whenever prepared by one of the processes of claim 1 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2826257A DE2826257C3 (en) | 1978-06-15 | 1978-06-15 | Hydrocortisone-17,21-diester and process for their preparation, pharmaceuticals containing them and hydrocortisone -17-propionate as an intermediate |
| DEP2826257.9 | 1978-06-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1135253A true CA1135253A (en) | 1982-11-09 |
Family
ID=6041871
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000329780A Expired CA1135253A (en) | 1978-06-15 | 1979-06-14 | Hydrocortisone - 17, 21-diesters and method of the production of same |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5540662A (en) |
| AT (1) | AT368757B (en) |
| AU (1) | AU4760479A (en) |
| BE (1) | BE877017A (en) |
| CA (1) | CA1135253A (en) |
| CH (1) | CH641476A5 (en) |
| DE (1) | DE2826257C3 (en) |
| ES (1) | ES481522A1 (en) |
| FR (1) | FR2428649A1 (en) |
| GB (1) | GB2023145A (en) |
| ZA (1) | ZA792952B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6040439B2 (en) * | 1978-03-29 | 1985-09-11 | 大正製薬株式会社 | hydrocortisone derivatives |
| AT389447B (en) * | 1983-01-27 | 1989-12-11 | Taisho Pharmaceutical Co Ltd | Process for the production of a topical steroid ointment |
| JPS59137408A (en) * | 1983-01-27 | 1984-08-07 | Taisho Pharmaceut Co Ltd | Ointment |
| JPS59139315A (en) * | 1983-01-31 | 1984-08-10 | Taisho Pharmaceut Co Ltd | Cream agent |
| DE3534743A1 (en) * | 1985-09-28 | 1987-04-02 | Beiersdorf Ag | HYDROCORTISON'S BEST CONTAINING O / W CREAM |
| DE3534742A1 (en) * | 1985-09-28 | 1987-04-09 | Beiersdorf Ag | HYDROCORTISON'S MOST CONTAINING W / O CREAM |
| DE4345186C2 (en) * | 1993-12-27 | 1997-08-14 | Galderma Sa | Hydrocortisone 21-acetate-17-propionate containing W / O lotions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2144405A1 (en) * | 1971-09-04 | 1973-03-08 | Merck Patent Gmbh | Saponification of pregnane series esters - using silica gel |
| SU427930A1 (en) * | 1972-03-16 | 1974-05-15 | А. А. Ахрем, И. С. Левина , Ю. А. Титов Институт органической химии Н. Д. Зелинского | METHOD FOR OBTAINING DERIVATIVE CORTICOSTEROIDS |
| JPS6040439B2 (en) * | 1978-03-29 | 1985-09-11 | 大正製薬株式会社 | hydrocortisone derivatives |
-
1978
- 1978-06-15 DE DE2826257A patent/DE2826257C3/en not_active Expired
-
1979
- 1979-05-30 AU AU47604/79A patent/AU4760479A/en not_active Abandoned
- 1979-06-13 JP JP7361279A patent/JPS5540662A/en active Pending
- 1979-06-13 FR FR7915150A patent/FR2428649A1/en active Granted
- 1979-06-13 ES ES481522A patent/ES481522A1/en not_active Expired
- 1979-06-13 AT AT0422179A patent/AT368757B/en not_active IP Right Cessation
- 1979-06-14 ZA ZA792952A patent/ZA792952B/en unknown
- 1979-06-14 GB GB7920782A patent/GB2023145A/en not_active Withdrawn
- 1979-06-14 CA CA000329780A patent/CA1135253A/en not_active Expired
- 1979-06-15 BE BE0/195771A patent/BE877017A/en not_active IP Right Cessation
- 1979-06-15 CH CH564479A patent/CH641476A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AT368757B (en) | 1982-11-10 |
| BE877017A (en) | 1979-12-17 |
| ZA792952B (en) | 1980-06-25 |
| FR2428649B1 (en) | 1982-06-11 |
| DE2826257A1 (en) | 1979-12-20 |
| DE2826257B2 (en) | 1980-03-06 |
| CH641476A5 (en) | 1984-02-29 |
| AU4760479A (en) | 1979-12-20 |
| GB2023145A (en) | 1979-12-28 |
| JPS5540662A (en) | 1980-03-22 |
| FR2428649A1 (en) | 1980-01-11 |
| ES481522A1 (en) | 1980-01-16 |
| DE2826257C3 (en) | 1980-12-04 |
| ATA422179A (en) | 1982-03-15 |
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| MKEX | Expiry |