CA1104124A - Derivatives of 9-fluoroprednisolone - Google Patents
Derivatives of 9-fluoroprednisoloneInfo
- Publication number
- CA1104124A CA1104124A CA299,299A CA299299A CA1104124A CA 1104124 A CA1104124 A CA 1104124A CA 299299 A CA299299 A CA 299299A CA 1104124 A CA1104124 A CA 1104124A
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- Prior art keywords
- alpha
- pregnadiene
- dione
- fluoro
- beta
- Prior art date
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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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Derivatives of 9-fluoroprednisolone which hav? only weak systemic action but when administered topically have a strong anti-inflammatory action. The compounds have the formula
Derivatives of 9-fluoroprednisolone which hav? only weak systemic action but when administered topically have a strong anti-inflammatory action. The compounds have the formula
Description
2~
The invention relates to derivatives of 9-fluoropre-nisolone, a process for their production and pharmaceutical preparations containing these active substances.
9-Fluoroprednisolone (9~-fluoro-11~,17~,21-trihydroxy-1,4-pregnadiene-3,2-dione) has been known for a long time. (See, for example, J. Amer. Chem. 50c., 77, 1955, 4181). This corti-coid is not a suitable active substance for pharmaceutical preparations which are used Eor the topical treatment of ~ inflammatory diseases since it has very strong systemic effects.
The present invention is based on the observation tha-t hitherto known derivatives of 9-fluoroprednisolone have only weak systemic action but, when administered ~opically, they have, surprisingly, a strong anti-inflammatory action that generally exceeds that of the most effective commercial corticoids.
The present invention provides a derivative of 9-fluoroprednisolone of the general formula (I) C=O
H0 ~` \ ~ ~ ; ~ ORl (I) oJ\~ ' wherein Rl represents a group of the general formula RC0- in which R represents a hydrogen atom or an alkyl group or a cyclo-alkyl or cycloalkylalkyl group or an alkyl-substituted cycloalkyl or cycloalkylalkyl group, and Rl has~from 1 to 8 carbon atoms, or in which R represents an aryl or aralkyl group or an alkyl substituted aryl or aralkyl group, and Rl has up to 9 carbon atoms and X represents a fluorine or chlorine atom or a group or the general formula R'C00- which has from 3 to B carbon atoms and in - 1 - ~ , ~ A~ ~
which R' represents an alkyl group or a cycloalkyl or cycloalkyl-alkyl group or an alkyl-substituted cycloalkyl or cycloalkyl-alkyl group.
. Thus, for example, Rl may represent a formyl group or an alkanoyl or cycloal~anoyl group having up to 8 carbon atoms or a benzoyl group or a phenylalkanoyl group having up to 9 carbon atoms, and X represent a fluorine or chlorine a~om or an alkanoyl or cycloalkanoyl group having from 3 to 8 carbon atoms.
An acyl group represented by Rl and an acyloxy group represented by X may be derived from a cyclic carboxylic acid or from an open-chained tstraight-chained or branched-chained) carboxylic acid, such as, for example, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethylacetic acid, caproic acid, t-butylacetic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid or caprylic acid or, in the case of Rl, from formic acid, acetic or propionic acid.
Particularly preferred alkanoyl groups Rl and alkanoy-loxy groups X are those that are derived from an alkanecarboxylic acid containing up to 6 carbon atoms.
9-Fluoroprednisolone derivatives of the general formula ~I) where X represents a chlorine atom, are for example:
17a-acetoxy-21-chloro-9a-fluoro-11~-hydroxy-1,4-pregnadiene
The invention relates to derivatives of 9-fluoropre-nisolone, a process for their production and pharmaceutical preparations containing these active substances.
9-Fluoroprednisolone (9~-fluoro-11~,17~,21-trihydroxy-1,4-pregnadiene-3,2-dione) has been known for a long time. (See, for example, J. Amer. Chem. 50c., 77, 1955, 4181). This corti-coid is not a suitable active substance for pharmaceutical preparations which are used Eor the topical treatment of ~ inflammatory diseases since it has very strong systemic effects.
The present invention is based on the observation tha-t hitherto known derivatives of 9-fluoroprednisolone have only weak systemic action but, when administered ~opically, they have, surprisingly, a strong anti-inflammatory action that generally exceeds that of the most effective commercial corticoids.
The present invention provides a derivative of 9-fluoroprednisolone of the general formula (I) C=O
H0 ~` \ ~ ~ ; ~ ORl (I) oJ\~ ' wherein Rl represents a group of the general formula RC0- in which R represents a hydrogen atom or an alkyl group or a cyclo-alkyl or cycloalkylalkyl group or an alkyl-substituted cycloalkyl or cycloalkylalkyl group, and Rl has~from 1 to 8 carbon atoms, or in which R represents an aryl or aralkyl group or an alkyl substituted aryl or aralkyl group, and Rl has up to 9 carbon atoms and X represents a fluorine or chlorine atom or a group or the general formula R'C00- which has from 3 to B carbon atoms and in - 1 - ~ , ~ A~ ~
which R' represents an alkyl group or a cycloalkyl or cycloalkyl-alkyl group or an alkyl-substituted cycloalkyl or cycloalkyl-alkyl group.
. Thus, for example, Rl may represent a formyl group or an alkanoyl or cycloal~anoyl group having up to 8 carbon atoms or a benzoyl group or a phenylalkanoyl group having up to 9 carbon atoms, and X represent a fluorine or chlorine a~om or an alkanoyl or cycloalkanoyl group having from 3 to 8 carbon atoms.
An acyl group represented by Rl and an acyloxy group represented by X may be derived from a cyclic carboxylic acid or from an open-chained tstraight-chained or branched-chained) carboxylic acid, such as, for example, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethylacetic acid, caproic acid, t-butylacetic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid or caprylic acid or, in the case of Rl, from formic acid, acetic or propionic acid.
Particularly preferred alkanoyl groups Rl and alkanoy-loxy groups X are those that are derived from an alkanecarboxylic acid containing up to 6 carbon atoms.
9-Fluoroprednisolone derivatives of the general formula ~I) where X represents a chlorine atom, are for example:
17a-acetoxy-21-chloro-9a-fluoro-11~-hydroxy-1,4-pregnadiene
3,20-dione, 21~chloro-9a-fluoro-11~-hydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione, 17a-butyryloxy-21-chloro-9a fluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione, 21-chloro-9a-fluoro-11~-hydroxy-17a-isobutyryloxy-1,4-pregnadiene-3,20-dione, 21-chloro-9a-fluoro-11~-hydroxy-17a-valeryloxy-1,4-pregnadiene-3,20-dione and 17a-benzoyloxy-21-chloro-9~-fluoro-11~-1,4-pregnadiene-3,20-dione.
_ ~ _ 9,21-Difluoroprednisolone derlvatives of the general formula (I) are, for example, 17~-acetoxy-9~,21-difluoro~ hydroxy-1,4-pregnadiene-3,20-dione, 9~,21-difluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione, 17a-butyryloxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3-20-dione and 9~,21-difluoro-11~-hydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione.
9-Fluoroprednisolone derivatives of the general formula (I) with X representing a group of the formula R'COO- are preferably those in which the radicals Rl and X together have 5 to 14 carbon atoms. Such fluoroprednisolone derivatives are, for example:
17~-acetoxy-9~-fluoro-11~-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione, 17~-acetoxy-21-butyryloxy-9~-fluoro-11~-1,4-pregnadiene-3,20-dione, 17~,-acetoxy-9~-fluoro-11~-hydroxy-21-isobutyryloxy-1,4-pregna~
diene-3,20-dione, 17~-acetoxy-9~-fluoro-11~-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione, 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-valeryloxy-1,~-pregnadiene-3,20-dione, 17~-benzoyloxy-21-butyryloxy-9~-fluoro-11~-hydroxy-1,4-pregna-diene-3,20-dione, 9~-fluoro-11~-hydroxy-17~,21-diisobutyryloxy-1,4-pregnadiene-3,20-dione and 9~-fluoro-11~-hydroxy-17~,21-divaleryloxy-1,4-pregnadiene~3,20-dione.
The present .invention also provides a process for the manufacture of the 9-fluoroprednisolone derivatives of the ene-al formula (I~ wherein a) the epoxide ring of a compound of the general formula (II) I
~ ~ (II), l J
~```~/ ' .
o \~
in which Rl and X have the meanings given above is opened with hydrogen fluoride, or b) a 9-fluoro derivative of the general formula (III) C-O
HO ~ ~, ~ 1 (III) ~ ~
od~
in which Rl has the meaning given above, i5 halogenated or esterified in the 21-position, or c) for the production of a 9-fluoroprednisolone derivative of the general formula (I) wherein X represents a fluorine or chlorine atom, an ortho ester of the general formula (IV) `\, /
co c / \
. ~ _O R3 (IV), ~ . /~
wherein R3 represents a hydrogen atom, an alkyl group or a cycloalkyl group having up to 7 carbon atoms or a phenyl group and R2 represents an alkyl group having 1 to 4 carbon atoms, is cleaved with a trimethylsilyl halide or a triphenylmethyl halide.
The process of the invention according to process variants (a) and ~b) may be carried out in a manner known per se under the conditions described in U.S. Specifications Nos.
3,678,034, 3,718,671 and 3,828,083. The starting compounds for these processes may be produced under the conditions described in U.S. Specification No. 3,152,154 and in German Offenlegung-sschriften Nos. 23,40,591 and 20,55,221.
The process of the invention according to process variant (a) may likewise be carried out under conditions known per se preferably by reacting a compound of general formula (II) with hydrogen fluoride contained in an inert solvent. Suitable inert solvents are, for example, ethers (e.g. diethyl ether, diisopropyl ether~ tetrahydrofuran or pyridine) and chlorinated hydrocarbons (e.g. methylene chloride, chloroform, carbon tetra-chloride or tetrachloroethane).
The process of the invention according to process variant (b) may likewise be carried out under conditions known p se.
lZ4 ~ h~s, for example, a ~ydroxy steriod of the genera~
formula (III) may be esterified with an acyl chloride or acid anhydride in the presence of an acid, such as, for example, hydrogen chloride, ~-toluenesulphonic acid or trifluoroacetic acid, or in the presence of a base such, for example, as potassium carbonate, pyridine, collidine or _-dimethylamino-pyridine.
A preferred method of chlorinating a compound of the general formula (III) comprises esterifying the 21-hydroxy group with a sulphonic acid, preferably with methanesulphonic acid or p~toluenesulphonic, and then exchanging the sulphonic acid group or chlorine. The 21-hydroxy group is esterified, for example, by causing a sulphonic acid chloride to act on tlle compound of formula ~III) in the presence of an organic base, such, for example, as pyridine, or in the presence of an aqueous alkali, The sulphonic acid group is exchanged for a chlorine atom pre-ferably by reacting the 21-sulphonic acid ester with an alkali metal chloride such as, for example, lithium chloride, in the presence of a polar solvent such, for example, as dimethylfor-mamide.
The process of the invention according to processvariant (c) may likewise be carried out under conditions known per se.
~=.~ = = _ The cleavage of an ortho ester of the general formula (IV) is preferably effected with trimethylsilyl fluoride, tri-¦ methylsilyl chloride or triphenylmethyl chloride, advantageously in an inert solvent such, for example, as a dipolar aprotic solvent (e.g. dimethylformamide, N-methylpyrrolidone, dimethyl sulphoxide or hexamethylphosphoric acid triamide), an ether (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxan or glycol dimethyl ether), a chlorinated hydrocarbon (e.g.
methylene chloride, chloroEorm or tetrachloroethane), a hydro~
carbon (e.g. benzene, toluene or cyclohexane) or a mixture of any two or more of these solvents.
The starting compound for the process according to the invention can thus be produced in a simple manner and with hiqh yields from prednisolone which can itself be synthesised relativ-ely easily from diosgenin. The result o~ this is -that compounds of the invention can be produced from diosgenin at relatively low expenditure and with a total yield of approximately 15%~ In contrast, the syntheses of the known highly effective corticoids from diosgenin requlre considerably more expendi-ture and the total yields obtained are significantly lower (approximately 0.5 to 5%).
In view of the growing difficulties in obtaining a sufficient quantity of suitable starting materials for the corticoid syntheses and with regard to the high cost of active substances, which is the disadvantage of corticoid-containing medicament specialities, this is not without significance.
As already mentioned, when the compounds oE the invention are administered topically they have a very strong anti-inflammatory activity but have only weak action when administered systemically.
The anti-inflammatory activity was determined as follows: A hyperaemia was produced on human skin in the following manner.
Part of the S-tratum corneum on the backs of male and female volunteers was stripped off by applying and tearing off 20 times from the same place a portion of "Tesa" (~egistered Trade Mark) self-adhesive tape 2 cm wide and a pronounced hyper~
aemia was thus produced.
Approximately 50 mg of the ointment preparations were applied to marked 4 cm2 zones inside the stripped area.
In order to obtain comparable starting values relative numbers were used since the colour of the untreated skin, as also the reddening of the hyperaemic area, differs from case to case.
The colour value of the untreated skin was se-t at 100 and that of the stripped skin at 0.
The skin colour value of the skin under vasoconstric-tion (100) was determined on a relative scale.
Relatively slight, average and a high degree of vaso-constriction was rated accordingly between 0 and 100.
The average values, which were derived from investi-gations of the various test persons and from various regions of the back, are given in the following Table A.
The system activity of the compounds was determined using the adjuvant-oedema test as follows:
SPF rats weighing 130 to 150 g were injected in the right hind leg with 0.1 ml of a 0.5~ Mycobacterium butyricum suspension (obtainable from the American firm Difko) in order to produce a focus of inflammation. The volume of the rats' legs was measured before injection and again 24 hours after injection to determine the extent of the oedema. Different quantities of the test substance were then administered orally to the rats.
After a further 24 hours the volume of the legs was determined once a~ain.
From the leg volumes obtained the quantity of test substance necessary to achieve 50~ healing of the oedema in the leg was determined in the normal manner.
The results obtained in the tests are given in the following Table A:
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Similar results are obtained if the systemic activity of the 9-fluoroprednisolone derivatives according to the invention is determined using the known thymolysis test or the known sodium/
potassium retention test.
In combination with the carriers conventionally used in galenical pharmacy compounds of the invention are suitable for the local treatment of contact dermatitis, eczemas of the most varied types, neurodermatoses, erythrodermia, burns, Pruritia vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, Lichen _ ruber planus et verrucosus and similar skin diseases.
~_ _ _ Accordingly, the present invention also provides a pharmaceutieal preparation which comprises a compound of the general formula (I), in admixture or conjunction with a pharma-ceutically suitable carrier.
The pharmaceutical preparations may be produced in a eonventional manner by converting the active substanees with suitable additives into the desired form of administration, such as, for example, solutions, lotions, ointments, creams or plasters. In the preparations formulated in -this manner the con-eentration o aetive substance depends on the form of administrat-ion. An active substance concentration of 0.001 to 1~ is preferably used in the case of lotions and ointments.
The present invention further provides a method of treating an animal to relive inflammation, which comprises applying a compound or preparation of the invention to the affected area.
In addition, compounds of the invention, optionally in combination with the conventional carriers and auxiliary agents, are also very suitable for the production of inhalants which can be used for the therapy of allergic diseases of the res-piratory system, such as, for example, bronchial asthma or rhinitis.
i ¦ A eompound or preparation of the present invention may also be used to alleviate inflammation caused by a medicament used for treating a non-inflammatory disease.
Aeeordingly, the present invention provides a pharma-eeutieal composition which comprises a compound of the general ! formula (I) in admixture with a medicament for the treatment of a non-inflammatory disease but which i5 liable to have an inflammatory aetion, and a pharmaceutical preparation which eomprises this eomposition in admixture or conjunetion with a ¦ 10 pharmaeeutieally suitable carrierO
¦ The present invention further provides a pack which ¦ eomprises a eompound of the general formula (I), or a pharma-I eeutieal preparation containing this, and a medicament for the ¦ treatment of a non-inflammatory disease but which is liable to ¦ have an inflammatory action.
¦ The following Examples illustrate the invention:
I-5yntheses Example 1 a) 5 g of 9~-fluoroprednisolone are added to 500 mg of pyridine tosylate, twice concentrated to dryness ln vacuo with benzene, in 500 ml of benzene and 40 ml of N,N-dimethylformamide.
At a bath temperature of 130C 50 ml of solvent are distilled off and 6 ml of orthoacetic acid triethyl ester are added. The remainder of the benzene is distilled off within 2.5 hours and after the addition of 2.4 ml of pyridine the whole is concen-trated in vacuo. 17~,21-~1-ethoxyethylidenedioxy)-9~fluoro-ll~-hydroxy-1,4-pregnadiene-3,20-diane is isolated as a yellow oily epimer mixture.
b) A solution of the oil thus obtained in 150 ml of methanol is refluxed for 1 hour at 90C with a mixture of 54 ml of 0.1 N acetic acid and 6 ml of 0.1 N aqueous sodium acetate solution. The mixture is concentrated to dryness in vacuo, added 2~
to water and extracted with ethyl acetate. The organic extracts are washed with water, dried and evaporated in vacuo. Yield:
9 g of 17~-acetoxy-9~-fluoro-11~-21-dihydroxy-1,4-pregnadiene-3,20-dione as a foam.
c) 3.0 g of 17~-acetoxy-9~-fluoro-11~,21-dihydroxy-1,4 pregnadiene-3,20-dione are stirred in 17 ml of pyridine and 8 ml of propionic anhydride for 1.5 hours at room temperature. After precipitating with ice water filtration is effected, the residue ~ is taken up in methylene chloride and is evaporated after washing and drying over sodium sulphate. 4.9 g are isolated which are chromatographed on 450 g of silica gel with a methylene chloride/
acetone gradient (0-15~ acetone). Yield: 2.96 g of 17~x-acetoxy-9~-fluoro-11~-hydroxy 21-propionyloxy-1,4-pregnadiene-3,20-dione.
Melting point 219C. [~]25 = +81 (pyridine). UV: ~239 =
(methanol).
Example 2
_ ~ _ 9,21-Difluoroprednisolone derlvatives of the general formula (I) are, for example, 17~-acetoxy-9~,21-difluoro~ hydroxy-1,4-pregnadiene-3,20-dione, 9~,21-difluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione, 17a-butyryloxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3-20-dione and 9~,21-difluoro-11~-hydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione.
9-Fluoroprednisolone derivatives of the general formula (I) with X representing a group of the formula R'COO- are preferably those in which the radicals Rl and X together have 5 to 14 carbon atoms. Such fluoroprednisolone derivatives are, for example:
17~-acetoxy-9~-fluoro-11~-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione, 17~-acetoxy-21-butyryloxy-9~-fluoro-11~-1,4-pregnadiene-3,20-dione, 17~,-acetoxy-9~-fluoro-11~-hydroxy-21-isobutyryloxy-1,4-pregna~
diene-3,20-dione, 17~-acetoxy-9~-fluoro-11~-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione, 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-valeryloxy-1,~-pregnadiene-3,20-dione, 17~-benzoyloxy-21-butyryloxy-9~-fluoro-11~-hydroxy-1,4-pregna-diene-3,20-dione, 9~-fluoro-11~-hydroxy-17~,21-diisobutyryloxy-1,4-pregnadiene-3,20-dione and 9~-fluoro-11~-hydroxy-17~,21-divaleryloxy-1,4-pregnadiene~3,20-dione.
The present .invention also provides a process for the manufacture of the 9-fluoroprednisolone derivatives of the ene-al formula (I~ wherein a) the epoxide ring of a compound of the general formula (II) I
~ ~ (II), l J
~```~/ ' .
o \~
in which Rl and X have the meanings given above is opened with hydrogen fluoride, or b) a 9-fluoro derivative of the general formula (III) C-O
HO ~ ~, ~ 1 (III) ~ ~
od~
in which Rl has the meaning given above, i5 halogenated or esterified in the 21-position, or c) for the production of a 9-fluoroprednisolone derivative of the general formula (I) wherein X represents a fluorine or chlorine atom, an ortho ester of the general formula (IV) `\, /
co c / \
. ~ _O R3 (IV), ~ . /~
wherein R3 represents a hydrogen atom, an alkyl group or a cycloalkyl group having up to 7 carbon atoms or a phenyl group and R2 represents an alkyl group having 1 to 4 carbon atoms, is cleaved with a trimethylsilyl halide or a triphenylmethyl halide.
The process of the invention according to process variants (a) and ~b) may be carried out in a manner known per se under the conditions described in U.S. Specifications Nos.
3,678,034, 3,718,671 and 3,828,083. The starting compounds for these processes may be produced under the conditions described in U.S. Specification No. 3,152,154 and in German Offenlegung-sschriften Nos. 23,40,591 and 20,55,221.
The process of the invention according to process variant (a) may likewise be carried out under conditions known per se preferably by reacting a compound of general formula (II) with hydrogen fluoride contained in an inert solvent. Suitable inert solvents are, for example, ethers (e.g. diethyl ether, diisopropyl ether~ tetrahydrofuran or pyridine) and chlorinated hydrocarbons (e.g. methylene chloride, chloroform, carbon tetra-chloride or tetrachloroethane).
The process of the invention according to process variant (b) may likewise be carried out under conditions known p se.
lZ4 ~ h~s, for example, a ~ydroxy steriod of the genera~
formula (III) may be esterified with an acyl chloride or acid anhydride in the presence of an acid, such as, for example, hydrogen chloride, ~-toluenesulphonic acid or trifluoroacetic acid, or in the presence of a base such, for example, as potassium carbonate, pyridine, collidine or _-dimethylamino-pyridine.
A preferred method of chlorinating a compound of the general formula (III) comprises esterifying the 21-hydroxy group with a sulphonic acid, preferably with methanesulphonic acid or p~toluenesulphonic, and then exchanging the sulphonic acid group or chlorine. The 21-hydroxy group is esterified, for example, by causing a sulphonic acid chloride to act on tlle compound of formula ~III) in the presence of an organic base, such, for example, as pyridine, or in the presence of an aqueous alkali, The sulphonic acid group is exchanged for a chlorine atom pre-ferably by reacting the 21-sulphonic acid ester with an alkali metal chloride such as, for example, lithium chloride, in the presence of a polar solvent such, for example, as dimethylfor-mamide.
The process of the invention according to processvariant (c) may likewise be carried out under conditions known per se.
~=.~ = = _ The cleavage of an ortho ester of the general formula (IV) is preferably effected with trimethylsilyl fluoride, tri-¦ methylsilyl chloride or triphenylmethyl chloride, advantageously in an inert solvent such, for example, as a dipolar aprotic solvent (e.g. dimethylformamide, N-methylpyrrolidone, dimethyl sulphoxide or hexamethylphosphoric acid triamide), an ether (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxan or glycol dimethyl ether), a chlorinated hydrocarbon (e.g.
methylene chloride, chloroEorm or tetrachloroethane), a hydro~
carbon (e.g. benzene, toluene or cyclohexane) or a mixture of any two or more of these solvents.
The starting compound for the process according to the invention can thus be produced in a simple manner and with hiqh yields from prednisolone which can itself be synthesised relativ-ely easily from diosgenin. The result o~ this is -that compounds of the invention can be produced from diosgenin at relatively low expenditure and with a total yield of approximately 15%~ In contrast, the syntheses of the known highly effective corticoids from diosgenin requlre considerably more expendi-ture and the total yields obtained are significantly lower (approximately 0.5 to 5%).
In view of the growing difficulties in obtaining a sufficient quantity of suitable starting materials for the corticoid syntheses and with regard to the high cost of active substances, which is the disadvantage of corticoid-containing medicament specialities, this is not without significance.
As already mentioned, when the compounds oE the invention are administered topically they have a very strong anti-inflammatory activity but have only weak action when administered systemically.
The anti-inflammatory activity was determined as follows: A hyperaemia was produced on human skin in the following manner.
Part of the S-tratum corneum on the backs of male and female volunteers was stripped off by applying and tearing off 20 times from the same place a portion of "Tesa" (~egistered Trade Mark) self-adhesive tape 2 cm wide and a pronounced hyper~
aemia was thus produced.
Approximately 50 mg of the ointment preparations were applied to marked 4 cm2 zones inside the stripped area.
In order to obtain comparable starting values relative numbers were used since the colour of the untreated skin, as also the reddening of the hyperaemic area, differs from case to case.
The colour value of the untreated skin was se-t at 100 and that of the stripped skin at 0.
The skin colour value of the skin under vasoconstric-tion (100) was determined on a relative scale.
Relatively slight, average and a high degree of vaso-constriction was rated accordingly between 0 and 100.
The average values, which were derived from investi-gations of the various test persons and from various regions of the back, are given in the following Table A.
The system activity of the compounds was determined using the adjuvant-oedema test as follows:
SPF rats weighing 130 to 150 g were injected in the right hind leg with 0.1 ml of a 0.5~ Mycobacterium butyricum suspension (obtainable from the American firm Difko) in order to produce a focus of inflammation. The volume of the rats' legs was measured before injection and again 24 hours after injection to determine the extent of the oedema. Different quantities of the test substance were then administered orally to the rats.
After a further 24 hours the volume of the legs was determined once a~ain.
From the leg volumes obtained the quantity of test substance necessary to achieve 50~ healing of the oedema in the leg was determined in the normal manner.
The results obtained in the tests are given in the following Table A:
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Similar results are obtained if the systemic activity of the 9-fluoroprednisolone derivatives according to the invention is determined using the known thymolysis test or the known sodium/
potassium retention test.
In combination with the carriers conventionally used in galenical pharmacy compounds of the invention are suitable for the local treatment of contact dermatitis, eczemas of the most varied types, neurodermatoses, erythrodermia, burns, Pruritia vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, Lichen _ ruber planus et verrucosus and similar skin diseases.
~_ _ _ Accordingly, the present invention also provides a pharmaceutieal preparation which comprises a compound of the general formula (I), in admixture or conjunction with a pharma-ceutically suitable carrier.
The pharmaceutical preparations may be produced in a eonventional manner by converting the active substanees with suitable additives into the desired form of administration, such as, for example, solutions, lotions, ointments, creams or plasters. In the preparations formulated in -this manner the con-eentration o aetive substance depends on the form of administrat-ion. An active substance concentration of 0.001 to 1~ is preferably used in the case of lotions and ointments.
The present invention further provides a method of treating an animal to relive inflammation, which comprises applying a compound or preparation of the invention to the affected area.
In addition, compounds of the invention, optionally in combination with the conventional carriers and auxiliary agents, are also very suitable for the production of inhalants which can be used for the therapy of allergic diseases of the res-piratory system, such as, for example, bronchial asthma or rhinitis.
i ¦ A eompound or preparation of the present invention may also be used to alleviate inflammation caused by a medicament used for treating a non-inflammatory disease.
Aeeordingly, the present invention provides a pharma-eeutieal composition which comprises a compound of the general ! formula (I) in admixture with a medicament for the treatment of a non-inflammatory disease but which i5 liable to have an inflammatory aetion, and a pharmaceutical preparation which eomprises this eomposition in admixture or conjunetion with a ¦ 10 pharmaeeutieally suitable carrierO
¦ The present invention further provides a pack which ¦ eomprises a eompound of the general formula (I), or a pharma-I eeutieal preparation containing this, and a medicament for the ¦ treatment of a non-inflammatory disease but which is liable to ¦ have an inflammatory action.
¦ The following Examples illustrate the invention:
I-5yntheses Example 1 a) 5 g of 9~-fluoroprednisolone are added to 500 mg of pyridine tosylate, twice concentrated to dryness ln vacuo with benzene, in 500 ml of benzene and 40 ml of N,N-dimethylformamide.
At a bath temperature of 130C 50 ml of solvent are distilled off and 6 ml of orthoacetic acid triethyl ester are added. The remainder of the benzene is distilled off within 2.5 hours and after the addition of 2.4 ml of pyridine the whole is concen-trated in vacuo. 17~,21-~1-ethoxyethylidenedioxy)-9~fluoro-ll~-hydroxy-1,4-pregnadiene-3,20-diane is isolated as a yellow oily epimer mixture.
b) A solution of the oil thus obtained in 150 ml of methanol is refluxed for 1 hour at 90C with a mixture of 54 ml of 0.1 N acetic acid and 6 ml of 0.1 N aqueous sodium acetate solution. The mixture is concentrated to dryness in vacuo, added 2~
to water and extracted with ethyl acetate. The organic extracts are washed with water, dried and evaporated in vacuo. Yield:
9 g of 17~-acetoxy-9~-fluoro-11~-21-dihydroxy-1,4-pregnadiene-3,20-dione as a foam.
c) 3.0 g of 17~-acetoxy-9~-fluoro-11~,21-dihydroxy-1,4 pregnadiene-3,20-dione are stirred in 17 ml of pyridine and 8 ml of propionic anhydride for 1.5 hours at room temperature. After precipitating with ice water filtration is effected, the residue ~ is taken up in methylene chloride and is evaporated after washing and drying over sodium sulphate. 4.9 g are isolated which are chromatographed on 450 g of silica gel with a methylene chloride/
acetone gradient (0-15~ acetone). Yield: 2.96 g of 17~x-acetoxy-9~-fluoro-11~-hydroxy 21-propionyloxy-1,4-pregnadiene-3,20-dione.
Melting point 219C. [~]25 = +81 (pyridine). UV: ~239 =
(methanol).
Example 2
4.5 g of 17~-acetoxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are stirred overnight at room temperature in 50 ml of pyridine and 25 ml of butyric anhydride. The reaction product is precipitated with ice water, filtered off and dissolved in methylene chloride. The solution is washed with water, dried over sodium sulphate and concentrated in vacuo.
The residue is chromatographed on 700 g of silica gel with a me~h."e~e ~1~ mc~y~chloride/acetone gradient (0-15% acetone). Yield: 3.6 g of 17~-acetoxy-21-butyryloxy-9~-fluoro-11~-hydroxy-1,4-pregn-adiene-3,20-dione. Melting point 218C.
Example 3 1.0 g of 17~-acetoxy 9~-fluoro~ -21-dihydroxy-1,4-pregnadiene-3,20-dione is reacted as in Example 2 ~n 10 ml of pyridine with 6 ml of valeric anhydride instead of butyric anhydride. Yield: 680 mg of 17~-acetoxy-9~-fluoro-11~-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 213C.
Example 4 3.0 g of 17~-acetoxy~9~-fluoro 11~,21-dihydroxy-1,4-pregnadiene-3,20-dione in 30 ml of pyridine are stirred with 15 ml of caproic anhydride for 1.5 hours at room temperature. The mixture is worked up as in Example 2. The crude product is purified on 450 g of silica gel with a methylene chloride/
acetone gradient (0-12~ acetone). 2.36 g of 17~-ace-toxy-9~-fluoro-21-hexanoyloxy-11~-hydroxy-1,4-pregnadiene-3,20-dioneO
Melting point 222C. [~]D = ~ (pyridine). UV: E239 - 15500 (methanol).
Example 5 .
3.0 g of 17~-acetoxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are stirred with 15 ml of trimethylacetic anhydride in 30 ml of pyridine for 48 hours at room temperature.
As described in Example 2 ! the crude product is isolated and chromatographed on 700 g of silica gel with a methylene chloride/
acetone gradient (0-12~ acetone). Yield: 2.06 g of 17~-acetoxy-9~-fluoro-11~-hydroxy-21-trimethylacekoxy-1,4-pregnadiene-3,20-dione. Melting point 227C. 1~]D5 = +79 (pyridine). W: ~239 =
15500 (methanol).
E ample 6
The residue is chromatographed on 700 g of silica gel with a me~h."e~e ~1~ mc~y~chloride/acetone gradient (0-15% acetone). Yield: 3.6 g of 17~-acetoxy-21-butyryloxy-9~-fluoro-11~-hydroxy-1,4-pregn-adiene-3,20-dione. Melting point 218C.
Example 3 1.0 g of 17~-acetoxy 9~-fluoro~ -21-dihydroxy-1,4-pregnadiene-3,20-dione is reacted as in Example 2 ~n 10 ml of pyridine with 6 ml of valeric anhydride instead of butyric anhydride. Yield: 680 mg of 17~-acetoxy-9~-fluoro-11~-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 213C.
Example 4 3.0 g of 17~-acetoxy~9~-fluoro 11~,21-dihydroxy-1,4-pregnadiene-3,20-dione in 30 ml of pyridine are stirred with 15 ml of caproic anhydride for 1.5 hours at room temperature. The mixture is worked up as in Example 2. The crude product is purified on 450 g of silica gel with a methylene chloride/
acetone gradient (0-12~ acetone). 2.36 g of 17~-ace-toxy-9~-fluoro-21-hexanoyloxy-11~-hydroxy-1,4-pregnadiene-3,20-dioneO
Melting point 222C. [~]D = ~ (pyridine). UV: E239 - 15500 (methanol).
Example 5 .
3.0 g of 17~-acetoxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are stirred with 15 ml of trimethylacetic anhydride in 30 ml of pyridine for 48 hours at room temperature.
As described in Example 2 ! the crude product is isolated and chromatographed on 700 g of silica gel with a methylene chloride/
acetone gradient (0-12~ acetone). Yield: 2.06 g of 17~-acetoxy-9~-fluoro-11~-hydroxy-21-trimethylacekoxy-1,4-pregnadiene-3,20-dione. Melting point 227C. 1~]D5 = +79 (pyridine). W: ~239 =
15500 (methanol).
E ample 6
5.0 g of 9~-fluoro-11~-21-dihydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione, produced as in Example la and lb from 9~-fluoroprednisolone using orthopropionic acid triethyl ester instead of orthoacetic acid triethyl ester, are stirred in 50 ml of pyridine with 25 ml of propionic anhydride for 2 hours at room temperature. The mixture is worked up as described in Example 2. 4.8 g of crude product are purified on 450 g of silica gel with a methylene chloride/acetone gradient (0-15%).
Yield: 4.62 g of 9~~fluoro~ -hydroxy-17~,21-dipropionyloxy-1,4-pregnadiene~3,20-dioneO Melting point 191C. [~]D ~ ~51 (chloroform). UV: ~239 = 15700 (methanol).
2~
Example 7 5.0 og 9(x-fluoro-11~,21-dihydroxy-17r~-propionyloxy-1,4-pregnadiene~3,20-dione are reacted as in Example 2 with butyric anhydride. The crude product is chromatographed on 450 g of silica gel with a methylene chloride/acetone gradient (0-12 acetone). 4.93 g of 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-3,20 dione. Melting point 179C.
1~]D = +51 ~chloroform). W : ~239 = 15700 (methanol).
Example 8 _ .
5 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione are reacted as in Example 2 with valeric anhydride ins-tead of butyric anhydride. The whole is likewise worked up as described in Example 2. The crude produce is purified on 750 g of silica gel with a methylene chloride/acetone gradient (0-15% acetone). Yield: 5.03 g of 9(Y-fluoro-ll~-hydroxy-17~-propionyloxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 190C. [a]D = +54 ~chloroform).
W: ~239 = 15800 (methanol).
Example 9 5.0 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione are reacted as in Example 2 with caproic anhydride instead of butyric anhydride. The crude pro-duct weighing 5.8 g is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-12~ acetone). 4.32 g of 9~-fluoro-21-hexanoyloxy-11~-hydroxy-17~-propionyloxy-1~4-pregnadiene-3,20-dione are isolated. Melting point 208C.
[~]D = +52 (chloroform). W : E239 - 15900 (methanol).
Example_10 5.0 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione are reacted and worked up as in Example 2 with trimethylacetic anhydride instead of butyric anhydride 5.9 g of crude product are chromatographed on 450 g of silica ~ 15 -LZ~
gel with a methylene chloride/acetone gradient (0-12~ acetone).
Yield: 2.23 g of 9~-fluoro~ -hydroxy-17~-propionyloxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione. Meltin~ point 214C. [~]25 = +53o (chloroform). W : ~2~9 = 15700 (methanol).
Example 11 ~___ _ a) 25 g of 9~ fluoroprednisolone are stirred overnight at room temperature in 250 ml of pyridine and 125 ml of butyric anhydride. After precipitating with ice water filtration is ' effected and the residue is dissolved in methylene chloride. The solution is washed in water, dried over sodium sulphate and concentrated ln vacuo. The residue is chromatographed on 2.5 kg of silica gel with a methylene chloride/acetone yradient (0-15 acetone). Yield: 23.1 g of 21-butyryloxy-9~-fluoro~ ,17~-dihydroxy-1,4-pregnadiene-3,20-dione~
b) 100 ml of a 5% solution of methyl lithium in ether are added dropwise at 0C under argon to a suspension of 24 g of copper tI) iodide in 480 ml of dry tetrahydrofuran. The yellow mixture is cooled to -30C and a solution of 22.3 g of 21-butyryloxy-9~-rluoro-11~,17~-dihydroxy-1,4-pregnadiene-3,20-dione in 400 ml of dry tetrahydrofuran is added. The whole is stirred for 3 - 4 hours at this temperature. The excess reagent i5 destroyed with an aqueous ammonium chloride solution. ~fter extraction with methylene chloride the organic phase is washed, dried over sodium sulphate and evaporated in vacuo. Yield. 20.3 g of 17~-butyryloxy-9~-fluoro~ ,21-dihydroxy-1,4-pregnadiene-3,20-dione.
c) 2.0 g of 17~-butyryloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted, worked up and purified as in Example lc with propionic anhydride. 1.4 g of 17~-butyryloxy-9~-fluoro-11~-hydroxy-21-propionyloxy-1,4-preynadiene-3,20-dione are isolated. Melting point 146~C.
Example 12 1.5 g o~ 17~-butyryloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene 3,20-dione are reacted as in Example 2 with valeric anhydride instead of butyric anhydride to form 17~-butyryloxy-9~-fluoro-11~-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 220C.
Example 13 1.4 g of 17~-butyryloxy-9~-fluoro~ ,21-dihydroxy-1,4-pregnadiene-3,20-dione are stirred overnight at room temper-ature in 15 ml of pyridine and 10 ml of oenanthic anhydride.
The mixture is then stirred into ice water and extracted with methylene chloride. The extract is washed ~Jith water, dried over sodium sulphate and evaporated ln vacuo. The excess oenanthic acid in the residue is removed by distillation with steam. The crude product is chromatographed on 250 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone).
790 mg of 17~-butyryloxy-9~-~luoro-21-heptanoyloxy-11~-hydroxy-1,4-pregnadiene-3,20-dione are isolated.
Example 14 4.5 g of 17~-butyryloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted as Example 2 except that isobutyric anhydride is used instead of butyric anhydride. The crude product is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone). Yield: 2.1 g of 17~-butyryloxy-9~-fluoro-11~-hydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20~dione.
Example 15 _ a) 3 g of 9~-fluoroprednisolone are stirred overnight at room temperature in 30 ml of pyridine and 15 ml of valeric anhydride. The mixture is then stirred into ice water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and evapora-ted 1n vacuo. The excess valeric acid is removed from the residue by distillation with steam. The crude product is chromatographed on 300 g of silica gel with a methylene chloride/acetone gradient (0-15%
acetone). Yield: 2.87 g of 9~-fluoro-11~,17~-dihydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione.
b) 2 g of 9~-fluoro-11~,17~-dihydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione are converted as in Example llb with lithium dimethyl cupràte to form 1.86 g of 9~-fluoro-11~,21-' dihydroxy-17~-valeryloxy-1,4-pregnadiene-3,20-dione.
c) 1.8 g of 9~-fluoro-11~,21-dihydroxy-17~-valeryloxy-1,~-pregnadiene-3,20-dione are reacted as in Example 2, except that propionic anhydride is used instead of butyric anhydride, to form 920 mg of 9~-fluoro-11~-hydroxy-21-propionyloxy-17(x-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 206C.
E ample 16 3.4 g of 9~-fluoro-11~,21-dihydroxy-17~-valeryloxy-1,4-pregnadiene-3,20-dione are treated as in Example 2 with butyric anhydride and is worked up in an appropriate manner.
1.96 g of 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-valeryloxy-1,4-pregnadiene-3,20-dione are isolated. Melting point 234C.
Example 17 A solution of 2.0 g of 9~-fluoro-11~,21-dihydroxy-17~-valeryloxy-1,4-pregnadiene-3,20-dione in 20 ml of pyridine is stirred with 10 ml of caproic anhydride for 1.5 hours at room temperature. The reaction product is precipitated with ice water, filtered off and dissolved in methylene chloride. The solution is washed with water, dried and evaporated ln vacuo. The residue 1.96 g of crude product, is chromatographed on 200 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone~.
Yield: 1.58 g of 9~fluoro-21-hexanoyloxy-11~-hydroxy-17~-valeryloxy-1,4-pregnadiene-3/20-dione.
2~
E ample 18 a) 12 g of 9~-fluoroprednisolone are reacted as in Example lla, except that isobutyric anhydride is used instead of butyric anhydride, to form 10.4 g of 9~-fluoro~ ,17~-dihydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione.
b) 10 g of 9~-fluoro~ ,17~-dihydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione are converted as in Example llb with lithium dimethyl cuprate to form 6.9 g of 9~-fluoro-11~,21-~ dihydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione.
c) 2.1 g of 9~-fluoro-11~,21-dihydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione are reacted as in Example lc with propionic anhydride to form 1.3 g of 9~-fluoro-11~-hydroxy-17~-iso~utyryloxy-21-propionyloxy-1,4-pregnadiene-3,20-dione.
Example 19 _ _ 1.2 g of 9~-fluoro-11~,21-dihydroxy-17~-isobutyryIoxy-1,4-pregnadiene-3,20-dione are reacted with butyric anhydride, worked up and chromatographed as in Example 2. 670 mg of 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione are isolated.
Example 20 a) 5.0 g of 9~-fluoro-11~,17~-dihydroxy-21--trimethyl-acetoxy-1,4-pregnadiene-3,20-dione are converted as in Example llb with lithium dimethyl cuprate to form 3.4 g of 9~-fluoro-11~,21-dihydroxy-17~-trimethylacetoxy-1,4-pregnadiene-3,20-dione~
b) 2.4 g of 9~-fluoro-11~,21-dihydroxy-17~-trimethyl-acetoxy-1,4-pregnadiene-3,20-dione are reacted as in Example lc with propionic anhydride to form 1.2 g of 9~-fluoro-11~-hydroxy-21-propionyloxy-17~-trimethylacetoxy~1,4-pregnadiene-3,20-dione.
Example 21 3.1 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione produced from 9~-fluoroprednisolone 29~
as in Example la and lb using orthobenzoic acid triethyl ester instead o~ orthoacetic acid triethyl ester are stirred in 30 ml of pyridine and 15 ml of propionic anhydride for 1 hour at room temperature. The whole is worked up as in Example lc. The crude product is purified on 450 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone). Yield: 1.34 g of 17~-benzoyloxy-9~-fluoro-11~-hydroxy-21-propionyloxy-1,4-preg-nadiene-3,20-dione. Melting point 235C (decomposition).
~ [~]25 = +22 (pyridine). UV: ~234 = 28800 (methanol).
Example 22 3.0 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted and worked up as in Example 2 in 30 ml of pyridine and 15 ml of butyric anhydride.
After purifying the crude product on 450 g of silica gel with a methylene chloride/acetone gradient (0-12~ acetone). 1.9 g of 17~-benzoyloxy-21-butyryloxy-9~-fluoro-11~-hydroxy-1,4-preg-nadiene-3,20-dione are isolated. Melting point 218C (decompos-ition). [~]D5 = +21 (pyridine). UV: ~234 = 28900 (methanol).
Example 23 2.8 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted and worked up as in Example 2 except that valeric anhydride is used instead of butyric anhydride. The crude product is purified on 450 g of e f ~J~ e silica gel with a meth,~ chloride/acetone gradient (0-12% acetone).
1.81 g of 17~-benzoyloxy-9~~fluoro-11~-hydroxy-21-valeryloxy 1,4-pregnadiene-3,20-dione are obtained. Mel-ting point 208~C.
I~]25 = +22 (pyridine). UV: ~234 = 29000 (methanol).
Example 24 2.1 g of 17~~benzoyloxy-9~-fluoro~ ,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted and worked up as in Example 2 with isobutyric anhydride instead of butyric anhydride. The crude product is chromatographed on 200 g of silica gel with a -- ~0 --methylene chloride/acetone gradient (0 12% acetone3. 1.09 y of 17~~~enzoyloxy-9~-fluoro-11~-hydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione are obtained.
Example 25 1.8 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted as in Example 2 with trimethylacetic anhydride instead of butyric anhydride, worked up in an appropriate manner and chromatographed as described in Example 2. 720 mg of 17~-benzoyloxy-9~-fluoro-11~-hydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione are isolated.
Example 26 10 ml of hexamethylphosphoric acid triamide are stirred with 1.3 ml of thionyl chloride for 30 minutes at 0C.
800 mg of 17~-acetoxy-9u-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are then added and stirring is continued for 5.5 hours at 0C. The mixture is added to ice water, extracted with ethyl acetate and the extracts are washed neutral with sodium hydrogen carbonate and water. The whole is dried over sodium sulphate and after concentration in vacuo 1 g of crude product is isolated which is purified on 65 g of silica gel with a methylene chloride/acetone gradient ~0-15~ acetone). Yield:
535 mg of 17~-acetoxy-21-chloro-9~-fluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione. Melting point 265C tdecomposition).
[~]25 = +101 ~pyridine). UV: ~239 = 15800 (methanol)~
Example _ 1.2 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione are reacted with thionyl chloride in hexamethylphosphoric acid triamide as in Example 26. The crude product is chromatographed on 150 g of silica gel with a methyl-ene chloride/acetone gradient (0-15~ acetone). Yield: 860 mg of 21-chloro-9~ fluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione. Melting point 229C (decomposition). [~]D ~ +98 ~4~
(pyridine). W: ~239 = 15900 (methanol).
Example 28 ___ 950 mg of 9~-fluoro-11~,21-dihydroxy-17(~-isobutyryloxy-1,4-pregnadiene-3,20-dione are treated as in ~xample 26 with thionyl chloride in hexamethylphosphoric acid triamide. The crude product is purified on 120 g of silica gel with a methylene chloride/acetone gradient (0-15~ acetone). Yield: 520 mg of 21-chloro-9~-fluoro~ -hydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione. Melting point 216~C.
Example 29 2.5 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are are reacted as in Example 26 and the crude product is purified on 250 g of silica yel with a methylene chloride/acetone gradient (0-12% acetone). Yield:
1.1 g of 17~-benzoyloxy-21-chloro-9~-fluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione. ~elting point 256~C (decomposition).
[~]D5 ~ ~15 (pyridine). UV: E234 = 28600 tme-thanol).
Example 30 a) A suspension of 8.7 g of 21-fluoro-17~-hydroxy-1,4,9 (11)-pregnatriene-3,20-dione in 100 ml of diethylene glycol dimethyl ether is stirred with 12 g of N,N-dimethylaminopyridine and 8.8 ml of acetanhydride for 6.5 hours at 80~C. The reaction mixture is diluted with methylene chloride and washed with 2 N
hydrochloric acid. After distillation with steam extraction is effected with methylene chloride drying is effected over sodium sulphate and afker evapora-tion 7.9 g of 17u-acetoxy-21-fluoro-1,4,9(11)-pregnatriene-3,20-dione are iso]ated.
b) 7.6 of 17~-acetoxy-21-fluoro-1,4,9(11)-pregnatriene-3,20-dione are dissolved in 7h ml of dioxan and 7.2 g of N~
bromo-succinimide are added. After the dropwise addition of 38 ml of 10% aqueous perchloric acid stirring is continued for 30 minutes at room temperature and the reaction solution i5 added to a solution of 3.5 g of sodium hydrogen sulphite in 350 ml of water. The precipitate ls sucked off and 10 g of 17~1-acetoxy-9~-bromo-21-fluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione are obtained after drying.
c) 10 g of ~he above crude product are refluxed for 2 hours at 110C in 600 ml of ethanol with 14.0 g of potassium acetate. The reaction solution is concentra-ted ln vacuo and is added to ice water. The precipitate is filtered off and the ' crude product is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-6% acetone). Yield: 3.4 g of 17~-acetoxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione.
d) 31 ml of a 70% (~IF) /pyridine solutioIl are cooled to -60C and a solution of 3 g of 17~-acetoxy-9,11~-epoxy-21-fluoro~
1,4~pregnadiene-3,20-dione in 3 rnl of pyridine is added~ The reaction solution is stirr~d for 10 hours at -5C and then stored for 3 days in a refrigerator. The whole is added to ammoniacal ice water and the precipitate is filtered off. The crude product is purified on 350 g of silica gel with a methylene chloride/acetone gradient (0-15% acetone). Yield: 2.15 y of 17~-acetoxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione. Melting point 276C (decomposition) [~]D = +16 (chloroform). W: ~239 = 15800 (methanol).
Example 31 a) 5 g of 21-fluoro-17~-propionyloxy-1,4,9(11)-pregnatriene-3,20-dione are produced as in Example 30a from 7~9 g of 21-fluoro-17a-hydroxy-1,4,9(11)-pregnatriene-3,20-dione and propionic anhydride and these 5 g are reacted with N-bromo-succinimide under the conditions described in Example 30b. Yield: 8.5 g of 9~-bromo-21-fluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione.
b) 8.5 g of the above crude product are reacted with potassium acetate under the conditions described in Example 30c.
The crude product is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-6% acetone). Yield: 5.3 g of 9,ll~~epoxy-21~fluoro-17~-propionyloxy-1,4-preynadiene-3~20-dione.
c) 5.0 g of 9,1]~-epoxy-21-fluoro--17~-propionyloxy-1,4-pregnadiene-3,20-dione are treated as in r~xample 30d with 70~
(HF)n/pyridine solution. The reac-tion product is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-15% acetone). Yield: 3.98 g of 9~,21-difluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione. Melting point 21~C. [~]25 = +15 (chloroform). UV: ~:239 = 15800 (methanol).
Example 32 a) 20.0 g of 17~-butyryloxy-21-fluoro-1,4,9(11)-pregna-triene-3,20 dione, produced as in Example 30a from 21-fluoro-17~-hydroxy-1,4,9~11)-pregnatriene-3,20-dione and butyric anhydride, are treated with N-bromosuccinimide as in Example 30b.
Yield: 24.9 g of 9~-butyryloxy-21-fluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione.
b) The above crude product is treated with potassium 2Q acetate under the conditions described in Example 3c. 16.1 g of 17~-butyryloxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione are isolated.
c) 15.1 g of 17~-butyryloxy-9,llR-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione are treated as in Example 30d with 70%
(HF)n/pyridine solution. The crude product is purified on 1.5 kg of silica gel with a methylene chloride/acetone gradient (0-15% acetone). 13.4 g of 17~-bu~yryloxy-9~,21--difluoro~
hydroxy-1,4-pregnadiene-3,20-dione are obtained. Melting point 126C. 1~]25 = -~11 (chloroform). UV: ~239 = 15300 (methanol).
Example 33 a) 7.1 g of 21-fluoro-17~-valeryloxy-1,4,9(11)-pregnatriene-3,20-dione are produced as in Example 30a from 9.0 g of 21-- 2~ -fluoro-17~-hydroxy-1,4,9(~ pregnatriene-3,20-dione and valeric ~ ob anhydride and these 7.1 g are treated as in ~xample ffl with N-bromosuccinimide. Yield: 8.7 g 9~-bromo-21-fluoro~ 3-hydroxy-17~-valeryloxy-1,4-pregnadiene-3t20-dione.
b) 6.0 g of the above crude product are reacted as in Example 30c with potassium acetate. After purifying the reaction product on 700 g of silica yel with a methylene chloride/ace-tone gradient (0-5~ acetone) 4.2 c~ of 9,llr~-epoxy-21-fluoro-17~-~ valeryloxy-1,4-pregnadiene-3,20-dione are obtained.
c) 3.1 g of 9~,21-difluoro-11~-hydroxy-17~-valeryloxy-1,4-pregnadiene-3,20~dione are produced as in Example 30d by the reaction of 3.8 g of 9,11~-epoxy-21-fluoro-17~-valeryloxy-1,4-pregnadiene-3,20-dione with a 70% (~IF) /pyridine solution, which 3.1 g are obtained after purification on 450 g of silica gel with a methylene chloride/acetone gradient (0-15% acetone).
Melting point 139C. [~]D5 = +10 (chloroform). W: ~239 =
15800 (methanol).
Exam~le 34 a) Under the conditions described in Example 30a 7.3 y of 21-fluoro-17a-hexanoyloxy-1,4,9(11)-pregnatriene-3,20-dione are produced from 8.9 g of 21-fluoro-17~-hydroxy-1,4,9(11)-preg-natriene-3,20-dione and caproic anhydride which 7.3 g are reacted as in Example 30b with N-bromosuccinimide~ Yield: 8.2 g of 9~-bromo-21-fluoro-17~-hexanoyloxy~ -hydroxy-1,4-preynadiene-3,20-dione.
b) 8.0 g of the above crude product are treated as in Example 30c wi-th potassium acetate and the crude product is purified with a methylene chloride/acetone yradient (0-5~ acetone).
5.8 g of 9,11~-epoxy-21-fluoro-17~-hexanoyloxy-1,4-pregnadiene-3,20-dione are isolated.
c) 3.2 g of 9,11~-epoxy-21-fluoro-17~-hexanoyloxy-1,4-pregnadiene-3,20-dione are treated, as described in Example 30d, with a 70% ~HF) /pyridine solution. The reaction product is purified on 350 g of silica gel wlth a methylene chloride/
acetone gradient (0-15% acetone). Yield: 2.6 g of 9~,21-difluoro-17~-hexanoyloxy-11~-hydroxy-1,4-pregnadiene-3,20-dione.
Example 35 .
a) 6.2 g of 21-fluoro-17(x-isobutyryloxy-1,4,9~ preg-natriene-3,20-dione are produced as in Example 30a from 8.1 g of 21-fluoro-17~-hydroxy-1,4,9(11)-pregnatriene-3,20-dione and isobutyric anhydride, which 6.2 g are reacted as in Example 30b with N-bromosuccinimide. Yield: 6.9 g of 9~-bromo-21-fluoro-ll~-hydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione.
b) 6.0 g of the above crude product are reacted as in Example 30c with potassium acetate and the reaction product is purified on 600 g of silica gel with a methylene chloride/acetone gradient (0-5% acetone). 4.1 g of 9,11~-epoxy-21-fluoro-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione are obtained.
c) 3.5 g of 9,11~-epoxy-21-fluoro-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione are reacted as in Example 30d with a 70%
(HF)n/pyridine solution. The crude product is purified on 400 g of silica gel with a methylene chloride/acetone gradient (0-15%
acetone). Yield: 2.9 g of 9~,21-difluoro-11~-hydroxy-17(~-isobutyryloxy-1,4-pregnadiene-3,20-dione.
Example 36 . _ a) 8.0 g of 21-fluoro-17(1-hydroxy-1,4,9(11)-pregnatriene-3,20-dione are added to a mixture of 80 ml of isovaleric acid and 32 ml of tri~luoroacetic anhydride and then stirred for 2.5 hours at 80C. The whole is then added to hot water in order to destroy the excess anhydride and is aEterwards extracted with methylene chloride. After neutralising with 1~ pyridine/water and drying over sodium sulphate the whole is evaporated in vacuo.
The substance is dissolved in small quantity of pyridine, added to ice water and the pyridine is neutralised with dilute hydro-chloric acid. After working up in the usual manner 5.8 g of 21-fluoro-17~-isovaleryloxy-1,4,9(11)-preynatriene-3,20-dione are isolated.
b) 5.3 g of 21-fluoro-17(1-isovaleryloxy-1,4,9(11)-pregnatriene ~20-dione are treated as in Example 30b with N-bromosuccinimide. 6.2 g of 9~-bromo-21-fluoro-11~-hydroxy-17~-isovaleryloxy-1,4-pregnadiene-3,20-dione are obtained.
c) 6.0 g of the above crude product are reacted as in ' Example 30c with potasslum acetate. The reaction product is purified on 600 g of silica gel with a methylene chloride/
acetone gradient (0-5% acetone). Yield: 3.7 g of 9,11~-epoxy-21-fluoro~17~-isovaleryloxy-1,4-pregnadiene-3,20-dione.
d) Under the conditions in Example 30d 3 g of 9~
epoxy-21-fluoro-17~-i`sovaleryloxy-1,4-pregnadiene-3,20-dione are reacted with a 70~ (IIF) /pyridine solution. The crude product is purified on 300 g of silica gel with a methylene chloride/
acetone gradient (0-15% acetone). Yield: 2.1 g of 9~,21~difluoro-ll~-hydroxy-17~-isovaleryloxy-1,4-pregnadiene-3,20-dione.
Example 37 .
a) As described in Example 30a 8.7 g of 21-fluoro-17~-hydroxy-1,4,9tll)-pregnatriene-3,20-dione and trimethyl acetan-hydride are reacted to form 6.3 g of 21-fluoro-17~-trimeth~l-acetoxy-1,4,9~11)-pregnatriene-3,20-dione, which 6.3 9 are treated as in Example 30b with N-bromosuccinimide. After working up in the usual manner 6.5 g of 9~~bromo-21-fluoro-11~-hydroxy-17~-trimethylacetoxy-1,4-pregnadiene-3,20-dione are isolated.
b) 6.0 g of the above crude product are reacted as in Example 30c with potassium acetate and the crude product is purified on 600 g of silica gel with a methylene chloride/
acetone gradient (0-5~ acetone). Yield: 3.1 g of 9,11~-epoxy-21-fluoro-17~-trinlRthylacetoxy-1,4-pregnadiene-3,20-dione.
c) 1.9 g of 9~,21-difluoro-11~-hydroxy-17~-trimethyl-acetoxy-1,4-pregnadiene-3,20-dione are produced as in Example 30d from 3.0 g of 9,11~-epoxy-21-fluoro-17~-trimethylacetoxy-1,4-pregnadiene-3,20-dione by reaction with a 70% (HF)n/pyridine solution, which 1.9 g are obtained after purification on 300 g of silica gel with a methylene chloride/ace-tone gradient (0-15% acetone).
Example 38 .
a) 7 0 g of 21-fluoro-17~-~3~phenylpropiony]oxy)-1,4,9 (ll)-pregnatriene-3,20-dione are produced as in Example 30a from 15.4 g of 21-fluoro-17~-hydroxy-1,~,9(11)-pregnatriene-3,20-dione and 3-phenylpropionic acid chloride, which 7.0 g are reacted as in Example 30b with N-bromosuccinimide. Yield: 6~9 g of 9~-bromo-21-fluoro-11~-hydroxy-17~-(3-phenyl-propionyloxy)-1,4-pregnadiene-3,20-dione.
b) 6.5 g of the above crude product are reacted with potassium acetate under the conditions of Example 30c. The crude product is purified on 650 g of silica gel with a methylene chloride/acetone gradient (0-5~ acetone). Yield: 3.8 g of 9, ll~-epoxy-21-fluoro-17~-(3-phenylpropionyloxy)-1,4-pregnadiene-3,20-dione.
c) 3.5 g of 9,11~-epoxy-21-fluoro-17~-(3-phenylpropiony-loxy)-l,~-pregnadiene-3,20-dione are treated as in Example 30d with a 70% (HF)n/pyridine solution and the crude product is purified on 400 g of silica gel with a methylene chloride/ ~;
acetone gradient (0-15% acetone). Yield: 2.1 g of 9~,21-difluoro-ll~-hydroxy-17~-(3-phenylpropionyloxy)-1,4-pregnadiene-3,20-dione.
Example 39 ...
a) 5.8 g of 17~-cyclopentanecarbonyloxy-21-fluoro-1,~,9 L.
(11)-pregnatriene-3,20-dione are produced as in Example 36 from 9.1 g of 21-fluoro-17~-hydroxy-1,4,9(11)-pregnatriene-3,20-dione, 91 ml of cyclopentanoic acid and 44 ml of trifluoroacetic 2~
; anhydride, which 5.8 g are treated as in Example 30b with ~ N-bromosuccinimide. After working up in the normal manner 5.1 j g of 9~-bromo-17~-cyclopentanecarbonyloxy-21-fluoro-11~-hydroxy-i 1,4-pregnadiene-3,20-dione are isolated.
b) 6.0 g of the above crude product are reacted as in Example 30c with potassium ace~ate and the crude product is purified on 600 g of silica gel with a methylene chloride/acetone gradient (0-5% acetone). 4.5 g of 17~-cyclopentanecarbonyloxy-9,11~-epoxy-21-fluoro-1,4~pregnadiene-3,20-dione are obtained.
c) 4.0 g of 17~-cyclopentanecarbonyloxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione are reacted as in Example 30d with a 70% (IIF) /pyridine solution. The crude product is purified on 400 g of silica gel with a methylene chloride/acetone gradient (0-15~ acetone). Yield: 2.8 g of 17~-cyclopentane-i carbonyloxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione.
Example 40 a) 5.8 g of 17~-cyclohexanecarbonyloxy-21-fluoro 1,4,9(11)-pregnatriene-3,20-dione are produced under the conditions of Example 36 from 9.2 g of 21-fluoro-17~-hydroxy-1,4,9(11)-preqnatriene-3,20-dione, 92 ml of cyclohexanecarboxylic acid and 40 ml of trifluoroacetic anhydride, which 5.8 g are reacted as ¦ in Example 30b with N-bromosuccinimide. Yield. 6.1 g of 9~-bromo-17~-cyclohexanecarbonyloxy-21-fluoro-11~-hydroxy 1,4-pregnadiene-3,20-dione.
b) 6.0 g of the above crude product are reacted as in ¦ Example 30c with potassium acetate and the crude product is ! - purified on 600 g of silica gel with a methylene chloride/acetone gradient (0-5% acetone). Yield: 3.4 g of 17~-cyclohexanecarbony-loxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione.
c) 2.4 g o~ 17~-cyclohexanecarbonyloxy-9~,21-difluoro--hydroxy-1,4-pregnadiene-3,20-dione are produced as in Example 30d from 3.1 g of 17~-cyclohexanecarbonyloxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione by reaction with a 70% (HF)n/
pyridine solution, which 2.4 g are obtained after purification on 300 g of silica ~el with a methylene chloride/acetone gradient (0-15% acetone).
Example 41 1 g of 17~,21-(1-ethoxybenzylidenedioxy)-9~ fluoro-~ -hydroxy-1,4-pregnadiene-3,20-dione is stirred in 40 ml of ¦ dimethylformamide with 4 ml of trimethylsilyl fluoride for 2 ¦ hours at room temperature. After precipitating with ice water and working up in the usual manner the whole is evaporated ln vacuo. The crude product is purified on 120 g of silica gel with a methylene chloride/acetone gradient (0-10~ acetone). Yield:
240 mg of 17~-benzoyloxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione.
II Pharmaceutical preparations Example 42 3 Composition of an ointment 1 0.03~ of 9~-fluoro-11~-hydroxy-17~,21-dipropionyloxy-1,4-pregnadiene-3,20-dione ` 20 2.50% Allercur hexachlorophenate, micronised, particle size ~ approximately 8 ~ (Allercur = Trade Mark for l-p-chlorobenzyl-¦ 2-pyrrolidylmethylbenæimidazole)
Yield: 4.62 g of 9~~fluoro~ -hydroxy-17~,21-dipropionyloxy-1,4-pregnadiene~3,20-dioneO Melting point 191C. [~]D ~ ~51 (chloroform). UV: ~239 = 15700 (methanol).
2~
Example 7 5.0 og 9(x-fluoro-11~,21-dihydroxy-17r~-propionyloxy-1,4-pregnadiene~3,20-dione are reacted as in Example 2 with butyric anhydride. The crude product is chromatographed on 450 g of silica gel with a methylene chloride/acetone gradient (0-12 acetone). 4.93 g of 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-3,20 dione. Melting point 179C.
1~]D = +51 ~chloroform). W : ~239 = 15700 (methanol).
Example 8 _ .
5 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione are reacted as in Example 2 with valeric anhydride ins-tead of butyric anhydride. The whole is likewise worked up as described in Example 2. The crude produce is purified on 750 g of silica gel with a methylene chloride/acetone gradient (0-15% acetone). Yield: 5.03 g of 9(Y-fluoro-ll~-hydroxy-17~-propionyloxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 190C. [a]D = +54 ~chloroform).
W: ~239 = 15800 (methanol).
Example 9 5.0 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione are reacted as in Example 2 with caproic anhydride instead of butyric anhydride. The crude pro-duct weighing 5.8 g is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-12~ acetone). 4.32 g of 9~-fluoro-21-hexanoyloxy-11~-hydroxy-17~-propionyloxy-1~4-pregnadiene-3,20-dione are isolated. Melting point 208C.
[~]D = +52 (chloroform). W : E239 - 15900 (methanol).
Example_10 5.0 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione are reacted and worked up as in Example 2 with trimethylacetic anhydride instead of butyric anhydride 5.9 g of crude product are chromatographed on 450 g of silica ~ 15 -LZ~
gel with a methylene chloride/acetone gradient (0-12~ acetone).
Yield: 2.23 g of 9~-fluoro~ -hydroxy-17~-propionyloxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione. Meltin~ point 214C. [~]25 = +53o (chloroform). W : ~2~9 = 15700 (methanol).
Example 11 ~___ _ a) 25 g of 9~ fluoroprednisolone are stirred overnight at room temperature in 250 ml of pyridine and 125 ml of butyric anhydride. After precipitating with ice water filtration is ' effected and the residue is dissolved in methylene chloride. The solution is washed in water, dried over sodium sulphate and concentrated ln vacuo. The residue is chromatographed on 2.5 kg of silica gel with a methylene chloride/acetone yradient (0-15 acetone). Yield: 23.1 g of 21-butyryloxy-9~-fluoro~ ,17~-dihydroxy-1,4-pregnadiene-3,20-dione~
b) 100 ml of a 5% solution of methyl lithium in ether are added dropwise at 0C under argon to a suspension of 24 g of copper tI) iodide in 480 ml of dry tetrahydrofuran. The yellow mixture is cooled to -30C and a solution of 22.3 g of 21-butyryloxy-9~-rluoro-11~,17~-dihydroxy-1,4-pregnadiene-3,20-dione in 400 ml of dry tetrahydrofuran is added. The whole is stirred for 3 - 4 hours at this temperature. The excess reagent i5 destroyed with an aqueous ammonium chloride solution. ~fter extraction with methylene chloride the organic phase is washed, dried over sodium sulphate and evaporated in vacuo. Yield. 20.3 g of 17~-butyryloxy-9~-fluoro~ ,21-dihydroxy-1,4-pregnadiene-3,20-dione.
c) 2.0 g of 17~-butyryloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted, worked up and purified as in Example lc with propionic anhydride. 1.4 g of 17~-butyryloxy-9~-fluoro-11~-hydroxy-21-propionyloxy-1,4-preynadiene-3,20-dione are isolated. Melting point 146~C.
Example 12 1.5 g o~ 17~-butyryloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene 3,20-dione are reacted as in Example 2 with valeric anhydride instead of butyric anhydride to form 17~-butyryloxy-9~-fluoro-11~-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 220C.
Example 13 1.4 g of 17~-butyryloxy-9~-fluoro~ ,21-dihydroxy-1,4-pregnadiene-3,20-dione are stirred overnight at room temper-ature in 15 ml of pyridine and 10 ml of oenanthic anhydride.
The mixture is then stirred into ice water and extracted with methylene chloride. The extract is washed ~Jith water, dried over sodium sulphate and evaporated ln vacuo. The excess oenanthic acid in the residue is removed by distillation with steam. The crude product is chromatographed on 250 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone).
790 mg of 17~-butyryloxy-9~-~luoro-21-heptanoyloxy-11~-hydroxy-1,4-pregnadiene-3,20-dione are isolated.
Example 14 4.5 g of 17~-butyryloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted as Example 2 except that isobutyric anhydride is used instead of butyric anhydride. The crude product is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone). Yield: 2.1 g of 17~-butyryloxy-9~-fluoro-11~-hydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20~dione.
Example 15 _ a) 3 g of 9~-fluoroprednisolone are stirred overnight at room temperature in 30 ml of pyridine and 15 ml of valeric anhydride. The mixture is then stirred into ice water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and evapora-ted 1n vacuo. The excess valeric acid is removed from the residue by distillation with steam. The crude product is chromatographed on 300 g of silica gel with a methylene chloride/acetone gradient (0-15%
acetone). Yield: 2.87 g of 9~-fluoro-11~,17~-dihydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione.
b) 2 g of 9~-fluoro-11~,17~-dihydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione are converted as in Example llb with lithium dimethyl cupràte to form 1.86 g of 9~-fluoro-11~,21-' dihydroxy-17~-valeryloxy-1,4-pregnadiene-3,20-dione.
c) 1.8 g of 9~-fluoro-11~,21-dihydroxy-17~-valeryloxy-1,~-pregnadiene-3,20-dione are reacted as in Example 2, except that propionic anhydride is used instead of butyric anhydride, to form 920 mg of 9~-fluoro-11~-hydroxy-21-propionyloxy-17(x-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 206C.
E ample 16 3.4 g of 9~-fluoro-11~,21-dihydroxy-17~-valeryloxy-1,4-pregnadiene-3,20-dione are treated as in Example 2 with butyric anhydride and is worked up in an appropriate manner.
1.96 g of 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-valeryloxy-1,4-pregnadiene-3,20-dione are isolated. Melting point 234C.
Example 17 A solution of 2.0 g of 9~-fluoro-11~,21-dihydroxy-17~-valeryloxy-1,4-pregnadiene-3,20-dione in 20 ml of pyridine is stirred with 10 ml of caproic anhydride for 1.5 hours at room temperature. The reaction product is precipitated with ice water, filtered off and dissolved in methylene chloride. The solution is washed with water, dried and evaporated ln vacuo. The residue 1.96 g of crude product, is chromatographed on 200 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone~.
Yield: 1.58 g of 9~fluoro-21-hexanoyloxy-11~-hydroxy-17~-valeryloxy-1,4-pregnadiene-3/20-dione.
2~
E ample 18 a) 12 g of 9~-fluoroprednisolone are reacted as in Example lla, except that isobutyric anhydride is used instead of butyric anhydride, to form 10.4 g of 9~-fluoro~ ,17~-dihydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione.
b) 10 g of 9~-fluoro~ ,17~-dihydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione are converted as in Example llb with lithium dimethyl cuprate to form 6.9 g of 9~-fluoro-11~,21-~ dihydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione.
c) 2.1 g of 9~-fluoro-11~,21-dihydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione are reacted as in Example lc with propionic anhydride to form 1.3 g of 9~-fluoro-11~-hydroxy-17~-iso~utyryloxy-21-propionyloxy-1,4-pregnadiene-3,20-dione.
Example 19 _ _ 1.2 g of 9~-fluoro-11~,21-dihydroxy-17~-isobutyryIoxy-1,4-pregnadiene-3,20-dione are reacted with butyric anhydride, worked up and chromatographed as in Example 2. 670 mg of 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione are isolated.
Example 20 a) 5.0 g of 9~-fluoro-11~,17~-dihydroxy-21--trimethyl-acetoxy-1,4-pregnadiene-3,20-dione are converted as in Example llb with lithium dimethyl cuprate to form 3.4 g of 9~-fluoro-11~,21-dihydroxy-17~-trimethylacetoxy-1,4-pregnadiene-3,20-dione~
b) 2.4 g of 9~-fluoro-11~,21-dihydroxy-17~-trimethyl-acetoxy-1,4-pregnadiene-3,20-dione are reacted as in Example lc with propionic anhydride to form 1.2 g of 9~-fluoro-11~-hydroxy-21-propionyloxy-17~-trimethylacetoxy~1,4-pregnadiene-3,20-dione.
Example 21 3.1 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione produced from 9~-fluoroprednisolone 29~
as in Example la and lb using orthobenzoic acid triethyl ester instead o~ orthoacetic acid triethyl ester are stirred in 30 ml of pyridine and 15 ml of propionic anhydride for 1 hour at room temperature. The whole is worked up as in Example lc. The crude product is purified on 450 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone). Yield: 1.34 g of 17~-benzoyloxy-9~-fluoro-11~-hydroxy-21-propionyloxy-1,4-preg-nadiene-3,20-dione. Melting point 235C (decomposition).
~ [~]25 = +22 (pyridine). UV: ~234 = 28800 (methanol).
Example 22 3.0 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted and worked up as in Example 2 in 30 ml of pyridine and 15 ml of butyric anhydride.
After purifying the crude product on 450 g of silica gel with a methylene chloride/acetone gradient (0-12~ acetone). 1.9 g of 17~-benzoyloxy-21-butyryloxy-9~-fluoro-11~-hydroxy-1,4-preg-nadiene-3,20-dione are isolated. Melting point 218C (decompos-ition). [~]D5 = +21 (pyridine). UV: ~234 = 28900 (methanol).
Example 23 2.8 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted and worked up as in Example 2 except that valeric anhydride is used instead of butyric anhydride. The crude product is purified on 450 g of e f ~J~ e silica gel with a meth,~ chloride/acetone gradient (0-12% acetone).
1.81 g of 17~-benzoyloxy-9~~fluoro-11~-hydroxy-21-valeryloxy 1,4-pregnadiene-3,20-dione are obtained. Mel-ting point 208~C.
I~]25 = +22 (pyridine). UV: ~234 = 29000 (methanol).
Example 24 2.1 g of 17~~benzoyloxy-9~-fluoro~ ,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted and worked up as in Example 2 with isobutyric anhydride instead of butyric anhydride. The crude product is chromatographed on 200 g of silica gel with a -- ~0 --methylene chloride/acetone gradient (0 12% acetone3. 1.09 y of 17~~~enzoyloxy-9~-fluoro-11~-hydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20-dione are obtained.
Example 25 1.8 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are reacted as in Example 2 with trimethylacetic anhydride instead of butyric anhydride, worked up in an appropriate manner and chromatographed as described in Example 2. 720 mg of 17~-benzoyloxy-9~-fluoro-11~-hydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione are isolated.
Example 26 10 ml of hexamethylphosphoric acid triamide are stirred with 1.3 ml of thionyl chloride for 30 minutes at 0C.
800 mg of 17~-acetoxy-9u-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are then added and stirring is continued for 5.5 hours at 0C. The mixture is added to ice water, extracted with ethyl acetate and the extracts are washed neutral with sodium hydrogen carbonate and water. The whole is dried over sodium sulphate and after concentration in vacuo 1 g of crude product is isolated which is purified on 65 g of silica gel with a methylene chloride/acetone gradient ~0-15~ acetone). Yield:
535 mg of 17~-acetoxy-21-chloro-9~-fluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione. Melting point 265C tdecomposition).
[~]25 = +101 ~pyridine). UV: ~239 = 15800 (methanol)~
Example _ 1.2 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione are reacted with thionyl chloride in hexamethylphosphoric acid triamide as in Example 26. The crude product is chromatographed on 150 g of silica gel with a methyl-ene chloride/acetone gradient (0-15~ acetone). Yield: 860 mg of 21-chloro-9~ fluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione. Melting point 229C (decomposition). [~]D ~ +98 ~4~
(pyridine). W: ~239 = 15900 (methanol).
Example 28 ___ 950 mg of 9~-fluoro-11~,21-dihydroxy-17(~-isobutyryloxy-1,4-pregnadiene-3,20-dione are treated as in ~xample 26 with thionyl chloride in hexamethylphosphoric acid triamide. The crude product is purified on 120 g of silica gel with a methylene chloride/acetone gradient (0-15~ acetone). Yield: 520 mg of 21-chloro-9~-fluoro~ -hydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione. Melting point 216~C.
Example 29 2.5 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-1,4-pregnadiene-3,20-dione are are reacted as in Example 26 and the crude product is purified on 250 g of silica yel with a methylene chloride/acetone gradient (0-12% acetone). Yield:
1.1 g of 17~-benzoyloxy-21-chloro-9~-fluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione. ~elting point 256~C (decomposition).
[~]D5 ~ ~15 (pyridine). UV: E234 = 28600 tme-thanol).
Example 30 a) A suspension of 8.7 g of 21-fluoro-17~-hydroxy-1,4,9 (11)-pregnatriene-3,20-dione in 100 ml of diethylene glycol dimethyl ether is stirred with 12 g of N,N-dimethylaminopyridine and 8.8 ml of acetanhydride for 6.5 hours at 80~C. The reaction mixture is diluted with methylene chloride and washed with 2 N
hydrochloric acid. After distillation with steam extraction is effected with methylene chloride drying is effected over sodium sulphate and afker evapora-tion 7.9 g of 17u-acetoxy-21-fluoro-1,4,9(11)-pregnatriene-3,20-dione are iso]ated.
b) 7.6 of 17~-acetoxy-21-fluoro-1,4,9(11)-pregnatriene-3,20-dione are dissolved in 7h ml of dioxan and 7.2 g of N~
bromo-succinimide are added. After the dropwise addition of 38 ml of 10% aqueous perchloric acid stirring is continued for 30 minutes at room temperature and the reaction solution i5 added to a solution of 3.5 g of sodium hydrogen sulphite in 350 ml of water. The precipitate ls sucked off and 10 g of 17~1-acetoxy-9~-bromo-21-fluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione are obtained after drying.
c) 10 g of ~he above crude product are refluxed for 2 hours at 110C in 600 ml of ethanol with 14.0 g of potassium acetate. The reaction solution is concentra-ted ln vacuo and is added to ice water. The precipitate is filtered off and the ' crude product is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-6% acetone). Yield: 3.4 g of 17~-acetoxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione.
d) 31 ml of a 70% (~IF) /pyridine solutioIl are cooled to -60C and a solution of 3 g of 17~-acetoxy-9,11~-epoxy-21-fluoro~
1,4~pregnadiene-3,20-dione in 3 rnl of pyridine is added~ The reaction solution is stirr~d for 10 hours at -5C and then stored for 3 days in a refrigerator. The whole is added to ammoniacal ice water and the precipitate is filtered off. The crude product is purified on 350 g of silica gel with a methylene chloride/acetone gradient (0-15% acetone). Yield: 2.15 y of 17~-acetoxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione. Melting point 276C (decomposition) [~]D = +16 (chloroform). W: ~239 = 15800 (methanol).
Example 31 a) 5 g of 21-fluoro-17~-propionyloxy-1,4,9(11)-pregnatriene-3,20-dione are produced as in Example 30a from 7~9 g of 21-fluoro-17a-hydroxy-1,4,9(11)-pregnatriene-3,20-dione and propionic anhydride and these 5 g are reacted with N-bromo-succinimide under the conditions described in Example 30b. Yield: 8.5 g of 9~-bromo-21-fluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione.
b) 8.5 g of the above crude product are reacted with potassium acetate under the conditions described in Example 30c.
The crude product is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-6% acetone). Yield: 5.3 g of 9,ll~~epoxy-21~fluoro-17~-propionyloxy-1,4-preynadiene-3~20-dione.
c) 5.0 g of 9,1]~-epoxy-21-fluoro--17~-propionyloxy-1,4-pregnadiene-3,20-dione are treated as in r~xample 30d with 70~
(HF)n/pyridine solution. The reac-tion product is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-15% acetone). Yield: 3.98 g of 9~,21-difluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-3,20-dione. Melting point 21~C. [~]25 = +15 (chloroform). UV: ~:239 = 15800 (methanol).
Example 32 a) 20.0 g of 17~-butyryloxy-21-fluoro-1,4,9(11)-pregna-triene-3,20 dione, produced as in Example 30a from 21-fluoro-17~-hydroxy-1,4,9~11)-pregnatriene-3,20-dione and butyric anhydride, are treated with N-bromosuccinimide as in Example 30b.
Yield: 24.9 g of 9~-butyryloxy-21-fluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione.
b) The above crude product is treated with potassium 2Q acetate under the conditions described in Example 3c. 16.1 g of 17~-butyryloxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione are isolated.
c) 15.1 g of 17~-butyryloxy-9,llR-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione are treated as in Example 30d with 70%
(HF)n/pyridine solution. The crude product is purified on 1.5 kg of silica gel with a methylene chloride/acetone gradient (0-15% acetone). 13.4 g of 17~-bu~yryloxy-9~,21--difluoro~
hydroxy-1,4-pregnadiene-3,20-dione are obtained. Melting point 126C. 1~]25 = -~11 (chloroform). UV: ~239 = 15300 (methanol).
Example 33 a) 7.1 g of 21-fluoro-17~-valeryloxy-1,4,9(11)-pregnatriene-3,20-dione are produced as in Example 30a from 9.0 g of 21-- 2~ -fluoro-17~-hydroxy-1,4,9(~ pregnatriene-3,20-dione and valeric ~ ob anhydride and these 7.1 g are treated as in ~xample ffl with N-bromosuccinimide. Yield: 8.7 g 9~-bromo-21-fluoro~ 3-hydroxy-17~-valeryloxy-1,4-pregnadiene-3t20-dione.
b) 6.0 g of the above crude product are reacted as in Example 30c with potassium acetate. After purifying the reaction product on 700 g of silica yel with a methylene chloride/ace-tone gradient (0-5~ acetone) 4.2 c~ of 9,llr~-epoxy-21-fluoro-17~-~ valeryloxy-1,4-pregnadiene-3,20-dione are obtained.
c) 3.1 g of 9~,21-difluoro-11~-hydroxy-17~-valeryloxy-1,4-pregnadiene-3,20~dione are produced as in Example 30d by the reaction of 3.8 g of 9,11~-epoxy-21-fluoro-17~-valeryloxy-1,4-pregnadiene-3,20-dione with a 70% (~IF) /pyridine solution, which 3.1 g are obtained after purification on 450 g of silica gel with a methylene chloride/acetone gradient (0-15% acetone).
Melting point 139C. [~]D5 = +10 (chloroform). W: ~239 =
15800 (methanol).
Exam~le 34 a) Under the conditions described in Example 30a 7.3 y of 21-fluoro-17a-hexanoyloxy-1,4,9(11)-pregnatriene-3,20-dione are produced from 8.9 g of 21-fluoro-17~-hydroxy-1,4,9(11)-preg-natriene-3,20-dione and caproic anhydride which 7.3 g are reacted as in Example 30b with N-bromosuccinimide~ Yield: 8.2 g of 9~-bromo-21-fluoro-17~-hexanoyloxy~ -hydroxy-1,4-preynadiene-3,20-dione.
b) 8.0 g of the above crude product are treated as in Example 30c wi-th potassium acetate and the crude product is purified with a methylene chloride/acetone yradient (0-5~ acetone).
5.8 g of 9,11~-epoxy-21-fluoro-17~-hexanoyloxy-1,4-pregnadiene-3,20-dione are isolated.
c) 3.2 g of 9,11~-epoxy-21-fluoro-17~-hexanoyloxy-1,4-pregnadiene-3,20-dione are treated, as described in Example 30d, with a 70% ~HF) /pyridine solution. The reaction product is purified on 350 g of silica gel wlth a methylene chloride/
acetone gradient (0-15% acetone). Yield: 2.6 g of 9~,21-difluoro-17~-hexanoyloxy-11~-hydroxy-1,4-pregnadiene-3,20-dione.
Example 35 .
a) 6.2 g of 21-fluoro-17(x-isobutyryloxy-1,4,9~ preg-natriene-3,20-dione are produced as in Example 30a from 8.1 g of 21-fluoro-17~-hydroxy-1,4,9(11)-pregnatriene-3,20-dione and isobutyric anhydride, which 6.2 g are reacted as in Example 30b with N-bromosuccinimide. Yield: 6.9 g of 9~-bromo-21-fluoro-ll~-hydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione.
b) 6.0 g of the above crude product are reacted as in Example 30c with potassium acetate and the reaction product is purified on 600 g of silica gel with a methylene chloride/acetone gradient (0-5% acetone). 4.1 g of 9,11~-epoxy-21-fluoro-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione are obtained.
c) 3.5 g of 9,11~-epoxy-21-fluoro-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione are reacted as in Example 30d with a 70%
(HF)n/pyridine solution. The crude product is purified on 400 g of silica gel with a methylene chloride/acetone gradient (0-15%
acetone). Yield: 2.9 g of 9~,21-difluoro-11~-hydroxy-17(~-isobutyryloxy-1,4-pregnadiene-3,20-dione.
Example 36 . _ a) 8.0 g of 21-fluoro-17(1-hydroxy-1,4,9(11)-pregnatriene-3,20-dione are added to a mixture of 80 ml of isovaleric acid and 32 ml of tri~luoroacetic anhydride and then stirred for 2.5 hours at 80C. The whole is then added to hot water in order to destroy the excess anhydride and is aEterwards extracted with methylene chloride. After neutralising with 1~ pyridine/water and drying over sodium sulphate the whole is evaporated in vacuo.
The substance is dissolved in small quantity of pyridine, added to ice water and the pyridine is neutralised with dilute hydro-chloric acid. After working up in the usual manner 5.8 g of 21-fluoro-17~-isovaleryloxy-1,4,9(11)-preynatriene-3,20-dione are isolated.
b) 5.3 g of 21-fluoro-17(1-isovaleryloxy-1,4,9(11)-pregnatriene ~20-dione are treated as in Example 30b with N-bromosuccinimide. 6.2 g of 9~-bromo-21-fluoro-11~-hydroxy-17~-isovaleryloxy-1,4-pregnadiene-3,20-dione are obtained.
c) 6.0 g of the above crude product are reacted as in ' Example 30c with potasslum acetate. The reaction product is purified on 600 g of silica gel with a methylene chloride/
acetone gradient (0-5% acetone). Yield: 3.7 g of 9,11~-epoxy-21-fluoro~17~-isovaleryloxy-1,4-pregnadiene-3,20-dione.
d) Under the conditions in Example 30d 3 g of 9~
epoxy-21-fluoro-17~-i`sovaleryloxy-1,4-pregnadiene-3,20-dione are reacted with a 70~ (IIF) /pyridine solution. The crude product is purified on 300 g of silica gel with a methylene chloride/
acetone gradient (0-15% acetone). Yield: 2.1 g of 9~,21~difluoro-ll~-hydroxy-17~-isovaleryloxy-1,4-pregnadiene-3,20-dione.
Example 37 .
a) As described in Example 30a 8.7 g of 21-fluoro-17~-hydroxy-1,4,9tll)-pregnatriene-3,20-dione and trimethyl acetan-hydride are reacted to form 6.3 g of 21-fluoro-17~-trimeth~l-acetoxy-1,4,9~11)-pregnatriene-3,20-dione, which 6.3 9 are treated as in Example 30b with N-bromosuccinimide. After working up in the usual manner 6.5 g of 9~~bromo-21-fluoro-11~-hydroxy-17~-trimethylacetoxy-1,4-pregnadiene-3,20-dione are isolated.
b) 6.0 g of the above crude product are reacted as in Example 30c with potassium acetate and the crude product is purified on 600 g of silica gel with a methylene chloride/
acetone gradient (0-5~ acetone). Yield: 3.1 g of 9,11~-epoxy-21-fluoro-17~-trinlRthylacetoxy-1,4-pregnadiene-3,20-dione.
c) 1.9 g of 9~,21-difluoro-11~-hydroxy-17~-trimethyl-acetoxy-1,4-pregnadiene-3,20-dione are produced as in Example 30d from 3.0 g of 9,11~-epoxy-21-fluoro-17~-trimethylacetoxy-1,4-pregnadiene-3,20-dione by reaction with a 70% (HF)n/pyridine solution, which 1.9 g are obtained after purification on 300 g of silica gel with a methylene chloride/ace-tone gradient (0-15% acetone).
Example 38 .
a) 7 0 g of 21-fluoro-17~-~3~phenylpropiony]oxy)-1,4,9 (ll)-pregnatriene-3,20-dione are produced as in Example 30a from 15.4 g of 21-fluoro-17~-hydroxy-1,~,9(11)-pregnatriene-3,20-dione and 3-phenylpropionic acid chloride, which 7.0 g are reacted as in Example 30b with N-bromosuccinimide. Yield: 6~9 g of 9~-bromo-21-fluoro-11~-hydroxy-17~-(3-phenyl-propionyloxy)-1,4-pregnadiene-3,20-dione.
b) 6.5 g of the above crude product are reacted with potassium acetate under the conditions of Example 30c. The crude product is purified on 650 g of silica gel with a methylene chloride/acetone gradient (0-5~ acetone). Yield: 3.8 g of 9, ll~-epoxy-21-fluoro-17~-(3-phenylpropionyloxy)-1,4-pregnadiene-3,20-dione.
c) 3.5 g of 9,11~-epoxy-21-fluoro-17~-(3-phenylpropiony-loxy)-l,~-pregnadiene-3,20-dione are treated as in Example 30d with a 70% (HF)n/pyridine solution and the crude product is purified on 400 g of silica gel with a methylene chloride/ ~;
acetone gradient (0-15% acetone). Yield: 2.1 g of 9~,21-difluoro-ll~-hydroxy-17~-(3-phenylpropionyloxy)-1,4-pregnadiene-3,20-dione.
Example 39 ...
a) 5.8 g of 17~-cyclopentanecarbonyloxy-21-fluoro-1,~,9 L.
(11)-pregnatriene-3,20-dione are produced as in Example 36 from 9.1 g of 21-fluoro-17~-hydroxy-1,4,9(11)-pregnatriene-3,20-dione, 91 ml of cyclopentanoic acid and 44 ml of trifluoroacetic 2~
; anhydride, which 5.8 g are treated as in Example 30b with ~ N-bromosuccinimide. After working up in the normal manner 5.1 j g of 9~-bromo-17~-cyclopentanecarbonyloxy-21-fluoro-11~-hydroxy-i 1,4-pregnadiene-3,20-dione are isolated.
b) 6.0 g of the above crude product are reacted as in Example 30c with potassium ace~ate and the crude product is purified on 600 g of silica gel with a methylene chloride/acetone gradient (0-5% acetone). 4.5 g of 17~-cyclopentanecarbonyloxy-9,11~-epoxy-21-fluoro-1,4~pregnadiene-3,20-dione are obtained.
c) 4.0 g of 17~-cyclopentanecarbonyloxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione are reacted as in Example 30d with a 70% (IIF) /pyridine solution. The crude product is purified on 400 g of silica gel with a methylene chloride/acetone gradient (0-15~ acetone). Yield: 2.8 g of 17~-cyclopentane-i carbonyloxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione.
Example 40 a) 5.8 g of 17~-cyclohexanecarbonyloxy-21-fluoro 1,4,9(11)-pregnatriene-3,20-dione are produced under the conditions of Example 36 from 9.2 g of 21-fluoro-17~-hydroxy-1,4,9(11)-preqnatriene-3,20-dione, 92 ml of cyclohexanecarboxylic acid and 40 ml of trifluoroacetic anhydride, which 5.8 g are reacted as ¦ in Example 30b with N-bromosuccinimide. Yield. 6.1 g of 9~-bromo-17~-cyclohexanecarbonyloxy-21-fluoro-11~-hydroxy 1,4-pregnadiene-3,20-dione.
b) 6.0 g of the above crude product are reacted as in ¦ Example 30c with potassium acetate and the crude product is ! - purified on 600 g of silica gel with a methylene chloride/acetone gradient (0-5% acetone). Yield: 3.4 g of 17~-cyclohexanecarbony-loxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione.
c) 2.4 g o~ 17~-cyclohexanecarbonyloxy-9~,21-difluoro--hydroxy-1,4-pregnadiene-3,20-dione are produced as in Example 30d from 3.1 g of 17~-cyclohexanecarbonyloxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione by reaction with a 70% (HF)n/
pyridine solution, which 2.4 g are obtained after purification on 300 g of silica ~el with a methylene chloride/acetone gradient (0-15% acetone).
Example 41 1 g of 17~,21-(1-ethoxybenzylidenedioxy)-9~ fluoro-~ -hydroxy-1,4-pregnadiene-3,20-dione is stirred in 40 ml of ¦ dimethylformamide with 4 ml of trimethylsilyl fluoride for 2 ¦ hours at room temperature. After precipitating with ice water and working up in the usual manner the whole is evaporated ln vacuo. The crude product is purified on 120 g of silica gel with a methylene chloride/acetone gradient (0-10~ acetone). Yield:
240 mg of 17~-benzoyloxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione.
II Pharmaceutical preparations Example 42 3 Composition of an ointment 1 0.03~ of 9~-fluoro-11~-hydroxy-17~,21-dipropionyloxy-1,4-pregnadiene-3,20-dione ` 20 2.50% Allercur hexachlorophenate, micronised, particle size ~ approximately 8 ~ (Allercur = Trade Mark for l-p-chlorobenzyl-¦ 2-pyrrolidylmethylbenæimidazole)
6.00% Hostaphat ~W 340 (Trade Mark) (tert. ester of O-phosphoric acid and wax alcohol tetra-glycol ether) 0.10% sorbic acid j 10.00% neutral oil (Migloyol 812 (Trade Mark)) ¦ 3.50~ stearyl alcohol 1.50% wool fat, anhydrous DAB 6 i 76.36% desalted water Example 43 Production of an inhalant 1.000 g of micronised 9~-fluoro-11~-hydroxy-17~,21-t dipropionyl-oxy-1,4-pregnadiene-3,20-dione (average particle size . smaller than 7 ~) and 39.00 g of ground lactose are mixed à together. A dose of 20 mg of inhalant is used per inhalation.
~ .
!
,1 .
; 20 ' 3 3o
~ .
!
,1 .
; 20 ' 3 3o
Claims (94)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a compound of the general formula I
wherein R1 represents a group of the general formula RCO- in which R represents a hydrogen atom or an alkyl group or a cycloalkyl or cycloalkylalkyl group or an alkyl-substituted cycloalkyl or cycloalkylalkyl group, and R1 has from 1 to 8 carbon atoms, or in which R represents an aryl or aralkyl group or an alkyl-substituted aryl or aralkyl group, and R1 has up to 9 carbon atoms, and X represents a fluorine or chlorine atom or a group of the general formula R'COO- which has from 3 to 8 carbon atoms and in which R' represents an alkyl group or a cycloalkyl or cycloalkylalkyl group or an alkyl-substituted cycloalkyl or cycloalkylalkyl group, wherein, a) the epoxide ring of a compound of the general formula (II) in which X and R1 have the meanings given above, is opened with hydrogen fluoride, or b) a 9-fluoro derivative of the general formula (III) wherein R1 has the meaning given above, is halogenated or esterified in the 21-position, or c) for the production of a 9-fluoroprednisolone derivative of the general formula (I) wherein X represents a fluorine or chlorine atom, an ortho ester of the general formula (IV) wherein R3 represents a hydrogen atom, an alkyl group or a cycloalkyl group having up to 7 carbon atoms or a phenyl group and R2 represents an alkyl group having 1 to 4 carbon atoms, is cleaved with a trimethylsilyl halide or a triphenylmethyl halide.
wherein R1 represents a group of the general formula RCO- in which R represents a hydrogen atom or an alkyl group or a cycloalkyl or cycloalkylalkyl group or an alkyl-substituted cycloalkyl or cycloalkylalkyl group, and R1 has from 1 to 8 carbon atoms, or in which R represents an aryl or aralkyl group or an alkyl-substituted aryl or aralkyl group, and R1 has up to 9 carbon atoms, and X represents a fluorine or chlorine atom or a group of the general formula R'COO- which has from 3 to 8 carbon atoms and in which R' represents an alkyl group or a cycloalkyl or cycloalkylalkyl group or an alkyl-substituted cycloalkyl or cycloalkylalkyl group, wherein, a) the epoxide ring of a compound of the general formula (II) in which X and R1 have the meanings given above, is opened with hydrogen fluoride, or b) a 9-fluoro derivative of the general formula (III) wherein R1 has the meaning given above, is halogenated or esterified in the 21-position, or c) for the production of a 9-fluoroprednisolone derivative of the general formula (I) wherein X represents a fluorine or chlorine atom, an ortho ester of the general formula (IV) wherein R3 represents a hydrogen atom, an alkyl group or a cycloalkyl group having up to 7 carbon atoms or a phenyl group and R2 represents an alkyl group having 1 to 4 carbon atoms, is cleaved with a trimethylsilyl halide or a triphenylmethyl halide.
2. A process as claimed in claim 1 in which the compound of formula II is treated with hydrogen fluoride in an inert solvent.
3. A process as claimed in claim 1 in which the compound of formula III is esterified with an acyl chloride or acid anhydride in the presence of an acid.
4. A process as claimed in claim 1 in which the compound of formula III is chlorinated by esterifying the 21-hydroxy group with a sulphoric acid and then exchanging the sulphonic acid group for chlorine.
5. A process as claimed in claim 1 in which the compound of formula IV is cleaved in an inert solvent.
6. A compound of the general formula (I) wherein R1 represents a group of the general formula RCO- in which R represents a hydrogen atom or an alkyl group or a cycloalkyl or cycloalkylalkyl group or an alkyl-substituted cycloalkylalkyl or cycloalkyl group, and R1 has from 1 to 8 carbon atoms, or in which R represents an aryl or aralkyl group or an alkyl-substituted aryl or aralkyl group, and R1 has up to 9 carbon atoms, X represents a fluorine or chlorine atom or a group of the general formula R'COO- which has from 3 to 8 carbon atoms and in which R' represents an alkyl group or a cycloalkyl or cycloalkylalkyl group or an alkyl-substituted cycloalkyl or cycloalkylalkyl group whenever prepared or produced by the process as claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.
7. A process as claimed in claim 1 in which in the reactants R1 represents a formyl group or an alkanoyl or cyclo-alkanoyl group having up to 8 carbon atoms or a benzoyl group, and X represents a fluorine or chlorine atom or an alkanoyl or cycloalkanoyl group having from 3 to 8 carbon atoms.
8. A compound of formula I given in claim 1 wherein R1 represents a formyl group or an alkanoyl or cycloalkanoyl group having up to 8 carbon atoms or a benzoyl group, and X represents a fluorine or chlorine atom or an alkanoyl or cycloalkanoyl group having from 3 to 8 carbon atoms whenever prepared or produced by the process as claimed in claim 7 or an obvious chemical equiva-lent thereof.
9. A process as claimed in claim 7 in which the reactants R1 represents a benzoyl group or an alkanoyl group having up to 6 carbon atoms.
10. A compound of formula I given in claim 1, wherein R1 represents a benzoyl group or an alkanoyl group having up to 6 carbon atoms, and X is as in claim 7 whenever prepared or produced by the process of claim 9 or an obvious chemical equiva-lent thereof.
11. A process as claimed in claim 9 in which in the reactants X represents a fluorine or chlorine atom or an alkanoyloxy group having up to 6 carbon atoms.
12. A compound of formula I given in claim 1, wherein X represents a fluorine or chlorine atom or an alkanoyloxy group having up to 6 carbon atoms and R1 is as in claim 9 whenever prepared or produced by the process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim 1 which comprises reacting17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with propionic anhydride.
14. 17.alpha.-Acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 13 or an obvious chemical equivalent thereof.
15. A process as claimed in claim 1 which comprises reacting 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with butyric anhydride.
16. 17.alpha.-Acetoxy-21-butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 15 or an obvious chemical equivalent thereof.
17. A process as claimed in claim 1 which comprises reacting 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with valeric anhydride.
18. 17.alpha.-Acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 17 or an obvious chemical equivalent thereof.
19. A process as claimed in claim 1 which comprises reacting 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with caproic anhydride.
20. 17.alpha.-Acetoxy-9.alpha.-fluoro-21-hexanoyloxy-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 19 or an obvious chemical equivalent thereof.
21. A process as claimed in claim 1 which comprises reacting 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with trimethyl acetic anhydride.
22. 17.alpha.-Acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 21 or an obvious chemical equivalent thereof.
23. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione in pyridine with propionic anhydride.
24. 9.alpha.-Fluoro-11.beta.-hydroxy-17.alpha.,21-dipropionyloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 23 or an obvious chemical equivalent thereof.
25. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione in pyridine with butyric anhydride.
26. 21-Butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 25 or an obvious chemical equivalent thereof.
27. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione in pyridine with valeric anhydride.
28. 9.alpha.-Fluoro-11.beta.-hydroxy-17.alpha.-propionyloxy-21-valeryloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 27 or an obvious chemical equivalent thereof.
29. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione in pyridine with caproic anhydride.
30. 9.alpha.-Fluoro-21-hexanoyloxy-11.beta.-hydroxy-17.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 29 or an obvious chemical equivalent thereof.
31. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione in pyridine with trimethyl acetic anhydride.
32. 9.alpha.-Fluoro-11.beta.-hydroxy-17.alpha.-propionyloxy-21-trimethyl-acetoxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 31 or an obvious chemical equivalent thereof.
33. A process as claimed in claim 1 which comprises reacting 17.alpha.-butyryloxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with propionic anhydride.
34. 17.alpha.-Butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-21-propiony-loxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 33 or an obvious chemical equivalent thereof.
35. A process as claimed in claim 1 which comprises reacting 17.alpha.-butyryloxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with valeric anhydride.
36. 17.alpha.-Butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-21-valery-loxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 35 or an obvious chemical equivalent thereof.
37. A process as claimed in claim 1 which comprises reacting 17.alpha.-butyryloxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with propionic anhydride and oenanthic anhydride.
38. 17.alpha.-Butyryloxy-9.alpha.-fluoro-21-heptanoyloxy-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared by the process as claimed in claim 37 or an obvious chemical equivalent thereof.
39. A process as claimed in claim 1 which comprises reacting 17.alpha.-butyryloxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with propionic anhydride and isobutyric anhydride.
40. 17.alpha.-Butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-21-isobutyry-loxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 39 or an obvious chemical equivalent thereof.
41. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-valeryloxy-1,4-pregnadiene-3,20-dione in pyridine with propionic anhydride.
42. 9.alpha.-Fluoro-11.beta.-hydroxy-21-propionyloxy-17.alpha.-valeryloxy-1,4-pregnadiene-3,20-dione whenever prepared or pro-duced by the process as claimed in claim 41 or an obvious chemical equivalent thereof.
43. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-valeryloxy-1,4-pregnadiene-3,20-dione in pyridine with butyric anhydride.
44. 21-Butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-valery-loxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 43 or an obvious chemical equivalent thereof.
45. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-valeryloxy-1,4-pregnadiene-3,20-dione in pyridine with caproic anhydride.
46. 9.alpha.-Fluoro-21-hexanoyloxy-11.beta.-hydroxy-17.alpha.-valeryloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 45 or an obvious chemical equivalent thereof.
47. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-isobutyryloxy-1,4-pregnadiene-3,20-dione in pyridine with propionic anhydride.
48. 9.alpha.-Fluoro-11.beta.-hydroxy-17.alpha.-isobutyryloxy-21-propionyloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 47 or an obvious chemical equivalent thereof.
49. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-isobutyryloxy-1,4-pregnadiene-3,20-dione in pyridine with butyric anhydride.
50. 21-Butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isobutyry-loxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 49 or an obvious chemical equivalent thereof.
51. A process as claimed in claim 1 which comprises reacting 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-trimethylacetoxy-1,4-pregnadiene-3,20-dione in pyridine with propionic anhydride.
52. 9.alpha.-Fluoro-11.beta.-hydroxy-21-propionyloxy-17.alpha.-trimethylacetoxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 51 or an obvious chemical equivalent thereof.
53. A process as claimed in claim 1 which comprises reacting 17.alpha.-benzoyloxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with propionic anhydride.
54. 17.alpha.-Benzoyloxy-9.alpha.-fluoro-11.beta.-hydroxy-21-propiony-loxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 53 or an obvious chemical equivalent thereof.
55. A process as claimed in claim 1 which comprises reacting 17.alpha.-benzoyloxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with butyric anhydride.
56. 17.alpha.-Benzoyloxy-21-butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 55 or an obvious chemical equivalent thereof.
57. A process as claimed in claim 1 which comprises reacting 17.alpha.-benzoyloxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with valeric anhydride.
58. 17.alpha.-Benzoyloxy-9.alpha.-fluoro-11.beta.-hydroxy-21-valery-loxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 57 or an obvious chemical equivalent thereof.
59. A process as claimed in claim 1 which comprises reacting 17.alpha.-benzoyloxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with propionic anhydride and isobutyric anhydride.
60. 17.alpha.-Benzoyloxy-9.alpha.-fluoro-11.beta.-hydroxy-21-isobutyry-loxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 59 or an obvious chemical equivalent thereof.
61. A process as claimed in claim 1 which comprises reacting 17.alpha.-benzoyloxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in pyridine with trimethyl acetic anhydride.
62. 17.alpha.-Benzoyloxy-9.alpha.-fluoro-11.beta.-hydroxy-21-trimethyl-acetoxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 61 or an obvious chemical equivalent thereof.
63. A process as claimed in claim 1 which comprises reacting thionyl chloride with 17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in the presence of hexa-methyl phosphoric acid triamide.
64. 17.alpha.-Acetoxy-21-chloro-9.alpha.-fluoro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 63 or an obvious chemical equivalent thereof.
65. A process as claimed in claim 1 which comprises reacting thionyl chloride with 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione in the presence of hexamethyl phosphoric acid triamide.
66. 21-Chloro-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 65 or an obvious chemical equivalent thereof.
67. A process as claimed in claim 1 which comprises reacting thionyl chloride with 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-isobutyryloxy-1,4-pregnadiene-3,20-dione in the presence of hexamethyl phosphoric acid triamide.
68. 21-Chloro-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isobutyryloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 67 or an obvious chemical equivalent thereof.
69. A process as claimed in claim 1 which comprises reacting thionyl chloride with 17.alpha.-benzoyloxy-9.alpha.-fluoro-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-dione in the presence of hexa-methyl phosphoric acid triamide.
70. 17.alpha.-Benzoyloxy-21-chloro-9.alpha.-fluoro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 69 or an obvious chemical equivalent thereof.
71. A process as claimed in claim 1 which comprises adding a solution of 17.alpha.-acetoxy-9,11.beta.-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70% (HF)n/pyridine solution.
72. 17.alpha.-Acetoxy-9.alpha.,21-difluoro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 71 or an obvious chemical equivalent thereof.
73. A process as claimed in claim 1 which comprises adding a solution of 9,11.beta.-epoxy-21-fluoro-17.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70% (HF)n/
pyridine solution.
pyridine solution.
74. 9.alpha.,21-Difluoro-11.beta.-hydroxy-l7.alpha.-propionyloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 73 or an obvious chemical equivalent thereof.
75. A process as claimed in claim 1 which comprises adding a solution of 17.alpha.-butyryloxy-9,11.beta.-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70% (HF)n/pyridine solution.
76. 17.alpha.-Butyryloxy-9.alpha.,21-difluoro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 75 or an obvious chemical equivalent thereof.
77. A process as claimed in claim 1 which comprises adding a solution of 9,11.beta.-epoxy-21-fluoro-17.alpha.-valeryloxy-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70% (HF)n/
pyridine solution.
pyridine solution.
78. 9.alpha.,21-Difluoro-11.beta.-hydroxy-17.alpha.-valerloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 77 or an obvious chemical equivalent thereof.
79. A process as claimed in claim 1 which comprises adding a solution of 9,11.beta.-epoxy-21-fluoro-17.alpha.-hexanoyloxy-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70% (HF)n/pyridine solution.
80. 9.alpha.,21-Difluoro-17.alpha.-hexanoyloxy-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 79 or an obvious chemical equivalent thereof.
81. A process as claimed in claim 1 which comprises adding a solution of 9,11.beta.-epoxy-21-fluoro-17.alpha.-isobutyryloxy-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70% (HF)n/pyridine solution.
82. 9.alpha.,21-Difluoro-11.beta.-hydroxy-17.alpha.-isobutyryloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 81 or an obvious chemical equivalent thereof.
83. A process as claimed in claim 1 which comprises adding a solution of 9,11.beta.-epoxy-21-fluoro-17.alpha.-isovaleryloxy-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70% (HF)n/
pyridine solution.
pyridine solution.
84. 9.alpha.,21-Difluoro-11.beta.-hydroxy-17.alpha.-isovaleryloxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 83 or an obvious chemical equivalent thereof.
85. A process as claimed in claim 1 which comprises adding a solution of 9.alpha.,21-difluoro-11.beta.-hydroxy-17.alpha.-trimethyl-acetoxy-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70%
(HF)n/pyridine solution.
(HF)n/pyridine solution.
86. 9.alpha.,21-Difluoro-11.beta.-hydroxy-17.alpha.-trimethylacetoxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 85 or an obvious chemical equivalent thereof.
87. A process as claimed in claim 1 which comprises adding a solution of 9,11.beta.-epoxy-21-fluoro-17.alpha.-(3-phenylpropionyl-oxy)-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70%
(HF)n/pyridine solution.
(HF)n/pyridine solution.
88. 9.alpha.,21-Difluoro-11.beta.-hydroxy-17.alpha.-(3-phenylpropiony-loxy)-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 87 or an obvious chemical equivalent thereof.
89. A process as claimed in claim 1 which comprises adding a solution of 17.alpha.-cyclopentanecarbonyloxy-9,11.beta.-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70%
(HF)n/pyridine solution.
(HF)n/pyridine solution.
90. 17.alpha.-Cyclopentanecarbonyloxy-9.alpha.,21-difluoro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 89 or an obvious chemical equivalent thereof.
91. A process as claimed in claim 1 which comprises adding a solution of 17.alpha.-cyclohexanecarbonyloxy-9,11.beta.-epoxy-21-f1uoro-1,4-pregnadiene-3,20-dione in pyridine to a cooled 70%
(HF)n/pyridine solution.
(HF)n/pyridine solution.
92. 17.alpha.-cyclohexanecarbonyloxy-9.alpha.,21-difluoro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 91 or an obvious chemical equivalent thereof.
93. A process as claimed in claim 1 which comprises treating 17.alpha.,21-(1-ethoxybenzylidenedioxy)-9.alpha.-fluoro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione with trimethylsilyl fluoride in dimethylformamide.
94. 17.alpha.-Benzoyloxy-9.alpha.,21-difluoro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione whenever prepared or produced by the process as claimed in claim 94 or an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2712862.7 | 1977-03-21 | ||
| DE2712862A DE2712862C2 (en) | 1977-03-21 | 1977-03-21 | Derivatives of 9-fluorprednisolone, process for their preparation and pharmaceuticals containing them |
| DEP2809732.7 | 1978-03-03 | ||
| DE19782809732 DE2809732C2 (en) | 1978-03-03 | 1978-03-03 | Derivatives of 9-fluorprednisolone, process for their production, and pharmaceutical preparations containing these active ingredients |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1104124A true CA1104124A (en) | 1981-06-30 |
Family
ID=25771793
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA299,299A Expired CA1104124A (en) | 1977-03-21 | 1978-03-20 | Derivatives of 9-fluoroprednisolone |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS53130651A (en) |
| AT (1) | AT365203B (en) |
| AU (1) | AU525614B2 (en) |
| CA (1) | CA1104124A (en) |
| CH (1) | CH638226A5 (en) |
| CS (1) | CS202591B2 (en) |
| DD (1) | DD134955A5 (en) |
| DK (1) | DK126378A (en) |
| ES (1) | ES468107A1 (en) |
| FR (1) | FR2384792A1 (en) |
| GB (1) | GB1603281A (en) |
| GR (1) | GR70385B (en) |
| IE (1) | IE46584B1 (en) |
| IL (1) | IL54308A (en) |
| IT (1) | IT1095477B (en) |
| LU (1) | LU79271A1 (en) |
| NO (1) | NO151043C (en) |
| NZ (1) | NZ186735A (en) |
| RO (1) | RO81525B (en) |
| SE (1) | SE431656B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2853785A1 (en) * | 1978-12-11 | 1980-06-19 | Schering Ag | NEW PREDNISON DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS AND THE USE THEREOF |
| JPH07116215B2 (en) * | 1989-04-19 | 1995-12-13 | エスエス製薬株式会社 | Novel steroid compound |
| JPH07213320A (en) * | 1994-02-04 | 1995-08-15 | Daiwa:Kk | Bag for long sized article |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2055221A1 (en) * | 1970-11-10 | 1972-05-18 | Laboratorio Chimico Farmaceutico Dr. P. Blasina S.R.L., Mailand (Italien) | 17-acyloxy-3-keto-pregn-4-enes prepn - by acylating 17-hydroxy steroids in presence ofstannic chloride |
| CH529739A (en) * | 1972-02-28 | 1972-10-31 | Sdc Steroidi Dev Co | 11,16,17,21-tetrahydroxy-3,20-diketo-1,4-pregnadienes prepn - - from cpds without 16-hydroxy grp |
| US3832366A (en) * | 1973-07-30 | 1974-08-27 | Squibb & Sons Inc | Process for preparing 21-chloro-17-acyloxy-20-ketosteroids |
-
1978
- 1978-03-17 CH CH296278A patent/CH638226A5/en not_active IP Right Cessation
- 1978-03-17 DD DD78204259A patent/DD134955A5/en unknown
- 1978-03-18 RO RO93558A patent/RO81525B/en unknown
- 1978-03-20 NO NO780984A patent/NO151043C/en unknown
- 1978-03-20 JP JP3225378A patent/JPS53130651A/en active Granted
- 1978-03-20 SE SE7803168A patent/SE431656B/en not_active IP Right Cessation
- 1978-03-20 AT AT0195978A patent/AT365203B/en not_active IP Right Cessation
- 1978-03-20 NZ NZ186735A patent/NZ186735A/en unknown
- 1978-03-20 LU LU79271A patent/LU79271A1/en unknown
- 1978-03-20 GR GR55756A patent/GR70385B/el unknown
- 1978-03-20 GB GB10925/78A patent/GB1603281A/en not_active Expired
- 1978-03-20 IT IT21364/78A patent/IT1095477B/en active
- 1978-03-20 CA CA299,299A patent/CA1104124A/en not_active Expired
- 1978-03-20 IE IE545/78A patent/IE46584B1/en unknown
- 1978-03-20 IL IL54308A patent/IL54308A/en unknown
- 1978-03-21 CS CS781785A patent/CS202591B2/en unknown
- 1978-03-21 ES ES468107A patent/ES468107A1/en not_active Expired
- 1978-03-21 AU AU34346/78A patent/AU525614B2/en not_active Expired
- 1978-03-21 FR FR7808099A patent/FR2384792A1/en active Granted
- 1978-03-21 DK DK126378A patent/DK126378A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AT365203B (en) | 1981-12-28 |
| LU79271A1 (en) | 1978-06-29 |
| IE780545L (en) | 1978-09-21 |
| IT1095477B (en) | 1985-08-10 |
| CS202591B2 (en) | 1981-01-30 |
| DD134955A5 (en) | 1979-04-04 |
| FR2384792A1 (en) | 1978-10-20 |
| IE46584B1 (en) | 1983-07-27 |
| AU525614B2 (en) | 1982-11-18 |
| IL54308A0 (en) | 1978-06-15 |
| RO81525A (en) | 1983-04-29 |
| JPS6131116B2 (en) | 1986-07-17 |
| GR70385B (en) | 1982-10-05 |
| NO151043C (en) | 1985-01-30 |
| SE7803168L (en) | 1978-09-22 |
| AU3434678A (en) | 1979-09-27 |
| RO81525B (en) | 1983-04-30 |
| GB1603281A (en) | 1981-11-25 |
| NZ186735A (en) | 1980-10-24 |
| DK126378A (en) | 1978-09-22 |
| NO780984L (en) | 1978-09-22 |
| CH638226A5 (en) | 1983-09-15 |
| ES468107A1 (en) | 1979-07-01 |
| FR2384792B1 (en) | 1980-04-04 |
| IL54308A (en) | 1984-03-30 |
| SE431656B (en) | 1984-02-20 |
| JPS53130651A (en) | 1978-11-14 |
| NO151043B (en) | 1984-10-22 |
| ATA195978A (en) | 1981-05-15 |
| IT7821364A0 (en) | 1978-03-20 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |