GB1603281A - Derivatives of 9-fluoroprednisolone - Google Patents
Derivatives of 9-fluoroprednisolone Download PDFInfo
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- GB1603281A GB1603281A GB10925/78A GB1092578A GB1603281A GB 1603281 A GB1603281 A GB 1603281A GB 10925/78 A GB10925/78 A GB 10925/78A GB 1092578 A GB1092578 A GB 1092578A GB 1603281 A GB1603281 A GB 1603281A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- 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
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- 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
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- 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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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The active compounds correspond to the general formula I <IMAGE> in which R1 denotes an alkanoyl group or cycloalkanoyl group having 1 to 8 carbon atoms or a benzoyl group and X represents a fluorine atome, a chlorine atom or an alkanoyloxy group having 3 to 8 carbon atoms. The novel 9-fluoroprednisolone derivatives can be obtained by opening corresponding 9,11 beta -epoxy compounds with hydrogen fluoride or halogenating or esterifying corresponding 9-fluoro derivatives in the 21-position or cleaving a corresponding 17 alpha -cycloalkanecarbonyloxy compound with a trimethylsilyl halide or triphenylmethyl halide. Medicaments which contain at least one of the abovementioned compounds as an active component can be used for the treatment of inflammations.
Description
(54) DERIVATIVES OF 9-FLUOROPREDNISOLONE
(71) We, SCHERING AKTIENGESELLSCHAFT, a Body Corporate organised according to the laws of the Federal Republic of Germany, of Berlin and Bergkamen, the
Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement :- The invention relates to derivatives of 9-fluoroprednisolone, a process for their production and pharmaceutical preparations containing these active substances.
9-Fluoroprednisolone (9a-fluoro-llp, 17a, 21-trihydroxy-1, 4-pregnadiene-3,2-dione) has been known for a long time. (See, for example, J. Amer. Chem. Soc., 77,1955,4181). This corticoid is not a suitable active substance for pharmaceutical preparations which are used for the topical treatment of inflammatory diseases since it has very strong systemic effects.
The present invention is based on the observation that hitherto unknown derivatives of 9-fluoroprednisolone have only weak systemic action but, when administered topically, 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)
wherein Rl represents a group of the general formula RCO-in which R represents a hydrogen
atom or an alkyl group or a cycloalkyl or cycloakylalkyl group or an alkyl-substituted
cycloalkyl or cycloalkylalkyl group. and R, 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 R, 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.
Thus, for example, R, may represent a formyl group or a alkanoyl or cycloalkanecarbonyt group having up to 8 carbon atoms or a benzoyl group or a phenylalkanoyl group having up to 9 carbon atoms, and X may represent a fluorine or chlorine atom or an alkanoyloxy or cycloalkanecarbonyloxy group having from 3 to 8 carbon atoms.
An acyl group represented by R, and an acyloxy group represented by X may be derived from a cyclic carboxylic acid or from an open-chained (straight-chained or branchedchained) 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 R,, from formic acid, acetic acid or propionic acid.
Particularly preferred alkanoyl groups R, and alkanoyloxy 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-11p-hydroxy-1, 4-pregnadiene-3,20-dione, 21-chloro-9a-fluoro-1 lss-hydroxy-17a-propionyloxy-1, 4-pregnadiene-3,20-dione, 17a-butyryloxy-21-chloro-9a-fluoro-11p-hydroxy-1, 4-pregnadiene-3, 20-dione.
21-chloro-9a-fluoro-llp-hydroxy-17a-isobutyryloxy-1, 4-pregnadiene-3,20-dione, 21-chloro-α-fluoro-11ss-hydroxy-17α-valeryloxy-1,4-pregnadiene-3, 20-dione and 17a-benzoyloxy-21-chloro-9a-fluoro-11p-hydroxy-1, 4-pregnadiene-3,20-dione.
9,21-Difluoroprednisolone derivatives of the general formula (I) are, for example, 17a-acetoxy-9a, 21-difluoro-1 (3-hydroxy-1, 4-pregnadiene-3, 20-dione, 9a, 21-difluoro-llp-hydroxy-17a-propionyloxy-1, 4-pregnadiene-3,20-dione, 17a-butyryloxy-9a, 21-difluoro-11p-hydroxy-1, 4-pregnadiene-3,20-dione and 9a, 21-difluoro-l1 (3-hydroxy-17a-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 R, and X together have 5 to 14 carbon atoms. Such fluoroprednisolone derivatives are, for example : 17a-acetoxy-9a-fluoro-11p-hydroxy-21-propionyloxy-1, 4-pregnadiene-3,20-dione, 17a-acetoxy-21-butyryloxy-9a-fluoro-lli-hydroxy-1, 4-pregnadiene-3, 20-dione, 17a-acetoxy-9a-fluoro-11li-hydroxy-21-isobutyryloxy-1, 4-pregnadiene-3, 20-dione, 17a-acetoxy-9a-fluoro-1 lp-hydroxy-21-valeryloxy-1, 4-pregnadiene-3, 20-dione, 21-butyryloxy-9a-fluoro-1 lss-hydroxy-17a-valeryloxy-1, 4-pregnadiene-3, 20-dione, 17a-benzoyloxy-21-butyryloxy-9a-fluoro-11p-hydroxy-1, 4-pregnadiene-3,20-dione, 9a-fluoro-llss-hydroxy-17a, 21-diisobutyryloxy-1, 4-pregnadiene-3,20-dione and 9a-fluoro-llss-hydroxy-17a, 21-divaleryloxy-1, 4-pregnadiene-3, 20-dione.
The present invention also provides a process for the manufacture of the 9fluoroprednisolone derivatives of the general formula (I) wherein a) the epoxide ring of a compound of the general formula (II)
in which R, and X have the meanings given above is opened with hydrogen fluoride, or b) a 9-fluoro derivative of the general formula (III)
in which R, 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.
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 Offenlegungsschriften 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 tetrachloride or tetrachloroethane).
The process of the invention according to process variant (b) may likewise be carried out under conditions known per se.
Thus, for example, a hydroxy steroid of the general formula (III) may be esterified with an acyl chloride or acid anhydride in the presence of an acid, such as, for example, hydrogen chloride, p-toluenesulphonic acid or trifluoroacetic acid, or in the presence of a base such, for example, as potassium carbonate, pyridine, collidine, or p dimethylaminopyridine.
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 for chlorine. The 21-hydroxy group is esterified, for example, by causing a sulphonic acid chloride to act on the 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 atoms preferably by reacting the 21-sulphonic acid ester with alkali metal chloride such as, for example, lithium chloride, in the presence of a polar solvent such, for example, as dimethylformamide.
The process of the invention according to process variant (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, trimethylsilyl chloride or triphenylmethyl chloride, advantageously in a 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, chloroform or tetrachlor- oethane), a hydrocarbon (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 high yields from prednisolone which can itself be synthesised relative easily from diosgenin. The result of this is that compounds of the invention can be produced from diosgenin at relative low expenditure and with a total yield of approximately 15 %. In contrast, the syntheses of the known highly effective corticoids from diosgenin require considerably more expenditure 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 of 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 Stratccm 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" (Registered
Trade Mark) self-adhesive tape 2 cm wide and a pronounced hyperaemia was thus produced. c2 Approximately 50 mg of the ointment preparations were applied to marked 4 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 set at 100 and that of the stripped skin at 0.
The skin colour value of the skin under vasoconstriction (100) was determined on a relative scale.
Relatively slight, average and a high degree of vasoconstriction were rated accordingly between 0 and 100.
The average values, which were derived from investigations of the various test persons and from various regions of the back, are given in the following Table A.
The systemic 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 % Mycobnereriam btyricum 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 again.
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: TABLE A
Vasoconstriction test
No. Substance Concentra- Results after Adjuvant-oedema test tion % 4 hours 8 hours ED50
I 6α,9α-Difluoro-11ss-hydroxy- 0.1 % 58 68 21-valeryloxy-1,4-pregnadiene- 0.001 % 54 66 0.04 mg/kg 3,20-dione(=Diflucortolone- 0.00001 % 32 36 valerate)
II 21-Acetoxy-9α-fluoro-11ss- 0.1 % 55 66 hydroxy-17α-valeryloxy-1,4- 0.001% 52 63 3.8 mg/kg pregnadiene-3,20-dione 0.00001 % 31 42 (DOS 20 55 221)
III 17α-Acetoxy-9α-fluoro-11ss- 0.1 % 67 78 hydroxy-21-hexanoyloxy-1,4- 0.001 % 60 74 7.7 mg/kg pregnadiene-3,20-dione 0.00001 % 23 36
IV 71α-Acetoxy-9α-fluoro-11ss- 0.1 % 57 74 hydroxy-21-trimethylacetoxy-1,4- 0.001 % 57 68 7.0 mg/kg pregnadiene-3,20-dione 0.00001 % 33 42
V 9α-Fluoro-11ss-hydroxy-17α,21- 0.1 % 65 83 dipropionyloxy-1,4-pregnadiene- 0.001 % 58 76 5.0 mg/kg 3,20-dione 0.00001 % 39 47 TABLE A (continued)
Vasoconstriction tes
No. Sbstance Concentra- Results after Adjuvat-oedema test tion % 4 hours 8 hours ED50
VI 21-Butyryloxy-9α-fluoro-11ss-hy- 0.1 % 62 83 droxy-17α-propionyloxy-1,4- 0.001% 58 76 5.7 mg/kg pregnadiene-3,20-dione 0.00001 % 43 47
VII 9α-fluoro-11ss-hydroxy-17α- 0.1 % 60 75 propionyloxy-21-valeryloxy- 0.001 % 57 76 6.0 mg/kg 1,4-pregnadiene-3,20-dione 0.00001 % 04 43
VIII 17α-Benzoyloxy-9α-fluoro-11ss- 0.1 % 62 78 hydroxy-21-propionyloxy-1,4- 0.001 % 59 70 over 10 mg/kg pregnadiene-3,20-dione 0.00001 % 40 43
IX 17α-Benzoyloxy-21-butyrloxy- 0.1 % 68 82 9α-fluoro-11ss-hydroxy-1,4-pregna- 0.001 % 67 80 over 10 mg/kg diene-3,20-dione
X 17α-Benzoyloxy-21-chloro-9α- 0.1 % 60 72 fluoro-11ss-hydroxy-1,4-pregna- 0.001 % 56 64 over 10 mg/kg diene-3,20-dione 0.00001 % 43 45 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, Pruritis vulvae et ani, rosacea,
Erthematodes cutaneus, psoriasis, Lichen ruber planus et verrucosus and similar skin diseases.
Accordingly, the present invention also provides a pharmaceutical preparation which comprises a compound of the general formula (I), in admixture or conjunction with a pharmaceutically suitable carrier.
The pharmaceutical preparations may be produced in a conventional manner by converting the active substances 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 concentration of active substance depends on the form of administration. 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 relieve 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 inhalant which can be used for the therapy of allergic diseases of the respiratory system, such as, for example, bronchial asthma or rhinitis.
A compound or preparation of the present invention may also be used to alleviate
inflammation caused by a medicament used for treating a non-inflammatory disease.
Accordingly, the present invention provides a pharmaceutical 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 is liable to have an inflammatory action,
and a pharmaceutical preparation which comprises this composition in admixture or conjunction with a pharmaceutically suitable carrier.
The present invention further provides a pack which comprises a compound of the
general formula (I), or a pharmaceutical 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-SYNTHESES
Example 1
a) 5 g of 9a-fluoroprednisolone are added to 500 mg of pyridine tosylate, twice
concentrated to dryness in vacuo with benzene, in 500 ml of benzene and 40 ml of N, N-dimethylformamide. At a bath temperature of 130 C 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
concentrated in vacuo. 17a, 21-(1-ethoxyethylidenedioxy)-9a-fluoro-11ss-hydroxy-1, 4 pregnadiene-3, 20-dione is isolated as a yellow oily epimer mixture.
b) A solution of the oil is thus obtained in 150 ml of methanol is refluxed for 1 hour at 90 C 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 to water and extracted
with ethyl acetate. The organic extracts are washed with water, dried and evaporated in
vacuo. Yield : 9g of 17a-acetoxy-9a-fluoro-11 (3, 21-dihydroxy-1, 4-pregnadiene-3,20-dione as
a foam.
c) 3.0 g of 17a-acetoxy-9a-fluoro-llp, 21-dihydroxy-1, 4-pregnadiene-3,20-dione are stir
red 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 17a-acetoxy-9a-fluoro-llp-hydroxy-21- propionyloxy-1, 4-pregnadiene-3,20-dione. Melting point 219 C. [ali25 = +81 (pyridine).
UV : E239 = 15100 (methanol).
Example 2
4.5 g of 17a-acetoxy-9a-fluoro-llp, 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 methylene chloride/acetone gradient (0-15 % acetone). Yield : 3.6 g of 17a-acetoxy-21-butyryloxy-9a fluoro-llp-hydroxy-1, 4-pregnadiene-3,20-dione. Melting point 218 C.
Example 3 1. 0 g of 17a-acetoxy-9a-fluoro-11ss, 21-dihydroxy-1, 4-pregnadiene-3, 20-dione is reacted as in Example 2 in 10 ml of pyridine with 6 ml of valeric anhydride instead of butyric anhydride. Yield : 680 mg of 17a-acetoxy-9a-fluoro-11ss-hydroxy-21-valeryloxy-1, 4pregnadiene-3, 20-dione. Melting point 213 C.
Example 4
3.0 g of 17α-acetoxy-9α-fluoro-11ss, 21-dihydroxy-1, 4-pregnadiene-3,20-dione in 30 mi 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 17α-acetoxy-9α- fluoro-21-hexanoyloxy-11ss-hydroxy-1, 4-pregnadiene-3,20-dione. Melting point 222 C.
[a] r25 = + 820 (pyridine). UV : = 15500 (methanol).
Example 5
3.0 g of 17a-acetoxy-9a-fluoro-llp, 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 chromatog-
raphed on 700 g of silica gel with a methylene chloride/acetone gradient (0-12 % acetone).
Yield : 2.06 g of 1ca-acetoxy-9a-fluoro-11p-hydroxy-21-trimethylacetoxy-1, 4-pregnadiene 3, 20-dione. Melting point 227 C. [aJDS = +79 (pyridine). UV: #239 = 15500 (methanol).
Example 6
5.0 g of 9a-fluoro-llp, 21-dihydroxy-17a-propionyloxy-I, 4-pregnadiene-3, 20-dione, produced as in Example la and lb from 9a-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 9α-fluoro-11ss-hydroxy- 17a, 21-dípropionyloxy-1, 4-pregnadiene-3, 20-dione. Melting point 191 C. [α]D25 = +51 (chloroform). UV: E, 39 = ID700 (methanOI) Example 7
5.0 g of 9a-fluoro-11 (3, 21-dihydroxy-17a-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-9a-fluoro-llp-hydroxy-17a-propionyloxy-l, 4-pregnadiene-3, 20-dione. Melting point 179 C. [α] = +51 (chloroform). UV: e239 = 15700 (methanol).
Example 8 5 g of 9a-fluoro-11p, 21-dihydroxy-17a-propionyloxy-1, 4-pregnadiene-3,20-dione are reacted as in Example 2 with valeric anhydride instead of butyric anhydride. The whole is likewise worked up as described in Example 2. The crude product is purified on 750 g of silica gel with a methylene chloride/acetone gradient (0-15 % acetone). Yield : 5.03 g of 9α-fluoro-11ss-hydroxy-17α-propionyloxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 190 C. [a] D5 = +54 (chloroform). UV : Er39 = 15800 (methanol).
Example 9 5. 0 g of 9a-fluoro-llp, 21-dihydroxy-17a-propionyloxy-l, -pregnadiene-3, 20-dione are reacted as in Example 2 with caproic anhydride instead of butyric anhydride. The crude product 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 9a-fluoro-21-hexanoyloxys-hydroxy-17a- propionyloxy-l, 4-pregnadiene-3, 20-dione are isolated. Melting point 208 C. [a] 25 = +52 (chloroform). UV: E239 = 15900 (methanol).
Example 10 5.0 g of 9α-fluoro-11ss-,21-dihydroxy-17ss-propionyloxy-1,4-pregnadiene-3,20-dione are reacted and worked up as in Example 2 with trimethvlacetic anhydride instead of butyric anhydride 5. 9 g of crude product are chromatographed on 450 g of silica gel with a methvtene chloride/acetone gradient (0-12 % acetone). Yield: 2.23 g of 9a-fluoro-llp- hydroxy-17a-propionyloxy-21-trimethylacetoxy-1, 4-pregnadiene-3, 20-dione. Melting point 214 C. [a] (12-1 = +53 (chloroform). UV: E239 = lS700 (methanol).
Example Il a) 25 g of 9a-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 in vacuo. The residue is chromatographed on 2.5 kg of silica gel with a methylene chloride/acetone gradient (0-15 % acetone). Yield : 23.1 g of 21-butyryloxy-9a-fluoro-llss, 17a-dihydroxy-1, 4-pregnadiene-3, 20-dione. b) 100 ml of a 5 % solution of methyl lithium in ether are added dropwise at 0 C under argon to a suspension of 24 g of copper (I) iodide in 480 ml of dry tetrahydrofuran. The yellow mixture is cooled to-30 C and a solution of 22.3 g of 21-butyryloxy-9a-fluoro- 11ss, 17a-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 is destroyed with an aqueous ammonium chloride solution. After extraction with methylene chloride the organic phase is washed, dried over sodium sulphate and evaporated in vacuo. Yield : 20.3 g of 17a-butyryloxy-9a-fluoro-llp, 21-dihydroxy-1, 4-pregnadiene-3,20-dione. c) 2.0 g of 17a-butyryloxy-9a-fluoro-llp, 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 17a-butyryloxy-9a-fluoro-1 (3-hydroxy-21-propionyloxy-1, 4-pregnadiene-3,20-dione are isolated. Melting point 146 C.
Example 12
1.5 g of 17a-butyryloxy-9a-fluoro-llp, 21-dihydroxy-1, 4-pregnadiene-3,20-dione are reacted as in Example 2 with valeric anhydride instead of butyric anhydride to form 17a-butyryloxy-9a-fluoro-llp-hydroxy-21-valeryloxy-1, 4-pregnadiene-3,20-dione. Melting point 220 C.
Example 13
1.4 g of 17a-butyryloxy-9a-fluoro-llp, 21-dihydroxy-1, 4-pregnadiene-3,20-dione are stirred overnight at room temperature in 15 mi 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 with water, dried over sodium sulphate and evaporated in 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 17a-butyryloxy-9a-fluoro-21-heptanoyloxy-ll (3- hydroxy-1, 4-pregnadiene-3,20-dione are isolated.
Example 14 4.5 g of 17a-butyryloxy-9a-fluoro-llp, 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 17a-butyry) oxy-9a-fluoro-llp-hydroxy-21- isobutyryloxy-1, 4-pregnadiene-3,20-dione.
Example 15 a) 3 g of 9a-fluoroprednisolone are stirred overnight at room temperature in 30 ml of
pyridine and 15 mi 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 evaporated in 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 9a-fluoro-llss, 17a- dihydroxy-21-valeryloxy-l, 4-pregnadiene-3,20-dione. b) 2 g of 9a-fluoro-llss, 17a-dihydroxy-21-valeryloxy-1, 4-pregnadiene-3,20-dione are converted as in Example 11b with lithium dimethyl cuprate to form 1.86 g of 9a-fluoro-llss, 21- dihydroxy-17a-valeryloxy-1, 4-pregnadiene-3,20-dione. c) 1.8 g of 9a-fluoro-llp, 21-dihydroxy-17a-valeryloxy-1, 4-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 9a-tluoro-llp-hydroxy-21-propionyloxy-17a-valeryloxy-1, 4pregnadiene-3,20-dione. Melting point 206 C.
Example 16
3.4 g of 9a-fluoro-11ss, 21-dihydroxy-17a-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-9a-fluoro-11p-hydroxy-17a-valeryloxy-1, 4-pregnadiene-3,20-dione are isolated. Melting point 234 C.
Example 17
A solution of 2.0 g of 9α-fluoro-11ss, 21-dihydroxy-17a-valeryloxy-1, 4-pregnadiene-3,20dione 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 ill 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 9a-fluoro-21- hexanoyloxy-11p-hydroxy-17a-valeryloxy-1, 4-pregnadiene-3, 20-dione.
Example 18 a) 12 g of 9a-fluoroprednisolone are reacted as in Example 11a, except that isobutyric anhydride is used instead of butyric anhydride, to form 10.4 g of 9a-fluoro-llp, 17α- dihydroxy-21-isobutyry)oxy-l,4-pregnadiene-3, 20-dione. b) 10 g of 9a-fluoro-110, 17a-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 9a-fluoro 1 (3, 21-dihydroxy-17a-isobutyryloxy-1, 4-pregnadiene-3, 20-dione. c) 2.1 g of 9α-fluoro-11ss,21-dihydroxy-17α-isobutyryloxy-1, 4-pregnadiene-3,20-dione are reacted as in Example le with propionic anhydride to form 1.3 g of 9a-fluoro-1 lss-hydroxy- 17a-isobutyryloxy-21-propionyloxy-1, 4-pregnadiene-3, 20-dione.
Erample 19 1.2 g of 9a-fluoro-llp, 21-dihydroxy-17a-isobutyryloxy-1, 4-pregnadiene-3,20-dione are reacted with butyric anhydride, worked up and chromatographed as in Example 2.670 mg of 21-butyryloxy-9a-fluoro-11p-hydroxy-17a-isobutyryloxy-1, 4-pregnadiene-3,20-dione are isolated.
Example 20 a) 5. 0 g of 9a-fluoro-llp, 17a-dihydroxy-21-trimethylacetoxy-1, 4-pregnadiene-3,20-dione are converted as in Example 11b with lithium dimethyl cuprate to form 3.4 g of 9cx-fluoro-Il (3, 21-dihydroxy-17a-trimethylacetoxy-1, 4-pregnadiene-3,20-dione. b) 2.4 g of 9a-fluoro-llp, 21-dihydroxy-17a-trimethylacetoxy-1, 4-pregnadiene-3, 20-dione are reacted as in Example lc with propionic anhydride to form 1.2 g of 9α-fluoro-11ss- hydroxy-21-propionyloxy-17α-trimethylacetoxy-1,4-pregnadiene-3, 20-dione.
Example 21 3. 1 g of 17a-benzoyloxy-9a-fluoro-Ilp, 21-dihydroxy-l, d-pregnadiene-3, 20-dione pro duced from 9a-fluoroprednisolone as in Example la and lb using orthobenzoic acid triethyl ester instead of orthoacetic acid triethyl ester are stiired 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 1c. 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 17a-benzoyloxy-9a-fluoro- 11ss-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione. Melting point 235 C (decomposition). [α]D25 = +22 (pyridine). UV : e, 3, = 28800 (methanol).
Example 22
3.0 g of 17a-benzoyloxy-9a-fluoro-llp. 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 chloridelacetone gradient (0-12 % acetone). 1.9 g of 17α-benzoyloxy-21-butyryloxy-9α-fluoro-11ss-hydroxy- 1, 20-dione are isolated. Nleiting point 218 C (decomposition).
[a) = +21 (pyridine). UV: e ; = 28900 (methanol).
Example 23
2.8 g of 17a-benzoyloxy-9a-fluoro-llp, 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 silica gel with a methylene chloride/acetone gradient (0-12 % acetone). 1.81 g of 17a-benzoyloxy-9a-fluoro-110- hydroxy-21-valeryloxy-1, 4-pregnadiene-3,20-dione are obtained. Melting point 208 C. [C (] D = 22 (pyridine). UV: #234 = 29000 (methanol).
Example 24 2.1 g of 17a-benzoyloxy-9a-fluoro-llp, 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 methylene chloride/acetone gradient (0-12 % acetone). 1.09 g of 17a-benzoyloxy-9a-fluoro-1 Iss- hydroxy-21-isobutyryloxy-1, 4-pregnadiene-3,20-dione are obtained.
Example 25
1.8 g of 17a-benzoyloxy-9a-fluoro-llp, 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 17a-benzoyloxy-9a-fluoro-llp-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 0 C. 800 mg of 17a-acetoxy-9a-fluoro-llp, 21-dihydroxy-1, 4-pregnadiene3,20-dione are then added and stirring is continued for 5.5 hours at 0 C. 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 17a-acetoxy-21-chloro-9a-fluoro-ll (3-hydroxy-1, 4 regnadiene-3, 20-dione. Melting point 265 C (decomposition). [a] = +101 (pyridine). UV: e239 = 15800 (methanol).
Example 27 1.2 g of 9a-fluoro-llp, 21-dihydroxy-17a-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 methylene chloride/acetone gradient (0-15 % acetone). Yield : 860 mg of 21-chloro-9a-fluoro-llp-hydroxy-17a- propionyloxy-1, 4-pregnadiene-3,20-dione. Melting point 229 C (decomposition).
QID = +98' (pyridine). UV: E239 = 15900 (methanol).
Example 28 950 mg of 9u-fluoro-llp, 21-dihydroxy-17a-isobutyryloxy-1, 4-pregnadiene-3,20-dione are treated as in Example 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-9a-fluoro-llp-hydroxy-17a-isobutyryloxy- 1, 4-pregnadiene-3,20-dione. Melting point 216'C.
Example 29
2.5 g of 17a-benzoyloxy-9a-fluoro-llss, 21-dihydroxy-1 4-pregnadiene-3, 20-dione are reacted as in Example 26 and the crude product is purified on 250 g of silica gel with a methylene chloride/acetone gradient (0-12 % acetone). Yield: 1.1 g of 17a-benzoyloxy-21 chloro-9a-fluoro-llp-hydroxy-1, 4-pregnadiene-3,20-dione. Melting point 256 C (decomposition). [a] = +15 (pyridine). UV: 8, 3. = 28600 (methanol).
Example 30 a) A suspension of 8.7 g of 21-fluoro-17a-hydroxy-1, 4,9 (11)-pregnatriene-3, 20-dione in 100 ml of diethylene glycol dimethyl ether is stirred with 12 g of N, Ndimethylaminopyridine 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 after evaporation 7.9 g of 17α-acetoxy-21-fluoro-1, 4,9 (11)- pregnatriene-3, 20-dione are isolated. b) 7.6 of 17a-acetoxy-21-fluoro-1, 4, 9 (11)-pregnatriene-3, 20-dione are dissolved in 76 ml of dioxan and 7.2 g of N-bromosuccinimide 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 is added to a solution of 3.5 g of sodium hydrogen sulphite in 350 ml of water. The precipitate is sucked off and 10 g of 17a-acetoxy-9a-bromo-21-tluoro-llss- hydroxy-1, 4-pregnadiene-3,20-dione are obtained after drying. c) 10 g of the above crude product are refluxed for 2 hours at 110 C in 600 ml of ethanol with 14.0 g of potassium acetate. The reaction solution is concentrated in vacuo and is added to ice water. The precipitate is filtered off and the crude product is purified on 700 g of si) ica set with a methvlene chloride/acetone gradient (0-6 % acetone). Yield : 3.4 g of 17a-acetoxy-9, 11ss-epoxy-21-fluoro-1,4-pregnadiene-3, 20-dione. d) 31 ml of a 70 % (HF) pyridine solution are cooled to-60 C and a solution of 3 g of 17a-acetoxy-9, llp-epoxy-21-fluoro-1, 4-pregnadiene-3,20-dione in 3 ml of pyridine is added. The reaction solution is stirred for 10 hours at-5 C 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 g of 17a-acetoxy-9a, 21-difluoro-ll-hydroxy-1, 4- pregnadiene-3, 20-dione. Nfelting point 976 C (decomposition) [alD5 = + 16 (chloroform).
UV: E239 = 15800 (methanol).
Example 31 a) 5 g of 21-fluoro-17a-propionyloxy-1, 4,9 (11)-pregnatriene-3, 20-dione are produced as in Example 30a from 7.9 g of 21-fluoro-17α-hydroxy-1, 4,9 (11)-pregnatriene-3, 20-dione and propionic anhydride and these 5 g are reacted with N-bromosuccinimide under the conditions described in Example 30b. Yield : 8.5 g of 9α-bromo-21-fluoro-11ss-hydroxy-17α- propionyloxy-l, 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 9,11ss-epoxy 21-fluoro-17a-propionyloxy-1, 4-pregnadiene-3, 20-dione. c) 5.0 g of 9, 1 (3-epoxy-21-fluoro-17a-propionyloxy-l, 4-pregnadiene-3, 20-dione are treated as in Example 30d with 70 % (HF) n/pyridine solution. The reaction product is purified on 700 g of silica gel with a methylene chloride/acetone gradient (0-15 % acetone). Yield : 3.98 g of 9a, 21-difluoro-llp-hydroxy-17a-propionyloxy-1, 4-pregnadiene-3,20-dione. Melting point 214 C. [a] + 15' (chloroform). UV : E239 = 15800 (methanol).
Example 32 a) 20.0 g of 17a-butyryloxy-21-fluoro-1, 4,9 (11)-pregnatriene-3, 20-dione, produced as in
Example 30a from 21-fluoro-17a-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 9a-bromo-17a-butyryloxy-21-fluoro-llp-hydroxy-1, 4-pregnadiene-3,20-dione. b) The above crude product is treated with potassium acetate under the conditions described in Example 30c. 16.1 g of 17a-butyryloxy-9, llp-epoxy-21-fluoro-1, 4- pregnadiene-3,20-dione are isolated. c) 15. 1 g of 17a-butyryloxy-9, llp-epoxy-21-fluoro-1, 4-pregnadiene-3, 20-dione are tre ated as in Example 30d with 70 % (HF) pyridine solution. The crude product is purified on
1.5 kg of silica gel with a methylene chtoride/acetone gradient (0-15 % acetone). 13.4 g of 17α-butyryloxy-9α,21-difluoro-11ss-hydroxy-1,4-pregnadiene-3, 20-dione are obtained.
Nlelting point 126 C. [a] D5 = + 11 (chloroform). UV: #239 = 15300 (methanol).
Exemple 33 a) 7.1 g of 21-fluoro-17a-valeryloxy-1, 4,9 (11)-pregnatriene-3, 20-dione are produced as in
Example 30a from 9.0 g of 21-fluoro-17a-hydroxy-1, 4,9 (11)-pregnatriene-3, 20-dione and valeric anhydride and these 7.1 g are treated as in Example 30b with N-bromosuccinimide.
Yield: 8.7 g 9a-bromo-21-fluoro-llp-hydroxy-17a-valeryloxy-l, 4-pregnadiene-3, 20-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 gel with a methylene chloridelacetone gradient (0-5 % acetone) 4. 2 g of 9, 11ss-epoxy-21-fluoro-17a-valeryloxy-1, 4-pregnadiene- 3,20-dione are obtained. c) 3.1 g of 9α, 21-difluoro-llp-hydroxy-17a-valeryloxy-1, 4-pregnadiene-3, 20-dione are produced as in Example 30d by the reaction of 3.8 g of 9, llp-epoxy-21-fluoro-17a- valeryloxy-1,4-pregnadiene-3, 20-dione with a 70 % (HF),,/pyridine solution, which 3.1 g are obtained after purification on 450 g of silica gel with a methylene chloridelacetone gradient (0-15 % acetone). Melting point 139 C. [a] , 5 = + 10 (chloroform). UV: E239 = 15800 (methanol).
Exasnple 34 a) Under the conditions described in Example 30a 7.3 g of 21-fluoro-17a-hexanoyloxy- l, 4, 9fll)-pregnatriene-3, 20-dione are produced from 8.9 g of 21-fluoro-17a-hydroxy- 1, 4, 9 (11)-pregnatriene-3, 20-dione and caproic anhydride which 7.3 g are reacted as in
Example 30b with N-bromosuccinimide. Yield : 8.2 g of 9a-bromo-21-fluoro-17a- hexanoyloxy-11p-hydroxy-1, 4-pregnadiene-3,''0-dione. b) 8.0 g of the above crude product are treated as in Example 30c with potassium acetate and the crude product is purified with a methylene chtoride/acetonegradient(0-5% acetone). 5.8 g of 9*-epoxy-~l-fluoro-17a-hexanoyloxyw-pregnadiene-3, 20-dione are isolated. c) 3.2 g of 9, llp-epoxy-21-fluoro-17a-hexanoyloxy-1, 4-pregnadiene-3,20-dione are treated, as described in Example 30d, with a 70 % (HF) nipyridine solution. The reaction product is purified on 350 g of silica gel with a methylene chloride/acetone gradient (0-15 % acetone). Yield : 2.6 g of 9a, 21-difluoro-17a-hexanoyloxy-llp-hydroxyl-1, 4-pregnadiene 3, 20-dione.
Example 35 a) 6.2 g of 21-fluoro-17a-isobutyryloxy-1, 4,9 (11)-pregnatriene-3, 20-dione are produced as in Example 30a from 8.1 g of 21-fluoro-17a-hydroxy-1, 4,9 (11)-pregnatriene-3, 20-dione and isobutyric anhydride, which 6.2 g are reacted as in Example 30b with Nbromosuccinimide. Yield : 6.9 g of 9u-bromo-21-fluoro-Ilp-hydroxy-17a-isobutyryloxy-l, 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, llp-epoxy-21-fluoro-17a-isobutyryloxy-1, 4pregnadiene-3, 20-dione are obtained. c) 3.5 g of 9,11ss-epoxy-21-fluoro-17a-isobutryloxy-1, 4-pregnadiene-3,20-dione are reacted as in Example 30d with a 70 % (HF) 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 9a, 21-difluoro-11p-hydroxy-17a-isobutyryloxy-1, 4-pregnadiene-3,20-dione.
Example 36 a) 8.0 g of 21-fluoro-17a-hydroxy-1, 4,9 (11)-pregnatriene-3, 20-dione are added to a mixture of 80 ml of isovaleric acid and 32 ml of tnlfuoroacetic anhydride and then stirred for 2.5 hours at 80 C. The whole is then added to hot water in order to destroy the excess anhydride and is afterwards 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 a small quantity of pyridine, added to ice water and the pyridine is neutralised with dilute hydrochloric acid. After working up in the usual manner 5.8 g of 21-fluoro-17a-isovaleryloxy-1, 4,9 (11)-pregnatriene-3, 20-dione are isolated. b) 5.3 gof 21-fluoro-17a-isovaleryloxy-1, 4,9 (11)-pregnatriene-3, 20-dione are treated as in
Example 30b with N-bromosuccinimide. 6.2 g of 9a-bromo-21-fluoro-ll (3-hydroxy-17a- isovateryloxy-1, 4-pregnadiene-3,20-dione are obtained. c) 6.0 g of the above crude product are reacted as in Example 30c with potassium 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, llp-epoxy-21-fluoro-17a-isovaleryloxy-1, 4pregnadiene-3,20-dione. d) Under the conditions in Example 30d 3 g of 9, llp-epoxy-21-fluoro-17a-isovaleryloxy- 1, 4-pregnadiene-3, 20-dione are reacted with a 70 % (HF) nlpyridine solution. The crude product is purified on 300 g of silica gel with a methylene chloridelacetone gradient (0-15 % acetone). Yield : 2.1 g of 9a, 21-difluoro-llp-hydroxy-17a-isovaleryloxy-1, 4-pregnadiene3,20-dione.
Example 37 a) As described in Example 30a 8.7 g of 21-fluoro-17a-hydroxy-1, A, 9 (11)-pregnatriene- 3,20-dione and trimethylacetic anhydride are reacted to form 6.3 g of 21-fluoro-17atrimethylacetoxy-1, 4, 9 (11)-pregnatriene-3, 20-dione, which 6.3 g are treated as in Example 30b with N-bromosuccinimide. After working up in the usual manner 6.5 g of 9a-bromo-21-fluoro-l (3-hydroxy-17a-trimethylacetoxy-l, 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, 11ss-epoxy-21-fluoro-17a-trimethylacetoxy-1, 4pregnadiene-3, 20-dione. c) 1. 9 g of 9a, 21-difluoro-11ss-hydroxy-17a-trimethylacetoxy-1, 4-pregnadiene-3, 20-dione are produced as in Example 30d from 3.0 g of 1, 4-pregnadiene-3,20-dione by reaction with a 70 % (HF) pyridine solution, which 1.9 g are obtained after purification on 300 g of silica gel with a methylene chloride/acetone gradient (0-15 % acetone).
Example 38 a) 7.0 g of 21-fluoro-17a- (3-phenylpropionyloxy)-1, 4,9 (11)-pregnatriene-3, 20-dione are produced as in Example 30a from 15. 4 g of 21-fluoro-17a-hydroxy-1, 4,9 (11)-pregnatriene3,20-dione and 3-phenylpropionic acid chloride, which 7.0 g are reacted as in Example 30b with N-bromosuccinimide. Yield : 6.9 g of 9a-bromo-21-fluoro-11ss-hydroxy-17a-(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 chloridelacetone gradient (0-5 % acetone). Yield: 3.8 g of 9, llp-epoxy-21- fluoro-17a- (3-phenylpropionyloxy)-1, 4-pregnadiene-3, 20-dione. c) 3.5 g of 9,11ss-epoxy-21-fluoro-17a-(3-phenylpropionyloxy)-1,4-pregnadiene-3,20dione 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 9a, 21-difluoro-115-hydroxy-17a-(3-phenylpropionyloxy)-1, 4pregnadiene-3,20-dione.
Example 39 a) 5.8 g of 17a-cyclopentanecarbonyloxy-21-fluoro-1, 4,9 (11)-pregnatriene-3, 20-dione are produced as in Example 36 from 9.1 g of 21-fluoro-17α-hydroxy-1, 4,9 (11)-pregnatriene3,20-dione, 91 ml of cyclopentanecarboxylic acid and 44 ml of trifluoroacetic anhydride, which 5.8 g are treated as in Example 30b with N-bromosuccinimide. After working up in the normal manner 6.1 g of 9a-bromo-17a-cyclopentanecarbonyloxy-21-fluoro-11 (3- hydroxy-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). 4.5 g of 17a-cyclopentanecarbonyloxy-9, llp-epoxy-21-fluoro- 1, 4-pregnadiene-3,20-dione are obtained. c) 4.0 g of 17a-cyclopentanecarbonyloxy-9, ll (3-epoxy-21-fluoro-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 : 2.8 g of 17α-cyclopentanecarbonyloxy-9α,21-difluoro-11ss-hydroxy-1, 4
pregnadiene-3, 20-dione.
Example 40 a) 5.8 g of 17a-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-17a-hydroxy
1, 4, 9 (11)-pregnatriene-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 Nbromosuccinimide. Yield : 6.1 g of 9a-bromo-17a-cyclohexanecarbonyloxy-21-fluoro-ll (3- 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 17a-cyclohexanecarbonyloxy-9, llp-epoxy-21fluoro-1, 4-pregnadiene-3, 20-dione. c) 2. 4 g of 17a-cyclohexanecarbonyloxy-9a, ? 1-difluoro-11p-hydroxy-1, 4-pregnadiene- 3,20-dione are produced as in Example 30d from 3.1 g of 17a-cyclohexanecarbonyloxy- 9,11ss-epoxv-21-fluoro-1, 4-pregnadiene-3, 90-dione by reaction with a 70 % (HF) pyridine solution, which 2.4 g are obtained after purification on 300 g of silica gel with a methylene chloride/acetone gradient (0-15 % acetone).
Example 41 1 g of 17a, 21- (a-ethoxybenzylidenedioxy)-9a-fluoro-11 (3-hydroxy-1, 4-pregnadiene-3, 20- dione is stirred in 40 nl of dimethylformamide with 4 mi of trimethylsilyl flouride for 2 hours at room temperature. After precipitating with ice water and working up in the usual manner the whole is evaporated in 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 17a-benzoyloxy-9a, 91-difluoro-l l-hydroxy-1, 4-pregnadiene-3, 20-dione.
II PHARMACEUTICAL PREPARATIONS
Example 42
Composition of an ointment 0. 03 % of 9a-fluoro-11 -hydroxy-17a, 21-dipropionvloxy-l, 4-pregnadiene-3, 20-dione 2.50 % Allercur hexachlorophenate, micronised, particle size approximately 8 u (Allercur = Trade Mark for 1-p-chlorobenzyl-2-pyrrolidylmethylbenzimidazole) 6.00 % Hostaphat KW 340 (Trade Mark) (tert. ester of O-phosophoric acid and wax alcohol tetra-glyclo ether) 0.10 % sorbic acid 10.00 % neutral oil (Migloyol 812 (Trade Mark)) 3.50 % stearyl alcohol 1.50 % wool fat, anhydrous DAB 6 76.36 % desalted water Example 43 Production of an inhalant 1. 000g of micronised 9a-fluoro-llp-hydroxy-17a, 21-dipropionyloxy-1, 4-pregnadiene-3,20dione (average particle size smaller than 7 > ) and 39.00 g of ground lactose are mixed together. A dose of 20 mg of inhalant is used per inhalation.
Claims (57)
1. A compound of the general formula (I)
wherein R, 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 R, 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 R,
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.
2. A compound as claimed in claim 1, wherein R, represents a formyl group or an alkanoyl or cycloalkanecarbonyl group having up to 8 carbon atoms or a benzoyl group, and
X represents a fluorine or chlorine atom or an alkanoyloxy or cycloalkanecarbonyloxy group having from 3 to 8 carbon atoms.
3. A compound as claimed in claim 1 or claim 2, wherein R, represents a benzoyl group or an alkanoyl group having up to 6 carbon atoms.
4. A compound as claimed in any one of claims 1 to 3, wherein X represents a fluorine or chlorine atom or an alkanoyloxy group having up to 6 carbon atoms.
5.17a-Acetoxy-9a-fluoro-1 lss-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione.
6.17a-Acetoxy-21-butyryloxy-9a-fluoro-11 ss-hydroxy-1,4-pregnadiene-3,20-dione.
7.17a-Acetoxy-9a-fluoro-llss-hydroxy-21-valeryloxy-1, 4-pregnadiene-3, 20-dione.
8.17a-Acetoxy-9a-fluoro-21-hexanoyloxy-11 ss-hydroxy-1,4-pregnadiene-3,20-dione.
9.17a-Acetoxy-9 -fluoro-11 ss-hydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20dione.
10.9a-Fluoro-llp-hydroxy-17a, 21-dipropionyloxy-1, 4-pregnadiene-3, 20-dione.
11. 21-Butyryloxy-9a-fluoro-Il (3-hydroxy-17a-propionyloxy-1, 4-pregnadiene-3, 20dione.
12.9a-Fluoro-11 ss-hydroxy-17a-propionyloxy-21-valeryloxy-1,4-pregnadiene-3,20dione.
13.9a-Fluoro-21-hexanoyloxy-llss-hydroxy-17a-propionyloxy-1,4-pregnadiene-3,20dione.
14.9a-Fluoro-llss-hydroxy-17a-propionyloxy-21-trimethylacetoxy-1, 4-pregnadiene3,20-dione.
15.17a-Butyryloxy-9a-fluoro-11p-hydroxy-21-propionyloxy-1, 4-pregnadiene-3, 20dione.
16.17a-Butyryloxy-9a-Quoro-llss-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione.
17.] 17α-Butyryloxy-9α-fluoro-21-heptanoyloxy-11ss-hydroxy-1,4-pregnadiene-3, 20dione.
18.17a-Butyryloxy-9a-fluoro-11 ss-hydroxy-21-isobutyryloxy-1, 4-pregnadiene-3,20dione.
19.9a-Fluoro-11-hydroxy-21-propionyloxy-17a-valeryloxy-1, 4-pregnadiene-3, 20dione.
20. 21-Butyryloxy-9α-fluoro-11 ss-hydroxy-17a-valeryloxy-1. 4-pregnadiene-3,20-dione.
21. 9α-Fluoro-21-hexanoyloxy-11ss-hydroxy-17α-valeryloxy-1,4-pregnadiiene-3, 20dione.
22. 9α-Fluoro-11ss-hydroxy-17α-isobutyryloxy-21-propionyloxy-1, 4-pregnadiene-3,20dione.
23.21-Butyryloxy-9a-fluoro-11 ss-hydroxy-17a-isobutyryloxy-1, 4-pregnadiene-3,20dione.
24. 9α-Fluoro-11 ss-hydroxy-21-propionyloxy-17α-trimethylacetoxy-1, 4-pregnadiene3,20-dione.
25. 17α-Benzyoyloxy-9α-fluoro-11ss-hydroxy-21-propionyloxy-1,4-pregnadiene-3, 20dione.
26.17a-Benzoyloxy-21-butyryloxy-9a-fluoro-llss-hydroxy-1,4-pregnadiene-3,20dione.
27.17a-Benzoyloxy-9a-fluoro-11 ss-hydroxy-21-valeryloxy-1, 4-pregnadiene-3,20-dione.
28.17a-Benzoyloxy-9a-fluoro-llp-hydroxy-21-isobutyryloxy-1,4-pregnadiene-3,20dione.
29.17a-Benzoyloxy-9a-fluoro-1 (3-hydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20dione.
30. 17α-Acetoxy-21-chloro-9α-fluoro-11ss-hydroxy-1, 4-pregnadiene-3,20-dione.
31.21-Chloro-9a-fluoro-11 ss-hydroxy-17a-propionyloxy-1, 4-pregnadiene-3,20-dione.
32.21-Chloro-9a-fluoro-1 (3-hydroxy-17a-isobutyryloxy-1,4-pregnadiene-3,20-dione.
33.17a-Benzoyloxy-21-chloro-9a-fluoro-11p-hydroxy-1,4-pregnadiene-3,20-dione.
34.17a-Acetoxy-9a, 21-difluoro-llss-hydroxy-1, 4-pregnadiene-3,20-dione.
35.9a, 21-Difluoro-llp-hydroxy-17a-propionyloxy-1, 4-pregnadiene-3,20-dione.
36.17a-Butyryloxy-9a, 21-difluoro-llp-hydroxy-1, 4-pregnadiene-3,20-dione.
37.9a, 21-Difluoro-llss-hydroxy-17a-valeryloxy-1, 4-pregnadiene-3,20-dione.
38.9a, 21-Difluoro-17a-hexanoyloxy-1lp-hydroxy-1, 4-pregnadiene-3, 20-dione.
39.9a, 21-Difluoro-llss-hydroxy-17a-isobutyryloxy-1, 4-pregnadiene-3,20-dione.
40.9a, 21-Difluoro-llp-hydroxy-17a-isovaleryloxy-I, 4-pregnadiene-3, 20-dione.
41. 9a, 21-Difluoro-I1 (3-hydroxy-17a-trimethylacetoxy-1, 4-pregnadiene-3, 20-dione.
42. 9α, 21-Difluoro-11ss-hydroxy-17α-(3'-phenylpropionyloxy)-1,4-pregnadiene-3,20- dione.
43. 17α-Cyclopentanecarbonyloxy-9α,21-difluoro-11ss-hydroxy-1,4-pregnadiene-3, 20dione.
44. 17a-Cyclohexanecarbonyloxy-9a, 21-difluoro-11p-hydroxy-1, 4-pregnadiene-3, 20dione.
45. 17α-Benzoyloxy-9α,21-difluoro-11ss-hydroxy-1,4-pregnadiene-3,20-dione.
46. A process for the manufacture of a compound as claimed in claim 1 wherein a) the epoxide ring of a compound of the general formula (II)
in which X and R, have the meanings given in claim 1 is opened with hydrogen fluoride, or b) a 9-fluoro derivative of the general formula (III)
wherein R has the meaning given in claim 1, 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.
47. A process as claimed in claim 46, carried out substantially as described in any one of the Examples 1 to 41 herein.
48. A compound as claimed in claim 1, whenever obtained by a process claimed in claim 46 or claim 47.
49. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 45 and 48, in admixture or conjunction with a pharmaceutically suitable carrier.
50. A pharmaceutical preparation as claimed in claim 49, which is in the form of an ointment.
51. A pharmaceutical preparation as claimed in claim 50, substantially as described in
Example 42 herein.
52. A pharmaceutical preparation as claimed in claim 49, which is in the form of an inhalant.
53. An inhalant as claimed in claim 52, substantially as described in Example 43 herein.
54. A pharmaceutical composition which comprises a compound as claimed in any one of claims I to 45 and 48, and a medicament for the treatment of a non-inflammatory disease but which is liable to have an inflammatory action.
55. A pharmaceutical preparation which comprises a composition as claimed in claim 54, in admixture or conjunction with a pharmaceutically suitable carrier.
56. A pack which comprises a compound as claimed in any one of claims 1 to 45 and 48, or a preparation as claimed in any one of claims 49 to 53, and a medicament for the treatment of a non-inflammatory disease but which is liable to have an inflammatory action.
57. A method of treating a non-human animal to relieve inflammation, which comprises applying to the affected area a compound as claimed in any one of claims 1 to 45 and 48 or a preparation or composition as claimed in any one of claims 49 to 53.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2712862A DE2712862C2 (en) | 1977-03-21 | 1977-03-21 | Derivatives of 9-fluorprednisolone, process for their preparation and pharmaceuticals containing them |
| 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 |
|---|---|
| GB1603281A true GB1603281A (en) | 1981-11-25 |
Family
ID=25771793
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB10925/78A Expired GB1603281A (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 |
| 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 |
| CA1104124A (en) | 1981-06-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |