EP0000742B1 - 17-Alcoylcarbonates de corticoides, leur procédé de préparation et compositions les contenant - Google Patents

17-Alcoylcarbonates de corticoides, leur procédé de préparation et compositions les contenant Download PDF

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Publication number
EP0000742B1
EP0000742B1 EP78100524A EP78100524A EP0000742B1 EP 0000742 B1 EP0000742 B1 EP 0000742B1 EP 78100524 A EP78100524 A EP 78100524A EP 78100524 A EP78100524 A EP 78100524A EP 0000742 B1 EP0000742 B1 EP 0000742B1
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Prior art keywords
carbonate
acid chloride
iso
methyl
chloroformate
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EP0000742A1 (fr
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Ulrich Dr. Stache
Werner Dr. Fritsch
Hans Georg Dr. Alpermann
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Hoechst AG
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Hoechst AG
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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
    • C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
    • C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036—Nitrogen-containing hetero ring
    • C07J71/0042—Nitrogen only
    • C07J71/0047—Nitrogen only at position 2(3)

Definitions

  • R 5 methyl, ethyl, propyl, phenyl and the other substituted phenyl radicals mentioned for R 5 , the substituents each being in the p-position.
  • a carboxylic acid such as, for example, ants, vinegars, propions, butter , Valerian, oxalic, maleic, fumaric, succinic or adipic acid, or an organic sulfonic acid, such as p-toluene, benzene, p- or o- or m-chloro- or bromobenzenesulfonic acid or one inorganic acid, such as hydrochloric, sulfuric, carbonic, nitric acid used.
  • a carboxylic acid such as, for example, ants, vinegars, propions, butter , Valerian, oxalic, maleic, fumaric, succinic or adipic acid, or an organic sulfonic acid, such as p-toluene, benzene, p- or o- or m-chloro- or bromobenzenesulfonic acid or one inorganic acid, such as hydrochloric, sulfuric, carbonic
  • water or / and inert organic solvents such as alcohols, linear or cyclic ethers, esters, dialkylformamides, dialkylsulfoxides or hexamethylphosphoric acid triamide, for dilution, often in addition to the dilution effect a catalytic or regioselective effect in the direction of the desired course of the reaction is brought about.
  • the course of the reaction in the desired direction is expediently followed by thin-layer chromatography. It is advantageous to terminate the reaction by neutralizing, for example, with dilute ammonia or adjusting the pH to above 7, if the thin-layer diagram, after optimal formation of the desired steroid-17 '-monoalkylcarbonate-21-hydroxy compounds, isometrized to the undesired steroid- Indicate 17-hydroxy-21-monoalkyl carbonate compounds.
  • the corticoid-17,21-orthoalkyl carbonate is preferably dissolved in a carboxylic acid, such as, for example, in acetic acid or propionic acid, preferably about 0.1 to 1% water is added and the mixture is left for up to about 8 hours at a temperature of 0 ° to react to the boiling point of the acid or solvent used.
  • a carboxylic acid such as, for example, in acetic acid or propionic acid
  • the reaction mixture is stirred into water or saline, neutralized, for example, with aqueous ammonia or another weak base, either the precipitate is suctioned off or extracted in a conventional manner with organic solvents, evaporates, recrystallizes the products obtained and chromatographs them, if the starting material or 21-alkyl carbonate is still detectable in the TLC diagram, if necessary on silica gel or aluminum oxide.
  • the steroid component is dissolved in an inert solvent, such as, for example, in an ether, such as dioxane, tetrahydrofuran, diglyme, or optionally halogenated hydrocarbon, such as benzene, toluene, cyclohexane, methylene chloride, chloroform or in a mixture of these solvents.
  • an ether such as dioxane, tetrahydrofuran, diglyme
  • optionally halogenated hydrocarbon such as benzene, toluene, cyclohexane, methylene chloride, chloroform or in a mixture of these solvents.
  • 1-1000 molar equivalents of a tertiary base such as pyridine, quinoline, triethylamine or dimethylaniline are added. You can also use an organic base such as sodium bicarbonate or calcium carbonate to remove the acid.
  • 1-200 molar equivalents, preferably 1-3 molar equivalents, of one of the above-mentioned acylating agents, optionally dissolved in one of the above-mentioned solvents, are added dropwise at a temperature between -40 ° C. and the boiling point of the solvent used, preferably between 0 ° C. and 25 ° C, too.
  • the reaction mixture is then left to stand for from one to 120 hours at a temperature between -40 ° C. and the boiling point of the solvent, preferably between 0 ° C. and 25 ° C.
  • reaction mixture For working up, the reaction mixture is poured into water, to which sodium bicarbonate has optionally been added, the reaction products generally precipitating out in crystalline form, often only after prolonged standing. Reaction products that have remained oily are enriched by shaking with a suitable extractant and evaporation. If necessary, the reaction products can be separated or purified by recrystallization or by chromatography. Intensive digestion in an organic solvent which dissolves the reaction product as little or as little as possible, such as diethyl ether or cyclohexane or a mixture of these components, is often sufficient for further purification of the reaction products.
  • an organic solvent which dissolves the reaction product as little or as little as possible, such as diethyl ether or cyclohexane or a mixture of these components, is often sufficient for further purification of the reaction products.
  • a hydroxy group in the 11-position can optionally be oxidized to the keto group by customary methods. This oxidation is preferably carried out with chromium trioxide in an acidic medium and in an inert organic solvent.
  • the process products have valuable pharmacological properties. They have a particularly strong local and topical anti-inflammatory activity and in some cases show an advantageous ratio of local to systemic anti-inflammatory activity, as can be derived from standard pharmacological tests.
  • the invention also relates to an agent for the treatment of inflammatory dermatoses consisting of or comprising a compound of the formula or II.
  • the process products can be used in veterinary and human therapy for the treatment of inflammatory dermatoses of various origins in the form of suspensions, ointments, creams, sprays, etc. When applied topically, they can be applied in the form of crystal suspensions - for example, during intra-articular injection. It should be emphasized as particularly advantageous for the local and topical form of therapy that the process products, due to their favorable ratio of local to systemic antiphlogistic effect, are also long-term in the case of high doses therapy can practically only cause minor systemic side effects. In addition, the process products used have a significantly better acid stability than the cyclic corticoid-17,21-ortho-carbonates on which they are based. This fact is of crucial importance for a safe and therapy-rich registration of the products according to the invention.
  • ointments, creams, suspensions, etc. with a concentration of 0.01 to 2% by weight are used, for topical administrations in the form of local (non-systemic) injections, doses of 0.1 mg to 100 mg .
  • the IR spectra (in KBr) are recorded with the Perkin-Elmer 521 grating spectrophotometer. Only the characteristic bands are listed.
  • the UV spectra (in methanol) were recorded with the Beckman DK 1 A spectrophotometer.
  • the mass spectrometric investigations (MS) are carried out with the MS 9 device (from AEI).
  • the dexamethasone 17-ethyl carbonate-21-butyrate of mp 202-205 ° C. is obtained.
  • the 4.45 g of 6 ⁇ -fluoro-prednisolone-17 ⁇ -ethyl carbonate obtained with a melting point of 133 ° -136 ° can thus be reacted immediately without further purification as follows.
  • the above substance is dissolved in 60 ml of absolute pyridine and, after cooling to 0 °, 2.3 ml of propionic acid chloride are added. After 1 hour at 0 ° and a further hour at 20 °, the reaction mixture is stirred into 500 ml of semi-saturated aqueous sodium chloride solution. The mixture is then extracted with methylene chloride, the organic phase is washed neutral with water, dilute hydrochloric acid and water, dried and evaporated to dryness in vacuo.
  • the 4.95 g of crude 6 ⁇ -fluoro-prednisolone-17 ⁇ -ethyl carbonate-21-propionate obtained can be purified as follows.
  • Example 2a chromatography is carried out on a column of 250 g of silica gel and worked up. At the end, the product is recrystallized from ether / petroleum ether and 2.55 g of 6 ⁇ -fluoro-prednisolone-17a-ethyl carbonate-21-propionate, mp.
  • the 6 ⁇ -fluoro-prednisolone-17 ⁇ , 21-diethyl orthocarbonate used as starting material is obtained analogously according to DBP 16 68 079 as follows.
  • a solution of 4.75 g of 6 ⁇ -fluoro-prednisolone in 180 ml of anhydrous dioxane is stirred for 15 hours at room temperature after the addition of 13 ml of tetraethyl orthocarbonate and 0 29 g of p-toluenesulfonic acid. Then the reaction mixture is poured into a solution of 1.5 g of sodium hydrogen carbonate in 950 ml of water. The precipitated crystals are collected, washed with water, dried and recrystallized from acetone.
  • reaction mixture is poured into a solution of 6.0 g of sodium hydrogen carbonate in 4.0 l of water.
  • the mixture is then worked up as described in Example 7. 21.1 g of 6a-methyl-prednisolone-17 ⁇ , 21-bis - (ethyl carbonate) of mp 109-112 were obtained.
  • prednisolone dimethyl orthocarbonate (R F -0.6) initially required for the reaction is prepared from prednisolone and tetra-methyl orthocarbonate according to DBP 1 668 079.
  • cortisone dimethyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from cortisone and tetramethyl orthocarbonate according to DBP 1 668 079.
  • cortisol dimethyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is produced from cortisol and tetramethyl orthocarbonate according to DBP 1 668 079.
  • betamethasone 17-methyl carbonate-21-p-toluenesulfonate or -21-p-chlorobenzenesulfonate is obtained.
  • the betamethasone dimethyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from betamethasone and tetra methyl orthocarbonate in accordance with DBP 1 668 079.
  • the former is then hydrolyzed to 6a, 16a or ⁇ -dimethyl-prednisolone-17-methyl carbonate (R F ⁇ 0.4) in the same manner as described in Example 1 c).
  • prednisolone diethyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from prednisolone and tetraethyl orthocarbonate in accordance with DBP 1 668 079.
  • prednisone diethyl orthocarbonate (R F -0.6) initially required for the reaction is prepared from prednisone and tetraethyl orthocarbonate according to DBP 1 668 079.
  • cortisone diethyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from cortisone and tetraethyl orthocarbonate according to DBP 1 668 079.
  • cortisol diethyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared according to DBP 1 668 079 from cortisol and tetraethyl orthocarbonate.
  • the betamethasone diethyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from betamethasone and tetraethyl orthocarbonate according to DBP 1 668 079.
  • the former is then hydrolyzed to 6a, 16 ⁇ - or ⁇ -dimethyl-prednisolone-17-ethyl carbonate (R f - 0.4) in the same manner as described in Example 1 c).
  • prednisolone di-n-propyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from prednisolone and tetra-n-propyl orthocarbonate according to DBP 1 668 079.
  • prednisone di-n-propyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from prednisone and tetra-n-propyl orthocarbonate according to DBP 1 668 079.
  • cortisone di-n-propyl orthocarbonate (R F - 0.6) initially required for the reaction is prepared from cortisone and tetra-n-propyl orthocarbonate in accordance with DBP 1 668 079.
  • cortisol di-n-propyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from cortisol and tetra-n-propyl orthocarbonate according to DBP 1 668 079.
  • the betamethasone di-n-propyl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared according to DBP 1 668079 from betamethasone and tetra-n-propyl orthocarbonate.
  • Example 2 f In the same manner as described in Example 2 f), 3 g of 6 ⁇ , 16 ⁇ - or ⁇ -dimethyl-prednisolone-17-n-propyl carbonate are reacted with methanesulfonic acid chloride and worked up. After crystallization from ether, 6a, 16a or ß-dimethyl-prednisolone-17-n-propyl carbonate-21-methanesulfonate is obtained.
  • the first is then hydrolyzed to 6 ⁇ , 16 ⁇ - or ⁇ -dimethyl-prednisolone-17-n-propyl-carbonate (R F ⁇ 0.4) in the same manner as described in Example 1 c).
  • prednisolone divaleryl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from prednisolone and tetravaleryl orthocarbonate according to DBP 1 6680 9. The former is then hydrolyzed to prednisolone-1 7-valeryl carbonate (R F ⁇ 0.4) in the same manner as described in Example 1 c).
  • prednisone di-valeryl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from prednisone and tetra-valeryl orthocarbonate in accordance with DBP 1 668 079. Then will the former hydrolysed to prednisone-1 7-valeryl carbonate (R F ⁇ 0.4) in the same way as described in Example 1 c).
  • cortisone di-valeryl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is produced from cortisone and tetra-valeryl orthocarbonate in accordance with DBP 1 668 079. The former is then hydrolyzed to cortisone 17-valeryl carbonate (R F -0.4) in the same manner as described in Example 1 c).
  • cortisol di-valeryl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from cortisol and tetra-valeryl orthocarbonate in accordance with DBP 1 668 079. The former is then hydrolyzed to cortisol-17-valeryl carbonate (R F ⁇ 0.4) in the same manner as described in Example 1 c).
  • betamethasone di-valeryl orthocarbonate (R F ⁇ 0.6) initially required for the reaction is prepared from betamethasone and tetravaleryl orthocarbonate in accordance with DBP 1 668 079. The former is then hydrolyzed to betamethasone-17-valeryl carbonate (R F ⁇ 0.4) in the same manner as described in Example 1 c).
  • bimedrazole-17-n-propyl carbonate (representation: bimedrazole + tetra-n-propyl orthocarbonate instead of tetraethyl orthocarbonate initially gives the amorphous bimedrazole - 17.21 - di - n - propyl orthocarbonate, which is then analogous is selectively solvolysed in glacial acetic acid / water), the corresponding -21-carboxylic acid esters, -21-carbonates and -21-sulfonic acid esters are shown.
  • the cortisol, cortisone, prednisolone, prednisone, 6 ⁇ -methylprednisolone, 6 ⁇ -fluoro-prednisolone, betamethasone beclomethasone, 9 ⁇ -chloro, 16 ⁇ -methyl-prednisolone, 9 ⁇ - Fluorine - dexamethasone - 17 - ethyl carbonate used in the reaction, the corresponding 21-chloroacetates of the above-mentioned corticoid 17-ethyl carbonates are obtained after analogous reaction and working up.
  • the homologous corticoid-17-n-propyl-ocarbonates are used in the reaction, the corresponding corticoid-17-n-propyl carbonate-21-chloroacetate is obtained after analogous reaction control and processing .
  • the foam obtained is recrystallized from acetone / diisopropyl ether and gives 2.1 g of 11-dehydrodexamethasone - 17.21 bis - [ethyl carbonate] of mp 212 ° C.
  • the corticoid 17-alkyl carbonates dargestellen in the preceded examples in the 11-position and a hydroxyl group in 21 - Position either an alkyl carbonate or alkyl carboxylic acid ester or alkyl or arylsulfonic acid ester group, used in the oxidation reaction just described, the corresponding 11-dehydro-corticoid-17-alkyl carbonate-21-alkyl carbonates or 21-alkyl carboxylic acid esters, or -21-alkyl sulfonic acid esters, or -21-aryl sulfonic acid esters.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Claims (5)

1. Composés de formule I ou II:
Figure imgb0024
dans lesquelles:
A représente =CHOH dans un arrangement stérique quelconque, =CH2 ou =CO,
Y représente l'hydrogène, le fluor ou le chlore,
Z représente l'hydrogène, le fluor, le chlore ou un groupe méthyle,
R3 représente l'hydrogène, le fluor ou un groupe a-méthyle, monofluorométhyle ou difluorométhyle,
R2 représente un group alcoyle ayant de 1 à 8 atomes de carbone,
R1 représente un groupe acyle de formule III:
Figure imgb0025
Carbonyloxyalcoyle de formule IV
Figure imgb0026
ou sulfoalcoyle de formule V:
Figure imgb0027
dans lesquelles:
R4 représente l'hydrogène, un groupe alcoyle ayant de 1 à 10 atomes de carbone, cycloalcoyle ayant de 3 à 6 atomes de carbone, ou quand n est différent de zéro, le fluor, le chlore, le brome ou un radical pipéridyle,
R5 représente un groupe alcoyle ayant de 1 à 4 atomes de carbone, phényle, méthylphényle, éthylphényle, fluorophényle, bromophényle ou chlorophényle,
n est un nombre entier compris entre 0 et 4.
2. 17-alcoylcarbonate-21-carboxylates de prednisolone selon la revendication 1.
3. 17-éthylcarbonate-21-propionate de prednisolone.
4. Procédé de préparation de composés selon la revendication 1, caractérisé en ce qu'on hydrolyse des composés de formules VI ou VII:
Figure imgb0028
avec un acide faible et on estérifie le composé 21-hydroxy obtenu avec un halogénure ou un anhydride d'un acide carboxylique de formule VIII:
Figure imgb0029
un halogénoformiate de formule IX:
Figure imgb0030
ou un halogénure d'un acide sulfonique de formule X:
Figure imgb0031
5. Médicament pour le traitement des dermatoses inflammatoires, constitué de, ou contenant un composé selon l'une quelconque des revendications 1 à 3.
EP78100524A 1977-08-04 1978-07-27 17-Alcoylcarbonates de corticoides, leur procédé de préparation et compositions les contenant Expired EP0000742B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19772735110 DE2735110A1 (de) 1977-08-04 1977-08-04 Corticoid-17-alkylcarbonate und verfahren zu ihrer herstellung
DE2735110 1977-08-04

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EP0000742A1 EP0000742A1 (fr) 1979-02-21
EP0000742B1 true EP0000742B1 (fr) 1982-05-12

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US (1) US4242334A (fr)
EP (1) EP0000742B1 (fr)
JP (1) JPS5436248A (fr)
AT (1) AT372093B (fr)
AU (1) AU522854B2 (fr)
CA (1) CA1118411A (fr)
DE (2) DE2735110A1 (fr)
DK (1) DK154145C (fr)
EG (1) EG13560A (fr)
ES (1) ES472147A1 (fr)
HU (1) HU182732B (fr)
IT (1) IT1097652B (fr)
ZA (1) ZA784417B (fr)

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DK344978A (da) 1979-02-05
DK154145B (da) 1988-10-17
AT372093B (de) 1983-08-25
IT1097652B (it) 1985-08-31
AU522854B2 (en) 1982-07-01
JPH0112758B2 (fr) 1989-03-02
JPS5436248A (en) 1979-03-16
EG13560A (en) 1981-12-31
DE2735110A1 (de) 1979-02-15
DK154145C (da) 1989-02-27
ES472147A1 (es) 1979-03-16
EP0000742A1 (fr) 1979-02-21
DE2861809D1 (en) 1982-07-01
ZA784417B (en) 1979-08-29
ATA564578A (de) 1983-01-15
AU3861178A (en) 1980-02-07
CA1118411A (fr) 1982-02-16
IT7826424A0 (it) 1978-08-02
US4242334A (en) 1980-12-30
HU182732B (en) 1984-03-28

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