EP0000809B1 - Entzündungshemmende 1-Phenylethanolamin-Derivate, deren pharmazeutischen Zusammensetzungen und Verfahren zu deren Herstellung - Google Patents

Entzündungshemmende 1-Phenylethanolamin-Derivate, deren pharmazeutischen Zusammensetzungen und Verfahren zu deren Herstellung Download PDF

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Publication number
EP0000809B1
EP0000809B1 EP78300153A EP78300153A EP0000809B1 EP 0000809 B1 EP0000809 B1 EP 0000809B1 EP 78300153 A EP78300153 A EP 78300153A EP 78300153 A EP78300153 A EP 78300153A EP 0000809 B1 EP0000809 B1 EP 0000809B1
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formula
pharmaceutically acceptable
hydrogen
radical
solution
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EP0000809A1 (de
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John Preston
Austin John Reeve
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Imperial Chemical Industries Ltd
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Imperial Chemical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • 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]

Definitions

  • This invention relates to 1-phenyl-ethanolamine derivatives which possess anti-inflammatory activity when applied topically to an area of inflammation, and in addition it relates to pharmaceutical compositions of, methods of manufacture of, and methods of treatment using such derivatives.
  • 1-phenylethanolamine derivatives such as 1-(4-amino-3,5-dichlorophenyl)-2-t-butylamino ethanol (which as its hydrochloride is known as clenbuterol) possess potent adrenergic ⁇ -receptor stimulatory properties. (Von G. Engelhardt, Arzneistoffforschung, 1976, 26, 1403-1420).
  • a compound of formula I possesses one or more asymmetric carbon atoms, and can therefore exist in one or more racemic, and two or more optically-active forms.
  • This invention relates to the racemic form of a compound of formula I and to any optically-active form which possesses anti-inflammatory activity, it being well known in the art how to prepare optically active forms by resolution of the racemic form, or by synthesis from optically-active starting materials, and how to determine the anti-inflammatory activity by the standard tests described hereinbelow.
  • R 1 when it is a C 2-6 -alkanoyl radical is, for example, a 2,2-dimethylpropionyl (pivaloyl) or 3,3-dimethylbutyryl radical.
  • R or R 3 when it is a C 1-4 -alkyl radical is, for example, a methyl radical.
  • a particular value for A is, for example, a methylene, ethylene, ethylidene or isopropylidene diradical, of which a methylene diradical is especially preferred.
  • a particular value for Q when it is a C 4-20 -alkanoyl radical is, for example, an octadecanoyl (stearoyl) radical.
  • a particular value for a halogen atom when present as an optional substituent as part of radical Q is, for example, a fluorine, chlorine or bromine atom.
  • Q is, for example, when it is an octadecanoyl, phenylacetyl, 4-methylphenylacetyl, 4-chlorophenylacetyl, phenoxyacetyl, 3-(trifluoromethyl)phenoxyacetyl, 4-methoxyphenoxyacetyl or phenylaminocarbonyl radical.
  • a particular acid-addition salt of a compound of formula I is, for example, a salt derived from an acid having a pharmaceutically acceptable anion, for example from an inorganic acid, for example hydrochloric, hydrobromic, phosphoric or sulphuric acid, or from an organic acid, for example oxalic tartaric, lactic, fumaric, citric, acetic, salicylic, benzoic, ⁇ -naphthoic, methane sulphonic or adipic acid.
  • These salts may contain one or two molecular equivalents of acid.
  • the compounds of formula I may be manufactured by any process known to be useful for the preparation of chemically analogous compounds. Such processes are provided as a further feature o the invention and are illustrated by the following in which R 1 , R 2 , R 3 , A and Q have any of the meaning: defined hereinbefore.
  • the reduction may be carried out using any agent generally known for reducing aromatic ketones, but which is compatible with the other substituents present in the starting material of formula II.
  • the reduction may be carried out by means of an alkali metal borohydride, for example sodium borohydride, in an appropriate diluent or solvent, for example methanol, ethanol or 2-propanol, or by means of catalytic hydrogenation, for example with hdyrogen in the presence of a palladium, platinum or nickel catalyst, in a diluent or solvent, for example ethanol or acetic acid, and in either case, at a temperature of, for example, -20° to 50°C., and conveniently at or near normal room temperature, for example at 15° to 30°C.
  • an alkali metal borohydride for example sodium borohydride
  • an appropriate diluent or solvent for example methanol, ethanol or 2-propanol
  • catalytic hydrogenation for example with hdyrogen in the presence of a
  • the starting materials of formula II may be obtained by reacting a phenacylhalide of the formula:- wherein Hal. is a chlorine or a bromine atom, with an amino compound of the formula:-
  • This reaction is conveniently carried out at or near normal room temperature, for example at 15 to 30°C., and in a diluent or solvent, for example, ethanol, dioxan, chloroform or acetonitrile. It may also be carried out in the presence of an acid-binding agent, for example pyridine, triethylamine an alkali metal carbonate or bicarbonate, or in an excess of the amino compound of formula IV.
  • a diluent or solvent for example, ethanol, dioxan, chloroform or acetonitrile.
  • an acid-binding agent for example pyridine, triethylamine an alkali metal carbonate or bicarbonate, or in an excess of the amino compound of formula IV.
  • the starting materials of formula III may themselves be obtained by conventional halogenation of the corresponding acetophenone of formula III, but wherein Hal, is replaced by hydrogen, for example, as described in the accompanying Examples.
  • the amino starting materials of formula IV may be obtained by conventional selective acylation of a diamine of formula IV but wherein Q is replaced by hydrogen, with an acylating agent derived structurally from an acid of the formula Q.OH, for example, by dropwise addition of the diamine to an excess of acylating agent in a solvent, for example ether, in which the hydrochloride of the compound of formula IV is insoluble.
  • the starting materials of formula II may conveniently be obtained and used in process (a) in the same reaction vessel without separate isolation and purification.
  • Particularly suitable reducing conditions are provided by using, for example, an alkalimetal. borohydride or cyanoborohydride, for example sodium borohydride or cyanoborohydride.
  • the process is conveniently carried out in a diluent or solvent, for example, acetonitrile, methanol, ethanol or 2-propanol and at a temperature for example, in the range -20° to 30°C.
  • a diluent or solvent for example, acetonitrile, methanol, ethanol or 2-propanol
  • sodium cyanoborohydride is used, the reaction is preferably carried out at or near pH4, for example in the presence of acetic acid.
  • process (b) is an example of the general process known as reductive alkylation, and proceeds at least in part through an intermediate of the formula:- and that process (b) may therefore be carried out by separate steps involving the preparation and subsequent reduction of an intermediate of formula VI.
  • a particularly suitable reductively removable protecting group is, for example a benzyl radical.
  • the reduction is preferably carried out by means of catalytic hydrogenation, for example with hydrogen in the presence of a palladium, platinum or nickel catalyst, in a diluent of solvent, for example ethanol or water, or a mixture thereof.
  • the reduction may be carried out at, for example, 15-35°C and, may optionally be performed under a pressure of hydrogen of, for example, up to 5 Kg./cm 2 .
  • the aryl ketones of formula VIII (which are also starting materials of formula VI wherein U is a carbonyl radical) are themselves obtained by reaction of the appropriate phenacyl halide of formula III with an amino compound of the formula:- wherein W has the meaning defined above, using analogous conditions to those described for the preparation of compounds of formula II in (a) hereinabove.
  • the amino starting materials of formula IX may be obtained by selective acylation of an amine of the formula:- (itself obtained by standard procedures known in the art), using an acylating agent structurally derived from an acid of the formula Q.OH, for example an acid chloride or bromide, and using known general procedures.
  • the starting materials of formula IX are preferably obtained by reductive alkylation of an amine of formula IV using benzaldehyde and sodium borohydride and by analogy with process (b) hereinabove.
  • Optically-active forms of a compound of formula I may be obtained, for example, by conventional resolution of the corresponding racemic form of a compound of formula I.
  • a racemic form of a compound of formula I is reacted with an optically-active acid, followed by fractional crystallisation of the diastereoisomeric mixture of salts thus obtained from a diluent or solvent, for example ethanol, whereafter the optically-active form of the compound of formula I is liberated by treatment with base under mild conditions.
  • a particularly suitable optically-active acid is, for example. (+)- or (-)-O,O-di-p-toluoyltartaric acid.
  • a compound of formula I in free base form may be converted into a pharmaceutically acceptable acid-addition salt by reaction with a suitable acid as defined hereinafter under conventional conditions.
  • the compounds of formula I possess anti-inflammatory activity when applied topically to an area of inflammation, and are particularly useful in treating by topical administration, inflammatory diseases or inflammatory conditions of the skin.
  • the anti-inflammatory properties of a compound of formula I may be demonstrated in a standard test involving the inhibition of croton oil induced inflammation on the mouse ear.
  • the activity of an individual compound of formula I in this test depends upon its particular chemical structure, but specific compounds of formula I as described herein produce a significant inhibition of the inflammation at a topically applied dose of 0.20 mg. per ear, or less.
  • a compound of the invention When used for the topical treatment of an area of inflammation affecting the skin of a warm-blooded animal, for example man, a compound of the invention may be administered topically at a total daily dose in the range 20 ⁇ g. to 15 mg., or at an equivalent dose of a pharmaceutically-acceptable acid-addition salt thereof, and conveniently, as a divided dose. It will be appreciated that the total daily amount of a compound of the invention administered depends on the extent and severity of the inflammation to be treated.
  • the invention when 1-(4-amino-3,5-dichlorophenyl)-2-[1,1-dimethyl-2-(2-phenylacetamido)ethylamino]ethanol is used for the topical treatment of an area of inflammation affecting the skin of a warm-blooded animal, for example man, a total daily dose in the range of 20 ⁇ g. to 5 mg., or an equivalent amount of a pharmaceutically acceptable acid-addition salt, is administered topically.
  • the compounds of formula I may be administered in the form of pharmaceutical compositions and according to a further feature of the invention there is provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable acid-addition salt thereof, in association with a pharmaceutically acceptable' diluent or carrier, and in a form suitable for topical administration.
  • a pharmaceutical composition according to this aspect of the invention may contain from 0.1% to 10% w/w of a compound of formula I or an equivalent amount of a pharmaceutically acceptable acid-addition salt thereof, hereinafter referred to as the active ingredient.
  • a pharmaceutical composition according to the invention may be in the form of an ointment, gel, aqueous or oily solution or suspension, emulsion or aerosol.
  • the compositions may be made by methods well known in the art using conventional pharmaceutically acceptable diluents or carriers together with conventional colouring chelating and preserving agents.
  • a suitable ointment formulation may be prepared by dispersing the active ingredient in a suitable organic diluent, for example soft paraffin, optionally in the presence of an emulsifying and/or thickening agent, for example sorbitan monostearate.
  • a suitable organic diluent for example soft paraffin
  • an emulsifying and/or thickening agent for example sorbitan monostearate.
  • a suitable gel formulation may be prepared by adding a gelling agent, for example carboxypolymethylene to a solution of the active ingredient in a suitable organic solvent, for example isopropyl alcohol.
  • a gelling agent for example carboxypolymethylene
  • a suitable organic solvent for example isopropyl alcohol.
  • a suitable emulsion formulation for example a cream or a lotion, may be prepared by mixing the active ingredient with a suitable conventional emulsifying system and water.
  • a composition according to the invention may comprise in addition to the active ingredient defined above, one or more pharmaceutical agents selected from corticosteroids, for example flucinolone acetonide, prednisolone, flumethasone pivalate, betamethasone valerate, hydrocortisone or dexamethasone; phosphodiesterase inhibitors, for example theophylline or caffeine; antibacterial agents, for example oxytetracycline, gentamicin neomycin, gramicidin, chlorhexidine or cetyltrimethylammonium bromide; anti-fungal agents, for example griseofulvin or nystatin; antihistamines, for example diphenhydramine or chlorphenamine; local anaesthetics, for example amylocaine, benzocaine or procaine and emollients, for example calomine.
  • corticosteroids for example flucinolone acetonide, prednisolone, flumethasone pivalate, beta
  • the compounds of formula I are envisaged to be useful primarily in the topical treatment of inflammatory diseases or conditions of the skin, they may also be useful in the topical treatment of such diseases or conditions which affect other areas of the body, such as those affecting the lungs.
  • the aqueous phase was basified to pH 12-13 by addition of aqueous ammonia solution (density 0.88), and extracted with ether (2 x 100 ml.). The combined extracts were dried (MgS0 4 ) and evaporated. The resultant oil was dissolved in propan-2-ol (5 ml.) and an ethereal solution of hydrogen chloride was added to bring the pH to 2-3.
  • a solution of sodium borohydride (0.5 g.) in water (2 ml.) was added to the methanolic solution and the mixture was stirred for 2 hours. This mixture was then acidified to pH 2-3 with concentrated hydrochloric acid and concentrated in vacuo. The residual solution was diluted with water and then extracted with ether (3 x 100 ml.). The aqueous phase was then basified to pH 12-13 by addition of aqueous ammonia solution (density 0.88), and extracted with ether (3 x 100 ml.).
  • N-benzyl-N'-(phenylacetyl)ethylene diamine was prepared as follows:-
  • Benzaldehyde (67.5 g., 0.637 mole) was added to a solution of N-(2-phenylacetyl)ethylene diamine (113.5 g., 0.637 mole) and the mixture was stirred for 18 hours.
  • Sodium borohydride (24.2 g.) was added in portions and the reaction mixture was stirred for an additional 1.5 hours. Acetic acid was then added until excess borohydride had been destroyed.
  • the reaction mixture was basified by addition of 2N sodium hydroxide solution and extracted with ethyl acetate (3 x 500 ml.). The extracts were washed with brine (300 ml.), dried (MgS0 4 ) and filtered.
  • the free base was liberated from the hydrochloride (15 g.) by basification of a solution in water (150 ml.) with solid sodium carbonate. The aqueous mixture was extracted with ethyl acetate (3 x 100 ml.) and the extracts were dried (MgS0 4 ) and evaporated to give N-benzyl-N'-(phenylacetyl)ethylene diamine as an oil (13.0 g.), which sldwly crystallised.
  • 1,1-Dimethyl-2-(2-phenylacetamido)ethylamine (1.03 g.) was added to a solution of 4-(pivaloylamino)-3,5-dichlorophenylglyoxal hydrate (1.6 g.) in methanol (50 ml.). The solution was stirred for 2 hours and then a solution of sodium borohydride (500 mg.) in water (5 ml.) was added. After a further 2 hours of stirring, sufficient acetic acid was added to bring the pH to 4-5. The solution was then evaporated and the residue was dissolved in water (50 ml.).
  • aqueous solution was extracted with ether (2 x 50 mi.) and then basified using 10% w/v aqueous sodium carbonate solution to give 1-[4-(pivaloylamino)-3,5-dichlorophenyl]-2-[1,1-dimethyl-2-12-phenylacetamido)ethylamino]-ethanol (0.8 g., 32%), m.p. 83-85°C.
  • the acetophenone derivative was itself obtained as follows:-
  • the free base form (m.p. 96-98°C) was obtained by adding the dihydrochloride to an excess of 10% v/v aqueous sodium carbonate and ether, and separation and evaporation of the dried (MgS0 4 ) extracts.
  • Example 2 In a similar manner an ointment containing as active ingredient a compound described in Example 2, 4, 5, 6 or 7 or the free base described in Example 8 may be obtained.
  • Carbopol 940 is a grade of carboxypolymethylene gelling agent available from B. F. Goodison Chemical Co., Cleveland, Ohio, USA; "Carbopol” is a trade-mark.

Claims (10)

1. 1-Phenyläthanolaminderivat der Formel:
Figure imgb0021
worin R1 Wasserstoff oder ein C2-6-Alkanoylradikal ist, Rz und R3, welche gleich oder verschieden sein können, Wasserstoff oder C1-4-Alkylradikale sind, A ein C1-4-Alkylendiradikal ist und Q ein C4-20-Alkanoylradikal oder ein Phenylacetyl-, Phenoxyacetyl- oder Phenylaminocarbonylradikal, das ggf. einen aus Halogenatomen und Methyl-, Methoxy- und Trifluoromethylradikalen ausgewählten aromatischen Substituenten trägt, ist, oder ein pharmazeutisch zulässiges Säureadditionssalz davon, in racemischer oder optisch aktiver Form mit antiinflammatorischer Aktivität.
2. 1-Phenyläthanolaminderivat nach Anspruch 1, worin R1 Wasserstoff oder ein 2,2-Dimethylpropionyl- oder 3,3-Dimethylbutyrylradikal ist, R2 und R3, welche gleich oder verschieden sein können, Wasserstoff oder Methylradikale sind, A ein Methylen-, Äthylen-, Äthyliden- oder Isopropylidendiradikal ist und Q ein Octadecanoylradikal oder ein Phenylacetyl-, Phenoxyacetyl- oder Phenylaminocarbonylradikal, das ggf. einen aus Fluor-, Chlor- und Bromatomen und Methyl-, Methoxy-und Trifluoromethylradikalen ausgewählten aromatischen Substituenten trägt, ist.
3. 1-Phenyläthanolaminderivat nach Anspruch 1, worin Q ein C4-12-Alkanoylradikal ist.
4. 1-Phenyläthanolaminderivat nach einem der Ansprüche 1 bis 3, worin R1 Wasserstoff ist, RZ und R3, welche gleich oder verschieden sein können, Wasserstoff oder Methylradikale sine und A ein Methylendiradikal ist.
5. 1-Phenyläthanolaminderivat der Formel worin R1 Wasserstoff ist, R2 und R3 beide Wasserstoff oder Methylradikale sind, A ein Methylendiradikal ist und Q ein Phenylacetyl-, Phenoxyacetyl-, Phenylaminocarbonyl- oder Octadecanoylradikal ist, oder ein pharmazeutisch zulässiges Säureadditionssalz davon, in racemischer oder optisch aktiver Form mit antiinflammatorischer Aktivität.
6. Das 1-Phenyläthanolaminderivat 1-(4-Amino-3,5-dichlorophenyl)-2-[1,1-dimethyl-2-(2-phenylacetamido)äthylamino]äthanol oder ein pharmazeutisch zulässiges Säureadditionssalz davon, in racemischer oder optisch aktiver Form mit antiinflammatorischer Aktivität.
7. Pharmazeutisch zulässiges Säureadditionssalz nach einem der vorhergehenden Ansprüche, welches sich von Salz-, Bromwasserstoff-, Phosphor-, Schwefel-, Oxal-, Wein-, Milch-, Fumar-, Citronen-, Essig-, Salicyl-, Benzoe-, β-Naphthoe-, Methansulfon- oder Adipinsäure ableitet.
8. Verfahren zur herstellung eines 1-Phenyläthanolaminderivats der Formel I oder eines pharmazeutisch zulässigen Säureadditionssalzes davon, wie sie in einem der vorhergehenden Ansprüche beansprucht werden, dadurch gekennzeichnet, daß man:
(a) ein Arylketon der Formel:
Figure imgb0022
reduziert;
(b) einen Aldehyd der Formel:
Figure imgb0023
mit einem Amin der Formel:
Figure imgb0024
unter reduzierenden Bedingungen umsetzt oder
(c) eine Verbindung der Formel:
Figure imgb0025
worin U ein Carbonyl- oder Hydroxymethylendiradikal ist und W eine reduktiv entfernbare Schutzgruppe ist, reduziert, wobei R1, R2, R3, A und Q eine der in einem der Ansprüche 1 bis 5 definierten Bedeutungen haben, worauf im Bedarfsfall ein racemisches 1-Phenyläthanolaminderivat in seine optisch aktive Form getrennt werden kann und im Bedarfsfall ein 1-Phenyläthanolaminderivat in der freien Basenform durch Umsetzung mit einer ein pharmazeutisch zulässiges Anion liefernden Säure in ein pharmazeutisch zulässiges Säureadditionssalz umgewandelt werden kann.
9. Pharmazeutische Zusammensetzung, welche ein 1-Phenyläthanolaminderivat der Formel I oder ein pharmazeutisch zulässiges Säureadditionssalz davon, wie sie in einem der Ansprüche 1 bis 7 beansprucht werden, gemeinsam mit einem pharmazeutisch zulässigen Verdünnungsmittel oder Trägermittel enthält und eine für topische Verabreichung geeignete Form besitzt.
10. Zusammensetzung nach Anspruch 9, welche die Form einer Salbe, eines Gels, einer wäßrigen oder öligen Lösung oder Suspension, einer Emulsion oder eines Aerosols aufweist.
EP78300153A 1977-08-16 1978-07-14 Entzündungshemmende 1-Phenylethanolamin-Derivate, deren pharmazeutischen Zusammensetzungen und Verfahren zu deren Herstellung Expired EP0000809B1 (de)

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US (1) US4355045A (de)
EP (1) EP0000809B1 (de)
JP (1) JPS5448727A (de)
AR (1) AR221704A1 (de)
AT (1) AT359481B (de)
AU (1) AU521456B2 (de)
BE (1) BE869639A (de)
CA (1) CA1108183A (de)
CS (1) CS207661B2 (de)
DE (2) DE2861733D1 (de)
DK (1) DK362178A (de)
ES (1) ES472591A1 (de)
FI (1) FI70008C (de)
FR (1) FR2400505A1 (de)
GR (1) GR66025B (de)
HU (1) HU177107B (de)
IE (1) IE47283B1 (de)
IL (1) IL55284A (de)
IT (1) IT1098051B (de)
NL (1) NL7808440A (de)
NO (1) NO145656C (de)
NZ (1) NZ188040A (de)
PL (2) PL114031B1 (de)
PT (1) PT68422A (de)
SU (1) SU820658A3 (de)
ZA (1) ZA784335B (de)

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IE54220B1 (en) * 1981-12-23 1989-07-19 Ici Plc Phenol esters
US5541188A (en) * 1987-09-15 1996-07-30 The Rowett Research Institute Therapeutic applications of beta-adrenergic agonists
US5530029A (en) * 1987-09-15 1996-06-25 The Rowett Research Institute Therapeutic applications of clenbuterol
FR2626878B1 (fr) * 1988-02-10 1990-06-08 Lafon Labor Derives de 1-(aminophenyl)-2-dimethylaminopropanone, procede de preparation et utilisation en therapeutique
US6421336B1 (en) * 1999-02-23 2002-07-16 Tantivy Communications, Inc. Variable rate orthogonally coded reverse link structure

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DE1618005A1 (de) * 1966-09-22 1971-09-09 Thomae Gmbh Dr K Verfahren zur Herstellung von neuen Amino-dihalogen-phenyl-aethylaminen
US3975443A (en) * 1972-06-06 1976-08-17 Allen & Hanburys Limited 1-(3,4-dichlorobenzamidomethyl)-cyclohexyldimethylamine
GB1460593A (en) * 1973-06-22 1977-01-06 Ici Ltd Ethanolamine derivatives
GB1468156A (en) * 1973-07-19 1977-03-23 Ici Ltd Phenylethylamine derivatives

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HU177107B (en) 1981-07-28
DE2835537A1 (de) 1979-03-01
IT7826671A0 (it) 1978-08-10
PL113842B1 (en) 1981-01-31
NO145656C (no) 1982-05-05
DE2861733D1 (en) 1982-05-27
US4355045A (en) 1982-10-19
IT1098051B (it) 1985-08-31
IL55284A (en) 1981-10-30
NO145656B (no) 1982-01-25
CS207661B2 (en) 1981-08-31
FR2400505B1 (de) 1981-01-30
EP0000809A1 (de) 1979-02-21
IL55284A0 (en) 1978-10-31
SU820658A3 (ru) 1981-04-07
JPS5448727A (en) 1979-04-17
PT68422A (en) 1978-09-01
NL7808440A (nl) 1979-02-20
IE781519L (en) 1979-02-16
IE47283B1 (en) 1984-02-08
FR2400505A1 (fr) 1979-03-16
GR66025B (de) 1981-01-13
AT359481B (de) 1980-11-10
NO782767L (no) 1979-02-19
DK362178A (da) 1979-02-17
FI70008B (fi) 1986-01-31
PL114031B1 (en) 1981-01-31
ATA595378A (de) 1980-04-15
FI70008C (fi) 1986-09-12
ES472591A1 (es) 1979-10-16
ZA784335B (en) 1979-07-25
AU3850578A (en) 1980-02-07
PL215005A1 (pl) 1979-12-17
FI782498A (fi) 1979-02-17
PL209049A1 (pl) 1979-08-27
AU521456B2 (en) 1982-04-01
AR221704A1 (es) 1981-03-13
CA1108183A (en) 1981-09-01
NZ188040A (en) 1981-07-13
BE869639A (fr) 1979-02-09

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