US3586676A - 1,2-oxazinyl phenyl alkanoic acids - Google Patents

1,2-oxazinyl phenyl alkanoic acids Download PDF

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US3586676A
US3586676A US818407A US3586676DA US3586676A US 3586676 A US3586676 A US 3586676A US 818407 A US818407 A US 818407A US 3586676D A US3586676D A US 3586676DA US 3586676 A US3586676 A US 3586676A
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phenyl
water
dihydro
solution
oxazin
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Rolf Denss
Niels Clauson-Kaas
Franz Ostermayer
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Novartis Corp
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Geigy Chemical Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines

Definitions

  • the compounds are of the class of [p-(3,6-dihydro-2H- 1,2-oxazin-2-yl)-phenyl]-alkanoic acids, the methyl and ethyl esters thereof, as well as the pharmaceutically acceptable salts thereof and have analgesic and anti-inflammatory activity; the compounds are active ingredients of pharmaceutical compositions and are useful for alleviating pain and treating inflammatory diseases in mammals; an illustrative embodiment is [p-(3,6-dihydro-2H-1,2-oxazin- 2-yl)-phenyl]-acetic acid.
  • the present invention concerns 1,2-oxazinyl phenyl alkanoic acid derivatives, pharmaceutical compositions comprising these compounds and a pharmaceutical carrier and methods of alleviating pain and treating inflammatory discases in mammals comprising administering them.
  • the present invention concerns compounds of the formula 2 wherein R is hydrogen, methyl or ethyl,
  • R is hydrogen or halogen up to the atomic number 35
  • R is hydrogen, methyl or ethyl
  • R as halogen up to the atomic number 35 can be fluoro, chloro or bromo.
  • a preferred subclass are the compounds of Formula I wherein R is hydrogen or methyl, R is hydrogen or chloro and R is hydrogen, and the pharmaceutically acceptable salts thereof.
  • Preferred members of the compounds of Formula I are [p-(3,6-dihydro-2H-1,2-oXazin-2-yl)-phenyl]-acetic acid, 2 [3 chloro 4 (3,6 dihydro 2H 1,2 oxazin 2 yl)-phenyl]-propionic acid and the pharmaceutically acceptable salts thereof.
  • the compounds of the present invention were found to have valuable pharmacological properties, in particular analgetic, anti-inflammatory and anti-pyretic activity, combined with a favorable therapeutic index.
  • the pharmacological activity of the compounds of the invention is determined in various standard tests with experimental animals.
  • mice The analgesic activity is demonstrated in the writhing test in mice. This test is described by E. Siegmund, R.
  • test substance is determined preventing in the test animals the syndrome produced by intraperitoneal injection of Z-phenyl-1,4-benzoquinone. Excellent results are obtained by oral administration of 10 mg./kg. of bodyweight of 2-[3-chloro-4-(3,6-dihydro-2H- l,2-oxazin-2-yl)phenyl]propionic acid.
  • Another group of rats having not obtained the test compound, but the bolus alba serves as control group.
  • Each group consists of male albino rats weighing about 110 to about 130 g.
  • the intensity of the swelling of the rats paw is determined 5 hours after the bolus alba injection, by measuring the weight differences of the unswollen left paws and the swollen right paws.
  • 2-[3-chloro 4-(3,6-dihydro-2H- 1,2-oxazin-2-yl -phenyl] -propionic acid administered in a dosage of about mg./kg. of bodyweight significantly inhibits the formation of the bolus alba edema indicating a pronounced anti-inflammatory activity.
  • the toxicity of the compounds of the invention on oral administration is of favorable low order.
  • the new l,2-oxazinylphenylalkanoic acids and esters of Formula I and their pharmaceutically acceptable salts with inorganic and organic bases are suitable as active ingredients for pharmaceutical compositions, which can be administered orally, rectally or parenterally, for the relief and removal of pains of varying origin and for the treatment of rheumatic and other inflammatory diseases.
  • the reaction of the nitroso compound of Formula II with butadiene is performed, for example, at temperatures between 0 and in an organic solvent such as chloroform, benzene or acetic acid, or in an excess of butadiene if necessary in a closed vessel.
  • the optionally subsequent hydrolysis is carried out in the usual manner, e.g. by reacting the obtained compound of Formula Ia with an alkanolic aqueous alkali solution such as ethanolic sodium hydroxide solution preferably at room temperature.
  • the 2-(p-nitrosophenyl)-alkanolic acid alkyl esters of Formula II which are used as starting materials for the reaction sequence according to the invention, are new compounds. They are produced, for example, by the re duction of corresponding p-nitro compounds, e.g. by means of zinc dust in ethanol, to give p-hydroxyamino compounds, and partial reoxidation of the latter, e.g. by means of iron (III)-chloride in aqueous-ethanolic solution.
  • Optionally produceable pharmaceutically acceptable salts of the acids falling under Formula I are derived from inorganic and organic bases via conventional methods.
  • Such salts include, for example the sodium, potassium, lithium, magnesium, calcium and ammonium salts, as well as salts derived from ethylamine, triethylamine, 2-aminoethanol, 2,2'-iminodiethanol, Z-dimethylaminoethanol, 2- diethylaminoethanol, ethylene diamine, benzylamine, procaine, pyrrolidine, piperidine, morpholine, l-ethyl piperidine, 2-piperidinoethanol and basic ion exchangers.
  • the new compounds of Formula I as well as the pharmaceutically acceptable salts of the acids of Formula I are administered orally, rectally or parenterially preferably in form of pharmaceutical compositions.
  • compositions according to the present invention contain, :as active ingredient, at least one compound of Formula I and/or a pharmaceutically acceptable salt of an acid embraced by Formula I in combination with an inert carrier and, if desired, other additives.
  • inventive compositions consist, preferably, of dosage unit forms Which are suitable for the oral, rectal or parenteral application of daily doses of 180 mg./kg. of a compound of the invention for mammals.
  • Suitable dosage unit forms for the oral or rectal application like drages, tablets, capsules, suppositories respectively, contain preferably 10 to 500 mg. of a compound of the invention.
  • the amount of active ingredient is preferably between and 90%.
  • the active ingredients for instance with solid powder-like carriers such as lactose, saccharose, sorbitol or mannitol; starches such as potato starch, corn starch or amylopectin, highly dispersed silicon dioxide, additional laminaria pow der or citrus pulp powder, cellulose derivatives or gelatine, if desired with the addition of lubricating agents like magnesium or calcium stearate or polyethylene glycols and presses the mixture into the desired form.
  • solid powder-like carriers such as lactose, saccharose, sorbitol or mannitol
  • starches such as potato starch, corn starch or amylopectin, highly dispersed silicon dioxide, additional laminaria pow der or citrus pulp powder, cellulose derivatives or gelatine, if desired with the addition of lubricating agents like magnesium or calcium stearate or polyethylene glycols and presses the mixture into the desired form.
  • the drage cores are coated, for instance, with concentrated sugar solutions which can also contain arabic gum, talc and/or titanium dioxide or with a light volatile organic solvent or solvent mixture which contains dissolved varnish.
  • To these coatings can be added pigments, for instance, to indicate different dosages of active substance.
  • As other oral dosage unit forms there are most suitable plugged capsules from gelatine and soft closed capsules from gelatine and a softening agent like glycerin.
  • the first named contain the active ingredient, preferably as granulate, if desired in mixture with diluting agents like corn starch, with lubricating agents, like talc or magnesium stearate, and if desired, stabilisers, like sodium metabisulfite (Na S O or ascorbic acid.
  • the active ingredient is preferably dissolved or suspended in suitable fluids, such as liquid polyethylene glycols, whereby, if desired, stabilisers can be added.
  • dosage unit forms for the rectal application are suitable, for instance, suppositories which consist of a combination of a compound of Formula I or a pharmaceutically acceptable salt of an acid embraced by Formula I, with a suppositorial ground mass, for instance, natural or synthetic triglycerides, or also gelatine rectal capsules which contain a combination of the active ingredient with polyethylene glycols.
  • Ampoule solutions for parenteral, especially intramuscular or intravenous administration contain, e.g. a compound of Formula I in a concentration of preferably 0.55% as an aqueous dispersion prepared with the aid of the usual dissolving agents and/or emulsifying agents as well as, optionally, stabilisers, or they contain an aqueous solution of a pharmaceutical acceptable, water solu ble salt of a free acid embraced by Formula I.
  • Suitable dosage units for parenteral administration are, e.g. lotions, tinctures and ointments, prepared with the usual auxiliary agents, for percutaneous application.
  • the present invention relates also to methods of alleviating pain and treating inflammatory diseases in mammals which methods comprise administering an effective amount of at least one compound of the invention, preferably in form of an inventive pharmaceutical composition.
  • the dosage administered will be dependent on the species, the age, health and weight of the recipient; the severity of the condition being treated; the kind of concurrent treatment, if any; the frequency of treatment and the nature of the effect desired.
  • the daily dosage of an active compound of Formula I will be from about 1 to about mg./ kg. of bodyweight.
  • a preferred range is from about 1 to about 60 mg./ kg. of .bodyweight per day.
  • the ethyl ester required as starting material is produced as follows:
  • the obtained clear solution which contains the (p-hydroxyamino-phenyl) -acetic acid ethyl ester, is rapidly cooled to 5 and is then poured, while vigorously stirring, into a solution of g. of iron (III)-chloro-hexahydrate in 375 ml. of water at room temperature.
  • a green solution is formed, from which the (p-nitrosophenyl)-acetic acid ethyl ester precipitates almost instantaneously in the form of yellow crystals. After 5 minutes the crystals are filtered off, thoroughly washed with water and dried for about 14 hours at 50.
  • EXAMPLE 2 15.5 g. of 2-(p-nitrosophenyl)-butyric acid methyl ester and 19 ml. of butadiene are dissolved in 75 ml. of chloroform and the solution is allowed to stand for 17 hours at 0. The reaction mixture is then concentrated by evaporation on a water-bath at 75 under 10 torr. The addition product remaining as a residue in crystalline form, M.P. 53-55" (18.9 g., 96% of theoretical value) is crystallised from water-methanol (1:10) by cooling to 25 during 30 minutes, whereby 15.9 g. of 2-[p-(3,6-dihydro-2H-1,2-
  • the methyl ester required as starting material is produced as follows:
  • Filtrate and washing liquid which contain the crude hydrochloride of the 2-(p-hydr0xyamino-phenyl)-butyric acid methyl ester, are added dropwise at 7 within 10 minutes, while stirring, to a solution of 90 g. of iron (III)-chloride-hexahydrate in 375 ml. of water at 5".
  • the solution turns green and the 2-(p-nitrosophenyl)- butyric acid methyl ester begins to precipitate immediately.
  • the solution is stirred for a further 5 minutes at 5, whereupon the suspension is cooled to l5 and filtered.
  • the reaction product which is filtered off, is washed with 30 ml. of watermethanol (1:1) and then with water.
  • EXAMPLE 3 A solution of 37.1 g. of [p-(3,6-dihydro-2H-1,2-oxazin- 2-yl)-phenyl]acetic acid ethyl ester [cf. Example 1] in 900 ml. of ethanol and 700 ml. of water is added to a solution of 7.4 g. of sodium hydroxide in 200ml. of water. The obtained emulsion is stirred at room temperature, whereby a clear solution is obtained after ca. 3 minutes. After stirring for one hour, 0.1 N hydrochloric acid is added until a pH value of 3.8 is obtained (ca. 1860 ml.) and the mixture is extracted four times with ether (500-160046004 300 ml.).
  • EXAMPLE 4 2.61 g. of 2-[-(3,6-dihydr0-2H-1,2-oxazin-2-yl) -phenyl]-butyric acid methyl ester [cf. Example 2] are dissolved in 55 ml. of ethanol and 57 ml. of 0.39 N sodium hydroxide solution and the solution is allowed to stand at room temperautre for 24 hours. 0.18 N hydrochloric acid is then added to obtain a pH value of 2.2 (ca. 122 ml.). The obtained crystalline precipitate is filtered off, washed with 10 m1. of ethanol-water (1:3) and then twice with water and dried for one hour under 1 torr at 50.
  • the oily residue was heated under reflux during 3 hours with 1160 ml. of ethanol, 580 ml. of water, and 93 g. of sodium hydroxide pellets. 900 ml. of water was added and the mixture distilled under 70 mm., until the distillation temperature was 50. About 2100 ml. of distillate was collected. The ethanol-free residue was cooled to 20 and extracted with five 250 ml. portions of ether. The aqueous phase was acidified to pH 2 with 180 .ml. of concentrated hydrochloric acid and the brown oil, which separated, extracted with two 500 ml. portions of ether. The combined ethereal extracts were washed with two 100 ml.
  • the clear, light yellow filtrate (pH 1.52.0) containing the hydrochloride of 2-(3-chloro- 4-hydroxylamine-phenyl)-propionic acid methyl ester was added to a solution of iron (III) chloride [210 g. of iron (III) chloride hexahydrate in 685 ml. of water] with vigorous stirring at to over a period of 15 minutes.
  • the green suspension was extracted three times with cold benzene (l500+500+500 ml.).
  • the combined benzene extracts were washed at 0 with two 450 ml. portions of N hydrochloric acid, 400 ml. of water, two 450 ml. portions of 20% potassium hydrogen carbonate solution, and finally again two 400 ml.
  • EXAMPLE 6 45.6 g. of 2-[3-chloro-4-(3,6-dihydro-2H-1,2-0xazin-2- yl)-phenyl]-propionic acid methyl ester are stirred with a solution of g. of sodium hydroxide in 100 ml. water and 200 ml. of methanol for an hour at -30". After acidification with 145 ml. of 3 N hydrochloric acid, precipitates an oil. This oil is twice extracted with 500 ml. of ether and the whole ether extract is washed with 100 ml. of water, dried with magnesium sulphide and concentrated by evaporation under reduced pressure. -An oil is obtained which, after coo-ling, crystallises partially. After recrystallisation of methanol water, the 2-[3-chloro- 4- (3 ,6-dihydro-2H-1,2-oxazin-2-yl)phenyl] -propionic acid is obtained, melting point 160l70
  • EXAMPLE 7 1000 g. of active substance, e.g. [p-(3,6-dihydro-2H- 1,2-oxazin-2-yl)phenyl]-acetic acid, are mixed with 550 g. of lactose and 292 g. of potato starch. The mixture is moistened with an alcoholic solution of 8 g. of gelatine and is granulated through a sieve. After drying, 60 g. of potato starch, 60 g. of talcum and 10 g. of magnesium stearate and 20 g. of highly dispersed silicon dioxide are mixed in. The mixture is then pressed into 10,000 tablets, each Weighing 200 mg. and each containing 100 mg. of active substance. Optionally, the tablets can be provided with grooves for more accurate adjustment of the dosage amount.
  • active substance e.g. [p-(3,6-dihydro-2H- 1,2-oxazin-2-yl)phenyl]-acetic acid.
  • EXAMPLE 8 200 g. of active substance, e.g. [p-dihydro-2H-1,2- oxazin-2-yl)-phenyl] acetic acid ethyl ester are mixed with 16 g. of maize starch and 6 g. of highly dispersed silicon dioxide. The mixture is moistened with a solution of 2 g. of stearic acid, 6 g. of ethyl cellulose and 6 g. of stearin in ca. 70 ml. of isopropyl alcohol and is granulated through a sieve III (Ph. Hel-v. V). The granulate is dried for ca. 14 hours and is then pressed through sieve III-IIIa.
  • active substance e.g. [p-dihydro-2H-1,2- oxazin-2-yl)-phenyl] acetic acid ethyl ester are mixed with 16 g. of maize starch and 6 g. of highly dis
  • EXAMPLE 9 50.0 g. of 2-[3-chloro-4-(3,6-dihydro-2H-1,2-oxazin-2- yl)-phenyl] -propionic acid are dissolved in a mixture of 218 ml. of 1 N sodium hydroxide solution and 500 ml. of boiled, pyrogen-free water and, with water treated in the same manner, the solution is then made up to 2000 ml. The solution is filtered and used to fill 1000 ampoules each containing 2 ml., and sterilised. A 2 ml. ampoule contains 50 mg. of 2- [p-1-pyrryl)-phenyl] -butyric acid as active substance in the form of the sodium salt.
  • EXAMPLE 10 50 g. of 2-[3-chloro-4-(3,6-dihydro-2H-1,2-oxazin-2- yl)-phenyl]-propionic acid and 1950 g. of finely ground suppository foundation substance (e.g. cocoa butter) are thoroughly mixed and then melted. The melt is maintained homogeneous by stirring and from it are made 1000 suppositories, each weighing 2 g. and each containing 50 mg. of active substance.
  • finely ground suppository foundation substance e.g. cocoa butter
  • EXAMPLE 11 60.0 g. of polyoxyethylene-sorbitan monostearate, 30.0 g. of sorbitan-monostearate, 150.0 g. of paraffin oil and 120.0 g. of stearyl alcohol are melted together. 50.0 g. of [p-(3-dihydro-2H-1,2-oxazin-2-yl)-phenyl]-acetic acid (finely pulverised) are then added and 590 m1. of water, preheated to 40, are used to form an emulsion. The emulsion is stirred until it has cooled to room temperature and is then poured into tubes.
  • R is hydrogen or halogen up to the atomic number 35
  • R is hydrogen, methyl or ethyl
  • R is hydrogen or methyl, R is hydrogen or chloro and R is hydrogen, or a pharmaceutically acceptable salt thereof.
  • a compound according to claim 1 which is [p-(3,6- dihydro-2H-1,2-oxazin-2-yl)-phenyl]-acetic acid or a pharmaceutically acceptable salt thereof.
  • a compound according to claim 1 which is 2-[3- chloro 4 (3,6 dihydro-2H-1,2-oxazin-2-yl)-phenyl]- propionic acid or a pharmaceutically acceptable salt thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US818407A 1968-04-29 1969-04-22 1,2-oxazinyl phenyl alkanoic acids Expired - Lifetime US3586676A (en)

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US (2) US3586676A (de)
AT (2) AT284108B (de)
BE (2) BE732234A (de)
CH (1) CH510015A (de)
DE (2) DE1921654A1 (de)
DK (2) DK120796B (de)
ES (2) ES366533A1 (de)
FR (2) FR2007552A1 (de)
IL (2) IL32087A0 (de)
NL (2) NL6906201A (de)
SE (2) SE338565B (de)

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US4339457A (en) * 1980-10-20 1982-07-13 Fmc Corporation 3-(Pyrrol-1-yl)phenylmethyl esters and intermediates
IT1203656B (it) * 1983-06-10 1989-02-15 Medosan Ind Biochimi Attivita' antiaggregante piastrinica,antiinfiammatoria e broncolitica di esteri aroilpirrol e pirrilfenil acetici delle 7 (w-ossialchil) teofilline

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FR5664E (fr) * 1898-04-27 1906-06-05 Gabriel Gaston Georges Guet Cheminée dite la récupératrice
DE1191379B (de) * 1963-02-19 1965-04-22 Esso A G Verfahren zur Herstellung von N-substituierten 3, 6-Dihydro-1, 2-oxazinen

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ES366534A1 (es) 1971-01-01
US3652586A (en) 1972-03-28
DE1921655A1 (de) 1969-11-13
SE338565B (de) 1971-09-13
DK119355B (da) 1970-12-21
NL6906201A (de) 1969-10-31
ES366533A1 (es) 1971-01-01
FR2007552A1 (de) 1970-01-09
BE732234A (de) 1969-10-28
AT284108B (de) 1970-09-10
AT285620B (de) 1970-11-10
IL32086A0 (en) 1969-06-25
SE339226B (de) 1971-10-04
NL6906202A (de) 1969-10-31
DK120796B (da) 1971-07-19
FR2007551A1 (de) 1970-01-09
CH510015A (de) 1971-07-15
IL32087A0 (en) 1969-06-25
DE1921654A1 (de) 1969-11-13

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