Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
  • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
  • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
  • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
  • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
  • C07C217/38—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system containing rings other than six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
  • C07D263/20—Oxygen atoms attached in position 2
  • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
  • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
  • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
  • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
  • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
  • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
  • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
  • C07D303/26—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds having one or more free hydroxyl radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

• R stands for hydrogen or an alkyl group and R stands for an alkyl group of not more than 6 carbon atoms, preferably branched such as isopropyl, isobutyl, sec-butyl, tert-butyl, and the like; cycloalkyl groups of not more than 7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl; lower alkenyl or aralkyl groups, any of which may be optionally substituted; R and R each stand for hydrogen, or hydroxy; R and R each stand for hydrogen, alkyl, or aralkyl; OR in which R is lower alkyl or lower alkenyl, aralkyl such as benzyl in which aryl may be optionally substituted by halogen, nitro, etc.; halogens such as F, Cl, Br or I; nitro, amino
• the hydroxypropylamine side chain can be attached to either the 5, 6 or 7 position of the aromatic ring. It has been found that under the conditions used for the preparation of these compounds it is not possible to attach the side chain to the 8 position.
• the compounds of this invention have fi-adrenergic blocking activity and are therefore useful in cases of angina pectoris, cardiac arrhythmia and other related cardiovascular ailments.
• a dose of about 0.1 to about 1 mg./kg. of body weight of the animal being treated, administered either orally or by injection, is prescribed.
• the present invention relates to compounds of the formula:
• drogen alkyl, or aralkyl
• 0R in which R is lower alkyl or lower alkenyl, aralkyl such as benzyl in which aryl may be optionally substituted by halogen, nitro, etc.; halogens such as F, Cl, Br or I; nitro, amino or acylamino, or sulfonamido; alkyl such as methyl and containing not more than 6 carbons.
• R R R R R R R and R lower alkyl includes 1 to 6 carbon atoms
• lower alkenyl includes 2 to 6 carbon atoms
• aryl includes both aromatic ring systems, such as phenyl, as well as heterocyclic ring systems such as pyridyl
• acyl includes those radicals derived from lower alkanoic acids, such as acetic, propionic, butyric, and the like, as well as benzoic acid.
• the compounds of this invention have been found to have B-adrenergic blocking activity both by injection and oral administration in mammals such as logs, cats, monkeys and the like.
• the ,B-adrenergic blocking activity of these compounds is determined by the administration of various doses of isoproterenol after dosage of the test animal with the compounds of this invention. It was found that the heart contractile force and heart rate response to isoproterenol is blocked by these compounds in varying degrees depending on the administered dose.
• the compound 5 [3 (tert-butylamino) 2-hydroxypropoxyJtetralone hydrochloride was administered intravenously to anesthetized dogs at a dose of 6.7 g/kg. The dogs were then given 0.3 ,ugJkg. isoproterenol. This compound was capable of suppressing 50% of the iso proterenol effects on the dogs heart rate.
• fl-adrenergic blocking agents such as for example, propranolol
• fl-adrenergic blocking agents such as for example, propranolol
• the dosage regimen may be varied according to the age, sex, body weight and species of the mammal being treated and is in the range of about 0.1 to about 1 mg./kg. of body weight, either orally or by injection.
• the present invention also incorporates within its scope pharmaceutically acceptable acid addition salts; for example, hydrochlorides, hydrobromides, phosphates, sulfates or salts derived from organic acids such as lactates, salicylates and the like.
• pharmaceutically acceptable acid addition salts for example, hydrochlorides, hydrobromides, phosphates, sulfates or salts derived from organic acids such as lactates, salicylates and the like.
• the present invention also embraces the dor l-optical isomers or the racemic mixture, as well as their salts or derivatives described above.
• keto group at the 1-position forms derivatives with reagents such as hydroxylamine, semicarbazide, thiosemicarbazide, hydrazine and substituted hyrazines and accordingly such derivatives are included in the scope of this invention.
• Suitable derivatives of the side chain such as the oxazolidine or oxazolidinone of the formula:
• a further feature of the aforesaid compounds is the provision of dosage forms suit-able for oral or parenteral administration.
• These pharmaceutical dosage forms suitable for oral administration may be in the form of tablets, capsules, aqueous or oily solutions and the like and suspensions which are readily compounded by methods known to the pharmaceutical art.
• tablets may be formulated by admixture of the selected active ingredient with known pharamaceutical excipients, such as calcium phosphate, lactose, mannitol, and granulated with agents such as acacia or a gelatin solution and then compressed into tablets.
• pharamaceutical excipients such as calcium phosphate, lactose, mannitol
• agents such as acacia or a gelatin solution and then compressed into tablets.
• These compounds may also be formulated to give a prolonged action in the animal body.
• Dosage forms suitable for parenteral administration may be formulated by dissolving or suspending the selected active ingredient in a parenterally
• these compounds may also be combined with sedatives such as phenobarbital, analgesics such as aspirin, or cardiovascular agents, such as pentaerythritol tetranitrate, pentaerythritol trinitrate, etc.
• sedatives such as phenobarbital, analgesics such as aspirin, or cardiovascular agents, such as pentaerythritol tetranitrate, pentaerythritol trinitrate, etc.
• the starting phenol A is obtained by treating the corresponding ether which is commercially available with hydrogen bromide in acetic acid.
• the temperature is maintained between 3237 by judicious use of ice 'bath.
• the reaction mixture becomes thick with a precipitate of NaI.
• the ice bath is removed and the heat of the reaction allowed to heat the reaction mixture up to 62 C. (a condenser is used at this point).
• the reaction mixture becomes slightly orange at this point and is cooled tod 53 C. at which point the temperature gradually sub- 51 e
• the mixture is poured onto ice and the aqueous extracted twice with toluene and the toluene washed with water and dried (MgSO
• the toluene extracts are distilled under reduced pressure rapidly.
• a cut at '98-130/.2 is taken 58.6 grams and redistilled using a short Vigreux column and a middle cut taken at 113-119/ .25 1.5547.
• EXAMPLE 2 CH3 m CH3 0 3 tat e CH O o 2,2-dimethyl-6-hydroxyl-tet'ralone
• EXAMPLE 3 5-(2,3-epoxypropyloxy)-l-tetralone
• a solution of 8.3 g. of NaOH in 36.5 ml. of water was diluted with 292 ml. of ethanol and then 28.5 g. of S-hydroxy-a-tetralone and 98 g. of epichlorohydrin were added. The mixture was stirred at room temperature for 16 hrs. and then left over the weekend. The solution was then evaporated and the residue was partitioned between 180 ml. of water and 250 ml. of chloroform.
• EXAMPLE 4 5- (2,3 -epoxypropyloxy) -8-methoxy-1-tetralone To a solution of 1.55 g. (38.8 millimoles) of sodium 'hydroxide in 50 ml. of methanol is added 6.76 g. (35.2 millimoles) of 5-hydroxy-8-methoxy-l-tetralone. After a solution has been obtained, epichlorohydrin. 32.4 g. (350 millimoles), is added and the resulting mixture is stirred at room temperature for 17 hours. After the reaction mixture has been evaporated in vacuo to give a liquid residue, the crude material is dissolved in 100 ml.
• EXAMPLE 7 7 -(3-cyclohexylamino-Z-hydroxypropyloxy)-8-hydroxyl-tetralone hydrochloride A mixture of 9.79 g. (41.9 millimoles) of 5-(2,3- epoxypropyloxy)-8-hydroxy-1-tetra1one, 50 ml. of cyclohexylamine and 50 m1. of methanol is refluxed for 1 hour. After evaporation of the reaction mixture has given the crude cyclohexylimino intermediate, the oily material is hydrolyzed to the 'free keto product in a mixture of concentrated hydrochloric acid and methanol (110 ml., 10% methanol) by heating at reflux temperature for 41 hours. Evaporation in vacuo of the reaction mixture gives the crude product as the hydrochloride salt which is purified by recrystallization from methanol; yield, 4.90 g. (31.5%), M.P. 193-195".
• a second preparation of the product yields analytical material with a M.P. 20l203.
• EXAMPLE 8 5 3-tert-butylamino-2-hydroxypropyloxy 8-hydroxyl-tetralone hydrochloride
• a methanolic solution (22 ml.) of 5.50 g. (23.5 millimoles) of 5-(2,3-epoxypropyloxy)-8-hydroxy-1-tetralone and 22 ml. of tert butylamine is heated at reflux temperature for 1 hour and then evaporated in vacuo to give a crude liquid product.
• This material is converted to its hydrochloride salt and purified by recrystallization from methanol-ether giving the analytically pure sample; yield 4.53 g. (56.0%), M.P. 208-212".
• EXAMPLE 14 o-ca (DH-CH O-CHQCHCHZ CH3 ⁇ 0/ 2 cs C(Cll3)3 5,8-dimethyl-7-(3-tert-butylamino-2-hydroxy-1- propyloxy)-1-tetralone hydrochloride
• Evaporation of the reaction mixture in vacuo gives a quantitative yield of liquid product which is converted to the hydrochloride salt; yield, 12.8 g. (84.2% M.P. 234-237 dec.
• the tan material is recrystallized from methanol-ether and the analytical sample is obtained; yield, 7.80 g. (51.3%), M.P. 236-240 de
• EXAMPLE 16 5- 3 -cyclohexy1amino-2-hydroxy- 1 -propyloxy) -1- tetralone hydrochloride A mixture of 9.63 g. (44.2 millimoles) of 5-(2,3-epoxyl-propyloxy)-1-tetralone, 30 ml. of cyclohexylamine and 30 ml. of, methanol is refluxed for 2 hours. After evaporation of the reaction mixture in vacuo has resulted in a crude oily material, the product is purified as its hydrochloride salt by recrystallization from methanol; 6.62 g., M.P. 265-270. The material is analyzed as the dihydrochloride salt of the l-cyclohexylimino derivative of the desired product.
• EXAMPLE 17 5- ⁇ 3- 1-hydroxy-2-methyl-2-propyl) amino] -2-hydroxy- 1-propyloxy ⁇ -l-tetralone hydrochloride
• reaction mixture is evaporated in vacuo to a residual oil which is dissolved in ethyl acetate (25 ml.) and dried with anhydrous magnesium sulfate. Evaporation of the ethyl acetate gives a crude oily product which is purified as the hydrochloride salt by recrystallization from methanol-ether; 2.23 g. (65.8%), M.P. 179184.
• N-carbophenoxy intermediate is then heated with 2.05 g. (38.0 millimoles) of sodium methoxide in ml. of toluene for 22 hours at reflux temperature. After the reaction mixture has been extracted with 1 N NaOH (2X 50 ml.), the organic phase is dried with anhydrous magnesium sulfate and evaporated in vacuo to a crude solid material. Recrystallization of the product from carbon tetrachloride gives the white crystalline, analytically pure sample; yield, 6.65 g. (66.5%), M.P. 132-135".
• EXAMPLE 21 1- 0101-1 -CH-CH (OCH CH-CH Cl) 3-(tetralone-5-oxy)-1,2-epoxy-propane S-(tetralone-S-oxy)-1-chloro-2-hydr0xy-propane 13.8 g. of S-hydroxytetralone was dissolved in 75 ml. of epichlorohydrin and the solution was refluxed for 44 hours. The excess epichlorohydrin was removed in vacuo by heating on a water bath, the residue was distilled in a short path bantam-ware distillation apparatus, and 5 fractions were taken, B.P. 160-210/ .2 mm. All had strong ketone absorption and the last two also had strong hydroxyl absorption.
• R is hydrogen, R is lower alkyl of 1 to 6 carbon atoms; and R R R and R are hydrogen and the propanolamine side chain is substituted on the 5, 6 or 7 position of the aromatic ring; or its pharmaceutically acceptable acid addition salts.
• R is hydrogen, R is branched lower alkyl of 3 to 5 carbon atoms and R R R and R are hydrogen, and the propanolamine side chain is substituted on the 5, 6 or 7 position of the aromatic nucleus; or its pharmaceutically acceptable acid addition salts.
• a compound according to claim 1 wherein the compound of Formula I is 5-(3-tert-butylamino-2 hydroxypropyloxy)-8-hydroxy-1-tetralone.
• a compound according to claim 1 wherein the compound of Formula I is 5-(1-tert-butylamino-2-hydroxy- 3-propyloxy)-8-methoxy-l-tetralone.
• a compound according to claim 1 wherein the compound of Formula I is 5,8-dimethyl-7-(3-isobutylamino- Z-hydroxy-1-propyloxy)-1-tetralone.
• a compound according to claim 1 wherein the compound of Formula I is 5,8-dimethy1-7-(3-terty-butylamino- Z-hydroxyl-propyloxy -1-tetra1one.
• a compound according to claim 1 wherein the compound of Formula I is 5 ,8-dimethyl-7-(Z-hydroxy-BIZ- propylarninoJpropyloxy)-l-tetra1one.
• a compound according to claim 1 wherein the compound of Formula I is 5-[2-hydroxy-3-isopropylamino) propyolxy] tetralone.

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• 1968
  • 1968-09-23 US US761857A patent/US3641152A/en not_active Expired - Lifetime
• 1969
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• 1971
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