Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
  • C07D277/30—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table

Definitions

• Y or Z is linked to the 2-position of the thiazole nucleus
• X stands for hydrogen or alkyl of up to 3 carbons
• Y stands for a phenyl radical
• Z stands for a group of the formula:
• R1 JJCO2R2 wherein R stands for hydrogen, alkali metal, alkyl of not more than 3 carbons, dialkylaminomethyl of not more than carbons, N-piperidinomethyl or N-morpholinomethyl, chlorine or bromine, and R and R stand for hydrogen or alkyl radical of not more than 3 carbons, provided that when R and R stand for hydrogen, R stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, and non-toxic pharmaceutically-acceptable salts thereof.
• phenyl-thiazole-rnalonic acid derivatives possess anti-inflammatory, analgesic and anti-pyretic activity. Processes for preparing these compounds, and pharmaceutical compositions containing the same are disclosed.
• a typical compounds is diethyl 4-(4-bromophenyl) thiazol-Z-ylmalonate.
• This invention relates to new heterocyclic compounds and more particularly it relates to new thiazole derivatives which have anti-inflammatory, analgesic and antipyretic activity.
• Y or Z is linked to the 2-position of the thiazole nucleus
• X stands for hydrogen or an alkyl radical of not more than 3 carbon atoms
• Y stands for the phenyl radical or a phenyl radical which is substituted by not more than two halogen atoms selected from fluorine, chlorine and bromine atoms
• Z stands for a group of the formula:
• R stands for hydrogen, an alkali metal atom, an alkyl radical of not more than 3 carbon atoms, a dialkylaminomethyl radical of not more than 5 carbon atoms, the N-piperidinomethyl or N-morpholinomethyl radical, or a chlorine or bromine atom, and R and R which may be the same or ditferent, stand for hydrogen or an alkyl radical of not more than 3 carbon atoms, provided that when R and R stand for hydrogen, R stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, and non-toxic, pharmaceutically-acceptable salts thereof.
• the thiazole nucleus is numbered as follows:
• X there may be mentioned, for example, hydrogen or the methyl radical.
• R there may be mentioned, for example, hydrogen or the methyl radical.
• R there may be mentioned, for example, hydrogen, the sodium or bromine atom, or the methyl, dimethylaminomethyl, N-piperidinomethyl or N- morpholinomethyl radical.
• R or R there may be mentioned, for example, hydrogen or the methyl or ethyl radical.
• suitable salts in the case where R and/or R stands for hydrogen there may be mentioned, for example, a salt formed from that carboxylic acid and a non-toxic, pharmaceutically-acceptable cation, for example an alkali metal salt, an alkaline earth metal, salt, or an aluminium or ammonium salt, or a salt with a non-toxic, pharmaceutically-acceptable organic base.
• suitable salts are non-toxic phar maceutically-acceptable acid-addition salts.
• Preferred specific compounds of the invention are dimethyl or [4 (4 bromophenyl)thiazol 2 yl] ccmethylmalonate, dimethyl 2-(4-chlo1ophenyl)thiazol-4- ylmalonate, the a-sodium derivative of dimethyl 2-(4- chlorophenyl)thiazol-4-ylmalonate, and dimethyl a-[2-(4- chlorophenyl) thiazol-4-yl] -a-methylmalonate.
• X X S wherein Y or ----CH(CO R).CO R is linked to the 2- position of the thiazole nucleus, and X stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, Y has the meaning stated above, and R and R which may be the same or different, stand for an alkyl radical of not more than 3 carbon atoms, and non-toxic pharmaceutically-acceptable acid-addition salts thereof, which comprises reacting a compound of the formula wherein Y or -CH R is linked to the 2-position of the thiazole nucleus, and, when R stands for hydrogen, CH R is linked to the 2-position of the thiazole nucleus, and X and Y have the meanings stated above, and R stands for hydrogen or a CO R group wherein R has the meaning stated above, with a carbonate of the formula R*O.CO.OR wherein R has the meaning stated above, and sodium or potassium or a hydride, amide or C alkoxide thereof.
• Suitable values for R and R are those stated above in respect of R and R but excluding hydrogen.
• the reaction may be carried out in an excess of the carbonate used as reactant and/or in an inert solvent, for example ether.
• the reaction may optionally be carried out under the influence of heat, for example at a temperature of 70- 150 C.
• R R and R have the meanings stated above, and M stands for an alkali metal atom.
• the reaction may be carried out in an excess of the appropriate malonate derivative and/or in an inert solvent, for example dimethylformamide.
• the reaction may optionally be accelerated or completed by the application of heat.
• the alkylation may be carried out by the interaction of an alkali metal derivative of the appropriate thiazole derivative with an alkyl halide of not more than 3 carbon atoms, for example methyl iodide.
• An organic solvent for example dimethylformamide, may optionally be present.
• reaction is conveniently carried out in an organic solvent, for example ether.
• Y or --CR (CO R -CO-,,R is linked to the 2- position of the thiazole nucleus, and R stands for a dialkylaminomethyl radical of not more than 5 carbon atoms or the N-piperidinomethyl or N-morpholinomethyl radical, and X, Y, R and R have the meanings stated above, and non-toxic pharmaceutically-acceptable acid addition salts thereof, which comprises reacting a compound which in one of its tautomeric forms has the formula:
• Y or CH(CO R -CO R is linked to the 2- position of the thiazole nucleus, and X, Y, R and R have the meanings stated above, with chlorine, bromine, N-bromosuccinimide or phenyltrimethylammonium perbromide.
• reaction may be carried out in an inert solvent, for example ether or tetrahydrofuran.
• the reaction involving chlorine or bromine itself may be carried out in glacial acetic acid in the presence of an alkali metal acetate.
• X and Y have the meanings stated above, and R stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, which comprises reacting a corresponding alkali metal salt, alkaline earth metal salt, aluminium salt or ammonium salt with an acid at a relatively low temperature.
• an inorganic acid for example hydrochloric acid
• a sufficiently strong organic acid for example acetic acid.
• the reaction should be carried out at a relatively low temperature, for example at or below 0 C., in order to prevent decomposition of the product.
• non-toxic, pharmaceutically-acceptable salts of the invention may be obtained by means of conventional procedures.
• compositions comprising at least one compound which in one of its tautomeric forms is a thiazole derivative of the formula:
• N YHqZ wherein Y or Z is linked to the 2-position of the thiazole nucleus, and X, Y and Z have the meanings stated above, or a non-toxic pharmaceutically-acceptable salt thereof, and a non-toxic pharmaceutically-acceptable diluent or carrier.
• compositions may, for example, be in the form of tablets, pills, capsules, suppositories, non-sterile aqueous or non-aqueous solutions or suspensions, sterile injectable aqueous or non-aqueous solutions or suspensions, creams, lotions, or ointments. These compositions may be obtained in conventional manner using conventional excipients.
• compositions may optionally contain, in addition to at least one of the compounds which characterise this invention, at least one known agent having anti-inflammatory or analgesic activity, for example aspirin, paracetamol, codeine, chloroquine, phenylbutazone, oxyphenbutazone, indomethacin, mefenamic acid, flufenamic acid, ibufenac, or an anti-inflammatory steroid, for example prednisolone.
• Those compositions intended for oral administration may, in addition, optionally contain an anti-cholinergic agent, for example homatropine methyl bromide, and/ or an antacid,
• compositions suitable for topical application may, in addition, optionally contain a vasodilating agents, for example tolazoline, or a vasoconstricting agent, for example adrenaline; a local anaesthetic, for example amethocaine, a counter-irritant, for example capsicum; and/or at least one agent chosen from the following classes of substances: anti-bacterial agents, which includes sulphonamides and antibiotics having antibacterial action, for example neomycin; antifungal agents, for example hydroxyquinoline; anti-histamic agents, for example promethazine; and rubefacient agents, for example methyl nicotinate.
• a vasodilating agents for example tolazoline, or a vasoconstricting agent, for example adrenaline
• a local anaesthetic for example amethocaine
• counter-irritant for example capsicum
• agent chosen from the following classes of substances anti-bacterial agents, which includes sulphonamides and antibiotics
• EXAMPLE 1 A mixture of sodium hydride (4.8 g., weighed as a 50% dispersion in oil, and subsequently washed free from oil by decantation with light petroleum), diethyl carbonate (36 ml.), and 4-(4-bromophenyl)-2-methy1- thiazole (5.1 g.) was stirred under reflux for 3 hours in an oil-bath at 135140 C. The mass, which was then of a thick consistency, was treated with suflicient ethanol to destroy the excess of sodium hydride.
• EXAMPLE 2 A mixture of sodium hydride (7.2 g., see Example 1 for procedural details), dimethyl carbonate (52 ml.), and 4#(4-bromophenyl)2-methylthiazole (7.6 g.) was stirred under reflux for 6 hours in an oil-bath at 105-1 15 C. The resulting thick suspension was cooled, and any excess of sodium hydride was destroyed by addition of methanol. Water ml.), and sufficient hydrochloric acid to give a pH of 7, were added. The solid present was extracted into methylene dichloride (3X80 ml.).
• EXAMPLE Sodium hydride (0.26 g.) was suspended in dry ether (60 ml.) and a solution of methyl 2-(4-chlorophenyl) thiazol-4-ylacetate (2.6 g.) in dry ether (60 ml.) was added dropwise with stirring over 30 minutes. A solution of dimethyl carbonate (1.8 g.) in dry ether ml.) was added over minutes, and the resulting mixture was stirred under nitrogen for 16 hours at room temperature. A further quantity of sodium hydride (0.26 g.) was then added and the mixture was stirred for a further 3 hours.
• This sodium derivative (2 g.) was suspended in a mixture of water ,(50 ml.) and ether (50 ml.), and N-aqueous hydrochloric acid (50 ml.) was added with vigorous stirring.
• the ether layer was separated, washed well with water, dried with anhydrous magnesium sulphate, and evaporated to dryness. The residue was crystallised from n-hexane to give dimethyl 2 (4-chlorophenyl triazol-4- ylmalonate, M.P. 46 C.
• EXAMPLE 7 An aqueous solution of dimethylamine (2.8 ml.) was added to a stirred solution of dimethyl 2-(4-chlorophenyl)thiazol-4-ylmalonate (8 g.) in methanol (16 ml.). To the resulting suspension there was added dropwise a 36% w./v. aqueous solution of formaldehyde (2.16 ml.) over 5 minutes at room temperature. After stirring the mixture for one hour, the product was collected by filtration and washed with aqueous ethanol. There was thus obtained dimethyl a-[2-(4-chloropheny1)-thiazol-4- yl]-a-dimethylaminomethylmalonate, M.P. 95-96" C.
• EXAMPLE 8 A mixture of sodium hydride (3.4 g.), 50% dispersion-see Example 1 for procedural details), dimethylcarbonate (21 ml.), and 5-(4-chlorophenyl)-2-methylthiazole (2.9 g.) was stirred under reflux in an oil-bath at 105-115 C. for 4 /2 hours. The mixture, which had become very thick, was cooled, diluted with ether (25 ml.), treated with sufficient methanol to destroy any remaining sodium hydride, and mixed with water (50 ml.).
• EXAMPLE 9 Dimethyl 5-(4-chloropheny1)thiazol-2-ylmalonate (3.9 g.) was added to a suspension of sodium hydride ,(0.6 g., 50% dispersion, treated as in Example 1) in dry dimethylformamide (35 ml.), and the mixture was stirred at 30- 35" C. for 30 minutes. Methyl iodide (7.1 g.) was added, and stirring at 30-35" C. was continued for a further hour. The liquor was then cooled to 15 C., and diluted with water (50 ml.).
• EXAMPLE 10 The a-sodium derivative of dimethyl 2-(4-chlorophenyl)tbiazol-4-ylmalonate (2.5 g.) was suspended in dry dimethylformamide (20 ml.), and methyl iodide (1 ml.) was added. The mixture was stood at 1520 C. for 16 hours. Water (200 ml.) was added, and the mixture was extracted with ether (100 ml.).
• EXAMPLE 11 A mixture of methyl 2-(4-chlorophenyl)-4-methylthiazol-S-ylacetate (14.6 g.), sodium hydride (2.5 g.) and dimethylcarbonate (50 ml.) was stirred at a bath temperature of l001l0 for 3 /2 hours. Methanol (10 ml.) was added to destroy the excess of sodium hydride, and immediately afterwards 10% v./v. aqueous acetic acid (200 ml.) was added. The resultant mixture was extracted with 3 separate portions of chloroform (50 ml. each). The combined chloroform extracts were washed with water (3X 100 ml.), dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The resultant solid residue was crystallised from cyclohexane to give dimethyl 2-(4-chlorophenyl)-4-methylthiazol-5- ylmalonate, M.P. 140-141 C.
• EXAMPLE 12 A solution of dimethyl 2-(4-chlorophenyl)thiazol-4-ylmalonate (3.25 g.) and piperidine (1 ml.) in methanol (15 ml.) was stirred at 15 C., and a 36% w./v. aqeous solution of formaldehyde (1 ml.) was added over minutes. After hours, water (5 ml.) was added, and after a further 12 hours a solid had precipitated. This solid was collected by filtration and washed with 50% aqueous methanol (10 ml.). There'was thus obtained dimethyl ct- [2- (4-chl0rophenyl thiazol-4-yl] -a- (N-piperidinomethyl)malonate, M.P. 9091 C.
• EXAMPLE 13 A mixture of methyl 2-(2,4-dichlor0phenyl)thiazol-4- ylacetate (1.6 g.), sodium hydride (0.7 g.) and dimethyl carbonate (10 ml.) was stirred under reflux (bath temperature 100-110 C.) for 3 hours. The mixture was cooled, and methanol (5 ml.) was added to destroy the excess of sodium hydride. An aqueous solution of 10% v./v. acetic acid (50 ml.) was added, and the resultant mixture was extracted with ether (3X 50 ml.).
• EXAMPLE 14 Diethyl a-methylmalonate (3.5 g.) was added to a suspension of sodium hydride (0.96 g., 50% dispersion, treated as in Example 1) in dry dimethylformarnide (12 ml.), and the mixture was stirred at ambient temperature until evolution of hydrogen and ceased. 2-bromo- 4-(4-bromophenyl)thiazole (3.2 g.) was added, and the mixture was stirred in an oil-bath at 110 C. for 1 /2 hours. The solution was cooled, diluted with water (50 ml.) was extracted thoroughly with methylene dichloride (3X 50 ml.).
• EXAMPLE 16 A mixture of dimethyl a-[4-(4-bromopheny1)thiazo1-2- yl]-a-methylmalonate g.) and maize starch (300 g.) was granulated with a suflicient quantity of 10% w./v. starch paste. The granules were passed through a 20- mesh screen, and were dried at a temperature not exceeding 50 C. The dried granules were blended with magnesium stearate (4 g.) and then compressed into tablets containing from 50 to 250 mg. of active ingredient. There were thus obtained tablets suitable for oral use for therapeuticpurposes. 1
• the thiazole derivatives of the invention are active in a test (Adjuvant induced arthritis in rats; Newbould, Brit. J. Pharmacol. Chemotherap, 1963 21, 127-136) which is standard in the art for testing for anti-inflammatory activity. It is well known and accepted in the art that non-steroidal anti-inflammatory compounds exhibit analgesic .and antipyretic activity. Accordingly, as the compounds of the invention are non-steroidal anti-infiammatory compounds, it is reasonable to conclude that they possess analgesic and antipyretic activity.
• the compounds of the invention are useful in the treatment of warm-blooded animals (including mammals) and for this purpose we recommend that one of said compounds be administered orally as a suitable dosage unit form, for example a tablet or capsule, and that the daily dosage be in the range 0.75 to 15 mg. per kg. of host.
• a suitable dosage unit form for example a tablet or capsule
• it be administered orally as a suitable dosage unit form for example a tablet or capsule, at a total daily dose of 50 to 1000 mg. of said compound per 70 kg. man.
• a compound which in one of its tautomeric forms is a thiazole derivative of the formula:
• Y or Z is linked to the 2-position of the thiazole nucleus
• X stands for hydrogen or an alkyl radical of not more than 3 carbon atoms
• Y stands for the phenyl radical which is substituted by not more than two halogen atoms selected from fluorine, chlorine and bromine atoms
• Z stands for a group of the formula:
• a compound as claimed in claim 1 which in one of its tautomeric forms is a thiazole derivative of the formula:
• R stands for hydrogen, the sodium or bromine atom, or the methyl, dimethylaminomethyl, N-piperidinomethyl or N-morpholinomethyl radical, and R and R which may be the same or different, stand for hydrogen or the methyl or ethyl radical, or an alkali metal salt, alkaline earth metal salt, aluminum or ammonium salt, or salt with a non-toxic pharmaceutically-acceptable organic base, or a non-toxic pharmaceutically-acceptable acid-addition salt.

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• Animal Behavior & Ethology (AREA)
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• Thiazole And Isothizaole Compounds (AREA)

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Cited By (8)

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• 1968
  • 1968-03-22 GB GB03989/68A patent/GB1192701A/en not_active Expired
  • 1968-03-23 BR BR207374/68A patent/BR6807374D0/pt unknown
• 1969
  • 1969-02-17 US US799963A patent/US3661920A/en not_active Expired - Lifetime
  • 1969-02-18 IE IE209/69A patent/IE32967B1/xx unknown
  • 1969-02-23 IL IL31679A patent/IL31679A/en unknown
  • 1969-02-24 CA CA043,831A patent/CA948199A/en not_active Expired
  • 1969-03-14 NL NL6903963A patent/NL6903963A/xx unknown
  • 1969-03-14 AT AT251269A patent/AT284841B/de not_active IP Right Cessation
  • 1969-03-17 DE DE19691913472 patent/DE1913472A1/de active Pending
  • 1969-03-18 CS CS810072*1A patent/CS154268B2/cs unknown
  • 1969-03-18 CS CS809972*1A patent/CS154267B2/cs unknown
  • 1969-03-18 CS CS193669A patent/CS154266B2/cs unknown
  • 1969-03-21 FR FR6908408A patent/FR2004544A1/fr not_active Withdrawn
  • 1969-03-21 DK DK157569AA patent/DK125251B/da unknown
  • 1969-03-21 BE BE730284D patent/BE730284A/xx unknown
  • 1969-03-21 CH CH806371A patent/CH553209A/xx not_active IP Right Cessation
  • 1969-03-21 CH CH434369A patent/CH513907A/de not_active IP Right Cessation
  • 1969-03-22 ES ES365089A patent/ES365089A1/es not_active Expired
• 1970
  • 1970-09-30 DK DK498870AA patent/DK125326B/da unknown
  • 1970-09-30 DK DK498970AA patent/DK122393B/da unknown

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