DK143159B - METHOD OF PREPARING 4-HYDROXYMETHYL-1-KETO-1,2-DIHYDROPHTHALAZINE OR ACID ADDITION SALTS THEREOF - Google Patents
METHOD OF PREPARING 4-HYDROXYMETHYL-1-KETO-1,2-DIHYDROPHTHALAZINE OR ACID ADDITION SALTS THEREOF Download PDFInfo
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- DK143159B DK143159B DK377872AA DK377872A DK143159B DK 143159 B DK143159 B DK 143159B DK 377872A A DK377872A A DK 377872AA DK 377872 A DK377872 A DK 377872A DK 143159 B DK143159 B DK 143159B
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- keto
- dihydrophthalazine
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- hydroxymethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Cosmetics (AREA)
Description
OISLAND
143169143169
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af den kendte 4-hydroxymethyl-l-keto--1,2-dihydrophthalazin såvel som syreadditionssalte deraf.The present invention relates to a particular process for the preparation of the known 4-hydroxymethyl-1-keto-1,2-dihydrophthalazine as well as its acid addition salts.
4-Hydroxymethyl-l-keto-l,2-dihydrophthalazin udtrykt 5 ved formlen (I)4-Hydroxymethyl-1-keto-1,2-dihydrophthalazine expressed by Formula (I)
CHo0HCHo0H
r c OO· (i> 10 „ o er en kendt forbindelse med smp. 204°C, jf. "Annual Report of Department of Pharmacy", Kanazawa University, Japan, bind 12, 1-6 (1961). Det har imidlertid hidtil overhovedet 15 ikke været kendt, at denne forbindelse har farmaceutisk virkning. I det ovenfor anførte litteratursted er anført, at forbindelsen med formlen (I) fremstilles ved bromering af o-acetylbenzoesyre, hydrolysering af produktet med en syre og omsætning af hydrolysatet med hydrazin, i overensstemmelse 20 med den i "Ber." 40, 72 (1907) beskrevne metode.rc OO · (i> 10 ° o is a known compound with mp 204 ° C, cf. "Annual Report of the Department of Pharmacy", Kanazawa University, Japan, Vol. 12, 1-6 (1961). The compound of formula (I) is prepared by bromination of o-acetylbenzoic acid, hydrolyzing the product with an acid, and reacting the hydrolyzate with hydrazine, according to the method described in "Ber." 40, 72 (1907).
I det nævnte litteratursted anføres intet om den fremstillede forbindelses eventuelle farmaceutiske virkninger eller dens eventuelle anvendelighed. Endvidere anføres det, at forbindelsen med formlen (I) fås i et meget lavt udbytte 25 fra nogle få procent op til 10% ved denne uhensigtsmæssige proces, der omfatter mange trin.In the mentioned literature nothing is mentioned about the possible pharmaceutical effects or the usefulness of the compound produced. Furthermore, it is stated that the compound of formula (I) is obtained in a very low yield 25 from a few percent up to 10% by this inconvenient process involving many steps.
Forbindelsen med formlen (I) har farmaceutisk virkning, især ved behandling, herunder forebyggelse og helbredelse, af blødningstilstande, thrombosis og atherosclero-30 sis, og den har ligeledes lav toksicitet (f.eks.The compound of formula (I) has a pharmaceutical effect, especially in the treatment, including prevention and cure, of bleeding conditions, thrombosis and atherosclerosis, and also has low toxicity (e.g.
LD^q>4500 mg/kg mus).LD> q> 4500 mg / kg mice).
Det har nu vist sig, at forbindelsen med formlen (I) let kan fremstilles i højt udbytte på over 90% ved ifølge opfindelsen at omsætte en forbindelse med formlen (II) 35 2It has now been found that the compound of formula (I) can be readily prepared in high yield of over 90% by reacting a compound of formula (II) according to the invention.
OISLAND
143159143159
CORCOR
i 5 (II)i 5 (II)
IIII
o i hvilken R er en alkoxygruppe med 1-5 carbonatomer eller et halogenatom, med et alkalimetalborhydrid i et indifferent 1° organisk opløsningsmiddel, og at forbindelsen med formlen (I) danner hidtil ukendte additionssalte med organiske eller uorganiske syrer, hvilke additionssalte har farmaceutiske virkninger, der svarer til virkningerne af forbindelserne med formlen (I) eller er disse overlegne.wherein R is an alkoxy group having 1 to 5 carbon atoms or a halogen atom, with an alkali metal borohydride in an inert 1 ° organic solvent, and that the compound of formula (I) forms novel addition salts with organic or inorganic acids which addition salts have pharmaceutical effects, corresponding to the effects of the compounds of formula (I) or are superior.
15 Det er kendt, at der sædvanligvis anvendes lithium- aluminiumhydrid til fremstilling af en primær alkohol ved reduktion af en carboxylsyreester, og at reaktionen ikke finder sted i væsentlig grad med natriumborhydrid, jf.It is known that lithium aluminum hydride is usually used to prepare a primary alcohol by reducing a carboxylic acid ester and that the reaction does not take place substantially with sodium borohydride, cf.
"Angew. Chem.", 73, 81 (1961) og H.C. Brown: "Hydroboration" 20 242 (1963). Det er ligeledes velkendt, at den nitrogenholdige heteroring let reduceres ved behandling af en nitrogenholdig heterocyclisk forbindelse, især en diazinforbindelse såsom phthalazin eller quinoxalin med lithiurnaluminiumhydrid, jf. "Jikken Kagaku Koza" eller "Lectures on Experimental 25 Chemistry", bind 17, side 61."Angew. Chem.", 73, 81 (1961) and H.C. Brown: "Hydroboration" 20 242 (1963). It is also well known that the nitrogen-containing heterocycle is easily reduced by treating a nitrogen-containing heterocyclic compound, especially a diazine compound such as phthalazine or quinoxaline with lithium aluminum hydride, cf. "Jikken Kagaku Koza" or "Lectures on Experimental 25 Chemistry", vol. .
I modsætning til hvad der kunne forventes ud fra den ovennævnte kendte teknik har det nu vist sig, at forbindelsen med formlen (I) kan fremstilles i højt udbytte ved omsætning af forbindelsen med formlen (II) med et alkalimetalborhydrid.Contrary to what might be expected from the foregoing prior art, it has now been found that the compound of formula (I) can be prepared in high yield by reacting the compound of formula (II) with an alkali metal borohydride.
20 Ifølge opfindelsen kan forbindelsen med formlen (I) således fremstilles i højt udbytte ud fra et billigt materiale ved en simpel omsætning, ved hvilken reaktionstrinnene forkortes meget.Thus, according to the invention, the compound of formula (I) can be prepared in high yield from a cheap material by a simple reaction at which the reaction steps are greatly shortened.
Den ved fremgangsmåden ifølge opfindelsen anvendte 25 forbindelse med formlen (II) kan let fremstilles ved en kendt metode. Den kan f.eks. let fremstilles ved den iThe compound of formula (II) used in the process of the invention can be readily prepared by a known method. It can e.g. easily manufactured by the i
OISLAND
143159 3 "J. Am. Chem. Soc.", bind 68, side 1316, beskrevne metode ved oxidation af naphthalen med kaliumpermanganat, omsætning af det oxiderede produkt med hydrazin og esterificering af den fremkomne 4-carboxy-l-keto-l,2-dihydrophthalazin ^ på gængs måde eller behandling af denne med thionylchlorid, hvorved den omdannes til syrechloridet.J. Am. Chem. Soc., Vol. 68, page 1316, described method of oxidizing the naphthalene with potassium permanganate, reacting the oxidized product with hydrazine, and esterifying the resulting 4-carboxy-1-keto-1, 2-dihydrophthalazine in a conventional manner or treatment thereof with thionyl chloride, thereby converting it to the acid chloride.
Som eksempler på forbindelser med formlen (II) kan nævnes 4-methoxycarbonyl-l-keto-l,2-dihydrophthalazin, 4-ethoxycarbonyl-l-keto-l,2-dihydrophthalazin, 4-propoxycar-10 bonyl-l-keto-1,2-dihydrophthalazin, 4-butoxyoarbonyl-l- -keto-1,2-dihydrophthalazin, 4-amyloxycarbony1-1-keto-l,2-dihydrophthalazin , 4-chlorcarbonyl-l-keto-l,2-dihydrophthalazin og 4-bromcarbonyl-l-keto-l,2-dihydrophthalazin.Examples of compounds of formula (II) include 4-methoxycarbonyl-1-keto-1,2-dihydrophthalazine, 4-ethoxycarbonyl-1-keto-1,2-dihydrophthalazine, 4-propoxycarbonyl-1-keto, 1,2-dihydrophthalazine, 4-butoxyoarbonyl-1-keto-1,2-dihydrophthalazine, 4-amyloxycarbonyl-1-keto-1,2-dihydrophthalazine, 4-chlorocarbonyl-1-keto-1,2-dihydrophthalazine and 4 -bromcarbonyl-l-keto-l, 2-dihydro-phthalazin.
Som alkalimetalborhydrid kan f.eks. anvendes lithium-15 borhydrid, natriumborhydrid, kaliumborhydrid eller natrium- trimethoxyborhydrid.As alkali metal borohydride, e.g. lithium borohydride, sodium borohydride, potassium borohydride or sodium trimethoxyborohydride are used.
Ved fremstilling af forbindelsen med formlen (I) anvendes alkalimetalborhydridet i en mængde på mellem 0,8 og 20 mol, fortrinsvis 1-3 mol pr. mol af forbindelsen med formlen (II), 2° og omsætningen gennemføres i et indifferent organisk opløsningsmiddel. Det har i praksis vist sig hensigtsmæssigt at gennemføre omsætningen i nærværelse af et metalhalogenid såsom calci-umchlorid, magnesiumbromid, lithiumchlorid, lithiumbromid eller lithiumiodid. Når R i formlen (II) er en alkoxygruppe, 25 kan der som opløsningsmiddel anvendes vand eller en C^_g aliphatisk alkohol såsom methanol, ethanol, propanol eller amylalkohol. Det foretrækkes at anvende C^_3-alkoholer.In the preparation of the compound of formula (I), the alkali metal borohydride is used in an amount of between 0.8 and 20 moles, preferably 1-3 moles per liter. mole of the compound of formula (II), 2 ° and the reaction is carried out in an inert organic solvent. In practice, it has been found convenient to carry out the reaction in the presence of a metal halide such as calcium chloride, magnesium bromide, lithium chloride, lithium bromide or lithium iodide. When R in formula (II) is an alkoxy group, water or a C Cgg aliphatic alcohol such as methanol, ethanol, propanol or amyl alcohol can be used as the solvent. C ^ C3 alcohols are preferred.
Når R i formlen (II) er et halogenatom, kan der som opløsningsmiddel anvendes gængse indifferente organiske 30 opløsningsmidler såsom benzen, ethylether, dioxan eller tetrahydrofuran eller blandinger deraf. Når R er et halogenatom, er det tilstrækkeligt at anvende alkalimetalborhydridet i en mængde på ca. 1 til ca. 5 mol pr. mol phthal-azinderivat. Omsætningen kan sædvanligvis gennemføres ved en 35 temperatur i området 0-250°c, fortrinsvis 0-200°C, 4Where R in the formula (II) is a halogen atom, common inert organic solvents such as benzene, ethyl ether, dioxane or tetrahydrofuran or mixtures thereof may be used as a solvent. When R is a halogen atom, it is sufficient to use the alkali metal borohydride in an amount of approx. 1 to approx. 5 mol. mole of phthalazin derivative. The reaction can usually be carried out at a temperature in the range 0-250 ° C, preferably 0-200 ° C.
OISLAND
1A3159 helst 0-100°C. Sædvanligvis er reaktionen tilendebragt i løbet af 0,5-3 timer, men reaktionen kan også gennemføres ved lave temperaturer i længere tid. Produktet kan let isole-res og renses.1A3159 is preferably 0-100 ° C. Usually the reaction is completed within 0.5-3 hours, but the reaction can also be carried out at low temperatures for a longer period. The product can be easily isolated and purified.
Fremgangsmåden ifølge opfindelsen illustreres nærmere i de efterfølgende eksempler.The process according to the invention is further illustrated in the following examples.
Eksempel 1 *·0 Til en opløsning af NaBH^ i ethanol, fremstillet ved opløsning af 19 g NaBH^ i 120 ml ethanol ved 0-10°C sættes 12 g 4-ethoxycarbonyl-l-keto-l,2-dihydrophthalazin ved 0-10°C under omrøring. Til den således fremstillede suspension sættes en opløsning af 3 g calciumchlorid i 36 ml ethanol, og reaktionsblandingen omrøres i yderligere 5 timer ved stuetemperatur. Ethanolen afdestilleres under formindsket tryk, og remanensen opløses i vand. Opløsningens pH-værdi indstilles på 6-7 med eddikesyre, og der tørres under formindsket tryk. Remanensen ekstraheres kontinuert med chloroform under Π anvendelse af et Soxhlet-apparat. Chloroformekstrakten afdestilleres, og remanensen omkrystalliseres af methanol, hvorved der fås 4-hydroxymethyl-l-keto-l,2-dihydrophthala-zin med smp. 206-208°C. Produktudbyttet er 8,6 g (90%).Example 1 * · 0 To a solution of NaBH 3 in ethanol prepared by dissolving 19 g NaBH 3 in 120 ml ethanol at 0-10 ° C, 12 g of 4-ethoxycarbonyl-1-keto-1,2-dihydrophthalazine is added at 0 -10 ° C with stirring. To the suspension thus prepared is added a solution of 3 g of calcium chloride in 36 ml of ethanol and the reaction mixture is stirred for an additional 5 hours at room temperature. The ethanol is distilled off under reduced pressure and the residue is dissolved in water. The pH of the solution is adjusted to 6-7 with acetic acid and dried under reduced pressure. The residue is extracted continuously with chloroform using a Soxhlet apparatus. The chloroform extract is distilled off and the residue is recrystallized from methanol to give 4-hydroxymethyl-1-keto-1,2-dihydrophthalazine with m.p. 206-208 ° C. The product yield is 8.6 g (90%).
25 UV-spektrum: Λ 225 ηιμ (e=l6.100), 245 ηιμ (e=7*T00),UV spectrum: Λ 225 ηιμ (e = 16.100), 245 ηιμ (e = 7 * T00),
IIlcwCIIlcwC
253 πιμ (e=8.200), 2θ1 ιημ (ε=β.4θθ), 300 πιμ (e=4.500), 312 πιμ (e=2.800).253 πιμ (e = 8,200), 2θ1 ιημ (ε = β.4θθ), 300 πιμ (e = 4,500), 312 πιμ (e = 2,800).
Eksempel 2 30 En blanding af 3 g 4-carboxy-l-keto-l,2-dihydrophthal- azin og 40 ml thionylchlorid tilbagesvales forsigtigt ved 70-80°C i 1 time på et vandbad. Overskud af thionylchlorid afdestilleres derpå, og remanensen opløses i 30 ml dioxan.Example 2 A mixture of 3 g of 4-carboxy-1-keto-1,2-dihydrophthalazine and 40 ml of thionyl chloride is gently refluxed at 70-80 ° C for 1 hour in a water bath. The excess thionyl chloride is then distilled off and the residue is dissolved in 30 ml of dioxane.
Til dioxanopløsningen sættes portionsvis 2 g natriumborhy-35 drid ved 0-10°C under omrøring. Reaktionsblandingen omrøres i yderligere 1 time, og derpå afdestilleres opløsningsmidlet.To the dioxane solution is added portionwise 2 g of sodium borohydride at 0-10 ° C with stirring. The reaction mixture is stirred for an additional hour and then the solvent is distilled off.
OISLAND
143159 5143159 5
Remanensen omkrystalliseres af vand, hvorved der fås 4-hydroxymethyl-l-keto-l,2-dihydrophthalazin med smp. 201-202°C. Produktudbyttet er 2,1 g (70%),The residue is recrystallized from water to give 4-hydroxymethyl-1-keto-1,2-dihydrophthalazine, m.p. 201-202 ° C. The product yield is 2.1 g (70%),
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5864371 | 1971-08-05 | ||
| JP46058643A JPS5116430B2 (en) | 1971-08-05 | 1971-08-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK143159B true DK143159B (en) | 1981-07-06 |
| DK143159C DK143159C (en) | 1981-11-16 |
Family
ID=13090247
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK366572A DK131857C (en) | 1971-08-05 | 1972-07-24 | ANALOGICAL PROCEDURE FOR THE PREPARATION OF 4-HYDROXYMETHYL-1-PHTHALAZONE DERIVATIVES OR ACID ADDITION SALTS THEREOF |
| DK377872A DK143159C (en) | 1971-08-05 | 1972-07-31 | METHOD OF PREPARING 4-HYDROXYMETHYL-1-KETO-1,2-DIHYDROPHTHALAZINE OR ACID ADDITION SALTS THEREOF |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK366572A DK131857C (en) | 1971-08-05 | 1972-07-24 | ANALOGICAL PROCEDURE FOR THE PREPARATION OF 4-HYDROXYMETHYL-1-PHTHALAZONE DERIVATIVES OR ACID ADDITION SALTS THEREOF |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US3864343A (en) |
| JP (1) | JPS5116430B2 (en) |
| AR (3) | AR197089A1 (en) |
| AT (2) | AT320658B (en) |
| AU (2) | AU461281B2 (en) |
| BE (2) | BE787138A (en) |
| CA (2) | CA966489A (en) |
| CH (2) | CH577980A5 (en) |
| CS (2) | CS180588B2 (en) |
| DE (2) | DE2237832A1 (en) |
| DK (2) | DK131857C (en) |
| ES (2) | ES405456A1 (en) |
| FR (2) | FR2150736B1 (en) |
| GB (2) | GB1404367A (en) |
| HU (2) | HU163726B (en) |
| IE (2) | IE36597B1 (en) |
| LU (2) | LU65855A1 (en) |
| NL (2) | NL151261B (en) |
| NO (1) | NO134113C (en) |
| SE (2) | SE408177B (en) |
| SU (2) | SU577986A3 (en) |
| YU (1) | YU35245B (en) |
| ZA (2) | ZA725203B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR205004A1 (en) * | 1973-10-30 | 1976-03-31 | Ishikawa M | PROCEDURE TO PREPARE 6,8-DIALKYL-7-ALCOXY-CARBONYL-4-HYDROXIMETHYL-1-PHTHALAZONE AND 7,8-LACTONE DERIVATIVES |
| NL7702763A (en) * | 1976-03-18 | 1977-09-20 | Takio Shimamoto En Masayuki Is | PROCESS FOR THE PREPARATION OF THROMBOXAN ANTAGONISTS AND OF PREPARATIONS CONTAINING THESE SUBSTANCES. |
| IE47592B1 (en) * | 1977-12-29 | 1984-05-02 | Ici Ltd | Enzyme inhibitory phthalazin-4-ylacetic acid derivatives, pharmaceutical compositions thereof,and process for their manufacture |
| US4293553A (en) * | 1978-08-11 | 1981-10-06 | Masayuki Ishikawa | 1-Phthalazone derivatives, and use thereof |
| US4861778A (en) * | 1986-06-16 | 1989-08-29 | Research Corporation | 2,3-dihydrophthalazine-1,4-diones |
| CH683965A5 (en) * | 1993-02-19 | 1994-06-30 | Limad Marketing Exp & Imp | Ftalidrazidici compounds of the class as an active substance in anti-inflammatory agents and anti-toxic. |
| DE102005011822A1 (en) * | 2005-03-15 | 2006-09-21 | Merck Patent Gmbh | phthalazinones |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE687916A (en) * | 1965-10-12 | 1967-03-16 |
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1971
- 1971-08-05 JP JP46058643A patent/JPS5116430B2/ja not_active Expired
-
1972
- 1972-07-21 AU AU44843/72A patent/AU461281B2/en not_active Expired
- 1972-07-24 DK DK366572A patent/DK131857C/en not_active IP Right Cessation
- 1972-07-24 AR AR243236A patent/AR197089A1/en active
- 1972-07-24 US US275171A patent/US3864343A/en not_active Expired - Lifetime
- 1972-07-24 AR AR243235A patent/AR194123A1/en active
- 1972-07-25 AU AU44940/72A patent/AU461018B2/en not_active Expired
- 1972-07-25 IE IE1046/72A patent/IE36597B1/en unknown
- 1972-07-25 GB GB3482172A patent/GB1404367A/en not_active Expired
- 1972-07-25 IE IE1047/72A patent/IE36598B1/en unknown
- 1972-07-25 GB GB3482072A patent/GB1404368A/en not_active Expired
- 1972-07-27 NL NL727210370A patent/NL151261B/en not_active IP Right Cessation
- 1972-07-27 ZA ZA725203A patent/ZA725203B/en unknown
- 1972-07-27 ZA ZA725202A patent/ZA725202B/en unknown
- 1972-07-27 NL NL7210369A patent/NL7210369A/xx unknown
- 1972-07-28 SE SE7209886A patent/SE408177B/en unknown
- 1972-07-31 DK DK377872A patent/DK143159C/en not_active IP Right Cessation
- 1972-08-01 DE DE2237832A patent/DE2237832A1/en active Pending
- 1972-08-02 ES ES405456A patent/ES405456A1/en not_active Expired
- 1972-08-03 BE BE787138A patent/BE787138A/en not_active IP Right Cessation
- 1972-08-03 YU YU2013/72A patent/YU35245B/en unknown
- 1972-08-03 SU SU7201817033A patent/SU577986A3/en active
- 1972-08-03 BE BE787139A patent/BE787139A/en not_active IP Right Cessation
- 1972-08-03 SE SE7210119A patent/SE406587B/en unknown
- 1972-08-04 CH CH1160472A patent/CH577980A5/xx not_active IP Right Cessation
- 1972-08-04 AT AT852473A patent/AT320658B/en not_active IP Right Cessation
- 1972-08-04 FR FR7228258A patent/FR2150736B1/fr not_active Expired
- 1972-08-04 AT AT06734/72A patent/AT317233B/en not_active IP Right Cessation
- 1972-08-04 DE DE2238566A patent/DE2238566A1/en active Pending
- 1972-08-04 CS CS7200005458A patent/CS180588B2/en unknown
- 1972-08-04 ES ES405555A patent/ES405555A1/en not_active Expired
- 1972-08-04 LU LU65855A patent/LU65855A1/xx unknown
- 1972-08-04 SU SU1814854A patent/SU513622A3/en active
- 1972-08-04 CA CA148,812A patent/CA966489A/en not_active Expired
- 1972-08-04 LU LU65856A patent/LU65856A1/xx unknown
- 1972-08-04 FR FR7228257A patent/FR2150735B1/fr not_active Expired
- 1972-08-04 HU HUIO185A patent/HU163726B/hu unknown
- 1972-08-04 CS CS7200005457A patent/CS180587B2/en unknown
- 1972-08-04 CH CH1160372A patent/CH580081A5/xx not_active IP Right Cessation
- 1972-08-04 HU HUIO186A patent/HU165815B/hu unknown
- 1972-08-04 CA CA148,813A patent/CA999236A/en not_active Expired
- 1972-08-04 NO NO2793/72A patent/NO134113C/no unknown
-
1973
- 1973-08-14 AR AR249572A patent/AR197156A1/en active
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