http://rdf.ncbi.nlm.nih.gov/pubchem/patent/NO-124645-B
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| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_966a6c1f382ec9bcb5e3839dfd73e5b8 |
| classificationCPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D243-24 |
| classificationIPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D- http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K- http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D243-26 |
| filingDate | 1969-06-11-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| inventor | http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_7af2ccea410e701d80fd0acf08b1187e http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_4c881d9aba636a904d0c2c387361d10b http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_e52b2812d0eb0fa9480c071e7b5d4ef2 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_90191c7248a70e5a6aebb0a288d91bfb http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_427716f5967930081ada9e3fa79c74f6 |
| publicationDate | 1972-05-15-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | NO-124645-B |
| abstract | The present invention relates to the preparation of 5- (2-pyrimidinyl) -1,4-benzodiazepines. The benzodiazepine derivatives of the present invention correspond to the general formula. wherein Ra and Ru are independently hydrogen, halogen, nitro or trifluoromethyl, Rhydrogen, lower alkyl, lower alkanoyl, lower haloalkyl or lower dialkylaminoalkyl, and Rd represents hydrogen or lower alkyl. The invention also encompasses acid addition salts of the compounds of formula I. The term " lower alkyl "refers to straight-chain or branched saturated hydrocarbon groups having 1-7, preferably 1-4 carbon atoms, such as e.g. methyl, ethyl, propyl and isopropyl. Unless otherwise expressly stated, "halogen" is to be understood as meaning all four halogens, i.e. fluorine, iodine, chlorine and bromine. A preferred aspect of the present invention relates to those compounds of formula I wherein R & is halogen, especially chlorine, Rfa hydrogen and Rog Any hydrogen or lower alkyl, especially methyl, Examples of these particularly preferred compounds are: The benzodiazepine derivatives of formula I and their acid addition salts can be prepared according to the invention, oxidizing with ruthenium tetraoxide a compound of formula, wherein Ra, Rtø, Rc have the aforementioned meaning, B represents a carbonyl or methylene group and A represents the structural element, A then having to represent the structural element - when B represents a carbonyl group, and, if desired, for the preparation of an acid addition salt converts an obtained free base with an acid. The oxidation by means of ruthenium tetraoxide leads in a light and simple manner to the desired product. According to a preferred embodiment, ruthenium tet is brought the oxide in molar excess to the reaction zone. The reaction is preferably carried out below room temperature, e.g. in a temperature range between approx. -20 and approx. + 15 °, especially between approx. 0 ° and approx. + 10 °. The reaction takes place advantageously in the presence of an inert organic solvent, and of the numerous suitable solvents, halogenated aliphatic hydrocarbons, such as chloroform and dichloromethane, should be mentioned. After allowing the reaction to proceed until the desired target is reached, the possible excess of ruthenium tetraoxide present in the reaction mixture is advantageously destroyed by the addition of a suitable reagent. For this purpose, a lower alkanol is preferably used, such as e.g. 2-propanol. As the preparation of the starting materials is not already known, they can easily take place corresponding to the examples given in the following reaction schemes. Of course, these schemes can be modified to introduce other substituents. In addition, it is possible to introduce an HN-C = group in the 5-position in a suitably substituted 1,4-benzodiazepine and from this to build up the pyrimidinyl ring analogously to the reactions 12 -> 13 - ^ 15 ^ 3. The oxidation by means of chromium trioxide can in this case (ie when the benzodiazepine system has already been formed in advance) will of course fall away. Furthermore, it is possible to change the substituents present according to methods known per se. Thus, e.g. a nitro group is reduced by hydrogenation to an amino group. The amino group can be replaced by a Sandmeyer reaction with halogen or hydrogen. As already stated, the compounds of formula I can be obtained in the form of their acid addition salts, in particular in the form of their pharmaceutically usable acid addition salts. Examples of inorganic and organic acids which form pharmaceutically usable salts are hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, acetic acid, formic acid, succinic acid, maleic acid and p-toluenesulfonic acid. These salts can be prepared from the free bases of the compounds of formula I according to generally known methods. In addition, the pharmaceutically usable acid addition salts of the aforementioned compounds are useful as intermediates for the preparation of pharmaceutically usable acid addition salts, which e.g. takes place by resalting or releasing the base and subsequent salt formation by means of a pharmaceutically usable acid according to methods known per se. The compounds according to the present invention can be used as medicaments. They excel at anticonvulsant, sedative and muscle relaxing properties. In addition, some of these compounds show antipyretic properties. The compounds can be administered to common pharmaceutical preparations, e.g. when mixed with common inert carriers suitable for parenteral or enteral administration, such as e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, gum arabic and the like, polyalkylene glycols or petroleum jelly. Their administration may take the form of conventional pharmaceutical preparations, e.g. in solid form (eg as tablets, dragees, capsules or suppositories) or in liquid form (eg as solutions, suspensions or emulsions). In addition, the pharmaceutical compositions containing the compounds of the present invention may be subjected to conventional pharmaceutical methods (such as sterilization) and may contain common pharmaceutical excipients such as preservatives, stabilizers, wetting or emulsifying agents, salts for altering the composition. osmotic pressure or buffer. In addition, the compositions may still contain other therapeutically valuable substances. A suitable pharmaceutical dosage unit may contain approx. , 1 to 500 mg of a compound of the present invention. Suitable daily doses for oral administration to mammals are in the range of approx. 0.1 mg / kg to approx. 300 mg / kg. For parenteral administration in mammals, a suitable daily dose is approx. 0.1 mg / kg to approx. 10 mg / kg. However, the specific dosage in any case, according to the professional judgment of the person carrying out and supervising the administration of the said compound, should be adapted to the individual needs. It is to be understood that the foregoing dosages are primarily to be construed in accordance with the examples. The following examples illustrate the invention. All temperatures are given in degrees Celsius. EXAMPLE 1. (A) To a solution of 54.4 g (.36 mol) of o-chlorophenylacetonitrile in 900 ml of dry tetrahydrofuran is added 17.2 g of 50% sodium hydride in mineral oil (0.36 mol) and heat the mixture for 30 minutes under reflux. Then a solution of 41.1 g (0.36 mol) of 2-chloropyrimidine in 200 ml of dry tetrahydrofuran is added over 10 minutes to the boiling solution and the mixture is heated for a further 3 hours. After cooling, 100 ml of water are added and the tetrahydrofuran is removed by distillation under reduced pressure. The remaining aqueous phase is extracted with methylene chloride, washed with water, dried over sodium sulfate and evaporated to dryness. Extraction of the residue with twice 375 ml of hot hexane removes 9.4 g of an oil. The residue crystallizes slowly from a mixture of benzene and hexane to give 23 g of 2- (2-chlorophenyl) -2- (2-pyrimidinyl) -acetonitrile. Crystallization of a sample from hexane gives colorless rhombuses with melting point 81 - 82 °; IR (C1) 2250 (C) cm (B) To a solution of 3 g (13 mmol) of 2- (2-chlorophenyl) -2- (2-pyrimidinyl) -acetonitrile in 250 ml of dry tetrahydrofuran is added 0.78 g sodium hydride (50%, in mineral oil). The mixture is heated for 2 hours with stirring under reflux, then cooled to room temperature and allowed to dry dry air in a strong stream for 16 hours. Then add 30 ml of 33% aqueous methanol and then carefully approx. 200 ml of water. The tetrahydrofuran is removed by distillation under reduced pressure and the solid formed is isolated by filtration to give 1.7 g of crude 2- (2-chlorobenzoyl) pyrimidine, m.p. 124 DEG-127 DEG C. IR (CHCl3) 1695 (CO) cm. (C) A solution of 11.9 g (55 mmol) of 2- (2-chlorobenzoyl) pyrimidine in 60 ml of concentrated sulfuric acid is cooled to 0 ° and then a mixture of 3 is added dropwise over 1 hour. .1 ml of 90% nitric acid and 7.7 ml of concentrated sulfuric acid. Stir for 1 hour at 0 ° and then for another 1 hour at room temperature. The reaction mixture is poured onto ice and made alkaline by adding dilute aqueous ammonia. The solid formed is removed by filtration to give 13.8 g (95%) of r, 2- (2-chloro-5-nitrobenzoyl) -pyrimidine, m.p. 143 - 146 °. Crystallization from benzene gives pale yellow rhombuses with m.p. 147-149 °; The IR (1) 1705 (CO), 1535, 1 J 1370 cm -1. The 2- (2-chlorobenzoyl) pyrimidine can also be prepared as follows:. () A suspension of 89.0 g (1.65 mol) of sodium methylate in 900 ml of anhydrous methanol is added with stirring and ice-cooling over 45 minutes portionwise 110.5 g (0.5 mol) of solid α- (2-chlorophenyl) -α-hydroxyacetamidine hydrochloride. Then 80.0 g (0.5 mol) of freshly distilled malonic acid diethyl ester are added dropwise and the mixture is stirred for a further 24 hours at room temperature. The sodium salt of the product formed is separated by filtration and washed successively with 125 ml of cold methanol, 500 ml of methanol-ether (1: 4) and then with ether. This salt is suspended for approx. 600 - 700 ml of water, stirring while cooling in an ice bath and adding until strongly acidic reaction concentrated hydrochloric acid (for which about 100 ml is necessary). After thorough cooling, the 2- (2-chloro-α-hydroxybenzyl) -4,6-dihydroxypyrimidine is filtered off and washed until almost neutral with ice-water and then with petroleum ether (b.p. 40-60 °) to give 63.5 g ( 50%) colorless crystals with melting point 223 - 225 ° (decomposition). Crystallization from water gives pale yellowish crystals with the same melting point (B ') A suspension of 25.3 g (0.1 mol) of 2- (2-chloro-α-hydroxybenzyl) -4,6-dihydroxypyrimidine in 250 ml of glacial acetic acid added over the course of 1 hour. dropwise a solution of 10.0 g (0.1 mol) of chromic anhydride in 15 ml of water, the color changing very rapidly to greenish black, and most of the material dissolving. The mixture is stirred overnight, then 5 ml of methanol are added to destroy the excess oxidizing agent, stirred for 2 hours and then evaporated at a temperature below 30 ° in vacuo. The rest is shredded with water; the semi-solid crude product is washed thoroughly with water and dried at 80 ° in vacuo to give 18.3 g (73%) of 2- (2-chlorobenzoyl) -4,6-dihydroxypyrimidine as a green-yellow solid with melting point approx. 233 °. Crystallization from water gives pale yellow prisms, m.p. 239 DEG-241 DEG. (C) A suspension of 12.08 g (48.2 mmol) of 2- (2-chlorobenzoyl) -4,6-dihydroxypyrimidine in 100 ml of distilled phosphoryl chloride is dissolved. x is heated under moisture exclusion for 3 hours in an oil bath under reflux. The mixture is concentrated under reduced pressure; the residue is suspended in methylene chloride and slowly added to a well-stirred mixture of ice and water. Aqueous sodium hydroxide solution is then added until a strong alkaline reaction of 40% (w / v) is filtered and the mixture is filtered to remove an insoluble precipitate. Careful evaporation of the methylene chloride layer of the filtrate gives the desired product as 6.60 g (48%) of a brownish, viscous oil. By distillation in beads at 115 - 205 ° / 0.3 mm, 4.02 g of 4,6-dichloro-2- (2-chlorobenzoyl) -pyrimidine are obtained in the form of yellow crystals; distillation once more at 100 DEG-135 DEG / 0.1 mm gives the product as colorless crystals, m.p. 95 DEG-98 DEG. -chlorobenzoyl) -pyrimidine in 20 ml of ethanol is added 100 mg of a 10% (w / w) palladium-carbon catalyst, which is thoroughly moistened with 10.0 ml (10 mmol) of aqueous N-sodium hydroxide solution. The mixture is hydrogenated at room temperature and normal pressure, the hydrogen uptake (1.65 mol) coming to a standstill after 2 hours. The catalyst is separated by filtration over a filter medium and washed with ethanol. The combined filtrates are diluted with 100 ml of water, acidified with dilute hydrochloric acid The aqueous residue is washed once with ether and then made alkaline with dilute sodium hydroxide solution. The precipitated 2- (2-chlorobenzoyl) pyrimidine is isolated by extraction with ether to give 0.39 g (52%). ) of a pale yellow, viscous oil, this material is shown by a comparison of the infrared spectrum and the rate of migration by thin layer chromatography in 2 solvent systems identical to an authentic sample of 2- (2-chlorobenzoyl) -pyrimidine. A mixture of 446.2 g (1.70 mol) of 2- (2-chloro-5-nitrobenzoyl) - pyrimidine, 510 g (8.5 mol) of ethylenediamine and 1700 ml of anhydrous pyridine are heated with stirring for 5 hours on the steam bath. Concentration under reduced pressure and then distillation with xylene and toluene remove most of the solvent. The resulting tar-like residue is mixed with 200 ml of methanol and 2.5 liters of aqueous 3-n hydrochloric acid. The solution is allowed to stand for 2 hours at room temperature, then cooled and adjusted alkaline with aqueous 5-sodium hydroxide solution. The precipitated crude product is separated by filtration, washed with water and dried. For purification, 1 kg of neutral alumina (activity I) is added to a slurry of the product in methanol and then the solvent is removed under reduced pressure. The dried mixture of product and alumina is continuously extracted in a Soxhlet apparatus with hot methylene chloride, until the extract does not. exhibits more product (which lasts for 4-5 days). Filtration of the extract gives 130.7 g of 2,3-dihydro-7-nitro-5- (2-pyrimidinyl) -1H-1,4-benzodiazepine, m.p. 22 DEG-2 DEG-24 DEG C. Additional portions are obtained by evaporation of the filtrate. ; the yield of the product with melting point 215 - 231 ° is a total of 195 g (43%) .- Crystallization from ethanol-benzene-hexane and then from methylene chloride-ethanol-hexane gives shiny yellow diamonds of the above-mentioned compound with melting point 230 - 232 ° (decomposition A solution of 14 7.7 g (0.55 mol) of 2,3-dihydro-7-nitro-5- (2-pyrimidinyl) -1H-1,4-benzodiazepine and 33.0 g (0.61 mol) sodium methylate in 1300 ml of anhydrous N, N-dimethylformamide is stirred for 1 hour at room temperature and then a solution of 77.0 g (0.61 mol) of dimethyl sulphate in 260 ml of dry dimethylformamide is added dropwise over 2 hours, the temperature in the reaction mixture is cooled to 0-5 ° by cooling in an ice bath. Stir for another 24 hours at room temperature and then pour the mixture into 6 liters of ice water. Then add until almost neutral reaction (pH 5-6) dry ice. Extraction with methylene chloride gives 156.8 g of crude product as a broad crystalline solid. This material is extracted with cold methylene chloride, unchanged starting material is filtered off and the filtrates are allowed to flow through 785 g of neutral alumina (activity III) for further purification. The methylene chloride eluates are evaporated and the residue obtained (94.0 g) is crystallized from benzene-hexane to give 71.8 g of 2,3-dihydro-1-methyl-7-nitro-5- (2-pyrimidinyl) - 1H-1,4-benzodiazepine, m.p. 179-181. From the mother liquors an additional portion (10.2 g) is obtained with melting point 177 - 179 °; the yield is 82.0 g (61%, calculated on the unrecovered starting material). Crystallization from methylene chloride-hexane gives the product as yellow rods, m.p. 181 DEG-183 DEG (decomposition). 944 mg (3.33 mmol) of 2,3-dihydro-1-methyl- are added to a 500 ml three-necked flask with magnetic stirrers. 7-Nitro-5- (2-pyrimidinyl) -1H-1,4-benzodiazepine under ice-cooling dropwise, over 30 minutes, 260 ml of a 0.058 M solution of ruthenium tetraoxide (15 mmol, ie 4.5 equivalents). Stir for another 30 minutes and then add 5 ml of 2-propanol. The reaction mixture is filtered and evaporated to dryness. The oil obtained is crystallized from methylene chloride-hexane to give 1,3-dihydro-1-methyl-7-nitro-5- (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one, m.p. 196.5 ° (decomposition). EXAMPLE 2. A suspension of 72 g (0.25 mol) of 2,3-dihydro-1-methyl-7-nitro-5- (2-pyrimidinyl) -1H-1,4- benzodiazepine in 1400 ml of methanol is hydrogenated at room temperature and atmospheric pressure over an alcohol-washed Raney nickel catalyst (5 teaspoons, activity about W-2), the hydrogen uptake (3.2 mol) coming to a standstill after 3 hours. By removing the catalyst and the solvent, the crude 7-amino compound which is not crystalline residue is obtained. For purification, a solution of this material in methylene chloride is filtered through a column containing 350 g of neutral alumina (activity III), the filtrates are evaporated to give 62.9 g (98%) of 7-amino-2,3-dihydro-1-methyl -5- (2-pyrimidinyl) -1H-1,4-benzodiazepine in the form of a brown foam, which can be used directly for the next step. A solution of 61.35 g (0.242 mol) of 7-amino-2,3 -dihydro-1-methyl-5- (2-pyrimidinyl) -1H-1,4-benzodiazepine in 483 ml (1.45 mol) of 3-n hydrochloric acid is added at -5 to -10 ° slowly a solution of 20.4 g (0.296 mol) of sodium nitrite in 100 ml of water and then a suspension of 52.8 g (0.534 mol) of cuprous chloride in a mixture of 250 ml of concentrated hydrochloric acid and 125 ml of water. The mixture is added with 500 ml of water, heated for 1 1/2 hours to 35 ° and then for 2 hours to 40 ° until the evolution of nitrogen comes to a standstill and the diazo test precipitates negatively with the aid of R-salt. The mixture is made alkaline by adding 28% (w / v) aqueous ammonia, and the product is isolated by extraction with methylene chloride. For purification, a methylene chloride solution of the material obtained is filtered through a column containing 315 g of neutral alumina (activity III). Evaporation of the eluate gives 23.4 g of 7-chloro-2,3-dihydro-1-methyl-5- (2-pyrimidinyl) -1H-1,4-benzodiazepine in the form of a yellow-brown crystalline residue, which by crystallization from benzene-hexane (1: 2) gives 22.5 g (34%) of a product, m.p. 106 DEG-109 DEG. Crystallization from methylene chloride-petroleum ether (b.p. 40-60 °) gives yellow needles with a melting point of 107 DEG-109 DEG C. 3 g of 55.3% of ruthenium dioxide are suspended (Engelhard Industries, i.e. 1.66 g, 12.4 mmol). RO) in 360 ml of chloroform, which has been washed beforehand with water to remove the ethanol. While stirring and cooling in an ice bath, a solution of 48.6 g (22 mmol) of sodium metaperiodate is added dropwise in 360 ml of water. Stir for another 2 hours and filter the mixture through a glass frit. The yellow organic phase is separated, washed immediately three times with ice-cold aqueous sodium metaperiodate solution (5 g in 250 ml) and then added with stirring and under ice-cooling over 2 hours dropwise to a yellow solution of 2 g (7.33 g). mmol) 7-chloro-2,3-dihydro-1-methyl-5- (2-pyrimidinyl) -1N-1,4-benzodiazepine in 50 ml of chloroform. The mixture is stirred for a further 15 minutes and then 10 ml of isopropanol are added dropwise to precipitate the excess ruthenium tetraoxide. The mixture is filtered to recover the precipitated ruthenium dioxide and washed with methylene chloride. The filtrates are combined, washed with water, dried over sodium sulfate and evaporated to leave 0.21 g of a green-brown gum-like mass. For purification, a methylene chloride solution of this material is filtered through a column containing 2.3 g of neutral alumina (activity III), evaporating the eluate to give 0.14 g (6.7%) of 7-chloro-1,3-dihydro- 1-methyl-5- (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one as a yellow rubber-like mass, which is triturated with ether to give, on recrystallization from methylene chloride-hexane, colorless flat prisms, m.p. 157 DEG-159 DEG. The pharmacological activity of a number of the compounds of the present invention has been determined by the following, generally common test devices:. Match test. This test is suitable for testing compounds with muscle relaxing properties and / or anxiolytic effects (sedatives). Two mice are placed under a velvet 1-liter beaker on a grid, which gives them blows to the feet. This puts the animals in a state of irritation, which manifests itself in random short duels. You select pairs of mice, which have fought at least five times during a 2-minute trial period, administer the test substance orally and repeat the experiment after 1 hour. Logarithmically increasing doses up to a maximum of 100 mg / kg are used. The dose, which in three out of three pairs of mice prevents a fight, is defined as a 100% inhibitory dose. Test on the inclined plane. This experiment establishes muscle relaxing and / or sedative properties. The test substance is administered in doses up to a maximum of 500 mg / kg to groups in each case 6 male mice, the animals are placed on an inclined plane and observed for at least 4 hours, if they slip off the plane due to paralysis phenomena. When such an effect is observed, the doses are varied until at least two doses have been determined, at which some, but not all of the animals, slip off the planet. Dosages are not taken into account at which the mice slip off due to toxicity or irritation. . PD is determined graphically, counting. the doses against the percentage of paralyzed mice: the PD value thus obtained defines the dose (in mg / kg) at which it can be expected that 50% of the mice glide off the planet. Test on awake cats. Cats are treated orally and symptoms occur (common ataxia). First, use a cat and a dose of 50 mg / kg. When an effect appears, the doses are varied and up to 3 cats are used per day. dose. The results show the minimally effective dose. This experiment is useful in determining muscle relaxant properties. Antimetrazole test. This experiment establishes anticonvulsant and / or sedative properties of compounds. The test substance is administered to groups of 4 mice each in different doses orally. After 1 hour, the animals are given metrazole subcutaneously at a predetermined dose (approximately 125 mg / kg) which triggers seizures in all experimental animals, and it is observed whether the animals are now protected against seizures. The number of animals protected against seizures is noted and the dose at which 50% of the animals are protected against seizures is defined as ED 50. Maximum electroshock. With this test, which is performed on mice, compounds can be tested for anticonvulsant properties. When the mice are given a current surge of 30mA (approximately 6 times the threshold value) in the course of 0.2 seconds by means of corneal electrodes, a maximum tonic-clonic seizure takes place. This maximal seizure in mice includes a stretching spasm in the hind foot (tonic phase) and a clonic phase of the body. 24 hours before the start of the main experiment, it is determined by means of a preliminary experiment, whether the animals react normally. In the main experiment, the test substance is administered orally in different doses in groups of 4 mice each. 1 hour after administration, the animals receive the said electroshock (30 mA). Criteria for the effect of the test substance are the absence of tension cramps in the hind foot. When the compound is found to be active in such a manner, it is administered in reduced doses to additional groups of 8 mice each, until the tension spasm reappears. The dose (in mg / kg) which in two out of four animals> prevents tensile cramps in the hind foot is referred to as FJ ^ q-. Minimal electroshock. This experiment, which is also performed on mice, serves to determine anticonvulsant properties. A current conducted by means of corneal electrodes on the animal eyes produces seizures (each gives a drop of physiological saline solution to the animal eyes and brings the eyes into direct contact with the electrodes). In a preliminary experiment, all mice were exposed to a 6.0 mA current shock for 0.2 seconds. In the main experiment, only those animals that have shown a minimal seizure are used. 24 hours after the pre-test, the substance to be tested is administered in different doses in groups of four animals each. 1 hour later, the animals again receive an electroshock of 6.0 mA. Thereby, the test substance is calculated as active when it protects the animals from the minimal seizure caused by this electroshock. When determining the ED value of active compounds, one uses per. dose groups of 8 animals each. The results of the above-described experiments for particular compounds of the present invention are summarized in the following Table I. |
| priorityDate | 1968-06-12-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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Total number of triples: 178.