RU2253653C2 - Method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride - Google Patents
Method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride Download PDFInfo
- Publication number
- RU2253653C2 RU2253653C2 RU2003105551/04A RU2003105551A RU2253653C2 RU 2253653 C2 RU2253653 C2 RU 2253653C2 RU 2003105551/04 A RU2003105551/04 A RU 2003105551/04A RU 2003105551 A RU2003105551 A RU 2003105551A RU 2253653 C2 RU2253653 C2 RU 2253653C2
- Authority
- RU
- Russia
- Prior art keywords
- chloro
- amino
- hydrochloride
- formula
- benzothiadiazole
- Prior art date
Links
- ZWUKMNZJRDGCTQ-UHFFFAOYSA-N Tizanidine hydrochloride Chemical compound Cl.ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 ZWUKMNZJRDGCTQ-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- -1 5-chloro-2,1,3-benzothiadiazol-4-yl Chemical group 0.000 claims description 5
- 229960002388 tizanidine hydrochloride Drugs 0.000 claims description 5
- MURNIACGGUSMAP-UHFFFAOYSA-N 5-chloro-2,1,3-benzothiadiazol-4-amine Chemical compound NC1=C(Cl)C=CC2=NSN=C12 MURNIACGGUSMAP-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003158 myorelaxant agent Substances 0.000 abstract description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 abstract 2
- LRXVUDBRSQYDBU-UHFFFAOYSA-N 5-chloro-1H-benzimidazol-4-amine Chemical compound ClC1=C(C2=C(NC=N2)C=C1)N LRXVUDBRSQYDBU-UHFFFAOYSA-N 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- NRNFKRFWZQQDMD-UHFFFAOYSA-M dichloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=C(Cl)Cl NRNFKRFWZQQDMD-UHFFFAOYSA-M 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 230000001670 myorelaxant effect Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 229960000488 tizanidine Drugs 0.000 description 8
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000003993 interaction Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- KUAZQDVKQLNFPE-UHFFFAOYSA-N thiram Chemical compound CN(C)C(=S)SSC(=S)N(C)C KUAZQDVKQLNFPE-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- RYTLGWCJESCDMY-UHFFFAOYSA-N carbamimidoyl chloride Chemical compound NC(Cl)=N RYTLGWCJESCDMY-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960002447 thiram Drugs 0.000 description 2
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical class C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 102100035593 POU domain, class 2, transcription factor 1 Human genes 0.000 description 1
- 101710084414 POU domain, class 2, transcription factor 1 Proteins 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Изобретение относится к области органической химии, а именно к способу получения 5-хлор-4-[(2-имидазолин-2-ил)амино]-2,1,3-бензтиадиазола гидрохлорида (тизанидина; I). Тизанидин в виде гидрохлорида является высокоэффективным лекарственным средством и применяется в медицинской практике в качестве миорелаксанта центрального действия.The invention relates to the field of organic chemistry, and in particular to a method for producing 5-chloro-4 - [(2-imidazolin-2-yl) amino] -2,1,3-benzothiadiazole hydrochloride (tizanidine; I). Tizanidine in the form of hydrochloride is a highly effective drug and is used in medical practice as a central muscle relaxant.
Известен ряд способов синтеза тизанидина [Патент США №3.843.668, кл. C 07 D 91/68, опубл. 22 окт. 1974 г.; Патент ФРГ №36.10.407, кл. C 07 D 417/12, опубл. 1 окт. 1987 г.], согласно которым препарат получают в результате взаимодействия этилендиамина с производными 2,1,3-бензтиадиазола формулы II-IV с выходом 40-70%:A number of methods for the synthesis of tizanidine are known [US Patent No. 3,843.668, cl. C 07 D 91/68, publ. Oct 22 1974; German patent No. 36.10.407, cl. C 07 D 417/12, publ. Oct 1 1987], according to which the drug is obtained as a result of the interaction of ethylenediamine with derivatives of 2,1,3-benzothiadiazole of formula II-IV with a yield of 40-70%:
Главным недостатком этих методов является технологическая сложность получения соединений II-IV, а также высокая токсичность летучих меркаптанов, выделяющихся в случае взаимодействия тиомочевин II, III с этилендиамином.The main drawback of these methods is the technological complexity of obtaining compounds II-IV, as well as the high toxicity of volatile mercaptans released in the case of the interaction of thioureas II, III with ethylene diamine.
Тизанидин (I) также может быть получен из имидазолинов V, VI при взаимодействии с 5-хлор-4-амино-2,1,3-бензтиадиазолом (VII) [Патент Японии №08176150, кл. C 07 D 417/12, опубл. 9 июля 1996 г.; Европейский патент №0.644.192, кл. C 07 D 417/12, опубл. 18 декабря 1996 г.] по схеме:Tizanidine (I) can also be obtained from imidazolines V, VI by reaction with 5-chloro-4-amino-2,1,3-benzothiadiazole (VII) [Japan Patent No. 08176150, cl. C 07 D 417/12, publ. July 9, 1996; European patent No. 0.644.192, cl. C 07 D 417/12, publ. December 18, 1996] according to the scheme:
В случае использования малодоступного 2-хлоримидазолина-2 (V) тизанидин получается в виде основания с выходом около 30%, а при взаимодействии 1-ацилимидазолидинона-2 (VI) с амином VII процесс проводят в течение 30-50 ч в присутствии 20-кратного избытка хлорокиси фосфора. Выход основания тизанидина при этом составляет 70-80%.In the case of using inaccessible 2-chlorimidazoline-2 (V), tizanidine is obtained in the form of a base with a yield of about 30%, and during the interaction of 1-acylimidazolidinone-2 (VI) with amine VII, the process is carried out for 30-50 hours in the presence of a 20-fold excess phosphorus oxychloride. The yield of tizanidine base in this case is 70-80%.
Нами разработан принципиально новый способ получения тизанидина I из амина VII и N,N-диметилдихлорметилениммоний хлорида (VIII). Согласно предлагаемому нами методу, “иммоний хлорид” VIII, полученный из тетраметилтиурамдисульфида (IX) [H.G.Vich, Z.Janousek, Angew.Chem., 85, №19, 837 (1973 г.)], конденсируют с амином VII в органическом растворителе, например в хлористом метилене, и получают N,N-диметил-N1-(5-хлор-2,1,3-бензтиадиазол-4-ил)-α-хлорформамидин (X). Из Х при взаимодействии с этилендиамином и последующим нагреванием образующегося N1N-диметил-N1-(5-хлор-2,1,3-бензтиадиазол-4-ил)-N11-(β-аминоэтил)гуанидина (XI) в органическом растворителе, например в этиленгликоле, в присутствии хлористого водорода получают тизанидин гидрохлорид I:We have developed a fundamentally new method for producing tizanidine I from amine VII and N, N-dimethyldichloromethyleneimmonium chloride (VIII). According to our proposed method, “ammonium chloride” VIII, obtained from tetramethylthiuramdisulfide (IX) [HGVich, Z. Janousek, Angew.Chem., 85, No. 19, 837 (1973)], is condensed with amine VII in an organic solvent, for example, in methylene chloride, and N, N-dimethyl-N 1 - (5-chloro-2,1,3-benzthiadiazol-4-yl) -α-chloroformamidine is obtained. From X, when reacted with ethylene diamine and subsequent heating of the resulting N 1 N-dimethyl-N 1 - (5-chloro-2,1,3-benzothiadiazol-4-yl) -N 11 - (β-aminoethyl) guanidine (XI) in an organic solvent, for example in ethylene glycol, in the presence of hydrogen chloride, tizanidine hydrochloride I is obtained:
Метод технологически прост, осуществляется с выделением только одного промежуточного продукта Х и обеспечивает высокий выход тизанидина, получаемого в процессе синтеза в виде гидрохлорида.The method is technologically simple, carried out with the isolation of only one intermediate product X and provides a high yield of tizanidine obtained in the process of synthesis in the form of hydrochloride.
Пример 1. Получение N,N-диметил-N1-(5-хлор-2,1,3-бензтиадиазол-4-ил)-α-хлорформамидина (X)Example 1. Obtaining N, N-dimethyl-N 1 - (5-chloro-2,1,3-benzthiadiazol-4-yl) -α-chloroformamidine (X)
К суспензии 8,6 г “иммоний хлорида” VIII, полученного из 7,05 г тиурама IX, в 40 мл хлористого метилена прибавляют при кипении 8,18 г амина VII в 40 мл хлористого метилена и кипятят 1,5 ч; затем растворитель отгоняют, остаток разбавляют петролейным эфиром, осадок отфильтровывают, получают 11 г Х (90%) т.пл. 88-90°С (из петролейного эфира).To a suspension of 8.6 g of “ammonium chloride” VIII, obtained from 7.05 g of thiuram IX in 40 ml of methylene chloride, 8.18 g of amine VII in 40 ml of methylene chloride are added at the boil and boiled for 1.5 hours; Then the solvent is distilled off, the residue is diluted with petroleum ether, the precipitate is filtered off, 11 g of X (90%) are obtained. 88-90 ° C (from petroleum ether).
Найдено, %: С 39.21; Н 3,05; N 20,41; S 11,47; Cl 25,82.Found,%: C 39.21; H 3.05; N, 20.41; S 11.47; Cl 25.82.
Вычислено, %: С 39.28; Н 2,92; N 20,36; S 11,65; Cl 25,77.Calculated,%: C 39.28; H 2.92; N, 20.36; S 11.65; Cl 25.77.
Пример 2. Получение 5-хлор-4-[(2-имидазолин-2-ил)амино]-2,1,3-бензтиадиазола гидрохлорида (I) (тизанидина гидрохлорида)Example 2. Obtaining 5-chloro-4 - [(2-imidazolin-2-yl) amino] -2,1,3-benzthiadiazole hydrochloride (I) (tizanidine hydrochloride)
К 22 мл этилендиамина прибавляют 11 г хлорформамидина Х и перемешивают при 25-40°С в течение 30 мин. Полученный раствор разбавляют 70 мл воды, осадок XI отфильтровывают, промывают 20 мл воды. Влажный продукт суспендируют в 25 мл воды, подкисляют до рН 1 35%-ной водной соляной кислотой, затем воду отгоняют в вакууме, к остатку прибавляют 25 мл этиленгликоля и кипятят 2 ч. После этого растворитель отгоняют в вакууме, к остатку прибавляют 10 мл воды, размешивают и осадок отфильтровывают, промывают водой и ацетоном. Получают 6 г тизанидина гидрохлорида, что составляет 52% от теоретического в расчете на хлорформамидин Х и 47,1% - в расчете на амин VII. Т.пл. 290-292°С.To 22 ml of ethylenediamine, 11 g of chloroformamidine X was added and stirred at 25-40 ° C for 30 minutes. The resulting solution was diluted with 70 ml of water, the precipitate XI was filtered off, washed with 20 ml of water. The wet product is suspended in 25 ml of water, acidified to pH 1 with 35% aqueous hydrochloric acid, then water is distilled off in vacuo, 25 ml of ethylene glycol is added to the residue and boiled for 2 hours. After this, the solvent is distilled off in vacuum, 10 ml of water is added to the residue. , stirred and the precipitate is filtered off, washed with water and acetone. 6 g of tizanidine hydrochloride are obtained, which is 52% of theory based on chloroformamidine X and 47.1% based on amine VII. Mp 290-292 ° C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2003105551/04A RU2253653C2 (en) | 2003-02-28 | 2003-02-28 | Method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2003105551/04A RU2253653C2 (en) | 2003-02-28 | 2003-02-28 | Method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2003105551A RU2003105551A (en) | 2004-10-10 |
| RU2253653C2 true RU2253653C2 (en) | 2005-06-10 |
Family
ID=35834769
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2003105551/04A RU2253653C2 (en) | 2003-02-28 | 2003-02-28 | Method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| RU (1) | RU2253653C2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ301889B6 (en) * | 2008-12-18 | 2010-07-21 | Farmak, A. S. | Process for preparing tizanidine hydrochloride |
| CN106496219A (en) * | 2016-11-01 | 2017-03-15 | 安徽省逸欣铭医药科技有限公司 | The method that high-purity technical metaplasia produces tizanidine hydrochloride |
| CN107778307A (en) * | 2016-08-24 | 2018-03-09 | 四川科瑞德制药股份有限公司 | A kind of preparation method of the adrenoceptor agonists of central α 2 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0644192A1 (en) * | 1993-09-09 | 1995-03-22 | Permachem Asia, Ltd. | A process for making a benzothiadiazole derivative |
-
2003
- 2003-02-28 RU RU2003105551/04A patent/RU2253653C2/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0644192A1 (en) * | 1993-09-09 | 1995-03-22 | Permachem Asia, Ltd. | A process for making a benzothiadiazole derivative |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ301889B6 (en) * | 2008-12-18 | 2010-07-21 | Farmak, A. S. | Process for preparing tizanidine hydrochloride |
| CN107778307A (en) * | 2016-08-24 | 2018-03-09 | 四川科瑞德制药股份有限公司 | A kind of preparation method of the adrenoceptor agonists of central α 2 |
| CN107778307B (en) * | 2016-08-24 | 2021-05-28 | 四川科瑞德制药股份有限公司 | Preparation method of central alpha 2 adrenoreceptor agonist |
| CN106496219A (en) * | 2016-11-01 | 2017-03-15 | 安徽省逸欣铭医药科技有限公司 | The method that high-purity technical metaplasia produces tizanidine hydrochloride |
| CN106496219B (en) * | 2016-11-01 | 2019-09-06 | 安徽恒星制药有限公司 | The method of high-purity technical metaplasia production Tizanidine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6559314B2 (en) | Method for the production of thiazolidin | |
| HU194802B (en) | Process for production of substituted derivatives of 1,2-diamin-cyclobuthen-3,4-dion | |
| CA2835229A1 (en) | Quinazoline derivatives for the treatment of viral infections and further diseases | |
| DE69116576T2 (en) | AROMATIC SULPHONAMIDE DERIVATIVES, THEIR USE AS ENZYMINHIBITORS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS | |
| JP2009534450A (en) | Novel imidazole derivatives, their preparation and their use as pharmaceuticals | |
| RU2253653C2 (en) | Method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride | |
| DE69432105T2 (en) | METHOD FOR PRODUCING POLYAZAMACROCYLENE | |
| EP0179408B1 (en) | Amidoalkyl melamines and aminoalkyl melamines, and process for their preparation | |
| RU2285003C1 (en) | Method for preparing 5-bromo-6-[(2-imidazolin-2-yl)amino]quinoxaline l-tartrate | |
| KR20110130487A (en) | Method for preparing doxazosin and salts thereof | |
| CH696542A5 (en) | A process for the preparation of substituted 2,6-dioxopiperidin-3-yl compounds. | |
| US3029239A (en) | Basic substituted 1-and 7-alkylxanthines or salts thereof | |
| RU2602504C1 (en) | Hydrogen halides of 11-[(4-tert-butyl)ethyl]- and 11-benzyl-substituted 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole, having alpha-glucosidase inhibitory activity | |
| FI58125C (en) | PROCEDURE FOR FRAMSTATING AV 6,7-DIMETOXY-4-AMINO-2- (4- (2-FUROYL) -1-PIPERAZINYL) QUINAZOLINE WITH BLODTRYCKSSAENKANDE VEKAN | |
| WO2005033077A1 (en) | Sequence selective pyrrole and imidazole polyamide metallocomplexes | |
| CN1333747A (en) | ((Aminoiminomethyl) amino) alkanecarboxamides and their applications in therapy | |
| FI89596C (en) | Process for the preparation of ranitidine or acid addition salts thereof | |
| RU2427574C2 (en) | Monohydrochlorides and sodium salts of tautomeric 5 (6)-alkoxycarbonylamino-derivatives of 2-aryl-1-hydroxybenzimidazole-3-oxide with high antifungal activity and synthesis method thereof | |
| RU2207340C2 (en) | Method for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazole-1-yl)methyl]-4h-carbazole-4-one or its pharmaceutically acceptable salts | |
| Gómez-SanJuan et al. | CN bond forming reactions in the synthesis of substituted 2-aminoimidazole derivatives | |
| SU402215A1 (en) | METHOD OF OBTAINING DERIVATIVES N-AMIHOALKYLAPILYLIMIHOIMIDAZOLIYHOB-212 | |
| JPS6360987A (en) | Production of quinazolinone derivative | |
| NO792276L (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-PHENYLAMINO-IMIDAZOLINE (2) DERIVATIVES | |
| CN1610667A (en) | Novel 3-nitropyridine derivative and pharmaceutical composition containing the same | |
| Kwartler et al. | Some 4-Aminoquinoline and 9-Aminoacridine Derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PC4A | Invention patent assignment |
Effective date: 20081117 |
|
| PC41 | Official registration of the transfer of exclusive right |
Effective date: 20100727 |
|
| PC41 | Official registration of the transfer of exclusive right |
Effective date: 20141124 |
|
| MM4A | The patent is invalid due to non-payment of fees |
Effective date: 20200229 |