CN107235911A - A kind of purposes of 2- methyl-4-nitro iminazoles derivative and preparation method thereof and Pharmaceutical composition - Google Patents
A kind of purposes of 2- methyl-4-nitro iminazoles derivative and preparation method thereof and Pharmaceutical composition Download PDFInfo
- Publication number
- CN107235911A CN107235911A CN201610181083.8A CN201610181083A CN107235911A CN 107235911 A CN107235911 A CN 107235911A CN 201610181083 A CN201610181083 A CN 201610181083A CN 107235911 A CN107235911 A CN 107235911A
- Authority
- CN
- China
- Prior art keywords
- methyl
- compound
- nitro
- preparation
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/93—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by halogen atoms, attached to other ring members
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
Abstract
The invention provides the derivative of the nitroimidazole of 2 methyl 4, invention additionally provides the preparation method of the nitro imidazole derivatives of 2 methyl 4.In addition, the pharmaceutical composition of the derivative of the nitroimidazole containing 2 methyl 4, which is applied to treatment, is bitten the multi-infection disease knitted caused by the sensitive anaerobic bacteria such as dimension bacterium, gum bacteroid as bacteroides fragilis, bacteroides disiens, ovum garden bacteroid, bacteroides thetaiotaomicron, bacteroides vulgatus, clostruidium, Eubacterium, peptococcus and peptostreptococcus, helicobacter pylori, bacaeroides melaninogenicus, Fusobacterium, CO2.
Description
Technical field
The invention belongs to chemicals technical field, more particularly to a kind of 2- methyl-4-nitro iminazoles derivative and its system
Preparation Method.The invention further relates to a kind of pharmaceutical composition of 2- methyl-4-nitro iminazoles derivative in treatment anaerobic infection, original
Application in insect infection and various other diseases.
Background technology
Ornidazole and laevo-ornidazole are the derivative of 2- 5-nitro imidazoles, be a kind of strength anaerobe resistant and
The medicine of antigen insect infection, is also that the curative effect that is made is higher, the course for the treatment of is shorter, tolerance is more preferable, in vivo after newly being developed after metronidazole
It is distributed wider array of third generation nitro imidazole derivatives.
Therefore third generation nitro imidazole derivatives are as a kind of new anti anaerobic bacteria infection medicine, to mitigating many patients
Pain, the quality of life for improving patient has very important significance, and has wide market and wilderness demand both at home and abroad.
In the further research to Ornidazole and laevo-ornidazole, it has been found that, it can be produced after use a certain degree of
Maincenter toxicity, side reaction is more, therefore the research of nitro imidazole derivatives turns into a new focus.
We to the research of 2- methyl-4-nitro iminazole derivatives by having found, by derivative, can obtain a variety of having
The derivative of curative effect, these derivatives have a certain degree of difference with Ornidazole in the chemically so that with preferably steady
Qualitative and preparations shaping, is the compound with further Development volue.
The content of the invention
It is an object of the invention to provide a kind of 2- methyl-4-nitro iminazoles derivative.
Its general structure is as follows：
Wherein, R1Can be hydroxyl, phosphorous acid ester group, phosphate-based.
Flow can be clicked another object of the present invention is to the preparation method for providing 2- methyl-4-nitro iminazole derivatives
Prepared：
In above-mentioned syntheti c route epoxychloropropane include racemic epoxide chloropropane,（S）- epoxychloropropane,（R）- epoxychloropropane.
Above-claimed cpd 1 includes raceme, S configurations, R configurations.
Above-claimed cpd 2 includes raceme, S configurations, R configurations.
Above-claimed cpd 3 includes raceme, S configurations, R configurations.
The third object of the present invention is to provide a kind of composition of the noval chemical compound containing treatment effective dose.
The fourth object of the present invention is to provide the purposes that a kind of noval chemical compound of the present invention is treated in anaerobe resistant.
2- methyl -4- the nitro-derivatives of the present invention include hydrate, pharmaceutical salts, solvated compoundses.
The present invention 2- methyl -4- nitro-derivatives pharmaceutical salts include hydrochloride, oxalates, fumarate, sulfate,
Phosphate, succinate, sodium salt, sylvite, magnesium salts, calcium salt.
2- methyl -4- the nitro-derivatives of the present invention have isomers, and the present invention includes such isomers.
The compounds of this invention can be administered in a unit, and method of administration can be enteron aisle or non-bowel, such as oral, flesh
Meat, subcutaneous, nasal cavity.
The present invention compound method of administration can be intravenously administrable, including intravenous injection, intramuscular injection, hypodermic injection and
Acupoint injection therapy etc..
Form of administration can be tablet, capsule, dispersible tablet, oral liquid, big transfusion, small pin, freeze-dried powder etc. pharmaceutically
Acceptable preparation.
The compound of the present invention can be used for preventing, improve and/or curing disease caused by anaerobic infection, be particularly suitable for
For the chemotherapeutic activity compound as people and veterinary medicament.
The compound of the present invention is administered by gross weight, in an amount of from every kg body weight 0.5-1000mg, the consumption of best 24 hours
For every kg body weight 1-500mg, medication several times can be also used.
The present invention is described in further detail with reference to embodiment, but should preferable the scope of the present invention is non-is only limitted to this
The scope of a little embodiments.
The 1- of embodiment 1 [the chloro- 2- hydroxypropyls of 3-] -2- methyl-4-nitro iminazoles（Compound A）Preparation
2- methyl-4-nitro iminazole 10g are taken, adds after ethyl acetate 200ml dissolvings, adds aluminum trichloride (anhydrous) 10g, stir
Cooling, is cooled to 0 DEG C, and epoxychloropropane 20g is added dropwise, and reaction solution is slowly added to water reclaimed water by insulation reaction, reaction after terminating
Solution, separates ethyl acetate layer, ethyl acetate layer is extracted with 10% hydrochloric acid solution, and last sour water layer adjusts pH to 7 with ammoniacal liquor, there is solid
Body is separated out, Filtration Filtration, is dried, is obtained compound A 5.6g
Embodiment 2 (S)-[the chloro- 2- hydroxypropyls of 3-] -2- methyl-4-nitro iminazoles（Compound B）Preparation
Prepare as described in Example 1, the difference is that epoxychloropropane is replaced with into S- epoxychloropropane.
Embodiment 3 (R)-[the chloro- 2- hydroxypropyls of 3-] -2- methyl-4-nitro iminazoles（Compound C）Preparation
Prepare as described in Example 1, the difference is that epoxychloropropane is replaced with into R- epoxychloropropane.
The chloro- 1- of the 3- of embodiment 4 (2- methyl -4- nitro -1H- imidazoles -1- bases) propane -2- base phosphite esters（Compound
D）Preparation
Take compound A 10g to be dissolved into 50ml ethyl acetate, phosphorus trichloride 5g is added dropwise, controlling reaction temperature is at 10-20 DEG C, instead
After should finishing, ethyl acetate is recovered under reduced pressure, residue is slowly added into purified water 50ml, hydrolyzes 1 hour, is slowly added into 10% carbonic acid
Sodium solution regulation pH be 6.0, pressurization is concentrated to dryness, add methanol 100ml, filtering, freeze crystallization, filtering, compound D,
8.2g
Embodiment 5（S）The chloro- 1- of -3- (2- methyl -4- nitro -1H- imidazoles -1- bases) propane -2- base phosphite esters（Compound
E）Preparation
Prepare as described in Example 4, the difference is that compound A is replaced with into compound B.
Embodiment 6（R）The chloro- 1- of -3- (2- methyl -4- nitro -1H- imidazoles -1- bases) propane -2- base phosphite esters（Change
Compound F）Preparation
Prepare as described in Example 4, the difference is that compound A is replaced with into compound C.
The chloro- 1- of the 3- of embodiment 7 (2- methyl -4- nitro -1H- imidazoles -1- bases) propane -2- base phosphates（Compound G）
Preparation
Prepare as described in Example 4, the difference is that phosphorus trichloride is replaced with into POCl3.
Embodiment 8（S）The chloro- 1- of -3- (2- methyl -4- nitro -1H- imidazoles -1- bases) propane -2- base phosphates（Chemical combination
Thing H）Preparation
Prepare as described in Example 5, the difference is that phosphorus trichloride is replaced with into POCl3.
Embodiment 9（R）The chloro- 1- of -3- (2- methyl -4- nitro -1H- imidazoles -1- bases) propane -2- base phosphates（Chemical combination
Thing I）Preparation
Prepare as described in Example 6, the difference is that phosphorus trichloride is replaced with into POCl3.
Embodiment 10（S）The chloro- 1- of -3- (2- methyl -4- nitro -1H- imidazoles -1- bases) propane -2- bases phosphite ester two
Sodium（Compound J）Preparation
Compound E 10g are taken, are dissolved with 20ml ethanol, then pH is adjusted to 7.0 with the sodium hydroxide solution of saturation, -10 are cooled to
DEG C stirring and crystallizing, filtering, obtains compound J 8.8g.
Embodiment 11（S）The chloro- 1- of -3- (2- methyl -4- nitro -1H- imidazoles -1- bases) propane -2- base disodium phosphates
（Compound K）Preparation
Prepare as described in Example 10, the difference is that compound E is replaced with into compound H.
Embodiment 12（S）The chloro- 1- of -3- (2- methyl -4- nitro -1H- imidazoles -1- bases) propane -2- base phosphate dipotassiums
（Compound L）Preparation
Prepare as described in Example 11, the difference is that sodium hydroxide is replaced with into potassium hydroxide.
The preparation of the compound A pieces of embodiment 13
Prescription：
Compound A 150g
Starch 70g
Microcrystalline cellulose 125g
Magnesium stearate 2.0g
Hydroxypropyl methyl cellulose（4% solution）In right amount
It is made 1000
Preparation method：4% Gonak is prepared, it is standby.Weighing 10g starch, to put 105 DEG C of dry 5h standby.40g is taken to form sediment
Compound A, the microcrystalline cellulose of powder and recipe quantity, mix, crushed 80 mesh sieves.With 4% Gonak by thing
Material softwood processed, is pelletized with 20 mesh sieves, is 3% or so in the 50-60 DEG C of moisture dried into particle, is crossed at 20 mesh sieve whole grains, addition
Dried starch, the magnesium stearate of side's amount, it is mixed eventually, survey intermediates content, stator weight, tabletting.
The preparation of the compound A sodium chloride of embodiment 14 transfusion
Prescription：
Compound A 20g
Sodium chloride 85g
Water for injection 10L
It is made 100 bottles
Preparation method：The compound A and sodium chloride of recipe quantity, plus water for injection 10L are weighed, is stirred, 0.1% activated carbon, stirring is being added
15 minutes, 5 microns of so good support charcoals, through 0.45 micron of filter cartridge and 0,22 microns of miillpore filter refined filtration, filling and 100ml
In vial, 115 DEG C of steam sterilizing 30min obtain compound A sodium chloride injections.
The preparation of the compound B sodium chloride of embodiment 15 transfusion
Prescription：
Compound B 1000g
Sodium chloride 4.25kg
Water for injection 500L
It is made 5000 bottles
Preparation method：The compound B and sodium chloride of recipe quantity, plus water for injection 500L are weighed, is stirred, 0.1% activated carbon is being added, is stirring
Mix 15 minutes, 5 microns of so good support charcoals, through 0.45 micron of filter cartridge and 0,22 microns of miillpore filter refined filtration, it is filling with
In 100ml vials, 115 DEG C of steam sterilizing 60min obtain compound A sodium chloride injections.
The injection compound H of embodiment 16 preparation
Prescription：
Compound H 100g
Water for injection 400ml
It is made 200 bottles
Preparation method：The compound H of recipe quantity, plus water for injection 400ml are weighed, is stirred, 0.1% medical charcoal is being added, is stirring 15 points
Clock, 5 microns of so good support charcoals, through 0.45 micron of filter cartridge and 0,22 microns of miillpore filter refined filtration, filling control cillin bottle
In, place and freeze-drying 48 hours is carried out in vacuum freezing drying oven, be capped butyl rubber plug, and Zha Gai obtains its freeze-dried powder.
The compound and Ornidazole studies on acute toxicity result of the present invention of embodiment 17 is as follows：
Using Ornidazole as the anxious poison experiment of the mouse of comparison medicine
Mouse tail vein injection LD50
Ornidazole LD50：314mg/kg
Compound A LD50:532mg/kg LD50Average fiducial limit：532±53.2mg/kg
Compound B LD50:673mg/kg LD50Average fiducial limit：673±67.3mg/kg
Compound C LD50:412mg/kg LD50Average fiducial limit：412±41.2mg/kg
Compound D LD50:973mg/kg LD50Average fiducial limit：973±97.3mg/kg
Compound E LD50:1034mg/kg LD50Average fiducial limit：1034±103.4mg/kg
Compound F LD50:884mg/kg LD50Average fiducial limit：884±88.4mg/kg
Compound G LD50:992mg/kg LD50Average fiducial limit：992±99.2mg/kg
Compound H LD50:1012mg/kg LD50Average fiducial limit：1012±101.2mg/kg
Compound I LD50:825mg/kg LD50Average fiducial limit：825±82.5mg/kg
Experiment shows the toxicity of compound respectively less than Ornidazole of the present invention.
The compound of the present invention of embodiment 18 and Ornidazole antibacterial activity in vitro research, it is as a result as follows：
Experiment shows that the in-vitro antibacterial effect of the compounds of this invention is better than Ornidazole.
Claims (4)
1.2- methyl-4-nitro iminazole derivant structure formulas are as follows：
Wherein R1For hydroxyl, phosphorous acid ester group, phosphate-based.
2. 2- methyl-4-nitro iminazoles derivative according to claim 1, it is characterised in that also including pharmaceutically acceptable
Salt, such as hydrochloride, oxalates, fumarate, sulfate, phosphate, succinate, sodium salt, sylvite, magnesium salts, calcium salt.
3. a kind of pharmaceutical composition, it is characterised in that contain the compound conduct as described in claim 1,2 for the treatment of effective dose
Active component and pharmaceutically acceptable carrier.
4. pharmaceutical composition according to claim 3, it is characterised in that the medicine for producing treatment anti anaerobic bacteria infection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610181083.8A CN107235911A (en) | 2016-03-28 | 2016-03-28 | A kind of purposes of 2- methyl-4-nitro iminazoles derivative and preparation method thereof and Pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610181083.8A CN107235911A (en) | 2016-03-28 | 2016-03-28 | A kind of purposes of 2- methyl-4-nitro iminazoles derivative and preparation method thereof and Pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107235911A true CN107235911A (en) | 2017-10-10 |
Family
ID=59983126
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610181083.8A Pending CN107235911A (en) | 2016-03-28 | 2016-03-28 | A kind of purposes of 2- methyl-4-nitro iminazoles derivative and preparation method thereof and Pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107235911A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778364A (en) * | 2019-11-06 | 2021-05-11 | 华创合成制药股份有限公司 | Nitroimidazole derivative and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3280139A (en) * | 1962-04-06 | 1966-10-18 | Delmar Chem | Substituted nitroimidazoles |
| GB1099787A (en) * | 1965-05-19 | 1968-01-17 | Hoffmann La Roche | Novel nitro-imidazole derivatives and the manufacture thereof |
| CN100999500A (en) * | 2006-12-18 | 2007-07-18 | 西安新安医药科技有限公司 | Onitrodazole precursor drug and its preparation process and use |
| CN101177433A (en) * | 2007-12-05 | 2008-05-14 | 陕西新安医药科技有限公司 | (s)-ornidazole disodium phosphate pentahydrate as well as preparation method and uses thereof |
| CN102516298A (en) * | 2011-12-09 | 2012-06-27 | 陕西合成药业有限公司 | Stable pharmaceutical salt of L-aonitrate phosphate ester, its preparation method and application |
-
2016
- 2016-03-28 CN CN201610181083.8A patent/CN107235911A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3280139A (en) * | 1962-04-06 | 1966-10-18 | Delmar Chem | Substituted nitroimidazoles |
| GB1099787A (en) * | 1965-05-19 | 1968-01-17 | Hoffmann La Roche | Novel nitro-imidazole derivatives and the manufacture thereof |
| CN100999500A (en) * | 2006-12-18 | 2007-07-18 | 西安新安医药科技有限公司 | Onitrodazole precursor drug and its preparation process and use |
| CN101177433A (en) * | 2007-12-05 | 2008-05-14 | 陕西新安医药科技有限公司 | (s)-ornidazole disodium phosphate pentahydrate as well as preparation method and uses thereof |
| CN102516298A (en) * | 2011-12-09 | 2012-06-27 | 陕西合成药业有限公司 | Stable pharmaceutical salt of L-aonitrate phosphate ester, its preparation method and application |
Non-Patent Citations (4)
| Title |
|---|
| K NAGARAJAN ET AL.: "Nitroimidazoles, part XXIII-Activity of satranidazole series against anaerobic infections", 《INDIAN JOURNAL OF EXPERIMENTAL BIOLOGY》 * |
| SKUPIN, ROLF ET AL.,: "Lipase-catalyzed resolution of both enantiomers of ornidazole and some analogs", 《TETRAHEDRON: ASYMMETRY》 * |
| W. BONE ET AL.: "Toxicity of ornidazole and its analogs to rat spermatozoa as reflected in motility parameters", 《INTERNATIONAL JOURNAL OF ANDROLOGY》 * |
| 向明 等: "《药物毒理学（第3版）》", 31 August 2015, 中国医药科技出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778364A (en) * | 2019-11-06 | 2021-05-11 | 华创合成制药股份有限公司 | Nitroimidazole derivative and preparation method and application thereof |
| CN112778364B (en) * | 2019-11-06 | 2023-12-08 | 华创合成制药股份有限公司 | Nitroimidazole derivative and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102670497A (en) | Stable S-oxiracetam preparation for injection and preparation method of same | |
| CN1314396C (en) | Application of levoornidazole in preparation of anti anaerobic bacteria infection medicine | |
| CN100451023C (en) | Levo-ornidazole phosphate, preparing process and use thereof | |
| CN1915222B (en) | Composition of liposome, and preparation method | |
| CN101991589A (en) | Glycerol fructose injection and preparation method thereof | |
| CN102516298A (en) | Stable pharmaceutical salt of L-aonitrate phosphate ester, its preparation method and application | |
| CN101961311A (en) | 5alpha-androstane (alkyl)-3beta,5,6beta-triol injection and preparation method thereof | |
| CN102481287B (en) | Pharmaceutical composition of temozolomide comprising vitamin c or vitamin c derivative and preparation method thereof | |
| CN104844652A (en) | Isavuconazole phosphate ester, preparation method therefor and application thereof | |
| CN102247373B (en) | Composition of methionine vitamin B1 compound | |
| CN107235911A (en) | A kind of purposes of 2- methyl-4-nitro iminazoles derivative and preparation method thereof and Pharmaceutical composition | |
| CN107365272A (en) | A kind of novel imidazole class compound and preparation method thereof and application medically | |
| CN1803811A (en) | Nitro imidazole derivative, its preparation method and uses | |
| CN103214382B (en) | Meclofenoxate hydrochloride compound and pharmaceutical composition thereof | |
| CN103110640B (en) | Pharmaceutical composition of injection ceftizoxime sodium and compound amino acid injection | |
| CN1729988A (en) | Composite medicine of creatine phosphate sodium and magnesium salt | |
| CN106146558A (en) | New oxazolidinones and preparation method thereof | |
| CN104940135A (en) | Fluconazole injection and preparation method thereof | |
| CN112778363B (en) | Nitroimidazole derivative and preparation method and application thereof | |
| CN102008461B (en) | A kind of ibuprofen drug composite for injection | |
| CN107556304B (en) | Nitroimidazole medicine and preparation method and application thereof | |
| CN101302201A (en) | Nitroimidazole derivate for therapy | |
| CN102757471A (en) | Novel active cytidine disodium triphosphate compound and pharmaceutical composition thereof | |
| CN103330932B (en) | The pharmaceutical composition of a kind of MFG or its salt | |
| CN108003104A (en) | A kind of novel imidazole class compound and preparation method thereof and application medically |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: Room 30803, Haijia Yunding commercial and residential building, No.2, Gaogao Road, Gaoxin Sanxin District, Xi'an City, Shaanxi Province, 710000 Applicant after: Huachuang Synthetic Pharmaceutical Co.,Ltd. Address before: Room 30803, Haijia Yunding commercial and residential building, No.2, Gaogao Road, Gaoxin Sanxin District, Xi'an City, Shaanxi Province, 710000 Applicant before: SHAANXI SYNTHETIC PHARMACEUTICAL Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210309 Address after: Room 30803, Haijia Yunding commercial and residential building, No.2, Gaogao Road, Gaoxin Sanxin District, Xi'an City, Shaanxi Province, 710000 Applicant after: SHAANXI SYNTHETIC PHARMACEUTICAL Co.,Ltd. Address before: Room 30803, Haijia Yunding commercial and residential building, No.2, Gaoxin Third Road, Xi'an City, Shaanxi Province, 710075 Applicant before: SHAANXI SYNTHETIC PHARMACEUTICAL Co.,Ltd. Applicant before: JIANGSU TIANDIRENHE PHARMACEUTICAL Co.,Ltd. |
|
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20171010 |