CN105777635B - Isoquinolin -1,3- (2H, the 4H)-diketone and its preparation method and purposes of the substitution of group containing methyl isobutyrate - Google Patents
Isoquinolin -1,3- (2H, the 4H)-diketone and its preparation method and purposes of the substitution of group containing methyl isobutyrate Download PDFInfo
- Publication number
- CN105777635B CN105777635B CN201610244125.8A CN201610244125A CN105777635B CN 105777635 B CN105777635 B CN 105777635B CN 201610244125 A CN201610244125 A CN 201610244125A CN 105777635 B CN105777635 B CN 105777635B
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparation
- isoquinolin
- compound
- dimethyl
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a kind of isoquinolin 1,3 (2 of the group of dimethyl phthalate containing isobutylH,4H) dione compounds and its preparation method and purposes.The compound has such as formula（I）Shown structure, preparation method be withNMethacrylylNAlkylbenzamide is substrate, and azo-bis-iso-dimethyl is radical source, using cuprous iodide as catalyst, K3PO4As alkali, using DMF as solvent, reaction carries out under air environment, and reaction temperature is 90 degree, after reacting 5 hours, purifies to obtain through column chromatography or TLC separation.The higher inhibition of compound on prostate cancer cell 22RV cells shows, row gland cancer aspect shows extraordinary future to some acquired compounds before the treatment, this provides splendid opportunity for lead compound of discovery treatment prostate cancer.And synthetic reaction is easy to operate, reaction system is mild, and condition is simple, at low cost, and yield is high, has great application value.
Description
Technical field
The present invention relates to the isoquinolin -1,3- (2 of one kind group containing methyl isobutyrate substitutionH,4H)-cyclohexadione compounds and
Its preparation method and purposes.
Background technology
In numerous heterocyclic compounds, isoquinolines and its derivative are since its significant pharmacology and bioactivity are by people
Extensive concern.Several typical isoquinolin -1,3- (2 as described in chemical formula 1H,4H)-dione compounds, they show weight
Physiological activity is wanted, is such as eased pain, antitumor, HIV-I RT inhibitor, 5-HT3 receptor receptor antagonists etc..Therefore development itrile group takes
The isoquinolin -1,3 (2 in generationH,4H)-dione compounds synthetic method has important practice and theory value.
Chemical formula 1
So far, isoquinolin -1,3 (2 of the 2- groups of dimethyl phthalate containing isobutyl substitutionH,4H)-diketone synthetic method is still
It has not been reported, it has been found thatNDimethyl allene-NMethyl N-methacrylyl-N- alkylbenzamides are as in cuprous iodide
Azo-bis-iso-dimethyl will effectively be contained to isobutyl dimethyl phthalate group attack under mild conditions for the first time different under catalysis
Quinoline -1,3 (2H,4H)-diketone.This synthetic method is simple and convenient, and yield is high, using cheap copper as catalyst one step to form the loop,
Main By product is harmless nitrogen gas gas, shows " green " and " Atom economy " characteristic, therefore with high practical popularization
Value.And tested by tumor suppression, this very high inhibitory activity of compound on prostate cancer 22RV cells shows, for hair
The isobioquin group lead compound of existing anti-prostate tumor provides important opportunity.
Invention content
The present invention is exactly to overcome the deficiencies of the prior art and provide a kind of completely new to contain isobutyric acid with important biomolecule is active
The isoquinolin -1,3 (2 of methyl esters group substitutionH,4H)-dione compounds and preparation method thereof.
In order to realize the object of the invention, the present invention provides isoquinolin -1,3 (2 of the substitution of group containing methyl isobutyrateH,
4HThe synthetic route of)-dione compounds, structural formula are shown below：
The isoquinolin -1,3 (2 of the above-mentioned group containing methyl isobutyrateH,4HThe preparation method of)-dione compounds is as follows：
WithNMethacrylyl-NAlkylbenzamide class compound is substrate, using cuprous iodide as catalyst, K3PO4
As alkali, with DMF (N,NDimethylformamide) it is used as solvent, reaction to be carried out under air environment, reaction temperature is 90 degree,
After reaction 5 hours, synthesize to obtain product by concatenated free radical addition/C-H cyclization processes（I）, reaction equation is as follows：
R in reaction formula1,R2Can be shown in following each group：
1: R1 = H, R2 = n-Bu
2: R1 = H, R2 = i-Pr
3: R1 = 4-CF3, R2 = n-Bu
4: R1 = 4-SMe, R2 = i-Pr
5: R1 = 4-F, R2 = n-Bu
6: R1 = 4-Me, R2 = n-Bu
7: R1 = 4-Me, R2 = CH2Ph
8: R1 = 2-pyridyl, R2 = n-Bu
9: R1 = 2-Me, R2 = i-Pr
10: R1 = 4-Br, R2 = n-Bu
11: R1 = 4-OMe, R2 = i-Pr
12: R1 = 3-Cl, R2 = n-Bu
13: R1 = 3-CO2Et, R2 = Me
Catalyst in above-mentioned reaction is cuprous iodide, K3PO4As alkali, with DMF (N,NDimethylformamide) conduct
Solvent carries out in the environment of air, and reaction temperature is 90 degree, and after reaction plus ethyl acetate extracts, then with saturation food
Salt is washed, collected organic layer, through drying, concentration, column chromatography（Or thin-layer chromatography）Obtain reaction product.
The isoquinolin -1,3 (2 for the substitution of group containing methyl isobutyrate that the present invention obtainsH,4H)-dione compounds are to forefront
Gland cancer 22RV cells also have preferable inhibitory activity, and new choosing is provided for the development and application of drugs for prostate cancer
It selects, and preparation method has operation simple, reaction system is mild, and condition is simple, at low cost, and yield is high, has great
Application value.
Specific implementation mode
Below in conjunction with specific embodiment, the present invention is further illustrated
Material synthesis
Reaction raw materialsNIsobutyryl-NButyl benzamide compound（B）Preparation, can be passed through by chlorobenzoyl chloride such as chemical
Two simple synthesis steps shown in formula 1 obtain, and also can directly buy.
Chemical formula 1
Step 1：
Chlorobenzoyl chloride is added in 100 mL round-bottomed flasks（10 mmol）With 10 mL of dry methylene chloride, then this is mixed
It closes object and the triethylamine for being dissolved in a small amount of dry methylene chloride is added under condition of ice bath（18 mmol, 1.8 eq）It is equally dissolved in few
Measure a n-butylamine of dry methylene chloride（10 mmol, 1 eq）5 min are stirred, ice bath is removed and then react 2-6 at room temperature
h.Mixture is washed through saturated common salt, filtering, and crude product is obtained after filtrate is distilled off.With ethyl acetate and petroleum ether（v:v =
1:10）For eluent, intermediate benzoyl butylamine C is detached to obtain using column chromatography.
Step 2：
Then α-methacrylic acid is added in another 100 mL round-bottomed flask（10 mmol）With dry methylene chloride 10
Then mL is slowly added into and is dissolved in 5-8 mL dry methylene chloride equivalents of oxalyl chloride（12.5 mmol, 1.25 eq）, 3-5 drops are added
DMF, then in unlimited system normal-temperature reaction 1-2 h.After having reacted, add into the mixture obtained by reaction under condition of ice bath
Enter the triethylamine for being dissolved in a small amount of dry methylene chloride（18 mmol, 1.8 eq）, intermediate benzoyl obtained by previous step is then added
Butylamine C increases temperature to room temperature the reaction was continued 3-8 h.After reaction, ethyl acetate is added, then salt is utilized to wash, water
Mutually it is extracted with ethyl acetate again.Organic phase is collected, dry, concentration detaches to obtain product using column chromatographyNButyl-NDiformazan
- 4 propylene N- methacrylyl-N- alkylbenzamides of base, weak yellow liquid, yield 78%.
The structure of wherein product be according to the nuclear-magnetism of product (1H NMR and13C NMR) data determine compared to relatively.
Compound A structure characterizes：1H NMR (400 MHz, CDCl3) δ: 8.05 (d, J = 7.9 Hz, 2H),
7.70 (t,J = 7.5 Hz, 1H), 7.66 (t, J = 7.6 Hz, 2H),5.79 (s, 1H), 5.70 (s, 1H),
4.12 (m,2H), 1.98 (s, 3H), 1.56 (s, 2H), 1.31 (m, 2H), 0.90 (t, J = 7.3Hz,
3H), 13C NMR (101 MHz, CDCl3) δ: 172.4, 164.5, 141.4, 134.2, 131.3, 128.8,
127.5,124.8,118.1,41.8,29.5,19.8,19.5,13.8;; HRMSm/z (EI) calcd
forC15H20NO2 [M]+ 246.1489, found: 246.1492.
According to the preparation method in above-described embodiment, can also equally prepare followingNIso-propionyl-NAlkyl benzoyl
Amine derivative（II）, reaction formula is as follows：
R in reaction formula1, R2Can be shown in following each group：
1: R1 = H, R2 = n-Bu
2: R1 = H, R2 = i-Pr
3: R1 = 4-CF3, R2 = n-Bu
4: R1 = 4-SMe, R2 = i-Pr
5: R1 = 4-F, R2 = n-Bu
6: R1 = 4-Me, R2 = n-Bu
7: R1 = 4-Me, R2 = CH2Ph
8: R1 = 2-pyridyl, R2 = n-Bu
9: R1 = 2-Me, R2 = i-Pr
10: R1 = 4-Br, R2 = n-Bu
11: R1 = 4-OMe, R2 = i-Pr
12: R1 = 3-Cl, R2 = n-Bu
13: R1 = 3-CO2Et, R2 = Me
It is prepared by target product A
The isoquinolin -1,3 (2 of target product group containing methyl isobutyrate substitution provided by the inventionH,4H)-diketone chemical combination
Object（I）Preparation method, with 3-（2,4- dimethyl -1,3- dioxies -1,2,3,4- tetrahydro isoquinolyls）2,2-Dimethylpropionic acid
For the preparation of methyl esters (A) (A)
It is sequentially added in reaction tubeNDimethyl allene-NMethyl benzamide (1.0 mmol), two isobutyric acid of azo
Dimethyl（4 mmol, 4 equiv）, cuprous iodide (0.2 mmol, 20 mol%）, K3PO4 (2.0 mmol, 2 equiv),
Add DMF (5.0 mL) to be used as solvent, is put into 90 degree of oil bath pan and reacts in air, after reaction (usual 5 h)
Afterwards, ethyl acetate is added, then salt is utilized to wash, water phase is extracted with ethyl acetate again.Organic phase is collected, dry, concentration, profit
Product 3- is detached to obtain with column chromatography（2,4- dimethyl -1,3- dioxies -1,2,3,4- tetrahydro isoquinolyls）- 2,2- dimethyl propylene
Sour methyl esters (A), weak yellow liquid, yield 92%.
Structural characterization：1H NMR (400 MHz, CDCl3) δ: 8.26 (d, J = 7.9 Hz, 1H), 7.64 –
7.55 (m, 1H), 7.41 (dd, J = 17.3, 7.8 Hz, 2H), 3.39 (s, 3H), 3.21 (s, 3H),
2.69 (d, J = 14.6 Hz, 1H), 2.56 (d, J = 14.6 Hz, 1H), 1.58 (s, 3H), 0.98 (s,
3H), 0.91 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 176.9, 176.3, 164.2, 142.0,
133.1, 129.0, 127.4, 126.7, 124.7, 51.6, 51.1, 45.9, 41.6, 33.5, 28.6, 27.2,
23.7; HRMS m/z (ESI) calcd for C17H22NO4 [M+H]+ 304.1544, found: 304.1545.
According to the preparation method in above-described embodiment, the isoquinoline of the group containing methyl isobutyrate below can also be equally prepared
Quinoline -1,3 (2H,4H)-dione compounds（I）, the general formula of reaction is as follows：
R in reaction formula1,R2Can be shown in following each group：
1: R1 = H, R2 = n-Bu
2: R1 = H, R2 = i-Pr
3: R1 = 4-CF3, R2 = n-Bu
4: R1 = 4-SMe, R2 = i-Pr
5: R1 = 4-F, R2 = n-Bu
6: R1 = 4-Me, R2 = n-Bu
7: R1 = 4-Me, R2 = CH2Ph
8: R1 = 2-pyridyl, R2 = n-Bu
9: R1 = 2-Me, R2 = i-Pr
10: R1 = 4-Br, R2 = n-Bu
11: R1 = 4-OMe, R2 = i-Pr
12: R1 = 3-Cl, R2 = n-Bu
13: R1 = 3-CO2Et, R2 = Me
As can be seen that isoquinolin -1,3 of the substitution of group containing methyl isobutyrate of the present invention from the above specific implementation mode
(2H,4H)-dione compounds（I）Preparation method has operation simple, and using cheap copper catalyst, reaction condition is mild,
Condition is simple, at low cost, and yield is high, can prepare isoquinolin -1,3 (2 of a variety of substitutions of group containing methyl isobutyrateH,4H)-two
Ketone derivatives have great application value.
Comparative example 1
It is sequentially added in reaction tubeNButyl-NDimethyl allene benzamide (1.0 mmol), trifluoromethane sulfonic acid
（1.0 equiv）, using dichloromethane (5.0 mL) as solvent, 10 h are reacted under 50 degree of temperature conditions.After reaction,
Ethyl acetate is added, then salt is utilized to wash, water phase is extracted with ethyl acetate again.Organic phase is collected, it is dry, it concentrates, utilizes
Column chromatography detaches to obtain product 2- butyl -4,4- dimethyl-isoquinolin -1,3 (2H,4H)-diketone (D), white solid, production
Rate 49%.
Compound D structural characterizations, white solid object:1H NMR (400 MHz, CDCl3) δ: 8.30 (dd, J
= 7.9, 1.2 Hz, 1H), 7.68 (m, 1H), 7.50 (td, J = 8.0, 1.1 Hz, 1H), 7.43 (d, J
= 7.9 Hz, 1H), 4.11 – 3.94 (m, 2H), 1.69（s, 3H）, 1.67 (s, 3H), 1.61 (m, 2H),
1.41 (dq, J = 14.8, 7.4 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H); HRMS m/z (ESI)
calcd for C16H19F3NO2 [M+H]+ 245.1411, found: 245.1413.
Tumor suppression is tested：
Select exponential phase adherent prostate cancer 22RV cells and liver cancer Hep3B cells, after being digested with pancreatin, with containing
The RPMIl640 culture mediums of 10% calf serum are made into the cell suspension of 5000/ml, are seeded in 96 well culture plates
In, often
Hole inoculation 100 μ l, 37 degree, 5% CO2Culture to cell monolayer is paved with bottom hole.
The culture medium for the embodiment sample containing various concentration that experimental group renews, control group then change the culture containing isometric solvent
Base, every group sets 3~5 parallel holes, 37 degree, 5% CO2Cultivate 4~5d.
Liquid is discarded supernatant, the serum free medium of the MTT containing 0.2mg/ml of 100 μ l Fresh is added per hole.37 degree
Continue to cultivate 4h.It is careful to abandon supernatant, and 100 μ l DMSO are added, after miniature ultrasonic oscillator mixing, in enzyme mark
With tested wavelength it is 570nm on instrument, reference wavelength is that 450nm measures OD value.
Inhibiting rate of the drug to growth of tumour cell is calculated as follows：
Growth of tumour cell inhibiting rate %=(1-OD experiments/OD controls) × 100%
Dose-effect curve, Cong Zhongqiu can be obtained to the mapping of growth of tumour cell inhibiting rate with the various concentration of same sample
Go out the half casualty-producing concentrations IC of sample50。
Table 1 is the IC of some compound on prostate cancer 22RV cells of the invention50Value：
Table 1
| Compound | IC50(μg/ml) |
| 3 | 21.0 |
| 4 | 31.9 |
| 9 | 16.1 |
| 13 | 7.2 |
| Comparative example 1 | 87.6 |
Table 2 is IC of some compounds of the invention to liver cancer Hep3B cells50Value：
Table 2
| Compound | IC50(μg/ml) |
| 3 | 41.2 |
| 4 | 52.7 |
| 9 | 27.0 |
| 13 | 59.5 |
| Comparative example 1 | 113.2 |
From the above, it can be seen that the compound of the present invention has significant inhibition to prostate cancer 22RV cells.
Above-mentioned only presently preferred embodiments of the present invention, is not intended to limit the present invention in any form.It is any to be familiar with sheet
The technical staff in field, without deviating from the scope of the technical scheme of the present invention, all using the technology contents of the disclosure above
Many possible changes and modifications are made to technical solution of the present invention, or are revised as the equivalent embodiment of equivalent variations.Therefore, all
It is the content without departing from technical solution of the present invention, technical spirit is made to the above embodiment according to the present invention any simply repaiies
Change, equivalent variations and modification, all shall fall within the protection scope of the technical scheme of the invention.
Claims (1)
1. application of the compound with structure as follows in preparing antiprostate cancer：
Wherein, R1For H, 4-Cl, 4-F, 4-Me, 4-SMe, 4-CF3, 4-OMe, 4-Br, 3-Cl, 3-CO2Et, 2-
Any one in pyridyl, 2-Me, R2Forn-Bu, i-Pr, -Me, -CH2Ph, -CH2CO2Any one in Et.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610244125.8A CN105777635B (en) | 2016-04-19 | 2016-04-19 | Isoquinolin -1,3- (2H, the 4H)-diketone and its preparation method and purposes of the substitution of group containing methyl isobutyrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610244125.8A CN105777635B (en) | 2016-04-19 | 2016-04-19 | Isoquinolin -1,3- (2H, the 4H)-diketone and its preparation method and purposes of the substitution of group containing methyl isobutyrate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105777635A CN105777635A (en) | 2016-07-20 |
| CN105777635B true CN105777635B (en) | 2018-10-16 |
Family
ID=56396841
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610244125.8A Expired - Fee Related CN105777635B (en) | 2016-04-19 | 2016-04-19 | Isoquinolin -1,3- (2H, the 4H)-diketone and its preparation method and purposes of the substitution of group containing methyl isobutyrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105777635B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153030A (en) * | 2015-10-14 | 2015-12-16 | 吉首大学 | Perfluoro group substituted isoquinoline-1,3(2H,4H)-diketone as well as preparation method and application thereof |
-
2016
- 2016-04-19 CN CN201610244125.8A patent/CN105777635B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153030A (en) * | 2015-10-14 | 2015-12-16 | 吉首大学 | Perfluoro group substituted isoquinoline-1,3(2H,4H)-diketone as well as preparation method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| 2-芳基-1,3-异喹啉二酮类抗肿瘤化合物的设计、合成和抗肿瘤活性;康博瑞,等.;《2011年全国药物化学学术会议——药物的源头创新》;20111119;第349页 * |
| Aerobic oxidative cyclization of benzamides via meta-selective C–H tert-alkylation: rapid entry to 7-alkylated isoquinolinediones;Shi Tang, et al.;《Chem.Commun.》;20160210;第52卷;第4471页Table 1 * |
| 连续的Ugi多组分/成环反应合成异喹啉-1,3（2H,4H）-二酮;袁玎,等.;《中国化学会第九届全国有机化学学术会议论文摘要集(3)》;20150728;第292页 * |
| 铱（Ⅲ）和碘单质催化的异喹啉、异吲哚啉酮类化合物合成方法研究;陈丹.;《中国优秀硕士学位论文全文数据库·工程科技I辑》;20120715;全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105777635A (en) | 2016-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105622607A (en) | Furazan NO donor type evodiamine derivatives with anti-tumor activity | |
| CN104292170B (en) | There is quinazoline-Arylurea derivatives and the application thereof of antitumor action | |
| CN105017259A (en) | Trifluoromethyl containing quinazoline derivative and preparation method and application thereof | |
| CN104072493A (en) | Naphthalimide compound containing 2-mercaptobenzothiazole and triazole heterocycle, preparation method and application thereof | |
| CN106632379B (en) | A kind of Bergenin azepine cinnamate derivative compound and its synthetic method having anti-tumor activity | |
| CN103554122B (en) | A kind of containing chromone structure pyrazoles norcantharidin derivative and preparation method thereof and application | |
| CN105153030B (en) | (2H, the 4H) diketone of isoquinolin 1,3 and its preparation method and purposes of full-fluorine group substitution | |
| CN106810560B (en) | A kind of synthetic method of 8- azepine cumarin and its application in anti-tumor drug | |
| CN104761482B (en) | 3 (2,2 dimethyl) third cyano group 3 alkane (virtue) base indolones and preparation method thereof | |
| CN103922992A (en) | Anti-cancer active indolone derivate as well as synthesis method and application thereof | |
| CN105777635B (en) | Isoquinolin -1,3- (2H, the 4H)-diketone and its preparation method and purposes of the substitution of group containing methyl isobutyrate | |
| CN105859618B (en) | (2H, the 4H) diketone of isoquinolin 1,3 and its preparation method and purposes of the nitrile group containing cycloalkyl | |
| CN108997341B (en) | Amide-troger's base derivative and its synthesis method and use | |
| CN105622507A (en) | Naphthalimide derivative and preparing method and application thereof | |
| CN110128343A (en) | A kind of hydrazide kind compound | |
| CN105646546A (en) | Acid-sensitive camptothecin-20-position ester derivative and antineoplastic application thereof | |
| CN103172575A (en) | Preparation method of one-class 1,3-dipole quinazoline compound | |
| CN113072481B (en) | Indolo-cyclobutane skeleton compound, synthesis method and application | |
| CN111646937B (en) | Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof | |
| CN107163028A (en) | A kind of benzamides Hedgehog inhibitor and its preparation method and application | |
| CN110511197A (en) | A kind of N- furanonyl arylsulfonyl hydrazone compounds and its synthetic method and application | |
| CN105566270B (en) | 3 aryl-coumarin derivatives and preparation method thereof | |
| CN105130896B (en) | The naphthalimide derivative of a kind of substituent containing thiocarbamide, its preparation method and application | |
| CN104530072A (en) | Bromo-norcantharidin mono-methyl ester, as well as synthesizing method and application thereof | |
| CN110256423A (en) | A method of preparing 3- bis- bromomethyl class imidazo [1,2- α] pyridine derivate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181016 Termination date: 20190419 |