CN1752087A - Adenine kind derivative and its synthesis method - Google Patents
Adenine kind derivative and its synthesis method Download PDFInfo
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- CN1752087A CN1752087A CN 200510031042 CN200510031042A CN1752087A CN 1752087 A CN1752087 A CN 1752087A CN 200510031042 CN200510031042 CN 200510031042 CN 200510031042 A CN200510031042 A CN 200510031042A CN 1752087 A CN1752087 A CN 1752087A
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Abstract
An adenine derivative series is prepared from bromobenze with borate radical through Dimroth rearranging reaction. Its advantage is high activity to suppress proinflammatory factor (tumor necrosis factor alpha) and splitting cell.
Description
Technical field
The present invention relates to a kind of adenine derivative and preparation method thereof.
Background technology
VITAMIN B4 is that people are known to one of vital organic compound of life.It is by pyrimidine and imidazole ring and closes the also member ring systems that forms that its chemical structure is as follows:
VITAMIN B4 is as one of important component part of Yeast Nucleic Acid (RNA) and thymus nucleic acid (DNA) structure.Their character and reactivity worth have significant effects to the character and the physiological function of nucleic acid.VITAMIN B4 still is the main moiety of Triphosaden (ATP) structure, and biological organism is played crucial effects, so VITAMIN B4 and its derivative and active research are subjected to the great attention of scientists.Wherein study maximum N that has
6-position replaces, N
9-position replaces and N
9, N
6The derivative of the two substituted adenines in-position.
But, above-mentioned disclosed N
6-position replaces, N
9-position replaces and N
9, N
6The derivative of the two substituted adenines in-position, exist a significant defective, its biological activity is low, the raw material sources difficulty, complicated process of preparation, can not satisfy the needs of relevant field development, it is raw material that prior art adopts 6-chloropurine and benzylamine more, and synthetic route is loaded down with trivial details, and toxicity is bigger, bring very big harm can for synthetic personnel itself, and the present invention to adopt the bromobenzyl of band boronate be raw material, use the DImroth rearrangement reaction, simple to operate, and toxicity is little, can not bring harm to the person, at present, various inflammatory diseases are having a strong impact on people's health, therefore, people expect to have the derivative of more new VITAMIN B4, to satisfy the needs along with the development of medical field.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of adenine kind derivative and synthetic method thereof, to overcome the above-mentioned defective that prior art exists, satisfy the needs of relevant field development.
The general structure of adenine kind derivative of the present invention is as follows:
Wherein:
R1 represents hydrogen atom;
R2 represents benzyl or 2,3,4-boronate benzyl;
R3 represents 2,3,4-boronate benzyl;
Preferred adenine kind derivative is:
N
9-(2-boronate) benzyladenine,
N
9-(3-boronate) benzyladenine,
N
9-(4-boronate) benzyladenine,
N
9-benzyl-N
6-(2-boronate) benzyladenine,
N
9-benzyl-N
6-(3-boronate) benzyladenine or
N
9-benzyl-N
6-(4-boronate) benzyladenine.
The preparation method of adenine kind derivative of the present invention comprises the steps:
VITAMIN B4, Anhydrous potassium carbonate are added N, in the dinethylformamide, obtain suspension, under 100～140 ℃, will be dissolved with the N of n-bromomethyl benzene boric acid, dinethylformamide solution, join in the suspension, back flow reaction 12～16 hours is collected target product then from reaction product.
Wherein: n=2,3 or 4;
Or comprise the steps:
9-benzyladenine, 2-bromomethyl benzene boric acid are dissolved in N, and in the dinethylformamide, 30～40 ℃ were reacted 65～80 hours, and collected target product then from reaction product.
Or comprise the steps:
The 9-benzyladenine is dissolved in N, in the dinethylformamide, adds 430mg (2mmol) 4-bromomethyl benzene boric acid, 30～40 ℃ were reacted 55～65 hours, and collected target product then from reaction product.
Adenine kind derivative of the present invention has higher biological activity, can be used for improving cytokine activity, thereby can improve the cytokine activity of plant, to improve the anti-inflammatory activity of animal.
Said adenine kind derivative is carried out biological activity detect, the result shows: compare more that plant cotyledon chlorophyll content increases with n cell mitogen 6-benzyladenine (BA).Its data see Table:
The new compound of various concentration and BA handle back cucumber cotyledons chlorophyll relative content
| Concentration (M) | D/D 0 | ||||||
| BA | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | |
| 10 -5 | 2.40 | 2.45 | 2.46 | 2.42 | 2.10 | 2.60 | 2.52 |
| 10 -6 | 2.29 | 2.31 | 2.33 | 2.30 | 2.30 | 2.41 | 2.34 |
| 10 -7 | 1.41 | 1.55 | 1.58 | 1.50 | 1.50 | 1.71 | 1.45 |
| 10 -8 | 1.12 | 1.16 | 1.21 | 1.18 | 1.22 | 1.37 | 1.27 |
| Blank | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
Said adenine kind derivative is carried out the test of animal anti-inflammatory activity, and the result shows: the present invention has stronger anti-inflammatory activity, and its detected result sees the following form:
Compound influences Turnover of Mouse Peritoneal Macrophages TNF α excretory
| Optical density O.D. value | Inhibiting rate % | |
| Blank | 0.669±0.041 | |
| LPS(2.5mg/ml) | 0.181±0.016 | |
| Example 1 | 0.197±0.003 | 13.2 |
| Example 2 | 0.360±0.005 *** | 36.6 |
| Example 3 | 0.333±0.017 *** | 31.0 |
| Example 4 | 0.237±0.006 ** | 11.5 |
| Example 5 | 0.329±0.044 ** | 30.0 |
| Example 6 | 0.230±0.049 | 10.0 |
By above-mentioned disclosed technical scheme as seen, adenine kind derivative of the present invention, the biological activity height, preparation is easy to industrializing implementation easily, can satisfy the needs of relevant department's development.
Embodiment
Embodiment 1
N
9Synthesizing of-(2-boronate) benzyladenine:
VITAMIN B4 with 270mg (2mmol), 300mg (2.15mmol) Anhydrous potassium carbonate joins among the new DMF that steams of 5ml, form suspension, stir down the suspension oil bath is heated to 120 ℃, in 60 minutes, 5ml is dissolved with the DMF solution of 515.5mg (2.4mmol) 2-bromomethyl benzene boric acid, dropwise join in the mixed solution, refluxed 14 hours, along with the carrying out of reaction, the suspension color deepens gradually, is drabon look at last, filtered while hot, dry DMF 10ml with heat divides washing for several times, merging filtrate, 45 ℃ of pressure reducing and steaming DMF, dissolve enriched material with small amount of methanol, thin-layer chromatography separate product, productive rate is 35.0% (developping agent is a methylene dichloride: methyl alcohol=8: 1, volume ratio).Physical property data sees Table 1, IR, H
1NMR and MS data see Table 2.
Embodiment 2
N
9Synthesizing of-(3-boronate) benzyladenine:
VITAMIN B4 with 270mg (2mmol), 300mg (2.15mmol) Anhydrous potassium carbonate joins among the new DMF that steams of 5ml, form suspension, stir down the suspension oil bath is heated to 120 ℃, in 60 minutes, 5ml is dissolved with the DMF solution of 515.5mg (2.4mmol) 3-bromomethyl benzene boric acid, dropwise join in the mixed solution, refluxed 14 hours, along with the carrying out of reaction, the suspension color deepens gradually, is drabon look at last, filtered while hot, dry DMF 10ml with heat divides washing for several times, merging filtrate, 45 ℃ of pressure reducing and steaming DMF, dissolve enriched material with small amount of methanol, thin-layer chromatography separate product, productive rate is 42.5% (developping agent is a methylene dichloride: methyl alcohol=8: 1, volume ratio).
Physical property data sees Table 1, IR, H
1NMR and MS data see Table 2.
Embodiment 3
N
9Synthesizing of-(4-boronate) benzyladenine
VITAMIN B4 with 270mg (2mmol), 300mg (2.15mmol) Anhydrous potassium carbonate joins among the new DMF that steams of 5ml, form suspension, stir down suspension is heated to 120 ℃, in 60 minutes, 5ml is dissolved with the DMF solution of 515.5mg (2.4mmol) 4-bromomethyl benzene boric acid, dropwise join in the mixed solution, refluxed 14 hours, along with the carrying out of reaction, the suspension color deepens gradually, be drabon look at last, occur a large amount of precipitations simultaneously, filtered while hot is with the dry DMF 10ml branch washing for several times of heat, last throw out wash with water white mass, drying is 1 hour in vacuum drying oven, gets the white granular material with recrystallizing methanol, and productive rate is: 46.1%.Physical property data sees Table 1, IR, H
1NMR and MS data see Table 2.
Embodiment 4
N
9-benzyl-N
6Synthesizing of-(2-boronate) benzyladenine:
With 225mg (1mmol) 9-benzyladenine, 430mg (2mmol) 2-bromomethyl benzene boric acid is dissolved among the new DMF that steams of 6ml, 35 ℃ of reactions of oil bath are after 72 hours, 45 ℃ of pressure reducing and steaming DMF, get the syrupy shape material, get white solid with the exsiccant washed with dichloromethane, drying is after 1 hour under infrared lamp, it is dissolved in 5ml is dissolved with in the 0.001M hydrochloric acid methanol, dropping ammonia transfers pH value between the 10-12,90 ℃ of reactions of oil bath 3 hours, reaction solution is cooled to room temperature and separates out white solid, filter, with distilled water flushing several times, in vacuum drying oven, did 2 hours, the a spot of dissolve with methanol of gained solid, (developping agent is CH in the thin-layer chromatography separation
2Cl
2: CH
3OH=8: 1, volume ratio), productive rate is 32.2%
Physical property data sees Table 1, IR, H
1NMR and MS data see Table 2.
Embodiment 5
N
9-benzyl-N
6Synthesizing of-(3-boronate) benzyladenine
With the 2-boronate cylite among the 3-boronate cylite replacement embodiment 5, synthetic method is with embodiment 4.Productive rate is: 37.5%
Physical property data sees Table 1, IR, H
1NMR and MS data see Table 2.
Embodiment 6
N
9-benzyl-N
6Synthesizing of-(4-boronate) benzyladenine:
225mg (1mmol) 9-benzyladenine is dissolved among the new DMF that steams of 6ml, outer bath adds 430mg (2mmol) 4-bromomethyl benzene boric acids for 35 ℃, after 60 hours, 45 ℃ of pressure reducing and steaming DMF get the syrupy shape material in reaction under this temperature, use the exsiccant washed with dichloromethane, get white solid matter, under infrared lamp, after dry 1 hour, it is dissolved in 5ml is dissolved with in the 0.001M hydrochloric acid methanol, splash into strong aqua and transfer pH value to 11,90 ℃ of stirring reactions of oil bath 3 hours.In reaction process, constantly add strong aqua, its pH value is remained between the 10-12, behind the stopped reaction, pressure reducing and steaming CH
3OH and unnecessary NH
3, separate out solid during the residue less water, filter, use distilled water wash three times, drying is 2 hours in vacuum drying oven, a spot of dissolve with methanol of gained solid, (developping agent is CH in the thin-layer chromatography separation
2Cl
2: CH
3OH=8: 1), productive rate is 43.5%.
Physical property data sees Table 1, IR, H
1NMR and MS data see Table 2.
Table 1
| Compound | Molecular formula | State | Fusing point (℃) | Productive rate (%) |
| Embodiment 1 | C 12H 12BN 5O 2 | White solid | 199-201 | 35.0 |
| Embodiment 2 | C 12H 12BN 5O 2 | White solid | 156-157 | 42.5 |
| Embodiment 3 | C 12H 12BN 5O 2 | White solid | 154-155 | 46.1 |
| Embodiment 4 | C 19H 18BN 5O 2 | White solid | 261-262 | 32.2 |
| Embodiment 5 | C 19H 18BN 5O 2 | White solid | 256-257 | 37.5 |
| Embodiment 6 | C 19H 18BN 5O 2 | White solid | 209-210 | 43.5 |
Table 2
| Compound | 1HNMR(DMSO or CH 3OD，TMS)δppm | IR(υcm -1) | MS(m/z) |
| Embodiment 1 | 5.51(s，2H，N 9-CH 2)； 7.37-7.75(m，4H)；8.00(s，1H，2-H)； 8.00(br s，1H，B(OH)；8.56(s，1H，8-H). | 3324(NH)，1659(C-N)， 1329(B-O)，740. | 269(M +) |
| Embodiment 2 | 5.46(s，2H，N 9-CH 2)； 7.26-7.59(m，4H)；8.15(s，1H，2-H)； 8.41(s，1H，8-H). | 3435(NH)，1650(C-N)， 1338(B＝O)，780，712 | 269(M +) |
| Embodiment 3 | 5.36(s，2H，N 9-CH 2)；7.25(s，2H，-NH 2)； 7.23(d，2H)；7.71(s，2H，)； 8.13(s，1H，2-H)；8.24(s，1H，8-H). | 3472(NH)，1638(C-N)， 1325(B-O)，796. | 269(M +) |
| Embodiment 4 | 5.36(s，4H，N 6-CH2，N 9-CH2)； 7.23-7.33(m，9H)； 8.14(s，1H，2-H)；8.25(s，1H，8-H)； | 3435(NH)，1645(C-N)， 1324(B-O)，733， | 359(M +) |
| Embodiment 5 | 4.70(s，2H，N 6-CH 2)；5.37(S，2H，N 9-CH 2)； 7.21-7.37(m，7H)；7.61(d，1H)； 8.03(s，2H B-OH)；8.20(s，2H，2-H)； 8.24(s，1H，8-H)；8.27(s，1H，-NH) | 3400(NH)，1621(C-N)， 1335(B-O)，794，724 | 359(M +) |
| Embodiment 6 | 4.70(s，2H，N 6-CH 2)；5.38(s，2H，N 9-CH)； 7.21-7.37(m，7H)；7.70(d，2H)； 8.01(s，2H B-OH)；8.19(s，1H，2-H)； 8.29(s，1H，8-H)；8.34(br s，1H，-NH) | 3436(NH)，1641(C-N)， 1338(B-O)，733 | 359(M +) |
Embodiment 8
Bioactive test:
Select for use respectively embodiment 1～6 compound under various concentration to the influence of cucumber cotyledons chlorophyll relative content, investigate its cytokine activity.Its test process is as follows:
The compound of embodiment (1)-(6) is dissolved in respectively among a small amount of DMSO (methyl-sulphoxide), and adding distil water stepwise dilution to concentration is 1 * 10
-5, 1 * 10
-6, 1 * 10
-7, 1 * 10
-8The sample solution of mol/L calculates DMSO content in each sample (control DMSO concentration≤1%).
The cucumber seeds cultivation on vermiculite power, is sprouted in 27 ℃ of dark, and 5 days cotyledon of clip is 5 pairs under sap green light, and (W weighs
1), put into the glass culture dish with cover that diameter 6cm contains the 5mL sample solution (with same DMSO content but the solvent that does not contain sample compare, be blank with water), in 27 ℃ of dark, cultivate 24hr., remove the culture dish lid, illumination 3hr. (fluorescent lamp), every group of cotyledon blotted with filter paper, and (W weighs
2), calculate rate of body weight gain, leached 24 hours in dark with 10mL 95% acetone-ethanolic soln [acetone-ethanol solution adding distil water with 2: 1 (v/v) is made into], make blank, use the absorbancy of UV755B spectrophotometric determination supernatant liquor with 95% acetone-ethanolic soln at 663 μ m and 645 μ m, utilize the Arnon formula to calculate chlorophyll concentration in the extraction liquid, be scaled the chlorophyll content in the cotyledon.
The concentration of chlorophyll a (mg/l): Ca=12.7A
663-2.69A
645
The concentration of chlorophyll b (mg/l): Cb=22.9A
645-4.68A
663
Chlorophyll total concn (mg/l): C=Ca+Cb
W1----cucumber cotyledons fresh weight.W2----[cultivates the fresh weight of back cucumber cotyledons.
New compound and the chlorophyllous relative content experimental result of BA processing back cucumber cotyledons with various concentration see Table 3.
Cucumber cotyledons chlorophyll relative content after the compound treatment of the various concentration of table 3
| Concentration (M) | D/D 0 | |||||
| Embodiment 6 | Embodiment 5 | Embodiment 4 | Embodiment 3 | Embodiment 2 | Embodiment 1 | |
| 10 -5 | 2.52 | 2.60 | 2.10 | 1.34 | 1.39 | 1.35 |
| 10 -6 | 2.34 | 2.41 | 2.30 | 1.22 | 1.33 | 1.18 |
| 10 -7 | 1.45 | 1.71 | 1.50 | 1.21 | 1.13 | 1.15 |
| 10 -8 | 1.27 | 1.37 | 1.22 | 1.18 | 1.09 | 1.06 |
| Blank | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
In the table, the various concentration of D representation compound are handled the chlorophyll content behind the cotyledon.
D
0Represent the blank solution chlorophyll content.
Experimental result shows: N
9-benzyl-N
6-(2-boronate) benzyladenine (7), N
9-benzyl-N
6-(3-boronate) benzyladenine (8), N
9-benzyl-N
6The cytokine activity of-(4-boronate) benzyladenine (9) is very strong.Wherein the cytokine activity of compound (7) and (8) is higher than commodity phytokinin N commonly used
6Benzyladenine (BA); In addition, find N after tested
9-(2-boronate) benzyladenine (2), N
9-(3-boronate) benzyladenine (3), N
9-(4-boronate) benzyladenine (4) shows higher cytokine activity.
Embodiment 9
Anti-inflammatory activity testing method and result: the research compound influences laboratory animal and cell to Turnover of Mouse Peritoneal Macrophages TNF α excretory:
The C57BL6J mouse, male, the 16-18 gram is purchased in Chinese Academy of Medical Sciences experimentation on animals center; The L929 cell stores the cell strain of body for this laboratory.
Specimen preparation:
Compound method: the time spent that is made into 0.1mol/L with DMSO dilutes with phosphate buffered saline buffer (PBS)
Experimental technique:
D57BL6J mouse peritoneal injection sodium thioglycollate substratum, injection back the 4th day be the mouse sacrificed by decapitation, abdominal injection D-Hank ' s physiological buffer 6-8ml, and abundant liquid in the sucking-off abdominal cavity slowly after the massage, centrifugal 5 minutes of 1000rpm, carefully inclining to go up liquid.Cell is resuspended with the RPMI1640 substratum.Cell concn is adjusted into 1*10
6Cell/ml is inoculated in the cell plate of 48 holes (0.5ml/ hole).37 ℃, 5%CO
2Adherent culture 2 hours.Incline and substratum, with D-Hank ' s physiological buffer flushing twice, remove not attached cell, every hole adds the RPMI1640 substratum 24 hours of 5% new life's who contains lipopolysaccharides (LPS) and different medicine bovine serum, collect supernatant liquor, measure the content of TNF α with following method.
With the L929 cell with 2 * 10
5Cells/ml concentration is inoculated in the flat culture plate in 96 holes, and every hole 100 μ l establish 3 multiple holes, 37 ℃, cultivate 24 hours under the 5%CO condition.Abandon supernatant, every hole adds the nutrient solution 100 μ l that contain 2 μ g/ml dactinomycins, and RPMI-1640 substratum or above-mentioned testing sample 100 μ l establish 3 multiple holes, and 37 ℃, 5%CO
2Cultivate after 20 hours under the condition, (MTT, 5mg/ml) 20 μ l cultivated 4 hours again to add Thiazolyl blue in supernatant.Supernatant discarded, every empty 100 μ lDMSO lysing cell 10 minutes place microplate reader 570nm place to measure the O.D value.Cultivating datum hole with RPMI1640 is contrast, and the cell toxicant percentage is represented the contained TNF alpha content of sample.
Statistical analysis
Each is organized data and represents that with Mean ± SD analysis is carried out statistical procedures with the t check between group
Experimental result
Table 3-3 compound influences Turnover of Mouse Peritoneal Macrophages TNF α excretory
| Optical density O.D. value | Inhibiting rate % | |
| Blank | 0.669±0.041 | |
| LPS(2.5mg/ml) | 0.181±0.016 | |
| Example 6 | 0.230±0.049 | 10.0 |
| Example 5 | 0.329±0.044 ** | 30.0 |
| Example 4 | 0.237±0.006 ** | 11.5 |
| Example 3 | 0.333±0.017 *** | 31.0 |
| Example 2 | 0.360±0.005 *** | 36.6 |
| Example 1 | 0.197±0.003 | 13.2 |
Annotate:
*P＜0.01,
* *Compare with LPS in P＜0.001
Experimental result shows, six new compounds (2,3,4,7,8,9) all have the excretory effect of the Turnover of Mouse Peritoneal Macrophages tumour necrosis factor (TNF α) of inhibition, wherein compound 3,4 and 8 and similar compound to compare Turnover of Mouse Peritoneal Macrophages TNF α excretory restraining effect stronger, with the stimulant group significant difference is arranged relatively, shown very strong anti-inflammatory action.
Claims (5)
1. adenine kind derivative is characterized in that general structure is as follows:
Wherein:
R1 represents hydrogen atom;
R2 represents benzyl or 2,3,4-boronate benzyl;
R3 represents 2,3,4-boronate benzyl.
2. adenine kind derivative according to claim 1 is characterized in that, adenine kind derivative is:
N
9-(2-boronate) benzyladenine,
N
9-(3-boronate) benzyladenine,
N
9-(4-boronate) benzyladenine,
N
9-benzyl-N
6-(2-boronate) benzyladenine,
N
9-benzyl-N
6-(3-boronate) benzyladenine or
N
9-benzyl-N
6-(4-boronate) benzyladenine.
3. the preparation method of adenine kind derivative according to claim 1 and 2 is characterized in that, comprises the steps:
VITAMIN B4, Anhydrous potassium carbonate are added N, in the dinethylformamide, obtain suspension, under 100～140 ℃, will be dissolved with the N of n-bromomethyl benzene boric acid, dinethylformamide solution, join in the suspension, back flow reaction 12～16 hours is collected target product then from reaction product;
Wherein: n=2,3 or 4;
Or comprise the steps:
9-benzyladenine, 2-bromomethyl benzene boric acid are dissolved in N, and in the dinethylformamide, 30～40 ℃ were reacted 65～80 hours, and collected target product then from reaction product;
Or comprise the steps:
The 9-benzyladenine is dissolved in N, in the dinethylformamide, adds 430mg (2mmol) 4-bromomethyl benzene boric acid, 30～40 ℃ were reacted 55～65 hours, and collected target product then from reaction product.
4. the application of adenine kind derivative according to claim 1 and 2 is characterized in that, is used to improve cytokine activity, improves chlorophyll content of plant, promotes cell fission, suppresses effects such as apical dominance, the growth of promotion lateral bud.
5. the application of adenine kind derivative according to claim 1 and 2 is characterized in that, is used to improve the secretion that suppresses animal proinflammatory factor-tumor necrosis factor alpha, thereby plays antiphlogistic effect.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103695928A (en) * | 2014-01-08 | 2014-04-02 | 西南石油大学 | Amino acid derivative corrosion inhibitor for oil pipeline of oil-gas field and preparation method of corrosion inhibitor |
| CN109970832A (en) * | 2019-04-09 | 2019-07-05 | 沈阳药科大学 | A kind of alkynyl-modified desoxyadenosine phosphoramidite monomer and preparation method thereof |
| CN114040915A (en) * | 2019-04-12 | 2022-02-11 | 里伯赛恩斯有限责任公司 | Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors |
-
2005
- 2005-10-21 CN CNB2005100310422A patent/CN100427488C/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103695928A (en) * | 2014-01-08 | 2014-04-02 | 西南石油大学 | Amino acid derivative corrosion inhibitor for oil pipeline of oil-gas field and preparation method of corrosion inhibitor |
| CN109970832A (en) * | 2019-04-09 | 2019-07-05 | 沈阳药科大学 | A kind of alkynyl-modified desoxyadenosine phosphoramidite monomer and preparation method thereof |
| CN109970832B (en) * | 2019-04-09 | 2022-06-03 | 沈阳药科大学 | Alkynyl-modified deoxyadenosine phosphoramidite monomer and preparation method thereof |
| CN114040915A (en) * | 2019-04-12 | 2022-02-11 | 里伯赛恩斯有限责任公司 | Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors |
| US12029744B2 (en) | 2019-04-12 | 2024-07-09 | Riboscience Llc | Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors |
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| Publication number | Publication date |
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| CN100427488C (en) | 2008-10-22 |
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