CN108997350A - A kind of 8 inhibitor of cyclin-dependent kinase - Google Patents
A kind of 8 inhibitor of cyclin-dependent kinase Download PDFInfo
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- CN108997350A CN108997350A CN201810722183.6A CN201810722183A CN108997350A CN 108997350 A CN108997350 A CN 108997350A CN 201810722183 A CN201810722183 A CN 201810722183A CN 108997350 A CN108997350 A CN 108997350A
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- cyclin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
The present invention provides a kind of compounds as 8 inhibitor of cyclin-dependent kinase, and chemical structure is novel, which is structure or its pharmaceutically acceptable salt shown in logical formula (I)；Invention also provides the preparation method of the compound, which is conducive to production；The activity of cyclin-dependent kinase 8 can be effectively suppressed in the compound, and then helpful to associated cancer treatment, and has lower toxicity as drug, has wide practical use.
Description
Technical field
The invention belongs to 8 inhibitor of medicinal chemistry arts more particularly to a kind of cyclin-dependent kinase.
Background technique
Cyclin-dependent kinase 8 is a kind of modulation, by the inhibition to the target, can be obtained to a variety of cancers
The therapeutic effect of disease.Basic research field just tentatively understands its pathology and crystalline texture several years ago, for the drug for the target
Road has been paved in exploitation.From 2014, many pharmacy major companies in the world all started the R&D work of this respect, but
It makes slow progress, there is presently no a kind of drug candidates to enter clinical test.
Summary of the invention
The purpose of the present invention is to provide the chemical combination that one kind can be used as cyclin-dependent kinase 8 (CDK8) inhibitor
Object, the compound structure is novel, has very strong activity not only for CDK8 target, and toxicity is lower, is widely used
Prospect.
The present invention is achieved by the following technical solutions:
A kind of 8 inhibitor of cyclin-dependent kinase, the inhibitor be compound with structure shown in logical formula (I) or
Its pharmaceutically acceptable salt；
In logical formula (I), R1Selected from any non-polar group；A1Or A2The atom strong selected from electronegativity；A3And A4It is selected from
Sulphur or oxygen atom；A5Or A6Selected from the atom or functional group that can be used as hydrogen acceptor.
The compound of structure shown in logical formula (I), specific structure are the compound of structure shown in logical formula (II), the compound
Or its pharmaceutically acceptable salt can be used as 8 inhibitor of cyclin-dependent kinase.
Compound as 8 inhibitor of cyclin-dependent kinase of the invention it is specific the preparation method is as follows:
Sequentially added into 100mL single port bottle 6.1g (0.05mol) thiocarbonic acid, 9.1g (0.1mol) thiosemicarbazides and
30.7g (0.2mol) phosphorus oxychloride, flow back 6h；PH=12 is cooled to room temperature and is adjusted to after reflux, stands 30min in ice bath,
It to a large amount of solids of precipitation, filters, washing, be dried, obtain crude product 2- amino -5- sulfenyl -1,3,4- thiadiazoles, this is thick
Product re crystallization from toluene, yield 90%.
2- amino -5- the sulfenyl -1,3 that will be obtained, 4- thiadiazoles 1.06g (0.008mol) are added into 7mL water and 14mL second
In NaOH (0.008mol) solution of alcohol, and it is cooling in ice bath, it is stirred to react mixture；It is added at one time 8- chlorine caffeine
1.82g (0.008mol) is to generate suspension；Suspension is heated to reflux 60min；Reaction mixture is placed in after reflux cold on ice
But, there is white precipitate；Precipitating is collected by filtration, is precipitated with 60mL ethanol washing；It recrystallizes and produces from 60mL ethyl alcohol at room temperature
Afterwards, then with 60mL ethanol washing crystal, product 8- (2- amino -5- sulfenyl -1,3,4- thiadiazoles) chlorine caffeine, yield are obtained
70%.
By obtained 8- (2- amino -5- sulfenyl -1,3,4- thiadiazoles) chlorine caffeine 1.8g (0.005mol) be added into
In triethylamine (0.005mol) solution of 15mL chloroform, it is stirred to react mixture；It is added at one time to ethyl aniline 0.61g
(0.005 mol) and phosgene 0.5g (0.005mol), flow back 3h；By reaction mixture in ice bath cooling and standings 30min；It takes out
Filter, is dried to get final product, yield 85% washing.
Logical formula (I) structure compound represented of the invention can use above-mentioned or similar above-mentioned preparation method to prepare
It obtains, selects corresponding raw material to carry out synthesis process according to the difference of the difference of substituent group and substituting group position corresponding to get arriving
Product.
New inhibitor of the invention has very strong activity for 8 target of cyclin-dependent kinase, and has
Low toxicity is with a wide range of applications, and corresponding preparation method provided by the invention is simple and efficient, and is conducive to large-scale raw
It produces and uses.
Specific embodiment
Invention is further explained With reference to embodiment.
Compound or its pharmaceutically acceptable salt with structure shown in logical formula (I) can be used as a kind of Cyclin-Dependent
Property 8 inhibitor of kinases；
In logical formula (I), R1Selected from any non-polar group；A1Or A2The atom strong selected from electronegativity；A3And A4It is selected from
Sulphur or oxygen atom；A5Or A6Selected from the atom or functional group that can be used as hydrogen acceptor.
In logical formula (I), if R1It is selected as ethyl, A1And A2It is selected as nitrogen-atoms, A3And A4It is selected as sulphur atom, A5Or A6It is selected as carbonyl
Base, then the compound is as shown in logical formula (II).
Compound shown in logical formula (II) specific the preparation method is as follows:
Step 1:
Sequentially added into 100mL single port bottle 6.1g (0.05mol) thiocarbonic acid, 9.1g (0.1mol) thiosemicarbazides and
30.7g (0.2mol) phosphorus oxychloride, flow back 6h；PH=12 is cooled to room temperature and is adjusted to after reflux, stands 30min in ice bath,
It to a large amount of solids of precipitation, filters, washing, be dried, obtain crude product 2- amino -5- sulfenyl -1,3,4- thiadiazoles, this is thick
Product re crystallization from toluene, yield 90%.
Step 2:
2- amino -5- the sulfenyl -1,3 that will be obtained, 4- thiadiazoles 1.06g (0.008mol) are added into 7mL water and 14mL second
In NaOH (0.008mol) solution of alcohol, and it is cooling in ice bath, it is stirred to react mixture；It is added at one time 8- chlorine caffeine
1.82g (0.008mol) is to generate suspension；Suspension is heated to reflux 60min；Reaction mixture is placed in after reflux cold on ice
But, there is white precipitate；Precipitating is collected by filtration, is precipitated with 60mL ethanol washing；It recrystallizes and produces from 60mL ethyl alcohol at room temperature
Afterwards, then with 60mL ethanol washing crystal, product 8- (2- amino -5- sulfenyl -1,3,4- thiadiazoles) chlorine caffeine, yield are obtained
70%.
Step 3:
By obtained 8- (2- amino -5- sulfenyl -1,3,4- thiadiazoles) chlorine caffeine 1.8g (0.005mol) be added into
In triethylamine (0.005mol) solution of 15mL chloroform, it is stirred to react mixture；It is added at one time to ethyl aniline 0.61g
(0.005 mol) and phosgene 0.5g (0.005mol), flow back 3h；By reaction mixture, cooling and standings 30min is taken out in ice bath
Filter, is dried to get final product, yield 85% washing.
The measurement of embodiment 1:IC50 value
The compounds of this invention and cyclin-dependent kinase are determined by Reporter Displacement Assay
The IC50 value of 8 (CDK8) effect.Reporter Displacement Assay is based on can combine target protein target site
Combination between Reporter, Reporter and protein generates optical signal；When the compound replaces Reporter and target protein
When target site combines, optical signal will weaken, and after the compound of addition various concentration, measure light signal strength at any time
To calculate the substituted value of Reporter.In order to ensure Reporter be substituted rate reflect compound combine rather than
The dissociation of Reporter, Reporter are designed to have quick dissociation rate.Measurement for IC50, when system reaches flat
The last one time point of weighing apparatus calculates the substituted percent value of Reporter, for each compound concentration, calculates
Reporter percentage is substituted value, it is mapped with compound concentration then, obtains result.
The compound and cyclin-dependent kinase 8 act on, and very strong inhibitory effect can be generated to it, to CDK8
IC50 value be measured as 5.7nM.
The experiment of the above measurement IC50 value is in addition to being directed to CDK8, also to one group of totally 19 kinds of kinases progress similar with CDK8
Experiment.This 19 kinds of kinases are as follows: CDK2, CDK9, GSK3 β, PLK1, ASK1, CK1 δ, PKA, ROCK1, PKC θ, CDC7,
AKT1, Aurora B, MEK1, MAPKAPK2, CHK1, EGFR, JAK1, RK1, p 38 alpha, under 1 μM of concentration the inhibitor with
Upper kinases is without activity.
Embodiment 2: animal toxicity experiment
Animal toxicity experiment was carried out using 3 months big IRC white mouse, and white mouse is divided into 3 groups, every group 12.
Using the oral contamination method for manually pouring into inhibitor to experimental animal, a given low is respectively 0.0 (control
Group), 1.25mg/kg weight and 2.5mg/kg weight, twice a day.
After two weeks, control group does not have the variation of weight, and the weight average of given low 1.25mg/kg weight group is reduced
0.7%, the weight average of given low 2.5mg/kg weight group reduces 15.3%.The toxicity test shows under median dose
The toxicity of the new inhibitor is very low.
The above only expresses the preferred embodiment of the present invention, and the description thereof is more specific and detailed, but can not be because
This and be interpreted as limitations on the scope of the patent of the present invention.It should be pointed out that for those of ordinary skill in the art,
Without departing from the inventive concept of the premise, several deformations can also be made, improves and substitutes, these belong to of the invention
Protection scope.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (3)
1. a kind of 8 inhibitor of cyclin-dependent kinase, which is characterized in that it is the chemical combination with structure shown in logical formula (I)
Object or its pharmaceutically acceptable salt；
In logical formula (I), R1Selected from any non-polar group；A1Or A2The atom strong selected from electronegativity；A3And A4Selected from sulphur or
Oxygen atom；A5Or A6Selected from the atom or functional group that can be used as hydrogen acceptor.
2. 8 inhibitor of cyclin-dependent kinase according to claim 1, which is characterized in that it is with general formula
(II) compound of structure shown in or its pharmaceutically acceptable salt:
3. a kind of 8 inhibitor of cyclin-dependent kinase, which is characterized in that its specific preparation process the following steps are included:
(1) thiocarbonic acid, thiosemicarbazides and phosphorus oxychloride are taken, is cooled to room temperature after reflux, pH is adjusted, is stood in ice bath, is precipitated
Solid filter, be washing, dry, obtain crude product；
(2) step (1) crude product is added in the NaOH solution of water and ethyl alcohol, it is cooling in ice bath, it is stirred to react mixture；
(3) it is added at one time 8- chlorine caffeine into step (2) reaction mixture and generates suspension, is heated to reflux, reaction is mixed
It closes object to be placed on ice, cooled and filtered collects white precipitate, with ethanol washing white precipitate；It is recrystallized from ethyl alcohol at room temperature,
With ethanol washing weight crystalline product；
(4) in the triethylamine solution for the chloroform that step (3) recrystallized product is added, it is stirred to react mixture；
(5) it is added at one time into step (4) reaction mixture to ethyl aniline and phosgene, cooling is quiet in ice bath after reflux
It sets, product is filtered, washed, is dry, obtains final product.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810722183.6A CN108997350B (en) | 2018-07-03 | 2018-07-03 | Cyclin-dependent kinase 8 inhibitor |
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| CN201810722183.6A CN108997350B (en) | 2018-07-03 | 2018-07-03 | Cyclin-dependent kinase 8 inhibitor |
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| CN108997350A true CN108997350A (en) | 2018-12-14 |
| CN108997350B CN108997350B (en) | 2021-03-02 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115181102A (en) * | 2022-07-19 | 2022-10-14 | 南昌大学抚州医学院 | CDK8 inhibitors containing 1H-pyrazolo [3,4-D ] pyrimidine structure |
Citations (4)
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| WO2009140519A1 (en) * | 2008-05-14 | 2009-11-19 | Hydra Biosciences, Inc. | Compounds and compositions for treating chemical warfare agent-induced injuries |
| WO2010036821A1 (en) * | 2008-09-24 | 2010-04-01 | Hydra Biosciences, Inc. | Methods and compositions for treating respiratory disorders |
| CN101801362A (en) * | 2007-06-22 | 2010-08-11 | 海德拉生物科学公司 | The method and composition that is used for the treatment of disease |
| CN104825456A (en) * | 2014-02-12 | 2015-08-12 | 北京大学 | Application of a urea transporter (UT) inhibitor Youti |
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2018
- 2018-07-03 CN CN201810722183.6A patent/CN108997350B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801362A (en) * | 2007-06-22 | 2010-08-11 | 海德拉生物科学公司 | The method and composition that is used for the treatment of disease |
| WO2009140519A1 (en) * | 2008-05-14 | 2009-11-19 | Hydra Biosciences, Inc. | Compounds and compositions for treating chemical warfare agent-induced injuries |
| WO2010036821A1 (en) * | 2008-09-24 | 2010-04-01 | Hydra Biosciences, Inc. | Methods and compositions for treating respiratory disorders |
| CN104825456A (en) * | 2014-02-12 | 2015-08-12 | 北京大学 | Application of a urea transporter (UT) inhibitor Youti |
Non-Patent Citations (1)
| Title |
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| COLUMBUS, OHIO, US REGISTRY[ONLINE]: ""STN检索报告"", 《STN REGISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115181102A (en) * | 2022-07-19 | 2022-10-14 | 南昌大学抚州医学院 | CDK8 inhibitors containing 1H-pyrazolo [3,4-D ] pyrimidine structure |
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