CN108191748A - A kind of oxime compound of amino containing heteroaromatic, preparation method and its usage - Google Patents
A kind of oxime compound of amino containing heteroaromatic, preparation method and its usage Download PDFInfo
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- CN108191748A CN108191748A CN201810070630.4A CN201810070630A CN108191748A CN 108191748 A CN108191748 A CN 108191748A CN 201810070630 A CN201810070630 A CN 201810070630A CN 108191748 A CN108191748 A CN 108191748A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention discloses a kind of oxime compound of amino containing heteroaromatic, preparation method and its usages.Its structure as shown in logical formula (I), wherein, the same specification of definition of R group and X.Such compound has stronger histon deacetylase (HDAC) rejection ability, can be used for the treatment of histon deacetylase (HDAC) high activity or high expression cancer.
Description
Technical field
The present invention relates to a kind of oxime compound of amino containing heteroaromatic as histon deacetylase (HDAC) inhibitor, systems
Preparation Method and application thereof.Belong to biomedicine field.
Background technology
Histon deacetylase (HDAC) inhibitor can regulate and control the intragentic expression of life entity, have in the treatment neighborhood of cancer
It is widely applied.The histon deacetylase (HDAC) inhibitor in open clinical stage has been listed or has been in mainly by hydroximic acid
Compound forms.But such compound is in vivo and unstable, can be hydrolyzed to carboxylic acid and the azanol with teratogenesis.
Therefore, it is necessary to develop more efficient and selective histon deacetylase (HDAC) inhibitor.
Amino oxime compound can chelate the transition metal ions including zinc ion and not allow facile hydrolysis, therefore,
Such compound has been developed to sewage-treating agent, is mainly used for removing the metal ion in sewage.In biomedicine field,
Amino oxime compound also has been developed to 1 inhibitor of histone demethylase (J.Med.Chem.2012,55,7378)
And histon deacetylase (HDAC) inhibitor (Bioorg.Med.Chem.Lett.2016,26,4679), still, the amino reported
The ability of oxime compound inhibition of histone deacetylase is weaker, the IC of best compound50Value is only 93nM.
The invention discloses a series of oxime compound of amino containing heteroaromatic structures, preparation method and its usages.
Invention content
1. the compound of the present invention has below general formula or is its prodrug or pharmaceutically acceptable salt：
Wherein：
X is N atoms；
R is：
Group；
Specific embodiment
With reference to embodiment, the present invention will be further elaborated, it should explanation, the description below merely to
It explains the present invention, its content is not defined.
Embodiment one：The preparation of 2- (β-phenyl ethylamine base)-N- (5- amino isonitroso pyridine -2- bases) acetamide (compound 1)
Compound 1
0.25mol6- amino nicotinic acid nitriles are scattered in 150ml acetonitriles, add in 0.3mol triethylamines, 0 DEG C of stirring.It will
0.3mol2- bromoacetyl chlorides instill above-mentioned solution.Reaction 3 hours adds in 1000ml water, a large amount of solids is precipitated, and filters, filter cake water
It washes, dries to obtain brown solid IM-1, yield 50%, liquid phase purity 82%, MS (ESI, m/z)：240.1[M+H].
0.1mol IM-1 are scattered in 250ml CH2Cl2In, 0.12mol triethylamines are added in, add 0.12mol benzene second
Amine is stirred at room temperature, and reacts 12 hours.CH2Cl2It mutually washes, anhydrous magnesium sulfate drying is concentrated to dryness, obtains brown solid IM-2, produces
Rate 78%, liquid phase purity 67%, MS (ESI, m/z)：281.1[M+H].
0.05mol IM-2 are dissolved in 100ml absolute ethyl alcohols, add in 0.25mol hydroxylamine hydrochlorides, add 100ml water with
0.25mol triethylamines are heated to reflux 6 hours, and white crystal is precipitated in cooling, are filtered, and crystal washing obtains compound 1, yield 9%,
Liquid phase purity 99%.MS (ESI, m/z)：314.1[M+H].1HNMR (300MHz, DMSO-d6) δ 10.27 (s, 1H), 9.55 (s,
1H), 8.22 (s, 1H), 7.75 (d, 1H), 7.45-7.13 (m, 6H), 6.03 (s, 2H), 3.17 (d, 2H), 2.56 (m, 4H),
1.88 (brs, 1H)；
Embodiment two：The preparation of 2- (β-phenyl ethylamine base)-N- (2- amino isonitroso pyridine -5- bases) acetamide (compound 2)
Compound 2
0.25mol 2- cyano -5- aminopyridines are scattered in 150ml acetonitriles, add in 0.3mol triethylamines, 0 DEG C is stirred
It mixes.0.3mol 2- bromoacetyl chlorides are instilled into above-mentioned solution.Reaction 3 hours adds in 1000ml water, a large amount of solids is precipitated, and filters,
Filter cake is washed, and dries to obtain brown solid IM-3, yield 56%, liquid phase purity 79%, MS (ESI, m/z)：240.1[M+H].
0.03mol IM-3 are scattered in 150ml CH2Cl2In, 0.045mol triethylamines are added in, add 0.045mol benzene
Ethamine is stirred at room temperature, and reacts 12 hours.CH2Cl2Mutually to wash, anhydrous magnesium sulfate drying is concentrated to dryness, obtains brown solid IM-4,
Yield 79%, liquid phase purity 71%, MS (ESI, m/z)：303.1[M+Na].
0.01mol IM-4 are dissolved in 100ml absolute ethyl alcohols, add in 0.05mol hydroxylamine hydrochlorides, add 100ml water with
0.05mol triethylamines are heated to reflux 6 hours, and white crystal is precipitated in cooling, are filtered, and crystal washing obtains compound 2, yield
11%, liquid phase purity 99%.MS (ESI, m/z)：314.1[M+H].1HNMR (300MHz, DMSO-d6) δ 9.82 (s, 1H),
9.56 (s, 1H), 8.13 (s, 1H), 7.73 (d, 1H), 7.21-7.09 (m, 6H), 5.45 (s, 2H), 3.58 (d, 2H), 2.35
(m, 4H), 1.97 (brs, 1H)；
Embodiment three：The preparation of 2- tryptamines bases-N- (5- amino isonitroso pyridine -2- bases) acetamide (compound 3)
Compound 3
The preparation method of IM-1 is the same as example one.
0.02mol IM-1 are scattered in 100ml CH2Cl2In, 0.024mol triethylamines are added in, add 0.02mol colors
Amine, nitrogen protection, is stirred at room temperature, and reacts 12 hours.It filters, solid is with CH2Cl2Washing, obtains brown solid IM-5, yield 36%,
Liquid phase purity 83%, MS (ESI, m/z)：342.1[M+Na].
0.005mol IM-5 are dissolved in 50ml absolute ethyl alcohols, add in 0.025mol hydroxylamine hydrochlorides, add 50ml water with
0.025mol triethylamines, nitrogen protection, are heated to reflux 6 hours, and solid is precipitated in cooling, filter, and solid washing obtains gray solid
Close object 3, yield 17%, liquid phase purity 95%.MS (ESI, m/z)：353.1[M+H].
Example IV：The preparation of 2- tryptamines bases-N- (2- amino isonitroso pyridine -5- bases) acetamide (compound 4)
Compound 4
The preparation method of IM-3 is the same as example two.
0.02mol IM-3 are scattered in 100ml CH2Cl2In, 0.024mol triethylamines are added in, add 0.02mol colors
Amine, nitrogen protection, is stirred at room temperature, and reacts 12 hours.It filters, solid is with CH2Cl2Washing, obtains brown solid IM-6, yield 29%,
Liquid phase purity 85%, MS (ESI, m/z)：320.1[M+H].
0.005mol IM-6 are dissolved in 50ml absolute ethyl alcohols, add in 0.025mol hydroxylamine hydrochlorides, add 50ml water with
0.025mol triethylamines, nitrogen protection, are heated to reflux 12 hours, and solid is precipitated in cooling, filter, and solid washing obtains gray solid
Compound 4, yield 21%, liquid phase purity 94%.MS (ESI, m/z)：353.1[M+H].
Embodiment five：The system of 2- (2- methyltryptamines base)-N- (5- amino isonitroso pyridine -2- bases) acetamide (compound 5)
It is standby
Compound 5
The preparation method of IM-1 is the same as example one.
0.02mol IM-1 are scattered in 100ml CH2Cl2In, 0.024mol triethylamines are added in, add 0.02mol 2-
Methyltryptamine, nitrogen protection, is stirred at room temperature, and reacts 12 hours.It filters, solid is with CH2Cl2Washing, obtains brown solid IM-7, produces
Rate 35%, liquid phase purity 81%, MS (ESI, m/z)：334.2[M+H].
0.005mol IM-5 are dissolved in 50ml absolute ethyl alcohols, add in 0.025mol hydroxylamine hydrochlorides, add 50ml water with
0.025mol triethylamines, nitrogen protection, are heated to reflux 12 hours, and solid is precipitated in cooling, filter, and solid washing obtains brown solid.
The solid is purified with column chromatography, obtains faint yellow solid compound 5, yield 13%, liquid phase purity 96%.MS (ESI, m/z)：
367.1[M+H]。
Embodiment six：The system of 2- (2- methyltryptamines base)-N- (2- amino isonitroso pyridine -5- bases) acetamide (compound 6)
It is standby
Compound 6
The preparation method of IM-3 is the same as example two.
0.02mol IM-3 are scattered in 100ml CH2Cl2In, 0.024mol triethylamines are added in, add 0.02mol 2-
Methyltryptamine, nitrogen protection, is stirred at room temperature, and reacts 12 hours.It filters, solid is with CH2Cl2Washing, obtains brown solid IM-8, produces
Rate 32%, liquid phase purity 81%, MS (ESI, m/z)：334.1[M+H].
0.005mol IM-8 are dissolved in 50ml absolute ethyl alcohols, add in 0.025mol hydroxylamine hydrochlorides, add 50ml water with
0.025mol triethylamines, nitrogen protection, are heated to reflux 12 hours, and solid is precipitated in cooling, filter, and solid washing obtains brown solid.
The solid is purified with column chromatography, obtains yellow solid compound 6, yield 16%, liquid phase purity 94%.MS (ESI, m/z)：367.1
[M+H]。
Embodiment seven：The oxime compound of amino containing heteroaromatic studies histon deacetylase (HDAC) rejection ability
Compound is to the rejection ability of histon deacetylase (HDAC) with AmpliteTM fluorimetric HDAC
Activity assay kit (AAT Bioquest) are analyzed.The step of experimentation is provided according to kit carries out.It will
HeLa nucleus extraction objects after 40 μ L dilutions are added in into 96 orifice plates, add in the untested compound of 10 μ L various concentrations, each
Concentration sets three Duplicate Samples.The buffer solution of kit institute band is made as blank, the HeLa nucleus extractions object of Trichostatin A processing
For negative control.96 orifice plates are put in 37 DEG C of incubators and are incubated 20min.50 μ L HDAC Green are added in into each holeTMSubstrate
Working solution continues to be incubated 60min in 37 DEG C of incubators, in the fluorescence intensity of Ex/Em=485/535nm wavelength detecting samples.Change
Close the IC that object inhibits histon deacetylase (HDAC)50Value is calculated with Sigmaplot by linear regression analysis.
Embodiment eight：The oxime compound of amino containing heteroaromatic is thin to human colon cancer cell HCT116, Non-small cell lung carcinoma
Born of the same parents A549 increment rejection ability researchs
Compound analyzes HCT116, A549 cell proliferation rejection ability in WST-1 methods.Experimentation is according to examination
The step of agent box provides carries out.By HCT116, A549 cell inoculation in 96 orifice plates, in 37 DEG C, 5%CO2It is cultivated in incubator, until
Cell coverage rate is 70%.Untested compound is dissolved in DMSO, dilutes to obtain the compound of concentration to be measured with culture medium.With compound
Processing with untreated cell in 37 DEG C, 5%CO272h is cultivated in incubator.To treat in gaging hole add in WST-1 (10 μ L,
Roche Applied Science), and 1min is shaken with shaking table, in Ex/Em=450/650nm wavelength detecting sample absorbances.
Compound is to HCT116, A549 cell proliferation rejection ability EC50Value is calculated with Sigmaplot by linear regression analysis.
The listed oxime compound of amino containing heteroaromatic of 1 present invention of table resists histon deacetylase (HDAC) rejection ability with external
Tumor promotion
Although the above-mentioned specific embodiment to the present invention is described, not to the limit of the scope of the present invention
System, based on the technical solutions of the present invention, those skilled in the art do not need to make the creative labor can make it is each
Kind modification or deformation are still within protection scope of the present invention.
Claims (3)
- A series of 1. oxime compounds of amino containing heteroaromatic, it is characterized in that it has below formula：In formula：X is N atoms；R is：Group.
- 2. the preparation method of logical formula (I) compound, this method comprises the following steps：1) IM-001 is obtained by the reaction in SM and 2- bromoacetic acids or 2- bromoacetyl chlorides2) IM-002 is obtained by the reaction in IM-001 and substitution amine3) TM is obtained by the reaction in IM-002 and hydroxylamine hydrochloride。
- 3. compound as described in claim 1 and its prodrug or pharmaceutically acceptable salt are used for histon deacetylase (HDAC) high activity Or the treatment of high expression cancer.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112218857A (en) * | 2018-02-16 | 2021-01-12 | 星座制药公司 | P300/CBP HAT inhibitors and methods of use thereof |
| CN112341380A (en) * | 2020-11-04 | 2021-02-09 | 齐鲁师范学院 | Small molecule immunomodulator and application thereof |
Citations (3)
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| CN101107220A (en) * | 2004-07-12 | 2008-01-16 | P.安杰莱蒂分子生物学研究所 | Amide derivatives as inhibitors of histone deacetylase |
| WO2013134467A1 (en) * | 2012-03-07 | 2013-09-12 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Selective histone deactylase 6 inhibitors |
| WO2015017546A1 (en) * | 2013-07-30 | 2015-02-05 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Selective histone deactylase 6 inhibitors |
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2018
- 2018-01-24 CN CN201810070630.4A patent/CN108191748A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101107220A (en) * | 2004-07-12 | 2008-01-16 | P.安杰莱蒂分子生物学研究所 | Amide derivatives as inhibitors of histone deacetylase |
| WO2013134467A1 (en) * | 2012-03-07 | 2013-09-12 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Selective histone deactylase 6 inhibitors |
| WO2015017546A1 (en) * | 2013-07-30 | 2015-02-05 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Selective histone deactylase 6 inhibitors |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112218857A (en) * | 2018-02-16 | 2021-01-12 | 星座制药公司 | P300/CBP HAT inhibitors and methods of use thereof |
| CN112218857B (en) * | 2018-02-16 | 2023-11-21 | 星座制药公司 | P300/CBP HAT inhibitors and methods of use thereof |
| CN112341380A (en) * | 2020-11-04 | 2021-02-09 | 齐鲁师范学院 | Small molecule immunomodulator and application thereof |
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