CN106831560A - A kind of PTP1B inhibitor containing niacin hydroxyacyl amine and aniline structure and application thereof - Google Patents
A kind of PTP1B inhibitor containing niacin hydroxyacyl amine and aniline structure and application thereof Download PDFInfo
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- CN106831560A CN106831560A CN201710074731.4A CN201710074731A CN106831560A CN 106831560 A CN106831560 A CN 106831560A CN 201710074731 A CN201710074731 A CN 201710074731A CN 106831560 A CN106831560 A CN 106831560A
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- inhibitor containing
- ptp1b inhibitor
- aniline structure
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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
- C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to the drug field related to type ii diabetes.Specifically, the present invention relates to a kind of PTP1B inhibitor containing niacin hydroxyacyl amine and aniline structure, its preparation method and the application in type ii diabetes medicine is prepared.
Description
Technical field
The present invention relates to the drug field of type ii diabetes treatment.More particularly, it relates to type ii diabetes
Have medicative a kind of PTP1B inhibitor, its preparation method containing niacin hydroxyacyl amine and aniline structure, and in pharmacy
Purposes.
Background technology
Type ii diabetes are a kind of common metabolic disturbance diseases, it is characterized in that periphery produces resistant function to film island element,
Insulin being shown as in molecular level, rear signal transduction missing is combined with insulin receptor.The phosphorylation level of protease propylhomoserin is
The important regulation factor of intracellular signal transduction, it is by protease histidine kinase (protein tyrosine kinase, PTK)
Regulate and control jointly with protease propylhomoserin phosphatase (protein tyrosine phosphatase, PTP).Research in recent years discovery, egg
White enzyme propylhomoserin phosphatase 1 B can play important negative regulation with dephosphorylation protease propylhomoserin in Insulin signaling pathway
Effect.PTPIB genes are knocked out, or suppresses the expression of internal PTP1B albumen and mRNA with antisense core former times acid (ASO), not only may be used
To significantly improve sensitiveness of the test mice to insulin, and can substantially reduce the ill probability of obesity.These research tables
Bright, PTP1B is likely to become the novel targets for the treatment of type ii diabetes.
The invention discloses a kind of novel PTP1B inhibitor containing niacin hydroxyacyl amine and aniline structure of structure, these chemical combination
Thing can be used to prepare the medicine for the treatment of type ii diabetes.
The content of the invention
It is an object of the present invention to provide a kind of PTP1B inhibitor of the excellent activity with Formulas I.
Method it is a further object to provide the compound with Formulas I is prepared.
It is also another object of the present invention to provide the compound containing Formulas I as active ingredient in treatment type ii diabetes side
The application in face.
Present invention is specifically described in conjunction with the purpose of the present invention.
Compound of the present invention with Formulas I has following structural formula：
Compound of formula I of the present invention is synthesized by following route：
There is substitution reaction in compound II, obtain compound IV with compound III in the presence of a base；Compound IV is in DCC
Reacted with compound V in the presence of (N, N'- dicyclohexyl carbodiimide), obtain VI；Compound VI is oxidized agent oxidation, obtains
Compound I.Compound II can prepare (Leon Katz according to literature method；et al,Journal of Organic
Chemistry,1954,19,711)。
Compound of formula I of the present invention has the inhibitory action of PTP1B, can be used to prepare II type glycosurias as active ingredient
Sick medicine.The activity of compound of formula I of the present invention is verified by receptor binding assays.
Compound of formula I of the invention is effective in comparatively wide dosage range.The dosage for example taken daily about exists
In the range of 1mg-1000mg/ people, it is divided into and once or is for several times administered.The dosage for actually taking formula I can be by doctor
Determined according to relevant situation.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.The various change that those skilled in the art's training centre of the invention is made all should
Within the protection domain required by the application claim.
The synthesis of the compound I of embodiment 1
A. the synthesis of compound IV-1
Compound II (1.55g, 10mmol), compound III-1 (1.86g, 10mmol) and solid K2CO3(5.53g,
40mmol) add in the dry DMF of 30mL, be stirred overnight at room temperature, TLC tracking finds that reaction is completed.Reactant mixture is toppled over
Enter in 200mL frozen water, stirring adjusts pH=4-5 with concentrated hydrochloric acid, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, use salt solution
Washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining uses post
Chromatographic purifying, obtains compound IV-1, white solid.ESI-MS, m/z=259 ([M-H]-)。
B. the synthesis of compound VI-1
Compound IV-1 (1.30g, 5mmol), compound V-1 (0.43g, 5mmol), DCC (1.24g, 6mmol) and 4- bis-
Methylamino pyridine (DMAP, 0.3g) is dissolved in dry 20mL THF, is stirred overnight at room temperature, and TLC tracking finds that reaction is completed.
Reactant mixture is poured into 200mL frozen water, stirring, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, dilute with 2% successively
Hydrochloric acid and salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and what is obtained is residual
Excess is purified using column chromatography, obtains compound VI-1, white solid.ESI-MS, m/z=328 ([M+H]+)。
C. the synthesis of compound I
Compound VI-1 (0.65g, 2mmol) is dissolved in 10mL CH2Cl2In, stir at room temperature, add metachloroperbenzoic acid
(mCPBA, 1.72g, 10mmol), reactant mixture is stirred at room temperature 1 hour, then temperature rising reflux 3 hours, and TLC detections are anti-
Should complete.Reactant mixture is poured into 200mL frozen water, stirring, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, successively
Use saturation NaHCO3Solution and salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is steamed on a rotary evaporator
Dry, the residue for obtaining is purified using column chromatography, obtains compound I, white solid.ESI-MS, m/z=376 ([M+H]+)。
The synthesis of the reference compound R-1 of embodiment 2
In order to further compare pharmacological effect of the invention, applicant describes be all applicant's invention in this application
Unknown compound R-1 (is not yet disclosed).
A. the synthesis of compound IV-2
Compound II (1.55g, 10mmol), compound III-2 (1.71g, 10mmol) and solid K2CO3(5.53g,
40mmol) add in the dry DMF of 30mL, be stirred overnight at room temperature, TLC tracking finds that reaction is completed.Reactant mixture is toppled over
Enter in 200mL frozen water, stirring adjusts pH=4-5 with concentrated hydrochloric acid, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, use salt solution
Washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining uses post
Chromatographic purifying, obtains compound IV-2, white solid.ESI-MS, m/z=244 ([M-H]-)。
B. the synthesis of compound VI-2
Compound IV-2 (1.23g, 5mmol), compound V-1 (0.43g, 5mmol), DCC (1.24g, 6mmol) and 4- bis-
Methylamino pyridine (DMAP, 0.3g) is dissolved in dry 20mL THF, is stirred overnight at room temperature, and TLC tracking finds that reaction is completed.
Reactant mixture is poured into 200mL frozen water, stirring, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, dilute with 2% successively
Hydrochloric acid and salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and what is obtained is residual
Excess is purified using column chromatography, obtains compound VI-2, white solid.ESI-MS, m/z=313 ([M+H]+)。
C. the synthesis of compound R -1
Compound VI-2 (0.62g, 2mmol) is dissolved in 10mL CH2Cl2In, stir at room temperature, add metachloroperbenzoic acid
(mCPBA, 1.72g, 10mmol), reactant mixture is stirred at room temperature 1 hour, then temperature rising reflux 3 hours, and TLC detections are anti-
Should complete.Reactant mixture is poured into 200mL frozen water, stirring, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, successively
Use saturation NaHCO3Solution and salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is steamed on a rotary evaporator
Dry, the residue for obtaining is purified using column chromatography, obtains compound R -1, white solid.ESI-MS, m/z=361 ([M+H]+)。
Suppression of the Compound ira vitro of embodiment 3 to PTP1B is tested
By original concentration for the compound solution of 50mM carries out 1/2 gradient dilution with 95%DMSO, 11 concentration are diluted altogether
Gradient.Enzyme activity reaction system amounts to 102 μ L, and it is 2 μ L that wherein compound adds volume.First, 50 μ are sequentially added in 96 orifice plates
L PTP1B albumen, the testing compound of 2 μ L various concentrations shakes 1min, 30 DEG C of incubation 30min, is subsequently adding 50 μ L pNPP
(para-nitro-pheneye phosphate), shakes 10s.Absorbance is surveyed once for 6 seconds with the change in reaction time under determining 405nm wavelength, surveys 60
It is individual, parallel determination three times, and course of reaction curve is drawn out, so as to calculate suppression of each compound to enzyme under various concentrations
Activity, non linear fit analysis are carried out using the softwares of software GraphPad Prism 5, with residual activity value as ordinate, chemical combination
Thing log concentration value is that abscissa draws curve, calculates the IC of the compound50Value.
Test result see the table below.
| Compound | |
| Reference compound R-1 | 18.6 |
| The compounds of this invention I | 8.9 |
Can be seen that compound of the invention from upper table result has very strong inhibitory action to PTP1B, can be as system
The medicine of standby treatment type ii diabetes.
Claims (2)
1. a kind of compound of Formulas I structure,
2. application of one of claim 1 compound of formula I in terms for the treatment of diabetes B medicine is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710074731.4A CN106831560A (en) | 2015-03-12 | 2015-03-12 | A kind of PTP1B inhibitor containing niacin hydroxyacyl amine and aniline structure and application thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710074731.4A CN106831560A (en) | 2015-03-12 | 2015-03-12 | A kind of PTP1B inhibitor containing niacin hydroxyacyl amine and aniline structure and application thereof |
| CN201510108699.8A CN104725310A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor containing nicotinic acid amide and aniline structures and use thereof |
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| CN201510108699.8A Division CN104725310A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor containing nicotinic acid amide and aniline structures and use thereof |
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| CN106831560A true CN106831560A (en) | 2017-06-13 |
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| CN201510108699.8A Pending CN104725310A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor containing nicotinic acid amide and aniline structures and use thereof |
| CN201710074731.4A Pending CN106831560A (en) | 2015-03-12 | 2015-03-12 | A kind of PTP1B inhibitor containing niacin hydroxyacyl amine and aniline structure and application thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484440A (en) * | 2006-07-06 | 2009-07-15 | 艾尼纳制药公司 | Modulators of metabolism and the treatment of disorders related thereto |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6262044B1 (en) * | 1998-03-12 | 2001-07-17 | Novo Nordisk A/S | Modulators of protein tyrosine phosphatases (PTPASES) |
| WO2002018321A2 (en) * | 2000-08-29 | 2002-03-07 | Abbott Laboratories | Amino(oxo)acetic acid protein tyrosine phosphatase inhibitors |
| GB0428212D0 (en) * | 2004-12-24 | 2005-01-26 | Prosidion Ltd | Compounds |
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- 2015-03-12 CN CN201510108699.8A patent/CN104725310A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484440A (en) * | 2006-07-06 | 2009-07-15 | 艾尼纳制药公司 | Modulators of metabolism and the treatment of disorders related thereto |
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