CN104725355A - PTP1B inhibitor containing nicotinic acid amide and piperidine structures and use thereof - Google Patents
PTP1B inhibitor containing nicotinic acid amide and piperidine structures and use thereof Download PDFInfo
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- CN104725355A CN104725355A CN201510108798.6A CN201510108798A CN104725355A CN 104725355 A CN104725355 A CN 104725355A CN 201510108798 A CN201510108798 A CN 201510108798A CN 104725355 A CN104725355 A CN 104725355A
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- compound
- ptp1b inhibitor
- acid amide
- nicotinic acid
- ptp1b
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- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicines related to type II diabetes and particularly relates to a PTP1B inhibitor containing nicotinic acid amide and piperidine structures, a preparation method thereof and application of the PTP1B inhibitor in preparation of medicines for treating the type II diabetes. The PTP1B inhibitor has a structure represented by a formula shown in descriptions.
Description
Technical field
The present invention relates to the pharmaceutical field of type ii diabetes treatment.More particularly, the present invention relates to medicative a kind of PTP1B inhibitor, its preparation method containing niacin hydroxyacyl amine and piperidine structure of type ii diabetes tool, and the purposes in pharmacy.
Background technology
Type ii diabetes is a kind of common metabolic disturbance diseases, it is characterized in that periphery produces resistant function to film island element, shows as Regular Insulin to be combined signal transduction afterwards with insulin receptor and to lack at molecular level.The phosphorylation level of proteolytic enzyme propylhomoserin is the important regulate factors of intracellular signal transduction, it is by proteolytic enzyme histidine kinase (protein tyrosine kinase, PTK) and proteolytic enzyme propylhomoserin Phosphoric acid esterase (protein tyrosine phosphatase, PTP) jointly regulate and control.Research in recent years finds, proteolytic enzyme propylhomoserin phosphatase 1 B can dephosphorylation proteolytic enzyme propylhomoserin, plays important negative regulation effect in Insulin signaling pathway.Knock out PTPIB gene, or use antisense core former times acid (ASO) to suppress the expression of PTP1B albumen and mRNA in body, not only can significantly improve the susceptibility of test mice to Regular Insulin, and obviously can reduce the ill probability of obesity.These researchs show, PTP1B likely becomes the novel targets for the treatment of type ii diabetes.
The invention discloses a kind of PTP1B inhibitor containing niacin hydroxyacyl amine and piperidine structure of novel structure, these compounds can be used for the medicine preparing treatment type ii diabetes.
Summary of the invention
An object of the present invention is to provide a kind of PTP1B inhibitor with the excellent activity of formula I.
Another object of the present invention is to provide the method that preparation has the compound of formula I.
The compound that another object of the present invention is to provide containing formula I is treating the application in type ii diabetes as effective constituent.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has formula I has following structural formula:
Formula I of the present invention is synthesized by following route:
Compound II per in the presence of a base with compound III generation substitution reaction, obtain compound IV; There is lower and compound V at DCC (N, N'-dicyclohexyl carbodiimide) and react in compound IV, obtains VI; The oxidation of oxidized dose of compound VI, obtains Compound I.Compound II per can prepare (Leon Katz according to literature method; Et al, Journal of Organic Chemistry, 1954,19,711).
Formula I of the present invention has the restraining effect of PTP1B, can be used as effective constituent for the preparation of type ii diabetes medicine.The activity of formula I of the present invention is verified by receptor binding assays.
Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking formula I can be decided according to relevant situation by doctor.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
the synthesis of embodiment 1 Compound I-1
A. the synthesis of compound IV-1
Compound II per (1.55g, 10mmol), compound III-1 (1.96g, 10mmol) and solid K
2cO
3(5.53g, 40mmol) adds in the DMF of 30mL drying, room temperature for overnight, and TLC follows the tracks of and finds that reaction completes.Reaction mixture pours in 200mL frozen water, stirs, regulates pH=4-5, use CH with concentrated hydrochloric acid
2cl
2(60mL × 3) extract, and merge extraction phase, use salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound IV-1, white solid.ESI-MS,m/z＝269([M-H]
-)。
B. the synthesis of compound VI-1
Compound IV-1 (1.35g, 5mmol), compound V-1 (0.50g, 5mmol), DCC (1.24g, 6mmol) with DMAP (DMAP, 0.3g) be dissolved in dry 20mL THF, room temperature for overnight, TLC follows the tracks of and finds that reaction completes.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use 2% dilute hydrochloric acid and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound VI-1, white solid.ESI-MS,m/z＝352([M+H]
+)。
C. the synthesis of Compound I
Compound VI-1 (0.70g, 2mmol) is dissolved in 10mL CH
2cl
2in, stirred at ambient temperature, add metachloroperbenzoic acid (mCPBA, 1.72g, 10mmol), reaction mixture at room temperature stirs 1 hour, then temperature rising reflux 3 hours, and TLC detection reaction completes.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use saturated NaHCO successively
3solution and salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound I, white solid.ESI-MS，m/z＝400([M+H]
+)。
embodiment 2
the synthesis of reference compound R-1
In order to pharmacological effect more of the present invention further, applicant describes the unknown compound R-1 (not yet open) being all applicant's invention in this application.
A. the synthesis of compound IV-2
Compound II per (1.55g, 10mmol), compound III-2 (1.71g, 10mmol) and solid K
2cO
3(5.53g, 40mmol) adds in the DMF of 30mL drying, room temperature for overnight, and TLC follows the tracks of and finds that reaction completes.Reaction mixture pours in 200mL frozen water, stirs, regulates pH=4-5, use CH with concentrated hydrochloric acid
2cl
2(60mL × 3) extract, and merge extraction phase, use salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, 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) with DMAP (DMAP, 0.3g) be dissolved in dry 20mL THF, room temperature for overnight, TLC follows the tracks of and finds that reaction completes.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use 2% dilute hydrochloric acid and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, 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 CH
2cl
2in, stirred at ambient temperature, add metachloroperbenzoic acid (mCPBA, 1.72g, 10mmol), reaction mixture at room temperature stirs 1 hour, then temperature rising reflux 3 hours, and TLC detection reaction completes.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use saturated NaHCO successively
3solution and salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound R-1, white solid.ESI-MS，m/z＝361([M+H]
+)。
embodiment 4 Compound ira vitro is to the inhibition test of PTP1B
Be that the compound solution 95%DMSO of 50mM carries out 1/2 gradient dilution by original concentration, dilute 11 concentration gradients altogether.Enzyme reaction system alive amounts to 102 μ L, and wherein compound adds volume is 2 μ L.First, in 96 orifice plates, add 50 μ L PTP1B albumen successively, the testing compound of 2 μ L different concns, concussion 1min, hatches 30min for 30 DEG C, then adds 50 μ L pNPP (para-nitro-pheneye phosphate), concussion 10s.Under mensuration 405nm wavelength, absorbancy is with the change in reaction times, within 6 seconds, survey once, survey 60 points, replicate(determination) three times, and draw out reaction process curve, thus under calculating different concns each compound to the inhibit activities of enzyme, software GraphPad Prism 5 software is utilized to carry out non linear fit analysis, with remaining activity value for ordinate zou, compound concentration logarithmic value is X-coordinate curve plotting, calculates the IC of this compound
50value.
Test result sees the following form.
| Compound | IC 50(nM) |
| Reference compound R-1 | 18.6 |
| The compounds of this invention I | 9.2 |
As can be seen from upper table result, compound of the present invention has very strong restraining effect to PTP1B, can as preparation treatment type ii diabetes medicine.
Claims (2)
1. there is the compound of formula I structure,
2. the application of compound of Formula I described in claim 1 in preparation treatment diabetes B medicine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510108798.6A CN104725355A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor containing nicotinic acid amide and piperidine structures and use thereof |
| CN201710091454.8A CN106749179A (en) | 2015-03-12 | 2015-03-12 | One kind contains niacin hydroxyacyl amine and piperidine structure PTP1B inhibitor and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510108798.6A CN104725355A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor containing nicotinic acid amide and piperidine structures and use thereof |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710091454.8A Division CN106749179A (en) | 2015-03-12 | 2015-03-12 | One kind contains niacin hydroxyacyl amine and piperidine structure PTP1B inhibitor and application thereof |
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|---|---|
| CN104725355A true CN104725355A (en) | 2015-06-24 |
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| CN201510108798.6A Pending CN104725355A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor containing nicotinic acid amide and piperidine structures and use thereof |
| CN201710091454.8A Pending CN106749179A (en) | 2015-03-12 | 2015-03-12 | One kind contains niacin hydroxyacyl amine and piperidine structure PTP1B inhibitor and application thereof |
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Citations (5)
| 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 |
| CN101123964A (en) * | 2004-12-24 | 2008-02-13 | 普罗西迪恩有限公司 | G-protein coupled receptor(GPR116) agonists and use thereof for treating obesity and diabetes |
| CN101466667A (en) * | 2006-04-11 | 2009-06-24 | 普罗西迪恩有限公司 | Azetidine derivatives as g-protein coupled receptor (GPR119) agonists |
| CN102884047A (en) * | 2009-12-04 | 2013-01-16 | 大正制药株式会社 | 2-pyridone compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200811140A (en) * | 2006-07-06 | 2008-03-01 | Arena Pharm Inc | Modulators of metabolism and the treatment of disorders related thereto |
-
2015
- 2015-03-12 CN CN201510108798.6A patent/CN104725355A/en active Pending
- 2015-03-12 CN CN201710091454.8A patent/CN106749179A/en active Pending
Patent Citations (5)
| 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 |
| CN101123964A (en) * | 2004-12-24 | 2008-02-13 | 普罗西迪恩有限公司 | G-protein coupled receptor(GPR116) agonists and use thereof for treating obesity and diabetes |
| CN101466667A (en) * | 2006-04-11 | 2009-06-24 | 普罗西迪恩有限公司 | Azetidine derivatives as g-protein coupled receptor (GPR119) agonists |
| CN102884047A (en) * | 2009-12-04 | 2013-01-16 | 大正制药株式会社 | 2-pyridone compounds |
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| Publication number | Publication date |
|---|---|
| CN106749179A (en) | 2017-05-31 |
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Application publication date: 20150624 |