CN104744386A - PTP1B inhibitor containing tetrazole structure and use of PTP1B inhibitor - Google Patents
PTP1B inhibitor containing tetrazole structure and use of PTP1B inhibitor Download PDFInfo
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- CN104744386A CN104744386A CN201510094474.1A CN201510094474A CN104744386A CN 104744386 A CN104744386 A CN 104744386A CN 201510094474 A CN201510094474 A CN 201510094474A CN 104744386 A CN104744386 A CN 104744386A
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- compound
- ptp1b inhibitor
- ptp1b
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Abstract
The invention relates to the field of drugs related to type II diabetes and specifically relates to a PTP1B inhibitor containing a tetrazole structure, a preparation method of the PTP1B inhibitor and the use of the PTP1B inhibitor in preparing the type II diabetes drugs. The formula I is as shown in the specification.
Description
Technical field
The present invention relates to the pharmaceutical field of type ii diabetes treatment.More particularly, the present invention relates to type ii diabetes tool medicative a kind of PTP1B inhibitor, its preparation method containing tetrazole structure, 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 tetrazole structure of novel structure, 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 can prepare (Vereshchagin, L.I. according to literature method; Et al, RussianJournal of Organic Chemistry, 2006,42 (7), 1049-1055).
Compound II per reacts with compound III in the presence of a base, obtains compound IV; Compound IV and compound V react, and obtain VI; Compound VI and compound VI I react under heating, obtain Compound I; Wherein, the definition of R as previously mentioned.
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
Compound II per (1.19g, 10mmol), compound III (1.49g, 10mmol) and solid K
2cO
3(4.15g, 30mmol) adds in 10mL DMF, gained mixture room temperature for overnight in nitrogen atmosphere, and TLC detects and finds that reaction completes.Reaction mixture pours in 100mL frozen water, stirs, regulates pH=2-3, 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, white solid.ESI-MS,m/z＝230([M-H]
-)。
B. the synthesis of compound VI-1
Compound IV (1.16g, 5mmol), compound V (0.61g, 5mmol) and solid K
2cO
3(2.07g, 15mmol) adds in 10mL DMF, and gained mixture stirs at 60 DEG C and spends the night in nitrogen atmosphere, and TLC detects and finds that reaction completes.Reaction mixture pours in 100mL frozen water, stirs, uses CH
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 VI-1, white solid.ESI-MS,m/z＝318([M+H]
+)。
C. the synthesis of Compound I
Compound VI (0.63g, 2mmol) and compound VI I (0.85g, 10mmol) are dissolved in the toluene of 2mL drying, and then reflux 5 hours in nitrogen atmosphere, TLC detection reaction completes.Reaction mixture pours in 100mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use 1% 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 I, white solid.ESI-MS,m/z＝371([M+H]
+)。
the synthesis of embodiment 2 reference compound D-1
Compound D-1 is all the compound (not yet open by the applying date) that the present inventor designs in research process.
A. the synthesis of compound IV-2
Compound II per (1.19g, 10mmol), compound III-2 (1.24g, 10mmol) and solid K
2cO
3(4.15g, 30mmol) adds in 10mL DMF, gained mixture room temperature for overnight in nitrogen atmosphere, and TLC detects and finds that reaction completes.Reaction mixture pours in 100mL frozen water, stirs, regulates pH=2-3, 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＝205([M-H]
-)。
B. the synthesis of compound VI-2
Compound IV-2 (1.03g, 5mmol), compound V-1 (0.61g, 5mmol) and solid K
2cO
3(2.07g, 15mmol) adds in 10mL DMF, and gained mixture stirs at 60 DEG C and spends the night in nitrogen atmosphere, and TLC detects and finds that reaction completes.Reaction mixture pours in 100mL frozen water, stirs, uses CH
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 VI-2, white solid.ESI-MS,m/z＝293([M+H]
+)。
C. the synthesis of Compound D-1
Compound VI-2 (0.58g, 2mmol) and compound VI I-1 (0.85g, 10mmol) are dissolved in the toluene of 2mL drying, and then reflux 5 hours in nitrogen atmosphere, TLC detection reaction completes.Reaction mixture pours in 100mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use 1% 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 D-1, white solid.ESI-MS,m/z＝346([M+H]
+)。
embodiment 3 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 D-1 | 16.6 |
| Compound I | 7.9 |
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 (3)
1. there is the compound of general formula I,
2. synthesize the method for the compound of formula I described in claim 1:
Compound II per reacts with compound III in the presence of a base, obtains compound IV; Compound IV and compound V react, and obtain VI; Compound VI and compound VI I react under heating, obtain Compound I.
3. the application of formula I described in claim 1 in preparation treatment diabetes B medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510094474.1A CN104744386A (en) | 2015-03-03 | 2015-03-03 | PTP1B inhibitor containing tetrazole structure and use of PTP1B inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510094474.1A CN104744386A (en) | 2015-03-03 | 2015-03-03 | PTP1B inhibitor containing tetrazole structure and use of PTP1B inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
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Family
ID=53584735
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|---|---|---|---|
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6214877B1 (en) * | 1998-05-12 | 2001-04-10 | John A. Butera | 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia |
| US20050043388A1 (en) * | 2001-10-30 | 2005-02-24 | Applied Research Systems Ars Holding N.V. | Oxindole hydrazide modulators of protein tyrosine phosphatases (ptps) |
| WO2007009911A1 (en) * | 2005-07-21 | 2007-01-25 | F. Hoffmann-La Roche Ag | PYRIDO [2 , 3-D] PYRIMIDINE-2 , 4-DIAMINE COMPOUNDS AS PTPlB INHIBITORS |
| CN101260086A (en) * | 2007-03-06 | 2008-09-10 | 中国科学院上海药物研究所 | Protein-tyrosine-phosphatase 1B inhibitor and its preparation method and use |
-
2015
- 2015-03-03 CN CN201510094474.1A patent/CN104744386A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6214877B1 (en) * | 1998-05-12 | 2001-04-10 | John A. Butera | 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia |
| US20050043388A1 (en) * | 2001-10-30 | 2005-02-24 | Applied Research Systems Ars Holding N.V. | Oxindole hydrazide modulators of protein tyrosine phosphatases (ptps) |
| WO2007009911A1 (en) * | 2005-07-21 | 2007-01-25 | F. Hoffmann-La Roche Ag | PYRIDO [2 , 3-D] PYRIMIDINE-2 , 4-DIAMINE COMPOUNDS AS PTPlB INHIBITORS |
| CN101260086A (en) * | 2007-03-06 | 2008-09-10 | 中国科学院上海药物研究所 | Protein-tyrosine-phosphatase 1B inhibitor and its preparation method and use |
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Application publication date: 20150701 |
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