CN104803977A - PTP1B derivatives containing tetrazole structures as well as preparation methods and applications of derivatives - Google Patents
PTP1B derivatives containing tetrazole structures as well as preparation methods and applications of derivatives Download PDFInfo
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- CN104803977A CN104803977A CN201510094669.6A CN201510094669A CN104803977A CN 104803977 A CN104803977 A CN 104803977A CN 201510094669 A CN201510094669 A CN 201510094669A CN 104803977 A CN104803977 A CN 104803977A
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- compound
- derivatives
- 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
Abstract
The invention relates to the field of drugs related to type-2 diabetes, in particular to PTP1B inhibitor derivatives containing tetrazole structures, preparation methods of the derivatives as well as applications to preparation of drugs for the type-2 diabetes.
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, Russian Journal 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.
embodiment
1
compound
i-1
synthesis
A. the synthesis of compound IV
Compound II per (1.19g, 10mmol), compound III (1.38g, 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-yellowish solid.ESI-MS,m/z＝219([M-H]
-)。
B. the synthesis of compound VI-1
Compound IV (1.10g, 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＝307([M+H]
+)。
C. the synthesis of Compound I
Compound VI (0.61g, 2mmol) and compound VI I (1.27g, 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＝402([M+H]
+)。
embodiment
2
reference compound
d-1
synthesis
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 pair
pTP1B
inhibition test
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 | 5.2 |
As can be seen from upper table result, compound of the present invention has very strong restraining effect to PTP1B, can as the medicine of preparation treatment type ii diabetes.
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 |
|---|---|---|---|
| CN201510094669.6A CN104803977A (en) | 2015-03-03 | 2015-03-03 | PTP1B derivatives containing tetrazole structures as well as preparation methods and applications of derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510094669.6A CN104803977A (en) | 2015-03-03 | 2015-03-03 | PTP1B derivatives containing tetrazole structures as well as preparation methods and applications of derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104803977A true CN104803977A (en) | 2015-07-29 |
Family
ID=53689209
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510094669.6A Pending CN104803977A (en) | 2015-03-03 | 2015-03-03 | PTP1B derivatives containing tetrazole structures as well as preparation methods and applications of derivatives |
Country Status (1)
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|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829729A (en) * | 2003-08-01 | 2006-09-06 | 田边制药株式会社 | Novel compounds |
-
2015
- 2015-03-03 CN CN201510094669.6A patent/CN104803977A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829729A (en) * | 2003-08-01 | 2006-09-06 | 田边制药株式会社 | Novel compounds |
Non-Patent Citations (3)
| Title |
|---|
| 万祺等: "治疗2型糖尿病新靶标及新先导化合物的研究进展", 《中国新药杂志》 * |
| 崔巍等: "新型二氟甲基磷酸类酪氨酸蛋白磷酸酯酶1B抑制剂的分子动力学模拟和结合自由能计算", 《物理化学学报》 * |
| 马开庆等: "酪氨酸蛋白磷酸酯酶1B抑制剂的构效关系", 《药学进展》 * |
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| EXSB | Decision made by sipo to initiate substantive examination | ||
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| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150729 |
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| RJ01 | Rejection of invention patent application after publication |