Summary of the invention
An object of the present invention is to provide a kind of PTP1B inhibitor with the excellent activity of general formula I.
Another object of the present invention is to provide the method that preparation has the compound of general formula I.
The compound that another object of the present invention is to provide containing general 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 general formula I has following structural formula:
Wherein, R is selected from C1-C3alkyl.
The compound of preferred formula I has following structure,
Compound of 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.
Compound of 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 compound of Formula I of the present invention is verified by receptor binding assays.
Compound of 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 compound of Formula I of the present invention 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.
embodiment1compoundi-1synthesis
A. the synthesis of compound IV-1
Compound II per (1.19g, 10mmol), compound III-1 (1.54g, 10mmol) and solid K2cO3(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 acid2cl2(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＝237([M-H]-)。
B. the synthesis of compound VI-1
Compound IV-1 (1.18g, 5mmol), compound V-1 (0.61g, 5mmol) and solid K2cO3(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 CH2cl2(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＝323([M+H]+)。
C. the synthesis of Compound I-1
Compound VI-1 (0.64g, 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 CH2cl2(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-1, white solid.ESI-MS,m/z＝376([M+H]+)。
embodiment2-6
With reference to embodiment 1 operation steps, synthesize compound listed in Table.
embodiment7compound ira vitro pairpTP1Binhibition 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 compound50value.
Test result sees the following form.
| Compound | IC50(nM) |
| Compound I-1 | 9.3 |
| Compound I-2 | 11.5 |
| Compound I-3 | 19.1 |
| Compound I-4 | 10.6 |
| Compound I-5 | 13.0 |
| Compound I-6 | 21.8 |
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.