One class contains PTP1B inhibitor of phenyl thiazole and cyclopentadiene structure and uses thereofTechnical field
The present invention relates to the pharmaceutical field of diabetes B treatment.More particularly, the present invention relates to the PTP1B inhibitor, its preparation method that the medicative class of diabetes B tool are contained to phenyl thiazole and cyclopentadiene structure, and the purposes in pharmacy.
Background technology
Diabetes B 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 the PTP1B inhibitor containing phenyl thiazole and cyclopentadiene structure of a class formation novelty, these compounds can be used for the medicine preparing treatment diabetes B.
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 diabetes B 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 H, C1-C3alkyl, C3-C8cycloalkyl.
The compound of preferred formula (I) has following structure,
General formula of the present invention (I) compound is synthesized by following route:
Compound V can be prepared according to literature method (rising sun is paid in war, etc., containing the design of the inhibitors of dipeptidyl IV of thiazole ring, synthesis and hypoglycemic activity research, organic chemistry, 2009,29 (8), 1236-1242).
Compound II per is first obtained by reacting its corresponding sylvite with KOH, and the latter reacts with compound III again, obtains compound IV; Compound IV is first obtained by reacting its corresponding sylvite with KOH, and the latter reacts with V again, obtains 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 diabetes B 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
Compound II per (1.32g, 20mmol) be dissolved in 10mL DMSO, stir, add solid KOH (2.81g, 50mmol), continue stirring under room temperature 1 hour, then add compound III (5.86g, 24mmol), gained mixture at room temperature stirs and spends the night, and TLC checks and finds that reaction completes.Reaction mixture pours in 150mL frozen water, stirs, and 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 IV, white solid.ESI-MS,m/z＝230([M+H]+)。
B. the synthesis of Compound I-1
Compound IV (2.29g, 10mmol) be dissolved in 20mL DMSO, stir, add solid KOH (2.81g, 50mmol), continue stirring under room temperature 1 hour, then add compound V-1 (3.19g, 12mmol), gained mixture at room temperature stirs and spends the night, and TLC checks and finds that reaction completes.Reaction mixture pours in 150mL frozen water, stirs, and 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 I-1, white solid.ESI-MS,m/z＝460([M+H]+)。
embodiment2-7
With reference to the method for embodiment 1, synthesize compound listed in Table.
embodiment8compound 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 | 6.4 |
| Compound I-2 | 13.9 |
| Compound I-3 | 7.7 |
| Compound I-4 | 12.3 |
| Compound I-5 | 9.1 |
| Compound I-6 | 10.4 |
| Compound I-7 | 15.2 |
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 diabetes B.