CN103467406B - Halogen-substituted tetrazole carboxylic acid compounds, and preparation method and application thereof - Google Patents
Halogen-substituted tetrazole carboxylic acid compounds, and preparation method and application thereof Download PDFInfo
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- CN103467406B CN103467406B CN201310418243.2A CN201310418243A CN103467406B CN 103467406 B CN103467406 B CN 103467406B CN 201310418243 A CN201310418243 A CN 201310418243A CN 103467406 B CN103467406 B CN 103467406B
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- VPJWIAVXJHXLQV-NSCUHMNNSA-N Bc(cc1/C=C/COc2ccc(C[n]3nnnc3C(O)=O)cc2)ccc1OC Chemical compound Bc(cc1/C=C/COc2ccc(C[n]3nnnc3C(O)=O)cc2)ccc1OC VPJWIAVXJHXLQV-NSCUHMNNSA-N 0.000 description 1
- WFRNLAIHQOXDMU-NSCUHMNNSA-N COC(C=CC(C1)Cl)=C1/C=C/COc1ccc(C[n]2nnnc2C(O)=O)cc1 Chemical compound COC(C=CC(C1)Cl)=C1/C=C/COc1ccc(C[n]2nnnc2C(O)=O)cc1 WFRNLAIHQOXDMU-NSCUHMNNSA-N 0.000 description 1
- VSRIOOXEWVBNBJ-NSCUHMNNSA-N COc(cc1)c(/C=C/COc2ccc(C[n]3nnnc3C(O)=O)cc2)cc1F Chemical compound COc(cc1)c(/C=C/COc2ccc(C[n]3nnnc3C(O)=O)cc2)cc1F VSRIOOXEWVBNBJ-NSCUHMNNSA-N 0.000 description 1
- QLJPRQYXJIGJJY-NSCUHMNNSA-N COc1c(/C=C/COc2ccc(C[n]3nnnc3C(O)=O)cc2)ccc(Cl)c1 Chemical compound COc1c(/C=C/COc2ccc(C[n]3nnnc3C(O)=O)cc2)ccc(Cl)c1 QLJPRQYXJIGJJY-NSCUHMNNSA-N 0.000 description 1
- FJWZYVXMTDOPNP-NSCUHMNNSA-N COc1cc(F)ccc1/C=C/COc1ccc(C[n]2nnnc2C(O)=O)cc1 Chemical compound COc1cc(F)ccc1/C=C/COc1ccc(C[n]2nnnc2C(O)=O)cc1 FJWZYVXMTDOPNP-NSCUHMNNSA-N 0.000 description 1
Abstract
The invention relates to the field of diabetes related medicines. The invention particularly relates to tetrazole-carboxylic-acid-containing compounds (disclosed as general formula I) capable of treating diabetes as a peroxisome proliferator-activated receptor (PPAR) agonist, and a preparation method and application thereof in treating diabetes. In the general formula I, the groups are defined in the specification.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes.Specifically, the present invention relates to peroxisome proliferator-activated property acceptor (PPAR) agonist of the medicative class of diabetes containing tetrazole carboxylic acid skeleton, its preparation method and the pharmaceutical composition containing them.
Background technology
Diabetes are diseases of Patients' rights blood sugar capability deteriorates, and patient loses ability insulin action being made to appropriate reaction to some extent.In diabetes, major part is type ii diabetes (i.e. non insulin dependent diabetes), account for 80%-90%, grind high discovery, the insulin resistant of peripheral tissues's (comprising skeletal muscle, liver and fatty tissue etc.) plays a part very important in the generation, development of type ii diabetes.Having introduced a class at present makes patient recover responsive class medicine, i.e. an insulin sensitizers to own insulin, returns to normally to make Regular Insulin and triglyceride level.In the treatment of research diabetes, peroxisome proliferator-activated property acceptor (PPARs) becomes desirable target, it is one of nuclear receptor superfamily member, several genes can be regulated and controled express simultaneously, take part in Adipocyte Differentiation, lipid metabolism adjustment and increase the physiological processs such as insulin sensitivity.There is three types in PPAR family: PPAR α, PPAR β (being also PPAR δ) and PPARa.PPAR α relates to the β-oxidation stimulating lipid acid, also relate to control HDL cholesterol levels, play an important role in Liver lipids metabolism, and PPAR γ acceptor relates to Adipocyte Differentiation program and must activate, insulin resistant can be improved and improve insulin sensitivity (Yang Jun, Zou Xiulan, PPAR α/γ double excitations machine and diabetes B, Medical review, 2008,14 (16): 2492-2496).PPAR γ is considered to the main molecules target of glitazone insulin sensitizers, although glitazone compound is the active drug for the treatment of type ii diabetes, but the side effect of this compounds clearly, such as serious toxin for liver type, body weight increase and anaemia, this mainly glitazone be the main of PPAR γ or full agonist (N A Jie, sieve D is thorough, her Feng of S, CN101098865A).Therefore, the dual agonists of PPAR α and PPAR γ just can alleviate the side effect even eliminating glitazone PPAR gamma agonist, except making blood sugar and Regular Insulin normalizing, also has the effect reducing blood fat and suppress cardiovascular complication.
The invention discloses the dual agonists of a class tetrazole carboxylic acid compound as PPAR α and PPAR γ, the medicine that these inhibitor may be used for the medicine, particularly non insulin dependent diabetes preparing treatment diabetes lays the foundation.
Summary of the invention
An object of the present invention is the shortcoming and defect overcoming prior art, provide one to have excellent activity, there is compound and the pharmacy acceptable salt thereof of general formula I.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for pharmacy acceptable salt thereof.
Another object of the present invention be to provide compound containing general formula I and pharmaceutically acceptable salt as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carrier, vehicle or thinners, and the application in treatment diabetes.
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 halogen.
Preferred following compound of Formula I
R is selected from F, Cl, Br.
The compound that preferred the present invention has general formula I is as follows:
Compound of Formula I of the present invention is synthesized by following steps:
Compd A and B react in the presence of an inorganic base, obtain Compound C; Compound C PBr3 process obtains Compound D, and D and E is obtained by reacting Compound I in the presence of a base.
The pharmacy acceptable salt of formula I of the present invention comprises, but be not limited to and various mineral alkali, such as, sodium carbonate, salt of wormwood, sodium bicarbonate, or organic bases, the pharmacy acceptable salt that such as methylamine, ethamine, dimethylamine, diethylamine, triethylamine etc. generate.The pharmaceutically acceptable ester of formula I of the present invention includes but not limited to methyl esters, ethyl ester, n-propyl, isopropyl ester, the positive pharmaceutically acceptable ester such as butyl ester, the tert-butyl ester.
Compound of Formula I of the present invention has the double excitations effect of PPAR α and PPAR γ, can be used as effective constituent for the preparation of the medicine of diabetes aspect can lose weight and increase and suppress cardiovascular complication disease.The activity of compound of Formula I of the present invention is by hypoglycemic in body and fall blood cholesterol levels and triglyceride level model is verified.
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 20mg-400mg/ 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.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
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
2.61g (10mmo1) compd A-1 and 1.24g (10mmol) compd B-1 are dissolved in 10mL DMF, add 4.15g (30mmo1) K
2cO
3, then spend the night at 120 DEG C of stirred under nitrogen atmosphere.In the slightly cold rear impouring 100mL frozen water of reaction mixture, stir, regulate pH=3-4 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL × 3, merge extraction phase, once, anhydrous sodium sulfate drying, boils off solvent at Rotary Evaporators and obtains a resistates in salt water washing, then column chromatography purification, obtain the sterling of C-1, ESI-MS, m/z=318 ([M+NH
4]
+).
2.43g (8mmo1) Compound C-1 is dissolved in the toluene of 10mL drying, slowly stirs, slowly drip 2.71g (10mmo1) PBr under ice-water bath cooling
3the solution that the methylene dichloride being dissolved in 2mL drying is made, dropwising rear reaction mixture at room temperature stirs after half an hour in impouring 100mL frozen water, stirs, with the dichloromethane extraction of 50mL × 3, merge extraction phase, once, anhydrous sodium sulfate drying, boils off solvent at Rotary Evaporators and obtains a resistates in salt water washing, then column chromatography purification, obtain the sterling of D-1, ESI-MS, m/z=and 368 ([M+H]
+).
1.83g (5mmo1) Compound D-1 and 0.57g (5mmo1) E-1 are dissolved in 10mL DMF, stir, add 2.07g (15mmo1) K
2cO
3, continue at 100 DEG C to stir until raw material consumption complete (12 hours).In reaction mixture impouring 100mL frozen water, stir, regulate pH:2 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL × 3, merge extraction phase, once, anhydrous sodium sulfate drying, boils off solvent at Rotary Evaporators and obtains a resistates in salt water washing, then column chromatography purification, obtain the sterling of I-1, white solid, fusing point 179 ~ 182 DEG C; ESI-MS, m/z=401 ([M+H]
-).
Embodiment 2-8
According to the method for embodiment 1, prepare the compound that the general formula shown in following table is I.
Embodiment 9
Sample is mixed with the suspension of 5mg/mL concentration with I% Xylo-Mucine, and administration volume is 0.4mL/20g body weight, is equivalent to 100mg/kg dosage.
Healthy ICR mouse, male and female half and half, body weight 20-24g, meets primary standard.Animal fasting 16 hours, gavage gives the dextrose in saline solution of testing compound 15 minutes pneumoretroperitoneum injection 2g/kg, after modeling, 0.5h, 1h, 15.h and 2h timing is taken kapillary and is got blood from mouse ball rear vein beard, centrifugation serum, with each time point serum glucose level of determination of glucose oxidase.Blank mouse neither gives glucose and does not also give testing compound, and model mice only gives glucose and do not give testing compound.
Data as can be seen from upper form, each administration all significantly can strengthen the mouse blood sugar dosis tolerata that glucose causes.
Embodiment 10
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, and administration capacity is 0.4mL/20g body weight, is equivalent to 100mg/kg dosage.
Healthy Wister rat, male and female half and half, about body weight 300g, meets primary standard.Animal feeds 30 days with high lipid food, measure cholesterol in serum and content of triglyceride, with cholesterol and content of triglyceride for standard random packet, after animal grouping, gavage gives testing compound 7 days continuously, fasting 12 hours before last administration, after medicine, 1h kapillary gets blood from rat ball rear vein beard, centrifugation serum, measures serum cholesterol and content of triglyceride with cholesterol and Triglyceride Reagent box.
Cholesterol level (g/d1)
Content of triglyceride (g/d1)
The data declaration of above-mentioned two tables, compound of the present invention can effectively reduce cholesterol and triglyceride level.
Claims (2)
1. following compounds, is selected from:
2. the purposes of the arbitrary compound of claim 1 in preparation treatment diabetes medicament.
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| CN103467406B true CN103467406B (en) | 2014-12-17 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1095716A (en) * | 1992-07-03 | 1994-11-30 | 史密丝克莱恩比彻姆有限公司 | Compounds with fabulous hypoglycemic activity |
| CN1537093A (en) * | 2001-07-30 | 2004-10-13 | ŵ��Ų�ڿ˹�˾ | Novel vinyl carboxylic acid derivatives and their use as antidiabetics etc. |
| CN1909902A (en) * | 2003-12-22 | 2007-02-07 | 伊莱利利公司 | Triazole, oxadiazole and thiadiazole derivatives as PPAR modulators for the treatment of diabetes |
-
2013
- 2013-09-03 CN CN201310418243.2A patent/CN103467406B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1095716A (en) * | 1992-07-03 | 1994-11-30 | 史密丝克莱恩比彻姆有限公司 | Compounds with fabulous hypoglycemic activity |
| CN1537093A (en) * | 2001-07-30 | 2004-10-13 | ŵ��Ų�ڿ˹�˾ | Novel vinyl carboxylic acid derivatives and their use as antidiabetics etc. |
| CN1909902A (en) * | 2003-12-22 | 2007-02-07 | 伊莱利利公司 | Triazole, oxadiazole and thiadiazole derivatives as PPAR modulators for the treatment of diabetes |
Non-Patent Citations (2)
| Title |
|---|
| 海洋天然产物BDB及其衍生物的合成与PTP1B抑制活性的研究;崔永超;《青岛科技大学硕士学位论文》;20120715;1-92 * |
| 贺师鹏等.受体药物的分子设计.《受体研究技术》.北京市:北京大学医学出版社,2011,(第2版),242-243. * |
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