CN103467408A - Tetrazole carboxylic acid compounds and application thereof - Google Patents
Tetrazole carboxylic acid compounds and application thereof Download PDFInfo
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- CN103467408A CN103467408A CN2013104182606A CN201310418260A CN103467408A CN 103467408 A CN103467408 A CN 103467408A CN 2013104182606 A CN2013104182606 A CN 2013104182606A CN 201310418260 A CN201310418260 A CN 201310418260A CN 103467408 A CN103467408 A CN 103467408A
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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.Particularly, the present invention relates to peroxisome proliferator-activated property acceptor (PPAR) agonist, its preparation method and the pharmaceutical composition that contains them containing tetrazole carboxylic acid skeleton to the medicative class of diabetes.
Background technology
Diabetes are that the patient controls the impaired disease of blood sugar ability, and the patient has lost the ability of insulin action being made to appropriate reaction to some extent.In diabetes, major part is type ii diabetes (being non insulin dependent diabetes), account for 80%-90%, research finds, the insulin resistant of peripheral tissues's (comprising skeletal muscle, liver and fatty tissue etc.) plays a part very important in the generation of type ii diabetes, development.Introduced at present a class and made the patient recover a responsive class medicine to self Regular Insulin, i.e. insulin sensitizers, so that Regular Insulin and triglyceride level return to normally.In the treatment of grinding high diabetes, peroxisome proliferator-activated property acceptor (PPARs) becomes desirable target, it is one of nuclear receptor superfamily member, can regulate and control several genes simultaneously and express, participate in the physiological processs such as Adipocyte Differentiation, lipid metabolism adjusting and increase insulin sensitivity.There is three types in PPAR family: PPAR α, PPAR β (also being PPAR δ) and PPAR γ.PPAR α relates to the β-oxidation that stimulates lipid acid, also relate to and control the HDL cholesterol levels, in the liver lipid metabolism, play an important role, and PPAR γ acceptor relates to the Adipocyte Differentiation program and must activate, can improve insulin resistant 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 the glitazone compound is the active drug for the treatment of type ii diabetes, but the side effect of this compounds is very obvious, for example serious toxin for liver type, body weight increase and anaemia, this is mainly that glitazone is main or full agonist (the N A Jie of PPAR γ, 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 of even eliminating glitazone PPAR gamma agonist, except making blood sugar and Regular Insulin normalizing, also has the effect that reduces 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, these inhibitor can lay the foundation for the preparation of the medicine of the medicine, particularly non insulin dependent diabetes for the treatment of diabetes.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, a kind of excellent activity that has is provided, there is compound and the pharmacy acceptable salt thereof of general formula I.
Another object of the present invention is to provide the method that preparation has compound and the pharmacy acceptable salt thereof of general formula I.
A further object of the present invention be to provide the compound that contains general formula I and pharmaceutically acceptable salt as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect the treatment diabetes.
Now in conjunction with purpose 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 NR
1r
2, R wherein
1, R
2independently be selected from the cycloalkyl of alkyl and the C3-C5 of C1-C5.
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 reacts under mineral alkali exists with B, obtains Compound C; Compound C PB
r3processing obtains Compound D, and D reacts and obtains Compound I under alkali exists with E.
The pharmacy acceptable salt of formula I compound of the present invention comprises, but be not limited to and various mineral alkalis, for example, sodium carbonate, salt of wormwood, sodium bicarbonate, or organic bases, the pharmacy acceptable salt that such as methylamine, ethamine, dimethylamine, diethylamine, triethylamine etc. generates.The pharmaceutically acceptable ester of formula I compound of the present invention includes but not limited to the pharmaceutically acceptable esters such as methyl esters, ethyl ester, n-propyl, isopropyl ester, positive 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, and can be used as effective constituent for the preparation of the medicine of diabetes aspect and losing weight increases and inhibition 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 the triglyceride level model is verified.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage of for example taking every day, in 20mg-400mg/ people's scope, is divided into once or administration for several times.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by the doctor.These situations comprise: the person's of being treated physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment is only for explanation, and not for limiting the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
Embodiment 1
2.70g (10mmol) compd A-1 is dissolved in 10mL DMF with 1.24g (10mmol) compd B-1, adds 4.15g (30mmol) K
2cO
3, then under 120 ℃ of nitrogen protections, stir and spend the night.In the slightly cold rear impouring 100mL frozen water of reaction mixture, stir, with concentrated hydrochloric acid, regulate pH=3-4, with the dichloromethane extraction of 50mL * 3, merge extraction phase, once, anhydrous sodium sulfate drying, boil off solvent at Rotary Evaporators and obtain a resistates in the salt water washing, column chromatography purification then, obtain the sterling of C-1, ESI-MS, m/z=331 ([M+NH
4]
+).
2.50g (8mmol) Compound C-1 is dissolved in the toluene of 10mL drying, slowly stirs under ice-water bath is cooling, slowly drips 2.71g (10mmol) PB
r3be dissolved in the solution that the methylene dichloride of 2mL drying is made, dropwise rear reaction mixture and at room temperature stir after half an hour in impouring 100mL frozen water, stir, with the dichloromethane extraction of 50mL * 3, merge extraction phase, once, anhydrous sodium sulfate drying, boil off solvent at Rotary Evaporators and obtain a resistates in the salt water washing, column chromatography purification then, obtain the sterling of D-1, ESI-MS, m/z=and 377 ([M+H]
+).
1.88g (5mmol) Compound D-1 and 0.57g (5mmol) E-1 is dissolved in 10mL DMF, stirs, and adds 2.07g (15mmol) K
2cO
3, continue under 100 ℃ to stir until raw material consumption complete (12 hours).In reaction mixture impouring 100mL frozen water, stir, with concentrated hydrochloric acid, regulate pH=2, with the dichloromethane extraction of 50mL * 3, merge extraction phase, once, anhydrous sodium sulfate drying, boil off solvent at Rotary Evaporators and obtain a resistates in the salt water washing, column chromatography purification then, obtain the sterling of I-1, faint yellow solid, 181~184 ℃ of fusing points; ESI-MS, m/z=410 ([M+H]
-).
Embodiment 2-5
According to the method for embodiment 1, prepared the compound that the general formula shown in following table is I.
Embodiment 6
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, the administration volume is the 0.4mL/20g body weight, is equivalent to 100mg/kg dosage.
Healthy ICR mouse, male and female half and half, body weight 20-24g, meet primary standard.Animal fasting 16 hours, gavage gives the dextrose in saline solution of 15 minutes pneumoretroperitoneum injection 2g/kg of testing compound, after modeling, 0.5h, 1h, 1.5h and 2h regularly take kapillary and get blood from mouse ball rear vein beard, centrifugation serum, with each time point serum glucose level of determination of glucose oxidase.Blank mouse does not neither give glucose also not
Give testing compound, model mice only gives glucose and does not give testing compound.
From in form data can find out, each administration all can significantly strengthen the mouse blood sugar dosis tolerata that glucose causes.
Embodiment 7
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, the administration capacity is the 0.4mL/20g body weight, is equivalent to 100mg/kg dosage.
Healthy Wister rat, male and female half and half, body weight 300g left and right, meet primary standard.Animal is fed 30 days with high lipid food, measure cholesterol in serum and content of triglyceride, take cholesterol and content of triglyceride as the standard random packet, after the animal grouping, continuous gavage gives testing compound 7 days, before the last administration, fasting is 12 hours, after medicine, 1h gets blood with kapillary from rat ball rear vein beard, and centrifugation serum is measured 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 (3)
3. the purposes of the arbitrary defined compound of Formula I of claim 1-2 aspect preparation treatment diabetes medicament.
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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 CN201310418260.6A patent/CN103467408B/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 |
---|
崔永超: "海洋天然产物BDB及其衍生物的合成与PTP1B抑制活性的研究", 《青岛科技大学硕士学位论文》 * |
贺师鹏等: "《受体研究技术》", 31 January 2011, 北京市:北京大学医学出版社 * |
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