CN103467405A - Tetrazole carboxylic acid compounds, and preparation method and application thereof - Google Patents
Tetrazole carboxylic acid compounds, and preparation method and application thereof Download PDFInfo
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- CN103467405A CN103467405A CN2013104182254A CN201310418225A CN103467405A CN 103467405 A CN103467405 A CN 103467405A CN 2013104182254 A CN2013104182254 A CN 2013104182254A CN 201310418225 A CN201310418225 A CN 201310418225A CN 103467405 A CN103467405 A CN 103467405A
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- PQJCOTVWPBLZNJ-GQCTYLIASA-N COc1c(/C=C/COc2ccc(C[n]3nnnc3C(O)=O)cc2)cccc1 Chemical compound COc1c(/C=C/COc2ccc(C[n]3nnnc3C(O)=O)cc2)cccc1 PQJCOTVWPBLZNJ-GQCTYLIASA-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.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 research 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 the alkyl of H, C1-C5, the cycloalkyl of C3-C5.
Preferred following compound of Formula I
R is selected from alkyl, the cyclopropyl of H, C1-C3.
It is as follows that preferred the present invention has the compound of general formula I:
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.
Formula I compound of the present invention, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made the formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention, can accept auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle on described pharmacy or bromatology.
Composition of the present invention, can accept auxiliary material on described pharmacy or bromatology.Weighting agent is one or more the composition that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
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
2.27g (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=288 ([M+NH
4]
+).
2.16g (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=333 and 335 ([M+H]
+).
1.67g (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, white solid, 214～217 ℃ of fusing points; ESI-MS, m/z=365 ([M-H]
-).
Embodiment 2-10
According to the method for embodiment 1, prepared the compound that the general formula shown in following table is I.
Embodiment 11
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix softwood processed, sieve, wet granular processed, in 50-60 ℃ of drying, by the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
Embodiment n
Embodiment 12
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix, softwood processed, sieve, and wet granular processed, in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, then join in above-mentioned particle, encapsulated, obtain.
Embodiment 13
In distilled water, first add distilled water and citric acid, stirring and dissolving and after, add sample, low-grade fever makes to dissolve again, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stir 20 minutes under room temperature, filter filtrate, strength of solution is determined in middle detection, by 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes, obtain injection liquid.
Embodiment 14
Preparation technology: get water for injection 80mL, after adding main ingredient, N.F,USP MANNITOL, lactose, poloxamer and being stirred to dissolve, the Citric Acid that adds 1mol/L is regulated PH to 7.0-9.0, mends and adds water to 100mL.Add the 0.5g gac, stir 20 minutes under 30 ℃, de-charcoal, adopt the filtering with microporous membrane degerming, filtrate is carried out packing by every 1mL, and pre-freeze is after 2 hours, freezing lower drying under reduced pressure 12 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal and get final product.
Embodiment 15
2% hypromellose (pure water preparation) QS
Preparation technology: main ingredient and auxiliary material are crossed respectively to 100 mesh sieves, fully mix, then take the recipe quantity auxiliary material and fully mix with main ingredient.Add tackiness agent softwood processed, 14 mesh sieves are granulated again, 55 ℃ of dryings, and the whole grain of 12 mesh sieves, measure heavily packing of bag.
Embodiment 16
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 neither gives glucose and does not also give testing compound, and model mice only gives glucose and do 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 17
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/dl)
Content of triglyceride (g/dl)
The data declaration of above-mentioned two tables, compound of the present invention can effectively reduce cholesterol and triglyceride level.
Claims (8)
1. the compound that there is the general formula I structure:
Wherein, R is selected from the alkyl of H, C1-C5, the cycloalkyl of C3-C5.
2. the defined compound with general formula I of claim 1:
Wherein, R is selected from alkyl, the cyclopropyl of H, C1-C3.
3. the defined compound of Formula I of claim 2 is selected from:
4. synthesize the method for the defined compound of Formula I of claim 1-3, comprise the 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.
5. the purposes of the arbitrary defined compound of Formula I of claim 1-3 aspect preparation treatment diabetes medicament.
6. a pharmaceutical composition, contain the arbitrary compound of Formula I of claim 1-3 and suitable carrier or vehicle.
7. pharmaceutical composition claimed in claim 6, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
8. solid and liquid oral medicine comprise according to claim 7: dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, described injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
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|---|---|---|---|
| CN201310418225.4A CN103467405B (en) | 2013-09-03 | 2013-09-03 | Tetrazole carboxylic acid compounds, and preparation method and application thereof |
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|---|---|---|---|
| CN201310418225.4A CN103467405B (en) | 2013-09-03 | 2013-09-03 | Tetrazole carboxylic acid compounds, and preparation method and application thereof |
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|---|---|
| CN103467405A true CN103467405A (en) | 2013-12-25 |
| CN103467405B CN103467405B (en) | 2015-01-07 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5869495A (en) * | 1992-07-03 | 1999-02-09 | Smithkline Beecham P.L.C. | Heterocyclic compounds as pharmaceutical |
| 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 |
| US20090298831A1 (en) * | 2008-05-29 | 2009-12-03 | Yonggil Kim | Phenyl piperazine compounds, pharmaceutical composition including the same and use thereof |
-
2013
- 2013-09-03 CN CN201310418225.4A patent/CN103467405B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5869495A (en) * | 1992-07-03 | 1999-02-09 | Smithkline Beecham P.L.C. | Heterocyclic compounds as pharmaceutical |
| 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 |
| US20090298831A1 (en) * | 2008-05-29 | 2009-12-03 | Yonggil Kim | Phenyl piperazine compounds, pharmaceutical composition including the same and use thereof |
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》, 15 July 2012 (2012-07-15) * |
| 贺师鹏等: "《受体研究技术》", 31 January 2011, article "ppars" * |
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Granted publication date: 20150107 Termination date: 20160903 |