CN103483281B - Triazole amide compound and preparing method and antidiabetic function thereof - Google Patents
Triazole amide compound and preparing method and antidiabetic function thereof Download PDFInfo
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- CN103483281B CN103483281B CN201310418208.0A CN201310418208A CN103483281B CN 103483281 B CN103483281 B CN 103483281B CN 201310418208 A CN201310418208 A CN 201310418208A CN 103483281 B CN103483281 B CN 103483281B
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- compound
- diabetes
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- ZVQCZVLUEQOSPK-UHFFFAOYSA-N Cc([n]1N)nnc1SCc(cc1)ccc1OCC(N(C)c1cc(F)ccc1)=O Chemical compound Cc([n]1N)nnc1SCc(cc1)ccc1OCC(N(C)c1cc(F)ccc1)=O ZVQCZVLUEQOSPK-UHFFFAOYSA-N 0.000 description 1
- NRTKPAHWWBAFDJ-UHFFFAOYSA-N Cc([n]1N)nnc1SCc(cc1)ccc1OCC(Nc1cccc(Cl)c1)=O Chemical compound Cc([n]1N)nnc1SCc(cc1)ccc1OCC(Nc1cccc(Cl)c1)=O NRTKPAHWWBAFDJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicines related to diabetes, in particular to a compound containing a pyrrodiazole acid amides structure, a preparing method of the compound and application of the compound in the treatment of diabetes, wherein the compound has a general formula I and can treat diabetes and serve as peroxysome proliferation PPAR agonist. Radical groups are defined in the description.
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 triazolylamide 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%, 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, 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 PPAR γ.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 triazolylamide compounds 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 the compound 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 salt and ester thereof.
Another object of the present invention is to provide the application of compound in treatment diabetes containing general formula I.
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
1be selected from phenyl, by F, Cl, Br, I, CN, NO
2the phenyl replaced;
R
2be selected from H, C1-C5 alkyl, phenyl, by F, Cl, Br, I, CN, NO
2the phenyl replaced;
R
3be selected from H, C1-C5 alkyl.
Preferred following compound of Formula I,
R
1be selected from phenyl, by F, C1, Br, I, CN, NO
2the phenyl replaced;
R
2be selected from H, C1-C3 alkyl, phenyl, by F, Cl, Br, I, CN, NO
2the phenyl replaced;
R
3be selected from H, C1-C3 alkyl.
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 PBr
3process 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 acid, such as, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, the pharmacy acceptable salt that such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid etc. generate.
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
2.48g (10mmol) compd A-1 and 1.24g (10mmol) compd B-1 are dissolved in 10mLDMF, add 4.15g (30mmol) 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=309 ([M+NH
4]
+).
2.47g (8mmol) Compound C-1 is dissolved in the toluene of 10mL drying, slowly stirs, slowly drip 2.71g (10mmol) 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=370 and 372 ([M+NH
4]
+).
1.85g (5mmol) Compound D-1 and 0.65g (5mmol) E-1 are dissolved in 5mL MeCN, stir, add 2.07g (15mmol) K
2cO
3, continue under room temperature to stir until raw material consumption complete (12-24 hour).In reaction mixture impouring 100mL frozen water, 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 I-1, white solid, fusing point 209-213 DEG C; ESI-MS, m/z=421 ([M+NH
4]
+).
Embodiment 2-11
With reference to the method for embodiment 1, prepare the compound that the general formula shown in following table is I.
Embodiment 12
Sample is mixed with the suspension of 5mg/mL concentration with 1% 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, 1.5h 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 13
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/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 (2)
1. following compounds:
2. the purposes of compound described in claim 1 in preparation treatment diabetes medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310418208.0A CN103483281B (en) | 2013-09-03 | 2013-09-03 | Triazole amide compound and preparing method and antidiabetic function thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310418208.0A CN103483281B (en) | 2013-09-03 | 2013-09-03 | Triazole amide compound and preparing method and antidiabetic function thereof |
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| Publication Number | Publication Date |
|---|---|
| CN103483281A CN103483281A (en) | 2014-01-01 |
| CN103483281B true CN103483281B (en) | 2015-04-22 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP3210469A1 (en) | 2016-02-23 | 2017-08-30 | Bayer Cropscience AG | Use of substituted thio-1,2,4-triazoles for increasing stress tolerance in plants |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060100235A1 (en) * | 2003-04-11 | 2006-05-11 | Novo Nordisk A/S | Pharmaceutical use of substituted 1,2,4-triazoles |
| BRPI0417947A (en) * | 2003-12-22 | 2007-04-17 | Lilly Co Eli | compound, pharmaceutical composition, manufacture of a medicament for use in the treatment and / or prevention of a metabolic disorder, and, pharmaceutical formulation |
| CN1934095A (en) * | 2004-03-08 | 2007-03-21 | 惠氏公司 | Ion channel modulators |
| BRPI0509172A (en) * | 2004-03-26 | 2007-08-28 | Amphora Discovery Corp | at least one chemical entity, pharmaceutical composition, methods for treating a patient, inhibiting at least one enzyme using atp, and treating at least one disease, use of at least one chemical entity, and method for the manufacture of a medicament |
| JP2007210929A (en) * | 2006-02-09 | 2007-08-23 | Sankyo Co Ltd | Medicine containing urea compound |
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