CN103554043A - Phenyl-substituted triazole amide compounds and application - Google Patents
Phenyl-substituted triazole amide compounds and application Download PDFInfo
- Publication number
- CN103554043A CN103554043A CN201310418222.0A CN201310418222A CN103554043A CN 103554043 A CN103554043 A CN 103554043A CN 201310418222 A CN201310418222 A CN 201310418222A CN 103554043 A CN103554043 A CN 103554043A
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- Prior art keywords
- compound
- phenyl
- diabetes
- ppar
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- 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
Abstract
The invention relates to the field of medicaments correlated to diabetes. Specifically, the invention relates to compounds containing triazole amide structure as a peroxisome proliferator-activated receptor (PPAR) agonist, and the compounds possess the treatment effect on diabetes and have the general formula I shown in the description, wherein the definition of groups are shown in the description; and also the invention relates to a preparation method and application thereof to treat diabetes.
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 triazolylamide skeleton to the medicative class of diabetes.
Background technology
Diabetes are that patient controls the impaired disease of blood sugar ability, and 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 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, participated in Adipocyte Differentiation, lipid metabolism adjusting and increased 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 that stimulates lipid acid, also relate to and control HDL cholesterol levels, in liver lipid metabolism, play an important role, and PPAR γ acceptor relates to 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 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 a class triazolylamide compounds as the dual agonists of PPAR α and PPAR γ, these inhibitor can lay the foundation for the preparation of the medicine for the treatment of the medicine, particularly non insulin dependent diabetes 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 the compound of general formula I.
Another object of the present invention is to provide the method that preparation has compound and salt and the ester of general formula I.
A further object of the present invention is to provide the application aspect treatment diabetes of the compound that contains 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 methyl;
R
2be selected from phenyl, by halogen, CN, NO
2the phenyl replacing.
Further,
R
1be selected from methyl;
R
2be selected from phenyl, by F, Cl, CN, NO
2between the phenyl that replaces of position.
Preferred following compound again:
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 PBr
3processing 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 acids, for example, 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. generates.
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 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, within the scope of 20mg-400mg/ people, 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 doctor.These situations comprise: the person's of being treated physical state, route of administration, age, body weight, the individual reaction to 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
2.63g (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, boils off solvent at Rotary Evaporators and obtains a resistates in salt water washing, column chromatography purification then, obtain the sterling of C-1, ESI-MS, m/z=319 ([M+NH
4]
+).
2.44g (8mmol) Compound C-1 is dissolved in the toluene that 10mL is dry, under ice-water bath is cooling, slowly stirs, and slowly drips 2.71g (10mmol) PBr
3be dissolved in the solution that methylene dichloride that 2mL is dry 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, boils off solvent at Rotary Evaporators and obtains a resistates in salt water washing, column chromatography purification then, obtain the sterling of D-1, ESI-MS, m/z=383 ([M+NH
4]
+).
1.91g (5mmol) Compound D-1 and 0.96g (5mmol) E-1 are dissolved in 5mL MeCN, stir, and add 2.07g (15mmol) K
2cO
3, under room temperature, continue to stir until raw material consumption complete (12-24 hour).In reaction mixture impouring 100mL frozen water, stir, with concentrated hydrochloric acid, regulate pH=3-4, 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, column chromatography purification then, obtain the sterling of I-1, white solid, fusing point 175-178 ℃; ESI-MS, m/z=493 ([M+NH4]
+).
Embodiment 2-6
With reference to the method for embodiment 1, prepared the compound that the general formula shown in following table is I.
Embodiment 7
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, 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 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 upper form, data can be found out, each administration all can significantly strengthen the mouse blood sugar dosis tolerata that glucose causes.
Embodiment 8
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, administration capacity is 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, meets 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 standard random packet, after animal grouping, gavage gives testing compound 7 days continuously, before 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 (4)
1. the compound with general formula I structure
Wherein,
R
1be selected from methyl;
R
2be selected from phenyl, by halogen, CN, NO
2the phenyl replacing.
2. the defined compound of Formula I of claim 1,
Wherein,
R
1be selected from methyl;
R
2be selected from phenyl, by F, Cl, CN, NO
2between the phenyl that replaces of position.
3. the defined compound of Formula I of claim 2, is selected from following compound:
4. the purposes of the arbitrary defined compound of Formula I of claim 1-3 aspect preparation treatment diabetes medicament.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310418222.0A CN103554043B (en) | 2013-09-03 | 2013-09-03 | Phenyl-substituted triazole amide compounds and application |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310418222.0A CN103554043B (en) | 2013-09-03 | 2013-09-03 | Phenyl-substituted triazole amide compounds and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103554043A true CN103554043A (en) | 2014-02-05 |
| CN103554043B CN103554043B (en) | 2015-04-01 |
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ID=50008447
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004009533A1 (en) * | 2002-07-24 | 2004-01-29 | Ptc Therapeutics, Inc. | Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease |
| WO2005097758A1 (en) * | 2004-03-26 | 2005-10-20 | Amphora Discovery Corporation | Certain triazole-based compounds, compositions, and uses thereof |
| 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 |
| CN101103018A (en) * | 2004-11-16 | 2008-01-09 | 神经化学（国际）有限公司 | Compounds for the treatment of CNS and amyloid associated diseases |
| CN102993109A (en) * | 2012-12-03 | 2013-03-27 | 浙江工业大学 | Preparation method of amidine compound |
-
2013
- 2013-09-03 CN CN201310418222.0A patent/CN103554043B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004009533A1 (en) * | 2002-07-24 | 2004-01-29 | Ptc Therapeutics, Inc. | Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease |
| 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 |
| WO2005097758A1 (en) * | 2004-03-26 | 2005-10-20 | Amphora Discovery Corporation | Certain triazole-based compounds, compositions, and uses thereof |
| CN101103018A (en) * | 2004-11-16 | 2008-01-09 | 神经化学（国际）有限公司 | Compounds for the treatment of CNS and amyloid associated diseases |
| CN102993109A (en) * | 2012-12-03 | 2013-03-27 | 浙江工业大学 | Preparation method of amidine compound |
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