CN103483282A - Phenyl-substituted triazole amide compounds and application - Google Patents

Abstract

The invention relates to the field of drugs relevant to the diabetes, in particular to compounds of triazole amide structures, a preparation method and an application in the aspect of treating the diabetes. The compounds have the general formula I, play a role in treating the diabetes and can be used as a PPAR agonist. The perssad definition is mentioned in the specification.

Description

Triazolylamide compounds and purposes that phenyl replaces

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 the triazolylamide 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 triazolylamide compounds 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 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 of compound aspect the treatment diabetes that contains general formula I.

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 ¹be selected from H, methyl, ethyl;

R ²be selected from the alkyl of H, C1-C5.

Preferred following compound of Formula I,

R ¹be selected from H, methyl, ethyl;

R ²be selected from the alkyl 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 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 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

1.37g (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, ESl-MS, m/z=199 ([M+NH4] ⁺).

1.45g (8mmol) Compound C-1 is dissolved in the toluene of 10mL drying, under ice-water bath is cooling, slowly stir, slowly drip the solution that methylene dichloride that 2.71g (10mmol) PBr3 is dissolved in the 2mL drying is made, dropwising rear reaction mixture at room temperature stirs after half an hour in impouring 100mL frozen water, stir, dichloromethane extraction with 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=258 ([M+NH4] ⁺).

1.22g (5mmol) Compound D-1 and 0.96g (5mmol) E-1 is dissolved in 5mL MeCN, stirs, and adds 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, 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, fusing point 183-186 ℃; ESI-MS, m/z=369 ([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, 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 8

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 (4)

1. the compound that there is the general formula I structure

Wherein,

R ¹be selected from H, methyl, ethyl;

R ²be selected from the alkyl of H, C1-C5.

2. the defined compound with general formula I of claim 1

Wherein,

R ¹be selected from H, methyl, ethyl;

R ²be selected from the alkyl of H, C1-C3.

3. the defined compound of Formula I of claim 2 is selected from:

4. the purposes of the arbitrary defined compound of Formula I of claim 1-3 aspect preparation treatment diabetes medicament.