CN103467398B - Triazole amide compounds, and preparation method and application thereof in resisting diabetes - Google Patents

Abstract

The invention relates to the field of medicine related to diabetes. Specifically, the present invention relates to a class of compound containing triazole amide structure having a general formula I that has a therapeutic effect on diabetes as a peroxisome proliferator-activated receptor (PPAR) agonist, its preparation method and its therapeutic effect on diabetes Applications in diabetes. Wherein, the definition of the group is as described in the description.

Description

Triazole amide compound, its preparation method and its antidiabetic use

technical field

The invention relates to the field of medicine related to diabetes. Specifically, the present invention relates to a class of peroxisome proliferator-activated receptor (PPAR) agonists containing a triazole amide skeleton, which have a therapeutic effect on diabetes, a preparation method thereof and a pharmaceutical composition containing them.

Background technique

Diabetes mellitus is a disease in which the patient's ability to control blood sugar is impaired, and the patient has lost, to varying degrees, the ability to respond appropriately to the action of insulin. Most of diabetes is type II diabetes (non-insulin-dependent diabetes), accounting for about 80%-90%. Studies have found that insulin resistance in peripheral tissues (including skeletal muscle, liver and adipose tissue, etc.) , development plays an extremely important role. A class of drugs that sensitize patients to their own insulin, insulin sensitizers, has been introduced to restore insulin and triglycerides to normal. In the treatment of diabetes, peroxisome proliferator-activated receptors (PPARs) become an ideal target. It is a member of the nuclear receptor superfamily, which can simultaneously regulate the expression of multiple genes, and is involved in adipocyte differentiation, Physiological processes such as lipid metabolism regulation and increased insulin sensitivity. There are three types of the PPAR family: PPARα, PPARβ (also called PPARδ) and PPARγ. PPARα is involved in stimulating the β-oxidation of fatty acids and controlling HDL cholesterol levels, which plays an important role in liver lipid metabolism, while PPARγ receptors are involved in the activation of adipocyte differentiation programs, which can improve insulin resistance and insulin sensitivity (Yang Jun, Zou Xiulan, PPARα/γ dual activator and type 2 diabetes, Medical Review, 2008, 14(16): 2492-2496). PPARγ is considered to be the main molecular target of glitazone insulin sensitizers. Although glitazones are effective drugs for the treatment of type II diabetes, the side effects of these compounds are very obvious, such as severe liver toxicity, weight gain And anemia, which is mainly due to the fact that glitazones are the main or complete agonists of PPARγ (N·Ajie, D·Rocher, S·Yvonne, CN101098865A). Therefore, the dual agonists of PPARα and PPARγ can reduce or even eliminate the side effects of glitazone PPARγ agonists, and besides normalizing blood sugar and insulin, they also have the effect of lowering blood lipid and inhibiting cardiovascular complications.

The invention discloses a class of triazole amide compounds as dual agonists of PPARα and PPARγ. These inhibitors can be used to prepare medicines for treating diabetes, especially laying the foundation for medicines for non-insulin-dependent diabetes.

Contents of the invention

An object of the present invention is to overcome the disadvantages and deficiencies of the prior art and provide a compound of general formula I with good activity.

Another object of the present invention is to provide processes for the preparation of compounds of general formula I and their salts and esters.

Another object of the present invention is to provide the application of the compound containing general formula I in the treatment of diabetes.

The content of the present invention will now be specifically described in conjunction with the purpose of the present invention.

Compounds of the present invention having general formula I have the following structural formula:

in,

R ¹ is selected from C3-C5 cycloalkyl;

R ² and R ³ are independently selected from H, C1-C5 alkyl.

Compounds of general formula I below are preferred,

Wherein, ^R is selected from cyclopropanyl, cyclopentanyl;

R ² and R ³ are independently selected from H, C1-C3 alkyl.

More preferred compounds of the present invention having general formula I are shown below:

The compound of general formula I of the present invention is synthesized through the following steps:

Compound A reacted with B in the presence of an inorganic base to obtain compound C; compound C was treated with PBr ₃ to obtain compound D, and D and E were reacted in the presence of a base to obtain compound I.

The pharmaceutically acceptable salts of the compound of formula I of the present invention include, but are not limited to, various inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as formic acid, acetic acid, citric acid, oxalic acid, Pharmaceutically acceptable salts formed from fumaric acid, maleic acid, amino acids, etc.

The compound of general formula I in the present invention has dual agonistic effects of PPARα and PPARγ, and can be used as an active ingredient in the preparation of therapeutic drugs for diabetes, and can reduce weight gain and inhibit cardiovascular complications. The activity of the compound of general formula I in the present invention is verified by in vivo hypoglycemic and blood cholesterol and triglyceride reduction models.

The compounds of general formula I according to the invention are effective over a fairly wide dosage range. For example, the daily dose is about 20mg-400mg/person, divided into one or several administrations. The actual dosage of the compound of general formula I of the present invention can be determined by a doctor according to relevant conditions. These conditions include: the physical state of the person being treated, the route of administration, age, weight, individual response to the drug, and the severity of symptoms.

Detailed ways

The present invention will be further described below in conjunction with embodiment. It should be noted that the following examples are only for illustration, but not for limiting the present invention. Various changes made by those skilled in the art according to the teaching of the present invention shall be within the scope of protection required by the claims of the present application.

Example 1

1.92g (10mmol) of compound A-1 and 1.24g (10mmol) of compound B-1 were dissolved in 10mL of DMF, 4.15g (30mmol) of K ₂ CO ₃ was added, and stirred overnight at 120°C under nitrogen protection. The reaction mixture was cooled slightly and poured into 100mL of ice water, stirred, adjusted to pH=3-4 with concentrated hydrochloric acid, extracted with 50mL×3 dichloromethane, combined the extract phases, washed once with brine, dried over anhydrous sodium sulfate, and evaporated on a rotary evaporator. The solvent was evaporated to obtain a residue, which was purified by column chromatography to obtain the pure product of C-1, ESI-MS, m/z=243 ([M+NH ₄ ] ⁺ ).

1.94g (8mmol) of compound C-1 was dissolved in 10mL of dry toluene, and slowly stirred under cooling in an ice-water bath, slowly added dropwise a solution made of 2.71g (10mmol) of _PBr3 dissolved in 2mL of dry dichloromethane, dropwise After the addition, the reaction mixture was stirred at room temperature for half an hour, then poured into 100 mL of ice water, stirred, extracted with 50 mL×3 dichloromethane, combined the extract phases, washed once with brine, dried over anhydrous sodium sulfate, and evaporated in a rotary evaporator. The solvent was used to obtain a residue, and then purified by column chromatography to obtain the pure product of D-1, ESI-MS, m/z=314 and 316 ([M+NH ₄ ] ⁺ ).

Dissolve 1.58g (5mmol) of compound D-1 and 0.65g (5mmol) of E-1 in 5mL of MeCN, stir, add 2.07g (15mmol) of K ₂ CO ₃ , and continue stirring at room temperature until the raw materials are consumed (12-24 hours ). The reaction mixture was poured into 100 mL of ice water, stirred, adjusted to pH=3-4 with concentrated hydrochloric acid, extracted with 50 mL×3 dichloromethane, combined the extract phases, washed with brine once, dried over anhydrous sodium sulfate, and evaporated in a rotary evaporator. The solvent was used to obtain a residue, and then purified by column chromatography to obtain the pure product of I-1, a white solid, melting point 177-181°C; ESI-MS, m/z=365 ([M+NH ₄ ] ⁺ ).

Example 2-8

Referring to the method of Example 1, the compounds of general formula I shown in the table below were prepared.

Example 9

The sample was formulated with 1% sodium carboxymethylcellulose into a suspension at a concentration of 5 mg/mL, and the administration volume was 0.4 mL/20 g body weight, which was equivalent to a dose of 100 mg/kg.

Healthy ICR mice, half male and half male, weighing 20-24g, meet the first-class standard. Animals were fasted for 16 hours, administered intragastrically with the compound to be tested for 15 minutes, and then intraperitoneally injected with 2 g/kg of glucose saline solution. At 0.5h, 1h, 1.5h and 2h after modeling, the capillary was taken from the retrobulbar venous plexus of the mouse at regular intervals. Blood was centrifuged to separate serum, and the serum glucose content at each time point was determined by glucose oxidase method. The blank mice were given neither glucose nor the test compound, and the model mice were only given glucose without the test compound.

It can be seen from the data in the above table that each administration can significantly enhance the blood sugar tolerance of mice induced by glucose.

Example 10

The sample was formulated with 1% sodium carboxymethylcellulose into a suspension at a concentration of 5 mg/mL, and the administration volume was 0.4 mL/20 g body weight, equivalent to a dose of 100 mg/kg.

Healthy Wister rats, half male and half male, weighing about 300g, meet the first-class standard. The animals were fed with high-fat feed for 30 days, the content of cholesterol and triglyceride in the serum was measured, and the content of cholesterol and triglyceride was used as the standard for random grouping. After the animals were grouped, they were given the compound to be tested by gavage for 7 days, and they were fasted before the last administration. 12 hours, 1 hour after the administration, blood was collected from the retrobulbar venous plexus of rats with a capillary tube, the serum was separated by centrifugation, and the content of cholesterol and triglyceride in serum was measured with a cholesterol and triglyceride kit.

Cholesterol content (g/dl)

Triglyceride content (g/dl)

The data in the above two tables demonstrate that the compounds of the present invention are effective in lowering cholesterol and triglycerides.

Claims (2)

1. The following compounds selected from:

2. use of a compound as defined in any one of claims 1 for the manufacture of a medicament for the treatment of diabetes.