CN103467408B - Tetrazole carboxylic acid compounds and application thereof - Google Patents

Abstract

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

Description

A class of tetrazole carboxylic acid compounds and uses thereof

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 tetrazolium carboxylic acid skeleton that has a therapeutic effect on diabetes, its preparation method and pharmaceutical compositions 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. Peroxisome proliferator-activated receptors (PPARs) become an ideal target in the treatment of Yankang diabetes. It is a member of the nuclear receptor superfamily, which can simultaneously regulate the expression of multiple genes and participate in the differentiation of adipocytes , lipid metabolism regulation and increased insulin sensitivity and other physiological processes. 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 tetrazole carboxylic acid 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 with general formula I and pharmaceutically acceptable salts thereof with good activity.

Another object of the present invention is to provide a process for the preparation of compounds of general formula I and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a pharmaceutical composition containing a compound of general formula I and a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers, excipients or diluents , and its application 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:

Wherein, R is selected from NR ¹ R ² , wherein R ¹ and R ² are independently selected from C1-C5 alkyl and C3-C5 cycloalkyl.

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 reacts with B in the presence of an inorganic base to obtain compound C; compound C is treated with PB _r3 to obtain compound D, and D and E react 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 bases, such as sodium carbonate, potassium carbonate, sodium bicarbonate, or organic bases, such as methylamine, ethylamine, dimethyl Pharmaceutically acceptable salts formed from amines, diethylamine, triethylamine, etc. The pharmaceutically acceptable esters of the compound of formula I in the present invention include but are not limited to pharmaceutically acceptable esters such as methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, tert-butyl ester and the like.

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 in the range of 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

2.70 g (10 mmol) of compound A-1 and 1.24 g (10 mmol) of compound B-1 were dissolved in 10 mL of DMF, 4.15 g (30 mmol) of K ₂ CO ₃ were 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=331 ([M+NH ₄ ] ⁺ ).

2.50g (8mmol) of compound C-1 was dissolved in 10mL of dry toluene, slowly stirred under cooling in an ice-water bath, and slowly added dropwise a solution prepared by dissolving 2.71g (10mmol) of PB _r3 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 = and 377 ([M+H] ⁺ ).

Dissolve 1.88g (5mmol) of compound D-1 and 0.57g (5mmol) of E-1 in 10mL of DMF, stir, add 2.07g (15mmol) of K ₂ CO ₃ , and continue stirring at 100°C until the raw materials are consumed (12 hours) . The reaction mixture was poured into 100mL of ice water, stirred, adjusted to pH=2 with concentrated hydrochloric acid, extracted with 50mL×3 dichloromethane, combined the extract phases, washed once with brine, dried over anhydrous sodium sulfate, and evaporated the solvent in a rotary evaporator to obtain The residue was purified by column chromatography to obtain the pure product I-1, a pale yellow solid with a melting point of 181-184°C; ESI-MS, m/z=410 ([M+H] ^- ).

Example 2-5

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

Example 6

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 of body weight, 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, given the compound to be tested by intraperitoneal injection of 2g/kg glucose saline solution for 15 minutes after intraperitoneal injection, and were regularly taken from the retrobulbar venous plexus of mice at 0.5h, 1h, 1.5h and 2h after modeling. Blood was centrifuged to separate serum, and the serum glucose content at each time point was determined by glucose oxidase method. Blank mice received neither glucose nor

The compound to be tested was given, and the model mice were only given glucose without the compound to be tested.

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 7

The sample was prepared into a suspension with a concentration of 5mg/mL with 1% sodium carboxymethylcellulose, and the administration volume was 0.4mL/20g body weight, which was equivalent to a dose of 100mg/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/d1)

Triglyceride content (g/d1)

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. The use of any compound of claim 1 in the preparation of a medicament for treating diabetes.