CN103467405B - A class of tetrazole carboxylic acid compounds, its preparation method and use - 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, its preparation method and 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 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. 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, it also has 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 H, C1-C5 alkyl, and C3-C5 cycloalkyl.

Compounds of general formula I below are preferred

R is selected from H, C1-C3 alkyl, cyclopropyl.

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 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 formula I in the present invention can be prepared into a pharmaceutical composition together with one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition can be made into solid oral preparations, liquid oral preparations, injections and other dosage forms. The solid and liquid oral preparations include: tablets, dispersible tablets, sugar-coated agents, granules, dry powders, capsules and solutions. The injections include: small needles, large infusions, freeze-dried powder injections and the like.

In the composition of the present invention, the pharmaceutically or food acceptable auxiliary materials are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials, or other excipients.

The composition of the present invention, the pharmaceutically or food acceptable excipients. The filler is a combination of one or more fillers including lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and microcrystalline cellulose; The binder includes one of sucrose, starch, povidone, sodium carboxymethylcellulose, hypromellose, hypromellose, methylcellulose, polyethylene glycol, pharmaceutical alcohol, water The composition of one or more kinds; the disintegrating agent includes starch, cross-linked polymicroketone, cross-linked carmellose sodium, low-substituted hydroxypropyl cellulose, carmellose sodium, effervescent disintegrating One or a combination of several agents.

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

2.27g (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=288 ([M+NH ₄ ] ⁺ ).

2.16g (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 made of 2.71g (10mmol) of PB _r3 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=333 and 335 ([M+H] ⁺ ).

Dissolve 1.67g (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 A residue was purified by column chromatography to obtain the pure product I-1, a white solid, melting point 214-217°C; ESI-MS, m/z=365 ([MH] ^- ).

Example 2-10

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

Example 11

Sieve the active ingredient, pregelatinized starch and microcrystalline cellulose, mix well, add polyvinylpyrrolidone solution, mix, make soft material, sieve, make wet granules, dry at 50-60°C, and carboxymethyl starch Sodium salt, magnesium stearate and talc are pre-screened and then added to the above granules for tableting.

Example n

Example 12

Sieve the active ingredient, pregelatinized starch and microcrystalline cellulose, mix well, add polyvinylpyrrolidone solution, mix, make soft material, sieve, make wet granules, dry at 50-60°C, and magnesium stearate and talc powder in advance, then added to the above-mentioned granules, packed into capsules, and obtained.

Example 13

In distilled water, first add distilled water and citric acid, stir to dissolve and then add the sample, slightly heat to dissolve, adjust the pH value to 4.0-5.0, add 0.2 g of activated carbon, stir at room temperature for 20 minutes, filter, filtrate, medium The concentration of the solution was determined by control, divided into 5 milliliters per ampoule, and sterilized at high temperature for 30 minutes to obtain the injection.

Example 14

Preparation process: Take 80 mL of water for injection, add the main drug, mannitol, lactose, and poloxamer and stir to dissolve, add 1 mol/L citric acid to adjust the pH to 7.0-9.0, and add water to 100 mL. Add 0.5g of activated carbon, stir at 30°C for 20 minutes, decarbonize, filter and sterilize with a microporous membrane, divide the filtrate into 1mL tubes, pre-freeze for 2 hours, and dry under reduced pressure for 12 hours under freezing until the sample After the temperature reaches room temperature, it is dried for another 5 hours to obtain a white loose block, which is sealed.

Example 15

2% hypromellose (prepared with pure water) QS

Preparation process: pass the main drug and auxiliary materials through a 100-mesh sieve respectively, fully mix, then weigh the prescription amount of auxiliary materials and fully mix with the main drug. Then add soft material made of binder, granulate with 14 mesh sieve, dry at 55°C, granulate with 12 mesh sieve, measure bag weight and pack.

Example 16

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 glucose content in serum 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 17

The sample was prepared into a suspension with a concentration of 5 mg/mL with 1% sodium carboxymethyl cellulose, and the administration volume was 0.4 mL/20 g body weight, which was 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 (6)

1. The following compounds, selected from: 2. the method for synthetic general formula I compound, comprises the following steps: Wherein, R is selected from H, C1-C5 alkyl, C3-C5 cycloalkyl; Compound A and B reacted 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. 3. The use of any compound of claim 1 in the preparation of a medicament for treating diabetes. 4. A pharmaceutical composition comprising any compound of claim 1 together with a suitable carrier or excipient. 5. The pharmaceutical composition according to claim 4, wherein the composition is a solid oral preparation, a liquid oral preparation or an injection. 6. The solid and liquid oral preparations according to claim 5 include: dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, granules, oral solutions, and the injection preparations include water for injection, jelly for injection Dry powder injection, large infusion, small infusion.