WO2008006319A1

WO2008006319A1 - BIBENZIMIDAZOLE DERIVATIVES HAVING PPARγ AGONIST ACTIVITY AND THEIR USES

Info

Publication number: WO2008006319A1
Application number: PCT/CN2007/070250
Authority: WO
Inventors: Jianhui Guo; Yong Jiang
Original assignee: Shanghai Allist Pharmaceutical., Inc.
Priority date: 2006-07-07
Filing date: 2007-07-06
Publication date: 2008-01-17
Also published as: CN101100458A; CN101511820A

Abstract

Bibenzimidazole derivatives having PPARγ agonist activity or its salts, their manufacturing methods, and their uses in treating PPARγ receptor-related diseases. The compounds is selective PPARγ agonist and have specific PPARγ-activated activity, and thus can be used to treat PPARγ receptor-related diseases, abnormal increased blood sugar-related diseases, in particularly, diabetes mellitus, or metabolic syndrome, etc.

Description

Bibenzimidazole derivatives having PPAR gamma agonist activity and application thereof

The present invention relates to compounds having PPAR gamma agonist activity, methods for their preparation, and their clinical use in the treatment of PPAR Y receptor related diseases such as diabetes or related complications. Background technique

Diabetes is a disease caused by a variety of genetic disorders, which plague a large part of the world. There are two types: (1) Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM), with little or no insulin secretion; (2) Type 11 diabetes or non-insulin-dependent diabetes mellitus (MDDM;), II The concentration of plasma insulin in patients with type 2 diabetes is basically the same as that of normal people. However, the patient's body is resistant to insulin, which further affects the metabolism of sugar and fat in insulin-sensitive tissues, muscle, liver and adipose tissue, and the concentration of insulin in plasma in patients with type 2 diabetes is insufficient to overcome this. Resistance. 90% of people with diabetes are type 2 diabetes.

In recent years, it has been found that type II diabetes is closely related to peroxisome proliferators-activated receptor (PPAR). PPAR belongs to a member of the ligand-activated transcription factor-nuclear hormone receptor superfamily and is divided into three subtypes, g卩PPAR (i, PPAR Y and PPAR S. PPAR and retinoic acid X receptor (RXR) It forms a heterodimer and activates gene expression by binding to a hormone response element on the target gene. PPAR / RXR heterodimer plays an important role in controlling cell lipid homeostasis and adipocyte differentiation. PPAR γ is mainly in fat It plays an important regulatory role in the expression and differentiation of tissue-related genes, and is also an important regulator of glucose and lipid metabolism target genes. PPAR ci stimulates the proliferation of peroxidase, accelerates the oxidation of fatty acids, and thus reduces fatty acids in the blood. The content, PPAR a agonist such as Fibrates is therefore used to treat dyslipidemia.

Oral hypoglycemic drugs currently on the market mainly include insulin, sulfonylureas, biguanides, glucosidase inhibitors and thiazolidinedione (TZD) drugs. TZD compounds are novel insulin sensitizers that target PPAR γ, which can improve the body's sensitivity to insulin, thereby improving abnormal glucose metabolism, reducing high glucose toxicity, and not exhibiting hypoglycemia. In addition, the compounds also have the advantages of preventing loss of islet cells and long duration of efficacy. TZD regulates the differentiation of adipocytes and increases sensitivity to insulin by activating PPAR gamma. Such drugs that agonize PPAR gamma receptors, such as rosiglitazone (Avandia) and pioglitazone (Pioglitazone, Atten, Actos;). Although TZD compounds have been clinically proven to be very effective Anti-type 2 diabetes drugs, but because these two drugs can cause side effects such as weight gain, edema, adipose tissue agitation, or changes in bone marrow fatty acids, it is necessary to find a new class of PPAR Y agonists. Summary of the invention

The present invention discloses a class of compounds having a selective activation of PPAR Y or a salt thereof.

The invention also discloses a process for the preparation of the compound or a salt thereof, and a clinical use of the compound as a PPAR Y receptor related disease, such as diabetes or related complications. In a first aspect of the invention, there is provided a compound of the formula ω or a pharmaceutically acceptable salt thereof:

Wherein R1, R2, and R3 are each a dC ₄ linear or branched alkyl group;

R4 can be the following substituents at any position:

a) -CHO

b) -CH ₂ OH

c) -COOR5

R5 is hydrogen, dC ₄ straight or branched alkyl; preferably hydrogen or methyl;

d) -OR6

1 6 is dC ₄ linear or branched alkyl; preferably methyl;

Wherein, in the definition of R1, R2, R3, R4, R5 and R6, each alkyl group may be an alkyl group which is unsubstituted or has 1-3 substituents, and the substituent is 1-3 selected from the group consisting of Groups: F, Cl, Br, -OH, NH ₂ ;

Additional conditions are the compound 4 ' -[(2-n-propyl-4-methyl-6-(1-methyl-benzoimidazol-2-ylbenzimidazol-1-yl)-methyl]-biphenyl Except for 2-carboxylic acid or a salt thereof.

In a preferred embodiment, R1, R2 are each a methyl group; and/or R3 is a propyl group;

In a preferred embodiment, the R4 substitution position is in the para position and the substituents are as described above.

In a more preferred embodiment, R1 and R2 are each a methyl group; R3 is a propyl group; and R4 is a substitution at the para position. More specifically, the following compounds are particularly preferred in the present invention:

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl-benzimidazole_μyl)-methyl]-biphenyl-2-methanol Or its salt;

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl-benzimidazole_μ)-methyl]-biphenyl-4-methyl An oxy group or a salt thereof;

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl-benzimidazole_μ)-methyl]-biphenyl-4-carboxylate Acid methyl ester or a salt thereof;

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl-benzimidazole_μ)-methyl]-biphenyl-4-carboxylate Acid or its salt;

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl-benzimidazole _ μ)-methyl]-biphenyl

-4-methanol or a salt thereof;

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl-benzimidazole_μyl)-methyl]-biphenyl-3-carbaldehyde Or its salt.

In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

In a third aspect of the present invention, there is provided the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a PPAR Y receptor-related disease: a disease associated with abnormal blood glucose elevation, diabetes, a lipid disorder , metabolic syndrome, cardiovascular disease, coronary artery disease, high blood cholesterol or obesity.

The present invention also provides a method for treating or preventing a PPAR Y receptor-associated disease, comprising the steps of: administering to a subject in need thereof, for example, 0.05 to 200 mg/kg body weight per day of a compound of the present invention or a pharmaceutically acceptable compound thereof salt.

In another preferred embodiment, the PPAR Y receptor-related diseases include diseases associated with abnormal blood glucose elevation, diabetes, lipid disorders, metabolic syndrome, cardiovascular disease, coronary artery disease, hypercholesterolemia or obesity.

In a fourth aspect of the invention, there is provided a method of preparing a pharmaceutical composition comprising mixing a compound of the invention, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier to form a pharmaceutical composition. detailed description

The inventors have extensively and extensively studied and screened a large number of compounds, and found for the first time that the compound of the formula (I) not only has a good activation effect on the ΡΡΑΙίγ receptor, but also has substantially no activation effect on the PPARoc receptor. Compared with the existing drugs, the side effects are small and do not cause a significant increase in the body weight of the patient. The present invention has been completed on this basis. Active ingredient

As used herein, the term "compound of the invention" refers to a compound of formula (I). The term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).

In the present invention, the compound can be converted into a "pharmaceutically acceptable salt" form. The salt refers to a relatively non-toxic inorganic acid addition salt or organic acid addition salt. These salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound with the appropriate organic or inorganic acid in its free base form, and separating the formed salt. Representative salts include hydrobromide, hydrochloride, sulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, boron Acid salt, benzoate, lactate, phosphate, citrate, maleate, fumarate, succinate, tartrate, benzoate, methanesulfonate, gluconate, Lactose salts and lauryl sulfonates, and the like. They may contain alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic amines, quaternary amines and amine cations and the like. Preparation

The compounds of the present invention can be prepared by the following route

In the above route, each substituent is as described above. The biimidazole is reacted with p-bromobenzyl bromide to obtain a bromidyl group-protected biimidazole, which is then reacted with a corresponding R4 group-substituted phenylboronic acid (R4 may be: an ester group, an aldehyde group or an alkoxy group; The ester, aldehyde or alkoxy target compound of the present invention; the ester compound is subjected to hydrolysis or hydrolysis to obtain an acid or alcohol target compound. Alternatively, the compounds of the invention may also be passed through a double microphone. The azole is directly reacted with a biphenyl compound.

In this scheme, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 90 ° C, preferably 0 ° C to 60 ° C). The reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 48 hours.

Pharmaceutical composition and method of administration

The compound obtained by the present invention or a salt thereof can be administered to a human, and the compound can be administered alone or in combination with other pharmaceutically acceptable compounds. It is to be noted that the compounds of the present invention can be administered in combination. It can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (powder, ointment or drops).

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. The solid dosage form usually contains 0.5 to 50% of the active ingredient, preferably 1 to 20% of the active ingredient, and most preferably 1 to 10% of the active ingredient. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier) such as: (a) a filler or compatibilizer, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerin; (d) disintegrants, for example, Agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) an absorption accelerator, for example, a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene Alcohol, sodium lauryl sulfate, or a mixture thereof.

Solid dosage forms such as tablets, troches, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.

In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, Sweeteners, flavorings and spices.

In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like. Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for the compounds of the invention for topical administration include ointments, powders, propellants and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

By "therapeutically effective amount" of the invention is meant an amount which is functional or active against humans and/or animals and which is acceptable to humans and/or animals. A therapeutically effective amount of the composition of the invention is between 0.01 and 200 mg/kg body weight per day. Any amount within the above range is an effective amount of the invention. The "therapeutically effective amount" can be used for single or combined treatment of the disease in question. Those skilled in the art will appreciate that the amount administered in the actual administration may be higher or lower than the above dosage range. The "therapeutically effective amount" and specific treatment regimen for a subject (eg mammalian-human;) can be influenced by a number of factors, including the pharmacodynamic activity of the compound or prodrug used, the age, weight, sex of the subject being administered , the progress of the disease, and the judgment of the doctor.

The compounds of the present invention can be administered clinically to mammals (including humans) by oral or injection means, particularly preferably orally. The dosage is 0.01 to 200 mg/kg body weight per day, preferably the dosage is 0.01 to 100 mg/kg body weight per day, and the optimal dosage is 0.01 to 50 mg/kg body weight per day. Meanwhile, the optimal dose is quantified according to the individual.

The compound of the present invention or a salt thereof can be used for the treatment or prevention of diseases associated with the regulation of RXR and ΡΡΑΙγ nuclear receptors, and can also be used for the treatment of diseases associated with abnormally elevated blood glucose. Specifically, the compound of the present invention or a salt thereof can be used for the treatment of diabetes, or for the treatment of lipid disorders, metabolic syndrome, cardiovascular disease, coronary artery disease, hypercholesterolemia or obesity. The main advantage of the present invention is that the compounds of the present invention have partial agonistic activity on the ΡΡΑΙ γ receptor compared to a complete ΡΡΑΙ γ receptor agonist such as rosiglitazone and do not cause an increase in body weight of a diabetic animal or patient. The invention will be further elucidated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, which do not specify the specific conditions, are usually in accordance with conventional conditions, such as those in the Besselstein Manual of Organic Chemistry (Chemical Industries Press, 1996;) or in accordance with the conditions recommended by the manufacturer. The ratios and percentages are based on weight unless otherwise stated.

Unless otherwise defined or indicated, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Example 1: 4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]- Biphenyl-2-methanol

Bisimidazole 608 mg (2 mmol) was dissolved in 30 ml of anhydrous DMF, and 60% NaH 88 mg was added thereto with stirring at room temperature, and then 610 mg of biphenyl starting material was added. After 6 h of reaction, the reaction was monitored by TLC. A large amount of ethyl acetate was diluted, washed with cold water, and the organic phase was dried to purify the product. The yield is 100%.

1H NMR (400Mz, CDC13): δ7.82-7.78(2Η, m), 7.54-7.45(2H, m), 7.44-7.33(3H, m), 7.32-7.21(5H, m), 7.09(2H, d, J=8.05Hz), 5.45(2H, s), 3.81(3H, s), 3.57(3H, s), 2.94(2H, t, J=7.78Hz), 2.77(3H, s), 1.95- 1.80(2H, m), 1.05(3H, t, J=7.41Hz).

The above product was dissolved in anhydrous THF and 100 mg of LiAl powder was added. After 1 h, the reaction was completely converted. The title compound was obtained as a white solid. (Expansion agent: dichloromethane / methanol (20: 1)).

1H NMR (400Mz, CDC13): δ 7.80 (1 Η, m), 7.55-7.47 (2H, m), 7.45-7.26 (7H, m), 7.25-7.20 (lH, m), 7.11 (2H, d, J=3.86Hz), 5.46(2H, s), 4.55(2H, s), 3.83(3 H, s), 2.95(2H, t, J=7.78Hz), 2.77(3H, m), 1.97-1.82 (2H, m), 1.06(3H, t, J=7.32Hz). Example 2: 4 '-[(2-n-propyl-4-methyl-6-(l-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]- Biphenyl-4-methoxy

3.04 g of diimidazole was dissolved in 30 ml of DMF, and 410 mg of 60% NaH was added thereto with stirring at room temperature, and 2.50 g of p-bromobenzyl bromide solid was added thereto, and the reaction was carried out at 60 ° C overnight. The system was diluted with water, extracted with ethyl acetate three times, and the organic phases were combined and washed with water. Purification by dry chromatography (developing solvent: dichloromethane / methanol = 10:1). The product was obtained as a viscous product which was crystallized from ethyl acetate to afford white crystals.

237 mg (0.5 mmol) of the above crystals, p-methoxyphenylboronic acid 88 mg K ₂ CO ₃ solid powder was dissolved in 15 ml of a mixed solution of THF/EtOH (l: l), and a catalyst Pd(PPh ₃ ) ₄ 60 mg was added and stirred. And the temperature is raised at 60 ° C. The color change of the system is yellow first, then blue, and then turned into light green. The reaction was terminated after lh. The solvent was removed and concentrated under reduced pressure, the residue was dissolved in ethyl acetate, with NaHCO _3, washed with NaCl solution, dried and purified by chromatography to give the title compound as a white solid. (Expansion agent: dichloromethane / methanol = 20: 1)

1H NMR (400Mz, CDC13): δ7.82-7.76(2Η, m), 7.50-7.40(4H, m), 7.39-7.26(4H, m), 7.12-7.04(2H, m), 6.98-6.90 ( 2H, m), 5.43(2H, s), 3.83(3 H, s), 2.96-2.83(2H, m), 2.74(3H, s), 1.95-1.80(2H, m), 1.05(3H, t , J = 6.56 Hz). Example 3: 4 '-[(2-n-propyl-4-methyl-6-(l-methyl-benzimidazol-2-yl)-benzimidazole-1- Methyl)-biphenyl-4-carboxylic acid methyl ester

Take 480mg (1.01mmol) of bromobenzyl protected diimidazole, 200mg of methyl formate phenylborate, and 276mg of K ₂ CO ₃ solid powder - dissolved in 30ml of THF/EtOH (l: 1) mixed solution, slowly The catalyst Pd(PPh ₃ ) ₄ 116 mg was added, stirred and heated at 60 ° C for the reaction. The color of the system gradually darkens and ends after lh Reaction. The solvent was removed and concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with NaCl solution, NaHCO _3, dried and purified by chromatography to give the title compound as a white solid. (Expansion agent: dichloromethane / methanol = 20: 1)

1H NMR (400Mz, CDC13): δ 8.07 (2 Η, d, J = 8.43 Hz), 7.80-7.77 (1 Η, m),

7.61-7.52(4H, m), 7.41-7.26(5H, m), 7.14(2H, d, J=7.88Hz), 5.46(2H, s), 3.92(3H, s), 3.80(3H, s) , 2.93(2H, t, J=7.79Hz), 2.78(3H, s), 1.96-1.85(2H, m), 1.05(3H, t,

J = 7.92 Hz). Example 4: 4 '-[(2-n-propyl-4-methyl-6-(l-methyl-benzimidazol-2-yl)-benzimidazol-1-yl ) - methyl]-biphenyl-4-carboxylic acid

Methyl bis-imidazole-dibenzoate 170 mg was dissolved in 30 ml of dioxane, 2 ml of 10% NaOH solution was added, and reacted at 90 ° C for 6 h. Concentration under reduced pressure, the residue was added water to a solution, and ethyl acetate was evaporated. The aqueous phase precipitated as a white solid, which was adjusted to pH neutral and filtered to give the title compound, i.

1H NMR (400Mz, CDC13): δ 8.41 (1Η, s), 7.92-7.88 (1Η, m), 7.75(2H, d,

J=8.25Hz ), 7.47-7.43(lH, m), 7.38-7.31(3H, m), 7.22(2H, d, J=8.44Hz), 7.16(2H, d, J= 8.43Hz), 7.02( 2H, d, J=8.35Hz), 5.50(2H, s), 3.99(3H, s), 2.80(3H, s), 2.78(2H, t, J=7.88Hz), 1.79-1.70(2H, m ), 0.95 (3H, t, J = 7.33 Hz). Example 5: 4 '-[(2-n-propyl-4-methyl-6-(l-methyl-benzimidazol-2-yl) -benzimidazol-1-yl)-methyl]-biphenyl-4-methanol

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1> . Activation of PPAR receptors

The full-length PPARy cDNA was cloned from adipose tissue by RT-PCR, and the amplified PCR product was inserted into a commercially available pcDNA3.1 expression vector and sequenced. The reporter gene was constructed using Promega's luciferase assay vector pGL3-Promoter. Transfection experiments were performed with U2OS cells in 96-well plates. The RXR and ΡΡΑΙγ genes were co-transfected at the same time as the transfection of the reporter gene. The compound to be tested was added 24 hours after transfection, and the final concentration of the solvent DMSO was maintained at 0.1. %. After 24 hours of compound action, the cells were lysed and tested for luciferase activity. The intensity of activation of the nuclear receptor by the compound can be known by observing the intensity of the luminescence. In order to correct the experimental error caused by factors such as transfection efficiency, cell inoculation amount and compound toxicity, GFP plasmid was also co-transfected as an internal reference. The luminescence values of all the test wells were corrected by GFP value in the analysis of the experimental results. The test results are expressed as relative activation multiples, and the solvent control has a value of 1, and a larger value indicates a higher activation ability. In the model screening, the activation of the receptor at six different concentrations was observed, and the concentration effect curve of the compound action was obtained, and the corresponding semi-effective concentration (EC ₅₀ ) was calculated. Activation of PPARa receptors

Analysis of Compound Activation of RXR/PPARa Heterodimer Activity by Firefly Luciferase Reporter System The full-length PPARpic DNA was cloned from adipose tissue by RT-PCR, and the amplified PCR product was inserted into a commercially available pcDNA3.1 expression vector and sequenced. The reporter gene was constructed using Promega's luciferase assay vector pGL3-Promoter. Transfection experiments were performed with U2OS cells in 96-well plates. The RXR and PPARa genes were co-transfected at the same time as the transfection of the reporter gene. The compound to be tested was added 24 hours after transfection, and the final concentration of the solvent DMSO was kept at 0.1%. . After 24 hours of compound action, cells were lysed and tested for luciferase activity. The intensity of activation of the nuclear receptor by the compound can be known by observing the intensity of the luminescence. In order to correct the experimental error caused by factors such as transfection efficiency, cell inoculation amount and compound toxicity, GFP plasmid was also co-transfected as an internal reference. The luminescence values of all the test wells were corrected by GFP values in the analysis of the experimental results. The test results are expressed as relative activation factors, and the value of the solvent control is 1. The larger the value, the higher the activation ability.

7.2 Results

The experimental results show that the compounds of the examples of the present invention have different degrees of activation of the ΡΡΑΙγ receptor, but no activation of the PPARa receptor. The specific results are detailed in Table 1 and Table 2 below: Table 1 PPAR y

Ia = inactivity (Example 8) hypoglycemic efficacy test

Healthy spontaneous type 2 diabetes animal model, male GK rats, 200g, animals fasted for 12 hours, blood glucose meter to determine fasting blood glucose levels, followed by continuous intragastric administration of compound 1-6, rosiglitazone (20 mg / kg) Or control solution 0.5% CMC (10 ml/kg), and the fasting blood glucose level was measured again after 10 days.

The results indicate that the compounds of the examples of the present invention have good hypoglycemic activity. In addition, with complete

Compared to rosiglitazone, a gamma receptor agonist, the compounds of the invention do not substantially cause an increase in body weight in diabetic animals. Example 9 Pharmaceutical Composition

Compound 1 (Example 1) 23g

Starch 140g

Microcrystalline cellulose 67g

The above materials were uniformly mixed according to a conventional method, and then filled into ordinary gelatin capsules to obtain 1000 capsules. Capsules containing Compound 2-6 were separately prepared in a similar manner. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it is to be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims

Rights request

A compound of the formula ω or a pharmaceutically acceptable salt thereof:

(I)

Wherein R1, R2, and R3 are each a dC ₄ linear or branched alkyl group;

R4 can be the following substituents at any position:

a) -CH0;

b) -CH ₂ 0H _;

c) -C00R5

13⁄4 is 11, dc ₄ linear or branched alkyl; or

d) -0R6

R6 is a dC ₄ linear or branched alkyl group;

Additional conditions are the compound 4 ' - [(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]- Except for biphenyl-2-carboxylic acid or its salt.

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1, R2 are each a methyl group; and/or R3 is a propyl group.

The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R4 is a substituent at the para position:

a) -CH0;

b) -CH ₂ 0H _;

c) -C00R5

1?5 is 11, dC ₄ linear or branched alkyl; or d) -0R6

R6 is a dC ₄ linear or branched alkyl group.

The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R5 is H or methyl; and R6 is methyl.

The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

4'-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2- Methanol or a salt thereof;

4'-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-4- Methoxy or a salt thereof;

4'-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-4- Methyl carboxylate or its salt

4'-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-4- a carboxylic acid or a salt thereof;

4'-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-4- Methanol or its salt; or

4'-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-3- Formaldehyde or its salt.

A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

7. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a PPARY receptor-associated disease.

A method for producing a pharmaceutical composition, which comprises mixing the compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier to form a pharmaceutical composition.

A method for treating or preventing a PPARY receptor-associated disease, comprising the steps of: administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof at a dose of 0.05 to 200 mg/kg body weight per day.

10. The method according to claim 9, wherein the PPARY receptor-related disease is selected from the group consisting of a disease associated with abnormal blood glucose elevation, diabetes, lipid disorder, lipid disorder, metabolic syndrome, heart Vascular disease, coronary artery disease, high blood cholesterol or obesity.