Wherein, compound 4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-diphenyl-2-carboxylic acid or its salt except.

In preferred scheme, R1, R2 are respectively methyl; R3 is a propyl group;

In preferred scheme, R4 the position of substitution is in contraposition, and substituting group as mentioned above.

In more preferred scheme, R1, R2 are respectively methyl; R3 is a propyl group; R4 is the replacement in the contraposition.

In particular, the especially preferred following compound of the present invention:

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-2-methyl alcohol or its salt;

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-methoxyl group or its salt;

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-carboxylic acid methyl esters or its salt;

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-carboxylic acid or its salt;

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-methyl alcohol or its salt;

4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-3-formaldehyde or its salt.

Compound of the present invention can prepare by following operational path:

In route shown in the last figure, each substituting group is as indicated above.Two imidazoles and the two imidazoles that the bromobenzyl bromine reaction obtained to the bromobenzyl protection react with the phenyl-boron dihydroxide (R4 can be: ester group, aldehyde radical or alkoxyl group) that corresponding R4 group replaces again, obtain ester class of the present invention, aldehydes or alcoxyl class target compound; Ester compound obtains acids or alcohols target compound behind hydrolysis or reductive hydrolysis.Perhaps, The compounds of this invention also can obtain by two imidazoles and biphenol compound direct reaction.

Among the present invention, compound can be changed into the form of " salt "." salt " is meant nontoxic relatively inorganic acid addition salt or organic acid addition salt.These salt can be in last separation of compound and purification process on-site preparation, or the compound of purifying is reacted with its free alkali form and suitable organic or inorganic acid, again the salt that forms is separated and makes.Exemplary salt comprises hydrobromate, hydrochloride, vitriol, sulphite, acetate, oxalate, valerate, oleate, palmitate, stearate, lauroleate, borate, benzoate, lactic acid salt, phosphoric acid salt, Citrate trianion, maleate, fumarate, succinate, tartrate, benzoate, mesylate, gluconate, Lactobionate and lauryl sulfonate etc.They can comprise the positively charged ion based on basic metal and alkaline-earth metal, as sodium, lithium, potassium, calcium, magnesium etc., and do not have toxic amine, quaternary amine and amine positively charged ion etc.

Utilize the compound or its salt of gained of the present invention can deliver medicine to the people, described compound can be individually dosed, perhaps with other pharmaceutically acceptable compound Combined Preparation.It may be noted that compound of the present invention can mix administration.Can be oral, rectum, parenteral (intravenously, intramuscular or subcutaneous), topical (pulvis, ointment or drops).

The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.Usually contain 0.5～50% activeconstituents in the solid dosage, preferable 1～20% the activeconstituents that contains, best 1～10% the activeconstituents that contains.In these solid dosages, active compound mixes with at least a conventional inert excipient (or carrier), as: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, lime carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and yellow soda ash; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example hexadecanol and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.

Solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that the release of active compound or compound can postpone in this composition certain part in digestive tube.In case of necessity, active compound also can with above-mentioned vehicle in one or more form microencapsulation form.

The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except the active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent that adopts in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials etc.

Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, the agent of tender flavor and spices.

Except the active ingredient beyond the region of objective existence, suspension can comprise suspension agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.

The composition that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion and be used for being dissolved into again the aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.

The formulation that is used for the The compounds of this invention of topical comprises ointment, powder, propellant and inhalation.Activeconstituents under aseptic condition with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need in case of necessity is mixed together.

Compound of the present invention can carry out medication to Mammals (comprising the people) by oral or injection system clinically, wherein especially with oral way the best.Dosage is 0.01～200mg/kg body weight every day, and preferable dosage is 0.01～100mg/kg body weight every day, and best dosage is 0.01～50mg/kg body weight every day, and simultaneously, optimal dose is looked individuality and quantitatively.

The compounds of this invention or its salt can be used for treating or prevention is regulated relevant disease with RXR and PPAR γ nuclear receptor, also can be used for treating the disease that pathoglycemia raises and is correlated with.Specifically, The compounds of this invention or its salt can be used for treating diabetes, or are used for the treatment of lipid disorders, metabolic syndrome, cardiovascular disorder, coronary artery disease, high blood cholesterol or obesity.

Adopt the method for reporter gene, utilize the screening model of screening nuclear receptor coactivator agent in a kind of viable cell that can activate principle design that its downstream gene transcribes behind the nuclear receptor activation, be used for verifying that compound activates the activity of PPAR acceptor, experimental technique is as follows:

PPAR γ acceptor

From fatty tissue, be cloned into the PPAR γ cDNA of total length with the RT-PCR method, the PCR product that increases is inserted the pcDNA3.1 expression vector after order-checking identify.Reporter gene detects carrier pGL3-Promoter structure with the luciferase of Promega company.Transfection experiment carries out in 96 orifice plates with the U2OS cell, cotransfection RXR and PPAR γ gene in the transfection reporter gene, and transfection adds compound to be detected after 24 hours, and makes the final concentration of solvent DMSO remain on 0.1%.Compound effects lysing cell and carry out the detection of uciferase activity after 24 hours.Can learn the intensity of activation of compound by observing luminous intensity to nuclear receptor.In order to proofread and correct the testing error that factors such as transfection efficiency, cell inoculation quantity and toxicity of compound cause, also simultaneously cotransfection the GFP plasmid as confidential reference items, the luminous value of all test holess is all proofreaied and correct with the GFP value when interpretation.Test-results represents that with activating multiple relatively the value of solvent control is 1, and the big more activation capability that shows of value is high more.In model discrimination, observed sample activation situation to acceptor under 6 kinds of different concns conditions, reacted the pharmacological property of compound more all sidedly, and carried out the concentration-response curve that iterative computation simulates compound effects, and calculated corresponding effective concentration 50 (EC according to following formula₅₀).

f (x) = a + \frac{b}{c + e^{- β (x - α)}}

PPAR α acceptor

Photinus pyralis LUC reporter gene system activates the active analysis of RXR/PPAR α heterodimer to compound.From fatty tissue, be cloned into the PPAR α cDNA of total length with the RT-PCR method, the PCR product that increases is inserted the pcDNA3.1 expression vector after order-checking identify.Reporter gene detects carrier pGL3-Promoter structure with the luciferase of Promega company.Transfection experiment carries out in 96 orifice plates with the U2OS cell, cotransfection RXR and PPAR α gene in the transfection reporter gene, and transfection adds compound to be detected after 24 hours, and makes the final concentration of solvent DMSO remain on 0.1%.Compound effects lysing cell and carry out the detection of uciferase activity after 24 hours.Can learn the intensity of activation of compound by observing luminous intensity to nuclear receptor.In order to proofread and correct the testing error that factors such as transfection efficiency, cell inoculation quantity and toxicity of compound cause, also simultaneously cotransfection the GFP plasmid as confidential reference items, the luminous value of all test holess is all proofreaied and correct with the GFP value when interpretation.Test-results represents that with activating multiple relatively the value of solvent control is 1, and the big more activation capability that shows of value is high more.

Further illustrate content of the present invention below in conjunction with embodiment, but protection scope of the present invention is not limited only to these embodiment.

Embodiment 1:4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-2-methyl alcohol

Two imidazoles 608mg, 2mmol are dissolved in the 30ml dry DMF, add 60%NaH88mg under the stirring at room, add biphenyl raw material 610mg again.Behind the reaction 6h, the TLC monitoring reaction is complete.A large amount of ethyl acetate diluted system, cold water washing, dry organic phase, purifying gets product.Yield 100%.

1H NMR(400Mz，CDCl3)：δ7.82-7.78(2H，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).

Above-mentioned product is dissolved in adding 100mg LiAlH among the anhydrous THF₄Powder, the 1h afterreaction transforms fully.Add a certain amount of ethyl acetate, the salt solution washing, dry organic phase concentrates, and chromatography purification gets white solid product.Developping agent: methylene chloride (20: 1).

1H NMR(400Mz，CDCl3)：δ7.80(1H，m)，7.55-7.47(2H，m)，7.45-7.26(7H，m)，7.25-7.20(1H，m)，7.11(2H，d，J＝3.86Hz)，5.46(2H，s)，4.55(2H，s)，3.83(3H，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).

Embodiment 2:4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-methoxyl group

Two imidazoles 3.04g are dissolved among the 30mlDMF, add 60%NaH 410mg under the stirring at room, add bromobenzyl bromine solid 2.50g, and 60 ℃ of following reactions are spent the night.The dilute with water system, ethyl acetate extraction 3 times merges organic phase, washes with water once again.Dry chromatography purification (developping agent: methylene chloride=10: 1).Get thick product, get the white granular crystallized product with re-crystallizing in ethyl acetate.

Get 237mg, the above-mentioned crystal of 0.5mmol, p-methoxyphenyl boric acid 88mg K₂CO₃Pressed powder is dissolved among THF/EtOH (1: 1) the mixing solutions 15ml together, adds catalyst P d (PPh₃)₄60mg, the 60 ℃ of reactions of stirring and heat up.The system colour-change is first yellow, and is indigo-blue again, after change into light green again.Termination reaction behind the 1h.Concentrating under reduced pressure removes and desolvates, the resistates acetic acid ethyl dissolution, and NaHCO3, the NaCl solution washing, dry back chromatography purification gets white solid product.(developping agent: methylene chloride=20: 1)

1H NMR(400Mz，CDCl3)：δ7.82-7.76(2H，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(3H，s)，2.96-2.83(2H，m)，2.74(3H，s)，1.95-1.80(2H，m)，1.05(3H，t，J＝6.56Hz).

Embodiment 3:4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-the biphenyl-4-carboxylic acid methyl esters

Get 480mg; 1.01mmol the two imidazoles to the bromobenzyl protection are dissolved among THF/EtOH (1: 1) the mixing solutions 30ml together to methyl-formiate phenyl-boron dihydroxide 200mg and K2CO3 pressed powder 276mg; slowly add catalyst P d (PPh3) 4116mg, the 60 ℃ of reactions of stirring and heat up.The deepening gradually of system color, termination reaction behind the 1h.Concentrating under reduced pressure removes and desolvates, the resistates acetic acid ethyl dissolution, and NaHCO3, the NaCl solution washing, dry back chromatography purification gets white solid product.(developping agent: methylene chloride=20: 1)

1H NMR(400Mz，CDCl3)：δ8.07(2H，d，J＝8.43Hz)，7.80-7.77(1H，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＝7.92Hz).

Embodiment 4:4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-carboxylic acid

Two imidazoles diphenic acid methyl esters 170mg are dissolved in the 30ml dioxane, add 10%NaOH solution 2ml, 90 ℃ of reaction 6h.Concentrating under reduced pressure, resistates add water and form solution, and ethyl acetate extraction once.Water is separated out white solid, transfers PH to become neutral, and filtration drying gets the two imidazoles diphenic acids of product.

1H NMR(400Mz，CDCl3)：δ8.41(1H，s)，7.92-7.88(1H，m)，7.75(2H，d，J＝8.25Hz)，7.47-7.43(1H，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＝7.33Hz).

Embodiment 5:4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-methyl alcohol

The two imidazoles diphenic acid methyl esters 106mg of raw material are dissolved in the 20ml methylene dichloride, and ice bath adds excessive LiAlH4 powder down, and system forms suspension liquid, and raw material transforms fully substantially behind the 1h, adds an amount of ethyl acetate.The system washing, dry back chromatography purification gets solid product 80mg, yield 80% (eluent: methylene chloride=60: 1-20: 1).

1H NMR(400Mz，CDCl3)：δ7.81-7.77(1H，m)，7.56-7.47(5H，m)，7.44-7.39(3H，m)，7.37-7.33(1H，m)，7.3 1-7.27(2H，m)，7.12(2H，d，J＝8.06Hz)，5.45(2H，s)，4.73(2H，s)，3.79(3H，s)，2.93(2H，t，J＝7.88Hz)，2.77(3H，s)，1.93-1.80(2H，m)，1.05(3H，t，J＝7.83Hz)。

Embodiment 6:4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-3-formaldehyde

Operate the same fully, to two imidazoles 237mg of bromobenzyl protection and an aldehyde radical phenyl-boron dihydroxide catalysis is coupled must solid product.(product point and raw material point are under methylene chloride=20: 1 expansion system, and the Rf value is almost completely overlapping).

1H NMR(400Mz，CDCl3)：δ10.06(1H，s)，8.04(1H，s)，7.86-7.75(3H，m)，7.62-7.52(3H，m)，7.49(1H，s)，7.44-7.39(1H，m)，7.38-7.26(3H，m)，7.15(2H，d，J＝8.25Hz)，5.46(2H，s)，3.80(3H，s)，3.92(2H，t，J＝7.88Hz)，2.78(3H，s)，1.96-1.80(2H，m)，1.05(3H，t，J＝7.43Hz).

The foregoing description compound by cytologic experiment, has been measured its agonist activity to PPAR γ, PPAR α acceptor, has obtained concentration/effect relation, and has calculated corresponding EC₅₀Value.Learn that from experimental result embodiment of the invention compound has in various degree activation to PPAR γ acceptor, and PPAR α acceptor is not had activation (ia:inactivity).Concrete outcome sees following table for details:

PPARγ：

The embodiment compound	Experimental result (activation multiple)						EC₅₀
	Experimental result (activation multiple)						EC₅₀	0.001uM	0.01uM	0.1uM	1uM	5uM	10uM	(uM)
	1	0.82	0.89	1.01	1.21	1.49	1.70	0.001uM	0.01uM	0.1uM	1uM	5uM	10uM	(uM)	2.95
2	1	0.82	0.89	1.01	1.21	1.49	1.70	1.04	0.94	1.33	1.74	2.99	3.54	3.24	2.95
2	3	1.09	1.03	1.39	2.68	5.10	5.17	1.04	0.94	1.33	1.74	2.99	3.54	3.24	1.35
4	3	1.09	1.03	1.39	2.68	5.10	5.17	0.91	0.81	1.26	1.73	12.16	10.85	0.50	1.35
4	5	1.00	0.76	1.09	0.96	1.69	1.85	0.91	0.81	1.26	1.73	12.16	10.85	0.50	3.39
6	5	1.00	0.76	1.09	0.96	1.69	1.85	0.88	0.75	0.97	1.86	3.27	3.57	2.04	3.39

PPARα：

The embodiment compound	Experimental result (activation multiple)						EC₅₀
	Experimental result (activation multiple)						EC₅₀	0.001uM	0.01uM	0.1uM	1uM	5uM	10uM	(uM)
	1	1.02	1.02	1.07	1.11	1.09	0.96	0.001uM	0.01uM	0.1uM	1uM	5uM	10uM	(uM)	ia
2	1	1.02	1.02	1.07	1.11	1.09	0.96	0.96	1.09	1.05	1.07	1.16	0.96	ia	ia
2	3	1.05	1.18	1.24	1.24	1.11	0.98	0.96	1.09	1.05	1.07	1.16	0.96	ia	ia
4	3	1.05	1.18	1.24	1.24	1.11	0.98	0.93	1.02	1.01	1.08	1.07	0.92	ia	ia
4	5	1.17	1.14	1.32	1.17	0.66	0.71	0.93	1.02	1.01	1.08	1.07	0.92	ia	ia
6	5	1.17	1.14	1.32	1.17	0.66	0.71	1.03	1.02	1.10	0.95	0.93	0.66	ia	ia

Claims

1. compound or its salt shown in the general structure (I):

Wherein, R1, R2, R3 are respectively C₁-C₄The straight or branched alkyl;

R4 can be arbitrary locational following substituting group:

a)-CHO；

b)--CH2OH；

c)---COOR5

R5 is H, C₁-C₄The straight or branched alkyl;

d)---OR6

R6 is C₁-C₄The straight or branched alkyl;

Compound 4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-diphenyl-2-carboxylic acid or its salt except.

2. compound or its salt according to claim 1, wherein, R1, R2 are respectively methyl; R3 is a propyl group.

3. as compound or its salt as described in the claim 2, wherein, R4 is the following substituting group in the contraposition:

a)-CHO；

b)--CH2OH；

c)---COOR5

R5 is H, C₁-C₄The straight or branched alkyl;

d)---OR6

R6 is C₁-C₄The straight or branched alkyl.

4. as compound or its salt as described in the claim 3, wherein, R5 is H or methyl; R6 is a methyl.

5.4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-2-methyl alcohol or its salt.

6.4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-methoxyl group or its salt.

7.4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-carboxylic acid methyl esters or its salt.

8.4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-carboxylic acid or its salt.

9.4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-4-methyl alcohol or its salt.

10.4 '-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline-1-yl)-methyl]-biphenyl-3-formaldehyde or its salt.

11. comprise the composition of the arbitrary described compound or its salt of claim 1～10.

12. with the arbitrary described compound or its salt of claim 1～10 is formulations of active ingredients.

13. the application of claim 1～10 a described compound or its salt in treatment PPAR γ receptor associated diseases.

14. the application of the arbitrary described compound or its salt of claim 1～10 in treatment pathoglycemia rising relative disease.

15. the application of the arbitrary described compound or its salt of claim 1～10 in the treatment diabetes.

16. the application of the arbitrary described compound or its salt of claim 1～10 in treatment lipid disorders, metabolic syndrome, cardiovascular disorder, coronary artery disease, high blood cholesterol or obesity.