Indian Patents. 220739:THE GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS, THE PREPARATION AND THE USE OF THE SAME

Title of Invention	THE GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS, THE PREPARATION AND THE USE OF THE SAME
Abstract	The present invention provides the glucagon-like peptide-1 receptor agonists. It is indicated that the agonists have good binding capability to glucagon-like peptide-1 receptor by pharmacological tests. The present invention also provides the preparation of the agonists.

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. THE GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS, THE PREPARATION AND THE USE OF THE SAME 2. (A) SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES (B) CHINA (C) 555 Zu Chong Zhi Road, Pudong New District, Shanghai 201203, China. The following specification particularly describes the invention and the manner in which it is to be performed. 1 FIELD OF THE INVENTION The present invention relates to a group of glucagon-like peptide-1 receptor (GLP-1R) agonists. In particularly, the present invention relates to a group of small molecular organic compounds of substituted five-membered heterocyclic ring derivatives which may be used as non-peptide GLP-1R agonists. The compounds of the present invention may be used as medicaments for treating the glycometabolism disturbance-related diseases such as type II diabetes, insensitivity to insulin and obesity etc. And, the present invention also relates to a process for manufacturing the said GLP-1R agonists. BACKGROUND OF THE INVENTION Diabetes mellitus (DM) is a common endocrine metabolic disease with heredity tendency. It is caused mainly by the absolute or relative hyposecretion of the insulin, and it causes metabolic disturbance of saccharide, fat, protein, and subsequently vitamin, water and electrolyte. The manifestations include the increase of glycemia and urine glucose, and the patients have the symptoms of polydipsia, polyphagia, polyuria, dry mouth, and general weakness. The morbidity rate of diabetes mellitus is 1 to 5%, and shows a trend of gradually increasing. Diabetes mellitus, cancer, and cardiovascular diseases are referred as three worldwide serious diseases. The object of treating diabetes mellitus is to correct the disturbance of carbohydrate metabolism, so as to eliminate the symptoms, promote restoration of the function of pancreatic islet, improve the insulin resistance, maintain the better healthy condition and physical strength, and prevent and treat various complications. Diabetes mellitus is commonly divided into two types: Insulin Dependent Diabetes Mellitus (type I, IDDM) and Non-Insulin Dependent Diabetes Mellitus (type II, NIDDM). Since the pathogenesis for theses two types of diabetes mellitus are different, the medicaments for treating them are far different, which are stated respectively as follows. Type I diabetes mellitus is caused by virus infection in hereditarily susceptible person which produce the paradoxical reaction of the islet cells through immunomechanism, so that the pancreatic islets begin to be damaged and even lost their function completely. About 5% of diabetes mellitus is type I. At present, the medicaments for treating type I diabetes mellitus mainly include exogenous insulin (including human insulin and animal insulin), drugs having the insulin-like effect, insulin-like growth factor-1 (IGF-1), novel long-acting insulin preparation, and Jin Qi hypoglycemic tablet, etc. A few of type II diabetes mellitus is caused by direct impair of \|3-islet cells which 2 decreases the secretion of insulin. And most of type II diabetes mellitus is caused by a combination of factors that may include genetic traits, life style, environmental contributors, metabolic disorders, obesity, and so on. In this disease state, muscular, hepatic and adipose tissues are insensitive to the insulin thereby decreasing the intake of the glucose. Most of diabetics suffer from type II diabetes mellitus. At present, the medicaments for the clinical treatment of NIDDM mainly include sulphonylureases, biguanides, other hypoglycemic drugs and adjuvants, etc. The sulphonylureas hypoglycemic drugs bind to the receptors on the cell membrane of p-islet cells to close the potassium ion channel thereby blocking flowout of potassium ion and inducing depolarization of the cell membrane, so that the calcium ion channels are opened to allow the extracellular calcium ions flow inwardly. The increase of intracellular calcium ions concentration triggers the release of the insulin. Sulphonylureas hypoglycemic drugs can be divided into two generations according to their time of coming into existence. The first generation includes tolpropamide, and the second generation includes glibenclamide (euglucan), gliclazide (diamicron), glipizide and gliquidone etc. Biguanide hypoglycemic drugs inhibit appetite, improve the binding of insulin to the receptors, promote the anaerobic glycolysis in cells, inhibit tissue respiration and inhibit hepatic gluconeogenesis. The biguanide hypoglycemic drugs mainly include metformin, phenformin and buformin. Other hypoglycemic drugs mainly include thiazolidinedione drugs (such as troglitazone, rosiglitazone, and pioglitazone, etc), (33-adrenoceptor regulators, glucagon receptor antagonists, fatty acid metabolism interfering agents, a-glycosidase inhibitors (such as acarbose, voglibose, miglitol), and aldose reductase inhibitors, etc. Recently, the development of research on glycometabolism related endogenous peptide hormone provides a new idea for the treatment of diabetes mellitus. When human body intakes nutrient materials, the enteroendocrine cells release enteropeptide hormone which mainly includes glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) and regulates metabolism by affecting the insulin generation, gastrointestinal peristalsis, and islet cell proliferation. Wherein, GLP-1 is secreted by entero-pancreatic cells, and activates the adenylate cyclase to synthesize cAMP by highly specifically binding to the GLP-1 receptor of p-islet cells, so as to further activate the protein kinase. The metabolic signal (glycometabolism) and kinase signal (binding of GLP-1) cooperate on the cell membrane level to finally cause the Ca2+ channel to open and the calcium ions to flow inwardly so that further stimulates the secretion of insulin while inhibiting the generation of glucagon, thereby decrease 3 the postprandial blood glucose to maintained blood glucose concentration at a constant level. Also, GLP-1 has the function of neuroregulation, and can retard gastric emptying, and inhibit appetite. All of these are greatly beneficial for control of diabetes mellitus. Normally, GLP-1 stimulates insulin secretion depending on the blood glucose concentration. As the blood glucose concentration decreases, the effect of GLP-1 on stimulating insulin secretion decreases. Therefore, the action of GLP-1 on decreasing blood glucose is self-limited, and can not cause hypoglycaemia. So, for treating diabetes mellitus, the medicaments with the GLP-1-like action are greatly desirable for the treatment of diabetes mellitus. GLP-1 R agonists have been one researching focus of the international drug development organizations. At present, the researches on GPL-1R mainly focus on the polypeptide regulators. For example, AC 2993 of Amylin Corporation has applied for clinic test in US (IND). AC2993 is a 39-amino acids polypeptide and has the effect of promoting the secretion of insulin as GPL-1. Since the polypeptide drugs is inconvenient for oral administration and is readily to degrade, non-peptides GLP-1 R regulator is the new researching direction at present. DISCLOSURE OF THE INVENTION The object of the present invention is to design a group of novel small molecular organic compound of substituted five-membered heterocyclic ring derivative which may be used as glucagon-like peptide-1 receptor (GLP-1 R) agonists, so as to prove a way for searching the leader compounds or the drugs for the medicaments against the diabetes mellitus. Another object of the present invention is to provide a process for preparing these compounds. The Glucagon-like peptide-1 receptor agonists according the present invention have the specific structural formula as follows: wherein, each of An and Ar2 independently is phenyl or substituted phenyl, and the substituent groups of the said substituted phenyl is one, two or three groups optionally selected from the following groups: alkyl; hydroxyl; substituted alkoxyl or alkylamino which contains subtitutent groups including halogen, alkoxyl, or hydroxyl; substituted alkanoylxy or alkanoylamino which contains the 4 subtitutent groups including halogen, alkoxyl, or hydroxyl; C2-C6 alkenyl substituted with oxygen or amine, phenyl, benzyl, C2-C6 enoyl, C3-C6 cycloalkanoyl, benzoyl, substituted benzoyl which contains optional one, two, or three substituent groups including alkoxyl and alkylamino, benzyloyl, thenoyl, amino; amide; alkoxycarbonyl; cycloalkoxycarbonyl; alkanoylxy; alkanoylamino; cycloalkanoylxy; cycloalkanoylamino; carbamido; urylene; alkanoyl; nitro ; carboxyl; and aldehyde group; wherein R1 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; tert-butoxycarbonyl; substituted benzoyl which contains optional one, two, or three substituent groups including alkoxyl and alkylamino; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and when X1 is O or NH, wherein R2 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; tert-butoxycarbonyl; substituted benzoyl 5 which contains optional one, two or three substituent groups including alkoxyl and alkylamino; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X2 is O or NH; wherein each of R3 and R4 independently is any one of the following substituent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; tert-butoxycarbonyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X1 is O or NH; X2 is O or NH. wherein each of R5 and R6 independently is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; when X1 is O or NH; and X2 is O or NH, wherein R2 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl, benzoyl, substituted benzoyl which contains optional one, two, or three substituent groups including alkoxyl and alkylamino; 6 tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X2 is O or NH; wherein each of R3 and R4 independently is any one of the following substituent groups respectively: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl, benzoyl, substituted benzoyl which contains optional one, two, or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X1 is O or NH; X2 is O or NH. The present invention is performed by the following steps. According to the chemical equation: wherein each of An and Ar2 independently is phenyl or substituted phenyl, and the substituent groups of the said substituted phenyl is one, two or three groups optionally selected from the following group: nitro; carboxyl; aldehyde; tert-butoxycarbonyl and thenoyl substituted with oxygen or amino; X is O, S or NH; and Y is O or S. Or, according to the following chemical equation: wherein R1, R2 and R3are optional any one of the following substitutent group: H; alkyl; substituted alkyl which contains substituent groups including halogen, 7 alkoxyl, or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; tert-butoxycarbonyl; substituted benzoyl which contains arbitrary one, two, or three substituent groups including alkoxyl and alkylamino; benzyloyl; thenoyl; adamantane formoxyl; X is O, S, or NH; Y is O or S; each of X1, X2 and X3 independently is O or NH; and X4 is CI or OH. The compound III is produced by condensing the compounds I with II. And, the condensation is performed in the following solvent: dichloromethane, acetic anhydride, tetrahydrofuran, dimethylfuran, dichloroethane, toluene, benzene, water, dioxane or the mixture of the above solvents. If necessary, some activators may be added into the reaction, such as pyridine, N-methylmorpholine, isobutyl chloroformate, triethylamine, diethylpropylethyl amine, or DMAP etc. According to reaction conditions of the compounds, the reaction temperature generally is -78°C to the room temperature (for example, for the compound Wng462 etc.), or is 50n to 230n by heating (for example, for the compound Wng520 etc). The reaction time is determined according to the specific reactants. Generally, the reaction progress is determined by tracing with TLC. After the completion of the reaction, the general post processing methods include filtrating with a pump, concentrating the reaction solution to remove the solvent, extracting and isolating with column chromatography etc. The final product III is verified with NMR detection. The process for synthesizing the structural unit of the substituted five-membered heterocyclic ring of the present invention refers to Organic Syntheses, CV 2, 55. The present invention designs and synthesizes the novel glucagon-like peptide-1 receptor (GLP-1R) agonists. The GLP-1R agonists of the present invention have the good capability of binding the GLP-1R, promote the synthesis of cAMP, may be used to prepare the medicaments for treating the glycometabolism disturbance-related diseases such as type II diabetes, insensitivity to insulin and obesity etc. And, they can overcome the defect that the polypeptides regulator medicaments is inconvenient for oral amnistration and readily to degrade in the prior art. The compounds of the present invention have the relative simple structure and are readily to be prepared. BRIEF DESCRIPTION OF THE DRAWINGS The figure 1 shows the detection result of the expression of the report gene for the compounds of the present invention, which is used to evaluate the activating activity of the said compounds on GLP-1R. In the figure 1, the relative activity of the luciferase induced by 30nM of positive standard GLP-1 is regarded as 8 100%. The figure 2 shows the affection of the compound 2f on the concentration of cAMP in 293/GLP-1R cells. EMBODIMENTS OF THE PRESENT INVENTION The present invention will be further explained with reference to the following specific examples, but they don't limit the present invention in any way. The preparation process for preparing the compounds in the following preparation examples 1 to 3 mainly includes three reaction operation procedures as follow. The compounds I and II, sodium acetate, and acetic anhydride are mixed, heated to melt (150D to 230oC), and maintained in the molten state for 1 hour. Subsequently, ethanol is added into the reaction mixture and cooled. The product is separated out by crystallization following by filtration. The residue liquid is concentrated to remove the solvents completely, and the product is isolated with column chromatography. The compound I is dissolved in dichloromethane, and cooled in the cryohydrate bath at -20°C following by adding trifluoroacetic acid and raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and 9 removing trifluoroacetic acid completely, the substrate is dissolved in dichloromethane, and cooled in the cryohydrate bath at -20D. Then, pyridine and acyl chloride are added orderly, the temperature is raised to the room temperature, and the reaction is traced with TLC. The reaction solution is concentrated, and the product is isolated with column chromatography. The compound I is dissolved in dichloromethane, and cooled in the cryohydrate bath at -20°C following by adding trifluoroacetic acid and raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely, following by concentrating the reaction system and removing trifluoroacetic acid completely. Then, the compound II is dissolved in tetrahydrofuran (THF), and cooled in the cryohydrate bath at -20! J. Then, N-methylmorpholine (NMM) and CICOO'Bu are added orderly. The reaction product of the compound I with trifluoroacetic acid is dissolved in tetrahydrofuran and then transferred into the above mixture with the syringe so as to react at the room temperature. The reaction is traced with TLC. After the reaction is completed, the reaction solution is concentrated, and the product is isolated with column chromatography. For the products, the compounds wang520, wang337, wang405, wang450, wang520-1 and wang462-1 are prepared by the reaction procedure 1, the compounds wang420, wang462, wang524, wang516, wang488, wang 568, wang502, wang530, wang504, wang866, 2f, wang582, wang538, and wang496 are prepared by the procedure 2 with the compound wang520, and the compounds wang516-1, and wang591 are prepared by the procedure 3 with the compound wang520. In the following preparation examples, NMR is measured with Mercury-Vx 300M manufactured by Varian cooperation. NMR criteria are 5H/C 7.26/7.77 ppm(CDCI3); 5H/C 2.50/39.51 ppm (DSMO-d6); and6H/C 3.31/49.15 ppm (Methyl-d3 Alcohol-d). The agents are provided by Shanghai Chemistry Agents Cooperation. And, the products are purified mainly by the column chromatography. The silica gel for separation is 200-300 mesh, and the model 10 of the silica gel for the column chromatography is thick and hollow (ZLX-II), and is produced by the branch factory of Qingdao Haiyang Chemical plant. Example 1 At the room temperature, the compound II (466mg, 1.78mmol), the compound I (576 mg, 1.96 mmol), sodium acetate (146mg, 1.78 mmol) and 2ml_ of acetic anhydride are mixed, following by heating to 170°C until the system melts, and maintaining in the molten state for 1 hour. Then, 2ml_ of ethanol is added into the resultant mixture, and then cooled to the room temperature. So the yellow solids are separated out and filtered. The residue liquid is concentrated, and the solvent is removed completely, to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (5:1 v/v) to obtain 556 mg of product, the compound wang520 (yield: 60%). 'H NMR (300 MHz, CDC13) 8 1.54 (s, 9H), 3.95 (s, 3H), 6.79 (br, 1H), 7.16 (s, 1H), 7.20 (dd, J = 4.8 Hz, 3.9 Hz, 1H), 7.25 (d, = 9.9 Hz, 1H), 7.53 (d, J - 9.0 Hz, 2H), 7.63 (dd, J - 8.4 Hz, 2.1 Hz, 1H), 7.69 (dd, /= 4.8 Hz, 1.2 Hz, 1H), 8.02 (dd, J- 3.9 Hz, 1.2 Hz, 1H), 8.06 (d, y- 8.7 Hz, 2H), 8.17 (d, J= 1.5 Hz, 1H); l3CNMR (75 MHz, CDC13) 8 28.17,55.79, 81.23,115.28,117.92, 119.11, 123.09, 125.74, 128.02, 129.29, 129.41, 132.18, 132.75, 133.29, 133.71, 134.99, 141.57, 143.46,151.37,152.08,159.93,163.13,167.46, At the room temperature, the compound II (466mg, 1.78mmol), the compound I (576 mg, 1.96 mmol), sodium acetate (146mg, 1.78 mmol) and 2mL of acetic anhydride are mixed, following by heating to 200°C until the system melts, and maintaining in the molten state for 1 hour. Then, 2mL of ethanol is added into the resultant mixture, and then cooled to the room temperature. The liquid is concentrated, and the solvent is removed completely, to obtain the crude n product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (1:1 v/v) to obtain 158 mg of the compound wang462-1. 'H NMR (300 MHz, CDCl3, wang520-l) 5 1.50 (s, 9H), 3.88 (s, 3H), 7.27 (s, 1H), 7.33-7.37 (2H), 7.69 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 8.07 (d, J= 3.9 Hz, 1H), 8.13 (d, /= 4.8 Hz, 1H), 8.22-8.26 (2H), 9.93 (s, 1H). !H NMR (300 MHz, CDCl3, wang4624) 6 2.22 (s, 3H), 3.91 (s, 3H), 7.07 (d, J •» 8.7 Hz, 1H), 7.14 (s, 1H), 7.21 (m, 1H), 7.42 (m, 1H), 7.66 (d, /- 8.1 Hz, 2H), 7.71 (d, J- 4.8 Hz, HI), 7.99 (d, /= 8.7 Hz, 1H), 8.05 (m, 1H), 8.10 (d, J= 8.4 Hz, 2H), 8.19 (in, 1H). At the room temperature, the compound II (1.46g, 9.6mmol), the compound I (1.9 g, 10.7 mmol), sodium acetate (0.8 g, 9.8 mmol) and 2.8mL of acetic anhydride are mixed, following by heating to 170°C until the system melts, and maintaining in the molten state for 1 hour. Then, 5mL of ethanol is added into the resultant mixture, and then cooled to the room temperature. So the yellow solids are separated out and filtered to obtain 2.0 g of product, the compound wang337 (yield: 62%). 'HNMR (300MHz, CDCI3) 5 2.35 (s,3H), 3.97 (s, 3H), 7.13 (d ,J= 8.4 Hz, 1H), 7.20 (a, 1H), 7.50-7.56 (2H), 7.59-7.65 (2H), 8.12-8.15 (3H). At the room temperature, the compound II (262mg, 1.0mmol), the compound I (200 mg, 1.1 mmol), sodium acetate (82mg, 1.0 mmol) and 1ml_ of acetic anhydride are mixed, following by heating to 170°C until the system melts, and maintaining in the molten state for 1 hour. Then, 5mL of ethanol is added into the 12 resultant mixture, and then cooled to the room temperature. So the yellow solids are separated out and filtered. The residue liquid is concentrated, and the solvent is removed completely, to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (6:1 v/v) to obtain 235 mg of product, the compound wang405 (yield: 58%). lHNMR (300MHz, CDCl3) 6 3.97 (s, 3H), 7.20 (dd, J At the room temperature, the compound II (262mg, 1.0 mmol), the compound I (250 mg, 1.1 mmol), sodium acetate (82mg, 1.0 mmol) and 4mL of acetic anhydride are mixed, following by heating, and maintaining the system at 210 to 230°C for 1 hour. Then, 5mL of ethanol is added into the resultant mixture, and then cooled to the room temperature. So the yellow solids are separated out and filtered to obtain 100mg of product, the compound wang450 (yield: 22%). 'HNMR(300MHZ5 CDCl3) 5 3.97 (s, 3H>, 7.21 (dd, J- 4.8 fife, 3.9 Hz, 1H), 7.30 (d, ./= 8.1 Hz, 1H), 7.37 (s, 1H), 7.70 (d, J= 5.1 Hz, 1H), 7.73 (dd, /- 9.9 Hz, 1.5 Hz, 1H), 8.02 (d, /= 3.9 Hz, 1H), 8.09 (d, J= 1.8 Hz, 1H), 8.33 (d, J=9.0 Hz, 2H), 8.40 (d, J~ 9.3Hz, 2H)« The compound I (50mg, 0.1 mmol) is dissolved into 2ml_ of dichloromethane, and is cooled in the cryohydrate bath at -20°C following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing 13 trifluoroacetic acid completely, then the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20D, following by adding 40 uL (0.6mmol) of pyridine, and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (2:1 v/v) to obtain 38 mg of product, the compound wang420 (yield: 90%). 'HNMR (300MHZ, CDC13) 8 3.94 (s, 3H), 7.20-7.24 (m, 2H), 7.27 (4 J= 1.8 Hz, 1H), 7.66 (dd, J- 8.1 Hz, 1.5 Hz, !H), 7.71 (dd, /= 4.8 Hz, 0.9 Hz, 1H), 7.76 (d, J= 9.0 Hz, 2H), 8.03 (dd, J= 3.6 Hz, 0.9 Hz, 1H), 8.07 (4./= 1.5 Hz, 1H), 8.14 (4J= 8.7 Hz, 2H), 8.20(br,2H). The compound I (50mg, 0.lmmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20°C following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20n, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (27uL, 0.39mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (1.5:1 v/v) to obtain 26mg of product, the compound wang462 (yield: 56%). 'H NMR (300 MHz, CDCI3) 8 2.19 (s, 3H), 3.88 (s, 3H), 7.12 (s, 1H), 7.20-7.24 (m, 2H), 7.55 (4 J- 1.5 Hz, 1H), 7.60 (4 J" 9.0 Hz, 2H), 7.71 (d4 J=4.8 Hz, 0.9 Hz, 1H), 7.77 (br, 1H), 7.97 (d, J « 8.7 Hz, 2H), 8.03 ( 14 The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20°C following by adding 1ml_ of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20n, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (5:1 v/v) to obtain 15mg of product, the compound wang524 (yield: 36%). ,HNMR (300MHz, DMSO-4,) 8 3.90 (s, 3HX 7.22 (d, J- 5,4 Hz, IH), 7.33 (d, J= 8.4 Hz, 2H), 7.39-7.44 (IH), 7.50-7.58 (2H), 7.83 (d, J- 8.4 Hz), 7.98 (d, J- 8.7 Hz, 2H), 8.04-8.22 (7H), 10.74 (s, IH). The compound I (40mg, 0.08mmol) is dissolved into 2ml_ of dichloromethane, and is cooled in the cryohydrate bath at -20°C following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20n, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (25uL, 0.2mmol) is and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (4:1 v/v) to obtain 25mg of product, the compound wang516 (yield: 62.5%). lHNMR(300 MHz, DMSO-d6) 6 1.57 (m, 2H), 1.63-1.77 (m, 4H), 1.80-1.89 (m, ZH), 2.84 (m, IH), 3.89 (s, 3H), 7.31 The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20°C following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20n, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (4:1 v/v) to obtain 25mg of product, the compound wang488 (yield: 64%). ]H NMR (300 MHz, DMSO-d6) 6 0.80 (m, 2H), 0.85 (m, 2H), 1.84 (m, IH), 3.88 (s, 3H), 7.28 (s, IH), 7.32 (dd, J=5A Hz,3.9Hz, 1H),7J9(4^-8.1 Hz, lH),7.85(d, J= 8.7Hz,2H),7.92(dd, J"8AHz, 1.5Hz, IH), 8.04 (m, IH), 8.05 (d, J= 8.7 Hz, 2H), 8.11 (dd, /» 4.8 Hz, 1.2 Hz, IH), 8.18 (d, J= 1.8 Hz, IH), 10.68 (s, IH); ,3C NMR 05 MHz, DMSO-d) 57.78,14.83, 55.97,115.71,118.73,118.93,123.53,125.32,128.54,128.81, 129.32,131.22,132.80,133.36,135.46,135.53,140.88,144.24,151.05,159.29,162.91,166.96, 172.44. 16 The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1ml_ of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20Q, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (4:1 v/v) to obtain 26mg of product, the compound wang568 (yield: 57%). 'H NMR (300 MHz, CDCl3) 6 3.95 (s, 3H), 4.13 (s, 2H), 4.68 (s, 2H), 7.18 (s, 1H), 7.19-7.26 (m, 2H), 7.39-7.50 (m, 5H), 7.63 (dd, /= 6.9 Hz, 0.9 Hz, 1H), 7.69 (dd, J- 4.8 Hz, 0.9 Hz, 1H), 7.74 (d, J™ 9.0 Hz, 2H), 8.01 (dd, ./= 3.6 Hz, 1.2 Hz, 1H), 8.10 (d, J= 8.7 Hz, 2H), 8.16 (d, J= 1.5 Hz, 1H), 8.56 (s, 1.H). The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1ml_ of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of 17 dichloromethane, and cooled in the cryohydrate bath at -20D, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (4:1 v/v) to obtain 22mg of product, the compound wang502 (yield: 56%). !H NMR (300 MHz, DMSO-d6) 5 1.81-1.94 (m, 2H), 2.12-2.28 (m, 4H), 3.29 (m, 1H), 3.89 (s, 3H), 7.31 (s, 1M), 733 (m, 1H), 7.40 (d, J- 7.5 Hz, 1H), 7.87 (d, J~ 8.1 Hz, 2H), 7.94 (d, /« 8.1 Hz, 2H), 8.04-8.08 (2H), 8.12 (d, J= 5.1 Hz, 1H), 8.19 (s, 1H), 10.20 (s, 1H). The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20n, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (4:1 v/v) to obtain 24mg of product, the compound wang530 (yield: 57%). 'H NMR (300 MHz, DMSO-d6) 8 t.20-1.48 ( 1.65-1.81 (4H), 2.39 (m 1H), 3.89 (s, 3H), 7.32 (s, 1H), 7.34 (m, 1H), 7.41 (d, /- 8.4 Hz, 1H), 7.87 (d, J» 8.1 Hz, 2H), 7.95 (d, ./= 8.1 Hz, 1H), 8.04 (m, 1H), 8.08 (d, J = 8.7 Hz, 2H), 8.12 (d, J" 4.8 Hz, 1H), 8.20 (m, 110,10-31 (s, 1H)« 18 The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20D, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (6:1 v/v) to obtain 4mg of product, the compound wang504 (yield: 10%). 'H NMR (300 MHz,CDCl3) 6 1.34 (s, 9 H), 3.94 (s, 3H), 7.15 (s, 1H), 7.20 (dd, J= 4.8 Hz, 3.6 Hz, 1H), 7.23 (s, 1H), 7.58 (br, 1H), 7.64-7.69 (2H), 7.72 (d, J= 8-7 Hz, 2H), 8.02 (dd, J~ 3.6 Hz, 1.5 Hz, 1H), 8.08 (d, J= 9.0 Hz. 2H), 8.11 (d, J- 1.8 Hz, 1H). The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of 19 dichloromethane, and cooled in the cryohydrate bath at -20D, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (27uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with CH2CI2 to obtain 40mg of product, the compound wang554 (yield: 89%). •H NMR (300 MHz, CDCl3,) 8 3.83 (s, 3H), 6.28 (s, IH), 7.05 (s, IH), 7.16 (d, J= 8.1 Hz, 1H), 7.20 (dd, J - 5.1 Hz, 3.6 Hz, IH), 7.39-7.41 (2H), 7.50-7.55 (3H), 7.60 (d, J= 9.0 Hz, 2H), 7.71 (dd, /« 5.1 Hz, 1.2 Hz, IH), 7.92 (d,./= 8.4 Hz, 2HX 7.99 (d, J= 1.2 Hz), 8.Q3 (dd, J= 3.6 Hz, 0.9 Hz, 2H), 8.24 (s, IH), 8.42 (s, IH). The compound I (52mg, 0.lmmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20D, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (10mg, 0.03mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with CH2CI2 to obtain 19mg of product, the compound wang866 (yield: 44%). 'H NMR (300 MHz, DMSO-) 8 3.89 (s, 6H), 7.33 (dd, J=4.8 Hz, 3.9 Hz, 2H), 7.36 (s, 2H), 7.41 (d, 7= 8.4 Hz, 2H), 7.93 -7.96 (2H), 7.96 (d, J - 8.7 Hz, 4H), 8.04 (dd, J» 3.3 Hz, 0.9 Hz, 2H), 8.12 (dd, /= 4.8 Hz, 0.9 Hz, 2H), 8.17 (d, J = 8.7 Hz, 4H), 8^0 (d, J= 1.8 Hz, 2H), 11.66 (s, 2H). 20 'H NMR (300 MHz, CDCI3) 6 1.41 (t, J- 6.9 Hz, 3H), 2.24 (s, 3H), 4.18 (q, /= 6.9 Hz, 2H), 7.11 (s, 1H), 7.19 (m, 1H), 7.45 (m, 2H), 7.62-7.70 (4H), 8.02 (m, 1H), 8.08 (d, J = 9.0 Hz, 2H). According the same process, the compound wang582 is prepared by using the reaction product of 1eq of the compound wang520 with trifluoroacetic acid and 1.5eq of diamantane formyl chloride (yield: 38%). !H NMR (300 MHz, CDCl3 6 1.76 (6H), 1.99 (6H), 2.12 (310, 3.95 (s, 3H), 7.14-7J23 (2H), 7.54 (s, 1H), 7.61-7.70 (2H), 7.73 (d, ./=> 9.0 Hz, 2H), 8.02 (dd, /- 3.9 Hz, 1H), 8.09 (d, J= 9.0 Hz, 2H), 8,12 (d, / = 1.8 Hz, 1H). According the same process, the compound wang538 is prepared by using the 21 reaction product of 1eq of the compound wang520 with trifluoroacetic acid and 1.5eq of benzyl acetyl chloride (yield: 58%). lHNMR (300 MHz, CDO,) 8 3.78 (s, 2H), 3.92 (s, 3H), 7.16 (s, 1H), 7.19-7.24 (2H), 7.34-7.74 ( According the same process, the compound wang496 is prepared by using the reaction product of 1eq of the compound wang520 with trifluoroacetic acid and 1.5eq of chloro acetyl chloride (yield: 70%). 'H mm. (300 MHz, DMSO-d6) 8 3.89 (s, 3H), 4.36 (s, 2H), 7.34 ($, IH),7.41 (d, J" 8.1 Hz, 1H), 7.88 (d, J= 9.0 Hz, 2H), 7.93-7.98 (2H), 8.05 (m, 1H), 8.12 (d, ./= 7.5 Hz, 2H), 8.22 (m, 1H), 8.89 (in, 1H), 10.95 (s, 1H). The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1ml_ of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the compound II (19 uL, 0.16mmol)is dissolved in 2 mL of tetrahydrofuran, and cooled in the cryohydrate bath at -20D with stirring for 10min at this temperature. Then, N-methylmorpholine (NMM) (53 uL, 0.48mmol) and CICOO'Bu (21 uL, 0.16mmol) are added orderly with stirring for 0.5 hour at -20D. The reaction product of the compound I with trifluoroacetic acid is dissolved in 1 mL of tetrahydrofuran and then transferred into the above 22 mixture with the syringe so as to react at the room temperature for about 15 hours. The reaction solution is concentrated and the solvents are removed completely to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (5:1 v/v) to obtain 12mg of product, the compound wang516-1 (yield: 30%). 'H NMR (300 MHz, CDCl3 8 1.74 (s, 3H), 1.87 (s, 3H), 3.18 ( 8.4 Hz, 2H), 8.02 (dd, .7- 3.6 Hz, 0.9 Hz, 1H), 8.09 (d, J-9.0 Hz, 2H), 8.16 (d, J« 2.1 Hz, 1H)„ According the same process, the compound wang591 is prepared by using the reaction product of 1eq of the compound wang520 with trifluoroacetic acid and 2.0eq of the compound Boc-Ala-OH (yield: 18%). The compound wang568 (11mg, 0.02mmol) is dissolved into 2ml_ of dichloromethane, and cooled at -78D for 10 minutes, following by adding 0.2ml_ of BCl3/n-hexane solution (1M) to continue reacting for 30 minutes at -78n. Then, the temperature is raised to -18D to react for 4 hours. 2mL of ether is added to quench the reaction with stirring for 30 minutes at the room temperature, following by adding 5mL of water. The water phase and the organic phase are separated. The water phase is extracted with dichloromethane, and the organic phase is combined, dried with anhydrous MgS04, and concentrated. The crude product is isolated over column chromatography with petroleum ether/ethyl acetate (1/2, v/v) to obtain the compound wang477 (1.5mg, yield: 17%). 23 1HNMR(30GMHz,CDei3) 8 1.86 (br, 1H), 3.95 (s, 3H), 4.26 (s,2H), 7.18 (s, IB), 7.20 (dd,./ - 8.7 Hz, 4.8 Hz, 1H), 7.23 (d, J= 3.3 Hz, 1H), 7.63 (d, > 8.1 Hz, 1H), 7.71 (dd, /- 5.1 Hz, 1.5 Hz, 1H), 7.75 (d, J= 8.7 Hz, 2H), 8.02 (d, J- 3.6 Hz, 1H), 8.08 (d, J= 8.7Hz, 2H), 8.14 (m, 1H), 8.57 (br, 1H), The compound wang591 (3mg) is dissolved into 1.5 mL of dichloromethane, and cooled in ice bath for 5 minutes, following by adding 0.15 mL of trifluoroacetic acid. Then, the temperature is gradually raised to the room temperature, and the reaction is traced with TLC. After the raw material disappears, the solvent and trifluoroacetic acid are removed by pumping to obtain 2mg of the product, the compound wang 605 (yield: 65%). 'H NMR (300 MHz, Methyl-**? Alcohol-d) 5 l.63 (d, /= 7.2 Hz, 3H), 3.95 (s, 3H), 4.09 (m, 1H), 7.265 (s,lH), 7.267 (d, J - 8.7 Hz, 1H), 7.29 (d,/=» 8.1 Hz, 1H),7.81 (dd,/ = 8.7 Hz, 2.1 Hz, 1H), 7.87 (d, J=9.0 Hz, 2H), 7.91 (dd,/= 5.1 Hz, 1.2 Hz, 1H), 8.01 (dd,/= 3.6 Hz, 0.9 Hz, 1H), 8.16 (d, y- 9.3 Hz, 2H), 8.25 (d, J=2.1 Hz, 1H). Example 4 Experiments testing on biological activity 1. Testing the expression of the report gene Upon that GLP-1R binds to GLP-1 or agonists, its Gasubunit is activated to stimulate the adenylate cyclase, which makes the increase in the concentration of intracellular cAMP. Since the promoter region of the proinsulin gene has the cAMP response element, upon binding of cAMP to this response element, the transcription of the proinsulin gene is activated, so as to increase the sensitivity of 6- islet cells to glucose, and improve the expression and secretion of insulin (Diabetes, 2000, vol.49:1156-1164). The screening model employs the human embryonal nephric cell strain which is stably transfected with the expression vector of GLP-1 R gene and the expression vector of luciferase report gene under the regulation of cAMP response element, to detect its response to the candidate compound (Cell Biology, 1992, Vol.89: 8641-8645; Proc. Natl. Acad. Sci. U.S.A. 1987, Vol.84: 3434-3438). When screening the candidate compounds, the compound which may induce the luciferase report gene to 24 express have the activity of activating GLP-1. 1.1 Experimental material and instruments Cell strain: HEK 293/GLP1R+Luc strain which stably express GLP-1 R and luciferase (National New Medicaments Screening Center) Fetal calf serum (GIBCO/BRL Cooperation) Steady-glo™ luciferase analysis system (Promega Cooperation) Standard GLP-1 (Sigma Cooperation) G418 (Invitrogen Cooperation) Forma carbon dioxide incubator (Forma Cooperation) Victor 2 counting machine (Wallac Cooperation) Candidate compound: the compounds wang524, wang520, wang462, 2f, wang516, wang516-2, wang502 and wang504; 1.2 Experimental process HEK 293/GLP1R+Luc cell in 20000 cells/100ul/well are inoculated into 96-well plate, are cultured at 37n overnight with DMEM culture medium containing 10% of fetal calf serum and 500ug/mL of G418. The candidate compounds wang516-2, wang502, and wang504 are respectively diluted to 2mM, 1mM, 0.3mM, 0.1 mM, 0.03mM, 0.01 mM, and 0.003mM, and the other candidate compounds are diluted gradually from 30mM for 8 times by a ratio of 1:3 to get a concentration gradient (i.e., 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.1mM, 0.03mM, and 0.01 mM), following by being added into the above 96-well plate at 1ul/well. Then, the cells are cultured at 37n in 5% of CO2 6 hours. The activity of luciferase is detected according to the specification of Steady-glo™ luciferase analysis system kit, and counting is performed with Victor 2 counting machine. The positive control adopts 30nM of standard GLP-1. 1.3 Experimental result The experimental result of the report gene for the candidate compounds is as shown in the figure 1 and the table 1. The figure 1 shows that the compound wang 520 in a final concentration of 30uM have the best relative activity (94%) which is improved greatly compared with the activity of the compound 2f. In addition, the compounds as shown in the table 1 have the dose dependency on the activity of GLP-1 R, wherein the median effective dose (EC50) of the compounds wang 520, wang 516. wang 554, 25 wang 488 wang516-2, wang502 and wang 504 is less than 10\|jM. Such result provides the direction for determining the superior structure of the interaction of the compounds with GLP-1R. The table 1 The number of the compound EC50/µM wang524 46.5 wang520 4.6 wang462 11.6 wang516 6.85 2f 13.0 wang866 54.41 wang554 5.24 wang488 6.73 wang516-2 6.06 wang502 3.31 wang504 4.87 2. Determination of the concentration of intracellular cAMP Since the determination of the concentration of intracellular cAMP indirectly by detecting the expression of the report gene is an indirect process, the functional re-screen is directly performed with the cAMP-detecting kit in order to make sure that the compound can surely increase the concentration of intracellular cAMP. 2.1 Experimental material and instruments cAMP-detecting kit (Applied Biosystems Cooperation) Forma carbon dioxide incubator (Forma Cooperation) Victor 2 according machine (Wallac Cooperation) HEK 293/GLP1R+Luc strain which stably express GLP-1 R and luciferase (National new medicaments screening center) Candidate compound: the compound 2f 26 Standard cAMP (provided in the kit, Applied Biosystems Cooperation ) 2.2 Experimental process HEK 293 cells are inoculated into 96-well plate in 20000 cells/100µl/well, are cultured at 37D overnight. The compound 2f is diluted to 1.00E-03M, 1.00E-04M, 1.00E-05M, 1.00E-06M and 1.00E-07M with dimethyl sulphoxide, following by being inoculated into the above 96-well plate in 1 l/well and being cultured at 37□ with 5% of CO2 for 1 hour. The concentration of intracellular cAMP is detected according to the specification of cAMP-Screen Direct TM system kit. 2.3 Experimental result The determining result of the concentration of intracellular cAMP is shown in the figure 2. As shown in the figure 2, with increase of the concentration of the compound 2f, the concentration of cAMP which is produced under this stimulation shows an exponential increase. This indicates that the compound 2f has a certain effect on signal transmission of GLP-1R as a GLP-1R agonist. When the concentration of the compound 2f increases to 30uM and 100uM, the concentration of cAMP shows the decreasing trend, which is caused by the cellulotoxic effect of the high concentration of the compound 2f. 3. The test on the ligand-binding activity In order to determine the binding activity of the compound to the ligand, the cells which highly express GLP-1R are prepared, GLP-1 labelled with 125l is used as the ligand, while adding into the candidate compound. When the candidate compound binds the 125l-labelled GLP-1 competitively, the isotope labels on the cell membrane reduce. Accordingly, the affinity of the candidate compound to the ligand can be evaluated (J Mol Endocrinol. 2000 Vol.25:321-35; J Biomol Screen, 2000 Vol. 5:377-84). 3.1 Experimental material and instruments HEK 293/GLPIR+Luc cell strain (National New Medicaments Screening Center) Labeled compound: 125l-labelled GLP-1 (Amersham Biosciences Cooperation) Wallac MicroBata work station (Perkin Elmer Cooperation) TomTech cell collector (TomTec Cooperation) The testing buffer solution: 20mM of tris-HCI (pH 7.4) (Shanghai Shenggong biological engineering technology LTD), 100mM of NaCI (Shanghai Chemical agents Cooperation), 15mM of NaF (Shanghai Chemical agents Cooperation), 2mM of 27 deoxypyridoxine (Sigma Cooperation), 0.2mM of phenylmethylsulfonyl fluoride (Sigma Cooperation), aprotinin (Shanghai Chemical agents Cooperation) (1 ug/ml), and leupeptin (Shanghai Chemical agents Cooperation) (1 ug/ml). The washing solution: 20mM of tris-HCI (pH 7.4), 100mM of NaCI, and 15mM NaF The scintillation liquid (Wallac Cooperation) The candidate compound is diluted with dimethyl sulphoxide at the concentration gradient of 0.1 nM, 1nM, 10nM, 100nM, 1000nM, 10,000nM, and 100,000 nM. 3.2 Experimental process 105 HEK 293/GLP1R+Luc cells in the logarithmic growth phase are incubated together with the 125l-labelled GLP-1 positive peptide (the final concentration of 40pM) in 200ul of the testing buffer solution at 25a for 4 hours, while adding into the non-labeled positive peptide or the candidate compound. The cells are collected with the cell collector, following by washing three times with the washing solution. The scintillation liquid is added into them, and each well is counted with Microbata counter. 3.3 Experimental result The result of the receptor-binding experiment is shown in the table 3. As shown in the table 3, the compound 2f has the better affinity to GLP-1 R, but the affinities of compounds wang520 and wang516 are little week, and the other compound substantially don't bind the receptor in the testing concentration rage. The table 3 The number of the compound EC50/µM wang524 >100µM wang450 >100µM wang405 >100µM wang327 >100µM wang520 60-1 OOµM wang462 >100µM wang866 >100µM 28 wang516 40-80µM wang420 >100µM 2f 31µM We Claim:- 1. A glucagon-like peptide-1 receptor agonist having the following structural formula: wherein, each of An and Ar2 independently is phenyl or substituted phenyl, and the substituent groups of the said substituted phenyl is one, two or three groups optionally selected from the following group: alkyl; hydroxyl; substituted alkoxyl or alkylamino which contains the substituent groups including halogen, alkoxyl or hydroxyl; substituted alkanoylxy or alkanoylamino which contains the substitutent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl substituted with oxygen or amine, phenyl, benzyl, C2-C6 enoyl, C3-C6 cycloalkanoyl, benzoyl, substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkanoylamino, benzyloyl, thenoyl, tert-butoxycarbonyl, adamantane formoxyl, and mandeloyl; alkoxyl; alkylamino; cycloalkoxyl; cycloalkylamino; amino; amide; alkoxycarbonyl; cycloalkoxycarbonyl; alkanoylxy; alkanoylamino; cycloalkanoylxy; cycloalkanoylamino; carbamido; urylene; alkanoyl; nitro; carboxyl; and aldehyde group; X is O, S, or NH; and Y is O or S. 2. The glucagon-like peptide-1 receptor agonist according to the claim 1, being characterized in that wherein R1 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three 30 substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and Xi is O or NH, wherein R2 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X2 is O or NH; wherein each of R3 and R4 independently is any one of the following substituent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X1 is O or NH; X2 is O or NH. 3. The glucagon-like peptide-1 receptor agonist according to the claim 1, being characterized in that, wherein each of R5 and R6 independently is any one of the following substituent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X1 31 wherein R2 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X2 is O or NH; wherein each of R3 and R4 independently is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X1 is O or NH; X2 is O or NH. 4. A process for preparing the glucagon-like peptide-1 receptor agonist according to the claim 1, being characterized in that, the said agonist is prepared by condensating independently is phenyl or substituted phenyl, wherein the substituent group of the said substituted phenyl is one, two or three groups optionally selected from the following group: nitro; carboxyl; aldehyde; tert-butoxycarbonyl and thenoyl substituted with oxygen or amino; X is O, S or NH; and Y is O or S. 5. A process for preparing the glucagon-like peptide-1 receptor agonist according to 32 trifluoroacetic acid with the compound R1COX4, wherein R1, R2 and R3 are any one of the following substitutent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; tert-butoxycarbonyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; X is O, S, or NH; Y is O or S; each of X1, X2 and X3 independently is O or NH; and X4 is CI or OH. 6. The processes for preparing the glucagon-like peptide-1 receptor agonist according the claims 4 or 5, being characterized in that, the solvent used in condensation reaction is dichloromethane, acetic anhydride, tetrahydrofuran, dimethylfuran, dichloroethane, toluene, benzene, water, dioxane or any mixture thereof. 7. The processes for preparing the glucagon-like peptide-1 receptor agonist according the claims 4 or 5, being characterized in that, the reaction temperature is from -78°C to the room temperature, or the heating temperature is from 50D to 230D. 8. The processes for preparing the glucagon-like peptide-1 receptor agonist according the claims 4 or 5, being characterized in that, pyridine, triethylamine, diethylpropylethyl amine, DMAP, N-methylmorpholine, or isobutyl chloroformate is used as activator in condensation reaction. 9. Use of the glucagon-like peptide-1 receptor agonist according to claim 1 as medicaments for treating the carbohydrate metabolism disturbance-related diseases such as type II diabetes, insensitivity to insulin or obesity, etc. 33 10. The A glucagon-like peptide-1 receptor agonists, the preparation and the use of the same as claimed as claimed substantially as herein described with forgoing description. Dated this 9th day of June 2006. Dr. Rajeshkumar H. Acharya Advocate & Patent Agent For and on Behalf of Applicant 34 ABSTRACT The present invention provides the glucagon-like peptide-1 receptor agonists. It is indicated that the agonists have good binding capability to glucagon-like peptide-1 receptor by pharmacological tests. The present invention also provides the preparation of the agonists.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13)
1. THE GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS, THE
PREPARATION AND THE USE OF THE SAME
2.
(A) SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES
(B) CHINA
(C) 555 Zu Chong Zhi Road, Pudong New District, Shanghai 201203, China.
The following specification particularly describes the invention and the manner in which it is to be performed.
1

FIELD OF THE INVENTION
The present invention relates to a group of glucagon-like peptide-1 receptor (GLP-1R) agonists. In particularly, the present invention relates to a group of small molecular organic compounds of substituted five-membered heterocyclic ring derivatives which may be used as non-peptide GLP-1R agonists. The compounds of the present invention may be used as medicaments for treating the glycometabolism disturbance-related diseases such as type II diabetes, insensitivity to insulin and obesity etc. And, the present invention also relates to a process for manufacturing the said GLP-1R agonists.
BACKGROUND OF THE INVENTION
Diabetes mellitus (DM) is a common endocrine metabolic disease with heredity tendency. It is caused mainly by the absolute or relative hyposecretion of the insulin, and it causes metabolic disturbance of saccharide, fat, protein, and subsequently vitamin, water and electrolyte. The manifestations include the increase of glycemia and urine glucose, and the patients have the symptoms of polydipsia, polyphagia, polyuria, dry mouth, and general weakness. The morbidity rate of diabetes mellitus is 1 to 5%, and shows a trend of gradually increasing. Diabetes mellitus, cancer, and cardiovascular diseases are referred as three worldwide serious diseases. The object of treating diabetes mellitus is to correct the disturbance of carbohydrate metabolism, so as to eliminate the symptoms, promote restoration of the function of pancreatic islet, improve the insulin resistance, maintain the better healthy condition and physical strength, and prevent and treat various complications.
Diabetes mellitus is commonly divided into two types: Insulin Dependent Diabetes Mellitus (type I, IDDM) and Non-Insulin Dependent Diabetes Mellitus (type II, NIDDM). Since the pathogenesis for theses two types of diabetes mellitus are different, the medicaments for treating them are far different, which are stated respectively as follows.
Type I diabetes mellitus is caused by virus infection in hereditarily susceptible person which produce the paradoxical reaction of the islet cells through immunomechanism, so that the pancreatic islets begin to be damaged and even lost their function completely. About 5% of diabetes mellitus is type I. At present, the medicaments for treating type I diabetes mellitus mainly include exogenous insulin (including human insulin and animal insulin), drugs having the insulin-like effect, insulin-like growth factor-1 (IGF-1), novel long-acting insulin preparation, and Jin Qi hypoglycemic tablet, etc.
A few of type II diabetes mellitus is caused by direct impair of |3-islet cells which
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decreases the secretion of insulin. And most of type II diabetes mellitus is caused by a combination of factors that may include genetic traits, life style, environmental contributors, metabolic disorders, obesity, and so on. In this disease state, muscular, hepatic and adipose tissues are insensitive to the insulin thereby decreasing the intake of the glucose. Most of diabetics suffer from type II diabetes mellitus. At present, the medicaments for the clinical treatment of NIDDM mainly include sulphonylureases, biguanides, other hypoglycemic drugs and adjuvants, etc.
The sulphonylureas hypoglycemic drugs bind to the receptors on the cell membrane of p-islet cells to close the potassium ion channel thereby blocking flowout of potassium ion and inducing depolarization of the cell membrane, so that the calcium ion channels are opened to allow the extracellular calcium ions flow inwardly. The increase of intracellular calcium ions concentration triggers the release of the insulin. Sulphonylureas hypoglycemic drugs can be divided into two generations according to their time of coming into existence. The first generation includes tolpropamide, and the second generation includes glibenclamide (euglucan), gliclazide (diamicron), glipizide and gliquidone etc.
Biguanide hypoglycemic drugs inhibit appetite, improve the binding of insulin to the receptors, promote the anaerobic glycolysis in cells, inhibit tissue respiration and inhibit hepatic gluconeogenesis. The biguanide hypoglycemic drugs mainly include metformin, phenformin and buformin.
Other hypoglycemic drugs mainly include thiazolidinedione drugs (such as troglitazone, rosiglitazone, and pioglitazone, etc), (33-adrenoceptor regulators, glucagon receptor antagonists, fatty acid metabolism interfering agents, a-glycosidase inhibitors (such as acarbose, voglibose, miglitol), and aldose reductase inhibitors, etc.
Recently, the development of research on glycometabolism related endogenous peptide hormone provides a new idea for the treatment of diabetes mellitus. When human body intakes nutrient materials, the enteroendocrine cells release enteropeptide hormone which mainly includes glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) and regulates metabolism by affecting the insulin generation, gastrointestinal peristalsis, and islet cell proliferation. Wherein, GLP-1 is secreted by entero-pancreatic cells, and activates the adenylate cyclase to synthesize cAMP by highly specifically binding to the GLP-1 receptor of p-islet cells, so as to further activate the protein kinase. The metabolic signal (glycometabolism) and kinase signal (binding of GLP-1) cooperate on the cell membrane level to finally cause the Ca2+ channel to open and the calcium ions to flow inwardly so that further stimulates the secretion of insulin while inhibiting the generation of glucagon, thereby decrease
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the postprandial blood glucose to maintained blood glucose concentration at a constant level. Also, GLP-1 has the function of neuroregulation, and can retard gastric emptying, and inhibit appetite. All of these are greatly beneficial for control of diabetes mellitus. Normally, GLP-1 stimulates insulin secretion depending on the blood glucose concentration. As the blood glucose concentration decreases, the effect of GLP-1 on stimulating insulin secretion decreases. Therefore, the action of GLP-1 on decreasing blood glucose is self-limited, and can not cause hypoglycaemia. So, for treating diabetes mellitus, the medicaments with the GLP-1-like action are greatly desirable for the treatment of diabetes mellitus. GLP-1 R agonists have been one researching focus of the international drug development organizations. At present, the researches on GPL-1R mainly focus on the polypeptide regulators. For example, AC 2993 of Amylin Corporation has applied for clinic test in US (IND). AC2993 is a 39-amino acids polypeptide and has the effect of promoting the secretion of insulin as GPL-1. Since the polypeptide drugs is inconvenient for oral administration and is readily to degrade, non-peptides GLP-1 R regulator is the new researching direction at present.
DISCLOSURE OF THE INVENTION
The object of the present invention is to design a group of novel small molecular organic compound of substituted five-membered heterocyclic ring derivative which may be used as glucagon-like peptide-1 receptor (GLP-1 R) agonists, so as to prove a way for searching the leader compounds or the drugs for the medicaments against the diabetes mellitus. Another object of the present invention is to provide a process for preparing these compounds.
The Glucagon-like peptide-1 receptor agonists according the present invention have the specific structural formula as follows:

wherein, each of An and Ar2 independently is phenyl or substituted phenyl, and the substituent groups of the said substituted phenyl is one, two or three groups optionally selected from the following groups: alkyl; hydroxyl; substituted alkoxyl or alkylamino which contains subtitutent groups including halogen, alkoxyl, or hydroxyl; substituted alkanoylxy or alkanoylamino which contains the
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subtitutent groups including halogen, alkoxyl, or hydroxyl; C2-C6 alkenyl substituted with oxygen or amine, phenyl, benzyl, C2-C6 enoyl, C3-C6 cycloalkanoyl, benzoyl, substituted benzoyl which contains optional one, two, or three substituent groups including alkoxyl and alkylamino, benzyloyl, thenoyl,

amino; amide; alkoxycarbonyl; cycloalkoxycarbonyl; alkanoylxy; alkanoylamino; cycloalkanoylxy; cycloalkanoylamino; carbamido; urylene; alkanoyl; nitro ; carboxyl; and aldehyde group;

wherein R1 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; tert-butoxycarbonyl; substituted benzoyl which contains optional one, two, or three substituent groups including alkoxyl and alkylamino; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and when X1 is O or NH,

wherein R2 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; tert-butoxycarbonyl; substituted benzoyl
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which contains optional one, two or three substituent groups including alkoxyl and alkylamino; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X2 is O or NH;

wherein each of R3 and R4 independently is any one of the following substituent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; tert-butoxycarbonyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X1 is O or NH; X2 is O or NH.

wherein each of R5 and R6 independently is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; when X1 is O or NH; and X2 is O or NH,

wherein R2 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl, benzoyl, substituted benzoyl which contains optional one, two, or three substituent groups including alkoxyl and alkylamino;
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tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X2 is O or NH;

wherein each of R3 and R4 independently is any one of the following substituent groups respectively: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl, benzoyl, substituted benzoyl which contains optional one, two, or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X1 is O or NH; X2 is O or NH.
The present invention is performed by the following steps. According to the chemical equation:

wherein each of An and Ar2 independently is phenyl or substituted phenyl, and the substituent groups of the said substituted phenyl is one, two or three groups optionally selected from the following group: nitro; carboxyl; aldehyde; tert-butoxycarbonyl and thenoyl substituted with oxygen or amino; X is O, S or NH; and Y is O or S.
Or, according to the following chemical equation:

wherein R1, R2 and R3are optional any one of the following substitutent group: H; alkyl; substituted alkyl which contains substituent groups including halogen,
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alkoxyl, or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl, or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; tert-butoxycarbonyl; substituted benzoyl which contains arbitrary one, two, or three substituent groups including alkoxyl and alkylamino; benzyloyl; thenoyl; adamantane formoxyl; X is O, S, or NH; Y is O or S; each of X1, X2 and X3 independently is O or NH; and X4 is CI or OH.
The compound III is produced by condensing the compounds I with II. And, the condensation is performed in the following solvent: dichloromethane, acetic anhydride, tetrahydrofuran, dimethylfuran, dichloroethane, toluene, benzene, water, dioxane or the mixture of the above solvents. If necessary, some activators may be added into the reaction, such as pyridine, N-methylmorpholine, isobutyl chloroformate, triethylamine, diethylpropylethyl amine, or DMAP etc. According to reaction conditions of the compounds, the reaction temperature generally is -78°C to the room temperature (for example, for the compound Wng462 etc.), or is 50n to 230n by heating (for example, for the compound Wng520 etc). The reaction time is determined according to the specific reactants. Generally, the reaction progress is determined by tracing with TLC. After the completion of the reaction, the general post processing methods include filtrating with a pump, concentrating the reaction solution to remove the solvent, extracting and isolating with column chromatography etc. The final product III is verified with NMR detection.
The process for synthesizing the structural unit of the substituted five-membered heterocyclic ring of the present invention refers to Organic Syntheses, CV 2, 55.
The present invention designs and synthesizes the novel glucagon-like peptide-1 receptor (GLP-1R) agonists. The GLP-1R agonists of the present invention have the good capability of binding the GLP-1R, promote the synthesis of cAMP, may be used to prepare the medicaments for treating the glycometabolism disturbance-related diseases such as type II diabetes, insensitivity to insulin and obesity etc. And, they can overcome the defect that the polypeptides regulator medicaments is inconvenient for oral amnistration and readily to degrade in the prior art. The compounds of the present invention have the relative simple structure and are readily to be prepared.
BRIEF DESCRIPTION OF THE DRAWINGS
The figure 1 shows the detection result of the expression of the report gene for the compounds of the present invention, which is used to evaluate the activating activity of the said compounds on GLP-1R. In the figure 1, the relative activity of the luciferase induced by 30nM of positive standard GLP-1 is regarded as
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100%.
The figure 2 shows the affection of the compound 2f on the concentration of cAMP in 293/GLP-1R cells.
EMBODIMENTS OF THE PRESENT INVENTION
The present invention will be further explained with reference to the following specific examples, but they don't limit the present invention in any way.
The preparation process for preparing the compounds in the following preparation examples 1 to 3 mainly includes three reaction operation procedures as follow.

The compounds I and II, sodium acetate, and acetic anhydride are mixed, heated to melt (150D to 230oC), and maintained in the molten state for 1 hour. Subsequently, ethanol is added into the reaction mixture and cooled. The product is separated out by crystallization following by filtration. The residue liquid is concentrated to remove the solvents completely, and the product is isolated with column chromatography.

The compound I is dissolved in dichloromethane, and cooled in the cryohydrate bath at -20°C following by adding trifluoroacetic acid and raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and
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removing trifluoroacetic acid completely, the substrate is dissolved in dichloromethane, and cooled in the cryohydrate bath at -20D. Then, pyridine and acyl chloride are added orderly, the temperature is raised to the room temperature, and the reaction is traced with TLC. The reaction solution is concentrated, and the product is isolated with column chromatography.

The compound I is dissolved in dichloromethane, and cooled in the cryohydrate bath at -20°C following by adding trifluoroacetic acid and raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely, following by concentrating the reaction system and removing trifluoroacetic acid completely. Then, the compound II is dissolved in tetrahydrofuran (THF), and cooled in the cryohydrate bath at -20! J. Then, N-methylmorpholine (NMM) and CICOO'Bu are added orderly. The reaction product of the compound I with trifluoroacetic acid is dissolved in tetrahydrofuran and then transferred into the above mixture with the syringe so as to react at the room temperature. The reaction is traced with TLC. After the reaction is completed, the reaction solution is concentrated, and the product is isolated with column chromatography.
For the products, the compounds wang520, wang337, wang405, wang450, wang520-1 and wang462-1 are prepared by the reaction procedure 1, the compounds wang420, wang462, wang524, wang516, wang488, wang 568, wang502, wang530, wang504, wang866, 2f, wang582, wang538, and wang496 are prepared by the procedure 2 with the compound wang520, and the compounds wang516-1, and wang591 are prepared by the procedure 3 with the compound wang520.
In the following preparation examples, NMR is measured with Mercury-Vx 300M manufactured by Varian cooperation. NMR criteria are 5H/C 7.26/7.77 ppm(CDCI3); 5H/C 2.50/39.51 ppm (DSMO-d6); and6H/C 3.31/49.15 ppm (Methyl-d3 Alcohol-d). The agents are provided by Shanghai Chemistry Agents Cooperation. And, the products are purified mainly by the column chromatography. The silica gel for separation is 200-300 mesh, and the model
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of the silica gel for the column chromatography is thick and hollow (ZLX-II), and is produced by the branch factory of Qingdao Haiyang Chemical plant.
Example 1

At the room temperature, the compound II (466mg, 1.78mmol), the compound I (576 mg, 1.96 mmol), sodium acetate (146mg, 1.78 mmol) and 2ml_ of acetic anhydride are mixed, following by heating to 170°C until the system melts, and maintaining in the molten state for 1 hour. Then, 2ml_ of ethanol is added into the resultant mixture, and then cooled to the room temperature. So the yellow solids are separated out and filtered. The residue liquid is concentrated, and the solvent is removed completely, to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (5:1 v/v) to obtain 556 mg of product, the compound wang520 (yield: 60%).
'H NMR (300 MHz, CDC13) 8 1.54 (s, 9H), 3.95 (s, 3H), 6.79 (br, 1H), 7.16 (s, 1H), 7.20 (dd, J
= 4.8 Hz, 3.9 Hz, 1H), 7.25 (d, = 9.9 Hz, 1H), 7.53 (d, J - 9.0 Hz, 2H), 7.63 (dd, J - 8.4 Hz, 2.1 Hz, 1H), 7.69 (dd, /= 4.8 Hz, 1.2 Hz, 1H), 8.02 (dd, J- 3.9 Hz, 1.2 Hz, 1H), 8.06 (d, y- 8.7 Hz, 2H), 8.17 (d, J= 1.5 Hz, 1H); l3CNMR (75 MHz, CDC13) 8 28.17,55.79, 81.23,115.28,117.92, 119.11, 123.09, 125.74, 128.02, 129.29, 129.41, 132.18, 132.75, 133.29, 133.71, 134.99, 141.57, 143.46,151.37,152.08,159.93,163.13,167.46,

At the room temperature, the compound II (466mg, 1.78mmol), the compound I (576 mg, 1.96 mmol), sodium acetate (146mg, 1.78 mmol) and 2mL of acetic anhydride are mixed, following by heating to 200°C until the system melts, and maintaining in the molten state for 1 hour. Then, 2mL of ethanol is added into the resultant mixture, and then cooled to the room temperature. The liquid is concentrated, and the solvent is removed completely, to obtain the crude
n

product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (1:1 v/v) to obtain 158 mg of the compound wang462-1.
'H NMR (300 MHz, CDCl3, wang520-l) 5 1.50 (s, 9H), 3.88 (s, 3H), 7.27 (s, 1H), 7.33-7.37 (2H), 7.69 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 8.07 (d, J= 3.9 Hz, 1H), 8.13 (d, /= 4.8 Hz, 1H), 8.22-8.26 (2H), 9.93 (s, 1H).
!H NMR (300 MHz, CDCl3, wang4624) 6 2.22 (s, 3H), 3.91 (s, 3H), 7.07 (d, J •» 8.7 Hz, 1H), 7.14 (s, 1H), 7.21 (m, 1H), 7.42 (m, 1H), 7.66 (d, /- 8.1 Hz, 2H), 7.71 (d, J- 4.8 Hz, HI), 7.99 (d, /= 8.7 Hz, 1H), 8.05 (m, 1H), 8.10 (d, J= 8.4 Hz, 2H), 8.19 (in, 1H).

At the room temperature, the compound II (1.46g, 9.6mmol), the compound I (1.9 g, 10.7 mmol), sodium acetate (0.8 g, 9.8 mmol) and 2.8mL of acetic anhydride are mixed, following by heating to 170°C until the system melts, and maintaining in the molten state for 1 hour. Then, 5mL of ethanol is added into the resultant mixture, and then cooled to the room temperature. So the yellow solids are separated out and filtered to obtain 2.0 g of product, the compound wang337 (yield: 62%).
'HNMR (300MHz, CDCI3) 5 2.35 (s,3H), 3.97 (s, 3H), 7.13 (d ,J= 8.4 Hz, 1H), 7.20 (a, 1H), 7.50-7.56 (2H), 7.59-7.65 (2H), 8.12-8.15 (3H).

At the room temperature, the compound II (262mg, 1.0mmol), the compound I (200 mg, 1.1 mmol), sodium acetate (82mg, 1.0 mmol) and 1ml_ of acetic anhydride are mixed, following by heating to 170°C until the system melts, and maintaining in the molten state for 1 hour. Then, 5mL of ethanol is added into the
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resultant mixture, and then cooled to the room temperature. So the yellow solids are separated out and filtered. The residue liquid is concentrated, and the solvent is removed completely, to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (6:1 v/v) to obtain 235 mg of product, the compound wang405 (yield: 58%).
lHNMR (300MHz, CDCl3) 6 3.97 (s, 3H), 7.20 (dd, J
At the room temperature, the compound II (262mg, 1.0 mmol), the compound I (250 mg, 1.1 mmol), sodium acetate (82mg, 1.0 mmol) and 4mL of acetic anhydride are mixed, following by heating, and maintaining the system at 210 to 230°C for 1 hour. Then, 5mL of ethanol is added into the resultant mixture, and then cooled to the room temperature. So the yellow solids are separated out and filtered to obtain 100mg of product, the compound wang450 (yield: 22%).
'HNMR(300MHZ5 CDCl3) 5 3.97 (s, 3H>, 7.21 (dd, J- 4.8 fife, 3.9 Hz, 1H), 7.30 (d, ./= 8.1 Hz, 1H), 7.37 (s, 1H), 7.70 (d, J= 5.1 Hz, 1H), 7.73 (dd, /- 9.9 Hz, 1.5 Hz, 1H), 8.02 (d, /= 3.9 Hz, 1H), 8.09 (d, J= 1.8 Hz, 1H), 8.33 (d, J=9.0 Hz, 2H), 8.40 (d, J~ 9.3Hz, 2H)«

The compound I (50mg, 0.1 mmol) is dissolved into 2ml_ of dichloromethane, and is cooled in the cryohydrate bath at -20°C following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing
13

trifluoroacetic acid completely, then the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20D, following by adding 40 uL (0.6mmol) of pyridine, and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (2:1 v/v) to obtain 38 mg of product, the compound wang420 (yield: 90%).
'HNMR (300MHZ, CDC13) 8 3.94 (s, 3H), 7.20-7.24 (m, 2H), 7.27 (4 J= 1.8 Hz, 1H), 7.66 (dd, J- 8.1 Hz, 1.5 Hz, !H), 7.71 (dd, /= 4.8 Hz, 0.9 Hz, 1H), 7.76 (d, J= 9.0 Hz, 2H), 8.03 (dd, J= 3.6 Hz, 0.9 Hz, 1H), 8.07 (4./= 1.5 Hz, 1H), 8.14 (4J= 8.7 Hz, 2H), 8.20(br,2H).

The compound I (50mg, 0.lmmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20°C following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20n, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (27uL, 0.39mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (1.5:1 v/v) to obtain 26mg of product, the compound wang462 (yield: 56%).
'H NMR (300 MHz, CDCI3) 8 2.19 (s, 3H), 3.88 (s, 3H), 7.12 (s, 1H), 7.20-7.24 (m, 2H), 7.55 (4 J- 1.5 Hz, 1H), 7.60 (4 J" 9.0 Hz, 2H), 7.71 (d4 J=4.8 Hz, 0.9 Hz, 1H), 7.77 (br, 1H), 7.97 (d, J « 8.7 Hz, 2H), 8.03 ( 14

The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20°C following by adding 1ml_ of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20n, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (5:1 v/v) to obtain 15mg of product, the compound wang524 (yield: 36%).
,HNMR (300MHz, DMSO-4,) 8 3.90 (s, 3HX 7.22 (d, J- 5,4 Hz, IH), 7.33 (d, J= 8.4 Hz, 2H), 7.39-7.44 (IH), 7.50-7.58 (2H), 7.83 (d, J- 8.4 Hz), 7.98 (d, J- 8.7 Hz, 2H), 8.04-8.22 (7H), 10.74 (s, IH).

The compound I (40mg, 0.08mmol) is dissolved into 2ml_ of dichloromethane, and is cooled in the cryohydrate bath at -20°C following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20n, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (25uL, 0.2mmol)
is

and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (4:1 v/v) to obtain 25mg of product, the compound wang516 (yield: 62.5%).
lHNMR(300 MHz, DMSO-d6) 6 1.57 (m, 2H), 1.63-1.77 (m, 4H), 1.80-1.89 (m, ZH), 2.84 (m, IH), 3.89 (s, 3H), 7.31
The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20°C following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20n, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (4:1 v/v) to obtain 25mg of product, the compound wang488 (yield: 64%).
]H NMR (300 MHz, DMSO-d6) 6 0.80 (m, 2H), 0.85 (m, 2H), 1.84 (m, IH), 3.88 (s, 3H), 7.28 (s, IH), 7.32 (dd, J=5A Hz,3.9Hz, 1H),7J9(4^-8.1 Hz, lH),7.85(d, J= 8.7Hz,2H),7.92(dd, J"8AHz, 1.5Hz, IH), 8.04 (m, IH), 8.05 (d, J= 8.7 Hz, 2H), 8.11 (dd, /» 4.8 Hz, 1.2 Hz, IH), 8.18 (d, J= 1.8 Hz, IH), 10.68 (s, IH); ,3C NMR 05 MHz, DMSO-d*) 57.78,14.83, 55.97,115.71,118.73,118.93,123.53,125.32,128.54,128.81, 129.32,131.22,132.80,133.36,135.46,135.53,140.88,144.24,151.05,159.29,162.91,166.96, 172.44.
16

The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1ml_ of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20Q, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (4:1 v/v) to obtain 26mg of product, the compound wang568 (yield: 57%).
'H NMR (300 MHz, CDCl3) 6 3.95 (s, 3H), 4.13 (s, 2H), 4.68 (s, 2H), 7.18 (s, 1H), 7.19-7.26 (m, 2H), 7.39-7.50 (m, 5H), 7.63 (dd, /= 6.9 Hz, 0.9 Hz, 1H), 7.69 (dd, J- 4.8 Hz, 0.9 Hz, 1H), 7.74 (d, J™ 9.0 Hz, 2H), 8.01 (dd, ./= 3.6 Hz, 1.2 Hz, 1H), 8.10 (d, J= 8.7 Hz, 2H), 8.16 (d, J= 1.5 Hz, 1H), 8.56 (s, 1.H).

The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1ml_ of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of
17

dichloromethane, and cooled in the cryohydrate bath at -20D, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (4:1 v/v) to obtain 22mg of product, the compound wang502 (yield: 56%).
!H NMR (300 MHz, DMSO-d6) 5 1.81-1.94 (m, 2H), 2.12-2.28 (m, 4H), 3.29 (m, 1H), 3.89 (s, 3H), 7.31 (s, 1M), 733 (m, 1H), 7.40 (d, J- 7.5 Hz, 1H), 7.87 (d, J~ 8.1 Hz, 2H), 7.94 (d, /« 8.1 Hz, 2H), 8.04-8.08 (2H), 8.12 (d, J= 5.1 Hz, 1H), 8.19 (s, 1H), 10.20 (s, 1H).

The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20n, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (4:1 v/v) to obtain 24mg of product, the compound wang530 (yield: 57%).
'H NMR (300 MHz, DMSO-d6) 8 t.20-1.48 ( 1.65-1.81 (4H), 2.39 (m 1H), 3.89 (s, 3H), 7.32 (s, 1H), 7.34 (m, 1H), 7.41 (d, /- 8.4 Hz, 1H), 7.87 (d, J» 8.1 Hz, 2H), 7.95 (d, ./= 8.1 Hz, 1H), 8.04 (m, 1H), 8.08 (d, J = 8.7 Hz, 2H), 8.12 (d, J" 4.8 Hz, 1H), 8.20 (m, 110,10-31 (s, 1H)«
18

The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20D, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (23uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (6:1 v/v) to obtain 4mg of product, the compound wang504 (yield: 10%).
'H NMR (300 MHz,CDCl3) 6 1.34 (s, 9 H), 3.94 (s, 3H), 7.15 (s, 1H), 7.20 (dd, J= 4.8 Hz, 3.6 Hz, 1H), 7.23 (s, 1H), 7.58 (br, 1H), 7.64-7.69 (2H), 7.72 (d, J= 8-7 Hz, 2H), 8.02 (dd, J~ 3.6 Hz, 1.5 Hz, 1H), 8.08 (d, J= 9.0 Hz. 2H), 8.11 (d, J- 1.8 Hz, 1H).

The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of
19

dichloromethane, and cooled in the cryohydrate bath at -20D, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (27uL, 0.2mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with CH2CI2 to obtain 40mg of product, the compound wang554 (yield: 89%).
•H NMR (300 MHz, CDCl3,) 8 3.83 (s, 3H), 6.28 (s, IH), 7.05 (s, IH), 7.16 (d, J= 8.1 Hz, 1H), 7.20 (dd, J -
5.1 Hz, 3.6 Hz, IH), 7.39-7.41 (2H), 7.50-7.55 (3H), 7.60 (d, J= 9.0 Hz, 2H), 7.71 (dd, /« 5.1 Hz, 1.2 Hz, IH), 7.92 (d,./= 8.4 Hz, 2HX 7.99 (d, J= 1.2 Hz), 8.Q3 (dd, J= 3.6 Hz, 0.9 Hz, 2H), 8.24 (s, IH), 8.42 (s, IH).

The compound I (52mg, 0.lmmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1mL of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the reaction intermediate is dissolved in 2 mL of dichloromethane, and cooled in the cryohydrate bath at -20D, following by adding 40 uL (0.6mmol) of pyridine, adding the compound II (10mg, 0.03mmol) and gradually raising the temperature to the room temperature. The reaction is traced with TLC. The reaction solution is concentrated, and the solvents are removed to obtain the crude product. The crude product is chromatographed over silica gel column with CH2CI2 to obtain 19mg of product, the compound wang866 (yield: 44%).
'H NMR (300 MHz, DMSO-*) 8 3.89 (s, 6H), 7.33 (dd, J=4.8 Hz, 3.9 Hz, 2H), 7.36 (s, 2H), 7.41 (d, 7= 8.4 Hz, 2H), 7.93 -7.96 (2H), 7.96 (d, J - 8.7 Hz, 4H), 8.04 (dd, J» 3.3 Hz, 0.9 Hz, 2H), 8.12 (dd, /= 4.8 Hz, 0.9 Hz, 2H), 8.17 (d, J = 8.7 Hz, 4H), 8^0 (d, J= 1.8 Hz, 2H), 11.66 (s, 2H).
20

'H NMR (300 MHz, CDCI3) 6 1.41 (t, J- 6.9 Hz, 3H), 2.24 (s, 3H), 4.18 (q, /= 6.9 Hz, 2H), 7.11 (s, 1H), 7.19 (m, 1H), 7.45 (m, 2H), 7.62-7.70 (4H), 8.02 (m, 1H), 8.08 (d, J = 9.0 Hz, 2H).

According the same process, the compound wang582 is prepared by using the reaction product of 1eq of the compound wang520 with trifluoroacetic acid and 1.5eq of diamantane formyl chloride (yield: 38%).
!H NMR (300 MHz, CDCl3 6 1.76 (6H), 1.99 (6H), 2.12 (310, 3.95 (s, 3H), 7.14-7J23 (2H), 7.54 (s, 1H), 7.61-7.70 (2H), 7.73 (d, ./=> 9.0 Hz, 2H), 8.02 (dd, /- 3.9 Hz, 1H), 8.09 (d, J= 9.0 Hz, 2H), 8,12 (d, / = 1.8 Hz, 1H).

According the same process, the compound wang538 is prepared by using the
21

reaction product of 1eq of the compound wang520 with trifluoroacetic acid and 1.5eq of benzyl acetyl chloride (yield: 58%).
lHNMR (300 MHz, CDO,) 8 3.78 (s, 2H), 3.92 (s, 3H), 7.16 (s, 1H), 7.19-7.24 (2H), 7.34-7.74 (
According the same process, the compound wang496 is prepared by using the reaction product of 1eq of the compound wang520 with trifluoroacetic acid and 1.5eq of chloro acetyl chloride (yield: 70%).
'H mm. (300 MHz, DMSO-d6) 8 3.89 (s, 3H), 4.36 (s, 2H), 7.34 ($, IH),7.41 (d, J" 8.1 Hz, 1H), 7.88 (d, J= 9.0 Hz, 2H), 7.93-7.98 (2H), 8.05 (m, 1H), 8.12 (d, ./= 7.5 Hz, 2H), 8.22 (m, 1H), 8.89 (in, 1H), 10.95 (s, 1H).

The compound I (40mg, 0.08mmol) is dissolved into 2mL of dichloromethane, and is cooled in the cryohydrate bath at -20D following by adding 1ml_ of trifluoroacetic acid and gradually raising the temperature to the room temperature. And, the reaction is traced with TLC until the compound I is reacted completely. After concentrating the reaction system and removing trifluoroacetic acid completely, the compound II (19 uL, 0.16mmol)is dissolved in 2 mL of tetrahydrofuran, and cooled in the cryohydrate bath at -20D with stirring for 10min at this temperature. Then, N-methylmorpholine (NMM) (53 uL, 0.48mmol) and CICOO'Bu (21 uL, 0.16mmol) are added orderly with stirring for 0.5 hour at -20D. The reaction product of the compound I with trifluoroacetic acid is dissolved in 1 mL of tetrahydrofuran and then transferred into the above
22

mixture with the syringe so as to react at the room temperature for about 15 hours. The reaction solution is concentrated and the solvents are removed completely to obtain the crude product. The crude product is chromatographed over silica gel column with petroleum ether/ethyl acetate (5:1 v/v) to obtain 12mg of product, the compound wang516-1 (yield: 30%).
'H NMR (300 MHz, CDCl3 8 1.74 (s, 3H), 1.87 (s, 3H), 3.18 ( 8.4 Hz, 2H), 8.02 (dd, .7- 3.6 Hz, 0.9 Hz, 1H), 8.09 (d, J-9.0 Hz, 2H), 8.16 (d, J« 2.1 Hz, 1H)„

According the same process, the compound wang591 is prepared by using the reaction product of 1eq of the compound wang520 with trifluoroacetic acid and 2.0eq of the compound Boc-Ala-OH (yield: 18%).

The compound wang568 (11mg, 0.02mmol) is dissolved into 2ml_ of dichloromethane, and cooled at -78D for 10 minutes, following by adding 0.2ml_ of BCl3/n-hexane solution (1M) to continue reacting for 30 minutes at -78n. Then, the temperature is raised to -18D to react for 4 hours. 2mL of ether is added to quench the reaction with stirring for 30 minutes at the room temperature, following by adding 5mL of water. The water phase and the organic phase are separated. The water phase is extracted with dichloromethane, and the organic phase is combined, dried with anhydrous MgS04, and concentrated. The crude product is isolated over column chromatography with petroleum ether/ethyl acetate (1/2, v/v) to obtain the compound wang477 (1.5mg, yield: 17%).
23

1HNMR(30GMHz,CDei3) 8 1.86 (br, 1H), 3.95 (s, 3H), 4.26 (s,2H), 7.18 (s, IB), 7.20 (dd,./ - 8.7 Hz, 4.8 Hz, 1H), 7.23 (d, J= 3.3 Hz, 1H), 7.63 (d, > 8.1 Hz, 1H), 7.71 (dd, /- 5.1 Hz, 1.5 Hz, 1H), 7.75 (d, J= 8.7 Hz, 2H), 8.02 (d, J- 3.6 Hz, 1H), 8.08 (d, J= 8.7Hz, 2H), 8.14 (m, 1H), 8.57 (br, 1H),

The compound wang591 (3mg) is dissolved into 1.5 mL of dichloromethane, and cooled in ice bath for 5 minutes, following by adding 0.15 mL of trifluoroacetic acid. Then, the temperature is gradually raised to the room temperature, and the reaction is traced with TLC. After the raw material disappears, the solvent and trifluoroacetic acid are removed by pumping to obtain 2mg of the product, the compound wang 605 (yield: 65%).
'H NMR (300 MHz, Methyl-**? Alcohol-d) 5 l.63 (d, /= 7.2 Hz, 3H), 3.95 (s, 3H), 4.09 (m, 1H), 7.265 (s,lH), 7.267 (d, J - 8.7 Hz, 1H), 7.29 (d,/=» 8.1 Hz, 1H),7.81 (dd,/ = 8.7 Hz, 2.1 Hz, 1H), 7.87 (d, J=9.0 Hz, 2H), 7.91 (dd,/= 5.1 Hz, 1.2 Hz, 1H), 8.01 (dd,/= 3.6 Hz, 0.9 Hz, 1H), 8.16 (d, y- 9.3 Hz, 2H), 8.25 (d, J=2.1 Hz, 1H).
Example 4 Experiments testing on biological activity
1. Testing the expression of the report gene
Upon that GLP-1R binds to GLP-1 or agonists, its Gasubunit is activated to stimulate the adenylate cyclase, which makes the increase in the concentration of intracellular cAMP. Since the promoter region of the proinsulin gene has the cAMP response element, upon binding of cAMP to this response element, the transcription of the proinsulin gene is activated, so as to increase the sensitivity of 6- islet cells to glucose, and improve the expression and secretion of insulin (Diabetes, 2000, vol.49:1156-1164). The screening model employs the human embryonal nephric cell strain which is stably transfected with the expression vector of GLP-1 R gene and the expression vector of luciferase report gene under the regulation of cAMP response element, to detect its response to the candidate compound (Cell Biology, 1992, Vol.89: 8641-8645; Proc. Natl. Acad. Sci. U.S.A. 1987, Vol.84: 3434-3438). When screening the candidate compounds, the compound which may induce the luciferase report gene to
24

express have the activity of activating GLP-1.
1.1 Experimental material and instruments
Cell strain: HEK 293/GLP1R+Luc strain which stably express GLP-1 R and luciferase (National New Medicaments Screening Center)
Fetal calf serum (GIBCO/BRL Cooperation)
Steady-glo™ luciferase analysis system (Promega Cooperation)
Standard GLP-1 (Sigma Cooperation)
G418 (Invitrogen Cooperation)
Forma carbon dioxide incubator (Forma Cooperation)
Victor 2 counting machine (Wallac Cooperation)
Candidate compound: the compounds wang524, wang520, wang462, 2f, wang516, wang516-2, wang502 and wang504;
1.2 Experimental process
HEK 293/GLP1R+Luc cell in 20000 cells/100ul/well are inoculated into 96-well plate, are cultured at 37n overnight with DMEM culture medium containing 10% of fetal calf serum and 500ug/mL of G418. The candidate compounds wang516-2, wang502, and wang504 are respectively diluted to 2mM, 1mM, 0.3mM, 0.1 mM, 0.03mM, 0.01 mM, and 0.003mM, and the other candidate compounds are diluted gradually from 30mM for 8 times by a ratio of 1:3 to get a concentration gradient (i.e., 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.1mM, 0.03mM, and 0.01 mM), following by being added into the above 96-well plate at 1ul/well. Then, the cells are cultured at 37n in 5% of CO2 6 hours. The activity of luciferase is detected according to the specification of Steady-glo™ luciferase analysis system kit, and counting is performed with Victor 2 counting machine. The positive control adopts 30nM of standard GLP-1.
1.3 Experimental result
The experimental result of the report gene for the candidate compounds is as shown in the figure 1 and the table 1.
The figure 1 shows that the compound wang 520 in a final concentration of 30uM have the best relative activity (94%) which is improved greatly compared with the activity of the compound 2f. In addition, the compounds as shown in the table 1 have the dose dependency on the activity of GLP-1 R, wherein the median effective dose (EC50) of the compounds wang 520, wang 516. wang 554,
25

wang 488 wang516-2, wang502 and wang 504 is less than 10|jM. Such result provides the direction for determining the superior structure of the interaction of the compounds with GLP-1R.

The table 1
The number of the compound EC50/µM
wang524 46.5
wang520 4.6
wang462 11.6
wang516 6.85
2f 13.0
wang866 54.41
wang554 5.24
wang488 6.73
wang516-2 6.06
wang502 3.31
wang504 4.87
2. Determination of the concentration of intracellular cAMP
Since the determination of the concentration of intracellular cAMP indirectly by detecting the expression of the report gene is an indirect process, the functional re-screen is directly performed with the cAMP-detecting kit in order to make sure that the compound can surely increase the concentration of intracellular cAMP.
2.1 Experimental material and instruments
cAMP-detecting kit (Applied Biosystems Cooperation)
Forma carbon dioxide incubator (Forma Cooperation)
Victor 2 according machine (Wallac Cooperation)
HEK 293/GLP1R+Luc strain which stably express GLP-1 R and luciferase (National new medicaments screening center)
Candidate compound: the compound 2f
26

Standard cAMP (provided in the kit, Applied Biosystems Cooperation )
2.2 Experimental process
HEK 293 cells are inoculated into 96-well plate in 20000 cells/100µl/well, are cultured at 37D overnight. The compound 2f is diluted to 1.00E-03M, 1.00E-04M, 1.00E-05M, 1.00E-06M and 1.00E-07M with dimethyl sulphoxide, following by being inoculated into the above 96-well plate in 1 l/well and being cultured at 37□ with 5% of CO2 for 1 hour. The concentration of intracellular cAMP is detected according to the specification of cAMP-Screen Direct TM system kit.
2.3 Experimental result
The determining result of the concentration of intracellular cAMP is shown in the figure 2. As shown in the figure 2, with increase of the concentration of the compound 2f, the concentration of cAMP which is produced under this stimulation shows an exponential increase. This indicates that the compound 2f has a certain effect on signal transmission of GLP-1R as a GLP-1R agonist. When the concentration of the compound 2f increases to 30uM and 100uM, the concentration of cAMP shows the decreasing trend, which is caused by the cellulotoxic effect of the high concentration of the compound 2f.
3. The test on the ligand-binding activity
In order to determine the binding activity of the compound to the ligand, the cells which highly express GLP-1R are prepared, GLP-1 labelled with 125l is used as the ligand, while adding into the candidate compound. When the candidate compound binds the 125l-labelled GLP-1 competitively, the isotope labels on the cell membrane reduce. Accordingly, the affinity of the candidate compound to the ligand can be evaluated (J Mol Endocrinol. 2000 Vol.25:321-35; J Biomol Screen, 2000 Vol. 5:377-84).
3.1 Experimental material and instruments
HEK 293/GLPIR+Luc cell strain (National New Medicaments Screening Center)
Labeled compound: 125l-labelled GLP-1 (Amersham Biosciences Cooperation)
Wallac MicroBata work station (Perkin Elmer Cooperation)
TomTech cell collector (TomTec Cooperation)
The testing buffer solution:
20mM of tris-HCI (pH 7.4) (Shanghai Shenggong biological engineering technology LTD), 100mM of NaCI (Shanghai Chemical agents Cooperation), 15mM of NaF (Shanghai Chemical agents Cooperation), 2mM of
27

deoxypyridoxine (Sigma Cooperation), 0.2mM of phenylmethylsulfonyl fluoride (Sigma Cooperation), aprotinin (Shanghai Chemical agents Cooperation) (1 ug/ml), and leupeptin (Shanghai Chemical agents Cooperation) (1 ug/ml).
The washing solution:
20mM of tris-HCI (pH 7.4), 100mM of NaCI, and 15mM NaF
The scintillation liquid (Wallac Cooperation)
The candidate compound is diluted with dimethyl sulphoxide at the concentration gradient of 0.1 nM, 1nM, 10nM, 100nM, 1000nM, 10,000nM, and 100,000 nM.
3.2 Experimental process
105 HEK 293/GLP1R+Luc cells in the logarithmic growth phase are incubated together with the 125l-labelled GLP-1 positive peptide (the final concentration of 40pM) in 200ul of the testing buffer solution at 25a for 4 hours, while adding into the non-labeled positive peptide or the candidate compound. The cells are collected with the cell collector, following by washing three times with the washing solution. The scintillation liquid is added into them, and each well is counted with Microbata counter.
3.3 Experimental result
The result of the receptor-binding experiment is shown in the table 3. As shown in the table 3, the compound 2f has the better affinity to GLP-1 R, but the affinities of compounds wang520 and wang516 are little week, and the other compound substantially don't bind the receptor in the testing concentration rage.

The table 3
The number of the compound EC50/µM
wang524 >100µM
wang450 >100µM
wang405 >100µM
wang327 >100µM
wang520 60-1 OOµM
wang462 >100µM
wang866 >100µM
28

wang516 40-80µM
wang420 >100µM
2f 31µM

We Claim:-
1. A glucagon-like peptide-1 receptor agonist having the following structural formula:

wherein, each of An and Ar2 independently is phenyl or substituted phenyl, and the substituent groups of the said substituted phenyl is one, two or three groups optionally selected from the following group: alkyl; hydroxyl; substituted alkoxyl or alkylamino which contains the substituent groups including halogen, alkoxyl or hydroxyl; substituted alkanoylxy or alkanoylamino which contains the substitutent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl substituted with oxygen or amine, phenyl, benzyl, C2-C6 enoyl, C3-C6 cycloalkanoyl, benzoyl, substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkanoylamino, benzyloyl, thenoyl, tert-butoxycarbonyl, adamantane formoxyl, and mandeloyl; alkoxyl; alkylamino; cycloalkoxyl; cycloalkylamino; amino; amide; alkoxycarbonyl; cycloalkoxycarbonyl; alkanoylxy; alkanoylamino; cycloalkanoylxy; cycloalkanoylamino; carbamido; urylene; alkanoyl; nitro; carboxyl; and aldehyde group;
X is O, S, or NH; and
Y is O or S.
2. The glucagon-like peptide-1 receptor agonist according to the claim 1, being characterized in that

wherein R1 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three
30

substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and Xi is O or NH,

wherein R2 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X2 is O or NH;

wherein each of R3 and R4 independently is any one of the following substituent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X1 is O or NH; X2 is O or NH.
3. The glucagon-like peptide-1 receptor agonist according to the claim 1, being characterized in that,

wherein each of R5 and R6 independently is any one of the following substituent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X1
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wherein R2 is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X2 is O or NH;

wherein each of R3 and R4 independently is any one of the following substituent groups: H; alkyl; substituted alkyl which contains substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; tert-butoxycarbonyl; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; and X1 is O or NH; X2 is O or NH.
4. A process for preparing the glucagon-like peptide-1 receptor agonist according to the claim 1, being characterized in that, the said agonist is prepared by condensating

independently is phenyl or substituted phenyl, wherein the substituent group of the said substituted phenyl is one, two or three groups optionally selected from the following group: nitro; carboxyl; aldehyde; tert-butoxycarbonyl and thenoyl substituted with oxygen or amino; X is O, S or NH; and Y is O or S.
5. A process for preparing the glucagon-like peptide-1 receptor agonist according to
32

trifluoroacetic acid with the compound R1COX4, wherein R1, R2 and R3 are any one of the following substitutent groups: H; alkyl; substituted alkyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 alkenyl; C3-C6 cycloalkyl; phenyl; benzyl; alkanoyl; substituted alkanoyl which contains the substituent groups including halogen, alkoxyl or hydroxyl; C2-C6 enoyl; C3-C6 cycloalkanoyl; benzoyl; tert-butoxycarbonyl; substituted benzoyl which contains optional one, two or three substituent groups including alkoxyl and alkylamino; benzyloyl; thenoyl; adamantane formoxyl; and mandeloyl; X is O, S, or NH; Y is O or S; each of X1, X2 and X3 independently is O or NH; and X4 is CI or OH.
6. The processes for preparing the glucagon-like peptide-1 receptor agonist according the claims 4 or 5, being characterized in that, the solvent used in condensation reaction is dichloromethane, acetic anhydride, tetrahydrofuran, dimethylfuran, dichloroethane, toluene, benzene, water, dioxane or any mixture thereof.
7. The processes for preparing the glucagon-like peptide-1 receptor agonist according the claims 4 or 5, being characterized in that, the reaction temperature is from -78°C to the room temperature, or the heating temperature is from 50D to 230D.
8. The processes for preparing the glucagon-like peptide-1 receptor agonist according the claims 4 or 5, being characterized in that, pyridine, triethylamine, diethylpropylethyl amine, DMAP, N-methylmorpholine, or isobutyl chloroformate is used as activator in condensation reaction.
9. Use of the glucagon-like peptide-1 receptor agonist according to claim 1 as medicaments for treating the carbohydrate metabolism disturbance-related diseases such as type II diabetes, insensitivity to insulin or obesity, etc.
33

10. The A glucagon-like peptide-1 receptor agonists, the preparation and the use of the same as claimed as claimed substantially as herein described with forgoing description.
Dated this 9th day of June 2006.

Dr. Rajeshkumar H. Acharya Advocate & Patent Agent For and on Behalf of Applicant
34

ABSTRACT
The present invention provides the glucagon-like peptide-1 receptor agonists. It is indicated that the agonists have good binding capability to glucagon-like peptide-1 receptor by pharmacological tests. The present invention also provides the preparation of the agonists.

Documents:

681-mumnp-2006-abstract(28-2-2008).pdf

681-mumnp-2006-abstract(granted)-(3-6-2008).pdf

681-mumnp-2006-abstract.doc

681-mumnp-2006-abstract.pdf

681-mumnp-2006-cancelled pages(28-2-2008).pdf

681-mumnp-2006-claims(28-2-2008).pdf

681-mumnp-2006-claims(amanded)-(28-2-2008).pdf

681-MUMNP-2006-CLAIMS(AMENDED)-(24-10-2007).pdf

681-mumnp-2006-claims(granted)-(3-6-2008).pdf

681-mumnp-2006-claims.doc

681-mumnp-2006-claims.pdf

681-mumnp-2006-correspondance-others.pdf

681-mumnp-2006-correspondance-received.pdf

681-mumnp-2006-correspondence(13-7-2010).pdf

681-MUMNP-2006-CORRESPONDENCE(18-11-2011).pdf

681-mumnp-2006-correspondence(29-3-2010).pdf

681-MUMNP-2006-CORRESPONDENCE(9-8-2010).pdf

681-mumnp-2006-correspondence(ipo)-(13-1-2009).pdf

681-MUMNP-2006-CORRESPONDENCE(IPO)-(9-3-2012).pdf

681-mumnp-2006-declaration(12-6-2006).pdf

681-MUMNP-2006-DECLARATION(13-7-2006).pdf

681-mumnp-2006-description (complete).pdf

681-mumnp-2006-description(complete)-(28-2-2008).pdf

681-mumnp-2006-description(granted)-(3-6-2008).pdf

681-mumnp-2006-drawing(28-2-2008).pdf

681-mumnp-2006-drawing(granted)-(3-6-2008).pdf

681-mumnp-2006-drawings.pdf

681-MUMNP-2006-ENGLISH TRANSLATION(12-6-2006).pdf

681-MUMNP-2006-FORM 1(12-6-2006).pdf

681-mumnp-2006-form 1(13-7-2006).pdf

681-mumnp-2006-form 18(7-7-2006).pdf

681-mumnp-2006-form 2(28-2-2008).pdf

681-mumnp-2006-form 2(granted)-(3-6-2008).pdf

681-mumnp-2006-form 2(title page)-(28-2-2008).pdf

681-mumnp-2006-form 2(title page)-(granted)-(3-6-2008).pdf

681-mumnp-2006-form 26(13-7-2006).pdf

681-mumnp-2006-form 3(12-6-2006).pdf

681-mumnp-2006-form 3(13-7-2006).pdf

681-mumnp-2006-form 5(12-6-2006).pdf

681-MUMNP-2006-FORM 5(13-7-2006).pdf

681-mumnp-2006-form-1.pdf

681-mumnp-2006-form-2.doc

681-mumnp-2006-form-2.pdf

681-mumnp-2006-form-3.pdf

681-mumnp-2006-form-5.pdf

681-mumnp-2006-marked copy(24-10-2007).pdf

681-MUMNP-2006FORM 2(TITLE PAGE)-(12-6-2006).pdf

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Patent Number

220739

Indian Patent Application Number

681/MUMNP/2006

PG Journal Number

33/2008

Publication Date

15-Aug-2008

Grant Date

03-Jun-2008

Date of Filing

12-Jun-2006

Name of Patentee

SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES

Applicant Address

555 ZU CHONG ZHI ROAD, PUDONG NEW DISTRICT, SHANGHAI 201203, CHINA

Inventors:

#	Inventor's Name	Inventor's Address
1	NAN FAJUN	THE NATIONAL CENTER FOR DRUG SCREENING NO.189, GUO SHOU JING ROAD, ZHANGJIANG HIGH-TECH PARK, PUDONG NEW DISTRICT, SHANGHAI 201203, CHINA
2	WANG, Mingwei	The National Center for Drug Screening No.189, Guo Shou Jing Road, Zhangjiang High-Tech Park, Pudong New District, Shanghai 201203, China.
3	ZHOU, Caihong	The National Center for Drug Screening No.189, Guo Shou Jing Road, Zhangjiang High-Tech Park, Pudong New District, Shanghai 201203, China.
4	WANG, Wenlong	The National Center for Drug Screening No.189, Guo Shou Jing Road, Zhangjiang High-Tech Park, Pudong New District, Shanghai 201203, China.

PCT International Classification Number

C07D 263/42

PCT International Application Number

PCT/CN2003/001115

PCT International Filing date

2003-12-25

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2003101093 31.0	2003-12-12	China