Benzimidazole derivative as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a benzimidazole derivative as well as a pharmaceutical composition and application thereof, the benzimidazole derivative is a new chemical small molecule, and compared with a polypeptide agonist, the small molecule drug has a remarkable advantage in bioavailability when being orally taken, is simpler and more convenient to take and is not limited by food or taking time. In addition, the imidazo heteroaryl derivative as a small molecule agonist shows a good curative effect on the cellular level, and has a good drug application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical pharmaceuticals, and specifically to benzimidazole derivatives, their pharmaceutical compositions and uses. Background Art

[0002] Diabetes is a group of metabolic diseases characterized by chronic hyperglycemia caused by defects in insulin secretion, insulin action, or both. The abnormal metabolism of carbohydrates, fats, and proteins observed in diabetic patients is the result of abnormal insulin action on target tissues and leads to structural changes in many organ systems of the body, particularly those related to the vascular system. The chronic hyperglycemia of diabetes is associated with severe long-term complications, including microvascular (such as retinopathy, nephropathy, and neuropathy) and macrovascular (including fatal and non-fatal myocardial infarctions, peripheral vascular disease, and stroke) diseases. Diabetes is not a single disease but a chronic syndrome that requires active and long-term medical treatment to limit its complications, effectively manage them when they develop, and prevent premature death. Therefore, in addition to blood glucose control, diabetic patients require continuous medical care, including multi-factorial risk reduction strategies.

[0003] Diabetes is divided into four major subtypes: type I, type II, gestational, and other (i.e., specific types of diabetes caused by other reasons).

[0004] The glucagon-like peptide-1 receptor (GLP-1R) controls the physiological response to the incretin hormone glucagon-like peptide-1 (GLP-1), and due to the wide-ranging effects mediated upon its activation, including promoting glucose-dependent insulin secretion, increasing insulin biosynthesis, preserving β-cell mass, improving peripheral insulin action, and promoting weight loss, is a major therapeutic target for the treatment of type 2 diabetes.

[0005] GLP-1 receptor agonists play an irreplaceable role in the treatment of diabetes. Since 2005, a total of 7 GLP-1 receptor agonists have been approved, including exenatide, liraglutide, dulaglutide, albiglutide, lixisenatide, semaglutide, and tirzepatide. Currently, all approved GLP-1 receptor agonists on the market are peptide agonists, and there are no marketed small molecule agonists (the fastest progressing is in phase II clinical trials). Compared with peptide agonists, small molecule drugs have significant advantages in oral bioavailability and are more convenient to take, without being restricted by food or dosing time.

[0006] There is still a need to research and develop new small molecule drugs for GLP-1 receptor agonists for the preparation of preventing and / or treating related diseases. Summary of the Invention

[0007] The present invention provides a benzimidazole derivative for promoting its application in the preparation of drugs as a new small molecule drug for GLP-1 receptor agonists.

[0008] In view of this, the solution of the present invention is as follows:

[0009] The first aspect of the present invention is to provide a benzimidazole derivative, which is a compound having the structure shown in formula I, or a pharmaceutically acceptable salt thereof:

[0010]

[0011] In formula I:

[0012] X 1 、X 2 、X 3 、X 4 and X 5 each independently selected from CR X or N, and R X is hydrogen, fluorine, cyano, methyl or chlorine;

[0013] Y 1 、Y 2 and Y 3 each independently selected from CR Y or N, and R Y is hydrogen, fluorine, cyano, methyl or chlorine.

[0014] Furthermore, the benzimidazole derivative is a compound having the structure shown in general formula II;

[0015]

[0016] In formula II, R X is fluorine, cyano, methyl or chlorine.

[0017] Furthermore, the benzimidazole derivatives are any of the following compounds:

[0018]

[0019] The second aspect of the present invention is to provide isomers of the benzimidazole derivatives described in the first aspect.

[0020] Furthermore, the isomers include at least one of tautomers, mesomers, racemates, enantiomers, and diastereoisomers.

[0021] The third aspect of the present invention is to provide a pharmaceutical composition, which comprises the benzimidazole derivatives described in the first aspect, and / or the isomers described in the second aspect, and a pharmaceutically acceptable carrier.

[0022] The fourth aspect of the present invention is to provide the use of the pharmaceutical composition in the preparation of a drug for activating GLP-1 receptor, wherein the pharmaceutical composition comprises the benzimidazole derivatives described in the first aspect, and / or the isomers described in the second aspect.

[0023] Furthermore, the drug is used for treating and / or preventing diseases selected from type I diabetes, type II diabetes, young adult-onset diabetes, latent autoimmune diabetes in adults, gestational diabetes, diabetic complications, obesity, malnutrition-related diabetes, hyperglycemia, glucose intolerance, cardiovascular diseases, cerebral infarction, stroke, non-alcoholic fatty liver disease, Parkinson's disease, dementia or indications caused by insulin resistance; preferably type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular diseases.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The benzimidazole derivatives provided by the present invention are new chemical small molecules. Compared with polypeptide agonists, small molecule drugs have significant advantages in oral bioavailability, and are more convenient to take, without being restricted by food or taking time. In addition, the imidazoheteroaryl derivatives show good efficacy at the cellular level as small molecule agonists and have good prospects for drug application. Detailed Embodiments

[0026] The technical solutions of the present invention will be clearly and completely described below in conjunction with preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts fall within the protection scope of the present invention.

[0027] In one embodiment, a benzimidazole derivative is provided, which is a compound having the structure of general formula I, or a tautomer, meso form, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0028]

[0029] In formula I: X 1 、X 2 、X 3 、X 4 and X 5 each independently selected from CR X or N, and R X is hydrogen, fluorine, cyano, methyl or chlorine; Y 1 、Y 2 and Y 3 each independently selected from CR Y or N, and R Y is hydrogen, fluorine, cyano, methyl or chlorine. The carbon atom adjacent to X 5 forms a six-membered ring with X 1 、X 2 、X 3 、X 4 and X 5 , and this six-membered ring is a benzene ring or a heterocyclic ring containing a nitrogen atom. Y 1 、Y 2 and Y 3 also form a six-membered ring with the adjacent carbon atoms, and this six-membered ring is a benzene ring or a heterocyclic ring containing a nitrogen atom, preferably a heterocyclic ring containing at least one nitrogen atom. The benzimidazole derivative with the above structure has agonist activity on GLP-1 receptors at the cellular level, can be used to prepare drugs for activating GLP-1 receptors, shows good efficacy as a chemical small molecule GLP-1 agonist, and has good prospects for drug application.

[0030] In the above embodiment, the benzimidazole derivative can be used for the prevention and treatment of type I diabetes, type II diabetes, young adult-onset diabetes, adult latent autoimmune diabetes, gestational diabetes, diabetic complications, obesity, malnutrition-related diabetes, hyperglycemia, glucose intolerance, cardiovascular diseases, cerebral infarction, stroke, non-alcoholic fatty liver disease, Parkinson's disease, dementia or indications caused by insulin resistance.

[0031] In a preferred embodiment, the benzimidazole derivative is preferably a compound having the structure of General Formula II; R in Formula II X is fluorine, cyano, methyl or chlorine, and Y 1 , Y 2 and Y 3 are the same as those in General Formula I.

[0032]

[0033] In a preferred embodiment, the compound having the structure of General Formula I is preferably a compound of Formula III to Formula VI having the following structures:

[0034]

[0035] In another embodiment, a preparation method of General Formula II having the following structure is provided, including the following steps:

[0036] (a) Compound 1 is reacted with methanesulfonyl chloride, pyridine, dichloromethane at room temperature to obtain Compound 2;

[0037] (b) Sodium iodide, DMF are added to Compound 2 and reacted at 100 °C to prepare Compound 3;

[0038] (c) Under the condition of palladium on carbon as a catalyst, ammonium formate and ethanol are added to Compound 3 and refluxed

[0039] to prepare Compound 4;

[0040] (d) Compound 4 is reacted with potassium carbonate, N,N-dimethylformamide at room temperature to obtain compound

[0041] 5;

[0042] (e) Trifluoroacetic acid and dichloromethane are added to Compound 5 and reacted at room temperature to obtain Compound 6;

[0043] (f) Pd(OAc) 2 , trixiephos, Cs 2 CO 3 , dioxane are added to Compound 6 and reacted at 100 °C

[0044] to prepare Compound 7;

[0045] (g) A base is added to Compound 7 and refluxed to obtain a compound of General Formula II.

[0046] The preparation routes of the above steps (a) to (g) are shown as follows:

[0047]

[0048] The following are the preferred preparation examples of benzimidazole derivatives. Unless otherwise specified, the raw materials used in the examples are commercially available standard reagents in the art, and the synthetic methods used are those well-known in the art. The synthesis processes of similar intermediates in the examples can be selectively replaced with reagents containing different substituents based on the synthesis principle.

[0049] Example 1

[0050] 1) Synthesis of Intermediate 2

[0051]

[0052] Dissolve the starting material INB-1 (10.00 g, 1.0 equivalent) in dichloromethane (150 mL). Sequentially add pyridine (3.8 mL, 1.5 equivalents) and methanesulfonyl chloride (3.93 g, 1.1 equivalents). React at room temperature overnight. After detecting the completion of the reaction by TLC, dilute with saturated aqueous sodium bicarbonate, extract three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain a brown residue. Purify by silica gel column chromatography to obtain 8.7 g of Intermediate 2 with a yield of 70%.

[0053] 2) Synthesis of Intermediate 3a

[0054]

[0055] Dissolve Intermediate 2 (4.00 g, 1.0 equivalent), sodium iodide (1.80 g, 1.2 equivalents), and 3-cyanophenol (3.57 g, 3.0 equivalents) in N,N-dimethylformamide (40 mL). React at 100 °C for 24 hours. After detecting the completion of the reaction by TLC, dilute with saturated aqueous sodium bicarbonate, extract three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel column chromatography to obtain 1.26 g of Intermediate 3a with a yield of 30%.

[0056] 3) Synthesis of Intermediate 4a

[0057]

[0058] Place Intermediate 3a (1.20 g, 1.0 equivalent), palladium on carbon (10%), and ammonium formate (0.90, 5.0 equivalents) in a reaction flask. Add ethanol (20 mL) and reflux under nitrogen protection for 6 hours. After detecting the completion of the reaction by TLC, filter through diatomaceous earth and purify by silica gel column chromatography to obtain 0.89 g of Intermediate 4a with a yield of 94%.

[0059] 4) Synthesis of Intermediate 5a

[0060]

[0061] Starting material INB-2 used:

[0062] Place intermediate 4a (0.80 g, 1.0 equivalent), starting material INB-2 (0.85 g, 1.2 equivalents), and sodium carbonate (0.77 g, 3.0 equivalents) in a reaction flask, add N,N-dimethylformamide (20 mL), and react at room temperature for 5 hours. After detecting the completion of the reaction by TLC, add 100 mL of water, extract 3 times with ethyl acetate, combine the organic phases, and purify by silica gel column chromatography to obtain 1.27 g of intermediate 5a with a yield of 89.7%.

[0063] 5) Synthesis of intermediate 6a

[0064]

[0065] Dissolve intermediate 5a (1.00 g, 1.0 equivalent) in dichloromethane (20 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 5 hours. After detecting the completion of the reaction by TLC, add an aqueous solution of sodium bicarbonate for neutralization, separate the layers, extract the aqueous phase 2 times with dichloromethane, combine the organic phases, and purify by silica gel column chromatography to obtain 0.79 g of intermediate 6a with a yield of 94.7%.

[0066] 6) Synthesis of intermediate 7a

[0067]

[0068] Intermediate 6a (0.2 g, 1.0 equivalent), 2-chloropyridine (1.05 equivalents), Pd(OAc) 2 (0.05 equivalent), Trixiephos (0.05 equivalent), and Cs 2 CO 3 (2.0 equivalents) are placed in a reaction vessel equipped with a reflux condenser, add an appropriate amount of 1,4-dioxane, react under a nitrogen atmosphere at 105 °C for 2 hours. After the reaction is completed, cool to room temperature, filter through diatomaceous earth, concentrate under reduced pressure, and elute by column chromatography to obtain 0.17 g of intermediate 7a with a yield of 73.4%.

[0069] 7) Synthesis of compound 8a

[0070] Dissolve LiOH (3.0 equivalents) in an appropriate amount of water and add it to an acetonitrile solution (5 times the volume of water) of intermediate 7 (1.0 equivalent), react at room temperature for 2 hours. After the reaction is completed, add dilute hydrochloric acid (1 N) to adjust the pH to acidic to precipitate a solid, filter by suction, and dry in vacuo to obtain the target compound 8a. MS (ESI): 551.5 [M - 1].

[0071] Example 2

[0072] 1) Synthesis of intermediate 3b

[0073]

[0074] The synthesis method was the same as that of 3a to obtain intermediate 3b with a yield of 33%.

[0075] 2) Synthesis of intermediate 4b

[0076]

[0077] 3) The synthesis method was the same as that of 4a to obtain intermediate 4a with a yield of 92%.

[0078] 4) Synthesis of intermediate 5b

[0079]

[0080] The synthesis method was the same as that of 5a to obtain intermediate 5b with a yield of 86%.

[0081] 5) Synthesis of intermediate 6b

[0082]

[0083] The synthesis method was the same as that of 6a to obtain intermediate 6b with a yield of 93%.

[0084] 6) Synthesis of intermediate 7b

[0085]

[0086] The synthesis method was the same as that of 7a to obtain intermediate 7b with a yield of 72%.

[0087] 7) Synthesis of compound 8b

[0088]

[0089] The synthesis method was the same as that of compound 8a to obtain compound 8b. MS(ESI): 561.0[M - 1].

[0090] Example 3

[0091] 1) Synthesis of intermediate 7c

[0092]

[0093] The synthesis method was the same as that of 7a to obtain intermediate 7c with a yield of 70%.

[0094] 2) Synthesis of compound 8c

[0095]

[0096] The synthesis method was the same as that of compound 8a to obtain compound 8c. MS(ESI): 552.5[M-1].

[0097] Example 4

[0098] 1) Synthesis of intermediate 7d

[0099]

[0100] The synthesis method was the same as that of 7a to obtain intermediate 7d with a yield of 68%.

[0101] 2) Synthesis of compound 8d

[0102]

[0103] The synthesis method was the same as that of compound 8a to obtain compound 8d. MS(ESI): 569.5[M-1].

[0104] Experimental Example: Evaluation of GLP-1 Receptor Agonist Activity

[0105] Experimental purpose: To test the agonist activity of the compound on GLP-1 receptor at the cellular level.

[0106] Test method: ONE-Glo TM luciferase assay system was used in this experiment. The principle is that after the activation of GLP-1 receptor, its downstream signaling pathway is activated, leading to an increase in the expression level of cAMP. cAMP binds to CRE to initiate the transcriptional expression of the luciferase gene downstream of CRE, and luciferase reacts with its substrate to emit fluorescence. Therefore, the activity of the compound activating GLP-1 receptor can be evaluated by detecting the fluorescence signal with ONE-Glo TM reagent. First, a stable cell line of CHO-K1 / CRE-luc / GLP-1 receptor was constructed. The cells were seeded in a 96-well cell culture plate at a density of 2.5×10 5 cells / mL and cultured for 16 hours. Then, the cells were treated with different concentrations of the compound for 6 hours. The 96-well cell culture plate was taken out, and the specified dose of ONE-Glo TM reagent was added according to the instruction manual, incubated at room temperature for 10 minutes, and the fluorescence signal was measured using a microplate reader.

[0107] Data analysis:

[0108] The data was processed and analyzed using Graphpad Prism 5. The EC 50 value of the compound was obtained, and the results are shown in the following table:

[0109]

[0110] The EC 50 (nM) of the agonist activities of Compounds 8a, 8b, 8c and 8d obtained in the above Examples 1 - 4 against the GLP-1 receptor, with the agonist activity of exenatide (1 μM) being 100%.

[0111] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A benzimidazole derivative, characterized in that: It is a compound having the structure shown in Formula I, or a pharmaceutically acceptable salt thereof: In Formula I: X1, X2, X3, X4 and X5 are each independently selected from CR X or N, R X is hydrogen, fluorine, cyano, methyl or chlorine; Y1, Y2 and Y3 are each independently selected from CR Y or N, R Y is hydrogen, fluorine, cyano, methyl or chlorine.

2. The benzimidazole derivative according to claim 1, characterized in that: The benzimidazole derivative is a compound of the structure described in general formula II; In Formula II, R X is fluorine, cyano, methyl or chlorine.

3. The benzimidazole derivative according to claim 1, characterized in that: It is any compound of the following structures:

4. The isomer of the benzimidazole derivative according to any one of claims 1 to 3.

5. The isomer according to claim 4, characterized in that It includes at least one of tautomers, mesomers, racemates, enantiomers, and diastereomers.

6. A pharmaceutical composition comprising the benzimidazole derivative according to any one of claims 1 to 3, and / or the isomer according to claim 4 or 5, and a pharmaceutically acceptable carrier.

7. Use of a pharmaceutical composition in the preparation of a drug for stimulating a GLP-1 receptor, characterized in that: The pharmaceutical composition comprises the benzimidazole derivative according to any one of claims 1 to 3, and / or the isomer according to claim 4 or 5.

8. The use according to claim 7, characterized in that: The drug is used to treat and / or prevent a disease selected from type I diabetes, type II diabetes, maturity-onset diabetes of the young, latent immune diabetes of adults, gestational diabetes, diabetic complications, obesity, malnutrition-related diabetes, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease, Parkinson's disease, dementia or indications caused by insulin resistance.

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