CN105820089A - 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-(4-methoxy-phenyl)-benzamide new compound and preparation method and application thereof - Google Patents

Abstract

The present invention provides a new compound named 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N -(4-methoxy-phenyl)-benzamide, the molecular weight of the compound is 600.6, the structure of the compound is shown in the structural formula (compound 1); meanwhile, the present invention provides a preparation method of the compound 1; the present invention provides The compound has good drug-like properties and can be used in the field of new drug research, especially in the field of type II diabetes innovative drug research.

Description

A 5-[3-(2,5-diethoxy-4-methanesulfonyl-benzyl)-ureido]-2-ethoxy-N-(4-methoxy-phenyl)- Novel benzamide compound, preparation method and use

technical field

The present invention relates to providing a 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-(4-methoxy- A new compound of phenyl)-benzamide, its preparation method and its application in the research of innovative drugs. The compound has small molecular weight, novel structure, stable properties and simple structure. It is suitable for the research and development of innovative drugs and belongs to the field of chemical technology.

Background technique

Urea compounds ( ) when combined with the active pocket of drug target molecules (proteins, enzymes and other macromolecules), since the hydrogen atom on the nitrogen atom in the ureido structure is a good combination with the key amino acid residues in the active pocket of the drug target molecule It is a hydrogen bond donor, and the carbonyl group in its urea group is a very good hydrogen bond acceptor for binding to the key amino acid residues in the active pocket of the drug target molecule. Therefore, in the compound design of innovative drug research, this type of group is very important. Good dominant group. Compound 5-[3-(2,5-diethoxy-4-methanesulfonyl-benzyl)-ureido]-2-ethoxy-N-(4-methoxy-phenyl)-benzene Formamide is a urea compound containing a urea group structure. The compound has a novel structure, stable properties, and a simple structure. In the docking study of computer-aided drug design, it was found that this compound can better combine with some drug targets for type II diabetes , has a certain prospect of innovative drug research and development.

Contents of the invention

1. A new compound, characterized in that the name of the compound is 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy -N-(4-methoxy-phenyl)-benzamide (compound 1), the molecular weight of this compound is 600.6, and the structural formula of this compound is shown as compound 1 below.

2. A new compound 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-(4-methoxy The method of -phenyl)-benzamide is characterized in that, comprises reaction step g6 shown in following reaction scheme 1, reaction step g7, reaction step g8, reaction step g, reaction step h, reaction step i following total 6 reactions Step, wherein the condition characteristics of these 3 steps of reaction step g, reaction step h, reaction step i are as follows:

The conditions of reaction step g are: the molar ratio range of 2,5-diethoxy-4-nitro-benzylamine to compound G is 0.8:1~1.3:1, and the molar ratio of triethylamine to compound G=0.8: 1~5:1), the solvent is N, N-dimethylformamide or dimethyl sulfoxide or acetone or 1,4-dioxane and other single solvent or a combination of solvents, the reaction temperature is 50~120 degrees, The reaction time is 5 to 18 hours. After the reaction is completed, the product compound H is purified by concentration, extraction, crystallization, etc., and the yield range is 50% to 90%. The conditions of the reaction step h are: nickel chloride hexahydrate and compound H moles The ratio range is 0.9:1~2.5:1, the molar ratio range of sodium borohydride and compound H is 0.9:1~4:1, the solvent is a single solvent or a combination of solvents such as dichloromethane or tetrahydrofuran or ether, and the reaction time is After 10 minutes to 12 hours, the product compound I was purified by extraction and crystallization after the reaction, and the yield range was 50% to 95%; the conditions of the reaction step i were: the molar ratio of alkylsulfonyl chloride to compound I was in the range of 0.8: 1~1.5:1, the molar ratio range of pyridine to compound I is 0.9:1~1.5:1, the solvent is dichloromethane, or tetrahydrofuran, or ether, or N,N-dimethylformamide, or dimethyl sulfoxide, or acetone, or 1,4 Dioxane and other single solvents or a combination of solvents, the reaction temperature is 0-80 degrees, the reaction time is 3-18 hours, after the reaction is completed, the product compound 1 is obtained by extraction, crystallization, column chromatography, etc., The yield range is 50%~95%. 3. The compounds provided by the present invention have good drug-like properties and can be used in the field of new drug research, especially in the field of innovative drug research for the treatment of type II diabetes.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 4, characterized in that, the pharmaceutical composition further contains one or more pharmaceutically acceptable carriers or excipients.

6. The pharmaceutical composition according to claim 4, characterized in that the active ingredient of the compound or its pharmaceutically acceptable salt accounts for 50%-99.5% of the total weight.

The present invention will be further described below in conjunction with specific examples, but the present invention is not limited.

specific embodiment

Example 1: 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-(4-methoxy-phenyl )-benzamide (compound 1) has the following structural formula:

Compound 5-[3-(2,5-diethoxy-4-methanesulfonyl-benzyl)-ureido]-2-ethoxy-N-(4-methoxy-phenyl)-benzene The synthetic route of formamide is as follows:

Compound 5-[3-(2,5-diethoxy-4-methanesulfonyl-benzyl)-ureido]-2-ethoxy-N-(4-methoxy-phenyl)-benzene The specific preparation method of formamide is as follows: Reaction step g6 (preparation of compound G1-6): add 2-ethoxy-5-nitro-benzoyl chloride (500mg, 2.18mmol) into a 100ml eggplant-shaped bottle, add two Dissolve the methyl chloride completely, then add p-methoxyaniline (303mg, 2.18mmol), then add triethylamine (242mg, 2.40mmol), react at room temperature for 0.5-2h, wash with 10% hydrochloric acid solution three times after the reaction, and depressurize Concentrate to obtain the crude product, which is quickly separated by column chromatography and eluted with dichloromethane to obtain the pure product 2-ethoxy-N-(4-methoxy-phenyl)-5-nitro-benzamide ( 550mg, 79.9%); reaction step g7 (preparation of compound G1-7): 2-ethoxy-N-(4-methoxy-phenyl)-5-nitro-benzamide (520mg, 1.65 mmol) into a 100ml eggplant-shaped bottle, add methanol, then add nickel chloride hexahydrate (671mg, 2.82mmol), after completely dissolving, add sodium borohydride (214mg, 5.64mmol), and react for 5-10 minutes. Concentrate under reduced pressure, add 10% hydrochloric acid solution, wash three times with ethyl acetate to obtain an aqueous phase, add ammonia water to adjust pH>11, wash three times with ethyl acetate to obtain an organic phase, and concentrate under reduced pressure to obtain a crude product. Separation by column chromatography, 100:1 dichloromethane/methanol as eluent, to obtain pure 5-amino-2-ethoxy-N-(4-methoxy-phenyl)-benzamide (360mg, 76.3%); Reaction step g8 (preparation of compound G1-8): Add phenyl chloroformate (180.6mg, 1.15mmol) into a 100ml eggplant-shaped bottle, add dichloromethane, and then add 5-amino- 2-Ethoxy-N-(4-methoxy-phenyl)-benzamide (330mg, 1.15mmol) and triethylamine (128mg, 1.27mmol), react at room temperature for 0.5-2h, after the reaction is completed, use 10 % hydrochloric acid solution washed 3 times, concentrated under reduced pressure to obtain the crude product, and recrystallized with ethanol to obtain the pure product [4-ethoxy-3-(4-methoxy-phenylcarbamoyl)-phenyl]- Phenyl carbamate (420 mg, yield 89.9%); reaction step g (preparation of compound H): 2,5-diethoxy-4-nitro-benzylamine (174 mg, 0.72 mmol), [4 -Ethoxy-3-(4-methoxy-phenylcarbamoyl)-phenyl]-carbamate (400mg, 0.72mmol) and triethylamine (0.73g, 7.2mmol) were added to 100ml of solanum Dioxane was added to a type bottle, heated to 60-80°C, and reacted overnight. After the reaction, concentrated under reduced pressure to obtain a crude product, which was recrystallized with methanol to obtain Pure 5-[3-(2,5-diethoxy-4-nitro-benzyl)-ureido]-2-ethoxy-N-(4-methoxy-phenyl)-benzene Formamide (300 mg, yield 75.5%); reaction step h (preparation of compound I): 5-[3-(2,5-diethoxy-4-nitro-benzyl)-ureido]- Add 2-ethoxy-N-(4-methoxy-phenyl)-benzamide (280mg, 0.51mmol) into a 100ml eggplant-shaped bottle, add methanol, and then add nickel chloride hexahydrate (207mg, 0.87 mmol), after completely dissolving, add sodium borohydride (66.1mg, 1.74mmol), react at room temperature for 5-10 minutes, concentrate under reduced pressure after the reaction, add 10% hydrochloric acid solution, wash three times with ethyl acetate to obtain Aqueous phase, add ammonia water to adjust pH>11, wash with ethyl acetate 3 times to get organic phase, concentrate under reduced pressure to get crude product, separate by column chromatography, 100:1 dichloromethane/methanol as eluent , to obtain pure 5-[3-(4-amino-2,5-diethoxy-benzyl)-ureido]-2-ethoxy-N-(4-methoxy-phenyl)- Benzamide (180mg, 67.7%);

Reaction step i (preparation of compound 1): 5-[3-(4-amino-2,5-diethoxy-benzyl)-ureido]-2-ethoxy-N-(4-methyl Add oxy-phenyl)-benzamide (150mg, 0.29mmol) into a 100ml eggplant-shaped bottle, add dichloromethane, then add pyridine (25.0mg, 0.32mmol), carry out nitrogen protection, and add methanesulfonyl chloride (32.9mg, 0.29mmol), reacted at room temperature overnight, after the reaction, washed three times with 10% hydrochloric acid solution to obtain the organic phase, concentrated under reduced pressure to obtain the crude product, separated by column chromatography, 100:1 dichloro Methane/methanol was used as eluent to obtain pure 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-(4 -methoxy-phenyl)-benzamide (110mg, 63.2%). ¹ HNMR(400MHz,DMSO)δ10.02(s,1H),8.80(s,1H),8.58(s,1H),7.73(d, J =2.6Hz,1H),7.61(d, J =8.9Hz ,2H),7.55(dd, J =8.9,2.6Hz,1H),7.05(d, J =9.0Hz,1H),6.92(dd, J =19.5,10.6Hz,4H),4.22(d, J = 5.7Hz, 2H), 4.13(q, J =7.0Hz, 2H), 3.99(qd, J =6.8, 3.3Hz, 4H), 3.73(s, 3H), 2.93(s, 3H), 1.43–1.27( m, 9H).

Claims (6)

1. A new compound, characterized in that the name of the compound is 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy -N-(4-methoxy-phenyl)-benzamide (compound 1), the molecular weight of this compound is 600.6, and the structural formula of this compound is shown as compound 1 below. 2. A new compound 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-(4-methoxy The method of -phenyl)-benzamide is characterized in that, comprises reaction step g6 shown in following reaction scheme 1, reaction step g7, reaction step g8, reaction step g, reaction step h, reaction step i following total 6 reactions Step, wherein the condition characteristics of these 3 steps of reaction step g, reaction step h, reaction step i are as follows: The conditions of reaction step g are: the molar ratio range of 2,5-diethoxy-4-nitro-benzylamine to compound G is 0.8:1~1.3:1, and the molar ratio of triethylamine to compound G=0.8: 1~5:1), the solvent is N, N-dimethylformamide or dimethyl sulfoxide or acetone or 1,4-dioxane and other single solvent or a combination of solvents, the reaction temperature is 50~120 degrees, The reaction time is 5 to 18 hours. After the reaction is completed, the product compound H is purified by concentration, extraction, crystallization, etc., and the yield range is 50% to 90%. The conditions of the reaction step h are: nickel chloride hexahydrate and compound H moles The ratio range is 0.9:1~2.5:1, the molar ratio range of sodium borohydride and compound H is 0.9:1~4:1, the solvent is a single solvent or a combination of solvents such as dichloromethane or tetrahydrofuran or ether, and the reaction time is After 10 minutes to 12 hours, the product compound I was purified by extraction and crystallization after the reaction, and the yield range was 50% to 95%; the conditions of the reaction step i were: the molar ratio of alkylsulfonyl chloride to compound I was in the range of 0.8: 1~1.5:1, the molar ratio range of pyridine to compound I is 0.9:1~1.5:1, the solvent is dichloromethane, or tetrahydrofuran, or ether, or N,N-dimethylformamide, or dimethyl sulfoxide, or acetone, or 1,4 Dioxane and other single solvents or a combination of solvents, the reaction temperature is 0-80 degrees, the reaction time is 3-18 hours, after the reaction is completed, the product compound 1 is obtained by extraction, crystallization, column chromatography, etc., The yield range is 50%~95%. 3. The compounds provided by the present invention have good drug-like properties and can be used in the field of new drug research, especially in the field of innovative drug research for the treatment of type II diabetes. 4. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof. 5. The pharmaceutical composition according to claim 4, characterized in that, the pharmaceutical composition further contains one or more pharmaceutically acceptable carriers or excipients. 6 . The pharmaceutical composition according to claim 4 , wherein the compound or a pharmaceutically acceptable salt thereof is used as an active ingredient in a total weight ratio of 50% to 99.5%.