CN105820080A - 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-ethyl-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 -Ethyl-benzamide, the molecular weight of this compound is 522.6, and the structure of this compound is shown in the structural formula (compound 1); at the same time, the present invention provides a preparation method for this compound 1; the compound provided by the present invention has better drug-like properties, It can be used in the field of new drug research, especially in the field of type II diabetes innovative drug research.

Description

A new 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-ethyl-benzamide compound and its preparation method and use

technical field

The present invention relates to providing a new 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-ethyl-benzamide The compound, its preparation method and its use in the research of innovative drugs, the compound has small molecular weight, novel structure, stable properties and simple structure, is applicable to 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. The compound 5-[3-(2,5-diethoxy-4-methanesulfonyl-benzyl)-ureido]-2-ethoxy-N-ethyl-benzamide contains a ureido structure Urea compound, the compound has a novel structure, stable properties, and simple structure. In the docking study of computer-aided drug design, it was found that the compound can better combine with some drug targets of type II diabetes, and has certain innovative drug research and development prospect.

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-ethyl-benzamide (compound 1), the molecular weight of this compound is 522.6, and the structural formula of this compound is shown in the following formula compound 1:

2. A new compound 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-ethyl-benzamide The method, is characterized in that, comprises reaction step g6 shown in following reaction route 1, reaction step g7, reaction step g8, reaction step g, reaction step h, reaction step i following total 6 reaction steps, wherein reaction step g, reaction The condition characteristics of these 3 step reactions of 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 10 minutes to 12 hours, after the reaction is completed, the product compound I is purified by extraction, crystallization, etc., and the yield ranges from 50% to 95%;

The conditions of reaction step i are: the molar ratio range of alkylsulfonyl chloride to compound I is 0.8:1~1.5:1, the molar ratio range of pyridine to compound I is 0.9:1~1.5:1, and the solvent is dichloromethane or tetrahydrofuran Or ether or N,N-dimethylformamide or dimethyl sulfoxide or acetone or 1,4-dioxane or a single solvent or a combination of solvents, the reaction temperature is 0~80 degrees, and the reaction time is 3~18 hours After the reaction, the product compound 1 was purified by extraction, crystallization, column chromatography, etc., and the yield ranged from 50% to 95%.

3. The compound provided by the present invention has 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-ethyl-benzamide (compound 1 ) has the following structural formula:

The synthetic route of compound 5-[3-(2,5-diethoxy-4-methanesulfonyl-benzyl)-ureido]-2-ethoxy-N-ethyl-benzamide is as follows:

The specific preparation method of compound 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-ethyl-benzamide 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 dichloromethane to dissolve completely, and then add ethyl Amine (98.1mg, 2.18mmol), then add triethylamine (242mg, 2.40mmol), react at room temperature for 0.5-2h, wash with 10% hydrochloric acid solution three times at the end of the reaction, concentrate under reduced pressure to obtain the crude product, and use column chromatography to quickly Separation and eluting with dichloromethane gave pure 2-ethoxy-N-ethyl-5-nitro-benzamide (440 mg, 84.9%); reaction step g7 (preparation of compound G1-7): Add 2-ethoxy-N-ethyl-5-nitro-benzamide (400mg, 1.68mmol) into a 100ml eggplant-shaped bottle, add methanol, then add nickel chloride hexahydrate (686mg, 2.88mmol), completely After dissolving, add sodium borohydride (219mg, 5.76mmol) and react for 5-10 minutes. After the reaction, concentrate under reduced pressure, add 10% hydrochloric acid solution, wash with ethyl acetate three times to obtain the aqueous phase, add ammonia water to adjust PH>11, washed 3 times with ethyl acetate to obtain the organic phase, concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography, using 100:1 dichloromethane/methanol as the eluent to obtain the pure product 5- Amino-2-ethoxy-N-ethyl-benzamide (310 mg, 88.6%); reaction step g8 (preparation of compound G1-8): phenyl chloroformate (224 mg, 1.43 mmol) was added to 100 ml of solanum In a type bottle, add dichloromethane, then add 5-amino-2-ethoxy-N-ethyl-benzamide (300mg, 1.44mmol) and triethylamine (159mg, 1.57mmol), and react at room temperature for 0.5- 2h, after the reaction is finished, wash with 10% hydrochloric acid solution for 3 times, concentrate under reduced pressure to obtain the crude product, and recrystallize with ethanol to obtain the pure product 4-ethoxy-3-ethylcarbamoyl-phenyl)-carbamic acid Phenyl ester (420mg, yield 88.8%); reaction step g (preparation of compound H): 2,5-diethoxy-4-nitro-benzylamine (300mg, 1.25mmol), (4- Ethoxy-3-ethylcarbamoyl-phenyl)-phenylcarbamate (410mg, 1.25mmol) and triethylamine (1.26g, 12.5mmol) were added to a 100ml eggplant-shaped bottle, and dioxane was added, Heat to 60-80°C, react overnight, concentrate under reduced pressure after the reaction to obtain the crude product, recrystallize with methanol to obtain the pure product 5-[3-(2,5-diethoxy-4-nitro-benzyl )-ureido]-2-ethoxy-N-ethyl-benzamide (500 mg, 84.4% yield) ; Reaction step h (preparation of compound I-17): 5-[3-(2,5-diethoxy-4-nitro-benzyl)-ureido]-2-ethoxy-N- Add ethyl-benzamide (474mg, 1.0mmol) into a 100ml eggplant-shaped bottle, add methanol, then add nickel chloride hexahydrate (408mg, 1.71mmol), after completely dissolving, add sodium borohydride (130.0mg, 3.43mmol), react at room temperature for 5-10 minutes, concentrate under reduced pressure after the reaction, add 10% hydrochloric acid solution, wash with ethyl acetate three times to obtain the aqueous phase, add ammonia water to adjust the pH>11, wash with ethyl acetate for 3 Once, the organic phase was obtained, and concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography, and the dichloromethane/methanol of 100:1 was the eluent to obtain the pure product 5-[3-(4-amino-2, 5-diethoxy-benzyl)-ureido]-2-ethoxy-N-ethyl-benzamide (350 mg, 80.6%); reaction step i (preparation of compound 1): 5-[ 3-(4-Amino-2,5-diethoxy-benzyl)-ureido]-2-ethoxy-N-ethyl-benzamide (300 mg, 0.69 mmol) was added to 100 ml of nightshade In the bottle, add dichloromethane, then add pyridine (60.1mg, 0.76mmol), carry out nitrogen protection, add methanesulfonyl chloride (79.0mg, 0.69mmol), and react overnight at room temperature. After the reaction, wash with 10% hydrochloric acid solution Washed three times to obtain the organic phase, concentrated under reduced pressure to obtain the crude product, separated by column chromatography, 100:1 dichloromethane/methanol as the eluent, to obtain the pure product 5-[3-(2,5-di Ethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-ethyl-benzamide (150mg, 41.6%). ¹ HNMR(400MHz,DMSO)δ8.81(s,1H),8.54(s,1H),8.11(t, J =5.4Hz,1H),7.69(d, J =2.8Hz,1H),7.54(dd , J =9.0,2.6Hz,1H),7.00(d, J =9.2Hz,1H),6.94(s,1H),6.87(s,1H),6.27(t, J =5.8Hz,1H),4.21 (d, J =5.6Hz, 2H), 4.08(q, J =6.8Hz, 2H), 3.99(m, 4H), 3.27(m, 2H), 2.93(s, 3H), 1.38–1.29(m, 9H), 1.11(t, J =7.2Hz, 3H).

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-ethyl-benzamide (compound 1), the molecular weight of this compound is 522.6, 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-ethyl-benzamide The method, is characterized in that, comprises reaction step g6 shown in following reaction route 1, reaction step g7, reaction step g8, reaction step g, reaction step h, reaction step i following total 6 reaction steps, wherein reaction step g, reaction The condition characteristics of these 3 step reactions of 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 10 minutes to 12 hours, after the reaction is completed, the product compound I is purified by extraction, crystallization, etc., and the yield ranges from 50% to 95%; The conditions of reaction step i are: the molar ratio range of alkylsulfonyl chloride to compound I is 0.8:1~1.5:1, the molar ratio range of pyridine to compound I is 0.9:1~1.5:1, and the solvent is dichloromethane or tetrahydrofuran Or ether or N,N-dimethylformamide or dimethyl sulfoxide or acetone or 1,4-dioxane or a single solvent or a combination of solvents, the reaction temperature is 0~80 degrees, and the reaction time is 3~18 hours After the reaction, the product compound 1 was purified by extraction, crystallization, column chromatography, etc., and the yield ranged from 50% to 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%.