CN105820082A - 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-isopropyl-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 -Isopropyl-benzamide, the molecular weight of the compound is 536.6, and 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 compound provided by the present invention has good drug-like properties , can be used in the field of new drug research, especially in the field of type II diabetes innovative drug research.

Description

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

technical field

The present invention relates to providing a kind of 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-isopropyl-benzamide The new compound, its preparation method and its use in the research of innovative medicines. The compound has small molecular weight, novel structure, stable properties and simple structure. It is suitable for the research and development of innovative medicines 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-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-isopropyl-benzamide is a ureido-containing structure The urea 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 type II diabetes drug targets, and has certain innovative drug research Development prospects.

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-isopropyl-benzamide (compound 1), the molecular weight of this compound is 536.6, 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-isopropyl-benzyl The method for amides is characterized in that it comprises the following 6 reaction steps of reaction step g6, reaction step g7, reaction step g8, reaction step g, reaction step h and reaction step i shown in reaction scheme 1, wherein reaction steps g, The condition characteristics of these 3 steps of 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 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, 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-isopropyl-benzamide (compound 1) The structural formula is as follows:

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

The specific preparation method of compound 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-isopropyl-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 Isopropylamine (129mg, 2.18mmol), then added triethylamine (242mg, 2.40mmol), reacted at room temperature for 0.5-2h, after the reaction was completed, washed with 10% hydrochloric acid solution three times, concentrated under reduced pressure to obtain the crude product, which was quickly purified by column chromatography Separation and eluting with dichloromethane gave pure 2-ethoxy-N-propyl-5-nitro-benzamide (470 mg, 85.3%); reaction step g7 (preparation of compound G1-7): Add 2-ethoxy-N-isopropyl-5-nitro-benzamide (400mg, 1.58mmol) into a 100ml eggplant-shaped bottle, add methanol, then add nickel chloride hexahydrate (645mg, 2.71mmol), After complete dissolution, add sodium borohydride (206mg, 5.42mmol) 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, and add ammonia water Adjust pH>11, wash 3 times with ethyl acetate to obtain organic phase, concentrate under reduced pressure to obtain crude product, separate by column chromatography, 100:1 dichloromethane/methanol as eluent, obtain pure product 5 -Amino-2-ethoxy-N-isopropyl-benzamide (310mg, 88.1%); reaction step g8 (preparation of compound G1-8): phenyl chloroformate (210mg, 1.34mmol) was added to 100ml In an eggplant-shaped bottle, add dichloromethane, then add 5-amino-2-ethoxy-N-isopropyl-benzamide (300mg, 1.34mmol) and triethylamine (149mg, 1.47mmol), room temperature React for 0.5-2h. After the reaction, 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-isopropylcarbamoyl-phenyl )-phenylcarbamate (420mg, yield 91.3%); reaction step g (preparation of compound H): 2,5-diethoxy-4-nitro-benzylamine (280mg, 1.17mmol) , (4-ethoxy-3-isopropylcarbamoyl-phenyl)-phenylcarbamate (401mg, 1.25mmol) and triethylamine (1.18g, 11.7mmol) were added to a 100ml eggplant-shaped bottle, Add dioxane, 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-isopropyl-benzamide (500 mg, yield yield 87.6%); reaction step h (preparation of compound I): 5-[3-(2,5-diethoxy-4-nitro-benzyl)-ureido]-2-ethoxy- Add N-isopropyl-benzamide (488mg, 1.0mmol) into a 100ml eggplant-shaped bottle, add methanol, then add nickel chloride hexahydrate (408mg, 1.71mmol), after completely dissolving, add sodium borohydride ( 130.0 mg, 3.43 mmol), 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, and use ethyl acetate The ester was washed 3 times to obtain the organic phase, which was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography, and 100:1 dichloromethane/methanol was used as the eluent to obtain the pure product 5-[3-(4-amino -2,5-diethoxy-benzyl)-ureido]-2-ethoxy-N-isopropyl-benzamide (340 mg, 74.2%); reaction step i (preparation of compound 1): 5-[3-(4-Amino-2,5-diethoxy-benzyl)-ureido]-2-ethoxy-N-isopropyl-benzamide (300mg, 0.66mmol) was added Put it into a 100ml eggplant-shaped bottle, add dichloromethane, then add pyridine (56.9mg, 0.72mmol), carry out nitrogen protection, add methanesulfonyl chloride (75.0mg, 0.66mmol), and react overnight at room temperature. After the reaction, use 10% hydrochloric acid solution was washed three times to obtain the organic phase, which was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography, and 100:1 dichloromethane/methanol was used as the eluent to obtain the pure product 5-[3-( 2,5-Diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-isopropyl-benzamide (180mg, 50.8%). ¹ HNMR(400MHz,DMSO)δ8.81(s,1H),8.54(s,1H),8.02(d, J =7.6Hz,1H),7.70(d, J =2.4Hz,1H),7.54(dd , J =8.8,2.8Hz,1H),6.99(d, J =8.8Hz,1H),6.94(s,1H),6.87(s,1H),6.27(t, J =5.8Hz,1H),4.21 (d, J =6.4Hz, 2H), 4.11–3.95 (m, 8H), 2.93 (s, 3H), 1.39–1.29 (m, 9H), 1.15 (d, J =6.4Hz, 6H).

Claims (6)

1. a noval chemical compound; it is characterized in that; entitled 5-[the 3-(2 of this compound; 5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups]-2-ethyoxyl-N-isopropyl-Benzoylamide (compound 1); the molecular weight of this compound is 536.6, and the structural formula of this compound is shown in following formula: compound 1.

2. prepare noval chemical compound 5-[3-(2 for one kind; 5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups] method of-2-ethyoxyl-N-isopropyl-Benzoylamide; it is characterized in that; including reactions steps g6 shown in following reaction scheme 1, reactions steps g7, reactions steps g8, reactions steps g, reactions steps h, following totally 6 reactions steps of reactions steps i, the condition flag that wherein reactions steps g, reactions steps h, this 3 step of reactions steps i are reacted is as follows:

The condition of reactions steps g is: 2,5-diethoxy-4-Nitro-benzyl amine and compound G molar ratio range are 0.8:1 ~ 1.3:1, triethylamine and compound G mol ratio=0.8:1 ~ 5:1), solvent is N, N dimethylformamide or dimethyl sulfoxide or single solvent or the combination of solvent such as acetone or Isosorbide-5-Nitrae dioxane, reaction temperature is 50 ~ 120 degree, response time is 5 ~ 18 hours, and reaction is purified to obtain product compound H, yield spectra 50% ~ 90% through concentrate, extract, crystallization etc. after terminating；The condition of reactions steps h is: Nickel dichloride hexahydrate and compound H molar ratio range are 0.9:1 ~ 2.5:1, sodium borohydride and compound H molar ratio range are 0.9:1 ~ 4:1, solvent is dichloromethane or the single solvent such as oxolane or ether or the combination of solvent, response time is 10 minutes ~ 12 hours, reaction is purified to obtain product compound I, yield spectra 50% ~ 95% through extraction, crystallization etc. after terminating；The condition of reactions steps i is: alkyl sulfonyl chloride and compound I molar ratio range are 0.8:1 ~ 1.5:1, pyridine and compound I molar ratio range are 0.9:1 ~ 1.5:1, solvent is dichloromethane or oxolane or ether or N, N dimethylformamide or dimethyl sulfoxide or acetone or 1, single solvent or the combinations of solvent such as 4 dioxane, reaction temperature is 0 ~ 80 degree, 3 ~ 18 hours response time, reaction is purified to obtain product compound 1, yield spectra 50% ~ 95% through extraction, crystallization, column chromatography etc. after terminating.

3. the compound that the present invention provides has good quasi-medicated property, can be used for new drug research field and especially treats type ii diabetes field of innovative medicine research.

4. a pharmaceutical composition, including the compound described in the claim 1 of therapeutically effective amount or its pharmaceutically acceptable salt.

Pharmaceutical composition the most according to claim 4, is characterized in that, this pharmaceutical composition contains one or more pharmaceutically acceptable carrier or excipient further.

Pharmaceutical composition the most according to claim 4, is characterized in that, described compound or its pharmaceutically acceptable salt account for gross weight ratio 50% ~ 99.5% as active component.