CN105820071A - N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide new compound and preparation method and application thereof - Google Patents

Abstract

The present invention provides a new compound named N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}- Methanesulfonamide, the molecular weight of this compound is 486.3, 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 good drug-like properties and can be used for new drug research field, especially in the field of type II diabetes innovative drug research.

Description

A new N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide compound, its preparation method and use

technical field

The present invention relates to providing a new compound of N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide and its preparation method The compound has small molecular weight, novel structure, stable properties and simple structure, and is suitable for the research and development of innovative drugs, belonging 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 N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide is a urea compound containing a ureido structure. The compound has a novel structure, stable properties, and simple structure. It was found in the docking research of computer-aided drug design that the compound can better combine with some type II diabetes drug targets, and has certain prospects for innovative drug research and development.

Contents of the invention

1. A new compound, characterized in that the name of the compound is N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl }-methanesulfonamide (compound 1), the molecular weight of this compound is 486.3, and the structural formula of this compound is shown in the following formula compound 1.

2. A method for preparing new compound N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide, which It is characterized in that, including following reaction scheme 1 shows reaction step g, reaction step h, reaction step i as follows total 3 reaction steps:

The conditions of the reaction step g are: the molar ratio of p-bromoaniline to compound G is in the range of 0.8:1~1.3:1, the molar ratio of triethylamine to compound G=0.8:1~5:1), and the solvent is N, N-two Methylformamide or dimethyl sulfoxide or acetone or 1,4-dioxane and other single solvents or a combination of solvents, the reaction temperature is 50-120 degrees, the reaction time is 5-18 hours, after the reaction is completed, it is concentrated, Extraction, crystallization, etc. are purified to obtain the product compound H, and the yield range is 50%~90%; the conditions of the reaction step h are: the molar ratio of nickel chloride hexahydrate to compound H is in the range of 0.9:1~2.5:1, sodium borohydride The molar ratio to compound H ranges from 0.9:1 to 4:1, the solvent is a single solvent or a combination of solvents such as dichloromethane, tetrahydrofuran or ether, and the reaction time is 10 minutes to 12 hours. After the reaction is completed, it is extracted, crystallized, etc. Purify to obtain product compound I, the yield range is 50%~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, and the molar ratio range of pyridine to compound I is 0.9:1~1.5:1, the solvent is dichloromethane, or tetrahydrofuran, or diethyl ether, or N,N-dimethylformamide, or dimethyl sulfoxide, or acetone, or 1,4-dioxane, or a single solvent or solvent Combination, the reaction temperature is 0-80 degrees, the reaction time is 3-18 hours, after the reaction is completed, the product compound 1 is purified by extraction, crystallization, column chromatography, etc., and the yield ranges 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: The structural formula of N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide (compound 1) is as follows :

The synthetic route of the compound N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide is as follows:

The specific preparation method of the compound N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide is as follows: Reaction step g: (2,5-Diethoxy-4-nitro-benzyl)-phenylcarbamate (0.5g, 1.39mmol), 4-bromo-aniline (239mg, 1.39mmol) and triethylamine (1.40g , 13.9mmol) into a 100ml eggplant-shaped bottle, add dioxane, heat to 60-80°C, and react overnight. Bromo-phenyl)-3-(2,5-diethoxy-4-nitro-benzyl)-urea (480 mg, yield 78.9%); Reaction step h: 1-(4-Bromo-benzene base)-3-(2,5-diethoxy-4-nitro-benzyl)-urea (400mg, 0.91mmol) was added to a 100ml eggplant-shaped bottle, methanol was added, and then nickel chloride hexahydrate ( 371mg, 1.56mmol), after completely dissolved, add sodium borohydride (119mg, 3.12mmol), 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, adding ammonia to adjust the pH > 11, washing with ethyl acetate 3 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 washing The agent was removed to obtain pure 1-(4-amino-2,5-diethoxy-benzyl)-3-(4-bromo-phenyl)-urea (300mg, 80.5%); reaction step i: 1-(4-Amino-2,5-diethoxy-benzyl)-3-(4-bromo-phenyl)-urea (260mg, 0.64mmol) was added to a 100ml eggplant bottle, and dichloro Methane, then add pyridine (55.6mg, 0.70mmol), carry out nitrogen protection, add methanesulfonyl chloride (73.3mg, 0.64mmol), react at room temperature overnight, after the reaction, wash with 10% hydrochloric acid solution three times to obtain the organic phase , and 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 N-{4-[3-(4-bromo-phenyl)- Caridomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide (170mg, 54.8%). ¹ H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.73 (s, 1H), 7.44 – 7.27 (m, 4H), 6.94 (s, 1H), 6.87 (s, 1H), 6.42 (t , J = 6.0 Hz, 1H), 4.21 (d, J = 5.6 Hz, 2H), 3.98 (q, J = 6.8 Hz, 4H), 2.92 (s, 3H), 1.32 (dd, J = 12.0, 6.4 Hz , 6H).

Claims (6)

1. a noval chemical compound, it is characterized in that, and the entitled N-{4-of this compound [the bromo-phenyl of 3-(4-)-ureidomethy]-2,5-diethoxy-phenyl }-Methanesulfomide (compound 1), the molecular weight of this compound is 486.3, and the structural formula of this compound is shown in following formula: compound 1:

。

2. prepare noval chemical compound N-{4-[the bromo-phenyl of 3-(4-)-ureidomethy]-2 for one kind, 5-diethoxy-phenyl } method of-Methanesulfomide, it is characterized in that, show following the most totally 3 reactions steps of reactions steps g, reactions steps h, reactions steps i including following reaction scheme 1:

The condition of reactions steps g is: para-bromoaniline 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 acetone or 1, single solvent or the combinations of solvent such as 4 dioxane, reaction temperature is 50 ~ 120 degree, and the response time is 5 ~ 18 hours, 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.