CN105820139A - 3-(pyrrolidine-1-carbonyl)-phenyl-based substituted methanesulfonamide new compound and preparation and application - Google Patents

Abstract

The present invention provides a new compound named N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(pyrrolidine-1-carbonyl)-benzene Base]-ureidomethyl}-phenyl)-methanesulfonamide, the molecular weight of the compound is 548.6, 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 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 new 3-(pyrrolidine-1-carbonyl)-phenyl-based substituted methanesulfonamide compound, its preparation and use

technical field

The present invention relates to providing a kind of N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(pyrrolidine-1-carbonyl)-phenyl]-ureidomethyl} -Phenyl)-methanesulfonamide 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 N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(pyrrolidine-1-carbonyl)-phenyl]-ureidomethyl}-phenyl)- Methylsulfonamide is a urea compound containing a ureido 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 the compound can have better interaction with some type II diabetes drug targets. Combined, it 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 N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(pyrrolidine-1-carbonyl) -phenyl]-ureidomethyl}-phenyl)-methanesulfonamide (compound 1), the molecular weight of this compound is 548.6, and the structural formula of this compound is shown in the following formula compound 1.

2. A new compound N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(pyrrolidine-1-carbonyl)-phenyl]-ureidomethyl) The method of }-phenyl)-methanesulfonamide is characterized in that, including 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 Reaction step, wherein reaction step g, reaction step h, reaction step i these 3 step reaction condition characteristics 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 0.9:1~1:1.5:1, 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 combinations of solvents, the reaction temperature is 0-80 degrees, the reaction time is 3-18 hours, after the reaction is completed, the product compound is purified by extraction, crystallization, column chromatography, etc. 1. 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: N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(pyrrolidine-1-carbonyl)-phenyl]-ureidomethyl}-benzene base)-methanesulfonamide (compound 1) has the following structural formula:

Compound N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(pyrrolidine-1-carbonyl)-phenyl]-ureidomethyl}-phenyl)- The synthetic route of methanesulfonamide is as follows:

Compound N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(pyrrolidine-1-carbonyl)-phenyl]-ureidomethyl}-phenyl)- The specific preparation method of methanesulfonamide 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 Dissolve dichloromethane completely, then add p-pyrrolidine (155mg, 2.18mmol), then add triethylamine (242mg, 2.40mmol), react at room temperature for 0.5-2 h, wash with 10% hydrochloric acid solution three times after the reaction, and reduce pressure Concentrate to obtain the crude product, which is quickly separated by column chromatography and eluted with dichloromethane to obtain the pure product (2-ethoxy-5-nitro-phenyl)-pyrrolidin-1-yl-methanone (500 mg, 69.5%); reaction step g7 (preparation of compound G1-7): add (2-ethoxy-5-nitro-phenyl)-pyrrolidin-1-yl-methanone (450 mg, 1.70 mmol) to 100 ml Add methanol to the eggplant-shaped bottle, then add nickel chloride hexahydrate (695mg, 2.92mmol), after completely dissolving, add sodium borohydride (222mg, 5.84mmol), react for 5-10 minutes, and concentrate under reduced pressure after the reaction , add 10% hydrochloric acid solution, wash three times with ethyl acetate to obtain the aqueous phase, add ammonia water to adjust the pH > 11, wash three times with ethyl acetate to obtain the organic phase, concentrate under reduced pressure to obtain the crude product, and use column chromatography Separation was carried out using 100:1 dichloromethane/methanol as the eluent to obtain pure (5-amino-2-ethoxyphenyl)-pyrrolidin-1-yl-methanone (310 mg, 77.7%);

Reaction step g8 (preparation of compound G1-8): Add phenyl chloroformate (156.5 mg, 1.0 mmol) into a 100 ml eggplant-shaped bottle, add dichloromethane, and then add (5-amino-2-ethoxybenzene base)-pyrrolidin-1-yl-methanone (234mg, 1.0mmol) and triethylamine (111mg, 1.1mmol), reacted at room temperature for 0.5-2 h, washed 3 times with 10% hydrochloric acid solution after the reaction, and reduced Concentrate under reduced pressure to obtain the crude product, and recrystallize with ethanol to obtain the pure product [4-ethoxy-3-(pyrrolidine-1-carbonyl)-phenyl]-carbamate phenyl ester (310mg, yield 87.6%); Step g (preparation of compound H): 2,5-diethoxy-4-nitro-benzylamine (203 mg, 0.85 mmol), [4-ethoxy-3-(pyrrolidine-1-carbonyl )-Phenyl]-carbamate phenyl ester (300mg, 0.85mmol) and triethylamine (0.86g, 8.5mmol) were added to a 100ml eggplant-shaped bottle, added dioxane, heated to 60-80°C, and reacted overnight. After the reaction was completed, the crude product was concentrated under reduced pressure to obtain the crude product, which was recrystallized with methanol to obtain the pure product 1-(2,5-diethoxy-4-nitro-benzyl)-3-[4-ethoxy-3- (pyrrolidine-1-carbonyl-phenyl]-urea (300mg, yield 70.6%); reaction step h (preparation of compound I): 1-(2,5-diethoxy-4-nitro- Benzyl)-3-[4-ethoxy-3-(pyrrolidine-1-carbonyl)-phenyl]-urea (250mg, 0.50 mmol) was added to a 100ml eggplant-shaped bottle, methanol was added, and hexahydrate Nickel chloride (204mg, 0.86mmol), after completely dissolved, then add sodium borohydride (65.1mg, 1.71mmol), react at room temperature for 5-10 minutes, concentrate under reduced pressure after the reaction, add 10% hydrochloric acid solution, use Wash with ethyl acetate three times to obtain the aqueous phase, add ammonia water to adjust PH > 11, wash with ethyl acetate three times to obtain the organic phase, concentrate under reduced pressure to obtain the crude product, separate by column chromatography, 100:1 dichloro Methane/methanol as the eluent gave pure 1-(4-amino-2,5-diethoxy-benzyl)-3-[4-ethoxy-3-(pyrrolidine-1-carbonyl) -phenyl]-urea (170 mg, 72.3%); reaction step i (preparation of compound 1): 1-(4-amino-2,5-diethoxy-benzyl)-3-[4-ethyl Oxygen-3-(pyrrolidine-1-carbonyl)-phenyl]-urea (150mg, 0.32mmol) was added to a 100ml eggplant-shaped bottle, dichloromethane was added, and pyridine (27.7mg, 0.35mmol) was added, Carry out nitrogen protection, add methanesulfonyl chloride (36.5mg, 0.32mmol), react at room temperature overnight, after the reaction, wash with 10% hydrochloric acid solution three times to obtain the organic phase, concentrate under reduced pressure The crude product can be obtained, which is separated by column chromatography, and the dichloromethane/methanol of 100:1 is used as the eluent to obtain the pure product N-(2,5-diethoxy-4-{3-[4-ethane Oxy-3-(pyrrolidine-1-carbonyl)-phenyl]-ureidomethyl}-phenyl)-methanesulfonamide (110 mg, 52.6%). ¹ H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.44 (s, 1H), 7.28 – 7.22 (m, 2H), 6.92 (d, J = 8.4Hz, 2H), 6.87 (s, 1H ), 6.31 (t, J = 5.6 Hz, 1H), 4.20 (d, J = 5.7 Hz, 2H), 4.02–3.94 (m, 6H), 3.40 (t, J = 6.8 Hz, 2H), 3.11 (t , J = 6.0 Hz, 2H), 2.93 (s, 3H), 1.81 (m, 4H), 1.32 (td, J = 6.9, 4.5 Hz, 6H), 1.24 (t, J = 6.8Hz, 3H).

Claims (6)

1. A new compound, characterized in that the name of the compound is N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(pyrrolidine-1-carbonyl) -phenyl]-ureidomethyl}-phenyl)-methanesulfonamide (compound 1), the molecular weight of this compound is 548.6, and the structural formula of this compound is shown in the following formula compound 1. 2. A new compound N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(pyrrolidine-1-carbonyl)-phenyl]-ureidomethyl) The method of }-phenyl)-methanesulfonamide is characterized in that, including 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 Reaction step, wherein reaction step g, reaction step h, reaction step i these 3 step reaction condition characteristics 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 better 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%.