CN105820093A - N-benzyl-5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethyoxyl benzamide new compound and preparation method and application thereof - Google Patents
N-benzyl-5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethyoxyl benzamide new compound and preparation method and application thereof Download PDFInfo
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- CN105820093A CN105820093A CN201510001359.5A CN201510001359A CN105820093A CN 105820093 A CN105820093 A CN 105820093A CN 201510001359 A CN201510001359 A CN 201510001359A CN 105820093 A CN105820093 A CN 105820093A
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Abstract
The invention provides a new compound. The name of the compound is N-benzyl-5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethyoxyl benzamide; molecular weight of the compound is 584.6; and structure of the compound is as shown in the structural formula (compound 1). Meanwhile, the invention provides a preparation method of the compound 1. The compound provided by the invention has good drug-likeness and can be used in the research field of new drugs, especially in the research field of type-II diabetes innovative drugs.
Description
Technical field
The present invention relates to a kind of N-benzyl-5-[3-(2 of offer; 5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups]-2-ethoxy benzamide noval chemical compound, preparation method and the purposes in innovation drug research thereof; this compound molecular weight is little; novel structure; stable in properties; simple in construction, it is adaptable to innovation drug research is developed, and belongs to technical field of chemistry.
Background technology
Carbamide compounds () when being combined with drug target molecule (macromole such as protein, enzyme) active pocket, owing to the hydrogen atom on nitrogen-atoms in urea groups structure is can critical amino acid residues is combined in drug target molecular activity pocket good hydrogen-bond donor, and carbonyl is the good hydrogen bond receptor that critical amino acid residues is combined in drug target molecular activity pocket in its urea groups, therefore in the compound design of innovation drug research, such group is good dominant group.Compound N-benzyl-5-[3-(2; 5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups]-2-ethoxy benzamide is the carbamide compounds containing urea groups structure; this compound structure is novel; stable in properties; simple in construction; in the docking research of Computer-Aided Drug Design, find that this compound can have preferably combination with the drug target of some type ii diabetes, there is certain innovation drug research DEVELOPMENT PROSPECT.
Summary of the invention
1, a kind of noval chemical compound; it is characterized in that; the entitled N-benzyl-5-[3-(2 of this compound; 5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups]-2-ethoxy benzamide (compound 1); the molecular weight of this compound is 584.6, and the structural formula of this compound is shown in following formula: compound 1.
2, one prepares noval chemical compound N-benzyl-5-[3-(2; 5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups] method of-2-ethoxy benzamide; 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 preferable quasi-medicated property, can be used for new drug research field and especially treats type ii diabetes field of innovative medicine research.
4, a kind of pharmaceutical composition, including the compound described in the claim 1 of therapeutically effective amount or its pharmaceutically acceptable salt.
5, pharmaceutical composition according to claim 4, is characterized in that, this pharmaceutical composition contains one or more pharmaceutically acceptable carrier or excipient further.
6, pharmaceutical composition 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.
Below in conjunction with specific embodiment, the present invention is further elaborated, but is not intended to the present invention.
Specific embodiment
The structural formula of embodiment 1:N-benzyl-5-[3-(2,5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups]-2-ethoxy benzamide (compound 1) is as follows:
The synthetic route of compound N-benzyl-5-[3-(2,5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups]-2-ethoxy benzamide is as follows:
The concrete preparation method of compound N-benzyl-5-[3-(2,5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups]-2-ethoxy benzamide is as follows:
The preparation of reactions steps g6(compound G1-6): by 2-ethyoxyl-5-nitro-benzoyl chloride (500mg, 2.18mmol) add in 100ml eggplant type bottle, add dichloromethane to be completely dissolved, add benzylamine (233mg, 2.18mmol), add triethylamine (242mg, 2.40mmol), room temperature reaction 0.5-2h, reaction terminates to wash three times with the hydrochloric acid solution of 10%, is concentrated under reduced pressure to give crude product, use column chromatography sharp separation, with dichloromethane eluent, obtain sterling 2-ethyoxyl-N-benzyl-5-nitro-benzamide (550mg, 84.1%)；nullThe preparation of reactions steps g7(compound G1-7): by 2-ethyoxyl-N-benzyl-5-nitro-benzamide (520mg，1.73mmol) add in 100ml eggplant type bottle and add methanol，Add Nickel dichloride hexahydrate (707mg，2.97mmol)，After being completely dissolved，Add sodium borohydride (226mg，5.94mmol)，React 5-10 minute，Reaction carries out concentrating under reduced pressure after terminating，Add the hydrochloric acid solution of 10%，Wash three times by ethyl acetate，Obtain aqueous phase，Add ammonia regulation PH > 11，Wash 3 times by ethyl acetate，Obtain organic facies，Concentrating under reduced pressure i.e. can get crude product，Separate by column chromatography，The methylene chloride/methanol of 100:1 is eluant，Obtain sterling 5-amino-2-ethyoxyl-N-benzyl-Benzoylamide (420mg，89.9%)；The preparation of reactions steps g8(compound G1-8): by phenyl chloroformate (232mg; 1.48mmol) add in the eggplant type bottle of 100ml; add dichloromethane; add 5-amino-2-ethyoxyl-N-benzyl-Benzoylamide (323mg; 1.48mmol) with triethylamine (179mg; 1.63mmol); room temperature reaction 0.5-2h; reaction is washed 3 times with the hydrochloric acid solution of 10% after terminating; it is concentrated under reduced pressure to give crude product; carry out recrystallization with ethanol and can get sterling 4-ethyoxyl-3-carbamovl-phenyl)-phenyl carbamates (540mg, productivity 93.6%)；The preparation of reactions steps g(compound H): by 2, 5-diethoxy-4-Nitro-benzyl amine (308mg, 1.28mmol), (4-ethyoxyl-3-benzyl formyl-phenyl)-phenyl carbamate (500mg, 1.28mmol) with triethylamine (1.29g, 12.8mmol) add in the eggplant type bottle of 100ml, add dioxanes, it is heated to 60-80 DEG C, reaction is overnight, reaction is concentrated under reduced pressure to give crude product after terminating, recrystallization is carried out with methanol, obtain sterling 5-[3-(2, 5-diethoxy-4-Nitro-benzyl)-urea groups]-2-ethyoxyl-N-benzyl-Benzoylamide (550mg, productivity 80.2%)；nullThe preparation of reactions steps h(compound I): by 5-[3-(2,5-diethoxy-4-Nitro-benzyl)-urea groups]-2-ethyoxyl-N-benzyl-Benzoylamide (536mg,1.0mmol) add in the eggplant type bottle of 100ml，Add methanol，Add Nickel dichloride hexahydrate (408mg，1.71mmol)，After being completely dissolved，Add sodium borohydride (130.0mg，3.43mmol)，Room temperature reaction 5-10 minute，Reaction carries out concentrating under reduced pressure after terminating，Add the hydrochloric acid solution of 10%，Wash three times by ethyl acetate，Obtain aqueous phase，Add ammonia regulation PH > 11，Wash 3 times by ethyl acetate，Obtain organic facies，Concentrating under reduced pressure i.e. can get crude product，Separate by column chromatography，The methylene chloride/methanol of 100:1 is eluant，Obtain sterling 5-[3-(4-amino-2,5-diethoxy-benzyl)-urea groups]-2-ethyoxyl-N-benzyl-Benzoylamide (350mg，69.2%)；nullThe preparation of reactions steps i(compound 1): by 5-[3-(4-amino-2,5-diethoxy-benzyl)-urea groups]-2-ethyl-N-benzyl-Benzoylamide (320mg，0.63mmol) add in the eggplant type bottle of 100ml，Add dichloromethane，Add pyridine (55.0mg，0.70mmol)，Carry out nitrogen protection，Add methylsufonyl chloride (72.4mg，0.63mmol)，Room temperature reaction is overnight，After reaction terminates，Hydrochloric acid solution with 10% washs three times，Obtain organic facies，Concentrating under reduced pressure i.e. can get crude product，Separate by column chromatography，The methylene chloride/methanol of 100:1 is eluant，Obtain sterling N-benzyl-5-[3-(2,5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups]-2-ethoxy benzamide (170mg，46.2%).1HNMR(400MHz,DMSO)δ8.82(s,1H),8.57(d,J=7.6Hz,2H),7.69(d,J=2.4Hz,1H),7.54(dd,J=9.0,2.4Hz,1H),7.33(dd,J=8.7,5.2Hz,4H),7.29–7.21(m,1H),7.00(d,J=9.2Hz,1H),6.94(s,1H),6.87(s,1H),6.28(t,J=5.8Hz,1H),4.49(d,J=6.4Hz,2H),4.21(d,J=5.6Hz,2H),4.07(q,J=6.9Hz,2H),3.98m,4H),2.92(s,3H),1.37–1.24(m,9H)。
Claims (6)
1. a noval chemical compound; it is characterized in that; the entitled N-benzyl-5-[3-(2 of this compound; 5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups]-2-ethoxy benzamide (compound 1); the molecular weight of this compound is 584.6, and the structural formula of this compound is shown in following formula: compound 1.
2. prepare noval chemical compound N-benzyl-5-[3-(2 for one kind; 5-diethoxy-4-Methanesulfonyl-benzYl)-urea groups] method of-2-ethoxy benzamide; 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 preferable 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.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106167456A (en) * | 2015-05-20 | 2016-11-30 | 齐鲁工业大学 | New Type Urea albuminoid tyrosine-phosphatase 1B inhibitor and preparation method thereof, pharmaceutical composition and purposes |
| CN106491576A (en) * | 2016-09-28 | 2017-03-15 | 齐鲁工业大学 | A kind of new 2 ethoxybenzene formyl Bian amine adjusts the compound and its medical usage of estrogen-related receptor activity |
| CN108929263A (en) * | 2017-05-26 | 2018-12-04 | 中国医学科学院药物研究所 | Aryl amide Kv2.1 inhibitor and preparation method thereof, pharmaceutical composition and purposes |
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| CN101142174A (en) * | 2005-03-19 | 2008-03-12 | 株式会社Amorepacific | Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist, and pharmaceutical compositions containing the same |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106167456A (en) * | 2015-05-20 | 2016-11-30 | 齐鲁工业大学 | New Type Urea albuminoid tyrosine-phosphatase 1B inhibitor and preparation method thereof, pharmaceutical composition and purposes |
| CN106491576A (en) * | 2016-09-28 | 2017-03-15 | 齐鲁工业大学 | A kind of new 2 ethoxybenzene formyl Bian amine adjusts the compound and its medical usage of estrogen-related receptor activity |
| CN106491576B (en) * | 2016-09-28 | 2020-02-18 | 齐鲁工业大学 | 2-ethoxy-benzoyl benzylamine compound for regulating estrogen related receptor activity and medical application thereof |
| CN108929263A (en) * | 2017-05-26 | 2018-12-04 | 中国医学科学院药物研究所 | Aryl amide Kv2.1 inhibitor and preparation method thereof, pharmaceutical composition and purposes |
| CN108929263B (en) * | 2017-05-26 | 2022-07-22 | 中国医学科学院药物研究所 | Arylamide Kv2.1 inhibitor and preparation method, pharmaceutical composition and application thereof |
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