CN105820075A - N-{4-[3-(3,4-dimethoxy-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide new compound and preparation method and application thereof - Google Patents
N-{4-[3-(3,4-dimethoxy-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide new compound and preparation method and application thereof Download PDFInfo
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- CN105820075A CN105820075A CN201510001196.0A CN201510001196A CN105820075A CN 105820075 A CN105820075 A CN 105820075A CN 201510001196 A CN201510001196 A CN 201510001196A CN 105820075 A CN105820075 A CN 105820075A
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Abstract
The invention relates to a novel urea PTP1B inhibitor having a structure as shown in the general formula or its pharmaceutically acceptable salt and a preparation method thereof. The invention also relates to a pharmaceutical composition containing the compound as shown in the general formula I or its pharmaceutically acceptable salt. The compound as shown in the general formula I or its pharmaceutically acceptable salt has an activity of inhibiting protein tyrosine phosphatase 1B (PTP1B). Thus, the compound can be used in preparing medicines for preventing and/or treating symptoms or diseases such as hyperglycemia, type-2 diabetes and the like.
Description
Technical field
The present invention relates to a kind of N-{4-[3-(3 of offer, 4-dimethoxy-phenylf)-ureidomethy]-2,5-diethoxy-phenyl }-Methanesulfomide 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 applicable to innovation drug research exploitation, 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-{ 4-[3-(3,4-dimethoxy-phenylf)-ureidomethy]-2,5-diethoxy-phenyl }-Methanesulfomide is the carbamide compounds containing urea groups structure, this compound structure is novel, stable in properties, simple in construction, finds that in the docking research of Computer-Aided Drug Design this compound can have preferably combination with the drug target of some type ii diabetes, has certain innovation drug research DEVELOPMENT PROSPECT.
Summary of the invention
1, a kind of noval chemical compound, it is characterized in that, entitled N-{4-[the 3-(3 of this compound, 4-dimethoxy-phenylf)-ureidomethy]-2,5-diethoxy-phenyl }-Methanesulfomide (compound 1), the molecular weight of this compound is 467.5, and the structural formula of this compound is shown in following formula: compound 1.
2, one prepares noval chemical compound N-{4-[3-(3,4-dimethoxy-phenylf)-ureidomethy]-2,5-diethoxy-phenyl } method of-Methanesulfomide, it is characterised in that include that following reaction scheme 1 shows following the most totally 3 reactions steps of reactions steps g, reactions steps h, reactions steps i:
The condition of reactions steps g is: 3,4-dimethoxyaniline 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 or 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 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
Embodiment 1:N-{4-[3-(3,4-dimethoxy-phenylf)-ureidomethy]-2,5-diethoxy-phenyl } structural formula of-Methanesulfomide (compound 1) is as follows.
The synthetic route of compound N-{ 4-[3-(3,4-dimethoxy-phenylf)-ureidomethy]-2,5-diethoxy-phenyl }-Methanesulfomide is as follows:
nullCompound N-{ 4-[3-(3,4-dimethoxy-phenylf)-ureidomethy]-2,5-diethoxy-phenyl } the concrete preparation method of-Methanesulfomide is as follows: reactions steps g:(2,5-diethoxy-4-Nitro-benzyl)-phenyl carbamates (0.5g1.39mmol)、3，4-dimethoxy-aniline (213mg，1.39mmol) with triethylamine (1.40g，13.9mmol) 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 1-(2,5-diethoxy-4-Nitro-benzyl)-3-(3,4-dimethoxy-phenylf)-urea (440mg，Productivity 75.6%)；nullReactions steps h: by 1-(2,5-diethoxy-4-Nitro-benzyl)-3-(3,4-dimethoxy-phenylf)-urea (400mg,0.95mmol) add in the eggplant type bottle of 100ml，Add methanol，Add Nickel dichloride hexahydrate (388mg，1.63mmol)，After being completely dissolved，Add sodium borohydride (124mg，3.26mmol)，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 1-(4-amino-2,5-diethoxy-benzyl)-3-(3,4-dimethoxy-phenylf)-urea (300mg，80.9%)；nullReactions steps i: by 1-(4-amino-2,5-diethoxy-benzyl)-3-(3,4-dimethoxy-phenylf)-urea (250mg，0.64mmol) add in the eggplant type bottle of 100ml，Add dichloromethane，Add pyridine (55.8mg，0.71mmol)，Carry out nitrogen protection，Add methylsufonyl chloride (73.3mg，0.64mmol)，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-{4-[3-(3,4-dimethoxy-phenylf)-ureidomethy]-2,5-diethoxy-phenyl }-Methanesulfomide (160mg，53.3%).1HNMR(400MHz,CDCl3): δ 7.08 (s, 1H), 6.94 (s, 1H), 6.89 (s, 1H), 6.82 6.73 (m, 2H), 6.70 (d,J=8.1Hz,1H),6.56(s,1H),4.36(s,2H),3.99(ddd,J=25.1,13.6,6.7Hz,4H),3.84(d,J=12.4Hz,6H),2.92(s,3H),1.38(t,J=6.7Hz,3H),1.27(t,J=5.6Hz,3H)。
Claims (6)
1. a noval chemical compound, it is characterized in that, entitled N-{4-[the 3-(3 of this compound, 4-dimethoxy-phenylf)-ureidomethy]-2,5-diethoxy-phenyl }-Methanesulfomide (compound 1), the molecular weight of this compound is 467.5, and the structural formula of this compound is shown in following formula: compound 1.
2. prepare noval chemical compound N-{4-[3-(3 for one kind, 4-dimethoxy-phenylf)-ureidomethy]-2,5-diethoxy-phenyl } method of-Methanesulfomide, it is characterised in that include that following reaction scheme 1 shows following the most totally 3 reactions steps of reactions steps g, reactions steps h, reactions steps i:
The condition of reactions steps g is: 3,4-dimethoxyaniline 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 or 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.
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Cited By (1)
| 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 |
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| WO2002092576A1 (en) * | 2001-05-16 | 2002-11-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | Diarylurea derivatives useful as anti-inflammatory agents |
| WO2003032989A1 (en) * | 2001-10-18 | 2003-04-24 | Boehringer Ingelheim Pharmaceuticals, Inc. | 1,4-disubstituted benzo-fused urea compounds as cytokine inhibitors |
| 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 |
| CN101516361A (en) * | 2006-09-28 | 2009-08-26 | 亚瑞特医疗公司 | Soluble epoxide hydrolase inhibitors |
| CN102869261A (en) * | 2010-03-01 | 2013-01-09 | 瑞科西有限公司 | Compounds and therapeutic uses thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002092576A1 (en) * | 2001-05-16 | 2002-11-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | Diarylurea derivatives useful as anti-inflammatory agents |
| WO2003032989A1 (en) * | 2001-10-18 | 2003-04-24 | Boehringer Ingelheim Pharmaceuticals, Inc. | 1,4-disubstituted benzo-fused urea compounds as cytokine inhibitors |
| 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 |
| CN101516361A (en) * | 2006-09-28 | 2009-08-26 | 亚瑞特医疗公司 | Soluble epoxide hydrolase inhibitors |
| CN102869261A (en) * | 2010-03-01 | 2013-01-09 | 瑞科西有限公司 | Compounds and therapeutic uses thereof |
Cited By (1)
| 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 |
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Application publication date: 20160803 |