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N-4-phenylsulfonamido--N'-1-desoxy-(2-desoxy-2-substituted-amino)-beta-D-glucopyransoylthiocarbamide compounds and application thereof

A kind of technology of glucopyranose amido group and benzenesulfonamide group, applied in N-4-benzenesulfonamide group-N'-1-deoxy-(2-deoxy-2-substituted amino)-β-D-pyran Glucosyl thiourea compounds and their application fields can solve the problem of difficulty in designing highly selective CAIX inhibitors

Active Publication Date: 2017-01-04
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This structure is roughly similar to the active centers of carbonic anhydrase CAI and CA II in the cytoplasm, and its functions are basically the same, but it also creates a great problem for designing highly selective CA IX inhibitors (Monti S.M., et al.Curr Med Chem, 2012, 19:821–830.)

Method used

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  • N-4-phenylsulfonamido--N'-1-desoxy-(2-desoxy-2-substituted-amino)-beta-D-glucopyransoylthiocarbamide compounds and application thereof
  • N-4-phenylsulfonamido--N'-1-desoxy-(2-desoxy-2-substituted-amino)-beta-D-glucopyransoylthiocarbamide compounds and application thereof
  • N-4-phenylsulfonamido--N'-1-desoxy-(2-desoxy-2-substituted-amino)-beta-D-glucopyransoylthiocarbamide compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: N-4-benzenesulfonamido-N'-1-deoxy-[(2-deoxy-2-amino-N-trans-4'-methoxycinnamoyl)-β-D-pyran Glucosamido]thiourea (A1)

[0028] Dissolve glucosamine hydrochloride (15g, 69mmol) in 150mL of water, add sodium bicarbonate (17.39g, 207mmol) and trichloroethyl chloroformate (11.45mL, 83mmol), react for 5h, filter with suction, and dry to obtain white 20 g of solid, 90% yield.

[0029] The above product was suspended in pyridine (50 mL), and 70 mL of benzoyl chloride was added dropwise under ice-cooling, and reacted for 5 h. After the solution is clarified, add 200 mL of water and stir for 20 min, extract with dichloromethane 3 times, wash the organic layer 3 times with water, adjust the pH to 5 with dilute hydrochloric acid, adjust the pH to 7 with saturated sodium bicarbonate, wash 2 times with water, and dry over anhydrous sodium sulfate . After filtration, the solvent was removed under reduced pressure to obtain intermediate 3.

[0030] Dissolve the above cru...

Embodiment 2

[0037] Example 2: N-4-Benzenesulfonamido-N'-1-deoxy-[(2-deoxy-2-amino-N-trans-3'-methoxycinnamoyl)-β-D-pyran Glucosamido]thiourea (A2)

[0038] The preparation method of the compound in Example 2 was the same as in Example 1, except that m-methoxycinnamoyl chloride was used instead of p-methoxycinnamoyl chloride to obtain 57.4 mg of white solid with a yield of 89.8%.

[0039] Mp 170.9–172.7°C; 1 H NMR (600MHz, DMSO-d 6 )δ10.38(s,1H),8.33(d,J=6.6Hz,1H),8.03(s,1H),7.73(d,J=8.9Hz,2H),7.69(d,J=8.7Hz, 2H), 7.41(d, J=15.5Hz, 1H), 7.33(t, J=7.9Hz, 1H), 7.29(s, 2H), 7.14(d, J=7.4Hz, 1H), 7.12(s, 1H),6.97–6.94(m,1H),6.66(d,J=15.5Hz,1H),5.43(s,1H),5.10(s,2H),3.83(d,J=9.0Hz,1H), 3.78(s,3H),3.64(d,J=11.0Hz,1H),3.51(dd,J=11.8,4.4Hz,1H),3.44(dd,J=14.0,7.0Hz,2H),3.23(t , J=9.1Hz, 1H), 3.16 (d, J=8.8Hz, 1H); ESI-MS (m / z): 575.4[M+Na] + .

Embodiment 3

[0040] Example 3: N-4-Benzenesulfonamido-N'-1-deoxy-[(2-deoxy-2-amino-N-trans-2'-methoxycinnamoyl)-β-D-pyran Glucosamido]thiourea (A3)

[0041] The preparation method of the compound in Example 3 was the same as in Example 1, except that o-methoxycinnamoyl chloride was used instead of p-methoxycinnamoyl chloride to obtain 53.2 mg of a white solid with a yield of 83.3%.

[0042] Mp 172.9–174.5°C; 1 H NMR (600MHz, DMSO-d 6 )δ10.37(s,1H),8.31(s,1H),8.01(s,1H),7.72(d,J=14.0,8.8Hz,5H),7.52(d,J=7.3Hz,1H), 7.37(t, J=7.8Hz, 1H), 7.27(s, 2H), 7.07(d, J=8.3Hz, 1H), 6.99(t, J=7.5Hz, 1H), 6.70(d, J=15.7 Hz,1H),5.43(s,1H),5.07(d,J=20.3Hz,2H),4.52(s,1H),3.85(s,3H),3.65(s,1H),3.55–3.50(m ,1H),3.44(dd,J=7.0,5.1Hz,2H),3.24(dd,J=14.8,9.0Hz,1H),3.16(d,J=6.6Hz,1H); ESI-MS(m / z):575.5[M+Na] + .

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Abstract

The invention discloses novel N-4-phenylsulfonamido--N'-1-desoxy-(2-desoxy-2-substituted-amino)-beta-D-glucopyransoylthiocarbamide compounds with the general formula disclosed in the specification, which have the activity of inhibiting carbonic anhydrase and further achieve the effect of resisting tumor metastasis and invasion. The compounds structurally have the three active segments sulfamine, substituted glucosamine and thiocarbamide, and the three active segments and Zn<2+> ions in the carbonic anhydrase form coordinate bonds, thereby inhibiting the catalytic activity of the enzyme and performing the function of resisting tumor metastasis and invasion. Thus, the compounds have application potential in the aspect of antitumor drugs. In the general formula, R is defined in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to N-4-benzenesulfonamide-N'-1-deoxy-(2-deoxy-2-substituted amino)-β-D-glucopyranosylthiourea compound and a preparation method thereof And medical use, be specifically related to novel N-4-benzenesulfonamido-N'-1-deoxy-(2-deoxy-2-substituted amino)-β-D-glucopyranosylthiourea compound and preparation method thereof and the inhibitory effect on carbonic anhydrase IX, and its application in the preparation of antitumor drugs. Background technique [0002] Carbonic anhydrases (Carbonic anhydrases, CAs) are ubiquitous in living organisms and are a class of zinc-containing metalloenzymes. Physiological processes are crucial. Among them, carbonic anhydrase IX (CA IX) is a transmembrane protein and has been identified as a tumor-associated protein. Except for certain expression in gastrointestinal mucosal tissue, it is almost not expressed in other normal tissues, but it is not expressed ...

Claims

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Application Information

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IPC IPC(8): C07H5/06C07H1/00A61K31/7008A61P35/00
CPCC07H1/00C07H5/06
Inventor 刘洋郭春侯状程卯生
Owner SHENYANG PHARMA UNIVERSITY
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