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7-aminocarbazolesulfonamide derivatives as well as preparation method and application thereof

A technology of aminocarbazole sulfonamide and carbazole sulfonamide, which is applied in the field of medicine and can solve the problems of poor tumor cell inhibitory effect and low antitumor activity

Inactive Publication Date: 2019-06-07
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the derivatives of combretastatin compounds reported so far have low antitumor activity and poor inhibitory effect on tumor cells.

Method used

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  • 7-aminocarbazolesulfonamide derivatives as well as preparation method and application thereof
  • 7-aminocarbazolesulfonamide derivatives as well as preparation method and application thereof
  • 7-aminocarbazolesulfonamide derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] N-(4-Methoxyphenyl)-7-amino-9-methyl-3-carbazole sulfonamide (9a)

[0101] Step 1. Synthesis of intermediate 9-methyl-7-nitrocarbazole

[0102]

[0103] Reaction a: Under anhydrous and oxygen-free conditions, dissolve 2'-bromoacetanilide and 4-nitrophenylboronic acid pinacol ester in the solvent toluene, then add anhydrous potassium phosphate and Pd(OAc) in sequence 2 And SPhOS, sealed, oil bath to control the reaction temperature around 90 ℃, after 24 hours of reaction, the reaction solution was extracted, washed with water, dried, spin-dried, and passed through the column (PE:EA=4:1) to obtain a yellow solid product. Namely compound 5.

[0104] Among them, the mass of anhydrous potassium phosphate is about twice the mass of 2’-bromoacetanilide, the catalyst Pd(OAc) 2 The amount of SPhOS is about 8% of 2'-bromoacetanilide, and the amount of SPhOS is about 16% of 2'-bromoacetanilide.

[0105] Reaction b: Under anhydrous conditions, dissolve compound 5 in DMSO, and then add mol...

Embodiment 2

[0122] N-(2,4-Dimethoxyphenyl)-7-amino-9-methyl-3-carbazole sulfonamide (9b)

[0123] See Example 1 for the synthesis process, and the specific conditions are as follows:

[0124] Step 3: Compound 1 (60mg, 0.18mmol), Compound 2 (34mg, 0.22mmol) (R 1 = 2,4-OMe), anhydrous K 2 CO 3 (49mg, 0.36mmol), DMF (3mL), room temperature: 8h, column chromatography (PE:EA=1:1).

[0125] The product (denoted as 3b) is a yellow solid, yield: 50%

[0126] 1 H NMR(500MHz, DMSO-d 6 )δppm 9.18(s,1H), 8.64(d,J=7.0Hz,2H), 8.52(d,J=8.5Hz,1H), 8.12(d,J=8.5Hz,1H), 7.86(m,2H ), 7.09(d,J=8.5Hz,1H), 6.43(d,J=8.5Hz,1H), 6.36(s,1H),4.05(s,3H),3.66(s,3H), 3.29(s ,3H). 13 C NMR(101MHz, DMSO-d 6 )δppm 158.6,154.4,145.9,144.3,140.4,132.2,127.9,126.4,121.4,121.3,119.7,117.9,114.6,110.102,106.2,104.6,98.9,55.3,55.2,29.8.MS m / z(%)440( M-1,100).

[0127] Step 4: Reactant 3b (40mg, 0.091mmol), Pd / C (5%) (20% equiv), H 2 : 40Psi, methanol / THF (1:1) 30mL, room temperature: 3-4h, column chromatography (PE:EA=2:3).

[0128] T...

Embodiment 3

[0131] N-(2,5-Dimethoxyphenyl)-7-amino-9-methyl-3-carbazole sulfonamide (9c)

[0132] See Example 1 for the synthesis process, and the specific conditions are as follows:

[0133] Step 3: Compound 1 (110mg, 0.34mmol), Compound 2 (60mg, 0.41mmol) (R 1 = 2,5-OMe), anhydrous K 2 CO 3 (94mg, 0.68mmol), DMF (3mL), room temperature: 4h, column chromatography (PE:EA=2:1)

[0134] The product (denoted as 3c) is a yellow solid, yield: 60.1%, melting point: 208.0-210.2°C.

[0135] 1 H NMR(500MHz, DMSO-d 6 )δppm 9.42(s,1H),8.79(s,1H),8.63(s,1H),8.55(d,J=9.0Hz,1H), 8.14(d,J=9.0Hz,1H),7.98(d ,J=9.0Hz,1H), 7.87(d,J=9.0Hz,1H), 6.86(d,J=2.5Hz,1H), 6.78(d,J=9.0Hz,1H), 6.60(dd,J =9.0,2.5Hz,1H),4.04(s,3H),3.62(s,3H),3.42(s,3H). 13 C NMR(101MHz, DMSO-d 6 )δppm 152.8, 146.0, 145.6, 144.4, 1405, 131.7, 126.7, 126.6, 126.2, 121.6, 119.9, 114.7, 112.6, 110.5, 110.0, 109.8, 106.2, 56.1, 55.3, 29.8.

[0136] Step 4: Reactant 3c (90mg, 0.20mmol), Pd / C (5%) (20% equiv), H 2 : 40Psi, methanol / THF (1:1) 50mL, roo...

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Abstract

The invention provides 7-aminocarbazolesulfonamide derivatives as well as a preparation method and application thereof, and relates to the technical field of medicine. The 7-aminocarbazolesulfonamidederivatives have a general formula (I) shown in the description, wherein R1 is one or more groups located on a benzene ring and at least one independently selected from the group consisting of a C1-C6lower alkoxy group, a C1-C6 lower alkyl group, an amino group and a halogen; and R2 is hydrogen or a C1-C6 lower alkyl group. The 7-aminocarbazolesulfonamide derivatives provided by the invention exhibit good inhibitory activity against various tumor cells, so that the derivatives can be well used for preparing antitumor drugs.

Description

Technical field [0001] The invention relates to a 7-aminocarbazole sulfonamide derivative and a preparation method and application thereof, belonging to the technical field of medicine. Background technique [0002] The growth and metastasis of tumors mainly depend on blood vessels, and fast-growing solid tumors require large amounts of oxygen and nutrients from tumor blood vessels. If there is no vascular system to provide oxygen and nutrients, the growth of solid tumors usually does not exceed 1 to 2 mm 3 [Ausprunk D H, Folkman J. Migration and proliferation of endot-helial cells inpreformed and ne-wly formed blood vessels during tumorsangiogenesis. Microvasc Res, 1977, 14(1): 53-65.]. Compared with normal mature blood vessels, tumor blood vessels have the characteristics of rapid differentiation and proliferation, tissue disorder, blind ends, high permeability and few red blood cells [Thorpe PE.Vascular targeting agents as cancer therapeutics.Clin Cancer Res 2004,10:415-27. ]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/88A61P35/00A61K31/403
Inventor 胡来兴王天琦白利平王晨曦郭未蔚刘永华
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI