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Naphthalimide-polyamine conjugate as well as preparation method and application thereof

A technology of naphthalimide and conjugates, which is applied in the field of naphthalimide-polyamine conjugates and its preparation, and can solve the problem that the side effects of bone marrow suppression are difficult to alleviate or eliminate

Active Publication Date: 2021-02-02
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A number of naphthalimide derivatives (such as DMP-840, Elinafide, Amonafide) have entered the clinical trial stage, but they have not been marketed due to various side effects such as bone marrow suppression, dose limitation, blood toxicity, etc.
Although the representative drug Amonafide has entered the phase III clinical research stage for the treatment of acute myeloid leukemia, its side effects such as bone marrow suppression, vomiting, and rash are still difficult to reduce or eliminate

Method used

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  • Naphthalimide-polyamine conjugate as well as preparation method and application thereof
  • Naphthalimide-polyamine conjugate as well as preparation method and application thereof
  • Naphthalimide-polyamine conjugate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]6{3-(1-Phenyl-1H-pyrazole)}-2-[4-4-(4-aminobutyl)-aminobutyl-aminobutyl]1H-benzisoquinoline-1, Synthesis of 3(2H)-diketone tetrahydrochloride (14a)

[0046]

[0047](1) Take 1.0g (6.5mmol) of compound 8, anhydrous AlCl3 1.29g (9.7mmol) was placed in a 100mL round bottom flask, dry dichloromethane was added as the reaction solvent, after stirring at room temperature for 15 minutes, slowly drop 0.48mL of dichloromethane solution containing 6.8mmol of acetyl chloride under ice bath conditions, dropwise After reaction at room temperature for 30 minutes. After 2h, pour into ice water, extract the organic layer with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, petroleum ether: ethyl acetate = 10:1 column separation and purification to obtain compound 9;

[0048](2) Weigh 1.3g (6.7mmol) of compound 9 obtained in step (1) into a 50mL round-bottomed flask, add 7mL DMF-DMA as the reactant and as the solvent at the same time, reflux for 1h, and evaporate...

Embodiment 2

[0054]6{3-(1-phenyl-1H-pyrazole)}-2-[3-3-(3-aminopropyl)-aminopropyl-aminopropyl]1H-benzisoquinoline-1, Synthesis of 3(2H)-diketone tetrahydrochloride (14b)

[0055]

[0056]Except that 5a is used instead of 5b in step (4), the other synthesis and purification methods are the same as in Example 1. The yield was 52%.

[0057]1H NMR (300MHz, DMSO-d6) δ: 8.46 (dd, J = 9.0, 6.0 Hz, 2H), 8.08 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 7.77 (dd,J=15.0,7.5Hz,2H),7.25-7.18(m,5H),6.83(s,1H),4.10(t,J=6.0Hz,2H),3.01-2.88(m,10H), 2.08-1.97(m,6H).13C NMR(75MHz,DMSO-d6)δ163.96,163.75,141.04,139.72,139.17,134.96,132.06,131.49,130.37,130.17,130.01,129.56,128.45,128.14,128.08,124.75, 123.04,122.93,111.44,45.25,44.30,44.22,37.71,36.32,24.88,23.89,22.63.ESI-MS m / z:511.47[M-4HCl+1]+.Elemental analysisfor C30H38Cl4N6O2: C, 54.89; H, 5.83; N, 12.80; Found: C, 54.73; H, 6.18; N, 12.73.

Embodiment 3

[0059]6{3-(1-phenyl-1H-pyrazole)}-2-[4-(4-aminobutyl)-aminobutyl]1H-benzisoquinoline-1,3(2H)-di Synthesis of ketone trihydrochloride (14c)

[0060]

[0061]Except that 3d is used instead of 5b in step (4), the other synthesis and purification methods are the same as in Example 1. The yield was 58%.

[0062]1H NMR(300MHz,DMSO-d6)δ:8.49-8.41(m,2H),8.12-8.03(m,1H),7.98(d,J=3.0Hz,1H),7.77(dd,J=13.5,7.5 Hz,2H),7.25-7.17(m,5H),6.84(d,J=3.0Hz,1H),4.05(s,2H),2.95-2.82(m,4H),2.79(d,J=6.0Hz ,2H),1.66(d,J=18.0Hz,8H).13C NMR (75MHz, DMSO-d6) δ163.77,163.58,141.05,139.70,139.16,134.96,132.08,131.53,130.42,130.20,130.00,129.56,128.48,128.06,124.73,122.94,122.83,111.43,46.74,46.26,38.28 ,25.21,24.34,23.59,22.84.ESI-MS m / z:482.43[M-3HCl+1]+.Elemental analysisfor C29H34Cl3N5O2·0.3H2O: C, 58.41; H, 5.85; N, 11.74; Found: C, 58.92; H, 5.52; N, 11.58.

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Abstract

The invention discloses a naphthalimide-polyamine conjugate, which has a structural general formula as shown in I, a novel skeleton, high efficiency, low toxicity and good inhibitory activity for tumor cells. The invention also discloses a preparation method of the conjugate. Firstly, 3-amino groups with toxic and side effects of amonafide are removed, a phenylpyrazole structure fragment is introduced to the naphthalimide parent naphthalene ring, and a naphthalimide side chain with a polyamine chain is modified, acetyltransferase in vivo is prevented from acetylating the amino groups on the naphthalene ring of amonafideand, and toxic and side effects are reduced; and further by introducing a low-toxicity phenyl pyrazole active structure fragment, the naphthalimide polyamine conjugate witha novel skeleton, high efficiency and low toxicity is synthesized; and secondly, quinazoline with low toxicity is introduced to replace hydrogen atoms of amonafide 3-amino, so that the naphthalimide polyamine conjugate with anti-tumor activity and low toxicity is obtained. The invention also discloses an application of the conjugate in preparation of antitumor drugs, and good development potentialis realized.

Description

Technical field[0001]The invention belongs to the field of medicinal chemistry, and relates to a naphthalimide-polyamine conjugate, and a preparation method and application thereof.Background technique[0002]As small antitumor molecules, naphthimide compounds have always been the research hotspots of medicinal chemists, and their application in antitumor drugs has been widely concerned by scientists. Many naphthimide derivatives (such as DMP-840, Elinafide, Amonafide) have entered the clinical trial stage, but they have not been marketed due to various side effects such as bone marrow suppression, dose limitation, and blood toxicity. The representative drug Amonafide, although used to treat acute myelogenous leukemia has entered the clinical phase III study stage, but its side effects such as bone marrow suppression, vomiting, and rash are still difficult to reduce or eliminate. Therefore, medicinal chemists have modified the naphthalimide compounds in a variety of structures in orde...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/473A61K31/5377A61P35/00A61K47/55A61K47/54
CPCA61K47/54A61K47/545A61K47/55A61P35/00C07D401/12
Inventor 王超杰罗稳苌聪聪戈超李景华
Owner HENAN UNIVERSITY
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