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A kind of naphthalimide-polyamine conjugate and its preparation method and application

A naphthalimide and conjugate technology, which is applied in the field of naphthalimide-polyamine conjugates and their preparation, can solve the problems of difficulty in reducing or eliminating the toxic and side effects of myelosuppression, and achieves good development potential and novel skeleton. , good inhibitory effect

Active Publication Date: 2021-12-07
HENAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • A kind of naphthalimide-polyamine conjugate and its preparation method and application
  • A kind of naphthalimide-polyamine conjugate and its preparation method and application
  • A kind of naphthalimide-polyamine conjugate and its preparation method and application

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) compound 8, anhydrous AlCl 3 1.29g (9.7mmol) was placed in a 100mL round-bottomed flask, and dry dichloromethane was added as a reaction solvent. After stirring at room temperature for 15 minutes, 0.48mL of a dichloromethane solution containing 6.8mmol of acetyl chloride was slowly added dropwise under ice-bath conditions. After that, react at room temperature for 30 minutes. After 2 hours, it was poured into ice water, the organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated 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 bottom flask, add 7mL DMF-DMA as a reactant and as a s...

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 replacing 5b with 5a in step (4), other synthesis and purification methods are the same as in Example 1. Yield 52%.

[0057] 1 H NMR (300MHz, DMSO-d6) δ: 8.46 (dd, J=9.0, 6.0Hz, 2H), 8.08 (d, J=9.0Hz, 1H), 7.98 (d, J=3.0Hz, 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)δ163.96,163.75,141.04,139.72,139.17,134.96,132.06,131.49,130.37,130.17,130.01,129.56,118.415,12 123.04,122.93,111.44,45.25,44.30,44.22,37.71,36.32,24.88,23.89,22.63.ESI-MS m / z:511.47[M-4HCl+1] + .Elemental analysis for C 30 h 38 C l4 N 6 o 2 : 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)-two Synthesis of Ketone Trihydrochloride (14c)

[0060]

[0061] Except that 3d is used to replace 5b in step (4), other synthesis and purification methods are the same as in Example 1. Yield 58%.

[0062] 1 H 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). 13 C 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 analysis for C 29 h 34 Cl 3 N 5 o 2 0.3H 2 O: 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 general structural formula as shown in I, has a novel skeleton, high efficiency and low toxicity, and has good inhibitory activity on tumor cells. The invention also discloses the preparation method of the above-mentioned compound, one of which is to remove the 3-amino group of the toxic side effect of naphthalene, introduce a phenylpyrazole structural fragment on the naphthalene ring of the naphthalene imide parent, and at the same time use the polyamine chain Modification of the naphthalimide side chain not only prevents the acetylation of the amino group on the naphthalene ring of acetyltransferase in the body, but also reduces the toxic and side effects; and synthesizes the skeleton by introducing the active structural fragment of phenylpyrazole with low toxicity Novel, high-efficiency and low-toxic naphthalimide-polyamine conjugates; the second is to replace the hydrogen atom of the aminonafete 3-amino group by introducing a quinazoline with low toxicity, and obtain a drug with anti-tumor activity and low toxicity. Naphthalimide‑polyamine conjugates. The invention also discloses the application of the above compound in the preparation of antitumor drugs, which shows good development potential.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a naphthalimide-polyamine conjugate, a preparation method and application thereof. Background technique [0002] As anti-tumor small molecules, naphthalimides have always been a research hotspot for medicinal chemists, and their application in anti-tumor drugs has been widely concerned by scientists. 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, and blood toxicity. Although the representative drug, Amonafide, has entered the clinical phase III 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. Therefore, medicinal chemists carry out various structural modifications on naphthalimide...

Claims

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Application Information

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Patent Type & Authority Patents(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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