Naphthalimide derivative using ester group for modifying amonafide naphthalene ring and preparation method and application of naphthalimide derivative

A technology of aminonaphthyl naphthalene ring and naphthalene imide, which is applied in the field of naphthalene imide derivatives and its preparation, to achieve good inhibitory ability and avoid unpredictable toxicity

Inactive Publication Date: 2016-06-08
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, most of them were abandoned due to various side

Method used

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  • Naphthalimide derivative using ester group for modifying amonafide naphthalene ring and preparation method and application of naphthalimide derivative
  • Naphthalimide derivative using ester group for modifying amonafide naphthalene ring and preparation method and application of naphthalimide derivative
  • Naphthalimide derivative using ester group for modifying amonafide naphthalene ring and preparation method and application of naphthalimide derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] 4-Formylmethyl-2-[2-(dimethylamino)-ethyl]1H-benzisoquinoline-1,3(2H)-dione hydrochloride (compound 7a)

[0023]

[0024] The preparation method is as follows:

[0025] (1) 3.6g (27mmol) AlCl 3 Dissolve in 20mL of dried dichloromethane, add 2.78g (27mmol) of acenaphthene (compound 1), control the temperature below 15°C, slowly add 1.4g (27mmol) of acetyl chloride in 10mL of dichloromethane solution, and the addition is complete. Continue the reaction for 1 h, add ice water to the reaction bottle to terminate the reaction, extract with dichloromethane, dry and concentrate, petroleum ether: ethyl acetate = 4:1 silica gel column separation and purification to obtain compound 2:

[0026] (2) Dissolve 1.96g (10mmol) of compound 2 in 22mL of glacial acetic acid, add 8.01g (27mmol) of sodium dichromate, control the reaction temperature at 90-100°C for 2h, then cool to room temperature, pour the reaction solution into ice water, Acidify with hydrochloric acid to pH 2-3, fi...

Embodiment 2

[0033] 4-Formyl ethyl ester-2-[2-(dimethylamino)-ethyl]1H-benzisoquinoline-1,3(2H)-dione hydrochloride (7b)

[0034]

[0035] Except that methanol is replaced with ethanol in the (4) step, other synthesis and purification methods are the same as in Example 1.

[0036] Yield: 59%, 1 HNMR (400MHz,D 2 O) δ8.56(d, J=53.0Hz, 1H), 8.03(d, J=11.43Hz, 3H), 7.58(d, J=36.1Hz, 1H), 4.46(d, J=7.0Hz, 2H ), 4.36(d, J=9.5Hz, 2H), 3.50~3.37(m, 2H), 3.16~2.79(m, 6H), 1.44(t, J=8.9Hz, 3H).ESI-MSm / z: 341.1 [M+1–HCl] + .Anal.calcdforC 19 h 21 ClN 2 o 4 1.1H 2 O: C57.53%, H5.90%, N7.06%; found C57.66%, H5.81%, N7.03%.

Embodiment 3

[0038] 4-Formylpropyl-2-[2-(dimethylamino)-ethyl]1H-benzisoquinoline-1,3(2H)-dione hydrochloride (7c)

[0039]

[0040] Except that methanol is replaced with propanol in the (4) step, other synthesis and purification methods are the same as in Example 1.

[0041] Yield: 42%, 1 HNMR (400MHz,D 2 O)δ8.52(s,1H),8.35~7.70(m,3H),7.53(s,1H),4.30(s,4H),3.36(d,J=6.1Hz,2H),3.17~2.60( m,6H),1.95~1.60(m,2H),1.17~0.71(m,3H).ESI-MSm / z:355.1[M+1–HCl] + .Anal.calcdforC 20 h 23 ClN 2 o 4 0.7H 2 O: C59.54%, H6.10%, N6.94%; found C59.38%, H6.31%, N6.89%.

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Abstract

The invention relates to a naphthalimide derivative using an ester group for modifying an amonafide naphthalene ring and a preparation method and application of the naphthalimide derivative. The naphthalimide derivative using the ester group for modifying the amonafide naphthalene ring and the preparation method and application of the naphthalimide derivative have the advantages that a carboxy group is introduced into the fourth position of the amonafide naphthalene ring to be coupled with fatty alcohol in different chain length, a 3-position amino group in an amonafide parent ring is removed, and accordingly acetylation of in-vivo acetyltransferase on the amino group on an amonafide ring is stopped, the possibility that N-acetylated amonafide causes unpredictable toxicity in vivo is avoided, and excellent in-vitro tumor cell inhibiting capability is achieved to obtain a new high-efficiency low-toxicity medicine.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a naphthalimide derivative modified with an ester group to modify a naphthalene ring, a preparation method and application thereof. Background technique [0002] Naphthalimides are a class of anticancer agents that have been proven to have broad application prospects. Many naphthalimide derivatives (such as DMP-840, Elinafide, Amonafide) have entered clinical phase I and phase II trials. But most of them were abandoned due to various side effects such as myelosuppression and dose limitation. The representative drug, Amonafide, is a drug combined with cytarabine that is undergoing clinical phase III trials in patients with acute myeloid leukemia. Its side effects include bone marrow suppression, vomiting, rash, and moderate phlebitis. The reason why Aminafetate causes toxic and side effects is that the 3-amino group on the naphthalene ring is easily acetylated by ...

Claims

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Application Information

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IPC IPC(8): C07D221/14A61P35/00A61P35/02
CPCC07D221/14
Inventor 王玉霞李景华李骞谢松强王超杰
Owner HENAN UNIVERSITY
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