A kind of naphthalimide indole heterocyclic compound, its preparation method and application

A technology of naphthalimide indole and heterocyclic compound, which is applied in the field of medicinal chemistry, can solve the problems of limited application, inhibition, vomiting, venous inflammation, central system toxicity, etc., and achieves increased intake and maximum tolerated dose. , improve the effect of effective combination

Active Publication Date: 2022-03-08
HENAN UNIVERSITY
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Problems solved by technology

As early as 1973, Brana's subject combined a series of naphthalimide-polyamine derivatives with anti-tumor activity, two of which, Amonafide and Mitonafide, entered the clinical stage. According to the phase test, Amonafidede has good inhibitory effect on leukemia cells (P388) and leukemia cells (L1210). Human bone marrow suppression, vomiting, venous inflammation and other effects in varying degrees; while Mitonafide will cause severe central system toxicity to the human body, which limits its clinical application, so it is enhanced by modifying the structure of naphthalimide Its targeting and solving its immunosuppressive problems have become the focus of research and development of chemotherapy drugs

Method used

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  • A kind of naphthalimide indole heterocyclic compound, its preparation method and application
  • A kind of naphthalimide indole heterocyclic compound, its preparation method and application
  • A kind of naphthalimide indole heterocyclic compound, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: 1b

[0057]

[0058] 1 H NMR(300MHz,DMSO-d6)δ8.71(s,1H),8.24(s,1H),8.06(s,1H),7.75(s,1H),4.26(d,4H), 2.94(t, J=27.2Hz, 6H), 2.01(d, J=24.3Hz, 4H). 13 C NMR (75MHz, D 2 O)δ167.17, 164.14, 163.39, 135.27, 134.36, 134.00, 131.51, 130.29, 127.77, 123.66, 121.97, 120.24, 45.36, 44.65, 44.55, 43.07, 37ion.51, 24.163, I [M-H] + calcd 365.19, obsd 365.19. Its preparation method is as follows:

[0059] (1) Add 100mmol (19.8g) of compound 8 (1,8 naphthalene dicarboxylate) and 100mL of concentrated sulfuric acid into a 250mL volumetric flask, stir and dissolve in an ice bath, measure 11.2mL of concentrated nitric acid and 50mL of concentrated sulfuric acid to prepare a mixed acid , dropped into the concentrated sulfuric acid solution of compound 8 under ice-bath conditions, continued to react for 2.5h after the drop, after the reaction was completed, poured the reaction solution into ice water, let it stand, filtered with suction, washed with water until neutral...

Embodiment 2

[0065] Example 2: 2b

[0066]

[0067] 1 H NMR(300MHz,DMSO-d6)δ8.69(d,J=14.3Hz,2H),8.36(s,1H),7.82(s,1H),4.42(s,2H), 4.11(s,2H) ,3.11–2.70(m,6H),2.05(s,2H),1.79–1.41(s,4H). 13 C NMR (75MHz,D 2 O)δ 167.33,164.43,163.73,135.40,134.49,130.70,130.32,127.63,123.14,122.53,121.86,120.31, 119.78,46.99,45.24,43.07,38.74,37.35,24.18,23.90,22.77.ESI-MS(positive ion mode) m / z [M+HCl] + calcd 417.10, obsd 417.10.

[0068] The difference between the preparation method of compound 2b in Example 2 and Example 1 is that in step (4)) compound 12a (1 mmol) and polyamine chain (2mmol) and acid anhydride (3mmol) were subjected to condensation reaction for 24-48h to obtain compounds with or without Boc protecting groups, and those with protecting groups removed the Boc protecting groups to obtain compound 2b.

[0069] The 2b synthetic route reaction formula of the polyamine analog modified by naphthalimide indole core is:

[0070]

Embodiment 3

[0071] Example 3: 3b

[0072]

[0073] 1 H NMR (300MHz, DMSO-d6) δ10.66(s, J=14.3Hz, 1H), 8.36(s, 1H), 8.81(s, 1H), 7.97(s, 1H), 7.78(s, 1H) ,4.10(s,2H),4.07(s,2H),2.68(s,2H),2.53(m,8H),1.78(s,2H),1.74(s,2H),1.5(s,3H), 1.38(s,4H). 13 C NMR (75MHz,D 2O) δ176.6, 159.3, 159.3, 145.2, 132.0, 131.6, 129.5, 128.1, 124.3, 123.6, 123.0, 117.1, 116.4, 56.1, 49.6, 49.6, 46.0, 46.0, 39.4, 35.6, 31.2, 33.2, ESI-MS(positive ion mode)m / z[M] + calcd 437.24, obsd 437.24.

[0074] The difference between the preparation method of compound 3b in embodiment 3 and embodiment 1 is that in step (4), compound 12a (1mmol) and polyamine chain (2mmol) and acid anhydride (3mmol) were subjected to condensation reaction for 24-48h to obtain a compound with or without a Boc protecting group, and the compound 3b was obtained by removing the Boc protecting group with a protecting group.

[0075] The 3b synthetic route reaction formula of the polyamine analog modified by naphthalimide indole core is...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and specifically relates to a naphthalimide indole heterocyclic compound, a preparation method and application thereof. The naphthalimide-indole heterocyclic compound of the present invention has good antitumor activity, and its antitumor activity in vivo and in vitro is better than that of naphthalene, and the antitumor spectrum is wider. Different from the classic amafite, the compound of the present invention targets the key enzyme PAO (polyamine oxidase) in the tumor polyamine microenvironment and three endogenous small molecules Put (putrescine), Spd (spermidine ) and Spm (spermine) content, regulate subcellular organelles and nuclear function to reverse drug resistance, and at the same time enhance anti-tumor immune response, and have good therapeutic potential for advanced metastatic tumors. The complex of the present invention also solves the problems of poor solubility, cumbersome clinical compatibility and poor immunity of patients in the clinical application of chemotherapeutic drugs of naphthalimide analogues represented by naphthalene in the past, and has good water solubility.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a naphthalimide indole heterocyclic compound, a preparation method and application thereof. Background technique [0002] The main reasons for the failure of chemotherapy drugs to treat cancer, especially metastatic cancer, are lack of targeting, drug resistance, weak anti-tumor metastasis activity and immunosuppression. Naphthimide and its derivatives, represented by naphthalene, are DNA intercalators with good antitumor effects, because the intercalation of planar aromatic rings in the structure between DNA base pairs will distort the conformation of the DNA main chain and Interfere with DNA-protein interaction to play an anti-tumor effect. As early as 1973, Brana's subject combined a series of naphthalimide-polyamine derivatives with anti-tumor activity, and two of them, Amonafide and Mitonafide, entered the clinical stage. According to the phase test,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/06A61K31/437A61P35/00
CPCC07D471/06A61P35/00Y02P20/55
Inventor 马静王佳佳田智勇方东孙华谢松强
Owner HENAN UNIVERSITY
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