阅读说明：本技术 一种1，8-萘酰亚胺衍生物及其应用 (1, 8-naphthalimide derivative and application thereof ) 是由 曾淑兰 张国海 彭艳 潘成学 李平平 于 2019-09-23 设计创作，主要内容包括：本发明公开了一种1,8-萘酰亚胺衍生物及其应用。该衍生物对非小细胞肺癌细胞株NCI-H460、人膀胱癌细胞T24以及人乳腺癌细胞MCF-7的具有显著的抑制活性,其中对非小细胞肺癌细胞株NCI-H460的抑制活性显著优于氨萘非特,且其对人正常细胞WI-38的毒副作用较氨萘非特更小,有望开发成靶向治疗药物。本发明所述1,8-萘酰亚胺衍生物的结构如下式(I)所示：<Image he="600" wi="516" file="DDA0002211332700000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a 1, 8-naphthalimide derivative and application thereof. The derivative has obvious inhibition activity on non-small cell lung cancer cell strains NCI-H460, human bladder cancer cell T24 and human breast cancer cell MCF-7, wherein the inhibition activity on the non-small cell lung cancer cell strains NCI-H460 is obviously better than amonafide, and the toxic and side effect on human normal cells WI-38 is smaller than that of the amonafide, so that the derivative is expected to be developed into a targeted therapeutic medicament. The structure of the 1, 8-naphthalimide derivative is shown as the following formula (I):)

1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof:

2. the use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-neoplastic drug.

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

Technical Field

The invention relates to a 1, 8-naphthalimide derivative and application thereof, belonging to the technical field of medicines.

Background

Naphthalimide derivatives have unique planar rigid structures, so that the naphthalimide derivatives have stronger DNA (deoxyribonucleic acid) embedding capacity, and more researches show that naphthalimide and derivatives thereof have good anti-tumor activity, have higher affinity to DNA molecules and can be combined with DNA through insertion.

The existing research shows that 1, 8-naphthalimide derivatives have important antitumor activity, the derivatives aminonaphthalimide (amonafide) and mitonafide (mitonafide) enter the phase II clinical test stage, but the toxic and side effects of the aminonaphthalimide derivatives and the mitonafide (mitonafide) are large, so that the toxic and side effects of the aminonaphthalimide derivatives and the mitonafide (mitonafide) are severely limited. Therefore, it is expected that a novel naphthalimide compound with remarkable biological activity and less toxic and side effects can be synthesized. At present, no report related to the introduction of aryl sulfide at the electron-deficient 4-position of a 1, 8-naphthalimide fluorophore is found.

Disclosure of Invention

The invention aims to provide a 1, 8-naphthalimide derivative with better activity and lower activity and application thereof.

The present invention relates to compounds having the following formula (I) or a pharmaceutically acceptable salt thereof:

the chemical name of the compound shown in the formula (I) is N- (2-N, N-dimethylamino) ethylamino-6- (4-fluorobenzene sulfinyl) -1, 8-naphthalimide, and the molecular weight is as follows: 410.46.

the preparation method of the compound shown in the formula (I) mainly comprises the following steps: putting a compound shown as a formula (II) and N, N-dimethylethylenediamine into an organic solvent for reaction, and recovering the solvent after the reaction is finished to obtain a crude product of the target compound;

in the preparation method of the present invention, the organic solvent may be one or a combination of two or more selected from ethanol, methanol, Dichloromethane (DCM), N-Dimethylformamide (DMF) and Petroleum Ether (PE). When the organic solvent is selected from the combination of two or more of the above substances, the ratio of the organic solvent to the organic solvent may be any ratio. The amount of the organic solvent to be used may be determined as required, and in general, all the starting materials to be reacted are dissolved in a total amount of 5 to 10mL of the organic solvent based on 1mmol of the compound represented by the formula (II).

In the preparation method of the present invention, the reaction may be carried out without heating or with heating, and preferably without heating. Whether the reaction was complete can be followed by TLC.

In the preparation method of the present invention, the amount ratio of the compound represented by the formula (II) to N, N-dimethylethylenediamine is a stoichiometric ratio, and in actual experimental operation, the amount ratio of the compound represented by the formula (II) to the amount of N, N-dimethylethylenediamine is generally: 1: 1.5-3.

The preparation method of the invention prepares the crude product of the compound shown in the formula (I), and the crude product can be purified by adopting the conventional purification method so as to improve the purity of the compound shown in the formula (I). The purification is usually carried out by silica gel column chromatography, and specifically, the crude target compound is subjected to silica gel column chromatography, and the volume ratio of the crude target compound is 5-20: 1, eluting with an eluent consisting of Ethyl Acetate (EA) and methanol, and evaporating the eluent to remove the solvent to obtain the purified target compound.

The chemical name of the compound shown as the raw material formula (II) related in the preparation method is 6- (4-fluorobenzenesulfinyl) -1, 8-naphthalimide, and the compound can be synthesized by referring to the existing literature and also can be synthesized by a self-designed route. The preparation is preferably carried out as follows:

1) putting 4-chloro-1, 8-naphthalic anhydride and p-fluorobenzenethiol into a first solvent, reacting under a heating condition under an alkaline condition of a system, recovering the solvent, acidifying the obtained reactant, separating out a precipitate, and collecting the precipitate to obtain a compound 2;

2) and (2) putting the compound 2 and m-chloroperoxybenzoic acid (m-CBPA) into a second solvent, reacting without heating, washing a reactant with a saturated NaHCO3 solution, extracting with an extracting agent, collecting an organic phase, and recovering the solvent to obtain a compound 3, namely the compound shown in the formula (II).

In step 1) of the method for preparing a compound represented by the formula (II), the first solvent is preferably N, N-dimethylformamide; the alkalescence substance (such as sodium bicarbonate or sodium carbonate and the like) is added into the system to adjust the system to be alkaline so as to be beneficial to the reaction; the reaction is generally carried out at 40 ℃ to the reflux temperature of the first solvent, and preferably under stirring, and the completion of the reaction is checked by TLC tracking; after the reaction is completed, the alkalinity of each system in an acid solution (usually a dilute hydrochloric acid solution, such as a5 v/v% hydrochloric acid solution) is adopted to maintain the system at a pH value of about 7. The product obtained in this step can be further purified (such as recrystallization, and the solvent for recrystallization can be common solvent such as ethanol) and then used for subsequent operation.

In step 2) of the method for preparing a compound represented by the above formula (II), the second solvent is preferably N, N-dimethylformamide; the reaction is usually carried out at normal temperature, and whether the reaction is complete or not is detected by TLC tracking; after the reaction is finished, the acid possibly existing in the system is removed by washing preferably by using saturated NaHCO3 solution; the extractant is preferably dichloromethane. The product obtained in this step is a crude product of the compound represented by formula (II), and is preferably purified by silica gel column chromatography (eluting with a mixed solvent composed of ethyl acetate and petroleum ether at a volume ratio of 1: 2-50, eluting with a mixed solvent composed of dichloromethane, ethyl acetate and methanol at a volume ratio of 9:3:1, and collecting the eluate eluted with the mixed solvent composed of dichloromethane, ethyl acetate and methanol) and then used in the subsequent operations.

The molar ratio of the starting materials in the reactions involved in the steps of the process for the preparation of the compound represented by the above formula (II) is the stoichiometric ratio.

The invention also discloses the application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in preparing antitumor drugs, in particular the application in preparing drugs for inhibiting human lung cancer cells, bladder cancer cells or breast cancer cells.

The invention also provides a pharmaceutical composition, which contains therapeutically effective dose of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof.

Compared with the prior art, the invention provides the 1, 8-naphthalimide derivative with a novel structure, and in vitro experiments of the applicant show that the derivative has obvious biological activity, particularly has extremely obvious inhibitory activity on a non-small cell lung cancer cell strain NCI-H460, a human bladder cancer cell T24 and a human breast cancer cell MCF-7, has smaller toxic and side effects on human normal cells WI-38 than amonafide, and is expected to be developed into a targeted therapeutic medicament.

Drawings

FIG. 1 is a fluorescence spectrum of a compound (i.e., blank group) as a fluorescent probe with an excitation wavelength of 405nm and an emission wavelength of 498nm, wherein the compound is represented by formula (I);

FIG. 2 is a fluorescence spectrum of a GSSG combined compound shown in formula (I) (i.e. experiment 2 group) as a fluorescent probe with an excitation wavelength of 405nm and an emission wavelength of 498 nm;

FIG. 3 shows the fluorescence spectrum of the GSH bound compound of formula (I) (i.e. experiment 1 group) as a fluorescent probe at an excitation wavelength of 405nm and an emission wavelength of 498 nm.

Detailed Description

The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.