CN102731396B - Polyamine naphthalimide compounds and application of same in preparation of pharmaceutical preparation - Google Patents

Abstract

The invention discloses a polyamine naphthalimide compound, the preparation method of which comprises the following steps (a) weighing 4-bromo-1,8-naphthalene anhydride, N,N-dimethyl ethylenediamine, mixed, heated, and reacted for 8-10 hours, filtered, and dried; (b) weigh the above intermediate and fatty amine, add it to ethylene glycol monomethyl ether solution, heat, react for 8-12 Hours, the ethylene glycol monomethyl ether solution was distilled off under reduced pressure, the obtained solid was dissolved in dichloromethane, the solution was separated through a silica gel column, and eluted with an eluent. The compounds provided by the present invention have obvious inhibitory effects on liver cancer cells Bel-7402, leukemia cells HL-60, human lung cancer cells A549 and human uterine cancer cells Hela, etc., and the anti-tumor activity of some compounds is better than that of commonly used anti-tumor drugs Shun platinum. Therefore, the inventors proposed for the first time that the compound be used in the preparation of antitumor drug preparations. In particular, the application in the preparation of pharmaceutical preparations for treating liver cancer; the application in the preparation of pharmaceutical preparations for treating leukemia; the application in the preparation of pharmaceutical preparations for treating uterine cancer are proposed.

Description

A polyamine naphthalimide compound and its application in the preparation of pharmaceutical preparations

technical field

The present invention relates to a new compound and its use, in particular to a polyamine compound and its use in the preparation of pharmaceutical preparations.

Background technique

The research of anti-tumor drugs with DNA as the target has always been a research hotspot. Among them, the research on naphthalimide compounds as DNA intercalating agents and topoisomerase inhibitors has aroused great interest. At present, the compounds that have entered the clinical phase II research include nafefide, mitonaftamide, elinefade and Bisnaphthide et al. This type of compound can inhibit the process of DNA and RNA replication by intercalating between the base pairs of DNA molecules, and can inhibit the activity of topoisomerase II, thereby inhibiting the growth of tumors (a) MF , A. Ramos. Curr. Med. Chem.-Anti-Cancer Agents, 2001, 1, 237-255; b) Laurent Ingrassia, Florence Lefranc, Robert Kiss, and Tatjana Mijatovic. Current Medicinal Chemistry, 2009, 16, 1192-1213 ; c) Min Lv and Hui Xu. Current Medicinal Chemistry, 2009, 16, 4797-4813.).

On the other hand, naphthalimide compounds have strong cell membrane penetrating ability and gene transfection effect, which can be combined with the phosphate group of DNA chain through electrostatic interaction, which can enhance the targeting of drug molecules (a) Otmane Boussif, Frank Lezoialc'h, Marla Antonietta Zanta, Mojgan Djavaheri Mergny, Daniel Scherman, Barbara Demeneix, Jean-Paul Behr.Proc.Natl.Acad.Sci.USA, 1995, 92, 7297-7301; b) Tae Gwan Park, Ji Hoon Jeong , Sung Wan Kim. Advanced Drug Delivery Reviews, 2006, 58, 467-486; c) Zhi-yong Tian, Song-qiang Xie, Zi-hou Mei, Jin Zhao, Wen-yuan Gao, Chao-jie Wang. Org. Biomol. Chem., 2009, 7, 4651-4660.).

Therefore, people are eager to obtain more selective and highly active naphthalimide compounds.

Contents of the invention

The purpose of the present invention is to provide people with more novel naphthalimide compounds, and at the same time provide an application of the invented compound in the preparation of pharmaceutical preparations.

The naphthalimide compound provided by the present invention is a polyamine naphthalimide compound, and its general chemical structure is as follows:

in

m=1, 2, 3 or 4

For the above compound (hereinafter referred to as the 4-position diamine naphthalimide compound), when m=1, 2, 3 or 4, R ₁ = ethylenediamine, propylenediamine, butylenediamine or pentamethylenediamine base;

Its preparation method comprises the following steps

(a) According to the molar ratio of 1:1, weigh 4-bromo-1,8-naphthalene anhydride, N,N-dimethylethylenediamine, 4-bromo-1,8-naphthalene anhydride, N,N - Add dimethylethylenediamine to anhydrous ethanol solution, heat to 70-80°C, keep for 1-3 hours, stop the reaction, cool the reaction solution to room temperature, filter, and dry to obtain a yellow solid intermediate N-(N, N-dimethyl-1,3-propanediamino)-1,8-naphthalene anhydride;

(b) According to the molar ratio of 1:10, weigh the above-mentioned intermediates and fatty amines, add them to the ethylene glycol monomethyl ether solution, heat to 100-150°C, keep the reaction for 8-12 hours, stop the reaction, and cool to At room temperature, the ethylene glycol monomethyl ether solution was evaporated under reduced pressure, and the obtained solid was dissolved in dichloromethane, and the solution was separated through a silica gel column, and the eluent was dichloromethane/methanol/trichlorohydrin at a volume ratio of 10:1:0.1. Ethylamine is eluted, and the eluate is the 4-position diamine naphthalimide compound; wherein the aliphatic amine is one of ethylenediamine, propylenediamine, butylenediamine, and pentamethylenediamine.

Another kind of polyamine naphthalimide compound provided by the present invention, its general chemical structure formula is as follows:

in

(n+2)HCl n=1, 2 or 3

The above compounds are referred to as 4-position polyamine naphthalimide compounds for short. When n=1, 2 or 3, R ₂ = diethylenetriamine, triethylenetetramine or tetraethylenepentamine hydrochloride;

Its preparation method comprises the following steps:

(a) According to the molar ratio of 1:1, weigh 4-bromo-1,8-naphthalene anhydride, N,N-dimethylethylenediamine, 4-bromo-1,8-naphthalene anhydride, N,N - Add dimethylethylenediamine to anhydrous ethanol solution, heat to 70-80°C, keep for 1-3 hours, stop the reaction, cool the reaction solution to room temperature, filter, and dry to obtain a yellow solid intermediate N-(N, N-dimethyl-1,3-propanediamino)-1,8-naphthalene anhydride;

(b) According to the molar ratio of 1:10, weigh the above-mentioned intermediates and fatty amines, add them to the ethylene glycol monomethyl ether solution, heat to 100-150°C, keep the reaction for 8-12 hours, stop the reaction, and cool to At room temperature, evaporate the ethylene glycol monomethyl ether solution under reduced pressure, and continue to react with di-tert-butoxyformic anhydride (Boc ₂ O) in a solution of dichloromethane and methanol with a volume ratio of 1/1 without separation , obtained the intermediate whose amino group was protected by Boc, evaporated the solvent under reduced pressure, and separated it through a silica gel column. The eluent was ethyl acetate/methanol with a volume ratio of 16/1. React in the solution (volume ratio 1/1) at room temperature for 2-12 hours, stop the reaction, add ethanol, centrifuge the reaction solution at 15000 rpm, pour out the supernatant, wash with ethanol three times, and dry to obtain 4-polyamine Naphthalimide compound; wherein the fatty amine is a hydrochloride of diethylenetriamine, triethylenetetramine, tetraethylenepentamine;

The above-mentioned 4-bromo-1,8-naphthalene anhydride is commercially available as a raw material for the synthesis of the present invention.

The compounds provided by the present invention have obvious inhibitory effects on liver cancer cells Bel-7402, leukemia cells HL-60, human lung cancer cells A549 and human uterine cancer cells Hela, etc., and the anti-tumor activity of some compounds is better than that of commonly used anti-tumor drugs Shun platinum.

Therefore, the present inventor proposed for the first time that the compound be used in the preparation of antitumor drug preparations.

In particular, the application in the preparation of pharmaceutical preparations for treating liver cancer; the application in the preparation of pharmaceutical preparations for treating leukemia; the application in the preparation of pharmaceutical preparations for treating uterine cancer are proposed.

The 4-position diamine naphthalimide compound of the present invention can be mixed with physiologically allowed inorganic acid (such as hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid), organic acid (such as acetic acid, propionic acid, citric acid , maleic acid, malic acid, tartaric acid, methanesulfonic acid) into salt.

For example, reacting the 4-position diamine naphthalimide compound of the present invention with hydrochloric acid can obtain the 4-position diamine naphthalimide hydrochloride. Its specific preparation method is as follows:

Dissolve the 4-position diamine naphthalimide compound in a mixture of absolute ethanol and 6M hydrochloric acid with a volume ratio of 1:1, react at room temperature for 2-12 hours, stop the reaction, add ethanol, and the reaction solution is at 15000 rpm Centrifuge, pour out the supernatant, wash with ethanol three times repeatedly, or directly evaporate the solvent under reduced pressure, and dry to obtain the 4-diaminenaphthalimide compound hydrochloride;

The compounds of the present invention can be uniformly mixed with pharmacologically acceptable carriers to prepare various forms of pharmaceutical preparations. For example, the compound of the present invention is used as an active ingredient, and water, sucrose, sorbitol sugar, fructose, etc. are prepared into oral liquid preparations; lactose, glucose, sucrose, mannitol sugar, etc. can also be used as excipients, and starch, etc., can be used as disintegrants , with stearic acid, talcum powder, etc. as lubricants, gelatin, polyvinyl alcohol as binders to prepare tablets or capsules; it can also be prepared into injections with physiological saline, glucose solution or a mixed carrier composed of saline and glucose.

After the compound of the present invention is prepared into a pharmaceutical preparation, it can be administered orally or intravenously according to different dosage forms. Dosage also varies with dosage forms. For adults, oral administration of 25-200 mg per day is more appropriate. Intramuscular or intravenous injection of 10 to 100 mg per day is more appropriate.

Description of drawings

Figure 1 is a graph showing the trend of antitumor activity of the compounds of the present invention.

Fig. 2 is a graph showing the trend of antitumor activity of the 4-position diaminenaphthalimide compound of the present invention.

1, 2, 3, 4, 5, 6, and 7 in the abscissas in Figure 1 and Figure 2 represent Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and Compound 7, respectively.

Detailed ways

Example 1:

Synthesis of intermediate N-(N,N-dimethyl-1,3-propanediamino)-1,8-naphthalene anhydride (hereinafter referred to as M1):

Add 4-bromo-1,8-naphthalene anhydride (5.0g, 18.1mmol), N,N-dimethylethylenediamine (2mL, 18.2mmol) to 100ml of absolute ethanol at room temperature; heat to 70- 80°C, keep the reaction for 1-3 hours. The reaction was stopped, cooled to room temperature, and the ethanol was distilled off under reduced pressure to obtain a light yellow solid (M ₁ ).

In order to obtain a purer intermediate, M ₁ can be dissolved with dichloromethane, passed through a silica gel column, and the eluent of dichloromethane/methanol (volume ratio 20/1) is used to obtain 4.8 grams of product (M ₁ ), the yield was 76%.

The prepared _M1 chemical structural formula is:

Proton nuclear magnetic resonance ¹ H NMR data is: ¹ H NMR (600MHz, CDCl ₃ ) δ (ppm) 2.35 (s, 6H, CH ₃ ), 2.66 (t, J=7.2Hz, 2H, CH ₂ ), 4.33 (t , J=7.2Hz, 6H, CH ₃ ), 7.85(t, J=7.8Hz, 1H, Ph), 8.05(d, J=8.4Hz, 1H, Ph), 8.42(d, J=7.8Hz, 1H , Ph), 8.57 (d, J=8.4Hz, 1H, Ph), 8.66 (d, J=7.2Hz, 1H, Ph).

Example 2:

Synthesis of N-(N,N-dimethyl-1,3-propanediamino)-4-ethylenediaminonaphthalimide (compound 1):

Add M ₁ (500mg, 1.4mmol), ethylenediamine (864mg, 14mmol), triethylamine (1mL, 7.0mmol) into 20ml of ethylene glycol monomethyl ether solution at room temperature; heat to 100-150°C , keep the reaction for 10 hours. The reaction was stopped, cooled to room temperature, and ethylene glycol monomethyl ether was evaporated under reduced pressure to obtain a yellow solid. The yellow solid was dissolved in dichloromethane, separated by silica gel column, and the eluent of dichloromethane/methanol/triethylamine (volume ratio 10/1/0.02) was used to obtain 187 mg of the product, and the yield was 40%. The solid Dissolve in 2mL of ethanol and 6M hydrochloric acid solution (volume ratio 1/1), stir at room temperature for 2-12 hours, add 10mL of ethanol, centrifuge at 15,000 rpm, pour out the upper liquid, and wash repeatedly 3 times to obtain N- (N,N-Dimethyl-1,3-propanediamino)-4-ethylenediaminonaphthalimide hydrochloride. The characterization data of the compound before protonation are as follows:

Yellow solid, m.p.174-175°C;

¹ H NMR data

¹ H NMR (600MHz, DMSO) δ(ppm) 2.19(s, 6H, CH ₃ ), 2.45(t, J=6.6Hz, 2H, CH ₂ ), 2.93(t, J=6.0Hz, 2H, CH ₂ ), 3.41(t, J=6.0Hz, 2H, CH ₂ ), 4.09(t, J=6.6Hz, 2H, CH ₂ ), 6.73(d, J=9.0Hz, 1H, Ph), 7.61(t, J=7.8Hz, 1H, Ph), 8.18(d, J=8.4Hz, 1H, Ph), 8.36(d, J=7.2Hz, 1H, Ph), 8.69(d, J=8.4Hz, 1H, Ph ), ¹³ C NMR (150MHz, DMSO) δ37.64, 41.80, 45.81, 45.97, 57.13, 104.27, 108.08, 120.61, 122.20, 124.64, 129.20, 129.84, 131.10, 134.66, 151.25, 163.23; m/z: 327.4 [M+H] ⁺ .

Example 3:

Synthesis of N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalimide (compound 2):

M ₁ (500mg, 1.4mmol), diethylenetriamine (1.44g, 14mmol), triethylamine (1mL, 7.0mmol) were added to 20ml of ethylene glycol monomethyl ether solution at room temperature; heated to 100-150 °C, keep the reaction for 8-12 hours. The reaction was stopped, cooled to room temperature, and ethylene glycol monomethyl ether was evaporated under reduced pressure to obtain a yellow oily liquid that was N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriamine Naphthalimide. Dissolve the yellow oily liquid with dichloromethane/methanol (volume ratio 1/1), and add N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriamine to the reaction system Di-tert-butoxyformic anhydride of 5 times the molar amount of naphthalimide was reacted at room temperature for 0.5-2 hours, the reaction was stopped, the solvent was evaporated under reduced pressure, the residue was passed through a silica gel column, and ethyl acetate/methanol/(volume The eluent of ratio 6/1) obtains product, and then this product is dissolved in the hydrochloric acid solution (volume ratio 1/1) of the ethanol of 2mL and 6M, stirs 2-12 hour at room temperature, adds 10mL ethanol, at 15000 turns Centrifuge down, pour out the upper layer liquid, and wash repeatedly 3 times to obtain a yellow solid, which is dried to obtain 288 mg of N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthoyl Imine hydrochloride, 40% yield over two steps. The characterization data of this compound are as follows:

Yellow solid, mp 192-193°C; ¹ H NMR (600MHz, D ₂ O) δ (ppm) 4.49 (s, 6H, CH ₃ ), 4.87-4.94 (m, 4H, CH ₂ ), 4.97-5.02 (m, 4H, CH ₂ ), 5.29 (t, J=6.6Hz, 2H, CH ₂ ), 5.72 (t, J=6.6Hz, 2H, CH ₂ ), 7.97 (d, J=8.4Hz, 1H, Ph), 8.81 (t, J = 8.4Hz, 1H, Ph) 9.26 (m, 1H, Ph), 9.41-9.42 (m, 2H, Ph), ¹³ C NMR (150MHz, D ₂ O) δ16.85, 35.19, 35.32 ，35.49，39.00，43.20，43.34，43.49，43.63，44.55，46.24，55.48，57.45，104.27，104.47，107.42，119.78，124.73，128.48，128.90，131.43，134.59，150.38，164.22，165.21；MALDI-MS：calcd for C ₂₀ H ₂₇ N ₅ O ₂ Na, 392.2062[M+Na-4HCl] ⁺ ; found 392.2073[M+Na-4HCl] ⁺ .

Example 4:

Synthesis of N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalimide (compound 3):

M ₁ (500mg, 1.4mmol), triethylenetetramine (2.04g, 14mmol), triethylamine (1mL, 7.0mmol) were added to 20ml ethylene glycol monomethyl ether solution at room temperature; heated to 100-150 °C, keep the reaction for 8-12 hours. The reaction was stopped, cooled to room temperature, and ethylene glycol monomethyl ether was evaporated under reduced pressure to obtain a yellow oily liquid. Dissolve yellow oily liquid N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalimide with dichloromethane/methanol (volume ratio 1/1), Add N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalimide 5 times the amount of di-tert-butoxyformic anhydride in the reaction system, at room temperature React for 0.5-2 hours, stop the reaction, evaporate the solvent under reduced pressure, pass the residue through a silica gel column, and obtain the product with an eluent of ethyl acetate/methanol/(volume ratio 6/1), and then dissolve the solid in 2 mL of Ethanol and 6M hydrochloric acid solution (volume ratio 1/1), stirred at room temperature for 2-12 hours, added 10mL of ethanol, centrifuged at 15000 rpm, poured out the upper liquid, washed repeatedly 3 times to obtain a yellow solid, dried to obtain N -(N,N-Dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalimide hydrochloride 291 mg, two-step yield 35%. The characterization data of this compound are as follows:

Brown-yellow solid, mp 192-193°C; ¹ H NMR (600MHz, D ₂ O) δ (ppm) 2.93 (s, 6H, CH ₃ ), 3.31-3.36 (m, 4H, CH ₂ ), 3.41-3.46 (m , 4H, CH ₂ ), 3.49-3.51 (m, 4H, CH ₂ ), 3.77 (t, J=6.0Hz, 2H, CH ₂ ), 4.23 (t, J=6.0Hz, 2H, CH ₂ ), 6.47 (d, J=9.0Hz, 1H, Ph), 7.34(t, J=8.4Hz, 1H, Ph), 7.78(d, J=9.0Hz, 1H, Ph), 7.94-7.96(m, 2H, Ph ), ¹³ C NMR (150MHz, D ₂ O) δ34.79, 35.25, 35.32, 35.49, 39.03, 43.32, 43.43, 43.49, 43.50, 44.62, 44.66, 46.41, 50.36, 50.73, 52.73, 55.63, 104.468, 107 119.69, 120.03, 124.80, 128.71, 128.97, 131.54, 134.69, 150.48, 164.47, 165.44; MALDI-MS: calcd for C ₂₂ H ₃₃ N ₆ O ₂ , 413.2665[M+H-5HCl] ⁺ ; H-5HCl] ⁺ .

Example 5:

Synthesis of N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalimide (compound 4):

At room temperature, M ₁ (500mg, 1.4mmol), tetraethylenepentamine (2.65g, 14mmol), triethylamine (1mL, 7.0mmol) were added to 20 ml of ethylene glycol monomethyl ether solution; the reaction system was heated to 100 -150°C, keep the reaction for 8-12 hours. The reaction was stopped, cooled to room temperature, and ethylene glycol monomethyl ether was evaporated under reduced pressure to obtain a yellow oily liquid that was N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriamine Naphthalimide. Dissolve the yellow oily liquid with dichloromethane/methanol (volume ratio 1/1), and add N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriamine to the reaction system Di-tert-butoxyformic anhydride of 5 times the amount of naphthalimide, reacted at room temperature for 0.5-2 hours, stopped the reaction, evaporated the solvent under reduced pressure, and the residue was passed through a silica gel column, and the mixture was washed with ethyl acetate/methanol/(volume ratio 6/1) eluent to obtain the product, and then the solid was dissolved in 2mL of ethanol and 6M hydrochloric acid solution (volume ratio 1/1), stirred at room temperature for 2-12 hours, added 10mL of ethanol, at 15000 rpm Centrifuge, pour out the upper layer liquid, wash repeatedly 3 times to get a yellow solid, dry to get N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalimide salt Salt 283 mg, two-step yield 30%. The characterization data of this compound are as follows:

Brown-yellow solid, mp 140-141°C; ¹ H NMR (600MHz, D ₂ O) δ (ppm) 2.94 (s, 6H, CH ₃ ), 3.47-3.31 (m, 16H, CH ₂ ), 3.79 (t, J = 6.0Hz, 2H, CH ₂ ), 4.27 (t, J = 6.0Hz, 2H, CH ₂ ), 6.54 (d, J = 9.0Hz, 1H, Ph), 7.39 (d, J = 7.8Hz, 1H, Ph), 7.88 (d, J=9.0Hz, 1H, Ph), 8.04 (d, J=7.8Hz, 1H, Ph); ¹³ C NMR (150MHz, D ₂ O): δ30.32, 35.33, 35.59, 39.10，43.50，43.69，43.78，43.85，44.69，46.42，55.78，104.61，107.92，119.89，120.29，124.96，128.95，129.07，131.72，134.89，150.62，164.71，165.66；MALDI-MS：calcd for C ₂₄ H ₃₈ N ₇ O ₂ , 456.3087 [M+H-6HCl] ⁺ ; found 456.3104 [M+H-6HCl] ⁺ .

Embodiment 6:

Synthesis of N-(N,N-dimethyl-1,3-propylenediamino)-4-propylenediaminonaphthalimide hydrochloride (compound 5):

Add M ₁ (500mg, 1.4mmol), propylenediamine (1.04g, 14mmol), triethylamine (1mL, 7.0mmol) into 20ml of ethylene glycol monomethyl ether solution at room temperature; heat to 100-150°C , keep the reaction for 8-12 hours. The reaction was stopped, cooled to room temperature, and ethylene glycol monomethyl ether was evaporated under reduced pressure to obtain a yellow solid. Dissolve the yellow solid in dichloromethane, pass through a silica gel column, and use the eluent of dichloromethane/methanol/triethylamine (volume ratio 10/1/0.02) to obtain 300 mg of the product with a yield of 63%. The solid dissolves In 2mL of ethanol and 6M hydrochloric acid solution (volume ratio 1/1), stir at room temperature for 2-12 hours, add 10mL of ethanol, centrifuge at 15000 rpm, pour out the upper layer liquid, and wash repeatedly 3 times to obtain N-( N,N-Dimethyl-1,3-propanediamino)-4-propanediaminonaphthalimide hydrochloride. The characterization data of the compound before protonation are as follows:

Yellow oily liquid, ¹ H NMR (600MHz, CDOD) δ (ppm) 1.89-1.94 (m, 2H, CH ₂ ), 2.33 (s, 6H, CH ₃ ), 2.56 (t, J=7.2Hz, 2H, CH ₂ ), 2.85(t, J=7.2Hz, 2H, CH ₂ ), 3.34(t, J=7.2Hz, 2H, CH ₂ ), 4.08(t, J=7.2Hz, 2H, CH ₂ ), 6.41( d, J=9.0Hz, 1H, Ph), 7.28(t, J=8.4Hz, 1H, Ph), 7.92(d, J=8.4Hz, 1H, Ph), 8.06-8.08(m, 2H, Ph) , ¹³ C NMR (150MHz, CDOD) δ32.12, 38.41, 40.50, 42.34, 45.79, 57.77, 104.77, 109.14, 121.36, 122.90, 125.03, 128.84, 130.71, 131.72, 135.45, 152.08, 16 (ES ) m/z: 341.3 [M+H] ⁺ .

Embodiment 7:

Synthesis of N-(N,N-dimethyl-1,3-propanediamino)-4-butanediaminonaphthalimide hydrochloride (compound 6):

Add M ₁ (500mg, 1.4mmol), butanediamine (1.23g, 14mmol), triethylamine (1mL, 7.0mmol) to 20ml of ethylene glycol monomethyl ether solution at room temperature;

The reaction system is heated to 100-150°C and kept for 8-12 hours. The reaction was stopped, cooled to room temperature, and ethylene glycol monomethyl ether was evaporated under reduced pressure to obtain a yellow solid. Dissolve the yellow solid with dichloromethane, pass through a silica gel column, and use the eluent of dichloromethane/methanol/triethylamine (volume ratio 10/1/0.02) to obtain 287 mg of the product, with a yield of 58%. The solid dissolves In 2mL of ethanol and 6M hydrochloric acid solution (volume ratio 1/1), stir at room temperature for 2-12 hours, add 10mL of ethanol, centrifuge at 15000 rpm, pour out the upper liquid, and wash repeatedly 3 times to obtain N-( N,N-Dimethyl-1,3-propanediamino)-4-butanediaminonaphthalimide hydrochloride. The characterization data of the compound before protonation are as follows:

Yellow oily liquid, ¹ H NMR (600MHz, CDOD) δ (ppm) 1.46-1.51 (m, 2H, CH ₂ ), 1.69-1.74 (m, 2H, CH ₂ ), 2.18 (s, 6H, CH ₃ ), 2.44(t, J=7.2Hz, 2H, _CH2 ), 2.59(t, J=6.6Hz, 2H, _CH2 ), 3.34(t, J=6.6Hz, 2H, _CH2 ), 4.08(t, J = 7.2Hz, 2H, CH ₂ ), 6.71 (d, J = 9.0Hz, 1H, Ph), 7.63 (t, J = 7.8Hz, 1H, Ph), 8.20 (d, J = 8.4Hz, 1H, Ph ), 8.37 (d, J=6.6Hz, 1H, Ph), 8.66 (d, J=8.4Hz, 1H, Ph), ¹³ C NMR (150MHz, CDOD) δ18.99, 25.83, 30.97, 37.61, 41.64, 43.25, 45.86, 57.12, 104.13, 107.75, 120.50, 122.17, 124.56, 129.07, 129.86, 131.05, 134.72, 151.13, 163.30, 164.19; MS (ESI) m/z: 355.3 [M+H] ⁺ .

Embodiment 8:

Synthesis of N-(N,N-dimethyl-1,3-propanediamino)-4-pentanediaminonaphthalimide hydrochloride (compound 7):

At room temperature, M ₁ (500mg, 1.4mmol), pentamethylenediamine (1.43mg, 14mmol), triethylamine (1mL, 7.0mmol) were added to 20ml of ethylene glycol monomethyl ether solution; the reaction system was heated to 100- 150°C, keep the reaction for 8-12 hours. The reaction was stopped, cooled to room temperature, and ethylene glycol monomethyl ether was evaporated under reduced pressure to obtain a yellow solid. Dissolve the yellow solid in dichloromethane, pass through a silica gel column, and use the eluent of dichloromethane/methanol/triethylamine (volume ratio 10/1/0.02) to obtain 335 mg of the product with a yield of 63%. The solid dissolves In 2mL of ethanol and 6M hydrochloric acid solution (volume ratio 1/1), stir at room temperature for 2-12 hours, distill off the solvent under reduced pressure to obtain yellow viscous N-(N,N-dimethyl-1, 3-Propanediamino)-4-pentanediaminonaphthalimide hydrochloride. The characterization data of the compound before protonation are as follows:

Yellow oily liquid, ¹ H NMR (600MHz, CDOD) δ (ppm) 1.41-1.45 (m, 4H, CH ₂ ), 1.52-1.50 (m, 2H, CH ₂ ), 1.72-1.70 (m, 2H, CH ₂ ), 2.19 (s, 6H, CH ₃ ), 2.61 (t, J=7.2Hz, 2H, CH ₂ ), 2.65 (t, J=6.6Hz, 2H, CH ₂ ), 3.38 (m, 2H, CH ₂ ), 4.12(t, J=7.2Hz, 2H, CH ₂ ), 6.78(d, J=8.4Hz, 1H, Ph), 7.67(t, J=7.8Hz, 1H, Ph), 8.27(d, J = 8.4Hz, 1H, Ph), 8.43 (d, J = 7.2Hz, 1H, Ph), 8.74 (d, J = 9.0Hz, 1H, Ph), ¹³ C NMR (150MHz, CDOD) δ23.49, 24.04 , 27.76, 26.13, 37.62, 43.06, 45.83, 57.12, 104.20, 107.87, 120.62, 122.25, 124.65, 129.25, 131.14, 134.78, 151.24, 163.36, 164.24 ^] . MS(ESI) m/z[M+H: 369 .

The synthetic route among the embodiment 1-8 is summarized as follows:

Embodiment 9:

Study on antitumor activity of 4-polyamine or diaminenaphthalimide compounds:

experiment method:

The compound synthesized above passed the anti-tumor activity test on four cell lines including liver cancer cell Bel-7402, leukemia cell HL-60, human lung cancer cell A549 and human uterine cancer cell Hela.

The 4-position polyamine and diamine naphthalimide compounds were configured into different concentrations of liquid medicines, and the reduction method of tetrazolium salt was used to treat human liver cancer cells Bel-7402, human leukemia cells HL-60, and human lung cancer cells. A549 and human breast cancer cell Hela were tested. According to different tumor growth rates, a certain number of tumor cells in the logarithmic growth phase were inoculated in a 96-well microculture plate at 90 μL/well, and the prepared drug solution was added after 24 hours of culture. 10 μL/well, for each cell line, each concentration was repeated in four wells, and a corresponding concentration of physiological saline was used as a control; tumor cells were cultured at 37°C and 5% CO ₂ for 48 hours, and MTT solution 5 mg/well was added. Prepare 20 μL/well with normal saline, continue to culture for 4 hours, add 100 μL DMSO to each well, and measure the OD ₅₇₀ value with a microplate reader after fully shaking; Inhibition rate of cell growth:

Tumor inhibition rate=(OD value of control group-OD value of treatment group)/OD value of control group×100%

Furthermore, IC ₅₀ values were calculated from the inhibition ratios.

The results are shown in Table 1.

The _IC50 value of the antitumor activity of the compound of table 1 to Bel-7402, HL-60, A549 and Hela

test results:

The compounds 1-7 have obvious tumor growth inhibitory activity on four cell lines of liver cancer cell Bel-7402, leukemia cell HL-60, human lung cancer cell A549 and human uterine cancer cell Hela. The specific performance is:

(1) The above-mentioned compounds 1-7 have certain selectivity to human lung cancer cell A549 cells, and have good antitumor activity. As can be seen from the _IC50 value, compounds 1, 2, 5, 6, and 7 are all superior to the activity of positive control cisplatin; therefore, compounds 1, 2, 5, 6, and 7 are preferred when used for the preparation of antitumor drug preparations ;

(2) The above compounds 1-7 all have inhibitory effect on leukemia cell line HL-60;

(3) For human lung cancer cell A549 and human uterine cancer cell Hela cell, the activity of compounds 1, 5, 6 and 7 is better than that of compounds 2, 3 and 4;

(4) For liver cancer cells Bel-7402, the antitumor activity of compounds 2, 3 and 4 showed a downward trend with the increase of ethyleneimine groups, (as shown in Figure 1); therefore, when used in the preparation of liver cancer Compounds 2 and 3 are more preferred in pharmaceutical preparations;

(5) For human lung cancer cell A549 and human uterine cancer cell Hela cells, the antitumor activity of compounds 1, 5, 6 and 7 tended to decrease with the growth of carbon chains (as shown in Figure 2); therefore Compounds 1 and 5 are more preferred when used in the preparation of pharmaceutical preparations for the treatment of lung cancer;

(6) Compounds 1, 5, 6 and 7 showed certain selectivity to human lung cancer cell A549 among the four tested cell lines, and the antitumor activity was lower than 4 μM.

Example 10:

N-(N,N-dimethyl-1,3-propanediamino)-4-ethylenediaminonaphthalimide (compound 1) injection:

Take 5000mg of N-(N,N-dimethyl-1,3-propanediamino)-4-ethylenediaminonaphthalimide hydrochloride, dissolve it in 500ml of water to make an aqueous solution, and adjust the pH to 5.5~ 6.5, heat to dissolve, mix evenly, dispense into injections of 100mg/10ml/bottle, and sterilize with steam for 30 minutes.

Example 11:

N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalimide (compound 2) oral solution:

50000mg N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalimide hydrochloride was dissolved in 2000ml water to make a 2.5% aqueous solution, Adjust the pH to 5.5-6.5, heat to dissolve, mix evenly, put into 10ml medicine bottle, seal and sterilize.

Example 12:

N-(N,N-Dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalimide (Compound 3) Tablets:

Get 200g N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriamine naphthalimide hydrochloride, add starch, dextrin, Magnesium stearate, etc., mixed to make wet granules, punched into tablets by machine, each tablet contains N-(N,N-dimethyl-1,3-propanediamino)-4-diethylenetriaminonaphthalene Amine 25 mg.

The pharmaceutical dosage form of the present invention is not limited thereto at all, and it can be prepared into more dosage forms, such as dropping pills, capsules, soft capsules, sustained and controlled release preparations and the like.

Claims (5)

1. a polyamine species naphthalimide compound, its chemical structure of general formula is as follows:

Wherein

。

Described in claim 1 compound in the application of preparing in anti-tumor medicinal preparation.

3. the application of compound in preparation treatment leukemia medicament preparation described in claim 1.

Described in claim 1 compound in the application of preparing in Hepatoma therapy pharmaceutical preparation.

5. the application of compound in preparation treatment uterus carcinoma pharmaceutical preparation described in claim 1.