Indolylmaleimide compound substituted with 3-amino alcohol, preparation method and application thereof

Abstract

The invention relates to an indolylmaleimide compound substituted with 3-amino alcohol, a preparation method and application thereof. The structure general formula of the compound is shown as follow, and the characteristic is a solid from light yellow to red. The preparation method comprises the step of reacting 3-bromine-4-indolylmaleimide with various substituted amines in the presence of N,N-dimethyl fomamide and triethylamine at 80-95 DEG C to obtain the indolylmaleimide compound, thereby being suitable for industrialized production. The compound is a protein kinase C inhibitor, therefore, the invention has a stronger tumor function for cells such as Hela, SMMC 7721, and the like in vitro, has an important function for preventing and treating the tumor and is prepared by a simple preparation method.

Description

technical field

[0001] The invention belongs to the field of indole maleimide compounds, their preparation and application, in particular to 3-aminoalcohol substituted indole maleimide compounds, their preparation and application. Background technique

[0002] In recent years, with the improvement of people's living standards, the acceleration of industrial modernization, the widespread use of chemicals in the fields of food, cosmetics and materials, and the aggravation of environmental pollution, the incidence of malignant tumors such as gastric cancer, lung cancer, leukemia and breast cancer has increased rapidly. rising trend year by year. At present, antineoplastic drugs such as cyclophosphamide (Cyclophosphamide), cisplatin (Cisplatin), fluorouracil (Fluorouracil), doxifluridine (Doxifluridine) and folic acid antineoplastic drugs such as methotrexate (methotrexate) used in clinical etc. have the disadvantages of toxicity and lack of broad-spectrum anti-tumor effect. ...

Examples

Embodiment 13

[0028] Example 13-(1H-indole-3)-4-(2-hydroxyethylamino)-1-methyl-1H-pyrrole-2,5-dione

[0029]

[0030] 2-bromo-3-(1H-indole-3)-N-methylmaleimide 0.5g (1.64mmol), ethanolamine 0.17g (2.8mmol), DMF 5mL, triethylamine 0.2g (1.98 mmol), react at 100°C for 10 hours, cool to room temperature, add 20mL of water, extract with ethyl acetate (20mL×3), combine the organic phases, wash with water, anhydrous Na 2 SO 4 After drying, the solvent was spin-dried and separated by column chromatography [V (ethyl acetate): V (petroleum ether) = 1:2-1:1] to obtain 0.28 g of a dark red solid with a yield of 61%.

[0031]The properties of 3-(1H-indole-3)-4-(2-hydroxyethylamino)-1H-pyrrole-2,5-dione are as follows:

[0032] This product is light red crystal, m.p.: 219~221℃.

[0033] IR(KBr): 3456, 3279, 1683, 1632, 1609, 1540, 1455, 1386, 1080, 746cm -1 ; 3456cm in the IR spectrum -1 Nearby are the absorption peaks of N-H stretching vibration on indole, 1683 and 1632 cm -1 C=O stretching vi...

Embodiment 23

[0036] Example 23-(1H-indole-3)-4-(2-hydroxyethylamino)-1H-pyrrole-2,5-dione

[0037]

[0038] 2-Bromo-3-(1H-indole-3)-maleimide 0.5g (1.7mmol), ethanolamine 0.13g (2.2mmol), DMF 5mL, triethylamine 0.2g (1.98mmol) were put into React at 100°C for 10 hours, cool to room temperature, add 20 mL of water, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with water, anhydrous Na 2 SO 4 After drying, the solvent was spin-dried, and then [V (ethyl acetate): V (petroleum ether)=1:2~1:1] was used as the eluent to carry out column chromatography to obtain 0.36g of dark red solid, yield 78% , m.p.: 178℃~180℃.

[0039] IR(KBr): 3461, 3316, 3218, 2930, 1699, 1644, 1550, 1358, 1056cm -1 ; 1 H NMR (400MHz, DMSO-d 6 , δppm): 3.06 (t, 2H, CH 2 ), 3.19(t, 2H, CH 2 ), 4.60(s, 1H, OH), 6.71(s, 1H, NH), 6.98(m, 1H, Ar-H), 7.07(m, 1H, Ar-H), 7.29(m, 1H, Ar-H) H), 7.38 (m, 2H, Ar-H), 10.34 (s, 1H, NH), 11.22 (s, 1H, NH); MS (EI) m / e: [M] + 271, 240, 197, 155, 129, 9...

Embodiment 33

[0040] Example 33-(1H-indole-3)-4-(3-hydroxypropylamino)-1H-pyrrole-2,5-dione

[0041]

[0042] 0.5g (1.7mmol) 3-bromo-4-(1H-indole-3)-N-methylmaleimide, 0.16g (2.1mmol) n-propanolamine, 5mL N,N-dimethylmethane Amide (DMF) and 0.2g (1.98mmol) triethylamine were added to a stirred round-bottomed flask in turn, reacted at 85°C for 10 hours, cooled to room temperature, added 20mL of water, extracted with ethyl acetate (20mL×3) , combined organic phases, washed with water, anhydrous Na 2 SO 4 After drying and spin-drying the solvent, column chromatography was performed with petroleum ether:ethyl acetate (1:1) as the eluent to obtain 0.35 g of a dark red solid, yield 71%, mp: 154-156°C. IR(KBr): 3385, 1709, 1655, 1550, 1355, 1066cm -1 ; 1 HNMR (400MHz, DMSO-d 6 , δppm): 1.32 (m, 2H, CH 2 ), 3.08(m, 4H, 2CH 2 ), 4.33(s, 1H, OH), 6.98(m, 2H, NH, Ar-H), 7.06(m, 1H, Ar-H), 7.27(m, 1H, Ar-H), 7.36(m, 2H, Ar-H), 10.31 (s, 1H, NH), 11.19 (s, 1H, NH); MS (EI) m / e: [M] + 285, 26...

technical field

[0001] The invention belongs to the field of indole maleimide compounds, their preparation and application, in particular to 3-aminoalcohol substituted indole maleimide compounds, their preparation and application. Background technique

[0002] In recent years, with the improvement of people's living standards, the acceleration of industrial modernization, the widespread use of chemicals in the fields of food, cosmetics and materials, and the aggravation of environmental pollution, the incidence of malignant tumors such as gastric cancer, lung cancer, leukemia and breast cancer has increased rapidly. rising trend year by year. At present, antineoplastic drugs such as cyclophosphamide (Cyclophosphamide), cisplatin (Cisplatin), fluorouracil (Fluorouracil), doxifluridine (Doxifluridine) and folic acid antineoplastic drugs such as methotrexate (methotrexate) used in clinical etc. have the disadvantages of toxicity and lack of broad-spectrum anti-tumor effect. ...

Examples

Embodiment 13

[0028] Example 13-(1H-indole-3)-4-(2-hydroxyethylamino)-1-methyl-1H-pyrrole-2,5-dione

[0029]

[0030] 2-bromo-3-(1H-indole-3)-N-methylmaleimide 0.5g (1.64mmol), ethanolamine 0.17g (2.8mmol), DMF 5mL, triethylamine 0.2g (1.98 mmol), react at 100°C for 10 hours, cool to room temperature, add 20mL of water, extract with ethyl acetate (20mL×3), combine the organic phases, wash with water, anhydrous Na 2 SO 4 After drying, the solvent was spin-dried and separated by column chromatography [V (ethyl acetate): V (petroleum ether) = 1:2-1:1] to obtain 0.28 g of a dark red solid with a yield of 61%.

[0031]The properties of 3-(1H-indole-3)-4-(2-hydroxyethylamino)-1H-pyrrole-2,5-dione are as follows:

[0032] This product is light red crystal, m.p.: 219~221℃.

[0033] IR(KBr): 3456, 3279, 1683, 1632, 1609, 1540, 1455, 1386, 1080, 746cm -1 ; 3456cm in the IR spectrum -1 Nearby are the absorption peaks of N-H stretching vibration on indole, 1683 and 1632 cm -1 C=O stretching vi...

Embodiment 23

[0036] Example 23-(1H-indole-3)-4-(2-hydroxyethylamino)-1H-pyrrole-2,5-dione

[0037]

[0038] 2-Bromo-3-(1H-indole-3)-maleimide 0.5g (1.7mmol), ethanolamine 0.13g (2.2mmol), DMF 5mL, triethylamine 0.2g (1.98mmol) were put into React at 100°C for 10 hours, cool to room temperature, add 20 mL of water, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with water, anhydrous Na 2 SO 4 After drying, the solvent was spin-dried, and then [V (ethyl acetate): V (petroleum ether)=1:2~1:1] was used as the eluent to carry out column chromatography to obtain 0.36g of dark red solid, yield 78% , m.p.: 178℃~180℃.

[0039] IR(KBr): 3461, 3316, 3218, 2930, 1699, 1644, 1550, 1358, 1056cm -1 ; 1 H NMR (400MHz, DMSO-d 6 , δppm): 3.06 (t, 2H, CH 2 ), 3.19(t, 2H, CH 2 ), 4.60(s, 1H, OH), 6.71(s, 1H, NH), 6.98(m, 1H, Ar-H), 7.07(m, 1H, Ar-H), 7.29(m, 1H, Ar-H) H), 7.38 (m, 2H, Ar-H), 10.34 (s, 1H, NH), 11.22 (s, 1H, NH); MS (EI) m / e: [M] + 271, 240, 197, 155, 129, 9...

Embodiment 33

[0040] Example 33-(1H-indole-3)-4-(3-hydroxypropylamino)-1H-pyrrole-2,5-dione

[0041]

[0042] 0.5g (1.7mmol) 3-bromo-4-(1H-indole-3)-N-methylmaleimide, 0.16g (2.1mmol) n-propanolamine, 5mL N,N-dimethylmethane Amide (DMF) and 0.2g (1.98mmol) triethylamine were added to a stirred round-bottomed flask in turn, reacted at 85°C for 10 hours, cooled to room temperature, added 20mL of water, extracted with ethyl acetate (20mL×3) , combined organic phases, washed with water, anhydrous Na 2 SO 4 After drying and spin-drying the solvent, column chromatography was performed with petroleum ether:ethyl acetate (1:1) as the eluent to obtain 0.35 g of a dark red solid, yield 71%, mp: 154-156°C. IR(KBr): 3385, 1709, 1655, 1550, 1355, 1066cm -1 ; 1 HNMR (400MHz, DMSO-d 6 , δppm): 1.32 (m, 2H, CH 2 ), 3.08(m, 4H, 2CH 2 ), 4.33(s, 1H, OH), 6.98(m, 2H, NH, Ar-H), 7.06(m, 1H, Ar-H), 7.27(m, 1H, Ar-H), 7.36(m, 2H, Ar-H), 10.31 (s, 1H, NH), 11.19 (s, 1H, NH); MS (EI) m / e: [M] + 285, 26...

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