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Nitrogen mustard beta-carboline derivatives as well as preparation method and application thereof

A nitrogen mustard and carbolin technology, applied in the field of natural medicine and medicinal chemistry, can solve the problems of lack of specificity in cell action, large toxic and side effects, and unsatisfactory therapeutic effect

Active Publication Date: 2021-10-29
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of drug is widely used clinically, but its toxic and side effects are relatively large, and it lacks specificity for cell action. Moreover, with the occurrence of tumor drug resistance in recent years, the therapeutic effect is not ideal

Method used

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  • Nitrogen mustard beta-carboline derivatives as well as preparation method and application thereof
  • Nitrogen mustard beta-carboline derivatives as well as preparation method and application thereof
  • Nitrogen mustard beta-carboline derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] (1) Dissolve 5 g of compound L-tryptophan 1 (24.51 mmol) in 60 mL of 0.4 N NaOH solution, then add 3 mL of 37% formaldehyde solution (36.97 mmol), and react at 37° C. for three days. TLC monitors, reaction is substantially complete, cools down, then adds glacial acetic acid, has precipitation generation, suction filtration, drying, obtains intermediate 2a (R 1 =-H) 4.64 g. Dissolve 4.64g of intermediate 2a (21.48mmol) in 50mL of anhydrous methanol, and add 3.68mL of SOCl dropwise under ice-bath conditions 2 (50.67mmol), and then reflux at 65°C for 6h. Monitored by TLC, the reaction was complete, cooled, concentrated the reaction liquid, then added 50mL saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, washed 1 time with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the intermediate 3a 3.5g. 3.5g of intermediate 3a (15.22mmol) was dissolved in 65mL of DMF, 7g of potassium permanganate ...

Embodiment 2

[0034]

[0035]The step of synthesizing 2a in step (1) of Example 1 is replaced by: dissolving 5g compound L-tryptophan 1 (24.51mmol) in 80mL 1,2-dichloroethane, then adding 1.52mL acetaldehyde (26.96mmol ), 3.64mL trifluoroacetic acid (49.02mmol), reflux at 110°C for 30min. TLC monitors, reaction is substantially complete, cooling, then add saturated sodium bicarbonate solution and saturated brine to wash reaction solution 1 time, dry over anhydrous sodium sulfate, filter, concentrate, obtain intermediate 2b (R 1 =-CH 3 ).

[0036] The remaining steps were prepared according to the synthetic method of Example 1 to obtain compound 8b, a yellow-white solid, with a yield of 13%. 1 HNMR (400MHz, CDCl 3 )δ:8.73(s,1H),8.19(s,1H),8.09(d,J=7.88Hz,1H),7.89(s,1H),7.56(m,2H),7.30(m,1H), 6.83(d, J=8.64Hz, 2H), 6.34(d, J=8.72Hz, 2H), 6.16(d, J=7.68Hz, 1H), 5.52(d, J=12.04Hz, 1H), 5.42( d, J=12.00Hz, 1H), 5.01(m, 1H), 3.51(m, 4H), 3.45(m, 4H), 3.09(m, 2H), 2.85(s, 3H); 13 C NMR (1...

Embodiment 3

[0038]

[0039] The step of synthesizing 2a in step (1) of Example 1 was replaced by: dissolving 5 g of compound L-tryptophan 1 (24.51 mmol) in 80 mL of 1,2-dichloroethane, and then adding 3.27 mL of p-methoxybenzene Formaldehyde (26.96mmol), 3.64mL trifluoroacetic acid (49.02mmol), reflux at 110°C for 30min. TLC monitors that the reaction is substantially complete, cooled, then added saturated sodium bicarbonate solution and saturated brine to wash the reaction solution once, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 2c (R 1 =p-CH 3 OPh-).

[0040] Referring to Example 1 for the rest of the steps, compound 8c was prepared as a yellow solid with a yield of 10%. 1 H NMR (400MHz, CDCl 3 )δ:8.63(s,1H),8.21(s,1H),8.16(d,J=7.92Hz,1H),8.00(s,1H),7.92(d,J=8.68Hz,2H),7.57( m, 2H), 7.34(m, 1H), 7.10(d, J=8.40Hz, 2H), 6.86(d, J=8.60Hz, 2H), 6.33(d, J=8.60Hz, 2H), 6.14( s,1H),5.64(d,J=12.04Hz,1H),5.50(d,J=12.08Hz,1H),5.04(m,1H),3.89(s,...

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Abstract

The invention discloses nitrogen mustard beta-carboline derivatives and application thereof, and belongs to the field of natural medicines and medicinal chemistry. The invention particularly relates to a preparation method of a series of nitrogen mustard beta-carboline derivatives with anti-tumor activity and novel application of the nitrogen mustard beta-carboline derivatives in the aspect of anti-tumor drugs. The nitrogen mustard beta-carboline derivatives and the pharmaceutically acceptable salt of the nitrogen mustard beta-carboline derivatives are shown as a general formula I in the description, wherein R1 and R2 are as described in the claims and the description.

Description

technical field [0001] The invention belongs to the field of natural medicine and medicinal chemistry, relates to a class of nitrogen mustard β-carbolin derivatives and their applications, and specifically relates to a series of preparation methods and methods for nitrogen mustard β-carbolin derivatives with antitumor activity Use in antitumor. Background technique [0002] β-carboline alkaloid (β-carboline) was first isolated from Peganum harmala L. in 1841 and has good antitumor activity. It mainly inhibits tumor cell proliferation and induces apoptosis through three mechanisms of action. First of all, β-carbolin alkaloids can interact with DNA and change DNA replication; in addition, it can inhibit cyclin-dependent kinases, topoisomerases and monoamine oxidase; finally, it is effective against benzodiazepines and 5- Receptors such as serotonin have high affinity. Many researchers have modified the structure of β-carbolin alkaloids to obtain anti-tumor candidate compoun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00
CPCC07D471/04A61P35/00
Inventor 李达翃华会明孙迦南续繁星李昊楠方豫喜
Owner SHENYANG PHARMA UNIVERSITY
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