3-position derivatives of beta-carboline as well as preparation method and application of 3-position derivatives

A technology of carbolin and its derivatives, which is applied in the field of natural medicine and medicinal chemistry, can solve the problems of side effects and drug resistance, and achieve the effect of anti-tumor cell proliferation

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

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Problems solved by technology

However, the use of large doses of nitrogen mustard will cause serious si

Method used

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  • 3-position derivatives of beta-carboline as well as preparation method and application of 3-position derivatives
  • 3-position derivatives of beta-carboline as well as preparation method and application of 3-position derivatives
  • 3-position derivatives of beta-carboline as well as preparation method and application of 3-position derivatives

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 3a3.5g. 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 monitoring showed that the reaction was almost 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 2b (R 1 =-CH 3 ).

[0036] The remaining steps were prepared according to the synthetic method of Example 1 to obtain compound 9b, an orange solid, with a yield of 13%. 1 HNMR (400MHz, CDCl 3 )δ:8.40(s,1H),8.11(d,J=7.80Hz,1H),7.89(s,1H),7.54(m,2H),7.29(m,1H),6.94(d,J=8.72 Hz,2H),6.55(d,J=8.76Hz,2H),6.10(d,J=7.76Hz,1H),5.38(s,2H),4.82(m,1H),3.71(s,3H), 3.67(m,4H),3.59(m,4H),2.99(m,2H),2.82(s,3H),2.76(m,2H),2.55(m,2H); 13 C NMR (100MHz, CDCl ...

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 monitoring showed that the reaction was almost 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] The remaining steps were prepared according to the synthetic method of Example 1 to obtain compound 9c, a yellow-white solid, with a yield of 8%. 1 H NMR (400MHz, CDCl 3 )δ: 8.69(s, 1H), 8.15(d, J=7.92Hz, 1H), 7.97(s, 1H), 7.87(d, J=8.76Hz, 2H), 7.53(m, 1H), 7.48( d,J=8.08Hz,1H),7.29(m,1H),7.06(d,J=8.76Hz,2H),6.92(d,J=8.68Hz,2H),6.53(d,J=8.76Hz, 2H), 6.10(d, J=7.76Hz, 1H), 5.4...

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Abstract

The invention discloses 3-position spliced nitrogen mustard derivatives of beta-carboline as well as a preparation method and application of the 3-position spliced nitrogen mustard derivatives, and belongs to the field of natural medicines and medicinal chemistry. The invention particularly relates to a preparation method of a series of 3-position spliced nitrogen mustard derivatives of beta-carboline with antitumor activity and novel application of the derivatives in antitumor drugs. The3-position spliced nitrogen mustard derivatives of beta-carboline and the pharmaceutically acceptable salt of the derivatives disclosed by the invention are shown as a general formula I defined in the description, wherein R1 and n are described in the claims and the description.

Description

technical field [0001] The invention belongs to the field of natural medicine and medicinal chemistry, and relates to a class of β-carbolin 3-position nitrogen mustard derivatives and their applications, in particular to a series of β-carbolin 3-position nitrogen mustard derivatives with antitumor activity The preparation method and its application in antitumor. Background technique [0002] β-carboline alkaloid (β-carboline) is composed of an indole ring and a pyridine ring, and has various pharmacological activities, including antispasmodic, anxiolytic, antidepressant, anticonvulsant, sedative, analgesic, and antimalarial , anti-parasites, etc., especially have good anti-tumor activity. Although β-carbolin alkaloids have the potential to be developed as tumor chemotherapy drugs, there are still problems, so many researchers have modified the structure of β-carbolin alkaloids. The purpose is to obtain anti-tumor candidate compounds with stronger activity, lower toxicity a...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P35/00
CPCC07D471/04A61P35/00
Inventor 李达翃华会明孙迦南王艳冰王茗莹侯永莲
Owner SHENYANG PHARMA UNIVERSITY
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