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Novel heptacyclic compound as well as synthesis, activity rating and application thereof

A technology for cyclic compounds and drugs, which is applied in the fields of new heptacyclic compounds, its synthesis, activity evaluation and application, and can solve problems such as reduction

Inactive Publication Date: 2018-02-13
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the effective dose of β-carboline, for example, the effective dose of 3S-3-carboxy-1,2,3,4-tetrahydro-β-carboline is as high as 5 μmol / kg, which still needs to be reduced.

Method used

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  • Novel heptacyclic compound as well as synthesis, activity rating and application thereof
  • Novel heptacyclic compound as well as synthesis, activity rating and application thereof
  • Novel heptacyclic compound as well as synthesis, activity rating and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Preparation of 1S, 3S-1-methyl-3-carboxy-1,2,3,4-tetrahydro-β-carboline

[0021] To 5.0g (24.5mmol) L-Trp, 25ml H 2 SO 4 Add 8ml of acetaldehyde (36-38%) to the compound of (1M) and 80ml of water. The reaction compound was stirred at room temperature for 2 h, adjusted to pH 7 with concentrated ammonia water, placed at 0°C for 12 h, and the resulting precipitate was filtered out. After recrystallization from acetone, 3.97 g (75%) of the title compound were obtained as colorless crystals. Mp:280-282℃; ESI / MS:217[M+H] + ;IR(KBr):3450,3200,3000,2950,2850,1700,1601,1452,1070,900cm -1 ; 1 HNMR (BHSC-500, DMSO-d6): δ10.99(s, 1H), 9.89(s, 1H), 7.30(t, J=7.5Hz, 1H), 7.22(t, J=8.0Hz, 1H) ,7.01(d,J=8.0Hz,1H),6.81(d,J=7.5Hz,1H),4.01(t,J=4.8Hz,1H),3.75(dd,J=10.5Hz,J=5.0Hz , 1H), 3.64 (dd, J=10.5Hz, J=2.4Hz, 1H), 2.91 (d, J=10.5Hz, 2H), 2.86 (s, 1H).

Embodiment 2

[0022] Embodiment 2 prepares ZMC

[0023] To 648mg (3mmol) 1S, 3S-1-methyl-3-carboxy-1,2,3,4-tetrahydro-β-carboline, 573mg (3mmol) EDC, 405mg (3mmol) HOBt and 20mL dry DMF The mixture was adjusted to pH 9 by adding 0.3 mL N-methylmorpholine. The reaction mixture was stirred at room temperature for 12 h, TLC (CH 2 Cl 2 / CH 3 OH, 15 / 1) indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure at 45 °C, and the residue was repeatedly triturated with water and acetone, and then purified by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH, 30 / 1), yielding 535 mg (90%) of the title compound as a colorless powder. FT-MS 425.19719[M+H] + . 1 H NMR (500MHz, DMSO): δ=11.054(s, 2H), 7.557(d, J=8.0Hz, 2H), 7.359(d, J=8.0Hz, 2H), 7.083(t, J=8.0Hz, 2H), 7.021(t, J=8.0Hz, 2H), 5.356(q, J=6.5Hz, 2H), 4.305(dd, J=12.0Hz, J=4.0Hz, 2H), 3.501(dd, J= 16.0Hz, J=4.0Hz, 2H), 2.931(dd, J=16Hz, J=12Hz, 2H), 1.453(t, J=6.5Hz, 2H). 13 C NMR (125 MH...

Embodiment 3

[0024] Embodiment 3 evaluates the antitumor activity of ZMC

[0025] 1) Suspend ZMC with 0.5% CMCNa, dissolve doxorubicin in normal saline as a positive control, and use 0.5% CMCNa as a negative control;

[0026] 2) Mice treated with ZMC and 0.5% CMCNa were intragastrically administered, the dosage of ZMC was 0.1, 0.01 and 0.001 μmol / kg, the dosage of 0.5% CMCNa was 0.2mL / 20g, and the dosage of doxorubicin The dose was 2μmol / kg, and it was administered continuously for 11 days, with a total of 11 administrations.

[0027] 3) The experimental animals are ICR male mice (clean grade), weighing 20±2g, with 12 mice in each group.

[0028] 4) The tumor source is mouse S180 sarcoma, which was purchased from the Animal Experiment Center of Peking University Health Science Center and maintained by self-passaging.

[0029] 5) Inoculate vigorously growing S180 ascites tumor fluid under sterile conditions, dilute it with normal saline (1:2) and mix thoroughly, stain the tumor cell suspe...

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Abstract

The invention discloses a novel heptacyclic compound (2'S,5'S)-tetrahydropyrazine[1',2':1,6]bis{(1S)-1-methyl-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]diindole}-1',4'-diketone (ZMC for short), discloses apreparation method thereof, discloses an anti- thrombosis function thereof, discloses an anti-inflammation effect thereof, disclosed an anti-tumor effect thereof, and further discloses a free radicalscavenging effect and a P-selectin expression inhibiting effect thereof. Thus, the invention discloses application of the ZMC to preparation of a P-selectin-targeted medicament capable of inhibitingthrombosis, inflammation and tumors. Since the thrombosis and the inflammation are most common complications of tumor patients, the ZMC disclosed by the invention can be used for not only treating thetumors, but also preventing the complications of the thrombosis and the inflammation in the tumor patients. The ZMC disclosed by the invention has a good clinical application prospect.

Description

field of invention [0001] The present invention relates to a novel seven-ring compound (2'S,5'S)-tetrahydropyrazine [1',2':1,6]bis{(1S)-1-methyl-2,3,4,9-tetrahydro -1H-pyridine[3,4-b]indole}-1',4'-dione (ZMC for short), related to its preparation method, related to its antithrombotic effect, related to its anti-inflammatory effect, related to Its anti-tumor effect further involves its free radical scavenging effect and the effect of inhibiting the expression of P-selectin. Therefore, the present invention relates to the application of ZMC in the preparation of drugs targeting P-selectin for inhibiting thrombus, inflammation and tumors. Since thrombus and inflammation are the most common complications of tumor patients, the ZMC of the present invention can not only treat tumors, but also prevent tumor patients from concurrent thrombosis and inflammation. The ZMC of the present invention has a good clinical application prospect. The invention belongs to the field of biomedici...

Claims

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Application Information

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IPC IPC(8): C07D471/22A61P35/00A61P7/02A61P29/00A61P39/06A61P9/10
CPCC07D471/22
Inventor 赵明彭师奇朱海梅
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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