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Pyranocarbazole alkaloid derivatives, and application thereof in treatment of nervous system diseases

A technology of pyranocarbazole and alkaloids, applied in the field of natural medicine and medicinal chemistry, can solve the problems of neuronal cell apoptosis, dysfunction, destruction of biomolecules, etc., to achieve increased solubility, avoid the risk of toxicity, The effect of improving bioavailability

Active Publication Date: 2021-08-06
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A small amount of ROS is beneficial to the body, but excessive ROS can damage various biomolecules, including DNA, proteins and lipids, and this oxidative damage may lead to mitochondrial dysfunction and neuronal apoptosis

Method used

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  • Pyranocarbazole alkaloid derivatives, and application thereof in treatment of nervous system diseases
  • Pyranocarbazole alkaloid derivatives, and application thereof in treatment of nervous system diseases
  • Pyranocarbazole alkaloid derivatives, and application thereof in treatment of nervous system diseases

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0057] The preparation of intermediate 1 can refer to literature (European Journal of Medicinal Chemistry, 143, (2018) 438-448) and patent (a class of pyranocarbazole alkaloids and their preparation methods, pharmaceutical compositions and uses thereof, application number : 201611213048.6), the synthesis method is as follows:

[0058]

[0059] Wherein (a)~(e) is reaction condition: (a)Pd(OAc) 2 , BINAP, Cs 2 CO 3 , reflux, 3–16h; (b)Pd(OAc) 2 ,AcOH, 60℃, 24h; (c) (BAF, (HF, 0℃~room temperature, 30min; (d) 3-methyl crotonaldehyde, (i(OPr i ) 4 , anhydrous toluene, room temperature; (e) DDQ, mixed solvent methanol-tetrahydrofuran-water, room temperature.

[0060] When R 1 =C(CH 3 ) 3 , R 2 =H, it is intermediate 1a; when R 1 =OCH 3 , R 2 = H, intermediate 1b.

Embodiment 1

[0061] Example 1 Preparation of 8-(tert-butyl)-3,3-dimethyl-5-(4-methylpiperazine-1-methyl)-3,11-dihydropyran[3,2-a ] Carbazole(1)

[0062]

[0063] Intermediate 1a (200mg, 1eq) was dissolved in tetrahydrofuran solution, acetic acid (72mg, 2eq) and N-methylpiperazine (120mg, 2eq) were added, and stirred at room temperature for 0.5h. Then, sodium acetate borohydride (253mg, 2eq) was added thereto to continue the reaction for 5h, and the reaction was stopped. Spin the tetrahydrofuran solution to dryness, add 50ml of ethyl acetate, wash the ethyl acetate layer twice with saturated sodium bicarbonate solution (20ml×2), wash the ethyl acetate layer once with 20ml of saturated brine, dry over anhydrous sodium sulfate, filter, and the filtrate Spin dry to get crude product. Purified by silica gel column chromatography to obtain 198 mg of white powder with a yield of 78.9%.

[0064] 1 H NMR (500MHz, Methanol-d 4 )δ7.95(d, J=2.2Hz, 1H), 7.83(s, 1H), 7.38(dd, J=8.4, 2.2Hz, 1H), ...

Embodiment 2

[0067] Example 2 Preparation of 8-(tert-butyl)-3,3-dimethyl-5-((4-(3-methylbenzyl)piperazin-1-yl)methyl)-3,11-di Hydropyrano[3,2-a]carbazole(2)

[0068] Intermediate 1a (200mg, 1eq), acetic acid (72mg, 2eq), sodium acetate borohydride (253mg, 2eq), 1-(3-methylbenzyl)piperazine (228mg, 2eq), refer to the synthesis of Example 1 Method, 200 mg of white powder was obtained with a yield of 65.7%.

[0069] 1 HNMR (400MHz, Acetone-d 6 )δ10.33(s,1H),8.08(s,1H),8.06(d,J=1.6Hz,1H),7.40(dd,J=1.6,8.8Hz,1H),7.35(d,J=8.8 Hz, 1H), 7.19-7.04(m, 4H), 6.94(d, J=9.8Hz, 1H), 5.78(d, J=9.8Hz, 1H), 3.96(s, 2H), 3.46(s, 2H ),2.85(s,4H),2.61(s,4H),2.28(s,3H),1.47(s,6H),1.40(s,9H).

[0070] 13 C NMR (100MHz, Acetone-d 6 )δ150.8, 143.0, 139.5, 139.4, 138.6, 138.0, 130.7, 130.2, 129.1, 128.7, 127.1, 124.4, 123.7, 123.4, 118.7, 118.5, 116.7, 111.2, 111.61, 105.3, 6.1, 23.1, 77 ,35.3,32.5,28.0,21.5.

[0071] HRESIMS m / z=508.33182[M+H] + (calcd for C 34 h 42 ON 3 ,508.33224).

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Abstract

The invention relates to the field of natural medicines and medicinal chemistry, and discloses pyranocarbazole alkaloid derivatives, a preparation method thereof, a pharmaceutical composition and application of the pyranocarbazole alkaloid derivatives to treatment of nervous system diseases. The alkaloids are prepared in an artificial synthesis mode, pharmacological experiments related to neuroprotection are carried out on the compounds shown in the general formulas I and II, and it is confirmed that the compounds have the application to preparation of drugs for preventing and / or treating various nervous system diseases.

Description

technical field [0001] The invention relates to the fields of natural medicine and medicinal chemistry, in particular to a class of pyrano[3,2-a]carbazole alkaloid derivatives. The invention also discloses the preparation method, pharmaceutical composition and application of the pyrano[3,2-a]carbazole alkaloid derivative in treating various nervous system diseases. Background technique [0002] my country has entered an aging society, and the aging rate is faster than the total population growth rate. The number and proportion of patients with various geriatric diseases are also on the rise. In developed countries, stroke, Alzheimer's disease, Parkinson's disease, depression and other neuropsychiatric diseases have become the third largest killer after cardiovascular disease and cancer. Serious threat to human life and health. In my country, due to the huge population base, the total number of patients with neuropsychiatric diseases has ranked among the top in the world. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/052A61P25/00A61P25/28A61P25/16A61P25/24A61P39/02A61K31/496A61K31/5377
CPCC07D491/052A61P25/00A61P25/28A61P25/16A61P25/24A61P39/02
Inventor 张东明张丹臧应达鲍秀琦李创军马洁臧彩霞刘珂刘慧
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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