CN109535157A - A kind of half calycanthine analog, its preparation method and use - Google Patents

A kind of half calycanthine analog, its preparation method and use Download PDF

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CN109535157A
CN109535157A CN201811465098.2A CN201811465098A CN109535157A CN 109535157 A CN109535157 A CN 109535157A CN 201811465098 A CN201811465098 A CN 201811465098A CN 109535157 A CN109535157 A CN 109535157A
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calycanthine
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郑绍军
朱瑞
魏洋
韩珂
唐冰
蔡星伟
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Jiangsu University of Science and Technology
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Abstract

The present invention relates to the purposes of a kind of half calycanthine analog, its synthetic method and its acetylcholine esterase inhibition activity.The preparation method of the half calycanthine analog is with 9- methyl-1 2,3,4,9,9a-6 hydrogen -4aH- pyridos [2,3-b] indoles -4a- alcohol be substrate, anhydrous pyridine dissolution is added, reaction reagent organic acid or acid anhydrides is slowly added dropwise, to fully reacting, quencher quenching reaction is added, it is concentrated under reduced pressure and removes methanol and pyridine, synthesis technology is simple, product purity is high, is able to suppress acetylcholine esterase active.

Description

A kind of half calycanthine analog, its preparation method and use
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to half calycanthine analog, its synthetic method and its application.
Background technique
A kind of cause of disease of Alzheimer disease (Alzheimer Disease, AD) and pathogenesis not yet illustrate completely Neurodegenerative disease shows as forfeiture, cognitive disorder and the personality change of decrease of memory and daily behavior ability.It is shadow The important diseases for ringing elderly population health, there is no effective prevention and treatment method at present.
Zhang Linlin etc. is summarized in terms of the pathogenesis of AD and therapeutic agent two: pathogenesis includes and microenvironment phase The A beta amyloid peptide cascade hypothesis of pass, cholinergic damage theory, dysimmunity theory etc., Tau albumen relevant to neuron Hypothesis, nerve cell apoptosis theory etc., 2 gene of 4 gene of apolipoprotein ε, presenilin 1 and presenilin, starch with gene-correlation Sample precursor protein gene etc.；Its drug therapy has western medicine, including acetylcholinesterase inhibitor, reduction beta-amyloid protein Generation, deposition of medicament, the antioxidant etc. of (A β)；Chinese medicine treatment, including deficiency tonifying kind drug, drug for invigorating blood circulation and eliminating stasis, resolving sputum and relieving asthma medicine Deng.
The researchs such as Ellman are a kind of methods for quickly measuring acetylcholinesterase inhibitor.Its principle are as follows: acetyl gallbladder Alkali esterase hydrolyzed substrate Butyryl thiocholine (acetylthiocholine), the product thiocholine of generation again with color developing agent two Sulphur dinitrobenzoic acid (DTNB) [5,5 '-dithiobis- (2-nitrobenzoic acid)] reaction is generated to be had at 410nm The compound 2- nitro -5- mercaptobenzoic acid (5-thio-2-nitrobenzoic acid) of characteristic absorption, by measuring 410nm The increment of the absorbance at place can be with the activity of indirect determination acetylcholinesterase.After the technology is reported for the first time to be come out, using can See that spectrophotometer and the activity of microplate reader measurement acetylcholinesterase inhibitor are used widely.On the basis of the technology On, the compound with choline enzyme inhibition activity can also be screened using TLC bioautography.
Acetylcholinesterase inhibitor is still the first-line drug for treating AD at present.Wherein Tacrine, donepezil, kappa are drawn Spit of fland and galanthamine are U.S. FDA approval drug.Wherein donepezil (Donepezil) is for treating light-moderate AD, centering The acetylcholinesterase of pivot nervous system has higher selectivity, inhibits the active duration of enzyme long and makees without periphery With central nervous system acetylcholine concentration can be significantly improved, so as to improve cognitive function.Rivastigmine energy Selective long-range DEPT brain The acetylcholine activity at the positions such as cortex and hippocampus, and the formation of APP can be slowed down.There are also Rivastigmines for other drugs (Rivastigmine), tor alkali first (Huperzine A), eserine (Physotigmine) and its derivative.
The degradation of limitation acetylcholine is to improve its active drug such as eserine: eserine is classical cholinesterase Inhibitor can increase the concentration of synaptic cleft acetylcholine after, improve central cholinergic system activity, improve the disease of AD patient Shape.Huperzine (Huperzine A) is that Shanghai Pharmaceutical Inst., Chinese Academy of Sciences therefrom extracts in studies on Huperzia serrata A kind of alkaloid is the drug of the pioneering treatment AD most promising at present in China.
Summary of the invention
For overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of half calycanthine analog, the half wax plums Alkali analog has good inhibitory activity to acetylcholinesterase.
In order to achieve the above-mentioned object of the invention, present invention employs technical solutions below:
The half calycanthine analog with logical formula (I):
The synthetic route of the half calycanthine analog with formula (I) is as follows:
The R1For following group any one:
Specifically, the synthesis technology of the half calycanthine analog with formula (I), steps are as follows:
Anhydrous pyridine is added in substrate 9- methyl-1,2,3,4,9,9a-6 hydrogen -4aH- pyrido [2,3-b] indoles -4a- alcohol Dissolution, then reaction reagent is slowly added dropwise thereto, TLC tracing detection is added dropwise methanol into reaction solution and is quenched instead to fully reacting It answers, is concentrated under reduced pressure and removes methanol and pyridine, merge organic phase, be concentrated under reduced pressure, crude product uses column chromatography, and obtains half calycanthine Analog.
Used reaction reagent be acetic anhydride, propionic andydride, butyric anhydride, isobutyric anhydride, valeric acid, caproic acid, enanthic acid, octanoic acid, O-fluorobenzoic acid, m-fluorobenzoic acid, parafluorobenzoic acid, meta-toluic acid, paratolunitrile or benzoic acid.
With structure, simple, raw material is easy to get half calycanthine analog provided by the invention, and reaction condition is mild, simple process The characteristics of, there is acetylcholine esterase inhibition activity, when sample concentration is 1mg/mL, the IC of compound 2 and 1150Value is respectively 0.01,0.13ng/mL has excellent application prospect.
Specific embodiment
Below with reference to embodiment, elaborate to the present invention.
Embodiment 1Synthesis
200mg substrate 9- methyl-1 is weighed, 2,3,4,9,9a-6 hydrogen -4aH- pyrido [2,3-b] indoles -4a- alcohol are placed in In 50mL dry round-bottomed flask, the anhydrous pyridine stirring and dissolving of 5mL is added, system is placed in 0 DEG C of ice-water bath, thereto Reaction reagent 0.07mL (0.72mmol) acetic anhydride is slowly added dropwise, wait be added dropwise completely, moves to room temperature, TLC tracing detection, wait react Completely, proper amount of methanol quenching reaction is added dropwise into reaction solution, is concentrated under reduced pressure and removes methanol and a small amount of pyridine, then extracted with ethyl acetate It takes 3 times, merges organic phase, successively with saturation CuSO4Solution washs 3 times, and saturation NaCl solution is washed 3 times, anhydrous Na SO4It is dry. It is concentrated under reduced pressure, crude product uses column chromatography (PE:EA=6:1), obtains N acetyl derivatives 1 (96%) of 216mg.
Characters Identification: colorless oil,1H-NMR(400MHz,CDCl3),δ7.34–7.14(m,2H),6.90–6.47(m, 2H), 5.24 (s, 1H), 4.45-3.57 (m, 1H), 3.31-3.22 (m, 1H), 2.81 (ddd, J=13.2,8.5,4.8Hz, 1H), 2.64 (d, J=27.4Hz, 3H), 2.19 (d, J=11.1Hz, 3H), 2.02-1.71 (m, 2H), 1.70-1.22 (m, 2H).13C NMR(100MHz,CDCl3)δ172.30(C),149.52(C),133.33(C),129.52(CH),129.36(CH), 122.05(CH),119.11(CH),108.34(CH),86.45(C),41.96(CH2),37.14(CH3),33.31(CH2), 22.14(CH3),19.02(CH2).MS(ESI(+))calcd for C14H18N2O2[M+H]+:246.3；found:247.0.
Chemical reagent used by embodiment 2-14 difference from Example 1 is is different, specific as shown in table 1:
The physicochemical constant of 1 half calycanthine analog of table
Embodiment 2
Synthesis
Colorless oil,1H-NMR(400MHz,CDCl3),δ7.34–7.04(m,2H),6.86–6.46(m,2H),5.30(s, 1H), 4.45-3.63 (m, 1H), 3.29-3.17 (m, 1H), 2.81 (ddd, J=13.1,8.3,4.8Hz, 1H), 2.64 (d, J= 25.6Hz, 3H), 2.58-2.34 (m, 2H), 1.96-1.72 (m, 2H), 1.67-1.24 (m, 2H), 1.17 (dt, J=10.0, 7.4Hz,3H).13C NMR(100MHz,CDCl3)δ175.45(C),149.54(C),133.41(C),129.52(CH), 129.33(CH),122.04(CH),119.06(CH),108.34(CH),85.36(C),40.95(CH2),37.20(CH3), 33.29(CH2),27.06(CH2),19.06,9.60(CH3)。
MS(ESI(+))calcd for C15H20N2O2[M+H]+:260.3；found:261.0.
Embodiment 3
Faint yellow oily,1H-NMR(400MHz,CDCl3),δ7.26(s,2H),6.84–6.45(m,2H),5.30(s, 1H), 4.44-3.62 (m, 1H), 3.22 (ddt, J=13.2,9.2,4.2Hz, 1H), 3.01 (s, 1H), 2.80 (ddd, J= 13.1,8.3,4.8Hz, 1H), 2.63 (d, J=32.5Hz, 3H), 2.55-2.23 (m, 2H), 1.96-1.74 (m, 2H), 1.73- 1.35 (m, 3H), 0.96 (dt, J=10.8,7.4Hz, 3H)13C NMR(100MHz,CDCl3)δ174.68(C),149.54 (C),133.48(C),129.27(CH×2),122.03(CH),119.02(CH),108.30(CH),85.35(C),41.10 (CH2),37.11(CH3),35.31(CH2),32.91(CH2),19.40(CH2),18.54(CH2),13.96.(CH3)。
MS(ESI(+))calcd for C16H22N2O2[M+H]+:274.4；found:275.1.
Embodiment 4
Colorless oil,1H-NMR(400MHz,CDCl3),δ7.72–7.12(m,2H),6.83–6.50(m,2H),5.35(s, 1H), 4.44-3.71 (m, 1H), 3.30-3.16 (m, 1H), 2.92 (dp, J=9.8,6.7Hz, 1H), 2.79 (ddd, J= 13.2,8.4,4.8Hz, 1H), 2.63 (d, J=26.5Hz, 3H), 1.98-1.83 (m, 1H), 1.82-1.61 (m, 2H), 1.55- 1.37(m,1H),1.22–1.14(m,6H).13C NMR(100MHz,CDCl3)δ178.69(C),149.55(C),133.44 (C),129.59(CH),129.32(CH),122.00(CH),119.02(CH),108.31(CH),84.92(C),40.74 (CH2),37.14(CH3),33.60(CH2),31.07(CH),19.78(CH3×2),18.52(CH2)。
MS(ESI(+))calcd for C16H22N2O2[M+H]+:274.4；found:275.0.
Embodiment 5
Colorless oil,1H-NMR(400MHz,CDCl3),δ7.82–6.92(m,2H),6.88–6.44(m,2H),5.31(s, 1H), 4.49-3.61 (m, 2H), 3.01 (ddd, J=13.1,8.8,5.5Hz, 1H), 2.63 (d, J=30.5Hz, 3H), 2.56- 2.26 (m, 3H), 1.95-1.72 (m, 2H), 1.70-1.55 (m, 3H), 1.41-1.33 (m, 2H), 0.92 (dt, J=13.4, 7.3Hz,3H).13C NMR(100MHz,CDCl3)δ175.01(C),149.52(C),133.47(C),129.49(CH), 129.27(CH),122.05(CH),119.06(CH),108.32(CH),85.37(C),41.16(CH2),37.16(CH3), 33.68(CH2),31.96(CH2),27.29(CH2),22.46(CH2),19.11(CH2),13.92(CH3)。
MS(ESI(+))calcd for C17H24N2O2[M+H]+:288.4；found:289.1.
Embodiment 6
White solid,1H-NMR(400MHz,CDCl3),δ7.76–7.07(m,2H),6.86–6.46(m,2H),5.30(s, 1H), 4.44-4.05 (m, 1H), 3.76-3.18 (m, 1H), 3.00 (s, 1H), 2.80 (ddd, J=13.1,8.3,4.8Hz, 1H), 2.63 (d, J=30.1Hz, 3H), 2.54-2.21 (m, 2H), 1.96-1.72 (m, 2H), 1.71-1.59 (m, 3H), 1.36–1.29(m,4H),0.92–0.87(m,3H).13C NMR(100MHz,CDCl3)δ174.93(C),149.53(C), 133.46(C),129.51(CH),129.28(CH),122.04(CH),119.04(CH),108.31(CH),85.37(C), 41.13(CH2),37.13(CH3),33.96(CH2),33.06(CH2),31.75(CH2),25.11(CH2),22.49(CH2), 19.11(CH2),14.01(CH3)。
MS(ESI(+))calcd for C18H26N2O2[M+H]+:302.4；found:303.1.
Embodiment 7
Faint yellow oily,1H-NMR(400MHz,CDCl3),δ7.71–7.13(m,2H),6.84–6.43(m,2H),5.31 (s, 1H), 4.43-4.03 (m, 1H), 3.68 (dt, J=11.8,4.4Hz, 1H), 3.02 (dddd, J=13.2,8.7,4.5Hz, 1H), 2.64 (d, J=27.7Hz, 3H), 2.57-2.24 (m, 3H), 1.96-1.71 (m, 2H), 1.63 (tdd, J=14.8, 11.4,7.3Hz,3H),1.32–1.27(m,6H),0.90–0.86(m,3H).13C NMR(100MHz,CDCl3)δ178.66 (C),175.14(C),149.52(C),133.40(CH),129.29(CH),122.06(CH),119.08(CH),108.13 (CH),85.38(C),41.17(CH2),37.17(CH3),33.92(CH2),33.09(CH2),31.67(CH2),29.03 (CH2),25.18(CH2),22.57(CH2),19.09(CH2),14.03(CH3)。
MS(ESI(+))calcd for C19H28N2O2[M+H]+:316.4；found:317.1.
Embodiment 8
Faint yellow oily,1H-NMR(400MHz,CDCl3),δ7.72–7.13(m,2H),6.87–6.24(m,2H),5.32 (s, 1H), 4.46-4.03 (m, 1H), 3.68 (dt, J=12.3,4.6Hz, 1H), 3.02 (ddd, J=13.1,8.6,4.4Hz, 1H), 2.64 (d, J=26.8Hz, 3H), 2.56-2.25 (m, 3H), 1.97-1.73 (m, 2H), 1.72-1.57 (m, 3H), 1.31-1.26 (m, 8H), 0.88 (t, J=4.7Hz, 3H)13C NMR(100MHz,CDCl3)δ178.69(C),175.12(C), 149.53(C),133.38(CH),129.31(CH),122.06(CH),119.08(CH),108.33(CH),85.39(C), 41.16(CH2),37.16(CH3),33.92(CH2),33.08(CH2),31.79(CH2),29.45(CH2),29.03(CH2), 25.22(CH2),22.61(CH2),19.09(CH2),14.08(CH3)。
MS(ESI(+))calcd for C20H30N2O2[M+H]+:330.5；found:331.2.
Embodiment 9
White oil,1H-NMR(400MHz,CDCl3),δ8.16–6.96(m,6H),6.87–6.37(m,2H),5.88– 4.62 (m, 1H), 4.53-4.01 (m, 1H), 3.47-3.20 (m, 1H), 3.06 (ddd, J=12.9,7.5,5.3Hz, 1H), 2.66(s,3H),2.09–1.68(m,2H),1.55–0.84(m,2H).13C NMR(100MHz,CDCl3)δ168.56(C), 159.05(C),148.87(C),134.95(C),133.28(CH),131.49(CH),129.61(C),129.42(CH), 129.02(CH),124.85(CH),124.39(CH),121.97(CH),119.31(CH),108.43(CH),87.02(C), 42.37(CH2),37.79(CH3),33.12(CH2),19.09(CH2)。
MS(ESI(+))calcd for C19H19FN2O2[M+H]+:326.4；found:327.0.
Embodiment 10
White oil,1H-NMR(400MHz,CDCl3),δ7.98–6.99(m,6H),6.88–6.39(m,2H),5.86– 4.72 (m, 1H), 4.44-4.01 (m, 1H), 3.66-3.17 (m, 1H), 3.10 (dt, J=12.9,6.1Hz, 1H), 2.64 (s, 3H),2.12–1.72(m,2H),1.56–0.84(m,2H).13C NMR(100MHz,CDCl3)δ171.52(C),164.58(C), 148.86(C),137.62(C),132.30(C),129.70(CH),125.85(CH),123.58(CH),122.10(CH), 120.40(CH),119.43(CH),117.06(CH),115.01(CH),108.24(CH),86.74(C),43.19(CH2), 38.25(CH3),34.19(CH2),18.29(CH2).
MS(ESI(+))calcd for C19H19FN2O2[M+H]+:326.4；found:327.0.
Embodiment 11
Colorless oil,1H-NMR(400MHz,CDCl3),δ7.74–7.37(m,2H),7.25–6.95(m,4H),6.88– 6.32(m,2H),5.28(s,1H),4.43–4.00(m,1H),3.64–3.16(m,1H),3.14–2.79(m,3H),2.60(m, 2H),2.09–1.67(m,1H),1.57–1.22(m,1H).13C NMR(100MHz,CDCl3)δ172.16(C),163.35(C), 148.92(C),133.43(C),132.32(C),131.63(CH),130.24(CH),130.15(CH),129.64(CH), 129.39(CH),122.15(CH),119.32(CH),115.65(CH),108.13(CH),86.84(C),43.31(CH2), 38.35(CH3),34.16(CH2),18.24(CH2)。
MS(ESI(+))calcd for C19H19FN2O2[M+H]+:326.4；found:327.0.
Embodiment 12.
White oil,1H-NMR(400MHz,CDCl3),δ7.33–7.08(m,6H),6.86–6.40(m,2H),5.93– 4.83 (m, 1H), 4.44-4.01 (m, 1H), 3.66-3.16 (m, 1H), 3.08 (dt, J=12.7,6.1Hz, 3H), 2.81- 2.28(m,3H),2.05–1.94(m,1H),1.94–1.69(m,2H),1.55–1.19(m,1H).13C NMR(100MHz, CDCl3)δ173.20(C),148.98(C),138.31(C),135.63(C),132.46(C),130.39(CH),129.61 (CH),128.34(CH),127.55(CH),124.79(CH),123.84(CH),122.10(CH),119.19(CH),108.06 (CH),86.69(C),43.13(CH2),38.03(CH3),34.15(CH2),21.41(CH3),18.38(CH2)。
MS(ESI(+))calcd for C20H22N2O2[M+H]+:322.4；found:323.1.
Embodiment 13.
Faint yellow solid,1H-NMR(400MHz,CDCl3), δ 7.99-7.51 (m, 1H), 7.38 (dd, J=13.3, 7.5Hz,2H),7.30–7.10(m,4H),6.84–6.37(m,2H),5.35(s,1H),4.43–3.52(m,1H),3.28– 2.95(m,1H),2.61(s,3H),2.43–2.28(m,3H),2.03–1.70(m,2H),1.54–0.83(m,2H).13C NMR (100MHz,CDCl3)δ173.37(C),148.98(C),144.10(C),139.80(C),132.68(C),130.16(CH), 129.10(CH),129.07(CH),127.90(CH),127.15(CH),127.00(CH),122.14(CH),119.16(CH), 108.01(CH),86.69(C),43.27(CH2),38.16(CH3),34.18(CH2),21.39(CH3),18.38(CH2)。
MS(ESI(+))calcd for C20H22N2O2[M+H]+:322.4；found:323.1.
Embodiment 14
White solid,1H-NMR(400MHz,CDCl3),δ7.51–7.03(m,7H),6.88–6.39(m,2H),5.78– 4.56 (m, 1H), 4.44-4.14 (m, 1H), 3.95-3.17 (m, 1H), 3.09 (dt, J=12.7,6.1Hz, 1H), 2.89- 2.45(m,3H),2.08–1.93(m,1H),1.87–1.70(m,1H),1.45–1.21(m,1H),0.99–0.82(m,1H).13C NMR(100MHz,CDCl3)δ173.04(C),148.94(C),135.67(C),132.43(C),130.03(CH),129.69 (CH),129.61(CH),129.38(CH),128.47(CH),127.76(CH),126.97(CH),122.11(CH),119.24 (CH),108.10(CH),86.69(C),43.18(CH2),38.09(CH3),34.17(CH2),18.37(CH2)。
MS(ESI(+))calcd for C19H20N2O2[M+H]+:308.4；found:309.1.
Embodiment 15
Gained compound measures the inhibiting rate of acetylcholinesterase, the results are shown in Table 2.Wherein C1-C14 respectively corresponds implementation The gained compound of example 1-14.
Inhibiting rate of 2 compound of table to acetylcholinesterase
As seen from table, the inhibiting activity of acetylcholinesterase with higher of compound 2 and 11, IC50Value respectively 0.01, 0.13ng/mL。

Claims (6)

1. half calycanthine analog shown in logical formula (I):
2. the synthesis technology of half calycanthine analog described in claim 1, which is characterized in that steps are as follows:
The R1For following group any one:
3. the synthesis technology of the half calycanthine analog with logical formula (I) described in claim 1, it is characterised in that step is such as Under: anhydrous pyridine dissolution is added in substrate 9- methyl-1,2,3,4,9,9a-6 hydrogen -4aH- pyrido [2,3-b] indoles -4a- alcohol, Reaction reagent is slowly added dropwise thereto again, methanol quenching reaction is added dropwise into reaction solution, subtracts to fully reacting for TLC tracing detection Pressure concentration removes methanol and pyridine, merges organic phase, is concentrated under reduced pressure, and crude product uses column chromatography, and it is similar to obtain half calycanthine Object.
4. the synthesis technology of the half calycanthine analog with logical formula (I) as claimed in claim 3, it is characterised in that reaction reagent For organic acid or acid anhydrides.
5. the synthesis technology of the half calycanthine analog with logical formula (I) as claimed in claim 4, it is characterised in that organic acid or Person's acid anhydrides is acetic anhydride, propionic andydride, butyric anhydride, isobutyric anhydride, valeric acid, caproic acid, enanthic acid, octanoic acid, o-fluorobenzoic acid, fluorobenzene first Acid, parafluorobenzoic acid, meta-toluic acid, paratolunitrile or benzoic acid.
6. the half calycanthine analog with logical formula (I) described in claim 1 is used to prepare treatment acetylcholine esterase inhibition The purposes of active class drug.
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