CN108191807B - A kind of synthetic method and its application of polysubstituted different coumarin derivative - Google Patents
A kind of synthetic method and its application of polysubstituted different coumarin derivative Download PDFInfo
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- CN108191807B CN108191807B CN201810061596.4A CN201810061596A CN108191807B CN 108191807 B CN108191807 B CN 108191807B CN 201810061596 A CN201810061596 A CN 201810061596A CN 108191807 B CN108191807 B CN 108191807B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
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Abstract
The present invention relates to the synthetic method and its application of a kind of polysubstituted different coumarin derivative, the polysubstituted different coumarin derivative has structure shown in Formulas I:
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to a kind of synthetic method of polysubstituted different coumarin derivative and its
Using.
Background technique
Senile dementia is a kind of disease of nervus retrogression, seriously affects the cognitive function of patient, memory function is led
Patient is caused to lose basic self care ability.With the continuous aggravation of world population astogeny, the morbidity of senile dementia
Rate is also increasing year by year.Studies have shown that the acetylcholine of senile dementia and central nervous system or peripheral neverous system
(AChE) concentration is too low related, and acetylcholinesterase inhibitor (AChEI) can be by acetylcholine esterase inhibition to acetyl gallbladder
The degradation of alkali is realized to reach the concentration for the acetylcholine for improving nervous centralis or peripheral neverous system to above-mentioned disease
Improvement and treatment.Thus, it is found that a kind of novel acetylcholinesterase inhibitor is for exploitation treatment senile dementia
Drug is significant.
Summary of the invention
The present invention provides a kind of polysubstituted different coumarin derivative or its pharmaceutically acceptable salt, it is characterised in that described
Polysubstituted different coumarin derivative has structure shown in Formulas I:
Another embodiment of the present invention provides the preparation method of above-mentioned compound of formula I, it is characterised in that including walking as follows
It is rapid:
Formula II compound and n-octyl alcohol, in the 4-dimethylaminopyridine of dicyclohexylcarbodiimide (DCC) and catalytic amount
(DMAP) compound of formula I is reacted to obtain under the action of.
Preferred 40-80 DEG C of the reaction temperature of above-mentioned preparation method, further preferred 50-60 DEG C；Reaction time preferred 8-
48h, further preferred 12-24h；Formula II compound: n-octyl alcohol: the molar ratio of DCC is 1:5-25:5-25, more preferably 1:10-
20:10-20.
Another embodiment of the present invention provides a kind of pharmaceutical composition, it is characterised in that the pharmaceutical composition is with above-mentioned formula
Compound I or its pharmaceutically acceptable salt are as effective component.The pharmaceutical composition may also include pharmaceutically acceptable medicine
Use auxiliary material.The pharmaceutical composition also optionally includes other acetylcholinesterase inhibitors.
Another embodiment of the present invention provides above-mentioned compound of formula I or its pharmaceutically acceptable salt in medicine preparation
Application.The drug is preferred for preventing and/or treating senile dementia.
Formula II compound (CAS registration number is 65718-85-6) of the present invention can be obtained by commercially available or natural extraction.
Another embodiment of the present invention provides above-mentioned compound of formula I or its pharmaceutically acceptable salt is preparing acetyl gallbladder
Application in alkali esterase inhibitor.
Term " pharmaceutically acceptable salt " refers to the addition of atoxic inorganic or organic acid and/or alkali in the present invention
Salt, reference can be made to " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201-217.
Specific embodiment
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But
It is that these embodiments are only not supposed to be a limitation to the present invention or implementation principle for better understanding invention, reality of the invention
The mode of applying is not limited to the following contents.
Embodiment 1
The DMAP heating of modus ponens II compound (1.0mmol), n-octyl alcohol (10.0mmol), DCC (10.0mmol), catalytic amount
To 50 DEG C, after being stirred to react for 24 hours, reaction solution wet process upper prop, through silica gel column chromatography (200~300 mesh of silica gel, ethyl acetate/petroleum
Ether=1/3 is eluant, eluent), compound of formula I 277mg is obtained, yield is about 73.2%, structural identification data: ESI-MS (m/z):
379.2[M+H]+,1H NMR(400MHz,CDCl3): δ 4.48 (q, J=6.3Hz, 1H, H-3), 4.02-3.97 (m, 2H,
OCH 2), 2.98 (q, J=6.6Hz, 1H, H-4), 1.99 (s, 3H, CH3-11),1.72–1.58(m,4H,OCH2CH 2CH 2),
1.33–1.27(m,8H,(CH2)4), 1.18 (d, J=6.3Hz, 3H, CH3- 9), 1.16 (d, J=6.6Hz, 3H, CH3-10),
0.88 (t, J=6.8Hz, 3H, CH2CH 3).
Embodiment 2
Modus ponens II compound (1.0mmol), n-octyl alcohol (20.0mmol), DCC (20.0mmol), catalytic amount DMAP
(0.1mmol) is heated to 60 DEG C, after being stirred to react 12h, reaction solution wet process upper prop, through silica gel column chromatography (200~300 mesh of silica gel,
Ethyl acetate/petroleum ether=1/3 be eluant, eluent), obtain compound of formula I 312mg, yield is about 82.4%, structural identification data with
Embodiment 1 is consistent.
Embodiment 3
Modus ponens II compound (1.0mmol), methanol (2.0mL), DCC (5.0mmol), DMAP (0.05mmol) are heated to 40
DEG C, after being stirred to react 8h, reaction solution wet process upper prop, through silica gel column chromatography (200~300 mesh of silica gel, ethyl acetate/petroleum ether=
1/3 is eluant, eluent), formula III compound 249mg is obtained, yield is about 88.9%, structural identification data: ESI-MS (m/z): 281.1
[M+H]+。
4 inhibiting activity of acetylcholinesterase of embodiment (AchE) test
According to Ellman method (such as document: Ellman G L, Courtney K D, Featherstone R M, et
al.Anew and rapid colorimetric determination of acetylcho-linesterase
Activity [J] .Biochemical Pharmacology, 1961,7 (2): 88-95) test formula I, Formula II, formula III
The inhibiting activity of acetylcholinesterase IC of compound50(μM), Tacrine the results are shown in Table 1 as positive control.
Table 1
| Compound | AchE inhibitory activity IC50(μM) |
| Formulas I | 5.02 |
| Formula II | >50 |
| Formula III | >50 |
| Tacrine | 0.25 |
Claims (9)
1. a kind of polysubstituted different coumarin derivative or its pharmaceutically acceptable salt, it is characterised in that the polysubstituted an unusually sweet smell beans
Plain derivative has structure shown in Formulas I:
2. the preparation method of Formulas I structural compounds described in claim 1, it is characterised in that include the following steps:
Formula II compound and n-octyl alcohol, in the 4-dimethylaminopyridine (DMAP) of dicyclohexylcarbodiimide (DCC) and catalytic amount
Under the action of react to obtain Formulas I structural compounds.
3. preparation method as claimed in claim 2, it is characterised in that reaction temperature is 40-80 DEG C, reaction time 8-48h, formula
II compound: n-octyl alcohol: the molar ratio of DCC is 1:5-25:5-25.
4. the described in any item preparation methods of claim 2-3, it is characterised in that reaction temperature is 50-60 DEG C, and the reaction time is
12-24h, Formula II compound: n-octyl alcohol: the molar ratio of DCC is 1:10-20:10-20.
5. a kind of pharmaceutical composition, it is characterised in that the pharmaceutical composition with Formulas I structural compounds described in claim 1 or its
Pharmaceutically acceptable salt is as effective component.
6. pharmaceutical composition described in claim 5, it is characterised in that the pharmaceutical composition further includes pharmaceutically acceptable medicine
Use auxiliary material.
7. the described in any item pharmaceutical compositions of claim 5-6, it is characterised in that the pharmaceutical composition further includes other acetyl
Anticholinesterase.
8. the application of Formulas I structural compounds described in claim 1 or its pharmaceutically acceptable salt in medicine preparation, special
Sign is the drug for preventing and/or treating senile dementia.
9. Formulas I structural compounds described in claim 1 or its pharmaceutically acceptable salt are preparing acetylcholinesterase inhibition
Application in agent.
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| CN108191807B true CN108191807B (en) | 2019-11-05 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101575327A (en) * | 2009-06-12 | 2009-11-11 | 中国科学院广州生物医药与健康研究院 | Antimalarial active isocumarans compound and composition, preparation method and application thereof |
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2018
- 2018-01-22 CN CN201810061596.4A patent/CN108191807B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101575327A (en) * | 2009-06-12 | 2009-11-11 | 中国科学院广州生物医药与健康研究院 | Antimalarial active isocumarans compound and composition, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| Karoon Sadorn et al..Antimicrobial activity and cytotoxicity of polyketides isolated from the mushroom Xerula sp.BCC56836.《RSC Adv.》.2016,第6卷94510-94523. * |
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Effective date of registration: 20230519 Address after: Room 2920, Building B, No. 9 Hisense Tianchen Road, Jinan City, Shandong Province, 250000 Patentee after: Zhuofan (Jinan) Technology Innovation Co.,Ltd. Address before: 225127 No. 199, Yang Hua Xi Road, Yangzhou, Jiangsu Patentee before: YANGZHOU POLYTECHNIC INSTITUTE |