CN108586418B - Preparation method and application of isocoumarin long-chain carboxylic ester compound - Google Patents
Preparation method and application of isocoumarin long-chain carboxylic ester compound Download PDFInfo
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- CN108586418B CN108586418B CN201810061598.3A CN201810061598A CN108586418B CN 108586418 B CN108586418 B CN 108586418B CN 201810061598 A CN201810061598 A CN 201810061598A CN 108586418 B CN108586418 B CN 108586418B
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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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- C—CHEMISTRY; METALLURGY
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- C07B2200/07—Optical isomers
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Abstract
The invention relates to a preparation method and application of isocoumarin long-chain carboxylic ester compounds, wherein the isocoumarin long-chain carboxylic ester compounds have a structure shown in a formula I:
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method and application of isocoumarin long-chain carboxylic ester compounds.
Background
Senile dementia is a neurodegenerative disease, which seriously affects the cognitive function and memory function of patients to cause the patients to lose basic self-care ability of life. With the increasing aging of the world population, the incidence of senile dementia is increasing year by year. Research shows that senile dementia is related to the low concentration of acetylcholine (AChE) in the central nervous system or the peripheral nervous system, and an acetylcholinesterase inhibitor (AChE) can improve the concentration of acetylcholine in the central nervous system or the peripheral nervous system by inhibiting the degradation of acetylcholine by acetylcholinesterase, so that the senile dementia can be improved and treated. Therefore, the discovery of a novel acetylcholinesterase inhibitor is of great significance for the development of drugs for treating senile dementia.
Disclosure of Invention
The invention provides an isocoumarin long-chain carboxylic acid ester compound or pharmaceutically acceptable salt thereof, which is characterized in that the isocoumarin long-chain carboxylic acid ester compound has a structure shown in a formula I:
another embodiment of the present invention provides a process for the preparation of a compound of formula I as described above, characterized by the steps of:
reacting the compound shown in the formula II with n-dodecanol under the action of Dicyclohexylcarbodiimide (DCC) and catalytic amount of 4-Dimethylaminopyridine (DMAP) to obtain the compound shown in the formula I.
The reaction temperature of the above preparation method is preferably 40-80 deg.C, and more preferably 60-70 deg.C; the reaction time is preferably 8-48h, and further preferably 12-24 h; a compound of formula II: n-dodecanol: 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 pharmaceutical composition characterized in that the pharmaceutical composition comprises the above compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition can also comprise pharmaceutically acceptable pharmaceutic adjuvants. The pharmaceutical composition may optionally further comprise other acetylcholinesterase inhibitors.
Another embodiment of the present invention provides the use of a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. The medicament is preferably used for preventing and/or treating senile dementia.
The compounds of formula II of the present invention (CAS registry number 65718-85-6) may be obtained commercially or by natural extraction.
In another embodiment of the invention there is provided the use of a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, in the preparation of an acetylcholinesterase inhibitor.
The term "pharmaceutically acceptable salts" as used herein refers to non-toxic inorganic or organic acid and/or base addition salts, as described in "Salt selection for basic drugs", int.J.pharm. (1986),33, 201-217.
Detailed Description
In order to facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the present invention and are not intended to limit the scope or the principle of the present invention, and the embodiments of the present invention are not limited to the following.
Example 1
Taking a compound (1.0mmol) of a formula II, n-dodecanol (10.0mmol), DCC (10.0mmol) and a catalytic amount of DMAP, heating to 60 ℃, stirring for reacting for 24 hours, feeding the reaction solution into a wet column while the reaction solution is hot, and performing silica gel column chromatography (silica gel 200-300 meshes, ethyl acetate/petroleum ether ═ 1/3 as an eluent) to obtain 311mg of a compound (shown in the formula I), wherein the yield is about 71.6%, and the data of the structure are confirmed: ESI-MS (m/z): 435.3[ M + H]+，1H NMR(400MHz,CDCl3):δ4.48(q,J＝6.3Hz,1H,H-3),4.00-3.94(m,2H,OCH 2),2.98(q,J＝6.6Hz,1H,H-4),1.99(s,3H,CH3-11),1.70–1.60(m,4H,OCH2C 2HC 2H),1.32–1.25(m,16H,(CH2)8),1.18(d,J＝6.3Hz,3H,CH3-9),1.16(d,J＝6.6Hz,3H,CH3-10),0.88(t,J＝6.7Hz,3H,CH2C 3H).
Example 2
Heating the compound (1.0mmol) of the formula II, n-dodecanol (20.0mmol), DCC (20.0mmol) and a catalytic amount of DMAP (0.1mmol) to 70 ℃, stirring for reaction for 12h, loading the reaction liquid on a wet column, and performing silica gel column chromatography (silica gel 200-300 meshes, ethyl acetate/petroleum ether ═ 1/3 as an eluent) to obtain 352mg of the compound (I) with the yield of about 81.0%, wherein the structure confirmation data are consistent with those in example 1.
Example 3
After heating the compound of formula II (1.0mmol), methanol (2.0mL), DCC (5.0mmol) and DMAP (0.05mmol) to 40 ℃ and stirring for 8 hours, the reaction mixture was subjected to wet column chromatography on silica gel (200-300 mesh silica gel, ethyl acetate/petroleum ether ═ 1/3 as an eluent) to obtain 249mg of the compound of formula III, the yield was about 88.9%, and the data of the structure was confirmed: ESI-MS (m/z): 281.1[ M + H]+。
Example 4 acetylcholinesterase inhibitory Activity (AchE) assay
According to the Ellman method (for example, the document: Ellman G L, Courtney K D, Featherstone R M, et. Anew and rapid colorimetric determination of acetyl-linolenic activity [ J)]Biochemical Pharmacology,1961,7(2):88-95) of the compounds of the formulae I, II, III according to the invention were tested for their acetylcholinesterase-inhibiting activity IC50(μ M), Tacrine as a positive control, results are shown in Table 1.
TABLE 1
| Compound (I) | AchE inhibitory activity IC50(μM) |
| Formula I | 8.75 |
| Formula II | >50 |
| Formula III | >50 |
| Tacrine | 0.25 |
Claims (9)
1. An isocoumarin long-chain carboxylic acid ester compound or a pharmaceutically acceptable salt thereof, characterized in that the isocoumarin long-chain carboxylic acid ester compound has a structure shown in formula I:
2. a process for the preparation of a compound of formula I according to claim 1, characterized in that it comprises the following steps:
reacting the compound shown in the formula II with n-dodecanol under the action of Dicyclohexylcarbodiimide (DCC) and catalytic amount of 4-Dimethylaminopyridine (DMAP) to obtain the compound shown in the formula I.
3. The process according to claim 2, wherein the reaction is carried out at a temperature of 40 to 80 ℃ for a period of 8 to 48 hours, and the compound of formula II: n-dodecanol: the molar ratio of DCC is 1: 5-25: 5-25.
4. The process according to any one of claims 2 to 3, wherein the reaction temperature is 60 to 70 ℃ and the reaction time is 12 to 24 hours, and the compound of formula II: n-dodecanol: the molar ratio of DCC is 1: 10-20: 10-20.
5. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises the compound with the structure of formula I as claimed in claim 1 or its pharmaceutically acceptable salt as an effective ingredient.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
7. Pharmaceutical composition according to any one of claims 5 to 6, characterized in that it further comprises other acetylcholinesterase inhibitors.
8. The use of a compound of the structure of formula I according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of senile dementia.
9. The use of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of an acetylcholinesterase inhibitor.
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| CN108586418B true CN108586418B (en) | 2020-04-21 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006046071A1 (en) * | 2004-10-29 | 2006-05-04 | Nipri Limited | Compounds and compositions useful in the treatment of neoplasia |
| 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 |
| CN102274211A (en) * | 2011-06-17 | 2011-12-14 | 淮海工学院 | New purpose of coumarin compound |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006046071A1 (en) * | 2004-10-29 | 2006-05-04 | Nipri Limited | Compounds and compositions useful in the treatment of neoplasia |
| 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 |
| CN102274211A (en) * | 2011-06-17 | 2011-12-14 | 淮海工学院 | New purpose of coumarin compound |
Non-Patent Citations (2)
| Title |
|---|
| Antimicrobial activity and cytotoxicity of polyketides isolated from the mushroom Xerula sp. BCC56836;Karoon Sadorn et al.;《RSC Advances》;20160929;第94510–94523页 * |
| Synthesis and in Vitro and in Vivo Evaluation of a Series of Dihydroisocoumarin Derivatives Conjugated with Fatty Acids, Alcohols, and Amines as Potential Anticancer Agents;Catherine A. Higgins et al.;《Bioconjugate Chem.》;20090826;第20卷;第1737–1751页 * |
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