CN111960978A - Synthesis method and application of S-allyl-L-cysteine substituted tyrosol derivative with neuroprotective activity - Google Patents

Synthesis method and application of S-allyl-L-cysteine substituted tyrosol derivative with neuroprotective activity Download PDF

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CN111960978A
CN111960978A CN201910415906.2A CN201910415906A CN111960978A CN 111960978 A CN111960978 A CN 111960978A CN 201910415906 A CN201910415906 A CN 201910415906A CN 111960978 A CN111960978 A CN 111960978A
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tyrosol
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李鸣
沈圆圆
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Shenzhen Hongjingtang Biomedical Technology Co ltd
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Abstract

The invention discloses a synthetic method and application of an S-allyl-L-cysteine substituted tyrosol derivative with neuroprotective activity. The compound comprises a tyrosol analogue parent nucleus and a substituent containing an S-allyl-L-cysteine structure, wherein X can be O, S or NH; r1 is taken from H, alkyl or alkanoyl; r2 is taken from H, alkyl, acyl, or carbamate; r3 is taken from H, halogen, hydroxy or alkoxy. The compound has multiple action mechanisms, including the functions of resisting oxidation and inflammation, improving mitochondrial function, improving glycometabolism, promoting nerve cell regeneration, inhibiting apoptosis and the like, and has high medicinal value when being applied to aging and neurodegenerative diseases.

Description

Synthesis method and application of S-allyl-L-cysteine substituted tyrosol derivative with neuroprotective activity
Technical Field
The invention belongs to the field of medical chemistry, and particularly relates to a synthetic method and application of an S-allyl-L-cysteine substituted tyrosol derivative with neuroprotective activity, wherein the application comprises aging, neurodegenerative diseases and the like.
Background
Neurodegenerative Diseases (ND) are chronic diseases including alzheimer's disease, parkinson's disease, huntington's disease, etc. which cause gradual death of neurons, and often cause great pain and burden to patients and families. With the aging population, ND is expected to replace cancer as the second major disease causing human death by 2040 years, however, no drug is available worldwide for the treatment of neurodegenerative diseases.
The pathology of neurodegenerative disease ND is closely related to oxidative stress, mitochondrial dysfunction, Ca2+ influx, immunoinflammation, autophagy, metal ions and the like, and the traditional development strategy of single-target high-selectivity medicaments is difficult to play a role in research and development of new ND medicaments for complex diseases with multiple causes. The traditional Chinese medicine has the advantages of multiple target points, small toxic and side effects, good synergistic effect and the like, and becomes a research hotspot of anti-ND medicines in recent years.
Tyrosol (Tyrosol), also known as p-hydroxyphenylethanol, is the main active ingredient in traditional Chinese medicine rhodiola rosea and is one of the first biological phenolic compounds found in olive oil. Tyrosol has strong oxidation resistance, is especially good at removing hydroxyl free radical with high toxicity, can antagonize beta-amyloid (Abeta), inhibit dopaminergic neuron apoptosis, prolong life, protect heart and prevent tumor. The tyrosol has mild property and almost no toxic or side effect, and has wide application prospect in the fields of medicine and food. However, the bioavailability is low due to the problems of instability and slow absorption in physiological environment, and the application of tyrosol is limited.
Disclosure of Invention
The invention aims to provide a medicament with neuroprotective activity, namely an S-allyl-L-cysteine substituted tyrosol derivative shown in a general formula I, wherein the compound comprises a substituted tyrosol mother nucleus and a substituent containing an S-allyl-L-cysteine structure.
In order to solve the technical problems, the invention provides the following technical scheme:
in a first aspect of the invention, a tyrosol derivative is provided, which derivative comprises a substituted tyrosol core and a substituent comprising an S-allyl-L-cysteine structure, represented by formula i:
Figure BDA0002064378980000011
wherein X can be O, S or NH; r1 is taken from H, alkyl or alkanoyl; r2 is taken from H, alkyl, acyl, or carbamate; r3 is taken from H, halogen, hydroxy or alkoxy.
Most preferred compounds of the invention are selected from the group consisting of:
Figure BDA0002064378980000021
in a second aspect, the present invention provides a pharmaceutical composition, which is characterized by comprising an effective dose of any one of the above derivatives and a common pharmaceutical carrier.
The third aspect of the invention provides a medicine for preventing and treating aging and neurodegenerative diseases, which takes the S-allyl-L-cysteine substituted tyrosol derivative as an active ingredient.
The fourth aspect of the invention provides the application of the S-allyl-L-cysteine substituted tyrosol derivative in preparing medicines for preventing and treating aging and neurodegenerative diseases. Especially senile dementia, Parkinson's disease, spinal cord lateral sclerosis, apoplexy, memory deterioration, etc.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 150mg/Kg body weight, preferably from 0.1 to 100mg/Kg body weight, more preferably from 1 to 60mg/Kg body weight, and most preferably from 2 to 30mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The fifth aspect of the invention provides a synthetic route of the derivatives SAO-1 to SAO-8, SAO-9 to SAO-16
Figure BDA0002064378980000031
Figure BDA0002064378980000041
Reagents and conditions for synthesis: (a) (Boc)2O, THF, rt,5 h; (b) tyrosol, TPP, DIAD, THF,48 h; (c) TFA, DCM,6 h; (d) acetyl Chloride, TEA, DCM,12 h; (e) carbamyl Chloride, DIEA, DCM,12 h; (f) HBTU, DIEA, DCM,12 h.
S-allyl-L-cysteine (SAC) is an organic sulfur compound extracted from garlic, and has various pharmacological activities of resisting inflammation, resisting oxidation, improving immunity, resisting tumor, protecting nerve and the like. SAC has stable chemical property, extremely low toxicity, good oral absorption in human body, half-life period of 10 hours and elimination time of 30 hours. In addition, the metabolic conversion products of SAC in vivo are mainly N-acetyl-S-allyl-L-cysteine (NAc-SAC), and also have good effects of scavenging free radicals and resisting oxidative damage.
The invention utilizes the principle of drug combination, selects the active ingredient tyrosol in the traditional Chinese medicine rhodiola rosea and other compounds with neuroprotective activity S-allyl-L-cysteine to carry out combination, so as to improve the bioavailability of tyrosol and provide a drug with neuroprotective activity.
The invention has the beneficial effect that the tyrosol derivative with special activity is realized through the combination of the tyrosol analogue mother nucleus and the substituent containing the S-allyl-L-cysteine structure. The tyrosol derivative has multiple action mechanisms, including antioxidant, antiinflammatory, mitochondrial function improving, glycometabolism improving, nerve cell regeneration promoting, and apoptosis inhibiting effects. Pharmacodynamic experiments prove that the novel tyrosol derivatives have obvious cytotoxic activity respectively, the activity of part of compounds is obviously higher than that of the traditional tyrosol, or the activity of the compounds is equivalent to that of a positive control medicament or higher than that of the positive control medicament, and other compounds all show certain cytotoxic activity in parallel tests. Part of the compounds are new compounds with great medicinal value in the aspects of aging and preventing and treating neurodegenerative diseases.
Drawings
FIG. 1 is a chemical structural formula of the derivative having neuroprotective activity of the present invention.
FIG. 2a and FIG. 2b are the effect of SAO-1 on the spatial memory of Alzheimer's disease mice, respectively. P <0.001vs. control, # # P <0.01vs.3xtg-AD, N ═ 8 ═ 10/group.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
The preparation process of the compounds SAO-1 to SAO-8 and SAO-9 to SAO-16.
Synthesis of Compound 1-1
Figure BDA0002064378980000042
Compound 1-0(16.1g,100mmol) was weighed out and dissolved in tetrahydrofuran (100ml), and di-tert-butyl dicarbonate (21.8g,100mmol) and a saturated sodium hydrogencarbonate solution (250ml) were successively added, followed by stirring at room temperature for 5 hours. After the reaction is finished, useDilute hydrochloric acid (1mol/L) to acidic pH was then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give product 1-1(22.2g, 85%). MS (ESI) M/z 260.1[ M-H ]]-.
Synthesis of Compound 1-2
Figure BDA0002064378980000051
Compound 1-1(2.61g,10mmol), triphenylphosphine (2.62g,10mmol) and tyrosol (1.38g,10mmol) were dissolved in anhydrous tetrahydrofuran (40ml) under nitrogen, and diisopropyl azodicarboxylate (2.02g,10mmol) was added dropwise under ice bath conditions, followed by reaction at room temperature for 48 hours. After the reaction, the solvent was concentrated, the reaction system was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain 1-2(3.16g, 83%) products. MS (ESI) M/z 382.0[ M + H ]]+.
Synthesis of Compound SAO-1
Figure BDA0002064378980000052
Compound 1-2(379mg,1mmol) was dissolved in a mixed solvent of dichloromethane (20ml) and trifluoroacetic acid (2ml), and stirred at room temperature for 6 hours. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain SAO-1(285mg, 75%). MS (ESI) M/z 281.9[ M + H ]]+。
Synthesis of Compound 2-1
Figure BDA0002064378980000053
Compound 1-1(2.61g,10mmol), triphenylphosphine (2.62g,10mmol) and p-methoxyphenethanol (1.52g,10mmol) were dissolved in anhydrous tetrahydrofuran (40ml) under nitrogen, and diisopropyl azodicarboxylate (2.02g,10mmol) was added dropwise under ice bath conditions, followed by reaction at room temperature for 48 hours. After the reaction is finished, the solvent is concentrated, the reaction system is diluted by ethyl acetate, and saturated solution is used in sequenceWashing with sodium bicarbonate water solution and saturated salt water, drying organic phase with anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography to obtain product 2-1(3.12g, 79%). MS (ESI) M/z 396.0[ M + H ]]+。
Synthesis of Compound SAO-2
Figure BDA0002064378980000054
Compound 2-1(395mg,1mmol) was dissolved in a mixed solvent of dichloromethane (20ml) and trifluoroacetic acid (2ml), and stirred at room temperature for 6 hours. After the reaction, the solvent was concentrated and the product SAO-2(227mg, 77%) was obtained by silica gel column chromatography. MS (ESI) M/z 296.0[ M + H ]]+。
Synthesis of Compound 3-1
Figure BDA0002064378980000055
Compound 1-2(381mg,1mmol) was dissolved in anhydrous dichloromethane (20ml), and triethylamine (0.1ml) and acetyl chloride (1ml) were added in this order, followed by stirring at room temperature overnight. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to give 3-1(363mg, 86%). MS (ESI) M/z 424.1[ M + H ]]+。
Synthesis of Compound SAO-3
Figure BDA0002064378980000061
Compound 3-1(423mg,1mmol) was dissolved in methylene chloride (20ml), and trifluoroacetic acid (2ml) was added thereto, followed by stirring at room temperature for 6 hours. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain SAO-3(235mg, 73%). MS (ESI) M/z 324.1[ M + H ]]+。
Synthesis of Compound 4-1
Figure BDA0002064378980000062
Mixing compound 1-2(381mg,1mmol) with methyl carbamateThe acid chloride (100mg,1mmol) was dissolved in anhydrous dichloromethane (20ml), followed by addition of N, N-diisopropylethylamine (0.1ml), and stirring was carried out at room temperature overnight. After the reaction, the solvent was concentrated and the product was purified by column chromatography on silica gel to give 4-1(332mg, 76%). MS (ESI) M/z 439.1[ M + H ]]+。
Synthesis of Compound SAO-4
Figure BDA0002064378980000063
Compound 4-1(438mg,1mmol) was dissolved in a mixed solvent of dichloromethane (20ml) and trifluoroacetic acid (2ml), and stirred at room temperature for 6 hours. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain SAO-4(253mg, 75%). MS (ESI) M/z 339.0[ M + H ]]+。
Synthesis of Compound 5-1
Figure BDA0002064378980000064
Compound 1-1(2.61g,10mmol) was dissolved in methylene chloride (40ml), and p-hydroxyphenylethylamine (1.51g,11mmol), HBTU (4.17g) and N, N-diisopropylethylamine (1.8ml) were added in this order, and the mixture was stirred at room temperature overnight. After the reaction, the solvent was concentrated and the product 5-1(3.31g, 87%) was obtained by silica gel column chromatography. MS (ESI) M/z 381.0[ M + H ]]+。
Synthesis of Compound SAO-5
Figure BDA0002064378980000065
Compound 5-1(380mg,1mmol) was dissolved in a mixed solvent of dichloromethane (20ml) and trifluoroacetic acid (2ml), and stirred at room temperature for 6 hours. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain SAO-5(204mg, 73%). MS (ESI) M/z 281.0[ M + H ]]+。
Synthesis of Compound 6-1
Figure BDA0002064378980000071
Compound 1-1(2.61g,10mmol) was dissolved in methylene chloride (40ml), and p-methoxyphenylethylamine (1.66g,11mmol), HBTU (4.17g) and N, N-diisopropylethylamine (1.8ml) were added in this order, and the mixture was stirred at room temperature overnight. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain 6-1(3.27g, 83%). MS (ESI) M/z 395.0[ M + H ]]+。
Synthesis of Compound SAO-6
Figure BDA0002064378980000072
Compound 6-1(394mg,1mmol) was dissolved in a mixed solvent of dichloromethane (20ml) and trifluoroacetic acid (2ml), and stirred at room temperature for 6 hours. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain SAO-6(256mg, 87%). MS (ESI) M/z 259.1[ M + H ]]+。
Synthesis of Compound 7-1
Figure BDA0002064378980000073
Compound 5-1(380mg,1mmol) and methylcarbamoyl chloride (100mg,1mmol) were dissolved in anhydrous dichloromethane (20ml), followed by addition of N, N-diisopropylethylamine (0.1ml), and the mixture was stirred at room temperature overnight. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain 7-1(375mg, 89%). MS (ESI) M/z 423.1[ M + H ]]+。
Synthesis of Compound SAO-7
Figure BDA0002064378980000074
Compound 7-1(422mg,1mmol) was dissolved in a mixed solvent of dichloromethane (20ml) and trifluoroacetic acid (2ml), and stirred at room temperature for 6 hours. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain SAO-7(293mg, 91%). MS (ESI) M/z 323.0[ M + H ]]+。
Synthesis of Compound 8-1
Figure BDA0002064378980000075
Compound 5-1(380mg,1mmol) and methylcarbamoyl chloride (100mg,1mmol) were dissolved in anhydrous dichloromethane (20ml), followed by addition of N, N-diisopropylethylamine (0.1ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was concentrated and subjected to silica gel column chromatography to give 8-1(266mg, 61%). MS (ESI) M/z 438.0[ M + H]+。
Synthesis of Compound SAO-8
Figure BDA0002064378980000076
Compound 8-1(218mg,0.5mmol) was dissolved in a mixed solvent of dichloromethane (20ml) and trifluoroacetic acid (2ml), and stirred at room temperature for 6 hours. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain SAO-8(141mg, 84%). MS (ESI) M/z 338.1[ M + H]+.
Synthesis of Compound SAO-9
Figure BDA0002064378980000081
Under nitrogen protection, compound 2-0(2.03g,10mmol), triphenylphosphine (2.62g,10mmol) and tyrosol (1.38g,10mmol) were dissolved in anhydrous tetrahydrofuran (40ml), and diisopropyl azodicarboxylate (2.02g,10mmol) was added dropwise under ice bath conditions, followed by reaction at room temperature for 48 hours. After the reaction is finished, the solvent is concentrated, the reaction system is diluted by ethyl acetate, the saturated sodium bicarbonate aqueous solution and the saturated common salt are sequentially used for washing, the organic phase is dried by anhydrous sodium sulfate, and the product SAO-9(2.84g, 88%) is obtained by filtration, concentration and silica gel column chromatography. MS (ESI) M/z 324.1[ M + H ]]+。
Synthesis of Compound SAO-10
Figure BDA0002064378980000082
Under the protection of nitrogen, compound 2-0(2.03g,10mmol), triphenylphosphine (2.62g,10mmol) and p-methoxyPhenethyl alcohol (1.52g,10mmol) was dissolved in anhydrous tetrahydrofuran (40ml), and diisopropyl azodicarboxylate (2.02g,10mmol) was added dropwise under ice-bath conditions, followed by reaction at room temperature for 48 hours. After the reaction is finished, the solvent is concentrated, the reaction system is diluted by ethyl acetate, the saturated sodium bicarbonate aqueous solution and the saturated common salt are sequentially used for washing, the organic phase is dried by anhydrous sodium sulfate, and the product SAO-10(2.62g, 78%) is obtained by filtration, concentration and silica gel column chromatography. MS (ESI) M/z 338.1[ M + H]+.
Synthesis of Compound SAO-11
Figure BDA0002064378980000083
Compound SAO-9(323mg,1mmol) was dissolved in anhydrous dichloromethane (20ml), and triethylamine (0.1ml) and acetyl chloride (1ml) were added successively, followed by stirring at room temperature overnight. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain SAO-11(339mg, 93%). MS (ESI) M/z 365.9[ M + H ]]+.
Synthesis of Compound SAO-12
Figure BDA0002064378980000084
Compound SAO-9(323mg,1mmol) and methylcarbamoyl chloride (100mg,1mmol) were dissolved in anhydrous dichloromethane (20ml), followed by addition of N, N-diisopropylethylamine (0.1ml), and stirring was carried out at room temperature overnight. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain SAO-12(332mg, 79%). MS (ESI) M/z 381.0[ M + H ]]+.
Synthesis of Compound SAO-13
Figure BDA0002064378980000091
Compound 2-0(2.03g,10mmol) was dissolved in methylene chloride (40ml), and p-hydroxyphenylethylamine (1.51g,11mmol), HBTU (4.17g) and N, N-diisopropylethylamine (1.8ml) were added in this order, and the mixture was stirred at room temperature overnight. After the reaction, the solvent was concentrated and the product SAO-13(3.01g, 94%) was obtained by silica gel column chromatography. MS (ESI) m/z of 323.0M+H]+.
Synthesis of Compound SAO-14
Figure BDA0002064378980000092
Compound 2-0(2.03g,10mmol) was dissolved in methylene chloride (40ml), and p-methoxyphenylethylamine (1.66g,11mmol), HBTU (4.17g) and N, N-diisopropylethylamine (1.8ml) were added in this order, and the mixture was stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated and subjected to silica gel column chromatography to obtain SAO-14(2.41g, 72%). MS (ESI) M/z 337.1[ M + H ]]+.
Synthesis of Compound SAO-15
Figure BDA0002064378980000093
Compound SAO-13(322mg,1mmol), methylcarbamoyl chloride (100mg,1mmol) was dissolved in anhydrous dichloromethane (20ml), followed by addition of N, N-diisopropylethylamine (0.1ml), and stirring at room temperature overnight. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to give SAO-15(305mg, 84%). MS (ESI) M/z 365.0[ M + H ]]+.
Synthesis of Compound SAO-16
Figure BDA0002064378980000094
Compound SAO-13(322mg,1mmol), methylcarbamoyl chloride (100mg,1mmol) was dissolved in anhydrous dichloromethane (20ml), followed by addition of N, N-diisopropylethylamine (0.1ml), and stirring at room temperature overnight. After the reaction, the solvent was concentrated and subjected to silica gel column chromatography to obtain SAO-16(250mg, 66%). MS (ESI) M/z 380.1[ M + H ]]+.
Example 2
Activity evaluation test of Compound of the present invention
After the transgenic mouse with Alzheimer disease (3xTg-AD, 8 months old) is treated by the compound SAO-1(5.0mg/kg and 20.0mg/kg) for 4 weeks, behavioral tests show that the synthesized representative small molecule compound SAO-1 can obviously improve the platform latency (A) of the mouse, and simultaneously reduce the error times (B) of the platform, and the effect is more obvious than that of the positive control drug memantine (5.0mg/kg), which indicates that SAO-1 can obviously improve the spatial memory of the transgenic mouse with Alzheimer disease.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (7)

1. A tyrosol derivative comprising a substituted tyrosol parent nucleus and a substituent comprising an S-allyl-L-cysteine structure, represented by formula i:
Figure RE-FDA0002174933060000011
wherein X can be O, S or NH; r1 is taken from H, alkyl or alkanoyl;
r2 is taken from H, alkyl, acyl, or carbamate;
r3 is taken from H, halogen, hydroxy or alkoxy.
2. The derivative according to claim 1, wherein the derivative is selected from the group consisting of:
Figure RE-FDA0002174933060000012
3. a pharmaceutical composition comprising an effective amount of a derivative according to any one of claims 1-2 and a pharmaceutically acceptable carrier.
4. A preventive or therapeutic agent for aging and neurodegenerative diseases, which comprises the derivative as claimed in claim 1 to 2 as an active ingredient.
5. Use of the derivative of any one of claims 1-2 for the preparation of a medicament for the prevention and treatment of aging and neurodegenerative diseases.
6. A synthetic route for preparing the derivatives SAO-1 to SAO-8 as claimed in claim 2 is as follows:
Figure RE-FDA0002174933060000021
7. a synthetic route for preparing the derivatives SAO-9 to SAO-16 as claimed in claim 2 is as follows:
Figure RE-FDA0002174933060000022
CN201910415906.2A 2019-05-19 2019-05-19 Synthesis method and application of S-allyl-L-cysteine substituted tyrosol derivative with neuroprotective activity Pending CN111960978A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116410160A (en) * 2023-03-21 2023-07-11 深圳市罗湖区人民医院 Arctigenin derivative and preparation method and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116410160A (en) * 2023-03-21 2023-07-11 深圳市罗湖区人民医院 Arctigenin derivative and preparation method and application thereof
CN116410160B (en) * 2023-03-21 2024-03-08 深圳市罗湖区人民医院 Arctigenin derivative and preparation method and application thereof

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