CN115466178A - Nervonic acid derivative and preparation method and application thereof - Google Patents

Nervonic acid derivative and preparation method and application thereof Download PDF

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CN115466178A
CN115466178A CN202110657902.2A CN202110657902A CN115466178A CN 115466178 A CN115466178 A CN 115466178A CN 202110657902 A CN202110657902 A CN 202110657902A CN 115466178 A CN115466178 A CN 115466178A
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hhs
nervonic acid
acid derivative
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condensing
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CN115466178B (en
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李峰
王世潇
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Qingdao Haihe Biotechnology Co ltd
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Abstract

The invention provides a nervonic acid derivative and a preparation method and application thereof. The nervonic acid derivative has a structure shown in a general formula (I), and specifically comprises ten different nervonic acid derivatives. The nervonic acid derivative has novel structure and simple preparation method. Pharmacological experiments prove that the nervonic acid derivative has good neuroprotective effect, can repair nerve cell injury and also has the function of obviously reducing blood fat, so the nervonic acid derivative has the biological activity and the pharmacological activity for remarkably treating and preventing nervous system, cardiovascular and cerebrovascular diseases or metabolic diseases, and has good safety, thereby having important significance for developing novel medicines for preventing or treating the nervous system, the cardiovascular and cerebrovascular diseases or the metabolic diseases.

Description

Nervonic acid derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemistry and medicine, and particularly relates to a nervonic acid derivative, and a preparation method and application thereof.
Background
Nervonic acid (Nervonic acid), also known as shark acid (Selachoeic acid), was first isolated from shark oil in 1926 by Tsujimoto et al and confirmed to be of cis-structure, chemically known as cis-15-tetracosenic acid (cis-15-tetracosenic acid), as white plate crystals, melting point 42-43 ℃, structural formula as follows:
Figure BDA0003111823580000011
nervonic acid is a core natural component of brain nerve cells and tissues, has special biological functions and plays an important role in human health. There are two main routes for the source of nervonic acid in humans: firstly, other fatty acids are converted into nervonic acid by a human body through a series of reactions; and the direct intake of nervonic acid is more beneficial to the rapid absorption of nervonic acid by human bodies, so that the nervonic acid is generally concerned by people through the exogenous intake of nervonic acid.
Research shows that when the content of the nervonic acid is lower than 0.1%, the nervonic acid and saturated twenty-four carbon fatty acid or partial twenty-carbon fatty acid present a competitive relationship to form myelin membrane structures of different components, and the predictable biological function changes are caused along with the changes of the membrane components and structures; however, at high levels, nervonic acid regulates gene expression mainly by direct binding to in vivo transcription factors, alters in vivo metabolism of fat and energy, and studies have also found that nervonic acid can inhibit DNA polymerase (DNA polymerase) in mammals. Thus, many biological functions and pharmacological activities of nervonic acid have been discovered. For example, after the brain takes up nervonic acid, the nerve cells are supplemented, the composition structure and function of the biomembrane are improved, and the normal operation of the brain function is promoted, so that the effects of promoting the brain development, enhancing the memory and preventing the cranial nerve aging are achieved. Nervonic acid content is associated with many cranial nerve disorder diseases or nervous system diseases. After the exogenous nervonic acid enters the human body, the nervonic acid has the function of promoting the synthesis of sphingosine ester (cerebroside, ganglioside) and sphingomyelin in the human body, thereby promoting the myelination of nerve fibers, regenerating the fallen myelin sheath, improving the sclerosis condition and promoting the recovery of damaged nerve fibers. In addition, nervonic acid is monounsaturated fatty acid and is essential fatty acid for human body, which provides heat on one hand, can rapidly decompose and remove redundant triglyceride and cholesterol in blood on the other hand, improves high density lipoprotein and plays a role in bidirectional regulation. Nervonic acid also has effects of keeping blood lipid content normal, scavenging free radicals in blood, improving blood viscosity, regulating blood pressure, dilating blood vessel, effectively preventing atherosclerosis, and promoting gastrointestinal motility.
In conclusion, nervonic acid has not only various biological activities but also various pharmacological activities. Therefore, chemical modification and reconstruction are carried out on the basis of the structure of the nervonic acid to enhance the pharmaceutical property, which is of great significance for developing novel drugs for preventing and treating diseases of nervous system or cardiovascular and cerebrovascular system.
Disclosure of Invention
The invention provides a nervonic acid derivative and a preparation method thereof, and also provides application of the nervonic acid derivative in medicaments for preventing and treating nervous system diseases, cardiovascular and cerebrovascular diseases or metabolic diseases.
In order to realize the purpose of the invention, the technical scheme of the invention is as follows:
the invention provides a nervonic acid derivative, which has a structure shown in a general formula (I):
Figure BDA0003111823580000021
in the formula (I), the compound is shown in the specification,
x is selected from O, NH, S,
Figure BDA0003111823580000022
The side chain of any one of natural or substituted amino acids, wherein n =1-10;
y is selected from hydrogen, side chain of any natural amino acid or substituted amino acid, o-hydroxybenzoic acid and derivatives thereof, leonurine or substituted leonurine, stachydrine or substituted stachydrine, myricetin or substituted myricetin, fucoxanthin or substituted fucoxanthin, protected or deprotected oligosaccharide group consisting of 1-5 monosaccharides, protected or deprotected oligosaccharide alkoxy group consisting of 1-5 monosaccharides and 1-5 carbon atoms, cinnamyl alcohol or substituted cinnamyl alcohol, capsaicin or substituted capsaicin, memantine or substituted memantine, galantamine or substituted galantamine, huperzine A or substituted huperzine A, rivastigmine derivatives or donepezil derivatives.
Further, the nervonic acid derivatives are specifically HHS-1, HHS-2, HHS-3, HHS-4, HHS-5, HHS-6, HHS-7, HHS-8, HHS-9 and HHS-10, and the structural formula is as follows:
Figure BDA0003111823580000031
Figure BDA0003111823580000041
the invention also provides a preparation method of the nervonic acid derivative, which specifically comprises the following steps:
condensing nervonic acid S1 serving as an initial raw material with ethylene glycol to obtain S2, and then condensing the S2 with o-hydroxybenzoic acid S3 and N-methyl-L-proline S4 respectively to obtain HHS-1 and HHS-2;
or esterifying S2 with p-toluenesulfonyl chloride to obtain S5, and condensing S5 with leonurine S6 and capsaicin S7 to obtain HHS-3 and HHS-4;
or etherifying S2 and acetyl lactose bromoglycoside S8 to obtain S9, and deprotecting S9 to obtain HHS-5;
or, condensing the nervonic acid S1 and glycine to obtain S10, and then condensing the S10 and the fucoxanthin S11 to obtain HHS-6;
or, respectively condensing nervonic acid S1 with arrowhead alcohol S12, memantine S13, galantamine S14 and huperzine A S15 to obtain HHS-7, HHS-8, HHS-9 and HHS-10;
wherein, the structural formulas of nervonic acid S1, o-hydroxybenzoic acid S3, N-methyl-L-proline S4, leonurine S6, capsaicin S7, acetyl lactose bromoglycoside S8, fucoxanthin S11, arrowhead S12, memantine S13, galanthamine S14, huperzine A S15, S2, S5, S9 and S10 are shown as follows:
Figure BDA0003111823580000042
Figure BDA0003111823580000051
further, in the step, the condensing agent used in the condensation is one or more of dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and diisopropylcarbodiimide.
In the step, the condensing agent used for condensation is one or two of dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, and diisopropylcarbodiimide.
The invention also provides the application of the nervonic acid derivative in preparing the medicine for preventing and treating nervous system diseases or cardiovascular and cerebrovascular diseases.
Further, the nervous system diseases include alzheimer disease, stroke, parkinson disease, cerebral palsy, brain atrophy, memory loss, insomnia, amnesia, neurasthenia, epilepsy, schizophrenia, confusion, attention deficit disorder; the cardiovascular and cerebrovascular diseases comprise hyperlipidemia, hypertension, hyperglycemia, atherosclerosis, cerebral arteriosclerosis, transient ischemic attack, and multiple sclerosis.
Further, the nervonic acid derivative has the effect of protecting nerve cells.
The invention also provides application of the nervonic acid derivative in preparing a medicament for preventing and treating metabolic diseases.
Further, the nervonic acid derivatives include HHS-1, HHS-2, HHS-3, HHS-5, HHS-6, HHS-7, HHS-8 and HHS-10.
Preferably, the nervonic acid derivatives are HHS-2, HHS-3 and HHS-7.
Further, the metabolic diseases include diabetes, diabetic ketoacidosis, hyperglycemia hyperostosis syndrome, and obesity.
Further, the concentration of the nervonic acid derivative is 10-20 μ M.
Further, the nervonic acid derivative has the effect of reducing blood fat.
Compared with the prior art, the invention has the advantages and beneficial effects that:
the invention prepares various nervonic acid derivatives on the basis of the structure of nervonic acid, and has novel structure and simple preparation method. Pharmacological experiments prove that the multiple nervonic acid derivatives have good neuroprotective effect, can repair nerve cell injury, and can play a role in obviously reducing blood fat, so the nervonic acid derivatives have biological activity and pharmacological activity for remarkably treating and preventing diseases of nerves, cardiovascular and cerebrovascular systems and metabolic diseases, and are very beneficial to preparation of medicaments for corresponding diseases. In addition, the nervonic acid derivative has good safety and further development value.
Detailed Description
The present invention will be further described with reference to the following examples. In the following examples, unless otherwise specified, the experimental methods used were all conventional methods, and materials, reagents and the like used were all available from biological or chemical reagents companies.
Example 1: the synthetic route of S2 is as follows:
Figure BDA0003111823580000061
adding nervonic acid S1 (3.66g, 10mmol) into 1,4-dioxane (50 mL), sequentially adding dicyclohexylcarbodiimide DCC (2.47g, 12mmol) and ethylene glycol (0.62g, 10mmol), reacting at room temperature for 24 hours, filtering, concentrating the mother liquor, evaporating to dryness, and performing column chromatography to obtain S2 with the yield of 55%. ESI-MS: (m/z,%) = 411M + H] + 。
Example 2: the synthetic route for HHS-1 is as follows:
Figure BDA0003111823580000062
adding S2 (0.4g, 1mmol) into 1,4-dioxane (30 mL), sequentially adding dicyclohexylcarbodiimide DCC (0.25g, 1.2mmol) and S3 (0.14g, 1mmol), reacting at room temperature for 24 hours, filtering, concentrating and evaporating mother liquor, and performing column chromatography to obtain HHS-1 with the yield of 35%. ESI-MS: (m/z,%) = 531M + H] + 。
Example 3: the synthetic route for HHS-2 is as follows:
Figure BDA0003111823580000071
adding S2 (0.4g, 1mmol) into 1,4-dioxane (30 mL), sequentially adding dicyclohexylcarbodiimide DCC (0.25g, 1.2mmol) and S4 (0.13g, 1mmol), reacting at room temperature for 24 hours, filtering, concentrating the mother liquor, evaporating to dryness, and performing column chromatography to obtain HHS-2 with the yield of 31%. ESI-MS: (m/z,%) = 522M + H] + 。
Example 4: the synthetic route of S5 is as follows:
Figure BDA0003111823580000072
adding S2 (4g, 10mmol) into 1,4-dioxane (30 mL), cooling to 0 ℃, and sequentially adding K 2 CO 3 (2.5 g, 20mmol) and p-toluenesulfonyl chloride (2g, 10mmol), heating to room temperature after adding, reacting for 24 hours, filtering, concentrating the mother liquor, evaporating to dryness, and performing column chromatography to obtain S5, wherein the yield is 95%. ESI-MS: (m/z,%) =565[ M ] +H] + 。
Example 5: the synthetic route of HHS-3 is as follows:
Figure BDA0003111823580000073
s6 (0.3g, 1mmol) is taken and added with 1,4-dioxane (30 mL), naH (0.026g, 1.1mmol) is added, after stirring for 30 minutes, S5 (0.56g, 1mmol) is added, reaction is carried out for 24 hours at room temperature, mother liquor is concentrated and evaporated to dryness, HHS-3 is obtained by column chromatography, and the yield is 45%. ESI-MS: (m/z,%) = 704M + H] + 。
Example 6: the synthetic route for HHS-4 is as follows:
Figure BDA0003111823580000074
s7 (0.3g, 1mmol) was added to 1,4-dioxane (30 mL), naH (0.026g, 1.1m) was addedmol), stirring for 30 min, adding S5 (0.56g, 1mmol), reacting at room temperature for 24h, concentrating the mother liquor, evaporating to dryness, and performing column chromatography to obtain HHS-4 with 53% yield. ESI-MS: (m/z,%) = 698M + H] + 。
Example 7: the synthetic route for HHS-5 is as follows:
Figure BDA0003111823580000081
s2 (0.4g, 1mmol) is taken and added with 1,4-dioxane (30 mL), and then aqueous solution (30 mL) of acetyl lactose bromoglycoside S8 (0.7g, 1mmol), tetrabutylammonium bromide (0.32g, 1mmol) and potassium carbonate (0.69g, 5mmol) are added in turn, the mixture is heated to 45 ℃ and stirred for 3 hours, water is added for layering, the organic phase is washed by water and saturated common salt solution, dried and subjected to column chromatography to obtain S9, the yield is 52%.
Adding S8 (0.5g, 0.5mmol) into anhydrous methanol (30 mL), slowly dropwise adding a 5.4mol/L sodium methoxide methanol solution (6.6 mL) at room temperature, continuously stirring for reacting for 4 hours, adding tetrahydrofuran (30 mL) after the reaction is completed, then adding cation exchange resin to adjust the pH value to acidity, continuously stirring for 12 hours, filtering, concentrating the mother solution, evaporating to dryness, and carrying out column chromatography to obtain HHS-5 with the yield of 75%. ESI-MS: (m/z,%) = 735M + H] + 。
Example 8: the synthetic route of S10 is as follows:
Figure BDA0003111823580000082
adding nervonic acid S1 (3.66g, 10mmol) into 1,4-dioxane (50 mL), sequentially adding dicyclohexylcarbodiimide DCC (2.47g, 12mmol) and glycine (0.75g, 10mmol), reacting at room temperature for 24 hours, filtering, concentrating the mother liquor, evaporating to dryness, and performing column chromatography to obtain S10, wherein the yield is 59%. ESI-MS: (m/z,%) =424[ M + ] H] + 。
Example 9: the synthetic route for HHS-6 is as follows:
Figure BDA0003111823580000083
s10 (0.42g, 1mmol) is added into 1,4-dioxane (30 mL), dicyclohexylcarbodiimide DCC (0.25g, 1.2mmol) and S11 (0.66g, 10mmol) are sequentially added, reaction is carried out for 24 hours at room temperature, filtration is carried out, mother liquor is concentrated and evaporated to dryness, and column chromatography is carried out to obtain HHS-6 with the yield of 29%. ESI-MS: (m/z,%) =1064[ M + ] H] + 。
Example 10: the synthetic route of HHS-7 is as follows:
Figure BDA0003111823580000091
adding nervonic acid S1 (3.66g, 10mmol) into 1,4-dioxane (50 mL), sequentially adding dicyclohexylcarbodiimide DCC (2.47g, 12mmol) and S12 (1.54g, 10mmol), reacting at room temperature for 24 hours, filtering, concentrating and evaporating mother liquor, and performing column chromatography to obtain HHS-7 with the yield of 45%. ESI-MS: (m/z,%) = 503M + H] + 。
Example 11: the synthetic route for HHS-8 is as follows:
Figure BDA0003111823580000092
adding nervonic acid S1 (3.66g, 10mmol) into 1,4-dioxane (50 mL), sequentially adding dicyclohexylcarbodiimide DCC (2.47g, 12mmol) and S13 (1.6g, 10mmol), reacting at room temperature for 24 hours, filtering, concentrating the mother liquor, evaporating to dryness, and performing column chromatography to obtain HHS-8 with the yield of 54%. ESI-MS: (m/z,%) =514[ M + ] H] + 。
Example 12: the synthetic route for HHS-9 is as follows:
Figure BDA0003111823580000093
adding nervonic acid S1 (3.66g, 10mmol) into 1,4-dioxane (50 mL), sequentially adding dicyclohexylcarbodiimide DCC (2.47g, 12mmol) and S14 (2.9g, 10mmol), reacting at room temperature for 24 hours, filtering, concentrating and evaporating mother liquor, and performing column chromatography to obtain HHS-9 with the yield of 35%. ESI-MS：(m/z，％)＝636[M+H] + 。
Example 13: the synthetic route for HHS-10 is as follows:
Figure BDA0003111823580000094
adding nervonic acid S1 (3.66g, 10mmol) into 1,4-dioxane (50 mL), sequentially adding dicyclohexylcarbodiimide DCC (2.47g, 12mmol) and S15 (2.4g, 10mmol), reacting at room temperature for 24 hours, filtering, concentrating and evaporating mother liquor, and performing column chromatography to obtain HHS-10 with the yield of 45%. ESI-MS: (m/z,%) = 591M + H] + 。
Example 14: determining the Effect of nervonic acid derivatives on a model of glutamate-induced neuronal cell injury
Grouping experiments: blank control group, model group (Glu, 200. Mu.M), positive drug group (MK-801), drug control group (nervonic acid), and 4 dose groups (1, 5, 10, 20. Mu. Mol) of test compound.
Sample treatment: the samples were dissolved in DMSO and stored at low temperature, and the concentration of DMSO in the final system was controlled within a range that did not affect the assay activity (0.1%).
The experimental method comprises the following steps: adding the drug to be screened on the sixth day after the primary rat cerebellar granule nerve cells are cultured (the drug should be diluted by 1000 times when being added into a 96-well plate); glutamic acid was added at a concentration of 200. Mu.M on day seven (100-fold dilution was required when adding 96-well plates); cell viability was measured on day eight using MTT (final concentration should be 0.5mg/ml when added to 96-well plates).
The results of the experiment are shown in table 1: in the glutamate induced nerve cell damage model, four doses of other compounds, except HHS-1 (1. Mu.M) and HHS-6 (1. Mu.M), showed different degrees of improvement in cell survival compared to the glutamate model group, indicating that these compounds have protective effects on nerve cells, especially the compounds HHS-1 (20. Mu.M), HHS-2 (10. Mu.M, 20. Mu.M), HHS-3 (20. Mu.M), HHS-4 (20. Mu.M), HHS-5 (10. Mu.M, 20. Mu.M), HHS-6 (20. Mu.M), HHS-7 (20. Mu.M), HHS-8 (20. Mu.M), HHS-9 (20. Mu.M) and HHS-10 (20. Mu.M), were significantly different from the glutamate-producing module, and the protective effects were superior to that of 20. Mu.M, indicating that these concentrations of compounds had superior neuroprotective effects to nervonic acids. Therefore, the nervonic acid derivative prepared by the invention has good neuroprotective effect.
Table 1: nerve cell survival rate test results
Figure BDA0003111823580000101
Figure BDA0003111823580000111
Figure BDA0003111823580000121
Example 15: assay for in vitro lipid-lowering Activity of nervonic acid derivatives
1. Experimental materials:
DMEM culture medium, american FBS serum, glutamine, penicillin, streptomycin, 96-well plate, human liver cancer cell HepG2, oil red O, isopropanol, DMSO and the like
2. The experimental method comprises the following steps:
1) 12000 HepG2 cells in the logarithmic growth phase are inoculated to a 96-well plate at 100 mu l/well; and then grouping: blank control group, model group (OA), positive drug group (simvastatin), drug control group (nervonic acid), and test compound (10 μmol);
2) After 12h, changing the medium into serum-free DMEM medium after the fusion degree reaches 70-80%, wherein each well is 80 mu l, and starving for 12h; after 12h, 20. Mu.l serum-free medium was added to the blank control, and 10. Mu.l of inducer OA (final concentration 80. Mu.M) was added to each well of the other groups; on the basis, the model group is supplemented with 10 mul of serum-free culture, the administration group is added with 10 mul of the compound to be tested, the final concentration is 10 mul, and the culture box is incubated for 24h;
3) After 24h incubation, removing the culture medium, washing with PBS (room temperature) buffer solution for 1 time, adding 80 μ l of 4% paraformaldehyde fixing solution into each well, fixing at room temperature for 0.5h, washing with PBS for 1 time, rinsing with 60% isopropanol for 10min, adding 60 μ l of 0.3% oil red O (Sigma O0625) dye solution into each well, dyeing at room temperature for 1h, and then washing with PBS buffer solution for 3 times;
4) Dissolved in DMSO, 100. Mu.l/well, and OD measured at 358nm with microplate reader.
3. The results are shown in Table 2: compared with OA in a model group, the OD values of HHS-1, HHS-2, HHS-3, HHS-5, HHS-6, HHS-7, HHS-8 and HHS-10 are all reduced, which shows that the compounds have better in-vitro lipid-lowering effect, and the lipid-lowering effect of HHS-2, HHS-3 and HHS-7 is obviously better than that of simvastatin and nervonic acid.
Table 2: assay for in vitro lipid-lowering Activity of nervonic acid derivatives
Figure BDA0003111823580000122
Figure BDA0003111823580000131
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.

Claims (10)

1. A nervonic acid derivative characterized by: the nervonic acid derivative has a structure shown in a general formula (I):
Figure FDA0003111823570000011
in the formula (I), the compound is shown in the specification,
x is selected from O, NH, S,
Figure FDA0003111823570000012
The side chain of any one of natural or substituted amino acids, wherein n =1-10;
y is selected from hydrogen, side chain of any natural amino acid or substituted amino acid, o-hydroxybenzoic acid and derivatives thereof, leonurine or substituted leonurine, stachydrine or substituted stachydrine, myricetin or substituted myricetin, fucoxanthin or substituted fucoxanthin, protected or deprotected oligosaccharide group consisting of 1-5 monosaccharides and 1-5 carbon atoms, arrowhead or substituted arrowhead, capsaicin or substituted capsaicin, memantine or substituted memantine, galantamine or substituted galantamine, huperzine A or substituted huperzine A, rivastigmine derivatives or donepezil derivatives.
2. The nervonic acid derivative according to claim 1, wherein: the nervonic acid derivatives are HHS-1, HHS-2, HHS-3, HHS-4, HHS-5, HHS-6, HHS-7, HHS-8, HHS-9 and HHS-10, and the structural formula is as follows:
Figure FDA0003111823570000013
Figure FDA0003111823570000021
3. the method for preparing a nervonic acid derivative according to claim 2, which comprises the following steps:
condensing nervonic acid S1 serving as an initial raw material with ethylene glycol to obtain S2, and then condensing the S2 with o-hydroxybenzoic acid S3 and N-methyl-L-proline S4 respectively to obtain HHS-1 and HHS-2;
or esterifying S2 with p-toluenesulfonyl chloride to obtain S5, and condensing S5 with leonurine S6 and capsaicin S7 to obtain HHS-3 and HHS-4;
or etherifying S2 and acetyl lactose bromoglycoside S8 to obtain S9, and deprotecting S9 to obtain HHS-5;
or, condensing the nervonic acid S1 and glycine to obtain S10, and then condensing the S10 and the fucoxanthin S11 to obtain HHS-6;
or, respectively condensing nervonic acid S1 with arrowhead S12, memantine S13, galantamine S14 and huperzine A S15 to obtain HHS-7, HHS-8, HHS-9 and HHS-10;
wherein, the structural formulas of nervonic acid S1, o-hydroxybenzoic acid S3, N-methyl-L-proline S4, leonurine S6, capsaicin S7, acetyl lactose bromoglycoside S8, fucoxanthin S11, arrowhead S12, memantine S13, galanthamine S14, huperzine A S15, S2, S5, S9 and S10 are shown as follows:
Figure FDA0003111823570000031
Figure FDA0003111823570000041
4. the production method according to claim 3, characterized in that: in the step, the condensing agent used in the condensation is one or more of dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and diisopropylcarbodiimide.
5. The use of a nervonic acid derivative as claimed in claim 1 or 2 in the preparation of a medicament for the prevention and treatment of neurological diseases or cardiovascular and cerebrovascular diseases.
6. The use according to claim 5, wherein the neurological disorders comprise Alzheimer's disease, stroke, parkinson's disease, cerebral palsy, brain atrophy, memory loss, insomnia, amnesia, neurasthenia, epilepsy, schizophrenia, confusion, attention deficit disorder; the cardiovascular and cerebrovascular diseases comprise hyperlipidemia, hypertension, hyperglycemia, atherosclerosis, cerebral arteriosclerosis, transient ischemic attack, and multiple sclerosis.
7. Use of the nervonic acid derivative of claim 1 or 2 for the preparation of a medicament for the prevention and treatment of metabolic diseases.
8. The use of claim 7, wherein the nervonic acid derivative comprises HHS-1, HHS-2, HHS-3, HHS-5, HHS-6, HHS-7, HHS-8 and HHS-10.
9. The use according to claim 7, wherein the metabolic disease comprises diabetes, diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, obesity.
10. The use according to claim 5 or claim 7, wherein the nervonic acid derivative is used at a concentration of 10 μ M to 20 μ M.
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