CN102675104A - Derivative of high veratryl alcohol and medical application of derivative of high veratryl alcohol - Google Patents
Derivative of high veratryl alcohol and medical application of derivative of high veratryl alcohol Download PDFInfo
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- CN102675104A CN102675104A CN2011103380210A CN201110338021A CN102675104A CN 102675104 A CN102675104 A CN 102675104A CN 2011103380210 A CN2011103380210 A CN 2011103380210A CN 201110338021 A CN201110338021 A CN 201110338021A CN 102675104 A CN102675104 A CN 102675104A
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- veratryl alcohol
- derivative
- atherosis
- compound
- general formula
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- 0 CC(C)(C(C1)C1O*)N* Chemical compound CC(C)(C(C1)C1O*)N* 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a derivative of high veratryl alcohol and medical application of the derivative of high veratryl alcohol and belongs to the field of medicines. A compound with biological activity is a compound with a general formula (I), and salt, solvate or hydrate of the compound, wherein X1 is H or R4, X2 is H or R4, X3 is H or R4, but X1, X2 and X3 are not all H, and the X1, X2 and X3 can be R4 simultaneously; R4 is a group with a general formula (II), R5 is an alkyl group with 1 to 6 carbon atoms, or can be substituted by R6 optionally and contains a four to seven-membered ring of one or more of additional hetero atoms such as O, S(O)n and NR7; R7 is a C4-6 heterocyclic ring alkyl ring of one or more of hetero atoms such as O, NR8 and S(O)n; n is 0 to 2; and R8 is an alkyl group with 1 to 6 carbon atoms. The derivative of high veratryl alcohol is used for preparing medicines for treating or preventing cardiovascular disease, cerebrovascular disease and peripheral vascular disease, and medicines for preventing and delaying atherosis and relative diseases of atherosis, treating atherosis and relative diseases of atherosis, and delaying the progress of atherosis or preventing relapse of atherosis.
Description
Technical field
The invention belongs to field of medicaments, particularly the verivate of high veratryl alcohol and their therepic use.
Technical background
High Li Lu alcohol is the isomers of trans-resveratrol, and it has cis and trans two kinds of configurations, and the latter is the rock steady structure of high Li Lu alcohol, and biological activity is more extensive.Its structural formula is:
Discover that high Li Lu alcohol has identical pharmacologically active with white lamb's-quarters lamb's-quarters alcohol.This compounds is to come to light as the degeneration-resistant material-plant of vitis spp antitoxin (Phytoalxeni) at first, in various plants, finds in succession again later on.Like medicinal plant Cassia tora, Li Lu, giant knotweed etc., have in addition be exactly food, like grape and peanut.Content can be variant because of the difference of kind in grape for this type of material; Since finding high Li Lu alcohol and white lamb's-quarters lamb's-quarters alcohol; People have carried out deep research to its pharmacologically active successively, and the most attractive two aspects are in its pharmacological action: (1) influences arachidonic metabolism.All direct or indirect relevant therewith of many physiological and pathological processes known today; Like inflammatory reaction, coagulation process, atherosclerotic generation, anaphylaxis, gastric acid secretion, adjusting neuroendocrine, short cell fission etc.; Res is to the double inhibition effect of lipoxygenase and epoxidase, and prompting Res has the value of further investigation in these areas.(2) have anti-oxidant, Green Tea Extract is active.The anti-oxidant activity of phenolic cpd receives people's attention at present, and radical is closely related with the cause and the change procedure of numerous diseases such as aging, cancer, radiation injury, viral hepatitis, ischemic reperfusion injury, senium praecox, mellitus, sacroiliitis.
But from the structure of high Li Lu alcohol and trans-resveratrol, analyze and find that this type of material is a mattress triphenol structure, the compound existence is prone to oxidation, t
1/2Shortcomings such as time weak point, patent medicine index are not suitable for have greatly limited its exploitation and have used.Content of the present invention is exactly under this background, and the high veratryl alcohol with physiologically active has been carried out structural modification and transformed also preferred its biological activity
Summary of the invention
The purpose of this invention is to provide a kind of verivate and therepic use thereof of high veratryl alcohol, new compound has good lipopenicillinase, is expected to be developed to a kind of novel fat-reducing medicament.
The verivate of high veratryl alcohol is characterized in that:
1.
"Compound or its salt, solvolyte or water and the thing of general formula (I),
X wherein
1Be H or R
4, and X
2Be H or R
4, and X
3Be H or R
4, but X
1, X
2And X
3Not all be H, and X
1, X
2And X
3Can be R simultaneously
4
2. R
4Be general formula (II), it is characterized in that:
3. R
5Be C
1-6Alkyl, or can be by R
6Choose replacement wantonly and can contain one or more O of being selected from, S (O)
nAnd NR
7Additional heteroatomic 4-7 unit ring;
4. R
7Be to contain one or more O of being selected from, NR
8And S (O)
nHeteroatomic C
4-6Heterocycloalkyl ring; Each n is 0-2;
5. R
8Be C
1-6Alkyl;
General formula (I) structure comprises its cis-trans-isomer or mixture.
Be used for preparing the application of the medicine of treatment or preventing cardiovascular disease, cerebrovascular disease, peripheral vascular disease.
Be used for the preparation prevention, delay atherosclerosis and relative disease generation, treatment atherosclerosis and relative disease delay its process or stop the application in the recurrence medicine.
Will be appreciated that compound of the present invention can contain one or more asymmetric substituted carbon atoms.The existence of one or more these asymmetric centers can produce steric isomer in formula (1), (2) compound; And under each situation, the present invention should be understood that to expand to all this steric isomers, comprises that enantiomer and Fei Nai reflect isomer; And composition thereof, comprise racemic mixture.
Term " C
1-6Alkyl " be meant straight or branched moieties with 1-6 carbon atom, for example comprise methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl etc.
Term " C
4-6Heterocyclylalkyl is meant that having 3-6 carbon atom is selected from the heteroatomic saturated heterocyclic part of N, O, S with one or more, and for example comprises azetidinyl, oxetanyl, pyrrolidyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl etc.
Term " halogen " is meant fluorine, chlorine, bromine or iodine.
The salt of formula (1), (2) compound comprises pharmacologically acceptable salts; For example from inorganic or organic acid deutero-acid salt, example hydrochloric acid salt, hydrobromide, right-tosylate, phosphoric acid salt, vitriol, perchlorate, acetate, trifluoroacetate, propionic salt, Citrate trianion, malonate, succinate, lactic acid salt, oxalate, tartrate and benzoate etc.
Can also form salt with alkali.This salt comprises from inorganic or organic bases deutero-salt, for example an alkali metal salt such as magnesium or calcium salt and organic amine salt such as morpholine, piperidines, n n dimetylaniline or diethyl amine salt etc.
The compound of formula (1), (2) can be through any proper method known in the art and/or through following method preparation.Will be appreciated that when needing the particular stereoisomer of formula (1), (2), can use compound method described herein and suitable homochiral starting substance, and/or can use conventional stripping technique (for example, HPLC) from mixture, to split isomer.
Compound of the present invention can be through following method preparation.In below the description and general formula, except as otherwise noted, radicals R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8, be as top defined.Will be appreciated that before any reaction begins the functional group that is present in the following all cpds and hopes to keep possibly be protected form like amino, hydroxyl or carboxyl.In this case, removing of blocking group can be the final step in the specific reactions.The suitable blocking group of this functionality will be apparent to those skilled in the art.
Can be according to the physical-chemical difference of component, in the known manner, end product or midbody with any mixture separation Cheng Chun of gained end product or midbody for example through chromatography, distillation method, fractional crystallization, or form salt under suitable or possible situation.
Beneficial effect of the present invention is that this high veratryl alcohol verivate is one type and has the active compound of obvious lipopenicillinase, is expected to be developed to a kind of novel fat-reducing medicament.
Below in conjunction with embodiment the present invention is described further
Embodiment
Embodiment 1
Synthesizing of high veratryl alcohol trioxy-ethyl isobutyrate
Get 2-isobutyl ethyl bromide 1.12g (6.24mmol) adding and have in the there-necked flask of whipping appts, add 20mlDMF, 0.5K under the stirring at room state successively
2CO
3, the 0.05g Tetrabutyl amonium bromide.Back dropping high veratryl alcohol of 0.39g (1.71mmol) and 10mlDMF mixed liquor stir; After dropwising; Be warming up to 55 ℃ and continue reaction 5h; Filter; Filtrate decompression is revolved steaming, reclaims organic solvent and gets yellow solid, separates through silica gel column chromatography; Get high veratryl alcohol trioxy-methyl isobutyrate 0.56g, yield is 62.3%.
1H-NMR(DMSO，300MHz)1.26(9H，m)，1.58-1.62(18H，m)，4.27(6H，m)，6.26(1H，t)，6.64(2H，d)，6.83(3H，m)，6.88(1H，m)，7.36(2H，m)，MS：570(M
+)。
Reaction formula:
The compound of embodiment 1 shows curative effect in experimental hyperlipidemia model.
Get 50 healthy Kunming mouses, except that the blank group, give fasting 16h mouse, cause experimental hyperlipidemia model with 0.5ml/ abdominal injection 75% yolk emulsion.Be divided at random type group, embodiment 1 compound medication group, high veratryl alcohol group (100mg/kg) and positive controls (fenofibrate, 60mg/kg), 10 every group.Gastric infusion (0.2ml/10g), normal control group and model control group wait capacity 1.0%CMC-Na solution respectively, once a day, and continuous irrigation stomach 6 days.Give fasting 16h mouse with 0.5ml/ abdominal injection 75% yolk emulsion after the last administration once more.The result shows: model group significantly raises serum TG, TC concentration.Significantly reduce serum TG, TC concentration after the compound medication group intervention of embodiment 1.
Experimental hyperlipidemia model experiment result
Compare with blank control group:
△P＜0.05
Compare with model group: * P＜0.05.
Claims (4)
1. the verivate of high veratryl alcohol is characterized in that:
1. compound or its salt, solvolyte or water and the thing of general formula (I),
X wherein
1Be H or R
4, and X
2Be H or R
4, and X
3Be H or R
4, but X
1, X
2And X
3Not all be H, and X
1, X
2And X
3Can be R simultaneously
4
2. R4 is general formula (II), it is characterized in that:
3. R
5Be C
1-6Alkyl, or can be by R
6Choose replacement wantonly and can contain one or more O of being selected from, S (O)
nAnd NR
7Additional heteroatomic 4-7 unit ring;
4. R
7Be to contain one or more O of being selected from, NR
8And S (O)
nHeteroatomic C
4-6Heterocycloalkyl ring; Each n is 0-2;
5. R
8Be C
1-6Alkyl.
2. according to the verivate of the high veratryl alcohol described in the claim 1, it is characterized in that: general formula (I) structure comprises its cis-trans-isomer or mixture.
3. according to the verivate of the described high veratryl alcohol in the claim 1, it is characterized in that: be used for preparing the application of the medicine of treatment or preventing cardiovascular disease, cerebrovascular disease, peripheral vascular disease.
4. according to the verivate of the described high veratryl alcohol in the claim 1; It is characterized in that: be used for the preparation prevention, delay atherosclerosis and relative disease generation; Treatment atherosclerosis and relative disease delay its process or stop the application in the recurrence medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103380210A CN102675104A (en) | 2011-10-31 | 2011-10-31 | Derivative of high veratryl alcohol and medical application of derivative of high veratryl alcohol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103380210A CN102675104A (en) | 2011-10-31 | 2011-10-31 | Derivative of high veratryl alcohol and medical application of derivative of high veratryl alcohol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102675104A true CN102675104A (en) | 2012-09-19 |
Family
ID=46807731
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011103380210A Withdrawn CN102675104A (en) | 2011-10-31 | 2011-10-31 | Derivative of high veratryl alcohol and medical application of derivative of high veratryl alcohol |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1546455A (en) * | 2003-12-12 | 2004-11-17 | 深圳海王药业有限公司 | Resveratrol oxo acid derivatives, their preparation and pharmaceutical compositions |
| CN101199504A (en) * | 2007-11-21 | 2008-06-18 | 深圳海王药业有限公司 | Function of stilbene oxygen acid or salt in preparing antiatheroscloresis medicament |
| CN102040516A (en) * | 2009-10-23 | 2011-05-04 | 中国人民解放军军事医学科学院毒物药物研究所 | Resveratrol derivative and medical application thereof |
| CN102040517A (en) * | 2009-10-23 | 2011-05-04 | 中国人民解放军军事医学科学院毒物药物研究所 | Resveratrol derivative and application thereof to medicament |
-
2011
- 2011-10-31 CN CN2011103380210A patent/CN102675104A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1546455A (en) * | 2003-12-12 | 2004-11-17 | 深圳海王药业有限公司 | Resveratrol oxo acid derivatives, their preparation and pharmaceutical compositions |
| CN101199504A (en) * | 2007-11-21 | 2008-06-18 | 深圳海王药业有限公司 | Function of stilbene oxygen acid or salt in preparing antiatheroscloresis medicament |
| CN102040516A (en) * | 2009-10-23 | 2011-05-04 | 中国人民解放军军事医学科学院毒物药物研究所 | Resveratrol derivative and medical application thereof |
| CN102040517A (en) * | 2009-10-23 | 2011-05-04 | 中国人民解放军军事医学科学院毒物药物研究所 | Resveratrol derivative and application thereof to medicament |
Non-Patent Citations (1)
| Title |
|---|
| 黄鹏等: "白藜芦醇烟酸酯抗炎、降脂和保肝药理作用研究", 《江西中医学院学报》 * |
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| PB01 | Publication | ||
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Application publication date: 20120919 |