CN1259329C - Kaempferol derivative and its medicinal use - Google Patents
Kaempferol derivative and its medicinal use Download PDFInfo
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- CN1259329C CN1259329C CN 01134610 CN01134610A CN1259329C CN 1259329 C CN1259329 C CN 1259329C CN 01134610 CN01134610 CN 01134610 CN 01134610 A CN01134610 A CN 01134610A CN 1259329 C CN1259329 C CN 1259329C
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- kaempferol
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- present
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Abstract
The present invention relates to kaempferol derivatives, a preparation method for the kaempferol derivatives, a medicinal composition containing the kaempferol derivatives, and the application of the kaempferol derivatives and the medicinal composition containing the kaempferol derivatives to preventing or treating 5HT1a acceptor related diseases, particularly preventing or treating athymia or dysphoria.
Description
The present invention relates to kaempferol derivative, its preparation method contain their pharmaceutical composition, and they is as prevention or treatment and 5HT
1AThe purposes of receptor related disease, especially prevention or treatment depression or anxiety.
The non-toxic cotton seed that belongs to the cotton seed class is the seed of non-toxic cotton mature fruit, general feed as livestock.Non-toxic cotton is called low gossypol cotton again.Up to the present, do not see the report that comprises contained kaempferia galamga phenols chemical ingredients in the non-toxic cotton seed and biological activity and medicinal use as yet.
Purpose of the present invention is a chemical monomer of seeking biologically active in the non-toxic cotton seed, and and then develops the medicinal use of this chemical monomer.
The present inventor is through extensively and profoundly research, now from for example extracting kaempferol derivative (compound 1, the R with formula I the non-toxic cotton seed
1, R
2, R
3All or be hydrogen atom), and prepared compound 1 alkylate (R by alkylated reaction
1, R
2, R
3All or part of is C1～C5 alkyl).Found that the compound with formula I is to 5HT
1AAcceptor has very high affinity, and demonstrates good curing and prevention and 5HT
1ADiseases associated and symptom, as: to the disease of cental system, as the prevention of dysthymia disorders, anxiety disorder etc. and therapeutic action and to the treatment and the regulating effect of the heart, cerebrovascular disease.The present invention is based on above discovery is accomplished.
The structural formula of formula I
R among the formula I
1, R
2, R
3Can all or part ofly be hydrogen atom or C1～C5 alkyl, C1～C5 alkyl comprises methyl, ethyl, propyl group (containing sec.-propyl and n-propyl), butyl (containing normal-butyl, isobutyl-and the tertiary butyl) and amyl group (containing n-pentyl, isopentyl etc.).R
1, R
2, R
3Be preferably hydrogen atom, the highly preferred compound of the present invention is kaempferol-3-O-β-D-apiose-(1 → 2)-[α-L-rhamnosyl (1 → 6)]-β-D-glycoside.
The present invention relates to kaempferol-3-O-β-D-apiose-(1 → 2)-[α-L-rhamnosyl (1 → 6)]-β-D-glycoside and the alkyl derivative thereof of structure suc as formula I, they can be used as 5HT
1AThe aglucon of acceptor and demonstrate good preventing or treatment and 5HT
1AThe activity of receptor system diseases associated, especially prevention or treatment depression and/or anxiety.
The invention still further relates to pharmaceutical composition, it comprises formula I compound and pharmaceutical carrier.
The invention still further relates to as prevention or treatment and 5HT
1AThe formula I compound of diseases associated or symptom, especially prevention or treatment depression and/or anxiety disorder
The invention still further relates to as prevention or treatment and 5HT
1AThe pharmaceutical composition that contains formula I compound of diseases related or symptom, especially prevention or treatment depression and/or anxiety.
According to the present invention, formula I compound of the present invention or pharmaceutical composition can be by oral, non-enteron aisle or topical routes, and form of administration can be a tablet for example, capsule, solution, suspension, injection liquid, drip liquid etc.
According to the present invention, pharmaceutical composition of the present invention can prepare by means known in the art, for example formula I compound is mixed with pharmaceutical carrier.
According to the present invention, the kaempferol in the formula I compound-3-O-β-D-apiose-(1 → 2)-[α-L-rhamnosyl (1 → 6)]-β-D-glycoside is from for example obtaining the non-toxic cotton seed.Used organism solvent comprises alcohols such as methyl alcohol, ethanol, propyl alcohol, butanols etc.; Halo alkanes such as methylene dichloride, trichloromethane etc.; Ester class such as methyl acetate, ethyl acetate, propyl acetate etc.; And ethers such as sherwood oil, ether.
According to the present invention, the alkyl derivative of the kaempferol in the formula I compound-3-O-β-D-apiose-(1 → 2)-[α-L-rhamnosyl (1 → 6)]-β-D-glycoside can be by obtaining the reaction of the haloalkane of kaempferol-3-O-β-D-apiose-(1 → 2)-[α-L-rhamnosyl (1 → 6)]-β-D-glycoside and calculated amount in alkaline alcohol solution.
The following examples and biological activity test are to further describe of the present invention, but do not mean that any limitation of the invention.
Embodiment 1
Formula I compound (R of the present invention
1, R
2, R
3Be hydrogen atom): the preparation of kaempferol-3-O-β-D-apiose-(1 → 2)-[α-L-rhamnosyl (1 → 6)]-β-D-glycoside (compound 1).
Non-toxic cotton seed 1kg is pulverized, cross 20 mesh sieves then, sieved the thing Petroleum ether extraction.Each with 3 liters of sherwood oils, extract 3 times.Dregs of a decoction extraction using alcohol is used 3 liters of ethanol at every turn, extracts 3 times, merges.Reduction vaporization is to weight.Obtain ethanol extraction 300g.The ethanol extraction water dissolution extracts it in n-butanol/water, obtain n-butanol extract 134g.Propyl carbinol is got silica gel column chromatography separation on the thing, and developping agent is a propyl carbinol: acetic acid: water=7: 1: 2 obtains formula I compound.
Compound 1 is a yellow powder.Phenol-H
2SO
4Reaction is reddish black (heating), and showing has sugar to exist.The HCl-Mg reaction shows red, shows it is flavonoid compound.IR spectrum (KBr) cm
-1: 3379 (v
-OH), 1655 (v
-C=O), showing has hydroxyl and carbonyl to exist; Behind UV spectrum (MeOH) and the adding displacement diagnostic reagent, change according to its absorbing wavelength, can determine that glucoside unit is kaempferol, the Compound I ultraviolet spectrum data sees Table 1.
The UV spectrum of table 1 compound 1 and the test result of diagnostic reagent
| Reagent | Band I | Band II | The result |
| MeOH MeONa AlCl 3 AlCl 3/HCl NaAc NaAc/H 3BO 3 | 345.5 394.0 398.0 397.5 375.0 348.0 | 266.5 274.5 275.5 276.0 274.0 267.0 | 3-O-replaces 4 '-OH 5-OH 5-OH 7-OH does not have o-dihydroxy |
Compound 1 negative ion ESI-MS provides m/z 725[M-H]
-, determine that its molecular weight is 726.Compound 1 nuclear magnetic data sees Table 2.
Table 2 compound 1
13C-NMR,
1H-NMR,
13C
-1H COSY and HMBC data
(DMSO-d
6，600MHz)
| No. | δ c | δ H(J，Hz) | Crosspeaks in HMBC spetrum |
| Kaempferol 3 4 5 6 7 8 9 10 1’ 2’，6’ 3’，5’ 4’ | 156.19 132.70 177.18 161.12 98.58 164.14 93.58 156.29 103.75 120.87 130.79 115.04 159.71 | 6.18(1H，d，2.02Hz) 6.39(1H，d，2.02Hz) 7.99(2H，d，8.79Hz) 6.87(2H，d，8.79Hz) | 161.12(5)，164.14(7)，93.58(8)，103.75(10) 98.58(6)，103.75(10)，156.29(9) 115.04(3’，5’)，156.19(2)，159.71(4’) 120.87(1’)，130.79(2’，6’)，159.71(4’) |
| Glucose 1 2 3 4 5 6 | 98.58 76.94 76.89 70.23 75.56 66.54 | 5.45(1H，d，7.33Hz) 3.38(1H，m) 3.38(1H，m) 3.01(1H.m) 3.19(1H，m) 3.62(1H，d，10.26Hz) 3.28(1H，m) | 132.70(3)，76.89(glc-3)，75.56(glc-5) 98.58(glc-1) 76.94(glc-2) 75.56(glc-5) 70.23(glc-4) 100.48(rha-1)，98.58(glc-1)， |
| Rhamnose 1 2 3 4 5 6 | 100.48 70.16 70.42 71.16 68.20 17.56 | 4.30(1H，s) 3.33(1H，m) 3.20(1H，m) 3.04(1H，m) 3.19(1H，m) 0.94(3H，d，6.23Hz) | 66.54(glc-6)，68.20(rha-5)，70.16(rha-2) 70.42(rha-3)，100.48(rha-1) 71.16(rha-4) 70.42(rha-3) 71.16(rha-4) 68.20(rha-5)，71.16(rha-4) |
| Apiose 1 2 3 4 5 | 108.56 76.12 79.16 73.91 64.20 | 5.33(1H，d，1.28Hz) 3.80(1H，d，3.85Hz) 3.84(1H，d，9.34Hz) 3.97(1H，d，9.34Hz) 3.44(1H，m) 3.41(1H，m) | 76.94(glc-2)，79.16(api-3)，73.91(api-4) 64.20(api-5) 79.16(api-3)，64.20(api-5) 73.91(api-4) |
Embodiment 2
Formula I compound of the present invention: the preparation method of kaempferol-3-O-β-D-apiose-(1 → 2)-[α-L-rhamnosyl (1 → 6)]-β-D-glycoside alkylate.With R
1, R
2, R
3All be that methyl is an example.
Get compound 120mg (2.75 * 10
-5Mol) and the 1ml methyl iodide be dissolved in the 30ml methanol solution, 50 ℃ of water-baths are stirred, and slowly add calculated amount (8.25 * 10
-5The methanol solution of sodium methylate mol).Leave standstill after dripping chloroform 20ml behind the reaction naturally cooling, remove by filter sodium iodide, filtrate decompression is dense to doing.Reaction product is crossed silica gel column chromatography, and with chloroform: methyl alcohol (7: 1) wash-out obtains R
1, R
2And R
3All be the derivative 5,7 of methyl, 4-trimethylammonium-3-O-β-D apiose (1 → 2)-[α-L-rhamnosyl (1 → 6)]-β-D-glycoside
Embodiment 3
Formula I compound of the present invention: the antidepressant experiment of kaempferol-3-O-β-D-apiose-(1 → 2)-[α-L-rhamnosyl (1 → 6)]-β-D-glycoside.
1. forced swimming experiment
(1) (Arch Int Pharmacodn Ther, 1977,229 (2): 327) method is carried out to press document.Mouse oral administration thing is after 60 minutes, put into open glass cylinder (high 19cm, diameter 12cm), depth of water 8cm in the cylinder, 22～23 ℃ of water temperatures, mouse were put in the water 6 minutes, resolved instrument with the Vidio motion and observed accumulative total dead time and the reactivity in 4 minutes behind the mouse, statistical method is the same, the results are shown in Table 3.
The behavior of 1 pair of mouse forced swimming of table 3 compound influence the result
| Medicine | Dosage (mg/kg) | Dead time (second) |
| The blank Compound I | 7.5 15 30 | 136.2±58.4 127.8±49.1 84.4±40.9 * 54.3±44.9 ** |
*P＜0.05,
*P＜0.01, medicine is oral in testing preceding 60 minutes.
(2) discuss
Mouse forced swimming behavioral experiment is classical depression model, animal places water to struggle before this, attempt is escaped, enter desperate state at last and transfixion, down can obviously shorten the dead time, and table 3 result shows that compound 1 can make the dead time significantly shorten among the formula I of the present invention under 15mg/kg dosage, therefore, its anti-strongly fragrant activity is stronger.
2.5HT
1AThe acceptor experiment
(1) method: get 1: 5 rat brain cortex membrane receptor suspension 50 μ l, mark aglucon (20nmol
3H-8-OH-DPAT) 20 μ l, the testing sample 20 μ l of different concns add buffered soln to cumulative volume 200 μ l, incubate temperature behind the mixing 30 minutes in 25 ℃ water-bath, behind quick suction filtration and washing membrane receptor, count on liquid scintillation instrument.Replace testing sample with 20 μ l 1mmol 5-HT sulfuric acid flesh liver liquid when measuring non-specific combination.Positive control drug is 5HT
1AThe acceptor portion agonist buspirone.It is right to utilize the radiation counter value to calculate testing sample
3H-OH-DPAT competes inhibiting rate.
(2) result: 5HT
1AThe acceptor experimental result is seen Fig. 1.Fig. 1 shows 1 couple of 5HT of compound
1AAcceptor has high affinity.
Claims (6)
1. formula I compound
R wherein
1, R
2, R
3Can all or part ofly be hydrogen atom or C1～C5 alkyl, C1～C5 alkyl comprises methyl, ethyl, sec.-propyl, n-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or isopentyl.
2. the compound of claim 1, wherein R
1, R
2, R
3It all is hydrogen atom.
3. claim 1 or 2 compound, wherein said compound is kaempferol-3-O-β-D-apiose-(1 → 2)-[α-L-rhamnosyl (1 → 6)]-β-D-glycoside.
4. contain the pharmaceutical composition that right requires arbitrary formula I compound of 1-3 and pharmaceutical carrier.
5. the arbitrary formula I compound of claim 1-3 is at preparation prevention or treatment and 5HT
1APurposes in the medicine of receptor related disease.
6. the purposes of claim 5, wherein said and 5HT
1AReceptor related disease or symptom are depression or anxiety.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01134610 CN1259329C (en) | 2001-11-07 | 2001-11-07 | Kaempferol derivative and its medicinal use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01134610 CN1259329C (en) | 2001-11-07 | 2001-11-07 | Kaempferol derivative and its medicinal use |
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| Publication Number | Publication Date |
|---|---|
| CN1417218A CN1417218A (en) | 2003-05-14 |
| CN1259329C true CN1259329C (en) | 2006-06-14 |
Family
ID=4672609
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 01134610 Expired - Fee Related CN1259329C (en) | 2001-11-07 | 2001-11-07 | Kaempferol derivative and its medicinal use |
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| Country | Link |
|---|---|
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100355744C (en) * | 2004-05-03 | 2007-12-19 | 深圳微芯生物科技有限责任公司 | Separation and extraction of flavone natural product active component for treating prostating disorders and medicinal preparation preparing and use thereof |
| CN100367970C (en) * | 2005-01-24 | 2008-02-13 | 中国人民解放军第二军医大学 | Use of kaempferol and its derivative in preparing medicines for depression or dementia |
| CN102845609B (en) * | 2012-08-21 | 2014-07-09 | 湖南农业大学 | Application of Kaempferitrin to animal edible additive |
| CN104041821B (en) * | 2014-07-02 | 2015-12-02 | 中国科学院西北高原生物研究所 | A kind of black fruit lyceum anthocyanidin chewable tablets |
| CN106883278A (en) * | 2017-03-21 | 2017-06-23 | 广东药科大学 | A kind of 3,5,7 trihydroxy 2 (4 hydroxy phenyl) ketone derivatives of chromene 4 |
| CN109942592B (en) * | 2019-05-09 | 2020-07-14 | 江西中医药大学 | Novel protopine type alkaloid and preparation method and application thereof |
-
2001
- 2001-11-07 CN CN 01134610 patent/CN1259329C/en not_active Expired - Fee Related
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|---|---|
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