CN1923790A - Kutkin derivative, preparation method and application thereof - Google Patents
Kutkin derivative, preparation method and application thereof Download PDFInfo
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- CN1923790A CN1923790A CN 200610037302 CN200610037302A CN1923790A CN 1923790 A CN1923790 A CN 1923790A CN 200610037302 CN200610037302 CN 200610037302 CN 200610037302 A CN200610037302 A CN 200610037302A CN 1923790 A CN1923790 A CN 1923790A
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- kutkin
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Abstract
The invention discloses a derivant of kutkin with chemical structural formula as formula I, wherein R1 is NO2, NH2 or amide; R2 is H, carbonyl or diaminocarbonyl. The preparing method comprises the following steps: nitrating kutkin to obtain kutkin derivant substituted by nitro group or kutkin derivant based on substituted nitro group; or kutkin derivant substituted by acetylamino.
Description
Technical field
The present invention relates to derivative of kutkin and preparation method thereof.
The invention still further relates to the application of derivative in pharmacy of described kutkin.
Background technology
Sacroiliitis (being called for short RA, down together) is a kind of chronic damaging Immunological diseases, can damage outside synovial tissue and the joint and organize.Immune particle accumulates in synovial membrane, causes the damage of patient's RA joint tissue.The net result of RA is to cause a series of pain, mobile difficulty, function damage and rheumatoid disease.
If existing arthritis drug main non-steroid antiinflammatory drug, yet, take this type of medicine for a long time and often produce gastrointestinal side effect.This class medicine proves in experimentation on animals and truly has cartilage injury, and is invalid to the ankle joint inflammation.
The Chinese medicine Rhizoma Picrorhizae is the dry rhizome of scrophulariaceae per nnial herb Rhizoma Picrorhizae, and bitter cold in nature has heat-clearing, dehumidifies, makes eye bright, tonifying liver, beneficial courage, parasiticidal effectiveness, cures mainly diseases such as consumptive disease heat cough, damp-heat dysentery, infantile malnutrition, hot eyes.
Summary of the invention
The object of the present invention is to provide a kind of derivative of kutkin.
The present invention also aims to provide the preparation method of the derivative of described kutkin.
The present invention also aims to provide the application of derivative in the medicine of preparation treatment similar rheumatism and similar rheumatism and arthritis disease of described kutkin.
The derivative of kutkin of the present invention, its chemical formula is shown in the I formula:
The I formula wherein, R
1Be NO
2, NH
2Or acid amides; R
2Be H, carbonyl or carbonyl diamide.Described carbonyl can be selected a kind of in the C1-C6 alkyl-carbonyl for use.
Described carbonyl also can be selected C (O)-NHN (CH for use
2CH
2)
2Or C (O)-NCH
3N (CH
2CH
2)
2
The preparation method of the derivative of kutkin of the present invention comprises:
---kutkin (compound 1) obtains the derivative (compound 2) of the kutkin of nitro replacement through nitration reaction; Or prepare the derivative of the kutkin that nitro replaces based on this, comprise
---the derivative (compound 2) of the kutkin that nitro replaces obtains the derivative (compound 3) of the amino kutkin that replaces again through nitro-reduction reaction; Or the derivative of the kutkin of the amino replacement of preparation based on this, comprise
---the derivative (compound 4) of the kutkin that obtains the kharophen replacement of derivative (compound 3) the process glycylization of the amino kutkin that replaces.
Its chemical equation is as follows:
The derivative of kutkin of the present invention can be used for preparation treatment immune dysfunction diseases, especially rheumatism, similar rheumatism and arthritic medicine.
Described medicine can be made oil-in-water emulsion, and its oil phase can be used vegetables oil such as peanut oil, sweet oil or mineral oil such as Witco 70 and their mixture; Emulsifying agent can be selected natural gummy class such as gum arabic, tragakanta for use, perhaps natural phospholipid such as soybean lecithin and derive from ester and the unsaturated ester class such as the sorbitol monooleate of lipid acid, hexitol or hexitol dehydrate extract to such an extent that the unsaturated ester class is carried out condensation and the product such as the polyethylene sorbitan monooleate that obtain in oxyethane and lipid acid, the hexitol dehydrate.Also can comprise sweeting agent, correctives and tinting material in the same emulsion.
Administering mode can adopt oral administration, also can adopt the intestines external administration, for example subcutaneous embedding, intravenous injection, inhalation, intranasal administration and intraperitoneal administration.In addition, can adopt intermittently administering mode, the heavy dose of medicine of the injection of loop cycle for example, once a day, two days are once, and three days are once, weekly, biweekly, biweekly, twice of January or menstrual regular injection.
The present invention compared with prior art has following advantage:
1, the derivative medicine of kutkin of the present invention also has the cartilage protection effect except having anti-immunocompetence.Its mechanism of action uniqueness is different from any one compound or antibody.Therefore, it will be more effective to the insensitive disease patient of other drug, not have toxic side effect.
2, the derivative raw material sources of kutkin are easy to get, and preparation technology is simple, and is with low cost, and compare other chemicalses or antibody are more economical effectively.And its medicine is used for the treatment of the disease significant side effects, can become clinical use medicine and have economic benefit.
Embodiment
Synthesizing of embodiment 1 4-acetoxy-3-methoxyacetophenone
(2g, 12mmol) (1.28ml 18mmol), and drips triethylamine under the condition of logical nitrogen, reaction solution progressively is warming up to room temperature and stirred 2 hours for dripping acetyl chloride in the 20ml ethyl acetate solution to the kutkin that is cooled to 0 ℃.Reactant washes (50ml * 3) with water 3 times, the organic layer anhydrous sodium sulfate drying, and obtain white crystals 1.8g, productive rate 72% with re-crystallizing in ethyl acetate.mp 56-57℃.
1H NMR(acetone-d
6，ppm)：7.67-7.56(m，2H，Ar-H)，7.21-7.13(d，1H，Ar-H)，3.88(s，3H，OCH
3)，2.57(s，3H，COCH
3)，2.27(s，3H，OCOCH
3)，MS 208。
The molecular formula of product 4-acetoxy-3-methoxyacetophenone is as follows:
Synthesizing of embodiment 2 4-hydroxyl-3-methoxyl group-5-nitro-acetophenone
To kutkin (10.2g, 61mmol) in the 500ml chloroformic solution, (70%, 16.3ml), reaction solution keeps stirring 2 hours to drip concentrated nitric acid at 0 ℃, reaction solution washes (70mlx7) with water 7 times, the organic layer anhydrous sodium sulfate drying, solvent is removed in decompression, adds 95% ethanol 250ml, crystallization is spent the night and is obtained yellow needle-like product 9.5g, productive rate 73%.mp 159-161℃.
1H NMR(CDCl
3，ppm)：11.13(s，1H，OH)，8.32-8.31(d，1H，Ar-H)，7.78-7.77(d，1H，Ar-H)，4.02(s，3H，OCH
3)，2.64(s，3H，COCH
3)，MS 211。
The molecular formula of product 4-hydroxyl-3-methoxyl group-5-nitro-acetophenone is as follows:
Synthesizing of embodiment 3 5-amino-4-hydroxy-3-methoxyl group-methyl phenyl ketone
(2g 9.5mmol) adds 10%Pd/C (200mg) in the ethyl acetate solution, reaction solution is at 40lb/inch to embodiment 2 products
2Hydrogenation 1 hour is filtered, and removes solvent, adds concentrated hydrochloric acid, and filtering-depositing obtains colourless crystallization 1.1g with ethyl alcohol recrystallization, productive rate 53%.
1H NMR(D
2O，ppm)：7.57-7.55(d，1H，Ar-H)，7.45-7.43(d，1H，Ar-H)，3.88(s，3H，OCH
3)，2.55(s，3H，COCH
3)，MS 181。
The molecular formula of product 5-amino-4-hydroxy-3-methoxyl group-methyl phenyl ketone is as follows:
Synthesizing of embodiment 4 5-acetylaminohydroxyphenylarsonic acid 4-hydroxyl-3-methoxyl group-methyl phenyl ketones
(2g 9.5mmol) adds 10%Pd/C (200mg) in the ethyl acetate solution, reaction solution is at 40lb/inch to embodiment 2 products
2Hydrogenation 1 hour is filtered, and not purified, filtrate is cooled to 0 ℃, and (1.0ml, 10.8mmol) with dimethyl aminopyridine 5mg, stirring at room 30 minutes is removed solvent, with THF and sherwood oil recrystallization, obtains brown crystallization 1.3g, productive rate 65% to add aceticanhydride.mp 180-181℃.
1H NMR(DMSO-d
6，ppm)：10.02(brs，1H，NH)，9.38(s，1H，OH)，8.07(d，1H，Ar-H)，7.30(s，1H，Ar-H)，3.87(s，3H，OCH
3)，2.48(s，3H，COCH
3)，2.11(s，3H，NHCOCH
3)，MS 223。
The molecular formula of product 5-kharophen 4-hydroxyl-3-methoxyl group-methyl phenyl ketone is as follows:
Embodiment 5 U937 cells discharge TNF-α test
The derivative of kutkin and embodiment 1-4 gained kutkin is used for investigate suppressing the U937 cell and discharges TNF-α test, reaches immunosuppressive action thereby the result shows the generation of the inhibition TNF-α that the derivative of all kutkins can both dose-dependently.IC50 result shows that the derivatives active of embodiment 1-4 gained kutkin all is better than kutkin, and wherein the effect of 5-kharophen 4-hydroxyl-3-methoxyl group-methyl phenyl ketone is best, sees Table 1.
Table 1 kutkin and derivative thereof suppress the U937 cell and discharge TNF-α
| Compound | IC50(μg/ml) |
| Kutkin | 64 |
| The derivative that embodiment 1 obtains | 43 |
| The derivative that embodiment 2 obtains | 90 |
| The derivative that embodiment 3 obtains | 80 |
| The derivative that embodiment 4 obtains | 37 |
Embodiment 6 mouse arthritis model evaluations
The rat random packet, 10 every group, establish the normal control group, negative control group, positive controls (kutkin) and be subjected to 3 dosage groups of reagent thing (derivative that embodiment 4 obtains) (1,5,20mg/kg/d), totally 6 groups.(0.1ml of 10mg bacille Calmette-Guerin vaccine/ml) causes inflammation and induces arthritic generation the above-mentioned adjuvant of the right back sufficient sole of the foot intradermal injection of every mouse.Cause beginning in scorching 8 days, the swelling degree is observed in administration every day 7 days.Result's (table 2) shows that the derivatives for treatment sacroiliitis activity that embodiment 4 obtains is better than kutkin, and conclusion is consistent with cell experiment.There is not toxic side effect.
The derivative that table 2 embodiment 4 obtains (being called for short embodiment 4) is to the rat assist agent arthritis therapeutic action of (being called for short AA)
| Group | Dosage mg/kg/d | n | Δ swelling degree | ||||
| D9 | d14 | d19 | d24 | d28 | |||
| Normally | -- | 5 | -- | -- | -- | -- | -- |
| AA | -- | 5 | -- | 0.41±0.10 | 0.57±0.16 | 0.76±0.38 | 0.60±0.30 |
| Embodiment 4 | 1 | 5 | 0.35±0.08 | 0.42±0.13 | 0.33±0.14** | 0.25±0.15** | 0.26±0.16** |
| 5 | 5 | 0.41±0.09 | 0.39±0.13 | 0.20±0.07** | 0.15±0.08** | 0.23±0.10** | |
| 20 | 5 | 0.40±0.12 | 0.39±0.16 | 0.30±0.08** | 0.27±0.09** | 0.24±0.14** | |
| Kutkin | 5 | 5 | 0.40±0.08 | 0.55±0.24 | 0.42±0.23* | 0.34±0.14** | 0.30±0.12** |
Through clinical trial, the derivative of kutkin does not have toxic side effect.
Claims (8)
1, a kind of derivative of kutkin is characterized in that its chemical formula is as follows:
Wherein, R
1Be NO
2, NH
2Or acid amides; R
2Be H, carbonyl or carbonyl diamide.
2, the derivative of kutkin according to claim 1 is characterized in that described carbonyl is a kind of in the C1-C6 alkyl-carbonyl.
3, the derivative of kutkin according to claim 1 is characterized in that described carbonyl is C (O)-NHN (CH
2CH
2)
2Or C (O)-NCH
3N (CH
2CH
2)
2
4, the preparation method of the derivative of the described kutkin of one of claim 1-3 is characterized in that, kutkin obtains the derivative of the kutkin of nitro replacement through nitration reaction.
5, the preparation method of the derivative of the described kutkin of one of claim 1-3 is characterized in that comprising the steps:
(1) kutkin obtains the derivative of the kutkin of nitro replacement through nitration reaction;
(2) derivative of the kutkin of nitro replacement obtains the derivative of the amino kutkin that replaces again through nitro-reduction reaction.
6, the preparation method of the derivative of the described kutkin of one of claim 1-3 is characterized in that comprising the steps:
(1) kutkin obtains the derivative of the kutkin of nitro replacement through nitration reaction;
(2) derivative of the kutkin of nitro replacement obtains the derivative of the amino kutkin that replaces again through nitro-reduction reaction;
(3) derivative of the amino kutkin that replaces is through the derivative of the kutkin that obtains the kharophen replacement of glycylization.
7, the application of the derivative of the described kutkin of one of claim 1-3 in preparation treatment immune dysfunction diseases medicine.
8, the application of the derivative of the described kutkin of one of claim 1-3 in preparation treatment rheumatism, similar rheumatism and arthritic medicine.
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|---|---|---|---|
| CN200610037302A CN100584816C (en) | 2006-08-25 | 2006-08-25 | Kutkin derivative, preparation method and application thereof |
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|---|---|---|---|
| CN200610037302A CN100584816C (en) | 2006-08-25 | 2006-08-25 | Kutkin derivative, preparation method and application thereof |
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|---|---|
| CN1923790A true CN1923790A (en) | 2007-03-07 |
| CN100584816C CN100584816C (en) | 2010-01-27 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260239A (en) * | 2010-05-28 | 2011-11-30 | 暨南大学新药研究所 | Kutkin derivatives, and preparation and application thereof |
| CN108947859A (en) * | 2017-05-17 | 2018-12-07 | 暨南大学 | The derivative or its pharmaceutically acceptable salt, preparation method and purposes of kutkin dimer analog JJA-D0 |
| CN111714476A (en) * | 2019-03-21 | 2020-09-29 | 暨南大学 | Application of kutkin dimer analogue derivative in preparation of medicine or health-care product for preventing and treating Parkinson's disease |
-
2006
- 2006-08-25 CN CN200610037302A patent/CN100584816C/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260239A (en) * | 2010-05-28 | 2011-11-30 | 暨南大学新药研究所 | Kutkin derivatives, and preparation and application thereof |
| CN102260239B (en) * | 2010-05-28 | 2014-10-08 | 暨南大学新药研究所 | Kutkin derivatives, and preparation and application thereof |
| CN108947859A (en) * | 2017-05-17 | 2018-12-07 | 暨南大学 | The derivative or its pharmaceutically acceptable salt, preparation method and purposes of kutkin dimer analog JJA-D0 |
| CN108947859B (en) * | 2017-05-17 | 2021-06-11 | 暨南大学 | Derivatives of kutkin dimer analogue JJA-D0 or pharmaceutically acceptable salts thereof, preparation method and application |
| CN111714476A (en) * | 2019-03-21 | 2020-09-29 | 暨南大学 | Application of kutkin dimer analogue derivative in preparation of medicine or health-care product for preventing and treating Parkinson's disease |
| CN111714476B (en) * | 2019-03-21 | 2021-09-21 | 暨南大学 | Application of kutkin dimer analogue derivative in preparation of medicine for preventing and treating Parkinson's disease |
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| Publication number | Publication date |
|---|---|
| CN100584816C (en) | 2010-01-27 |
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