CN107417758A - A kind of small molecule gel for auristilla and its preparation method and application - Google Patents
A kind of small molecule gel for auristilla and its preparation method and application Download PDFInfo
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- CN107417758A CN107417758A CN201710353697.4A CN201710353697A CN107417758A CN 107417758 A CN107417758 A CN 107417758A CN 201710353697 A CN201710353697 A CN 201710353697A CN 107417758 A CN107417758 A CN 107417758A
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- small molecule
- auristilla
- gel
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- coumarin
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- NZSLQJAQHSFQCK-PLNGDYQASA-N CC([I]=C1)=C(/C=C\C=C)OC1=O Chemical compound CC([I]=C1)=C(/C=C\C=C)OC1=O NZSLQJAQHSFQCK-PLNGDYQASA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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Abstract
The invention discloses a kind of small molecule gel for auristilla and its preparation method and application, the structural formula of the small molecule gelling agent isR is represented in formulaIn any one, wherein R1、R2、R3、R4、R5、R6Each independent representative H, C1~C4Alkyl, C1~C4Any one in alkoxy；N is 2~10 integer.The present invention synthesizes the small molecule gel by Williamson reactions and esterification, simple to operate, and product yield and purity are high.Small molecule gel of the present invention can prevent decoction from losing as the auxiliary material of the mutual modification gel auristilla of solid-liquid for the treatment of tympanitis, the gel auristilla, extend drug treating time, improve curative effect, and have no toxic side effect.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of for the small molecule gel of auristilla and its preparation side
Method.
Background technology
Tympanitis can be divided into secretory otitis media and otitis media suppurative, and patient has the symptoms such as tinnitus, otalgia, can lead
Cause the serious diseases such as deafness, meningitis, brain abscess, thrombophlebitis, cancer of middle ear.Auristilla is for treating duct disease
Common formulations, but such medicament dropping can flow out after entering duct, cause decoction to lose, or duct need to be clogged with a little absorbent cotton, make
Into medication inconvenience.
The content of the invention
The shortcomings that technical problems to be solved by the invention are to overcome current auristilla, there is provided one kind can make auristilla
The small molecule gel of liquid-solid change, and provide a kind of preparation method simple to operate for the small molecule gelling agent.
Technical scheme is that the structural formula of the small molecule gelling agent is as follows used by solution above-mentioned technical problem：
R is represented in formulaIn any one, wherein R1、
R2、R3、R4、R5、R6Each independent representative H, C1~C4Alkyl, C1~C4Any one in alkoxy；N be 2~10 it is whole
Number.
Above-mentioned R1、R2、R3、R4、R5、R6It is preferred that any one in respective independent representative H, methyl, methoxyl group, n is excellent
Select 2~5 integer.
The preparation method of small molecule gelling agent of the present invention is made up of following step：
1st, Williamson reacts
Using acetone as solvent, by coumarin kind compound, bromhydrin, catalyst, K2CO3It is 1 in molar ratio:1.1~2.1:
0.2:0.6~1.2, back flow reaction 2~10 hours, product is isolated and purified, obtains coumarin derivative.
When above-mentioned coumarin kind compound is compound of formula I, the structural formula of gained coumarin derivative for Formulas I '：
When above-mentioned coumarin kind compound is Formula II compound, the structural formula of gained coumarin derivative for Formula II '：
When above-mentioned coumarin kind compound is formula III compound, the structural formula of gained coumarin derivative for formula III '：
Above-mentioned bromhydrin is ethylene bromohyrin, 3- bromopropyl alcohols, 4- bromobutanols, 5- bromines amylalcohol, 6- bromines hexanol, 7- bromines enanthol, 8-
Any one in bromine octanol, 9- bromines nonyl alcohol, 10- bromine decyl alcohol；Catalyst is tetra-n-butyl ammonium bromide, tetraethylammonium bromide, four
Any one in N-propyl bromide, cetyl trimethylammonium bromide, triphenylamine, triphenylphosphine.
2nd, esterification
With cholesteryl chloroformate it is 1 in molar ratio by the gained coumarin derivative of step/1 using DMF as solvent:1.1~
2.1, react 2~4 hours at room temperature, isolate and purify product, obtain small molecule gelling agent.
Application of the small molecule gel of the present invention in gel preparations auristilla is prepared, specifically used method are：In drop ear
The small molecule gel of its quality 0.1%~5% is added in agent, you can obtain the auristilla of gel preparations.
Small molecule gel of the present invention using Williamson reaction, esterification synthesis, it is simple to operate, product yield and
Purity is high.Small molecule gel of the present invention is added in the auristilla for the treatment of tympanitis, auristilla can be made to be changed into gel, made
Used time can be so that it becomes liquid, a period of time, auristilla be stood after being added drop-wise in human ear by the auristilla shaking of gel preparations
Solid or semisolid are converted into by liquid again, therefore can prevent decoction from losing, extends drug treating time, improves curative effect, and it is right
The therapeutic effect of rat middle ear inflammation model is notable, and has no toxic side effect, can be used as treatment tympanitis gel preparations auristilla
Auxiliary material.
Embodiment
With reference to embodiment, the present invention is described in more detail, but protection scope of the present invention is not limited only to these realities
Apply example.
Embodiment 1
The following small molecule gelling agent of preparation structure formula
1st, Williamson reacts
By 16.2g (0.10mol) umbelliferone, 6.44g (0.02mol) tetra-n-butyl ammonium bromide, 14.31g
(0.11mol) 3- bromopropyl alcohols are dissolved in acetone, add 15.20g (0.11mol) K2CO3, back flow reaction 8 hours, after having reacted, add
Water, it is extracted with ethyl acetate three times, merges recovery organic phase, (eluant, eluent is that petroleum ether is with ethyl acetate volume ratio to column chromatography
2:1 mixed liquor) purifying, white solid 7- propoxyl coumarin 1 9.82g are obtained, its yield is 90%, structural characterization data
For：1H NMR(CDCl3,TMS):7.64-7.62 (1H, d, J=9.6Hz), 7.36 (1H, s), 6.86-6.80 (2H, m), 6.24-
6.25 (1H, d, J=9.6Hz), 4.17-4.18 (1H, t), 3.88-3.87 (1H, t), 2.07-2.08 (1H, m), 1.10 (1H,
s)；13C NMR(CDCl3):162,161,155,143,128,114,113,112,101,65,59,31。
2nd, esterification
2.20g (0.01mol) 7- propoxyl cumarins are dissolved in DMF, ice-water bath is cooled to 5 DEG C, and 12mL is added dropwise and contains
The dichloromethane solution of 5.36g (0.012mol) cholesteryl chloroformate, is added dropwise, is warmed to room temperature naturally, and it is small to continue reaction 3
When, add water, be extracted with ethyl acetate three times, merge recovery organic phase, (eluant, eluent is petroleum ether and ethyl acetate volume to column chromatography
Than for 8:1 mixed liquor) purifying, small molecule gelling agent 5.75g is obtained, its yield is 91%, and structural characterization data are：1H NMR
(CDCl3,TMS):7.64-7.62 (1H, d, J=9.6Hz), 7.36 (1H, s), 6.86-6.80 (2H, m), 6.24-6.25 (1H,
D, J=9.6Hz), 5.37 (1H, s), 4.17-4.18 (2H, t), 3.90 (1H, s), 3.88-3.87 (2H, t), 3.50 (1H, s),
2.07-2.08(2H,m),0.67-1.85(43H)。
Embodiment 2
The following small molecule gelling agent of preparation structure formula
In the present embodiment, with the umbelliferone in equimolar Hymecromone alternative embodiment 1, its
His step is same as Example 1, obtains small molecule gelling agent, and its total recovery is 81%, and structural characterization data are：1H NMR
(CDCl3,TMS):7.50-7.48 (1H, d, J=6.0Hz), 6.87-6.85 (1H, d, J=6.0Hz), 6.83 (1H, s), 6.14
(1H,s),5.37(1H,s),4.19-4.18(2H,t),3.90(1H,s),3.88-3.87(2H,t),2.40(3H,s),2.07-
2.08(2H,m),0.67-1.85(43H)。
Embodiment 3
The following small molecule gelling agent of preparation structure formula
In the present embodiment, with the umbelliferone in equimolar 4 hydroxy coumarin alternative embodiment 1, other steps with
Embodiment 1 is identical, obtains small molecule gelling agent, and its total recovery is 78%.
Embodiment 4
The following small molecule gelling agent of preparation structure formula
In the present embodiment, with the umbelliferone in equimolar 3- carboxyl cumarins alternative embodiment 1, other steps with
Embodiment 1 is identical, obtains small molecule gelling agent, and its total recovery is 79%.
Embodiment 5
The following small molecule gelling agent of preparation structure formula
In the present embodiment, with the umbelliferone in equimolar scopoletin alternative embodiment 1,
Other steps are same as Example 1, obtain small molecule gelling agent, and its total recovery is 80%.
Embodiment 6
The application of small molecule gel prepared by embodiment 1 in gel preparations auristilla is prepared
The small molecule gel that inventor is prepared using embodiment 1 has carried out substantial amounts of laboratory research experiment, specific examination
It is as follows to test situation：
Emgel agent：1.0g erythromycin, 1.0g small molecules gelling agent, 100g atoleines, 0.10g benzoic acid are existed
It is heated to being completely dissolved in oil bath, obtains the Emgel agent for treating tympanitis.
Erythromycin paraffin liquid：1.0g erythromycin, 100g atoleines, 0.10g benzoic acid are heated to completely in oil bath
Dissolving, obtains the erythromycin paraffin liquid for treating tympanitis.
Ofloxacin gel agent：By 0.3g Ofloxacins, 1.0g small molecules gelling agent, 100g atoleines, 0.10g benzene first
Acid is heated to being completely dissolved in oil bath, obtains the ofloxacin gel agent for treating tympanitis.
Ofloxacin paraffin liquid：0.3g Ofloxacins, 100g atoleines, 0.10g benzoic acid are heated in oil bath
It is completely dissolved, obtains the Ofloxacin paraffin liquid for treating tympanitis.
Rat secretory otitis media model is divided into five groups：Blank group, erythromycin paraffin liquid group, Emgel agent group,
Ofloxacin gel agent group, Ofloxacin paraffin liquid group, wherein blank group give atoleine, erythromycin paraffin liquid group give it is red
Mycin paraffin liquid, Ofloxacin paraffin liquid group give Ofloxacin paraffin liquid, animal freely activity after administration；Emgel agent
Group gives Emgel agent and ofloxacin gel agent group gives ofloxacin gel agent, keeps rat head static after administration
1 minute (gel is changed into solid-state or semisolid by liquid, ensure that drag residence in duct, does not flow out, long duration of action in
Focus, have the function that medicament slow release, to improve curative effect) and then animal freely activity.Administration 0.20mL every time, 2 times/day, 7 days
For 1 course for the treatment of, 2 courses for the treatment of are used in conjunction.
After the completion of total Test, Animal Anesthesia is put to death, and takes bilateral otic capsule, is fixed with the paraformaldehyde that mass fraction is 4%,
Increased again with the aqueous solution of nitric acid decalcification that mass fraction is 5%, specimens paraffin embedding slices, conventional H E colored light Microscopic observations mucosa of tympanic cavity
Raw situation, measurement each group middle-ear mucosa thickness (mucosa of tympanic cavity thickness is measured with micrometer under light microscopic).As a result show：Oxygen fluorine is husky
The middle-ear mucosa thickness of star glucosamine gel group and Emgel agent group rat is with blank group without significant difference, hence it is evident that is thinner than erythromycin
Paraffin liquid group and Ofloxacin paraffin liquid group, illustrate that the therapeutic effect of ofloxacin gel agent group and Emgel agent group is obvious
Better than Ofloxacin paraffin liquid group and erythromycin paraffin liquid group.
Claims (6)
1. a kind of small molecule gel for auristilla, it is characterised in that the structural formula of the small molecule gelling agent is as follows：
R is represented in formulaIn any one, wherein R1、R2、
R3、R4、R5、R6Each independent representative H, C1~C4Alkyl, C1~C4Any one in alkoxy；N is 2~10 integer.
2. the small molecule gel according to claim 1 for auristilla, it is characterised in that：Described R1、R2、R3、R4、
R5、R6Each any one in independent representative H, methyl, methoxyl group.
3. the small molecule gel according to claim 1 or 2 for auristilla, it is characterised in that：Described n is 2~5
Integer.
4. the preparation method of the small molecule gelling agent described in a kind of claim 1, it is characterised in that it is made up of following step：
(1) Williamson reacts
Using acetone as solvent, by coumarin kind compound, bromhydrin, catalyst, K2CO3It is 1 in molar ratio:1.1~2.1:0.2:
0.6~1.2, back flow reaction 2~10 hours, product is isolated and purified, obtains coumarin derivative；
When above-mentioned coumarin kind compound is compound of formula I, the structural formula of gained coumarin derivative for Formulas I '：
When above-mentioned coumarin kind compound is Formula II compound, the structural formula of gained coumarin derivative for Formula II '：
When above-mentioned coumarin kind compound is formula III compound, the structural formula of gained coumarin derivative for formula III '：
Above-mentioned R1、R2、R3、R4、R5、R6Each independent representative H, C1~C4Alkyl, C1~C4Any one in alkoxy, n 2
~10 integer；
Above-mentioned bromhydrin is that ethylene bromohyrin, 3- bromopropyl alcohols, 4- bromobutanols, 5- bromines amylalcohol, 6- bromines hexanol, 7- bromines enanthol, 8- bromines are pungent
Any one in alcohol, 9- bromines nonyl alcohol, 10- bromine decyl alcohol；Catalyst is tetra-n-butyl ammonium bromide, tetraethylammonium bromide, four positive third
Any one in base ammonium bromide, cetyl trimethylammonium bromide, triphenylamine, triphenylphosphine；
(2) esterification
It is 1 in molar ratio by coumarin derivative obtained by step (1) and cholesteryl chloroformate using DMF as solvent:1.1~
2.1, react 2~4 hours at room temperature, isolate and purify product, obtain small molecule gelling agent.
5. application of the small molecule gel in gel preparations auristilla is prepared described in claim 1.
6. application of the small molecule gel according to claim 5 in gel preparations auristilla is prepared, it is characterised in that：
The small molecule gel of its quality 0.1%~5% is added in auristilla, you can obtain the auristilla of gel preparations.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109125250A (en) * | 2018-08-30 | 2019-01-04 | 陕西中医药大学 | A kind of small molecule gelling agent and preparation method and gynaecology's mutual modification gel preparation of solid-liquid |
| CN114478502A (en) * | 2021-12-31 | 2022-05-13 | 哈尔滨医科大学 | Coumarin compound and synthesis method thereof |
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| CN102887932A (en) * | 2012-10-25 | 2013-01-23 | 陕西师范大学 | Preparation method of self-healing micro-molecular gel |
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2017
- 2017-05-18 CN CN201710353697.4A patent/CN107417758A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102887932A (en) * | 2012-10-25 | 2013-01-23 | 陕西师范大学 | Preparation method of self-healing micro-molecular gel |
Non-Patent Citations (4)
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| 侯秋飞: "小分子凝胶因子的设计合成及其性质研究", 《吉林大学博士学位论文》 * |
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| 高玉霞等: "Water tuned nano/micro-structures in a redoxresponsive supramolecular gel", 《RSC ADV.》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109125250A (en) * | 2018-08-30 | 2019-01-04 | 陕西中医药大学 | A kind of small molecule gelling agent and preparation method and gynaecology's mutual modification gel preparation of solid-liquid |
| CN114478502A (en) * | 2021-12-31 | 2022-05-13 | 哈尔滨医科大学 | Coumarin compound and synthesis method thereof |
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Application publication date: 20171201 |