CN108558906A - It is a kind of to treat cataract medicine Ben Bing Naphthoxazines and preparation method thereof - Google Patents
It is a kind of to treat cataract medicine Ben Bing Naphthoxazines and preparation method thereof Download PDFInfo
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
Cataract medicine Ben Bing Naphthoxazines and preparation method thereof are treated the present invention provides a kind of, the treatment cataract medicine Ben Bing Naphthoxazines have following chemical structural formula：
Description
Technical field
The present invention relates to pharmaceutical technology fields, specifically, treating cataract medicine Ben Bing Fen Evil the present invention relates to a kind of
Piperazine class compound and preparation method thereof further relates to the pharmaceutical composition of Ben Bing Naphthoxazines preparation in cataract conditions
Application.
Background technology
Cataract is a kind of common eye disease, including cataract of old people, traumatic cataract, mild diabetes
Cataract, complicated cataract and congenital cataract are a kind of diseases that can lead to blindness, cause cataract because
Plain very much, main and nutrient metabolic, sunlight and ultraviolet light, extraneous temperature, anoxic, endocrine disturbance, human body are dehydrated
Etc. factors it is related, such as aging, heredity, metabolic disorder, wound, radiation, poisoning and local malnutrition are responsible for crystalline lens
Cyst membrane damage or lead to crystalline lens metabolic disorder, cause crystallin occur denaturation and it is muddy.The symptom of cataract is to regard object
It is fuzzy, it keeps in dark place, mostly increase depending on, myopia degree, see object color is dark or being in yellow or even ghost image and see the symptoms such as deformation of body,
The decline of eyesight progressive is shown as, sometimes it can be seen that fixed stain under bright background.According to investigation, cataract is most
Common blinding and reason with visual disabilities, the mankind about 25% suffer from cataract, and the incidence of 50-60 Sui cataract of old people is
60-70% reaches 80% in 70 years old or more, and 80 years old or more the elderly nearly reaches 100%.
It can be used for treating cataract there are many drug at present, such as Bercomine, tathion eye drops, look unfamiliar
Element, card Tallin eye drops, An Tai Dian Eye Dropes and Succus Cineraria Maritima etc..
Bercomine：There is activator protein catabolic enzyme, penetrate into decomposable asymmetric choice net in crystalline lens and absorbs albuminate
Matter improves the metabolism of ocular tissue, maintains crystalline lens transparent, prevents cataract development, is mainly used for early stage senile cataract.
Tathion eye drops：Phacoscotasmusization can be prevented to prevent the progress of cataract, or be allowed to restore transparent.It can
For the treatment of early-stage senile cataract, a few peoples are likely to occur itch, excitement, eye hyperemia, transient eyesight after
The symptoms such as fuzzy, disappear after drug withdrawal.
Eye drops：Ingredient is various amino acid, polypeptide, nucleotide and micro-calcium, magnesium etc., has the new old generation of enhancing eye
The effects that thanking, promoting corneal epithelial tissue's regeneration.
Card Tallin eye drops：The abnormal metabolism of energy blocked amino acid makes crystal keep transparent, can prevent cataract development.
An Tai Dian Eye Dropes：Ammonia peptide iodine is that one kind is biochemical made of Hydrolysis kinetics in animal viscera (eyeball and thyroid gland)
Drug can promote eye capilary to expand containing a variety of amino acid such as glutamic acid, cystine and the ingredients such as organic compound iodine and polypeptide
It opens and blood circulation promotes the absorption of lesion and exudate so as to improve the metabolism of sick eye.
Succus Cineraria Maritima：The sterile water solution being formulated by the immersion liquid of witch hazel leaf, glycerine, boron etc., can promote ocular tissue
Blood circulation maintains its eubolism, and phacoscotasmus is promoted to absorb, and prevents cataract progression of the disease.
Although can be used for treating cataract there are many drug, the process that drug can make cataract there is no to reverse.Therefore,
Also need to the drug that more can be used in treating cataract.The formation of cataract and the Specific mefabolites quinone of ArAA
Imidic acid is related, and quinone imines acid is combined with crystalline lens water-solubility protein, so that it is deformed and muddy related.And Ben Bing phenoxazine classes
The metabolic disorder of ArAA can be improved by closing object, restrain the generation of the compound of quinones, have with crystalline lens water soluble protein
Stronger affinity, contestable inhibit quinones substance to act on the oxidation, denaturation, opacification of crystalline lens soluble protein,
And then prevent the development of the cataract state of an illness.
Invention content
For the existing above problem, cataract medicine benzo is treated one of the objects of the present invention is to provide a kind of
Naphthoxazines.
An object of the present invention, which also resides in, provides a kind of preparation for treating cataract medicine Ben Bing Naphthoxazines
Method.
An object of the present invention also reside in offer comprising Ben Bing Naphthoxazines, its pharmaceutically acceptable salt,
The pharmaceutical composition of isomer or solvate as active constituent.
An object of the present invention also resides in the application for providing aforementioned pharmaceutical compositions in treating cataract conditions.
To achieve the above object, cataract medicine Ben Bing Naphthoxazines are treated the present invention provides a kind of, with pyrrole
The substituted compound of pyridine and the substituted compound of phenol carry out preparing Ben Bing Naphthoxazines as raw material, and raw material is easy to get,
And synthetic route is short, reaction condition is mild, and operation post-processing is simple, high income, the treatment cataract medicine Ben Bing phenoxazines
Class compound has following chemical structural formula：
,
X is selected from hydrogen, halogen, cyano, amino, nitro or carboxyl, and X is located at at least one in phenyl ring residue binding site, X and benzene
Carbon atom on ring is covalently attached；
R be selected from C1-C6 alkoxies, C3-C7 naphthenic base, halogenated C1-C6 alkyl, C1-C6 alkyl-carbonyls, C1-C6 alkoxy carbonyls,
C1-C6 alkyl aminos, two (C1-C6 alkyl) amino, C1-C6 alkyl sulphonyls, C6-C10 aryl or C2-C10 heterocycles, wherein
C1-C6 alkoxies, C3-C7 naphthenic base, halogenated C1-C6 alkyl, C1-C6 alkyl-carbonyls, C1-C6 alkoxy carbonyls, C1-C6 alkyl
Amino, two (C1-C6 alkyl) amino, C1-C6 alkyl sulphonyls, C6-C10 aryl or C2-C10 heterocycles are optionally selected by 1 to 3
Replace from group below：Halogen, C1-C4 alkyl or hydroxyl；R is located at at least one in phenyl ring residue binding site.
Further, the halogen is fluorine（F）, chlorine（Cl）, bromine（Br）Or iodine（I）, the alkyl refers to 1-6 carbon
The linear or branched alkyl group of atom, it is non-limiting such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary fourth
Base, n-pentyl or n-hexyl.
The present invention also provides a kind of preparation method for treating cataract medicine Ben Bing Naphthoxazines, the preparation sides
Method includes following synthesis step：
Pure water, compound is added in the first step in the three-neck flask equipped with blender, thermometer and condenser pipe（1）And succinic acid
Acid anhydride, warming-in-water keep temperature control at 80-85 DEG C, potassium permanganate to be added to potassium permanganate after 80 DEG C, is added in three batches
The reaction was complete, the solution in reaction bulb be dark brown without purple when, add next group potassium permanganate, so carry out, wait for whole
Potassium permanganate after completion of the reaction, is kept for 80-85 DEG C stir minimum 45 minutes, filtered while hot, remove manganese dioxide, obtained containing change
Close object（2）Solution；
Second step will contain compound in the first step（2）Solution with concentrated hydrochloric acid adjust solution PH so that PH 3.2-3.3, mix
Stirring 30 minutes is closed, is concentrated in vacuo in rotary evaporator, ethyl alcohol is added after being evaporated and flows back at 68 DEG C 2h, after reflux,
Object cooling to be mixed is filtered, and is taken filtrate and is dried, obtains compound（3）；
Third walks, by compound（3）With compound（4）Mixing is dissolved in anhydrous DMF, is heated to reflux 30min, solution is by orange change
For navy blue, TLC detection reactions terminate, are cooled to room temperature, mixed liquor is poured into sodium hydrate aqueous solution, water layer is with extractant
After elution, merge organic phase, anhydrous sodium sulfate dries 2h, is filtered to remove anhydrous sodium sulfate, obtains compound（5）；
4th step, by compound（5）It is added at 0-20 DEG C in the acetone soln containing pure water, catalyst is added, fully stirs
Mix 1h, after be slowly added dropwise sulfuric acid, TLC detection reactions terminate, and are cooled to room temperature, ethyl acetate extraction, collect organic phase, saturation food
Salt water washing three times, filter by anhydrous magnesium sulfate drying, and filtrate decompression distills to obtain crude product, and crude product is filtered through silica gel, recrystallized
To compound（6）.
The preparation method includes following synthetic route：
。
Further, manganese dioxide is washed several times with hot distilled water in the synthesis step first step, until filtrate is
Colourless transparent solution.
Further, the temperature being concentrated in vacuo in rotary evaporator in the synthesis step second step is 45-50 DEG C.
Further, extractant is dichloromethane and DCM in the synthesis step third step and methanol volume ratio is 10:
1 mixed liquor, is first eluted with dichloromethane, then with DCM and methanol volume ratio is 10:1 mixed liquor is eluted.
Further, the catalyst in the 4th step of the synthesis step is chromium trioxide.
The present invention also provides a kind of pharmaceutical composition, described pharmaceutical composition be comprising Ben Bing Naphthoxazines,
The pharmaceutical composition of its pharmaceutically acceptable salt, isomer or solvate as active constituent.
Further, buffer salt, osmotic pressure regulator are also contained in pharmaceutical composition of the present invention.According to pharmaceutical composition
Dosage form, it is also optional in pharmaceutical composition to contain preservative, thickener.
Further, its pH range of pharmaceutical composition of the present invention is preferably maintained at 6.8-8.0.In order to maintain this hair
Bright pharmaceutical composition pH is maintained at 6.8-8.0, and adoptable buffer salt is selected from boric acid-borax, disodium hydrogen phosphate-biphosphate
Sodium, boric acid-sodium carbonate or boric acid-sodium acetate.
Further, in pharmaceutical composition of the present invention, its preferred osmotic pressure keeps 260-340mosm/L.
Further, in order to maintain the osmotic pressure of pharmaceutical composition of the present invention, adoptable osmotic pressure regulator is selected from chlorine
Change sodium, potassium chloride, glycerine, glucose, propylene glycol or mannitol.
Further, the preservative suitable for pharmaceutical composition of the present invention is selected from ethyl hydroxy benzoate, gluconic acid chlorine
Oneself fixed, chlorhexidine hydrochloride, chlorhexidine acetate, cetrimonium bromide, benzalkonium chloride, benzalkonium bromide, Phenoxyethanol or anesin.
Further, the thickener suitable for pharmaceutical composition of the present invention is selected from sodium hyaluronate, polyvinyl alcohol, gathers
Tie up ketone or water soluble chitosan.
Contain reactive compound 0.8-15.0% in described pharmaceutical composition (by weight percentage).Work as pharmaceutical composition
In contain preservative or thickener when, preservative be 0.001-5% (by weight percentage), thickener be 0.01-3% (press
Weight percent meter).
The present invention also provides application of the aforementioned pharmaceutical compositions in treating cataract conditions.
Compared with the existing technology, the invention has the advantages that：
1, benzene provided by the invention and Naphthoxazines are mydriasis drug, similar to xanthommatin compound, can with it is crystalline
Body water soluble protein has stronger affinity, contestable inhibit quinoid substance to the oxidation of crystalline lens soluble protein,
Denaturation, opacification effect, prevent the development of cataract, to cataract of old people, to cataract caused by diabetes, injure elder generation outside
Its cataract, retinitis pigmentosa have good therapeutic effect, can be used for the further investigations of cataract conditions and open
Hair.
2, the present invention carries out preparing Ben Bing Fen Evil using the substituted compound of the substituted compound of pyridine and phenol as raw material
Piperazine class compound, raw material is easy to get, and synthetic route is short, and reaction condition is mild, and operation post-processing is simple, and high income especially exists
In second step reaction, with high-efficient liquid phase chromatogram technology analysis of compounds（3）Yield be 86% or more；It is anti-in third of the present invention step
Ying Zhong is 10 by dichloromethane and DCM and methanol volume ratio:1 mixed liquor is eluted, and polarity maximum point can be obtained
Target compound（5）, substantially increase reaction yield.
3, in four-step reaction of the invention, oxidizing process is used（CrO3-H2SO4Acetone）, this method can be selective
By compound（5）It is oxidized to ketone, without influencing other sensitive groups（Such as unsaturated bond）, the rearrangement of structure is not also influenced, it is right
The synthesis and industrialization of Ben Bing Naphthoxazines have more real meaning.
4, the present invention proves Ben Bing Naphthoxazines for cataract with very aobvious by rat and rabbit experiment
The therapeutic effect of work, in addition be substantially better than it is current in the treatment preferable glutathione of cataract effect, and it is free of toxic effects.
Now by following embodiment come the particular compound of the present invention is more fully described Ben Bing Naphthoxazines
Reaction process and purposes.However, it should be noted that these embodiments are to provide by way of illustration and unrestricted.
Specific implementation mode
Present invention is further elaborated in following combination specific embodiment.
Cataract medicine Ben Bing Naphthoxazines, the treatment cataract medicine benzene are treated the present invention provides a kind of
Bing Naphthoxazines have following chemical structural formula：
。
Ben Bing Naphthoxazines are selected from 1- methoxyl group -5- oxygen -9- amino -5H- pyrroles to the present invention in one embodiment
Pyridine simultaneously-[3,2-a]-phenoxazine -3- carboxylic acids.
Ben Bing Naphthoxazines are selected from the chloro- 5H- pyridines of 1- methoxyl group -5- oxygen -9- to the present invention in one embodiment
And-[3,2-a]-phenoxazine -3- carboxylic acids.
Ben Bing Naphthoxazines are selected from 1- methoxyl group -5- oxygen -9- carboxyl -5H- pyrroles to the present invention in one embodiment
Pyridine simultaneously-[3,2-a]-phenoxazine -3- carboxylic acids.
Ben Bing Naphthoxazines are selected from 2- methyl carbonyl -5- oxygen -5H- pyridos-to the present invention in one embodiment
[3,2-a]-phenoxazine -3- carboxylic acids.
Ben Bing Naphthoxazines are selected from 1- cyclopropyl -5- oxygen -9- itrile group -5H- pyrroles to the present invention in one embodiment
Pyridine simultaneously-[3,2-a]-phenoxazine -3- carboxylic acids.
Ben Bing Naphthoxazines are selected from 2- chloromethyl -5- oxygen -9- itrile group -5H- pyrroles to the present invention in one embodiment
Pyridine simultaneously-[3,2-a]-phenoxazine -3- carboxylic acids.
Ben Bing Naphthoxazines are selected from 2- phenyl -5- oxygen -9- nitro -5H- pyridines to the present invention in one embodiment
And-[3,2-a]-phenoxazine -3- carboxylic acids.
Ben Bing Naphthoxazines are selected from 2- phenyl -5- oxygen -9- piperidyl -5H- pyrroles to the present invention in one embodiment
Pyridine simultaneously-[3,2-a]-phenoxazine -3- carboxylic acids.
Embodiment 1
The preparation of-phenoxazine -3- carboxylic acids of 1- methoxyl group -5- oxygen -9- amino -5H- pyrido-[3,2-a].
Synthesis step is：
Pure water is added in the three-neck flask equipped with blender, thermometer and condenser pipe in the first step（50ml）, 4- methoxyl groups -2-
Methyl-pyridyl compound（1）（10g）And succinic anhydride（8g）, potassium permanganate is added to after 80 DEG C in warming-in-water in three batches（Altogether
6g）, keep temperature control at 84 DEG C, the reaction was complete for potassium permanganate to be added, and the solution in reaction bulb is dark brown without purple
When, next group potassium permanganate is added, so carries out, waits for whole potassium permanganate after completion of the reaction, keeps 82 DEG C of stirrings minimum 45
Minute, it filters while hot, removes manganese dioxide, manganese dioxide is washed several times with hot distilled water, until filtrate is that water white transparency is molten
Liquid is obtained containing 1- methoxyl groups -5- hydroxyls-benzo pyridine-3-carboxylic acid potassium compound（2）Solution, separation 1- need not be carried out
Methoxyl group -5- hydroxyls-benzo pyridine-3-carboxylic acid potassium compound（2）；
Second step will contain 1- methoxyl groups -5- hydroxyls-benzo pyridine-3-carboxylic acid potassium compound in the first step（2）Solution with dense
Hydrochloric acid conditioning solution PH so that PH 3.25 is mixed 30 minutes, is concentrated in vacuo in rotary evaporator, and temperature is 46 DEG C,
Ethyl alcohol is added after being evaporated to flow back at 68 DEG C 2h, after reflux, object cooling to be mixed is filtered, and is taken filtrate and is dried, obtains
To 1- methoxyl groups -5- hydroxyls-benzo pyridine-3-carboxylic acid compound（3）（10.36g）, its receipts is analyzed with high-efficient liquid phase chromatogram technology
Rate is 86.2%；
Third walks, by 1- methoxyl groups -5- hydroxyls-benzo pyridine-3-carboxylic acid compound（3）（10.36g）With 2- nitroso 3- amino
Oxybenzene compound（4）（11.5g）Mixing is dissolved in anhydrous DMF（100ml）In, it is heated to reflux 30min, solution becomes dark blue from orange
Color, TLC detection reactions terminate, are cooled to room temperature, mixed liquor is poured into 5% sodium hydrate aqueous solution（20ml）In, water layer is with dichloro
Methane（30ml）And DCM and methanol volume ratio are 10:1 mixed liquor（50ml）After elution, merge organic phase, anhydrous sodium sulfate
Dry 2h, is filtered to remove anhydrous sodium sulfate, obtains 1- methoxyl group -5- hydroxyl -9- amino -5H- pyridos-[3,2-a]-Fen Evil
Piperazine -3- carboxylic acid compounds（5）（19.67g）；
4th step, by-phenoxazine -3- carboxylic acid compounds of pyrido-[3,2-a] 1- methoxyl group -5- hydroxyl -9- amino -5H-（5）
（19.67g）It is added to containing pure water at 10 DEG C（20ml）Acetone soln（40ml）In, catalyst chromium trioxide is added
（1.2g）, be sufficiently stirred 1h, after sulfuric acid is slowly added dropwise（30ml）, TLC detections, which are reacted, to be terminated, and is cooled to room temperature, ethyl acetate extraction
It takes, collects organic phase, saturated common salt water washing three times, filter, and filtrate decompression distills to obtain crude product, slightly by anhydrous magnesium sulfate drying
Product are filtered through silica gel, to be recrystallized to give-phenoxazine -3- of 1- methoxyl group -5- oxygen -9- amino -5H- pyrido-[3,2-a] Carboxylation
Close object（6）（17.7g）, yield 85.9%.
Synthetic route is：
。
Embodiment 2
The preparation of the chloro--phenoxazine -3- carboxylic acids of 5H- pyridos-[3,2-a] of 1- methoxyl group -5- oxygen -9-.
Synthesis step is：
Pure water is added in the three-neck flask equipped with blender, thermometer and condenser pipe in the first step（50ml）, 4- methoxyl groups -2-
Methyl-pyridyl compound（1）（15g）And succinic anhydride（8.9g）, potassium permanganate is added to after 80 DEG C in warming-in-water in three batches（Altogether
8g）, keep temperature control at 80 DEG C, the reaction was complete for potassium permanganate to be added, and the solution in reaction bulb is dark brown without purple
When, next group potassium permanganate is added, so carries out, waits for whole potassium permanganate after completion of the reaction, keeps 82 DEG C of stirrings minimum 45
Minute, it filters while hot, removes manganese dioxide, manganese dioxide is washed several times with hot distilled water, until filtrate is that water white transparency is molten
Liquid is obtained containing 1- methoxyl groups -5- hydroxyls-benzo pyridine-3-carboxylic acid potassium compound（2）Solution, separation 1- need not be carried out
Methoxyl group -5- hydroxyls-benzo pyridine-3-carboxylic acid potassium compound（2）；
Second step will contain 1- methoxyl groups -5- hydroxyls-benzo pyridine-3-carboxylic acid potassium compound in the first step（2）Solution with dense
Hydrochloric acid conditioning solution PH so that PH 3.2 is mixed 30 minutes, is concentrated in vacuo in rotary evaporator, and temperature is 46 DEG C,
Ethyl alcohol is added after being evaporated to flow back at 68 DEG C 2h, after reflux, object cooling to be mixed is filtered, and is taken filtrate and is dried, obtains
To 1- methoxyl groups -5- hydroxyls-benzo pyridine-3-carboxylic acid compound（3）（15.52g）, its receipts is analyzed with high-efficient liquid phase chromatogram technology
Rate is 86.32%；
Third walks, by 1- methoxyl groups -5- hydroxyls-benzo pyridine-3-carboxylic acid compound（3）（15.52g）With 2- nitroso 3- chlorobenzenes
Phenolic compounds（4）（16g）Mixing is dissolved in anhydrous DMF（120ml）In, it is heated to reflux 30min, solution becomes navy blue from orange,
TLC detection reactions terminate, and are cooled to room temperature, mixed liquor is poured into 5% sodium hydrate aqueous solution（25ml）In, water layer is with dichloromethane
Alkane（40ml）And DCM and methanol volume ratio are 10:1 mixed liquor（50ml）After elution, merge organic phase, anhydrous sodium sulfate is dry
Dry 2h, is filtered to remove anhydrous sodium sulfate, obtains the chloro--phenoxazine -3- of 5H- pyridos-[3,2-a] of 1- methoxyl group -5- hydroxyls -9-
Carboxylic acid compound（5）（29.21g）；
4th step, by-phenoxazine -3- carboxylic acid compounds of pyrido-[3,2-a] 1- methoxyl group -5- hydroxyl -9- amino -5H-（5）
（29.21g）It is added to containing pure water at 0 DEG C（30ml）Acetone soln（60ml）In, catalyst chromium trioxide is added
（1.8g）, be sufficiently stirred 1h, after sulfuric acid is slowly added dropwise（50ml）, TLC detections, which are reacted, to be terminated, and is cooled to room temperature, ethyl acetate extraction
It takes, collects organic phase, saturated common salt water washing three times, filter, and filtrate decompression distills to obtain crude product, slightly by anhydrous magnesium sulfate drying
Product filter through silica gel, are recrystallized to give the chloro- 5H- pyridos-[3,2-a] of 1- methoxyl group -5- oxygen -9--phenoxazine -3- carboxylic acid chemical combination
Object（6）（26.88g）, yield 85.1%.
Synthetic route is：
。
According to method similar to Example 1, following compound i.e. embodiment 3- embodiments 8 are synthesized.
3 compound 1- methoxyl group -5- oxygen -9- carboxyl -5H- pyrido-[3,2-a] of embodiment,-phenoxazine -3- carboxylic acids.
4 compound 2- methyl carbonyl -5- oxygen -5H- pyrido-[3,2-a] of embodiment,-phenoxazine -3- carboxylic acids.
5 compound 1-cyclopropyl base -5- oxygen -9- itrile group -5H- pyrido-[3,2-a] of embodiment,-phenoxazine -3- carboxylic acids.
6 compound 2- chloromethyl -5- oxygen -9- itrile group -5H- pyrido-[3,2-a] of embodiment,-phenoxazine -3- carboxylic acids.
7 compound 2- phenyl -5- oxygen -9- nitro -5H- pyrido-[3,2-a] of embodiment,-phenoxazine -3- carboxylic acids.
8 compound 2- phenyl -5- oxygen -9- piperidyl -5H- pyrido-[3,2-a] of embodiment,-phenoxazine -3- carboxylic acids.
The final compound obtained to embodiment 1-8 forms pharmaceutical composition respectively as active constituent.
The present invention is specifically described below with embodiment 1-8 obtained final compounds, but the present invention and not only
It is limited to this.
The final compound that 1-8 of the embodiment of the present invention is obtained analyzes the therapeutic effect of cataract below.
（1）, by the following method the obtained final compounds of embodiment 1-8 are made into eye drops：
Carbopol 941 10g is taken, water about 700g is added, is stood, is made its swelling, with phosphate buffer tune pH value to neutrality, obtain
Matrix.The final compound that another Example 1-8 is obtained（Experimental group compound）10g, benzalkonium chloride 5g add appropriate amount of water stirring to make
Resulting mixture is slowly added into above-mentioned matrix, stirs evenly, and adds water to 1000g, and vacuum outgas sterilizes at 100 DEG C
30min is to get clarification, transparent gel for eye.
（2）, cataract therapy effect experiment
The Wistar rats that the quality of choosing health pure lines is 160-210g, half male and half female body are subcutaneously injected low dose of (4mg/kg)
Sodium selenite, the next day 1 time, continuous 3 times, carry out cataract rat modeling.Modeling success rat 80 is taken, is randomly divided into 10 groups,
Respectively model group, experimental group 1-8 groups and positive controls, wherein model group give water for injection eye drops, experimental group 1-8 groups
The eye drops that the final compound that 1-8 containing embodiment is obtained is made into respectively is given respectively, and the dosage of reactive compound is
1mg/kg；Positive controls give the eye drops containing glutathione, and the dosage of glutathione is 1mg/kg.Each administration group is every
Day administration 2 times, successive administration 4 weeks.
At the end of experiment, each group experimental rat pupil of both eyes is dissipated greatly with Tropicamide eye drops, uses slit-lamp microscopy
It looks into and records phacoscotasmus situation.Phacoscotasmus degree reference literature (Song Nianyi, Liu Liansheng, Gao Qiuhua, in zinc supplementation dialogue
Hinder the influence of LDH and CuZn-SOD in rat blood and crystalline lens, ophthalmology research) standard grading："-" shows no muddiness, i.e., brilliant
Shape body is transparent；"+" shows core muddiness, i.e., lens nucleus occurs muddy, but cortex portion is still limpid；" ++ " shows full muddiness, i.e. crystalline lens
Core and cortex are become turbid.
Experimental result is shown in following tables.
Test result shows that Ben Bing Naphthoxazines of the present invention have very significant treatment effect for cataract
Fruit, the rat of experimental group 1-8 groups are substantially better than current preferable in treatment cataract effect that there is a phenomenon where full muddinesses
Glutathione.Therefore, the compounds of this invention is very suitable for being used as the drug for the treatment of cataract, and effect is fabulous.
Toxicity test is carried out to the eye drops that the obtained final compounds of embodiment 1-8 in above-mentioned experiment are made into.
To 40（Divide 5 groups）The eye drops that 200-260g white rabbits are made into the obtained final compounds of embodiment 1-8,
Five times a day, after being used in conjunction 20 weeks, visual inspection, histopathologic examination and Scanning election microscope is carried out, is not as a result found to eye group
It is woven with any stimulation or damage.
It to sum up states and shows that Ben Bing Naphthoxazines of the present invention are free of toxic effects.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of from which, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended right
It is required that rather than above description limit, it is intended that all changes that will be fallen within the meaning and scope of the equivalent requirements of the claims
Change is included within the present invention.Any label in claim should not be considered as and be limited the claims involved.
Based on the embodiments of the present invention, those of ordinary skill in the art are obtained without making creative work
The every other embodiment obtained, shall fall within the protection scope of the present invention.
Claims (10)
1. a kind for the treatment of cataract medicine Ben Bing Naphthoxazines, which is characterized in that the treatment cataract medicine benzo
Naphthoxazines have following chemical structural formula：
,
X is selected from hydrogen, halogen, cyano, amino, nitro or carboxyl, and X is located at at least one in phenyl ring residue binding site, X and benzene
Carbon atom on ring is covalently attached；
R be selected from C1-C6 alkoxies, C3-C7 naphthenic base, halogenated C1-C6 alkyl, C1-C6 alkyl-carbonyls, C1-C6 alkoxy carbonyls,
C1-C6 alkyl aminos, two (C1-C6 alkyl) amino, C1-C6 alkyl sulphonyls, C6-C10 aryl or C2-C10 heterocycles, wherein
C1-C6 alkoxies, C3-C7 naphthenic base, halogenated C1-C6 alkyl, C1-C6 alkyl-carbonyls, C1-C6 alkoxy carbonyls, C1-C6 alkyl
Amino, two (C1-C6 alkyl) amino, C1-C6 alkyl sulphonyls, C6-C10 aryl or C2-C10 heterocycles are optionally selected by 1 to 3
Replace from group below：Halogen, C1-C4 alkyl or hydroxyl；R is located at at least one in phenyl ring residue binding site.
2. a kind of cataract medicine Ben Bing Naphthoxazines are treated according to claim 1, which is characterized in that described
Halogen is fluorine（F）, chlorine（Cl）, bromine（Br）Or iodine（I）, the alkyl refers to the linear or branched alkyl group for having 1-6 carbon atom,
It is non-limiting such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, n-pentyl or n-hexyl.
3. a kind of preparation method for treating cataract medicine Ben Bing Naphthoxazines, which is characterized in that the preparation method packet
Containing following synthesis step：
Pure water, compound is added in the first step in the three-neck flask equipped with blender, thermometer and condenser pipe（1）And succinic acid
Acid anhydride, warming-in-water keep temperature control at 80-85 DEG C, potassium permanganate to be added to potassium permanganate after 80 DEG C, is added in three batches
The reaction was complete, the solution in reaction bulb be dark brown without purple when, add next group potassium permanganate, so carry out, wait for whole
Potassium permanganate after completion of the reaction, is kept for 80-85 DEG C and stirred
It mixes minimum 45 minutes, filters while hot, remove manganese dioxide, obtain containing compound（2）Solution；
Second step will contain compound in the first step（2）Solution with concentrated hydrochloric acid adjust solution PH so that PH 3.2-3.3, mix
Stirring 30 minutes is closed, is concentrated in vacuo in rotary evaporator, ethyl alcohol is added after being evaporated and flows back at 68 DEG C 2h, after reflux,
Object cooling to be mixed is filtered, and is taken filtrate and is dried, obtains compound（3）；
Third walks, by compound（3）With compound（4）Mixing is dissolved in anhydrous DMF, is heated to reflux 30min, solution is by orange change
For navy blue, TLC detection reactions terminate, are cooled to room temperature, mixed liquor is poured into sodium hydrate aqueous solution, water layer is with extractant
After elution, merge organic phase, anhydrous sodium sulfate dries 2h, is filtered to remove anhydrous sodium sulfate, obtains compound（5）；
4th step, by compound（5）It is added at 0-20 DEG C in the acetone soln containing pure water, addition is urged
Agent is sufficiently stirred 1h, after be slowly added dropwise sulfuric acid, TLC detection reactions terminate, and are cooled to room temperature, and ethyl acetate extraction is received
Collect organic phase, saturated common salt water washing three times, filter, and filtrate decompression distills to obtain crude product, and crude product is through silicon by anhydrous magnesium sulfate drying
Glue filtering is recrystallized to give compound（6）.
4. a kind of preparation method for treating cataract medicine Ben Bing Naphthoxazines according to claim 3, special
Sign is that the preparation method includes following synthetic route：
。
5. a kind of preparation for treating cataract medicine Ben Bing Naphthoxazines according to claim 3
Method, which is characterized in that manganese dioxide is washed several times with hot distilled water in the synthesis step first step, until filtrate
For colourless transparent solution.
6. a kind of preparation method for treating cataract medicine Ben Bing Naphthoxazines according to claim 3, special
Sign is that the temperature being concentrated in vacuo in rotary evaporator in the synthesis step second step is 45-50 DEG C.
7. a kind of preparation method for treating cataract medicine Ben Bing Naphthoxazines according to claim 3, special
Sign is that extractant is dichloromethane and DCM in the synthesis step third step and methanol volume ratio is 10:1 mixed liquor,
It is first eluted with dichloromethane, then with DCM and methanol volume ratio is 10:1 mixed liquor is eluted.
8. a kind of preparation method for treating cataract medicine Ben Bing Naphthoxazines according to claim 3, special
Sign is that the catalyst in the 4th step of the synthesis step is chromium trioxide.
9. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition is comprising Ben Bing Naphthoxazines, its pharmacy
The upper pharmaceutical composition of acceptable salt, isomer or solvate as active constituent.
10. a kind of pharmaceutical composition according to claim 9, described pharmaceutical composition answering in treating cataract conditions
With.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115160341A (en) * | 2022-07-18 | 2022-10-11 | 中国医学科学院医学实验动物研究所 | Benzoxazine compound and pharmaceutical use thereof |
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