CN108191888A - A kind of 1,4- sulphur azatropylidene medicinal compounds nursed for skin ulcer and its preparation method and application - Google Patents

A kind of 1,4- sulphur azatropylidene medicinal compounds nursed for skin ulcer and its preparation method and application Download PDF

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CN108191888A
CN108191888A CN201810131654.6A CN201810131654A CN108191888A CN 108191888 A CN108191888 A CN 108191888A CN 201810131654 A CN201810131654 A CN 201810131654A CN 108191888 A CN108191888 A CN 108191888A
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compound
reaction
added
skin ulcer
sulphur azatropylidene
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CN108191888A8 (en
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贾利利
耿水英
王璐
潘丽娜
高魏丽
张金金
王晓东
路遥
毛龙飞
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First Affiliated Hospital of Henan University of Science and Technology
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First Affiliated Hospital of Henan University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Abstract

The invention discloses a kind of for Isosorbide-5-Nitrae sulphur azatropylidene medicinal compound of skin ulcer nursing and its preparation method and application, belong to medical synthesis technical field.Technical scheme of the present invention main points are：A kind of Isosorbide-5-Nitrae sulphur azatropylidene medicinal compound for skin ulcer nursing, structural formula are：

Description

A kind of 1,4- sulphur azatropylidene medicinal compounds and its system for skin ulcer nursing Preparation Method and application
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a kind of Isosorbide-5-Nitrae-sulphur azatropylidene for skin ulcer nursing Medicinal compound and its preparation method and application.
Background technology
Skin ulcer is common skin secondary lesion, and defect of skin or destruction are up to corium or corium hereinafter, single-shot or more Acute phase ulcer expands rapidly, and surface is covered with slough, exudate, incrustation, and ulcer margin red swelling of the skin is answered with the cause of disease It is miscellaneous, the course of disease is long, easily repeatedly the features such as.After wrapping up patient skin ulcer spot, if ulcer alleviation is bad, it can cause Bandage for dressing is bonded with ulcer wound, and during dressing, very big pain can be brought to patient by more changing a bandage, therefore, how right Patient skin ulcer is effectively nursed, and is all medical staff's very concern all the time.At present, in order to reduce patient Pain in nursing process, medical staff are generally applied in clinic using silver ion dressing, had by using silver ion Bactericidal effect makes ulcer spot quickly be formed a scab, and reduces the viscosity of bandage and wound, it is possible to reduce patient was more changing a bandage Pain in journey is flamazine than more typical silver ion dressing.
Nitrogenous sulfur heterocyclic compound is when it is with good bioactivity in human healths and the agriculture such as medicine and pesticide It plays an important role in industry production.Particularly sulphur azatropylidene is exactly a kind of important seven member ring heterocyclic compounds object, such chemical combination Object can improve cardiac muscle due to receiving people's concern, such compound with unique medical value and wide spectrum biological activity Blood supply reduces myocardial oxygen consumption, for treating angina pectoris, has minimum side effect, such as diltiazem；Such compound is still G protein coupled receptor antagonist has the effects that the compound of such structural unit also has a calm, hypnosis, for example, it is stable and Clotiapine；Such compound also is able to promote growth hormone secretion, can be used to treat the children growth phase slow；Such compound is also It is the compound of a kind of antiulcer activity, can be used for protecting stomach lining, for the treatment of chronic gastric ulcer；In addition sulphur azatropylidene Or a kind of compound with preferable antibacterial activity shows Staphylococcus aureus and some fungies to inhibit to make well With；It has recently been demonstrated that sulphur azatropylidene compound has certain effect in terms of AIDS is treated, it is that hiv reverse transcriptase inhibits Agent, researcher carry out structural modification to it, to find the drug of more preferable anti-AIDS effect.
Invention content
The technical problem to be solved by the present invention is to provide a kind of synthetic method is simple, molecular structure is novel and bactericidal effect is shown 1,4- sulphur azatropylidene medicinal compounds nursed for skin ulcer write and its preparation method and application.
It is of the invention to adopt the following technical scheme that solve above-mentioned technical problem, a kind of Isosorbide-5-Nitrae-sulphur for skin ulcer nursing Azatropylidene medicinal compound, it is characterised in that the structural formula of the Isosorbide-5-Nitrae-sulphur azatropylidene medicinal compound is：
A kind of preparation method of Isosorbide-5-Nitrae-sulphur azatropylidene medicinal compound for skin ulcer nursing, it is characterised in that tool Body step is：
(1) under nitrogen protection, compoundIt is added in n,N-Dimethylformamide, reaction temperature N-chlorosuccinimide is added portionwise after being cooled to 10 DEG C, restores after adding to reacting at room temperature, monitoring raw material is after the reaction was complete Add in ethyl acetate, then in saturated nacl aqueous solution washing reaction liquid to organic phase be free of n,N-Dimethylformamide, it is organic N-hexane is mutually added in after anhydrous magnesium sulfate drying, concentration, cooling and stirring is beaten, and compound is dried to obtain after suction filtration
(2) compound2-chloroethyl amine and alkali compounds are added in tetrahydrofuran, neutral and alkali Compound is sodium hydride or hydrofining, and with heating reflux reaction after reaction system with nitrogen gas, raw material is dropped after the reaction was complete To room temperature, dichloroethanes is added in, filtering reacting liquid after stirring adds in water and hydrochloric acid solution, with acetic acid second after filtrate decompression concentration The mixed solution of ester and n-hexane extraction reaction solution removes impurity, and it is 11, then use that water phase adjusts pH through saturation sodium hydroxide solution Chloroform extracts, and compound is concentrated to give after being dried with anhydrous sodium sulfate
(3) compoundIt is added in water and dichloromethane, stirs evenly with sodium bicarbonate After be cooled to 0 DEG C, the dichloromethane solution dissolved with benzyl chloroformate is added dropwise, reacts to raw material and has reacted at room temperature after dripping Entirely, separate organic phase, water phase is extracted with dichloromethane, be dried over anhydrous sodium sulfate after organic phase, concentrate after obtain compound
(4) compoundIt is added in toluene with sulfonic compound, wherein sulfonic acid Class compound is pyrovinic acid or p-methyl benzenesulfonic acid, is heated to 70 DEG C, adds paraformaldehyde, after adding under the conditions of 70 DEG C To raw material, the reaction was complete for reaction, is cooled to room temperature, filtering reacting liquid, filtrate is washed through saturated sodium bicarbonate solution, is separated organic Phase is dried over anhydrous sodium sulfate rear filtering and concentrating, then purifies through column chromatography for separation to obtain compound
(5) under nitrogen protection, compoundIt is added in reaction bulb, adds with DMSO Connection boric acid pinacol ester and potassium acetate are passed through reaction system with nitrogen gas and add in catalyst Pd (dppf) Cl afterwards three times2Or Pd(OAc)2, it is passed through hydrogen displacement reaction system gas again and is heated to 100 DEG C afterwards three times and is reacted, monitoring raw material has reacted Reaction system is cooled to room temperature after complete, ethyl acetate is added in, is washed repeatedly with saturated nacl aqueous solution, then use anhydrous magnesium sulfate Dry organic phase purifies after concentration through column chromatography for separation to obtain compound
(6) under nitrogen protection, compoundIt is added to 1,4- dioxane and deionization In the mixed solution of water, the chloro- 4- methyl formates yl pyridines of 2- and potassium phosphate are added, is passed through reaction system with nitrogen gas three Catalyst Pd (dppf) Cl is added in after secondary2, it is passed through reaction system with nitrogen gas again and is heated to 90 DEG C of progress afterwards three times instead Should up to raw material, the reaction was complete, reaction temperature be cooled to room temperature after add in ethyl acetate extraction reaction solution, merge organic phase after use Saturated nacl aqueous solution washs, then is concentrated after being dried with anhydrous sodium sulfate, then purifies to obtain compound through column chromatography for separation
(7) under nitrogen protection, compoundIn the mixed solvent is added to, wherein Mixed solvent be by volume ratio be 2:2:The mixed solution that 1 tetrahydrofuran, methanol and deionized water forms, adds hydroxide Lithium, be warming up to 50 DEG C carry out reaction up to raw material, the reaction was complete, reaction solution is cooled to room temperature, vacuum is dense after filtering reacting liquid Contracting, adds dichloroethanes, and cooling and stirring mashing filters drying and obtains compound
(8) under nitrogen protection, compoundIt is added in anhydrous tetrahydro furan, then (R) -2- (diethylin) propyl -1- amine, HATU and DIEA are added in, is heated to back flow reaction, reacts that the reaction was complete to raw material, then Ethyl acetate is added in, it is multiple with saturated nacl aqueous solution washing reaction liquid, it is dried, concentrated with anhydrous sodium sulfate after separating organic phase Purifying to obtain target compound by column chromatography for separation has
Further preferably, compound described in step (2)Molar ratio with alkali compounds is 3:4。
Further preferably, compound described in step (4)With sulfonic compound Molar ratio is 5:1.
Further preferably, compound described in step (5)With the inventory mass ratio of catalyst It is 50:1.
A kind of Isosorbide-5-Nitrae-sulphur azatropylidene class pharmaceutical composition for skin ulcer nursing, it is characterised in that this is used for skin and bursts Ulcer nursing 1,4- sulphur azatropylidene class pharmaceutical compositions be by mass ratio be 5:4:12:4:0.5:20:1.5:5:3:3:2:40 CompoundMonoglyceride, IPP, albolene, Nepal's gold propyl ester, the third two The drug ointment that alcohol, Nepal's tortoise beetle ester, glycerine, MAP emulsifiers, essence, peppermint oil and water are formulated.
Further preferably, the skin ulcer is as caused by bacillus anthracis or/and Staphylococcus aureus.
The comprehensive sulphur azatropylidene class compound of the present invention has calmness, promotes growth hormone secretion, antiulcer and sterilization etc. excellent Point has synthesized a kind of Isosorbide-5-Nitrae-sulphur azatropylidene medicinal compound for skin ulcer nursing and has carried out antibacterial activity test, It was found that such compound all has preferable inhibitory activity to the bacillus anthracis and Staphylococcus aureus that easily cause skin ulcer, And then ointment is made and carries out clinical care experiment, it is found that nursing efficacy is obvious.
Specific embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this The range for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair Bright range.
Embodiment 1
Under nitrogen protection, compound150g (1mol) is added to N.N- dimethylformamides In 2000mL, reaction temperature is cooled to after 10 DEG C is separately added into N-chlorosuccinimide 65g in three batches, altogether 195g (1.5mol) restores to add in ethyl acetate 10000mL after the reaction was complete to room temperature reaction 12h, LCMS monitoring raw material after adding, stir It is used after mixing 10min without n,N-Dimethylformamide in saturated nacl aqueous solution washing reaction liquid to organic phase, organic phase is through nothing Water magnesium sulfate 300g is dried, addition n-hexane 1000mL after concentration, the stirring to pulp under the conditions of 0 DEG C, being dried to obtain after suction filtration Close object200g, yield 87.3% ,-HRMS ((+)-ESI):M/z=231.0971 (calcd.231.0975for C6H5BrN3S,[M+H]+).
Embodiment 2
In reaction bulb, compound35g (0.15mol), 2-chloroethyl amine 17.4g (0.15mol) and The sodium hydride 8g (0.2mol) of 60wt% contents is added in tetrahydrofuran 100mL, with reaction system with nitrogen gas three times, Then heating reflux reaction 10h, TLC monitoring raw material are down to room temperature after the reaction was complete, and dichloroethanes is added in into reaction system 200mL stirs filtering reacting liquid after 10min, adds in water 100mL after filtrate decompression concentration, add hydrochloric acid solution 20mL, use body Product is than being 1:1 ethyl acetate and the mixed solution 100mL of n-hexane extract reaction solution 2 times, and water phase is molten through saturation sodium hydroxide It is 11 that liquid, which adjusts pH, then is extracted 3 times with chloroform 100mL, merges organic phase, compound is concentrated to give after being dried with anhydrous sodium sulfate33g, yield 81%；1H NMR(CDCl3,400MHz)δ8.43-8.42(m,1H),7.83 (d, J=12.0,1H), 7.29 (d, J=12.0,1H), 5.39 (s, 2H), 3.57-3.55 (m, 2H), 3.04 (d, J=8.0, 2H)。
Embodiment 3
In reaction bulb, compound35g (0.15mol), 2-chloroethyl amine 17.4g (0.15mol) and Hydrofining 8g (0.2mol) is added in tetrahydrofuran 100mL, with reaction system with nitrogen gas three times, is then heated to reflux anti- Answer 10h, TLC monitoring raw material is down to room temperature after the reaction was complete, dichloroethanes 200mL is added in into reaction system, after stirring 10min Filtering reacting liquid adds in water 100mL after filtrate decompression concentration, adds hydrochloric acid solution 20mL, is 1 with volume ratio:1 acetic acid second The mixed solution 100mL of ester and n-hexane extractions reaction solution 2 times, it is 11, then use that water phase adjusts pH through saturation sodium hydroxide solution Chloroform 100mL is extracted 3 times, merges organic phase, compound is concentrated to give after being dried with anhydrous sodium sulfate35.5g, yield 87%；1H NMR(CDCl3,400MHz)δ8.43-8.42(m,1H),7.83 (d, J=12.0,1H), 7.29 (d, J=12.0,1H), 5.39 (s, 2H), 3.57-3.55 (m, 2H), 3.04 (d, J=8.0, 2H)
Embodiment 4
In reaction bulb, compound35g (0.13mol) and sodium bicarbonate 16.8g (0.2mol) is added in water 100mL and dichloromethane 200mL, and 0 DEG C is cooled to after stirring evenly, is slowly added dropwise dissolved with chloro-carbonic acid The dichloromethane solution 100mL of benzyl ester 24g (0.14mol), reacts 2h at room temperature after dripping, TLC monitoring raw materials have reacted Quan Hou separates organic phase, and water phase is extracted twice with dichloromethane 100mL, is dried over anhydrous sodium sulfate after merging organic phase, concentrates After obtain compound49g, yield 93%.
Embodiment 5
In reaction bulb, compound20g (0.05mol) and pyrovinic acid 1g (0.01mol) is added in toluene 500mL, is slowly heated to 70 DEG C, is slow added into paraformaldehyde 15g (0.5mol), is added 10h is reacted under the conditions of 70 DEG C afterwards, the reaction was complete for TLC monitoring raw material, is cooled to room temperature, filtering reacting liquid, filtrate is through saturated carbon Sour hydrogen sodium solution 100mL is washed 1 time, is separated organic phase, is dried over anhydrous sodium sulfate rear filtering and concentrating, then through column chromatography (VPE: VEA=10:1) separating-purifying obtains compound14g, yield 70% ,-HRMS ((+)-ESI):m/z =420.3023 (calcd.420.3011for C17H16BrN4O2S,[M+H]+).。
Embodiment 6
In reaction bulb, compound20g (0.05mol) and p-methyl benzenesulfonic acid 2g (0.01mol) is added in toluene 500mL, is slowly heated to 70 DEG C, is slow added into paraformaldehyde 15g (0.5mol), is added 10h is reacted under the conditions of 70 DEG C afterwards, the reaction was complete for TLC monitoring raw material, is cooled to room temperature, filtering reacting liquid, filtrate is through saturated carbon Sour hydrogen sodium solution 100mL is washed 1 time, is separated organic phase, is dried over anhydrous sodium sulfate rear filtering and concentrating, then through column chromatography (VPE: VEA=10:1) separating-purifying obtains compound17g, yield 85%.
Embodiment 7
Under nitrogen protection, compound280g (1mol) and DMSO 2800mL are added to instead It answers in bottle, adds connection boric acid pinacol ester 510g (2mol) and potassium acetate 300g (3mol), be passed through reaction system with nitrogen Gas adds in catalyst Pd (dppf) Cl afterwards three times25.6g slowly adds after being passed through hydrogen displacement reaction system gas again three times Heat is reacted to 100 DEG C, is reacted after 2h and to be monitored raw material by LCMS the reaction was complete, reaction system is cooled to room temperature, and adds in second Acetoacetic ester 1400mL uses saturated nacl aqueous solution 500mL washing reaction liquids 4 times after stirring 30min, then is dried with anhydrous magnesium sulfate Organic phase, through column chromatography (V after concentrationPE:VEA=5:1) separating-purifying obtains compound220g is received Rate 72.6%；1H NMR(CDCl3, 400MHz) and δ 8.65 (d, J=8.0,1H), 8.14 (d, J=12.0,1H), 3.97 (d, J= 12.0,2H), 3.53-3.51 (m, 2H), 2.97 (d, J=8.0,2H), 1.27-1.22 (m, 12H)
Embodiment 8
Under nitrogen protection, compound280g (1mol) and DMSO 2800mL are added to instead It answers in bottle, adds connection boric acid pinacol ester 510g (2mol) and potassium acetate 300g (3mol), be passed through reaction system with nitrogen Gas adds in catalyst Pd (OAc) afterwards three times25.6g is passed through reaction system with nitrogen gas and is slowly heated afterwards three times again It is reacted to 100 DEG C, by LCMS monitoring raw material, the reaction was complete after reaction 2h, and reaction system is cooled to room temperature, and adds in acetic acid Ethyl ester 1400mL uses saturated nacl aqueous solution 500mL washing reaction liquids 4 times after stirring 30min, then has with anhydrous magnesium sulfate drying Machine phase, through column chromatography (V after concentrationPE:VEA=5:1) separating-purifying obtains compound270g, yield 81.8%.
Embodiment 9
Under nitrogen protection, compound(1mol) is added to 1,4- dioxane 2500mL In deionized water 500mL, the chloro- 4- methyl formates yl pyridines (400g, 1.2mol) of 2- and potassium phosphate 424g (2mol) are added, It is passed through reaction system with nitrogen gas and adds in catalyst Pd (dppf) Cl afterwards three times213g is passed through nitrogen displacement reaction again System gas is slowly heated to 90 DEG C and is reacted afterwards three times, and by LCMS monitoring raw material, the reaction was complete after reaction 3h, reaction temperature Degree adds in ethyl acetate 3000mL extractions reaction solution 3 times after being cooled to room temperature, washed after merging organic phase with saturated nacl aqueous solution It washs 1 time, then is concentrated after being dried with anhydrous sodium sulfate, through column chromatography (VPE:VEA=5：1) separating-purifying obtains compound
Embodiment 10
Under nitrogen protection, compound34g (0.1mol) is added to tetrahydrofuran The in the mixed solvent of 400mL, methanol 400mL and deionized water 200mL add lithium hydroxide 5g (0.2mol), slowly heat up It is reacted to 50 DEG C, the reaction was complete for LCMS monitoring raw material after reacting 2h, and reaction solution is cooled to room temperature, true after filtering reacting liquid Sky concentration, adds dichloroethanes 400mL, the stirring to pulp under the conditions of 0 DEG C, filters drying and obtains compound29g, yield 88.7%；1H NMR(CDCl3, 400MHz) and δ 9.34 (d, J=8.0,1H), 8.26 (d, J=8.0,1H), 8.01 (d, J=8.0,1H), 7.87 (s, 1H), 7.64 (s, 1H), 4.22 (d, J=8.0,1H), 3.82 (s, 2H), 3.09 (d, J=8.0,2H), 2.85 (d, J=8.0,2H)
Embodiment 11
Under nitrogen protection, compoundIt is anhydrous that 33g (0.1mol) is added to 800mL (R) -2- (diethylin) propyl -1- amine 20g (0.15mol) in tetrahydrofuran, is added, is added after stirring 10min HATU42g (0.11mol) and DIEA 39g (0.3mol) is slowly heated to back flow reaction, and LCMS monitoring raw materials are anti-after reacting 2h Should be complete, ethyl acetate 2000mL is added, saturated nacl aqueous solution 1000mL washing reaction liquids is used 2 times after stirring 1h, separates It is dried after organic phase with anhydrous sodium sulfate, purifies through column chromatography for separation to obtain target compound after concentration41g, yield 93.2%；1H NMR(CDCl3,400MHz)δ9.12(d,J =8.0,1H), 8.23-8.21 (m, 2H), 8.04 (s, 1H), 7.87 (s, 1H), 7.66-7.64 (m, 2H), 4.22 (d, J= 8.0,1H),3.72(d,J1=12.0, J2=8.0,2H), 3.42 (s, 1H), 3.14 (d, J=8.4,2H), 3.01 (d, J= 8.4,2H),2.37-2.35(m,4H),1.25(s,3H),1.05-1.02(m,6H)；MS m/z=440.5697 (Calcd 440.5689forC22H29N7OS+H).Anal.Calcd for C22H29N7OS:C,60.11；H,6.65；N,22.30.Found: C,60.24；H,6.71；N,22.35
Embodiment 12
The present embodiment selects bacillus anthracis and golden yellow glucose coccus as antibacterial activity test object.It is preparation solution first Peptone 1g, yeast extract 0.5g, sodium chloride 1g, distilled water 100mL (are placed in 250mL conical flasks, are placed on electric furnace by body culture medium On heat while stirring, it is to be mixed clarification it is uniform when, stop heating, bottleneck gauze and brown paper are sealed for use successively) and Peptone 1g, yeast extract 0.5g, sodium chloride 1g, agar 2g, distilled water 100mL (are placed in 250mL conical flasks by solid medium In, it is placed on electric furnace and heats while stirring, when clarification to be mixed is uniform, stop heating, by bottleneck gauze and brown paper successively Sealing is for use)；Then sterilization treatment is carried out to culture medium by high-pressure sterilizing pot.Secondly the preparation of bacterium solution, Escherichia coli After golden yellow glucose coccus actication of culture, the bacterium solution after pipetting 100 μ L activation with liquid-transfering gun is placed in sterilized 100mL and steams It is uniformly mixed in distilled water.It sterilizes to tablet finally by ultraviolet lamp, then culture medium is quickly poured into tablet while hot, it is thick About 0.15cm is spent, is uniformly paved, stands, allows its slow solidification, be put into cultivate one day in 37 DEG C of incubator after solidification and do without miscellaneous Bacterium detects.
Synthesized target compound and control compound solution is respectively configured with DMF, is placed in volumetric flask for use.With beating Hole device punches on filter paper, and aperture 5mm is immersed in after then filter paper is sterilized in the sample solution of a concentration of 0.1mg/mL For use.
On superclean bench, alcolhol burner is lighted, the 10 diluted culture solutions of μ L is taken to be added to solid culture base table with liquid-transfering gun Face, and be coated with uniform.The garden impregnated filter paper is taken to be taped against media surface with aseptic nipper.Each tablet puts 4, carries out 3 Secondary parallel laboratory test, wherein a piece of carry out blank control.The tablet for being placed with tablet is placed in 37 DEG C of insulating boxs and is cultivated for 24 hours, observation Phenomenon.It, can by measuring antibacterial circle diameter by occurring different size of transparent ring-inhibition zone on agar medium respectively To find out the bacteriostatic activity size of each sample.
Embodiment 13
Under the conditions of 10 DEG C, water 40g and propylene glycol 20g is added in stirring container, adds glycerine 5g and peppermint oil 2g starts stirring, adds in compoundSequentially add monoglyceride 4g, IPP 12g, albolene 4g, Nepal gold propyl ester 0.5g, Nepal tortoise beetle ester 1.5g, MAP emulsifier 3g and essence 3g are kept 2h is stirred at a temperature of 10 DEG C, both obtains drug ointment.
Embodiment 14
The drug ointment prepared using embodiment 13 protects 30 diabetic skin ulcers caused by pressure sore Reason treatment.Skin ulcer multidigit is before shin, shank lower part, dorsal portion and toes portion.Ulcer area maximum 4.0cm × 5.0cm, most It is small for 1.0cm × 1.5cm, depth 0.2-1.0cm, part ulcer basal part has different degrees of suppuration or purulence blood sexual secretion And a small amount of slough.
Conventional iodophor disinfection is carried out first, and such as trauma surface infestation is pressed again after first cleaning its dense sexual secretion with 3wt% hydrogen peroxide Program debridement, the excessive surface of a wound of slough preferably use a small amount of multiple debridement method.Medical staff applies ointment in treatment group In the surface of a wound, the covering of external use sterile gauze, fixed, primary every dressing on the two, the daily dressing of severe infection person is primary, until healing. Blank control group uses petrolatum oil gauze, is covered in the surface of a wound after soaking 1wt% gentamicins, daily dressing is primary.
From the point of view of therapeutic effect is by ulcer surface healing rate, the 7th day average healing rate for the treatment of group is (0.42 ± 0.15) cm2/ day, hence it is evident that be faster than (0.33 ± 0.15) cm of blank control group2/ day.
Basic principle, main features and advantages embodiment above describes the present invention, the technical staff of the industry should Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe the originals of the present invention Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within In the scope of protection of the invention.

Claims (7)

  1. A kind of 1. Isosorbide-5-Nitrae-sulphur azatropylidene medicinal compound for skin ulcer nursing, it is characterised in that the Isosorbide-5-Nitrae-sulphur azatropylidene The structural formula of medicinal compound is：
  2. 2. a kind of preparation side of the 1,4- sulphur azatropylidene medicinal compounds described in claim 1 for skin ulcer nursing Method, it is characterised in that the specific steps are：
    (1) under nitrogen protection, compoundIt is added in n,N-Dimethylformamide, reaction temperature cooling N-chlorosuccinimide is added portionwise after to 10 DEG C, restores after adding to reacting at room temperature, monitoring raw material is added in after the reaction was complete Ethyl acetate, then with n,N-Dimethylformamide is free of in saturated nacl aqueous solution washing reaction liquid to organic phase, organic phase passes through Anhydrous magnesium sulfate is dry, n-hexane is added in after concentration, cooling and stirring mashing, and compound is dried to obtain after suction filtration
    (2) compound2-chloroethyl amine and alkali compounds are added in tetrahydrofuran, wherein alkaline chemical combination Object is sodium hydride or hydrofining, and with heating reflux reaction after reaction system with nitrogen gas, raw material is down to room after the reaction was complete Temperature adds in dichloroethanes, and filtering reacting liquid after stirring adds in water and hydrochloric acid solution after filtrate decompression concentration, with ethyl acetate and The mixed solution extraction reaction solution of n-hexane removes impurity, and it is 11, then use chloroform that water phase adjusts pH through saturation sodium hydroxide solution Extraction, compound is concentrated to give after being dried with anhydrous sodium sulfate
    (3) compoundIt is added in water and dichloromethane with sodium bicarbonate, is dropped after stirring evenly The dichloromethane solution dissolved with benzyl chloroformate is added dropwise to 0 DEG C in temperature, reacts that the reaction was complete to raw material after dripping at room temperature, Separate organic phase, water phase is extracted with dichloromethane, be dried over anhydrous sodium sulfate after organic phase, concentrate after obtain compound
    (4) compoundIt is added in toluene with sulfonic compound, wherein sulphonic acids chemical combination Object is pyrovinic acid or p-methyl benzenesulfonic acid, is heated to 70 DEG C, adds paraformaldehyde, reacted under the conditions of 70 DEG C after adding to The reaction was complete for raw material, is cooled to room temperature, and filtering reacting liquid, filtrate is washed through saturated sodium bicarbonate solution, separates organic phase, through nothing Filtering and concentrating after aqueous sodium persulfate drying, then purify through column chromatography for separation to obtain compound
    (5) under nitrogen protection, compoundIt is added in reaction bulb with DMSO, adds connection boron Sour pinacol ester and potassium acetate are passed through reaction system with nitrogen gas and add in catalyst Pd (dppf) Cl afterwards three times2Or Pd (OAc)2, it is passed through hydrogen displacement reaction system gas again and is heated to 100 DEG C afterwards three times and is reacted, the reaction was complete for monitoring raw material Reaction system is cooled to room temperature afterwards, ethyl acetate is added in, is washed repeatedly with saturated nacl aqueous solution, then done with anhydrous magnesium sulfate Dry organic phase purifies after concentration through column chromatography for separation to obtain compound
    (6) under nitrogen protection, compoundIt is added to 1,4- dioxane and deionized water In mixed solution, the chloro- 4- methyl formates yl pyridines of 2- and potassium phosphate are added, after being passed through reaction system with nitrogen gas three times Add in catalyst Pd (dppf) Cl2, it is passed through reaction system with nitrogen gas again it is heated to 90 DEG C afterwards three times and carries out reacting straight To raw material, the reaction was complete, and reaction temperature adds in ethyl acetate extraction reaction solution after being cooled to room temperature, saturation is used after merging organic phase Sodium chloride solution washs, then is concentrated after being dried with anhydrous sodium sulfate, then purifies to obtain compound through column chromatography for separation
    (7) under nitrogen protection, compoundIn the mixed solvent is added to, wherein mixing Solvent be by volume ratio be 2:2:The mixed solution that 1 tetrahydrofuran, methanol and deionized water forms, adds lithium hydroxide, Be warming up to 50 DEG C carry out reaction up to raw material, the reaction was complete, reaction solution is cooled to room temperature, is concentrated in vacuo after filtering reacting liquid, then Dichloroethanes is added in, cooling and stirring mashing filters drying and obtains compound
    (8) under nitrogen protection, compoundIt is added in anhydrous tetrahydro furan, adds (R) -2- (diethylin) propyl -1- amine, HATU and DIEA, are heated to back flow reaction, react that the reaction was complete to raw material, add Ethyl acetate, it is multiple with saturated nacl aqueous solution washing reaction liquid, it is dried with anhydrous sodium sulfate after separating organic phase, is passed through after concentration Column chromatography for separation, which purifies to obtain target compound, to be had
  3. 3. the preparation side of the 1,4- sulphur azatropylidene medicinal compounds according to claim 2 for skin ulcer nursing Method, it is characterised in that：Compound described in step (2)Molar ratio with alkali compounds is 3:4.
  4. 4. the preparation side of the 1,4- sulphur azatropylidene medicinal compounds according to claim 2 for skin ulcer nursing Method, it is characterised in that：Compound described in step (4)It rubs with feeding intake for sulfonic compound You are than being 5:1.
  5. 5. the preparation side of the 1,4- sulphur azatropylidene medicinal compounds according to claim 2 for skin ulcer nursing Method, it is characterised in that：Compound described in step (5)Inventory mass ratio with catalyst is 50: 1。
  6. 6. a kind of Isosorbide-5-Nitrae-sulphur azatropylidene class pharmaceutical composition for skin ulcer nursing, it is characterised in that this is used for skin ulcer The 1,4- sulphur azatropylidene class pharmaceutical compositions of nursing be by mass ratio be 5:4:12:4:0.5:20:1.5:5:3:3:2:40 power Profit requires the compound described in 1Monoglyceride, IPP, albolene, Nepal The drug that golden propyl ester, propylene glycol, Nepal's tortoise beetle ester, glycerine, MAP emulsifiers, essence, peppermint oil and water are formulated is soft Cream.
  7. 7. Isosorbide-5-Nitrae-sulphur azatropylidene class pharmaceutical composition according to claim 6 for skin ulcer nursing, feature exists In：The skin ulcer is as caused by bacillus anthracis or/and Staphylococcus aureus.
CN201810131654.6A 2018-02-09 2018-02-09 A kind of 1,4- sulphur azatropylidene medicinal compounds nursed for skin ulcer and its preparation method and application Pending CN108191888A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108912147A (en) * 2018-02-09 2018-11-30 河南科技大学第附属医院 A kind of sulphur azatropylidene medicinal compound and preparation method thereof for human burn skin nursing
CN108997381A (en) * 2018-02-09 2018-12-14 河南科技大学第附属医院 A kind of pyrazolo [1,5-a] pyridines drug and preparation method thereof, composition and the application in skin ulcer patient nursing

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* Cited by examiner, † Cited by third party
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CN103772319A (en) * 2014-01-02 2014-05-07 成都医路康医学技术服务有限公司 Synthetic method of thiazepine compound
CN106543102B (en) * 2016-10-28 2018-09-14 石家庄学院 1,5- benzothiazepines analog derivative and its application

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108912147A (en) * 2018-02-09 2018-11-30 河南科技大学第附属医院 A kind of sulphur azatropylidene medicinal compound and preparation method thereof for human burn skin nursing
CN108997381A (en) * 2018-02-09 2018-12-14 河南科技大学第附属医院 A kind of pyrazolo [1,5-a] pyridines drug and preparation method thereof, composition and the application in skin ulcer patient nursing

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