CN109053770A - A kind of 1,4- sulphur azatropylidene medicinal compound and its preparation method and application for skin ulcer nursing - Google Patents

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

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CN109053770A
CN109053770A CN201810880258.3A CN201810880258A CN109053770A CN 109053770 A CN109053770 A CN 109053770A CN 201810880258 A CN201810880258 A CN 201810880258A CN 109053770 A CN109053770 A CN 109053770A
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compound
added
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skin ulcer
sulphur azatropylidene
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贾利利
耿水英
李启华
王璐
潘丽娜
单远
秦定坤
王晓东
路遥
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First Affiliated Hospital of Henan University of Science and Technology
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

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

Description

A kind of 1,4- sulphur azatropylidene medicinal compound 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 technique
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 necrotic tissue, exudate, incrustation, and ulcer margin red swelling of the skin is multiple 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 will lead to Bandage for dressing and ulcer wound bond, 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.Currently, in order to reduce patient Pain in nursing process, medical staff generally use silver ion dressing to apply in clinic, have 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 due to it is with good bioactivity in human healths and the agriculture such as medicine and pesticide It plays an important role in industry production.Especially sulphur azatropylidene is exactly a kind of important seven member ring heterocyclic compounds object, such chemical combination For object due to paying close attention to unique medical value and wide spectrum biological activity by people, such compound can improve cardiac muscle Blood supply reduces myocardial oxygen consumption, for treating angina pectoris, has minimum side effect, such as diltiazem；Such compound is still G protein coupling acceptor 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 can also 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 to protect stomach lining, the treatment for chronic gastric ulcer；Furthermore sulphur azatropylidene Or a kind of compound with preferable antibacterial activity shows to inhibit to make well to Staphylococcus aureus and some fungies With；It has recently been demonstrated that sulphur azatropylidene compound has certain effect in terms for the treatment of AIDS, 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.
Summary of the invention
That the technical problem to be solved by the present invention is to provide a kind of synthetic methods is simple, molecular structure is novel and bactericidal effect is aobvious The 1,4- sulphur azatropylidene medicinal compound and its preparation method and application for skin ulcer nursing write.
The present invention adopts 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 Isosorbide-5-Nitrae-sulphur azatropylidene medicinal compound structural formula are as follows:
A kind of Isosorbide-5-Nitrae-sulphur azatropylidene medicinal compound preparation method for skin ulcer nursing, it is characterised in that tool Body step are as follows:
(1) under nitrogen protection, compoundIt is added in n,N-Dimethylformamide, reaction temperature N-bromosuccinimide is added portionwise after being cooled to 10 DEG C, restores after adding to room temperature reaction, after monitoring raw material fully reacting Ethyl acetate is added, then is free of n,N-Dimethylformamide into organic phase with saturated sodium chloride solution washing reaction liquid, it is organic N-hexane is added after mutually dry through anhydrous magnesium sulfate, concentration, cooling and stirring is beaten, and is dried to obtain compound after suction filtration
(2) compound2-chloroethyl amine and alkali compounds are added in tetrahydrofuran, neutral and alkali Compound is that sodium hydride or hydrofining are dropped after raw material fully reacting with heating reflux reaction after reaction system with nitrogen gas To room temperature, dichloroethanes is added, water and hydrochloric acid solution is added after filtrate decompression concentration, with acetic acid second in filtering reacting liquid after stirring The mixed solution of ester and n-hexane extracts reaction solution and removes impurity, and it is 11 that water phase, which adjusts pH through saturation sodium hydroxide solution, then is used Chloroform extraction, is concentrated to get compound after being dried with anhydrous sodium sulfate
(3) compoundIt is added in water and methylene chloride, 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, be concentrated after obtain compound
(4) compoundIt is added in toluene with sulfonic compound, wherein sulfonic acid Class compound is methane sulfonic acid or p-methyl benzenesulfonic acid, is heated to 70 DEG C, adds paraformaldehyde, after adding under the conditions of 70 DEG C Reaction is cooled to room temperature, filtering reacting liquid, filtrate is washed through saturated sodium bicarbonate solution, is separated organic to raw material fully reacting Phase is dried over anhydrous sodium sulfate rear filtering and concentrating, then purifies to obtain compound through column chromatography for separation
(5) under nitrogen protection, compoundIt is added in reaction flask, adds with DMSO Connection boric acid pinacol ester and potassium acetate are passed through reaction system with nitrogen gas and catalyst Pd (dppf) Cl are added 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, is washed repeatedly with saturated sodium chloride solution, then use anhydrous magnesium sulfate Dry organic phase, purifies to obtain compound through column chromatography for separation after concentration
(6) under nitrogen protection, compoundIt is added to 1,4- dioxane and deionization In the mixed solution of water, the chloro- 4- methyl formate yl pyridines of 2- and potassium phosphate are added, reaction system with nitrogen gas three is passed through Catalyst Pd (dppf) Cl is added 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 Ethyl acetate extraction reaction solution should be added after raw material fully reacting, reaction temperature are cooled to room temperature, used after merging organic phase Saturated sodium chloride solution washing, then with being concentrated after anhydrous sodium sulfate drying, then purify to obtain compound through column chromatography for separation
(7) under nitrogen protection, compoundIt is added in the mixed solvent, wherein The mixed solution that mixed solvent is made of tetrahydrofuran, methanol and deionized water that volume ratio is 2:2:1, adds hydroxide Lithium is warming up to 50 DEG C and carries out reaction until raw material fully reacting, is cooled to room temperature reaction solution, 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 is added, is heated to back flow reaction, reacts to raw material fully reacting, then Ethyl acetate is added, it is multiple with saturated sodium chloride solution washing reaction liquid, separate, concentration dry with anhydrous sodium sulfate after 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 For 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 It is 5:4:12:4:0.5:20:1.5:5:3:3:2:40 that the 1,4- sulphur azatropylidene class pharmaceutical composition of ulcer nursing, which is by mass ratio, CompoundMonoglyceride, IPP, albolene, Nepal's gold propyl ester, the third two The drug ointment that alcohol, nepal Gold methyl ester, glycerine, MAP emulsifier, essence, peppermint oil and water are formulated.
Further preferably, the skin ulcer is as caused by staphylococcus epidermis or/and Staphylococcus aureus.
The comprehensive sulphur azatropylidene class compound of the present invention has calm, promotion growth hormone secretion, antiulcer and sterilization etc. excellent Point, synthesized it is a kind of for skin ulcer nursing Isosorbide-5-Nitrae-sulphur azatropylidene medicinal compound and carried out antibacterial activity test, It was found that such compound all has preferable inhibition to the staphylococcus epidermis and Staphylococcus aureus that easily cause skin ulcer Activity, and then ointment is made and carries out clinical care experiment, discovery nursing efficacy is obvious.
Specific embodiment
Above content of the 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 embodiment below, and all technologies realized based on above content of the present invention belong to this hair Bright range.
Embodiment 1
Under nitrogen protection, compound150g (1mol) is added to N.N- dimethylformamide In 2000mL, reaction temperature be cooled to after 10 DEG C be separately added into three batches N-bromosuccinimide 90g (total 270g, 1.5mol), restore that ethyl acetate 10000mL is added after monitoring raw material fully reacting to room temperature reaction 12h, LCMS after adding, stir Use saturated sodium chloride solution washing reaction liquid into organic phase without n,N-Dimethylformamide after mixing 10min, organic phase is through nothing Water magnesium sulfate 300g is dry, addition n-hexane 1000mL after concentration, stirring to pulp under the conditions of 0 DEG C, being dried to obtain after suction filtration Close object200g, yield 87.3%,1H NMR(CDCl3,400MHz)δ12.79(s,1H),9.23 (d,J =4.0,1H), 7.35 (s, 1H), 6.94 (d, J=4.0,1H)；13C NMR(CDCl3,400MHz)δ168.4,138.1, 136.9,129.7,107.3,86.7。
Embodiment 2
In reaction flask, compound35g (0.15mol), 2-chloroethyl amine 12g (0.15mol) and The sodium hydride 8g (0.2mol) of 60wt% content is added in tetrahydrofuran 100mL, three times with reaction system with nitrogen gas, Then it is down to room temperature after heating reflux reaction 10h, TLC monitoring raw material fully reacting, dichloroethanes is added into reaction system 200mL stirs filtering reacting liquid after 10min, water 100mL is added after filtrate decompression concentration, adds hydrochloric acid solution 20mL, uses body Product extracts reaction solution 2 times than the mixed solution 100mL of the ethyl acetate and n-hexane that are 1:1, and water phase is molten through saturation sodium hydroxide Liquid adjust pH be 11, then with chloroform 100mL extract 3 times, merge organic phase, with anhydrous sodium sulfate drying after be concentrated to get compound33g, yield 81%；1H NMR(CDCl3,400MHz)δ 8.43-8.42(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 flask, compound35g (0.15mol), 2-chloroethyl amine 12g (0.15mol) and hydrogen Change potassium 8g (0.2mol) to be added in tetrahydrofuran 100mL, three times with reaction system with nitrogen gas, then heating reflux reaction It is down to room temperature after 10h, TLC monitoring raw material fully reacting, dichloroethanes 200mL is added into reaction system, after stirring 10min Filtering reacting liquid is added water 100mL after filtrate decompression concentration, adds hydrochloric acid solution 20mL, the acetic acid second for being 1:1 with volume ratio The mixed solution 100mL of ester and n-hexane is extracted reaction solution 2 times, and it is 11 that water phase, which adjusts pH through saturation sodium hydroxide solution, then is used Chloroform 100mL is extracted 3 times, merges organic phase, is concentrated to get compound 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 flask, compound35g (0.13mol) and sodium bicarbonate 16.8g (0.2mol) is added in water 100mL and methylene chloride 200mL, is cooled to 0 DEG C after mixing evenly, is slowly added dropwise dissolved with chloromethane The dichloromethane solution 100mL of acid benzyl ester 24g (0.14mol), reacts 2h at room temperature after dripping, TLC monitors raw material reaction After completely, organic phase is separated, water phase is extracted twice with methylene chloride 100mL, is dried over anhydrous sodium sulfate after merging organic phase, dense Compound is obtained after contracting49g, yield 93%.
Embodiment 5
In reaction flask, compound20g (0.05mol) and methane sulfonic acid 1g (0.01mol) is added in toluene 500mL, is slowly heated to 70 DEG C, is slow added into paraformaldehyde 15g (0.5mol, with first Aldehyde amount calculates), 10h is reacted after adding under the conditions of 70 DEG C, TLC monitors raw material fully reacting, is cooled to room temperature, filtering reaction Liquid, filtrate wash 1 time through saturated sodium bicarbonate solution 100mL, separate organic phase, be dried over anhydrous sodium sulfate rear filtering and concentrating, (V is chromatographed through column againPE:VEA=10:1) separating-purifying obtains compound14g, yield 70%,1H NMR(CDCl3, 400MHz) and δ 8.95 (s, 1H), 8.16 (s, 1H), 7.67 (d, J=4.0,2H), 7.44-7.42 (m, 3H), 6.33 (s, 2H), 4.71 (s, 2H), 4.02 (d, J=4.0,2H), 3.75 (d, J=4.0,2H)；13C NMR(CDCl3,400 MHz)δ163.4,151.5,133.8,133.4,130.7,129.9,128.4,122.9,116.7,103.6,89.3,88.5, 63.3, 59.8,51.1。
Embodiment 6
In reaction flask, 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, with formaldehyde Amount calculates), 10h is reacted after adding under the conditions of 70 DEG C, TLC monitors raw material fully reacting, is cooled to room temperature, filtering reacting liquid, Filtrate is washed 1 time through saturated sodium bicarbonate solution 100mL, is separated organic phase, is dried over anhydrous sodium sulfate rear filtering and concentrating, then pass through Column chromatographs (VPE:VEA=10:1) separating-purifying obtains compound17g, yield 85%；1H NMR (CDCl3, 400MHz) and δ 8.95 (s, 1H), 8.16 (s, 1H), 7.67 (d, J=4.0,2H), 7.44-7.42 (m, 3H), 6.33 (s, 2H), 4.71 (s, 2H), 4.02 (d, J=4.0,2H), 3.75 (d, J=4.0,2H)；13C NMR(CDCl3,400MHz)δ 163.4,151.5,133.8,133.4,130.7,129.9,128.4,122.9,116.7,103.6, 89.3,88.5,63.3, 59.8,51.1。
Embodiment 7
Under nitrogen protection, compound420g (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 Catalyst Pd (dppf) Cl is added in gas afterwards three times28.5g slowly adds after being passed through hydrogen displacement reaction system gas again three times Heat is reacted to 100 DEG C, is reacted and is monitored raw material fully reacting by LCMS after 2h, reaction system is cooled to room temperature, addition second Acetoacetic ester 1400mL is used saturated sodium chloride solution 500mL washing reaction liquid 4 times after stirring 30min, then dry with anhydrous magnesium sulfate Organic phase, through silica gel column chromatography (V after concentrationPE:VEA=5:1) separating-purifying obtains compound 220g, yield 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, compound420g (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 Catalyst Pd (OAc) is added afterwards three times in gas28.5g is passed through reaction system with nitrogen gas again and is slowly heated afterwards three times It is reacted to 100 DEG C, raw material fully reacting is monitored by LCMS after reaction 2h, reaction system is cooled to room temperature, and acetic acid is added Ethyl ester 1400mL is used saturated sodium chloride solution 500mL washing reaction liquid 4 times after stirring 30min, then is had with anhydrous magnesium sulfate drying Machine phase, through silica gel column chromatography (V after concentrationPE:VEA=5:1) separating-purifying obtains compound270g, Yield 81.8%；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 9
Under nitrogen protection, compound330g (1mol) is added to 1,4- dioxane In 2500mL and deionized water 500mL, the chloro- 4- methyl formate yl pyridines (200g, 1.2mol) of 2- and potassium phosphate 424g are added (2mol) is passed through reaction system with nitrogen gas and catalyst Pd (dppf) Cl is added afterwards three times216g is passed through nitrogen again and sets It changes reaction system gas and is slowly heated to 90 DEG C afterwards three times and reacted, reacted after 3h through LCMS monitoring raw material fully reacting, Reaction temperature is added ethyl acetate 3000mL after being cooled to room temperature and extracts reaction solution 3 times, uses saturated sodium-chloride after merging organic phase Solution washs 1 time, then with being concentrated after anhydrous sodium sulfate drying, through silica gel column chromatography (VPE:VEA=10:1) separating-purifying Close object190g, yield 56%.
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, LCMS monitors raw material fully reacting after reacting 2h, and reaction solution is cooled to room temperature, true after filtering reacting liquid Sky concentration, adds dichloroethanes 400mL, stirring to pulp under the conditions of 0 DEG C, filters drying and obtains compound29g, yield 88.7%；1H NMR(CDCl3, 400MHz) 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, adds HATU after stirring 10min 42g (0.11mol) and DIEA 39g (0.3mol) is slowly heated to back flow reaction, and LCMS monitoring raw material has reacted after reacting 2h Entirely, ethyl acetate 2000mL is added, uses saturated sodium chloride solution 1000mL washing reaction liquid 2 times, separates organic after stirring 1h It is dry with anhydrous sodium sulfate after phase, it purifies to obtain target compound through column chromatography for separation 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 440.5689for C22H29N7OS+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 staphylococcus epidermis and Staphylococcus aureus as antibacterial activity test object.It prepares first Peptone 1g, yeast extract 0.5g, sodium chloride 1g, distilled water 100mL (are placed in 250mL conical flask, are placed on electricity by fluid nutrient medium Heated while stirring on furnace, it is to be mixed clarification it is uniform when, stop heating, bottleneck gauze and brown paper are successively sealed for use) (peptone 1g, yeast extract 0.5g, sodium chloride 1g, agar 2g, distilled water 100mL are placed in 250mL conical flask with solid medium In, it is placed on electric furnace and heats while stirring, when clarification to be mixed is uniform, stop heating, successively by bottleneck gauze and brown paper Sealing is stand-by)；Then sterilization treatment is carried out to culture medium by high-pressure sterilizing pot.The followed by preparation of bacterium solution, epidermis grape After coccus and Staphylococcus aureus actication of culture, the bacterium solution after 100 μ L are activated is pipetted with liquid-transfering gun, is placed in sterilized 100mL It is uniformly mixed in distilled water.It sterilizes finally by ultraviolet lamp to plate, then culture medium is quickly poured into plate while hot, Thickness about 0.15cm, is uniformly paved, and is stood, is allowed its slow solidification, is put into cultivate one day in 37 DEG C of incubator after solidification and does nothing Detection.
Synthesized target compound and control compound solution are respectively configured with DMF, is placed in volumetric flask stand-by.With beating Hole device punches on filter paper, aperture 5mm, is immersed in the sample solution that concentration is 0.1mg/mL after then filter paper sterilizes For use.
On superclean bench, alcolhol burner is lighted, takes the 10 diluted culture solutions of μ L to be added to solid culture base table with liquid-transfering gun Face, and be coated with uniform.The garden filter paper impregnated is taken to be taped against media surface with aseptic nipper.Each plate puts 4, carries out 3 Secondary parallel laboratory test, wherein a piece of carry out blank control.The plate 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 measurement 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, and compound is added5g, sequentially add monoglyceride 4g, IPP 12g, albolene 4g, Nepal gold propyl ester 0.5g, nepal Gold methyl ester 1.5g, MAP emulsifier 3g and essence 3g are protected Hold 10 DEG C at a temperature of stir 2h, both obtain drug ointment.
Embodiment 14
The drug ointment prepared using embodiment 13, to 30 diabetics because skin ulcer caused by pressure sore protects Reason treatment.Skin ulcer multidigit is before shin, shank lower part, dorsal portion and toes portion.Ulcer area maximum 4.0cm × 5.0cm, most Small is 1.0cm × 1.5cm, depth 0.2-1.0cm, and part ulcer basal part has different degrees of suppuration or purulence blood sexual secretion And a small amount of necrotic tissue.
Conventional iodophor disinfection is carried out first, and such as trauma surface infestation is pressed again after first cleaning its concentrated secretion with 3wt% hydrogen peroxide Program debridement, the excessive surface of a wound of necrotic tissue 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% gentamicin, 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.
Embodiment above describes basic principles and main features of the invention and advantage, 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 originals of the 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 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 are as follows:
2. a kind of preparation side of the 1,4- sulphur azatropylidene medicinal compound described in claim 1 for skin ulcer nursing Method, it is characterised in that specific steps are as follows:
(1) under nitrogen protection, compoundIt is added in n,N-Dimethylformamide, reaction temperature is cooling N-bromosuccinimide is added portionwise after to 10 DEG C, restores after adding to reacting at room temperature, is added after monitoring raw material fully reacting Ethyl acetate, then n,N-Dimethylformamide, organic phase warp are free of into organic phase with saturated sodium chloride solution washing reaction liquid N-hexane is added after anhydrous magnesium sulfate drying, concentration, cooling and stirring is beaten, and is dried to obtain compound after suction filtration
(2) compound2-chloroethyl amine and alkali compounds are added in tetrahydrofuran, wherein alkaline chemical combination Object is down to room after raw material fully reacting with heating reflux reaction after reaction system with nitrogen gas for sodium hydride or hydrofining Dichloroethanes is added in temperature, and water and hydrochloric acid solution is added after filtrate decompression concentration in filtering reacting liquid after stirring, with ethyl acetate and The mixed solution extraction reaction solution of n-hexane removes impurity, and it is 11 that water phase, which adjusts pH through saturation sodium hydroxide solution, then uses chloroform Extraction is concentrated to get compound after being dried with anhydrous sodium sulfate
(3) compoundIt is added in water and methylene chloride with sodium bicarbonate, drops after mixing evenly Temperature is added dropwise the dichloromethane solution dissolved with benzyl chloroformate, is reacted at room temperature after dripping to raw material fully reacting to 0 DEG C, Separate organic phase, water phase is extracted with dichloromethane, be dried over anhydrous sodium sulfate after organic phase, be concentrated after obtain compound
(4) compoundIt is added in toluene with sulfonic compound, wherein sulphonic acids chemical combination Object be methane sulfonic acid or p-methyl benzenesulfonic acid, be heated to 70 DEG C, add paraformaldehyde, reacted under the conditions of 70 DEG C after adding to Raw material fully reacting, 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 is dry, then purify to obtain compound through column chromatography for separation
(5) under nitrogen protection, compoundIt is added in reaction flask with DMSO, adds connection boric acid Pinacol ester and potassium acetate are passed through reaction system with nitrogen gas and catalyst Pd (dppf) Cl are added 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, monitors raw material fully reacting Reaction system is cooled to room temperature afterwards, ethyl acetate is added, is washed repeatedly with saturated sodium chloride solution, then is dry with anhydrous magnesium sulfate Dry organic phase purifies to obtain compound through column chromatography for separation after concentration
(6) under nitrogen protection, compoundIt is added to the mixed of 1,4- dioxane and deionized water It closes in solution, adds the chloro- 4- methyl formate yl pyridines of 2- and potassium phosphate, be passed through reaction system with nitrogen gas and add afterwards three times Enter catalyst Pd (dppf) Cl2, be passed through again reaction system with nitrogen gas be heated to afterwards three times 90 DEG C carry out reaction until Ethyl acetate extraction reaction solution is added in raw material fully reacting, reaction temperature after being cooled to room temperature, use saturation chlorine after merging organic phase Change sodium solution washing, then with being concentrated after anhydrous sodium sulfate drying, then purifies to obtain compound through column chromatography for separation
(7) under nitrogen protection, compoundIt is added in the mixed solvent, wherein mixing molten The mixed solution that agent is made of tetrahydrofuran, methanol and deionized water that volume ratio is 2:2:1, adds lithium hydroxide, rises Temperature react up to raw material fully reacting to 50 DEG C, and reaction solution is cooled to room temperature, is concentrated in vacuo after filtering reacting liquid, then plus Enter dichloroethanes, 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 to raw material fully reacting, add Ethyl acetate, it is multiple with saturated sodium chloride solution washing reaction liquid, it is dried after separating organic phase with anhydrous sodium sulfate, is passed through after concentration Column chromatography for separation, which purifies to obtain target compound, to be had
3. the preparation side of the 1,4- sulphur azatropylidene medicinal compound 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. the preparation side of the 1,4- sulphur azatropylidene medicinal compound 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. the preparation side of the 1,4- sulphur azatropylidene medicinal compound 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. 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 composition of nursing is the power for being 5:4:12:4:0.5:20:1.5:5:3:3:2:40 by mass ratio Benefit require 1 described in compoundMonoglyceride, IPP, albolene, Nepal The drug that golden propyl ester, propylene glycol, nepal Gold methyl ester, glycerine, MAP emulsifier, essence, peppermint oil and water are formulated is soft Cream.
7. Isosorbide-5-Nitrae-sulphur azatropylidene class pharmaceutical composition according to claim 6 for skin ulcer nursing, feature exist In: the skin ulcer is as caused by staphylococcus epidermis or/and Staphylococcus aureus.
CN201810880258.3A 2018-02-09 2018-08-03 A kind of 1,4- sulphur azatropylidene medicinal compound and its preparation method and application for skin ulcer nursing Pending CN109053770A (en)

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Application publication date: 20181221