CN108440508A - Pyrazine medicaments and preparation method thereof, composition and the application in stomach and intestine patient care - Google Patents
Pyrazine medicaments and preparation method thereof, composition and the application in stomach and intestine patient care Download PDFInfo
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- IVTPSLHTAVVNMF-UHFFFAOYSA-N O=C1NC(C2C=CNC2)=C(C2C=CNC2)N=C1 Chemical compound O=C1NC(C2C=CNC2)=C(C2C=CNC2)N=C1 IVTPSLHTAVVNMF-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention provides a kind of pyrazine medicaments of new-type molecular structure, with following formula：
Description
Technical field
The present invention relates to clinical care field more particularly to a kind of pyrazine medicaments and preparation method thereof, composition and in stomach
The application of intestines patient care.
Background technology
Skin ulcer is common skin secondary lesion, defect of skin or is destroyed up to corium or corium hereinafter, single-shot or more
Hair, acute stage ulcer expand rapidly, and surface is covered with slough, exudate, incrustation, and ulcer margin red swelling of the skin has the cause of disease
It is complicated, the course of disease is long, easily repeatedly the features such as.In division of gastroenterology, often there is patient to cause exocuticle skin to be burst because of ulcerative colitis
Ulcer, nursing staff after wrapping up patient skin ulcer spot, if ulcer alleviate it is bad, can cause bandage for dressing with
Ulcer wound bonds, and during dressing, very big pain can be brought to patient by more changing a bandage, and therefore, how to burst to patient skin
Ulcer is effectively nursed, and is all medical staff's very concern all the time.Currently, being nursed to reduce patient
Pain in journey, medical staff are generally applied using silver ion dressing in clinic, by using silver ion there is sterilization to make
With, so that ulcer spot is quickly formed a scab, reduce bandage and wound viscosity, it is possible to reduce patient is during more changing a bandage
Pain, be flamazine than more typical silver ion dressing.
Currently, nitrogen-containing heterocycle compound due to good bioactivity in medicine and human healths and the agriculture such as pesticide
It plays an important role in industry production.But in the nursing that treatment leads to exocuticle skin ulcer because of ulcerative colitis,
Nitrogen-containing heterocycle compound is mostly endo-medicine, and the externally applied drug for directly using nitrogen-containing heterocycle compound as treatment skin ulcer is compared
Few, the selection that doctor and patient face is also fewer, thus be badly in need of synthesizing a kind of new nitrogen-containing heterocycle compound for treat because
Ulcerative colitis leads to exocuticle skin ulcer.
Invention content
In view of this, the present invention provides a kind of pyrazine medicaments of new-type molecular structure and preparation method thereof, pharmaceutical compositions
And in nursing because ulcerative colitis leads to the purposes with good result on exocuticle skin ulcer.
Pyrroles can be used as certain medicine intermediates, occupy highly important status in medical research exploitation.For example, can
Using as adenosine receptor antagonists, cyclin-dependent kinase inhibitor and phosphodiesterase inhibitors etc..In doctoral thesis
In " design, synthesis and its bioactivity research of novel vascular formation inhibitor-Thalidomide (THD) analog ", Zuo Zheji
Its team synthesizes a variety of pyrrolo-es [3,4-d] pyrimidines and as a result shows majority of compounds by preliminary screening
There are the increment activity for inhibiting vascular endothelial cell and anti-lung cancer, inhibit human leukemia cell and inhibit people's original myeloid leukemia
The activity of cell.Hao Baoyu etc. synthesizes a series of pyrroles [2,3-d] pyrimidines with effective protease inhibitors effect and spreads out
Biology can efficiently and selectively inhibit JAK3, and can block the gene table of cytokine signaling and cytokine induction
It reaches, and there is no inhibiting effect for other cell factors and the related JAK enzyme families member of receptor phosphorylation, can be used for organ
Transplant and treat various autoimmune diseases；Moreover, pyrroles [2,3-d] pyrimidine derivatives can also effectively treat
Rheumatoid-arthritis, psoriasis, colitis and diabetes and other diseases.
Pyrazine group is very important heterocycle containing dinitrogen, such compound has the antibacterial action of highly significant, such as
The pyrazinamide clinically used infiltrates through after phagocyte and enters in tubercle bacillus thalline, and endobacillary amidase makes it
Amide groups is sloughed, pyrazine acid is converted into and plays antibacterial action.Separately because pyrazinamide is similar to niacinamide in chemical constitution,
Dehydrogenase is interfered by replacing niacinamide, prevents dehydrogenation, interferes utilization of the tubercle bacillus to oxygen, and influences bacterium
Eubolism causes death.
The technological means that the present invention uses in conjunction with the characteristics of pyrroles and pyrazine is as follows：
A kind of pyrazine medicaments have good antibacterial and bactericidal effect, especially to bacillus anthracis and Staphylococcus aureus
All there is preferable activity suppression, with following formula：
In addition, can by any means well known by persons skilled in the art by the present invention formula (1) compound be converted to as
Arbitrary salt as described herein.Similarly, the formula (1) of the present invention can be changed by any means well known by persons skilled in the art
The arbitrary salt for closing object converts free compound.
Another aspect of the present invention provides a kind of preparation method to above-mentioned formula (1) pyrazine medicaments, includes the following steps：
A) the two amido -2- butylene of 1,4- dinitriles -2,3- of formula (6) passes through acylation reaction and amine aldehyde condensation reaction
Obtain the compound of formula (5)；
B) compound of formula (4) is obtained by the reaction by catalysis itrile group hydrogenating reduction amino for the compound of formula (5)；
C) compound of formula (4) obtains the compound of formula (3) by diazo-reaction and amine aldehyde condensation reaction；
D) compound of formula (3) obtains the compound of formula (2) by Fischer indole ring-closure reaction；
E) compound of the compound of formula (2) Jing Guo decarboxylic reaction production (1).
A kind of preparation method of formula (1) pyrazine medicaments provided by the invention, synthesis path is relatively short, and yield reaches substantially
To 70% or more.
In addition, the present invention also provides a kind of pharmaceutical composition, it includes：The compound and its pharmacy of formula (1) can
The salt of receiving or their mixture and one or more pharmaceutically acceptable carriers.
The pharmaceutical composition can also include one or more medicaments selected from the following：Monoglyceride, IPP, albolene,
Nepal's gold propyl ester, propylene glycol, Nepal's tortoise beetle ester, glycerine, MAP emulsifiers, essence, peppermint oil and water.In nursing because bursting
Ulcer colitis causes to be a kind of new pharmaceutical composition on exocuticle skin ulcer, in clinical care experiment, to the skin of patient
The curative effect highly significant of skin ulcer, hence it is evident that shorten the time of healing.
It is drug ointment according to the pharmaceutical composition provided by the invention.
Preferably, nursing of the pharmaceutical composition provided by the invention in the exocuticle skin ulcer caused by gastrointestinal disorders
On application.
Especially the pharmaceutical composition is used for the skin ulcer nursing caused by bacillus anthracis or/and Staphylococcus aureus.This
Composition is to the bacillus anthracis for easily causing skin ulcer and golden yellow grape ball made of formula (1) pyrazine compounds of invention
Bacterium all has preferable activity suppression, causes exocuticle skin ulcer to have well by ulcerative colitis to curing major part
Effect.
Specific implementation mode
The principle and features of the present invention are described below in conjunction with the following examples, and the given examples are served only to explain the present invention, not uses
In restriction the scope of the present invention.
A kind of pyrazine medicaments have good antibacterial and bactericidal effect, especially to bacillus anthracis and Staphylococcus aureus
All there is preferable activity suppression, with following formula：
In addition, can by any means well known by persons skilled in the art by the present invention formula (1) compound be converted to as
Arbitrary salt as described herein.Similarly, the formula (1) of the present invention can be changed by any means well known by persons skilled in the art
The arbitrary salt for closing object converts free compound.Wherein, the salt of formula (1) compound can be pharmaceutical substituent group substitution pyrrole
The piperazine ring either H in any one or more than two N-H of pyrrole ring, becomes salt that can be medicinal, or as salt
Free compound.
Another aspect of the present invention provides first preparation method, is a kind of preparation to above-mentioned formula (1) pyrazine medicaments
Method is a kind of preferably using synthetic method of the bis- amido -2- butylene of Isosorbide-5-Nitrae-dinitrile -2,3- as raw material, and is not had to
In formula (1) pyrazine compounds for limiting the present invention, building-up process is as shown in following scheme 1：
Flow 1
Two amido -2- butylene of the 1,4- dinitriles -2,3- of formula (6) is synthesized to the chemical combination of formula (5) for initial feed first
Object；The compound of the formula (5) of above-mentioned synthesis is further synthesized to the compound of formula (4)；By the chemical combination of the formula (4) of above-mentioned synthesis
Object further synthesizes the compound of formula (3)；Then the compound of the formula (3) of above-mentioned synthesis is further synthesized to the chemical combination of formula (2)
Object；Finally by the compound of the further synthesising target compound formula (1) of the compound of the formula (2) of above-mentioned synthesis.
Specifically include the following steps：
A) the two amido -2- butylene of 1,4- dinitriles -2,3- of formula (6) passes through acylation reaction and amine aldehyde condensation reaction
Obtain the compound of formula (5)；
B) compound of formula (4) is obtained by the reaction by catalysis itrile group hydrogenating reduction amino for the compound of formula (5)；Wherein make
Catalyst includes but is not limited to Raney's nickel, palladium, platinum etc., and reaction under high pressure carries out.
C) compound of formula (4) obtains the compound of formula (3) by diazo-reaction and amine aldehyde condensation reaction；
D) compound of formula (3) obtains the compound of formula (2) by Fischer indole ring-closure reaction；
E) compound of the compound of formula (2) Jing Guo decarboxylic reaction production (1).
Wherein, term " acylation reaction ", " amine aldehyde condensation reaction ", " catalysis itrile group hydrogenating reduction ", " diazotising is anti-
Answer ", " condensation reaction of amine aldehyde ", " Fischer indole ring-closure reaction ", " decarboxylic reaction " and " hydrolysis " that is subsequently noted answer
It is interpreted as using reagent known in the art and condition, occurs that there is the corresponding combination reaction of its title.
In another aspect of this invention, second of preparation method is provided, be another kind to above-mentioned formula (1) pyrazine medicaments
Preparation method is a kind of preferably using synthetic method of the bis- amido -2- butylene of Isosorbide-5-Nitrae-dinitrile -2,3- as raw material, and
Formula (1) pyrazine compounds for limiting the present invention are not used in, building-up process is as shown in following scheme 2：
Flow 2
Two amido -2- butylene of the 1,4- dinitriles -2,3- of formula (6) is synthesized to the chemical combination of formula (5) for initial feed first
Object；The compound of the formula (5) of above-mentioned synthesis is further synthesized to the compound of formula (4)；By the chemical combination of the formula (4) of above-mentioned synthesis
Object further synthesizes the compound of formula (3)；The compound of the formula (3) of above-mentioned synthesis is further synthesized to the compound of formula (2)；
Relative to former preparation method, the compound of the formula (2) of above-mentioned synthesis is most further synthesized the chemical combination of formula (7) by this method
Object, finally by by the compound of the further synthesising target compound formula (1) of the compound of the formula (7) of above-mentioned synthesis.Former
Preparation method preparation path is shorter, and operating process is fairly simple, but required reaction temperature is higher, and our rule is in centre
The compound of formula (7), then synthesising target compound (1) are first synthesized on the basis of compound (2), reaction condition is more mild,
Controllability higher.
Specifically include the following steps：
A) the two amido -2- butylene of 1,4- dinitriles -2,3- of formula (6) passes through acylation reaction and amine aldehyde condensation reaction
Obtain the compound of formula (5)；
B) compound of formula (4) is obtained by the reaction by catalysis itrile group hydrogenating reduction amino for the compound of formula (5)；
C) compound of formula (4) obtains the compound of formula (3) by diazo-reaction and amine aldehyde condensation reaction；
D) compound of formula (3) obtains the compound of formula (2) by Fischer indole ring-closure reaction；
F) compound of formula (2) obtains the compound of formula (7) by hydrolysis；
G) compound of the compound of formula (7) Jing Guo decarboxylic reaction production (1).
Embodiment one：
Step a)：Two amido -2- the butylene of 1,4- dinitriles -2,3- of formula (6) passes through acylation reaction and amine aldehyde cyclic condensation
The compound of formula (5) is obtained by the reaction：Under the conditions of 0 DEG C, slowly the concentrated sulfuric acid is added in water, Isosorbide-5-Nitrae-dintrile is added after dripping
Bis- amido -2- butylene of base -2,3-, then slowly heating, continues the aqueous solution that glyoxalic acid is slowly added dropwise, is continuously heating to flow back
Reaction, then slowly cools to 0 DEG C, and stirring suction filtration reaction solution after ice ethyl alcohol is added into reaction solution, obtains the chemical combination of formula (5)
Object.Wherein acylation reaction and amine aldehyde condensation reaction occurs simultaneously in the reaction system；Occur acylation reaction in addition to raw material with
Outer reagent includes but is not limited to the inorganic acids such as the concentrated sulfuric acid, perchloric acid, tetrafluoro boric acid, hydrogen chloride gas and benzene sulfonic acid, to first
The organic acids such as benzene sulfonic acid.And the reagent of amine aldehyde condensation reaction includes a variety of acid, alkali, or can be metallic catalyst
Catalysis is lower to be carried out, it is not limited to the glyoxalic acid of the present embodiment.
Specifically：In reaction bulb, under the conditions of 0 DEG C, concentrated sulfuric acid 18g (0.18mol) is slowly added drop-wise to water 1000mL
In, bis- amido -2- butylene 244g (1.8mol) of Isosorbide-5-Nitrae-dinitrile -2,3- is added after dripping, is then to slowly warm up to 50 DEG C,
The aqueous solution 270g (mass concentration 50%, 1.8mol) of glyoxalic acid is slowly added dropwise, about 1h is added dropwise, and is continuously heating to back
Stream slowly cools to 0 DEG C after reacting 5h, has a large amount of white solids to be precipitated in cooling procedure, and ice ethyl alcohol is added into reaction solution
500mL filters reaction solution after stirring 10min, obtains260g, yield 83%.
Step b)：The compound of formula (4) is obtained by the reaction by catalysis itrile group hydrogenating reduction amino for the compound of formula (5)：
In autoclave be added absolute ethyl alcohol, formula (5) compound and nickel catalyst, sealing hydrogenation pressurize simultaneously slowly heats up
Reaction then cools to room temperature addition dilute acid soln, filters reaction solution, and concentration filtrate obtains the compound of formula (4).Wherein make
Catalyst includes but is not limited to nickel, Raney's nickel, palladium, platinum etc., and reaction under high pressure carries out.
Specifically, in autoclave, absolute ethyl alcohol 500mL is added, adds17g
(0.1mol), adds Raney's nickel 3g, and closed reactor makes the pressure in kettle with hydrogen is passed through after nitrogen displacement twice gas
Reach 0.2MPa, be to slowly warm up to 60 DEG C, at this time due to the rising of reaction temperature, the interior reaction of kettle is violent, and pressure increases to
Pressure reduction is at this time largely single reduzate in reaction solution, continues to supplement hydrogen to 0.3MPa after 0.4MPa, reaction 30min
Gas makes pressure reach 0.4MPa, after reacting 2h, is cooled to room temperature, and a certain amount of dilute hydrochloric acid solution is added, and filters reaction solution, dense
Contracting filtrate obtainsHydrochloride 22g, yield 88%.
Step c)：The compound of formula (4) obtains the compound of formula (3) by diazo-reaction and amine aldehyde condensation reaction：
The compound of formula (4) is added in the mixed solution of water and hydrochloric acid, and 0 DEG C is cooled to after stirring evenly, under agitation, by
It is added dropwise to the aqueous solution dissolved with sodium nitrite, is uniformly mixed and obtains solution A；The aqueous solution dissolved with potassium hydroxide is configured, at 0 DEG C
Under the conditions of, the ethyl alcohol dissolved with ethyl acetoacetate is slowly added dropwise, stirring evenly preparation after dripping obtains solution B；In 0 DEG C of item
Under part, solution B is slowly added dropwise to solution A, rear temperature reaction is dripped, then reaction solution is extracted with ether, after merging organic phase
It is dried with anhydrous magnesium sulfate, the compound through the isolated formula of silica gel column chromatography (3) after concentration.Diazo-reaction wherein occurs
Required reagent includes but is not limited to hydrochloric acid, sulfuric acid, crosses inorganic acids and the sodium nitrites such as chloric acid, fluoboric acid；The condensation of amine aldehyde is anti-
The reagent answered includes a variety of acid, alkali, or can be carried out under the catalysis of metallic catalyst, it is not limited to the present embodiment
Potassium hydroxide.
Specifically, in reaction bulb,Water 3000mL and hydrochloric acid is added in 55g (0.3mol)
In the mixed solution of 2000mL, it is cooled to 0 DEG C after stirring evenly, under agitation, is added dropwise dissolved with sodium nitrite 24g
The aqueous solution 1000mL of (0.34mol) is uniformly mixed after dripping and obtains solution A；Configuration is dissolved with hydrogen in another reaction bulb
The aqueous solution 3000mL of potassium oxide 156g (2.8mol) is slowly added dropwise under the conditions of 0 DEG C dissolved with ethyl acetoacetate 60g
The ethyl alcohol 250mL of (0.46mol) stirs evenly preparation after dripping and obtains solution B；Solution A as under the conditions of 0 DEG C, slowly
It obtains and solution B is added dropwise to solution A, 40 DEG C of reaction 10min are warming up to after dripping, then reaction solution three is extracted with ether 1000mL
It is secondary, it is dried with anhydrous magnesium sulfate after merging organic phase, (PE is detached through silica gel column chromatography after concentration:EA=9:1) it obtains95g, yield 78%.
Step d)：The compound of formula (3) obtains the compound of formula (2), wushu (3) by Fischer indole ring-closure reaction
Compound and polyphosphoric acids be added in toluene, heating stirring reaction, vacuum divides exactly toluene, is taken out after ice water stirring is then added
Filter reaction solution, compound of the filter cake through the isolated formula of silica gel column chromatography (2).Fischer indole ring-closure reaction wherein occurs
Reagent includes but is not limited to the Bronsted acids such as hydrochloric acid, sulfuric acid, polyphosphoric acids, p-methyl benzenesulfonic acid and zinc chloride, iron chloride, chlorination
The lewis acids such as aluminium, boron trifluoride.
Specifically, in reaction bulb,First is added in 111g (0.273mol) and polyphosphoric acids 500g
In benzene 1000mL, 45 DEG C are heated, vacuum is opened after being stirred to react 1h, divides exactly toluene, ice water 2000mL, stirring is then added
Reaction solution is filtered after 10min, filter cake detaches (PE through silica gel column chromatography:EA=9:1) it obtains87g, yield are
85%.
Step e)：Compound of the compound of formula (2) Jing Guo decarboxylic reaction production (1)；The compound of wushu (2) adds
Enter in hydrochloric acid solution, be heated to back flow reaction, be cooled to room temperature, filters reaction solution, the chemical combination of formula (1) is obtained after filter cake drying
Object.
Specifically, in reaction bulb,37g (0.1m) is added in the HCl 500mL of 2M, is heated to
Reflux is cooled to room temperature after reacting 15h, is filtered reaction solution, is obtained after filter cake drying11g, yield are
79%；1H NMR(600MHz,CDCl3):δ8.09(s,1H),7.59(s, 1H),7.43-7.41(m,2H),5.79-5.77
(m, 2H), 4.96 (d, J=6.0Hz, 1H), 4.91 (d, J=6.0Hz, 1H), 3.13-3.11 (m, 2H), 2.88 (d, J=
12.0Hz, 2H), 2.62 (d, J=12.0Hz, 2H) .13C NMR (100MHz, CDCl3):δ155.57,149.32,137.24,
137.09,129.36,119.06,102.84,43.69, 41.05,39.23,38.65.–HRMS((+)-ESI):M/z=
231.2776(calcd.231.2768for C12H14N4O,[M+H]+)
Embodiment two：
Step a)~d in the present embodiment) with step a)~d of embodiment one) it is similar, the present embodiment is no longer repeated；
Step e)：Compound of the compound of formula (2) Jing Guo decarboxylic reaction production (1)；The compound of wushu (2) adds
Enter in boric acid solution, be heated to back flow reaction, be cooled to room temperature, filters reaction solution, the chemical combination of formula (1) is obtained after filter cake drying
Object.
Specifically, in reaction bulb,37g (0.1m) is added in the saturated aqueous solution of boric acid, heating
It is cooled to room temperature after reacting 30h to reflux, filters reaction solution, obtained after filter cake drying16g, yield are
70%；1H NMR(600MHz,CDCl3):δ8.09(s,1H),7.59(s, 1H),7.43-7.41(m,2H),5.79-5.77
(m, 2H), 4.96 (d, J=6.0Hz, 1H), 4.91 (d, J=6.0Hz, 1H), 3.13-3.11 (m, 2H), 2.88 (d, J=
12.0Hz, 2H), 2.62 (d, J=12.0Hz, 2H) .13C NMR (100MHz, CDCl3):δ155.57,149.32,137.24,
137.09,129.36,119.06,102.84,43.69, 41.05,39.23,38.65.–HRMS((+)-ESI):M/z=
231.2776(calcd.231.2768for C12H14N4O,[M+H]+)
Embodiment three：
Step a)~d in the present embodiment) with step a)~d of embodiment one) it is similar, the present embodiment is no longer repeated；
Step e)：Compound of the compound of formula (2) Jing Guo decarboxylic reaction production (1)；The compound of wushu (2) adds
Enter in lithium chloride solution, be heated to back flow reaction, be cooled to room temperature, filters reaction solution, the change of formula (1) is obtained after filter cake drying
Close object.
Specifically, in reaction bulb,37g (0.1mol) and lithium chloride 8.5g (0.2mol) is added
In DMSO 200mL, 180 DEG C are heated to, after reacting 10h, reaction solution is poured into ice water, there are a large amount of solids to be precipitated after stirring,
Reaction solution is filtered, is obtained after filter cake drying17g, yield 74%； 1H NMR(600MHz,CDCl3):δ
8.09 (s, 1H), 7.59 (s, 1H), 7.43-7.41 (m, 2H), 5.79-5.77 (m, 2H), 4.96 (d, J=6.0Hz, 1H),
4.91 (d, J=6.0Hz, 1H), 3.13-3.11 (m, 2H), 2.88 (d, J=12.0Hz, 2H), 2.62 (d, J=12.0Hz,
2H).13C NMR(100MHz,CDCl3):δ 155.57,149.32,137.24,137.09,129.36,119.06,102.84,
43.69,41.05,39.23,38.65. –HRMS((+)-ESI):M/z=231.2776 (calcd.231.2768for
C12H14N4O,[M+H]+)
Example IV：
Step a)~d in the present embodiment) with step a)~d of embodiment one) it is similar, the present embodiment is no longer repeated；
Step e)：Compound of the compound of formula (2) Jing Guo decarboxylic reaction production (1)；The compound of wushu (2) adds
Enter in lithium chloride solution, be heated to back flow reaction, be cooled to room temperature, filters reaction solution, the change of formula (1) is obtained after filter cake drying
Close object.
In reaction bulb,DMSO is added in 37g (0.1mol) and lithium hydroxide 4.8g (0.2mol)
In 200mL, 180 DEG C are heated to, after reacting 10h, reaction solution is poured into ice water, there are a large amount of solids to be precipitated after stirring, is filtered anti-
Liquid is answered, is obtained after filter cake drying18g, yield 78%；1H NMR(600MHz,CDCl3):δ8.09
(s, 1H), 7.59 (s, 1H), 7.43-7.41 (m, 2H), 5.79-5.77 (m, 2H), 4.96 (d, J=6.0Hz, 1H), 4.91
(d, J=6.0Hz, 1H), 3.13-3.11 (m, 2H), 2.88 (d, J=12.0Hz, 2H), 2.62 (d, J=12.0Hz, 2H)
.13C NMR(100MHz,CDCl3):δ 155.57,149.32,137.24,137.09,129.36,119.06,102.84,
43.69,41.05,39.23,38.65. –HRMS((+)-ESI):M/z=231.2776 (calcd.231.2768for
C12H14N4O,[M+H]+)
Embodiment five：
Step a)~d in the present embodiment) with step a)~d of embodiment one) it is similar, the present embodiment is no longer repeated；
For in second of approach, step f)：The compound of formula (7)：The compound of formula (2) is anti-by hydrolysis
It should obtain the compound of formula (7)；The compound of wushu (2) is added in dilute acid soln, and room temperature is down to after heating reaction, filters anti-
Liquid, filter cake is answered to dry to obtain the compound of formula (7)；The diluted acid that hydrolysis uses, which wherein occurs, includes but is not limited to：Dilute salt
Acid, dilute sulfuric acid, dust technology etc..
Specifically, in reaction bulb,37g (0.1mol) is added in dilute hydrochloric acid 200mL, is heated to
60 DEG C, it is down to room temperature after reacting 5h, reaction solution is filtered, is obtained after filter cake drying30g, yield 94%；1H
NMR(600MHz,CDCl3):δ 9.47 (s, 1H), 8.33 (s, 1H), 7.49-7.48 (m, 2H), 5.97 (d, J=6.0Hz,
1H), 5.92 (d, J=6.0Hz, 1H), 3.52-3.51 (m, 2H), 2.74 (d, J=12.0Hz, 2H), 2.55 (d, J=
12.0Hz,2H).13C NMR(100MHz, CDCl3):δ169.93,168.45,153.32,146.50,141.22,141.05,
127.81,118.34,102.85, 58.31,43.61,43.16,41.29,40.26。
Its step g)：The compound of formula (7) prepares the compound of target compounds of formula (1)：The compound of formula (7) is passed through
The compound of the compound of decarboxylic reaction production (1), wushu (7) is added in pyrazine, adds basic copper carbonate, and heating is anti-
It answers, after complete reaction filtering reacting liquid, adds a certain amount of dichloromethane, washing concentrating obtains formula through column chromatography for separation
(1) compound.
Specifically, in reaction bulb,32g (0.1mol) is added in pyrazine 200mL, adds alkali formula
Copper carbonate 3.2g, the heating reaction 1h at 120 DEG C, TLC monitors raw material, and the reaction was complete, and filtering reacting liquid adds a certain amount of two
Chloromethanes is concentrated after being washed with water, is most obtained afterwards through column chromatography for separation21g, yield 91%；1H NMR
(600MHz,CDCl3):δ8.09(s,1H),7.59 (s,1H),7.43-7.41(m,2H),5.79-5.77(m,2H),4.96
(d, J=6.0Hz, 1H), 4.91 (d, J=6.0Hz, 1H), 3.13-3.11 (m, 2H), 2.88 (d, J=12.0Hz, 2H),
2.62 (d, J=12.0Hz, 2H) 13C NMR (100MHz, CDCl3):δ155.57,149.32,137.24,137.09,
129.36,119.06, 102.84,43.69,41.05,39.23,38.65.–HRMS((+)-ESI):M/z=231.2776
(calcd. 231.2768for C12H14N4O,[M+H]+)。
Embodiment six：
In addition, the present embodiment provides a kind of pharmaceutical composition, it includes：The compound and its pharmacy of formula (1) can
The salt of receiving or their mixture；
The pharmaceutical composition can also include one or more medicaments selected from the following：Monoglyceride, IPP, albolene,
Nepal's gold propyl ester, propylene glycol, Nepal's tortoise beetle ester, glycerine, MAP emulsifiers, essence, peppermint oil and water.Wherein formula (1)
CompoundWith monoglyceride, IPP, albolene, Nepal's gold propyl ester, propylene glycol, Nepal's tortoise beetle
Ester, glycerine, MAP emulsifiers, essence, peppermint oil and water mass ratio be：4.2~5.3:3.6~4.2:10~14:3~
6:0.3~0.6:18~24:1.0~1.6:4~7:1~4:1~4:1~2.5:35~45.
Preferably, the compound of the present embodiment Chinese style (1)With monoglyceride, IPP, albolene,
Nepal's gold propyl ester, propylene glycol, Nepal's tortoise beetle ester, glycerine, MAP emulsifiers, essence, peppermint oil and water mass ratio be：
5:4:12:4:0.5:20:1.5:5:3:3:2:40。
It is drug ointment according to the pharmaceutical composition provided by the invention.
Specifically, the preparation method of the drug ointment of the pharmaceutical composition is：Under the conditions of 10 DEG C, in stirring container
Water 40g and propylene glycol 20g is added, adds glycerine 5g and peppermint oil 2g, starts stirring, the compound of formula (1) is added5g sequentially adds monoglyceride 4g, IPP 12g, albolene 4g, Nepal gold propyl ester 0.5g, Buddhist nun
Pool that tortoise beetle ester 1.5g, MAP emulsifier 3g and essence 3g, stir 2h, both obtain drug ointment at a temperature of being maintained at 10 DEG C.
Embodiment seven：
The present embodiment is the compound of (1)Antibacterial experiment.Select bacillus anthracis and golden yellow grape
Sugar ball bacterium is as antibacterial activity test object.It is to prepare fluid nutrient medium (by peptone 1g, yeast extract 0.5g, sodium chloride first
1g, distilled water 100mL are placed in 250mL conical flasks, are placed on electric furnace and are heated 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 solid medium (by peptone 1g, yeast extract 0.5g, chlorine
Change sodium 1g, agar 2g, distilled water 100mL to be placed in 250mL conical flasks, is placed on electric furnace and heats while stirring, clarification to be mixed
When uniform, stop heating, bottleneck gauze and brown paper are sealed for use successively)；Then by high-pressure sterilizing pot to culture medium
Carry out sterilization treatment.The followed by preparation of bacterium solution uses liquid-transfering gun after Escherichia coli and golden yellow glucose coccus actication of culture
The bacterium solution after 100 μ L activation is pipetted, is placed in sterilized 100mL distilled water and is uniformly mixed.Finally by ultraviolet lamp to tablet
It sterilizes, then culture medium is quickly poured into tablet while hot, thickness about 0.15cm is uniformly paved, and is stood, and makes it slow
Solidification, is put into cultivate one day in 37 DEG C of incubator after solidification and does no Detection.
Synthesized target compound and control compound solution is respectively configured with DMF, is placed in volumetric flask for use.With
Card punch punches on filter paper, aperture 5mm, and the sample that a concentration of 0.1mg/mL is immersed in after then filter paper sterilizes is molten
It is for use in liquid.
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 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.By occurring different size of transparent ring-inhibition zone on agar medium respectively, by measuring antibacterial circle diameter just
It can be seen that the bacteriostatic activity size of each sample.
It can be found that a kind of compound of formula (1) provided by the invention has good antibacterial and bactericidal effect, especially
It is that all there is preferable activity suppression to bacillus anthracis and Staphylococcus aureus.
Embodiment eight：
The present embodiment is clinical test example, is the drug ointment for pharmaceutical composition outer caused by gastrointestinal disorders
Application in the nursing of epidermal skin ulcer.
Liu, male, 43 years old, because ulcerative colitis causes interruption mucopurulent bloody stool to enter within more than 2 years with limbs skin ulcer
Institute.There is mucus pus and blood stool in being admitted to hospital first 2 years without apparent inducement in patient, and 3~4 times/day, erythema occurs in limbs skin, rapid to send out
Exhibition is abscess and ulcer occurs, based on double lower limb, can occasionally involve shirtfront skin, and the heat that occurs together, cough, expectoration symptom, body temperature is most
It is high 39 DEG C or more reachable.
Human health screening：Anaemia looks, double lung auscultation breath sound thickenings, bowel sounds active, the closely naked portion's visible dermis purulence of double lower limb
Swollen healing, ulcer area maximum 3.0cm × 4.5cm, minimum 1.5cm × 1.5cm, depth is 0.1~0.5cm, part ulcer
Basal part has different degrees of suppuration or purulence blood sexual secretion.
The conventional iodophor disinfection of progress first, such as trauma surface infestation, after first cleaning its dense sexual secretion with 3wt% hydrogen peroxide again
By program debridement, the excessive surface of a wound of slough preferably uses a small amount of multiple debridement method.Medical staff will be soft in treatment group
Cream spreads on the surface of a wound, and 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 (0.37 ± 0.12)
Cm2/ days, hence it is evident that be faster than (0.33 ± 0.15) of blank control group cm2/ days.
In nursing because ulcerative colitis causes to be a kind of new pharmaceutical composition on exocuticle skin ulcer, protected in clinic
In reason experiment, the healing speed of the skin ulcer of patient is greater than control group, hence it is evident that shortens the time of healing.
Especially the pharmaceutical composition is used for the skin ulcer nursing caused by bacillus anthracis or/and Staphylococcus aureus.This
Composition is to the bacillus anthracis for easily causing skin ulcer and golden yellow grape ball made of formula (1) pyrazine compounds of invention
Bacterium all has preferable activity suppression, causes exocuticle skin ulcer to have well by ulcerative colitis to curing major part
Effect.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
With within principle, any modification, equivalent substitution, improvement and etc. done should be included within the scope of protection of the invention god.
Claims (10)
1. a kind of pyrazine medicaments, which is characterized in that it is with following formula：
2. a kind of method preparing pyrazine medicaments described in claim 1, which is characterized in that include the following steps：
A) the two amido -2- butylene of 1,4- dinitriles -2,3- of formula (6) obtains formula by acylation reaction and amine aldehyde condensation reaction
(5) compound；
B) compound of formula (4) is obtained by the reaction by catalysis itrile group hydrogenating reduction amino for the compound of formula (5)；
C) compound of formula (4) obtains the compound of formula (3) by diazo-reaction and amine aldehyde condensation reaction；
D) compound of formula (3) obtains the compound of formula (2) by Fischer indole ring-closure reaction；
E) compound of the compound of formula (2) Jing Guo decarboxylic reaction production (1).
3. the preparation method of pyrazine medicaments according to claim 2, which is characterized in that in the step a), in 0 DEG C of condition
Under, slowly the concentrated sulfuric acid is added in water, bis- amido -2- butylene of Isosorbide-5-Nitrae-dinitrile -2,3- is added after dripping, is then slowly risen
Temperature continues the aqueous solution that glyoxalic acid is slowly added dropwise, and is continuously heating to back flow reaction, 0 DEG C is then slowly cooled to, into reaction solution
Stirring filters reaction solution after ice ethyl alcohol is added, and obtains the compound of formula (5).
4. the preparation method of pyrazine medicaments according to claim 2, which is characterized in that anti-in high pressure in the step b)
Answer in kettle be added absolute ethyl alcohol, formula (5) compound and nickel catalyst, sealing hydrogenation pressurization and slow temperature reaction, so
Dilute acid soln is added in postcooling to room temperature, filters reaction solution, and concentration filtrate obtains the compound of formula (4).
5. the preparation method of pyrazine medicaments according to claim 2, which is characterized in that in the step c), wushu (4)
Compound is added in the mixed solution of water and hydrochloric acid, and 0 DEG C is cooled to after stirring evenly, and under agitation, is added dropwise molten
There is the aqueous solution of sodium nitrite, is uniformly mixed and obtains solution A；The aqueous solution dissolved with potassium hydroxide is configured, under the conditions of 0 DEG C, is delayed
The slow ethyl alcohol being added dropwise dissolved with ethyl acetoacetate, stirs evenly preparation after dripping and obtains solution B；Under the conditions of 0 DEG C, slow handle
Solution B is added dropwise to solution A, drips rear temperature reaction, then extract reaction solution with ether, anhydrous magnesium sulfate is used after merging organic phase
It is dry, the compound through the isolated formula of silica gel column chromatography (3) after concentration.
6. the preparation method of pyrazine medicaments according to claim 2, which is characterized in that in the step d), wushu (3)
It compound and is added in toluene with polyphosphoric acids, heating stirring reaction, vacuum divides exactly toluene, is filtered after ice water stirring is then added
Reaction solution, compound of the filter cake through the isolated formula of silica gel column chromatography (2).
7. the preparation method of pyrazine medicaments according to claim 2, which is characterized in that in the step e), wushu (2)
Compound is added in acid solution or lithium salt solution, is heated to back flow reaction, is cooled to room temperature, and filters reaction solution, filter cake drying
The compound of formula (1) is obtained afterwards.
8. a kind of pharmaceutical composition, which is characterized in that it includes：The compound and its medicine of formula (1) described in claim 1
Learn acceptable salt or their mixture；
And one or more medicaments selected from the following：Monoglyceride, IPP, albolene, Nepal's gold propyl ester, propylene glycol, Ni Bo
That tortoise beetle ester, glycerine, MAP emulsifiers, essence, peppermint oil and water.
9. pharmaceutical composition according to claim 8, which is characterized in that the pharmaceutical composition is drug ointment.
10. a kind of pharmaceutical composition according to claim 8 or 9 is in the application of stomach and intestine patient care, which is characterized in that
Described pharmaceutical composition is in the purposes caused by gastrointestinal disorders in the nursing of exocuticle skin ulcer.
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| CN101490040B (en) * | 2006-05-08 | 2013-06-12 | 阿斯利康(瑞典)有限公司 | 2-pyrazinone derivatives for the treatment of disease or condition in which inhibition of neutrophil elastase activity is beneficial |
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| KWAKU KYEREMEH等: "Butrepyrazinone, a New Pyrazinone with an Unusual Methylation Pattern from a Ghanaian Verrucosispora sp. K51G", 《MARINE DRUGS》 * |
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