CN108440508B - Pyrazine medicine, preparation method and composition thereof, and application of pyrazine medicine in gastrointestinal patient nursing - Google Patents
Pyrazine medicine, preparation method and composition thereof, and application of pyrazine medicine in gastrointestinal patient nursing Download PDFInfo
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Abstract
The invention provides a novel molecular structure pyrazine drug, which has the following formula:
Description
Technical Field
The invention relates to the field of clinical care, in particular to a pyrazine medicine, a preparation method and a composition thereof, and application of the pyrazine medicine in gastrointestinal patient care.
Background
Skin ulcer is common secondary damage of skin, skin defect or damage reaches dermis or below dermis, single or multiple times, acute stage ulcer is rapidly enlarged, necrotic tissues, exudates and scabs are covered on the surface, skin around the ulcer is red and swollen, and the skin ulcer has the characteristics of complex etiology, long course of disease, easiness in repetition and the like. In gastroenterology, often the patient leads to the ulcer of epidermis skin because of ulcerative colitis, and nursing staff wraps the back to patient's skin ulcer position, if the ulcer alleviates poorly, can lead to wrapping bandage and ulcer wound bonding, and in the process of changing dressings, changing the bandage can bring very big misery to the patient, therefore, how to carry out effective nursing to patient's skin ulcer, all the time is the problem that medical staff cared for very much. At present, in order to reduce the pain of a patient in the nursing process, medical staff generally adopt silver ion dressing to be applied in clinic, the ulcer part is rapidly scabbed by adopting the bactericidal effect of silver ions, the viscosity of a bandage and a wound is reduced, the pain of the patient in the bandage replacing process can be reduced, and the silver ion dressing is more typical and is silver sulfadiazine.
At present, nitrogen-containing heterocyclic compounds have good biological activity and play an important role in human health and agricultural production such as medicines and pesticides. However, in the nursing of treating the outer skin ulcer caused by ulcerative colitis, the nitrogen-containing heterocyclic compound is mostly an oral medicament, the direct use of the nitrogen-containing heterocyclic compound as an external medicament for treating the skin ulcer is less, and the selection of doctors and patients is less, so that a new nitrogen-containing heterocyclic compound for treating the outer skin ulcer caused by ulcerative colitis is urgently needed to be synthesized.
Disclosure of Invention
In view of the above, the invention provides a novel pyrazine medicine with a molecular structure, a preparation method thereof, a medicine composition thereof and an application thereof in nursing of outer skin ulcer caused by ulcerative colitis.
Pyrrole can be used as a certain medical intermediate and plays an important role in medical research and development. For example, it is useful as an adenosine receptor antagonist, a cyclin-dependent kinase inhibitor, a phosphodiesterase inhibitor, etc. In doctor's paper "the research on the design, synthesis and biological activity of novel angiogenesis inhibitor-Thalidomide (THD) analogue", authors and their team synthesized several pyrrolo [3,4-d ] pyrimidine compounds, and the results of primary screening showed that most of the compounds have the activities of inhibiting proliferation of vascular endothelial cells and the activities of resisting lung cancer, inhibiting human leukemia cells and inhibiting human primitive myeloid leukemia cells. A series of pyrrole [2,3-d ] pyrimidine derivatives with effective protease inhibitor effect are synthesized by Huobaoyu, and the like, can effectively and selectively inhibit JAK3, can block cytokine signals and cytokine-induced gene expression, has no inhibition effect on JAK enzyme family members related to other cytokines and receptor phosphorylation, and can be used for organ transplantation and treatment of various autoimmune diseases; furthermore, the pyrrole [2,3-d ] pyrimidine derivatives are also effective in the treatment of rheumatic arthritis, psoriasis, colitis, diabetes and the like.
Pyrazine groups are very important dinitrogen-containing heterocycles, and the compounds have very obvious antibacterial action, for example, clinically used pyrazinamide permeates into phagocytes and enters into mycobacterium tuberculosis bacteria, and amidase in the bacteria removes amide groups and converts the amide groups into pyrazinoic acid to play an antibacterial action. Moreover, pyrazinamide is similar to nicotinamide in chemical structure, and can interfere dehydrogenase by substituting nicotinamide, prevent dehydrogenation, prevent oxygen utilization of mycobacterium tuberculosis, influence normal metabolism of bacteria, and cause death.
The technical means adopted by the invention by combining the characteristics of pyrrole and pyrazine are as follows:
a pyrazine medicine has good antibacterial and bactericidal effects, especially has good activity inhibition on Bacillus anthracis and Staphylococcus aureus, and has the following formula:
in addition, the compounds of formula (1) of the present invention may be converted into any salt as described herein by any method known to those skilled in the art. Similarly, any salt of the compound of formula (1) of the present invention may be converted to the free compound by any method known to those skilled in the art.
In another aspect of the present invention, there is provided a method for preparing a pyrazine drug of formula (1) above, comprising the following steps:
a) carrying out acylation reaction and amine aldehyde condensation cyclization reaction on 1, 4-dinitrile-2, 3-diamino-2-butene in a formula (6) to obtain a compound in a formula (5);
b) the compound of the formula (5) is subjected to a nitrile group catalytic hydrogenation reduction amino reaction to obtain a compound of a formula (4);
c) carrying out diazotization reaction and amine-aldehyde condensation reaction on the compound of the formula (4) to obtain a compound of a formula (3);
d) carrying out Fischer indole cyclization reaction on the compound of the formula (3) to obtain a compound of a formula (2);
e) the compound of formula (2) undergoes decarboxylation to produce the compound of formula (1).
The preparation method of the pyrazine medicament shown in the formula (1) provided by the invention has a relatively short synthesis path and the yield basically reaches more than 70%.
In addition, the present invention also provides a pharmaceutical composition comprising: a compound of formula (1), and pharmaceutically acceptable salts thereof, or mixtures thereof and one or more pharmaceutically acceptable carriers.
The pharmaceutical composition may further comprise one or more agents selected from the group consisting of: monoglyceride, IPP, white vaseline, propyl hydroxybenzoate, propylene glycol, methyl hydroxybenzoate, glycerol, MAP emulsifier, essence, oleum Menthae Dementholatum and water. The pharmaceutical composition is a new pharmaceutical composition for nursing the skin ulcer on the outer surface caused by the ulcerative colitis, has very obvious curative effect on the skin ulcer of a patient in clinical nursing experiments, and obviously shortens the curative time.
The pharmaceutical composition provided by the invention is a pharmaceutical ointment.
Preferably, the pharmaceutical combination provided by the invention is applied to the nursing of the external skin ulcer caused by gastrointestinal diseases.
In particular, the pharmaceutical composition is used for nursing skin ulcer caused by bacillus anthracis or/and staphylococcus aureus. The composition prepared from the pyrazine compound shown in the formula (1) has good activity inhibition on bacillus anthracis and staphylococcus aureus which are easy to cause skin ulcer, and has a good effect on curing most of external skin ulcer caused by ulcerative colitis.
Detailed Description
The principles and features of this invention are described in conjunction with the following examples, which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
A pyrazine medicine has good antibacterial and bactericidal effects, especially has good activity inhibition on Bacillus anthracis and Staphylococcus aureus, and has the following formula:
in addition, the compounds of formula (1) of the present invention may be converted into any salt as described herein by any method known to those skilled in the art. Similarly, any salt of the compound of formula (1) of the present invention may be converted to the free compound by any method known to those skilled in the art. Wherein, the salt of the compound of the formula (1) can be a free compound which is formed by substituting one or more than two of N-H in a pyrazine ring or a pyrrole ring with a pharmaceutically acceptable substituent to form a pharmaceutically acceptable salt or a salt.
In another aspect of the present invention, there is provided a first preparation method for the pyrazine compound of formula (1), which is a preferred synthesis method using 1, 4-dicyano-2, 3-diamino-2-butene as a raw material, and is not intended to limit the pyrazine compound of formula (1) of the present invention, and the synthesis process is as shown in the following scheme 1:
firstly, 1, 4-dinitrile-2, 3-diamino-2-butene in a formula (6) is taken as an initial raw material to synthesize a compound in a formula (5); further synthesizing a compound of formula (4) from the compound of formula (5) synthesized above; further synthesizing a compound of formula (3) from the compound of formula (4) synthesized above; then further synthesizing the compound of formula (2) from the compound of formula (3) synthesized above; finally, the compound of formula (2) synthesized above is further synthesized into the target compound of formula (1).
The method specifically comprises the following steps:
a) carrying out acylation reaction and amine aldehyde condensation cyclization reaction on 1, 4-dinitrile-2, 3-diamino-2-butene in a formula (6) to obtain a compound in a formula (5);
b) the compound of the formula (5) is subjected to a nitrile group catalytic hydrogenation reduction amino reaction to obtain a compound of a formula (4); the catalyst used therein includes, but is not limited to, raney nickel, palladium, platinum, etc., and the reaction is carried out under high pressure.
c) Carrying out diazotization reaction and amine-aldehyde condensation reaction on the compound of the formula (4) to obtain a compound of a formula (3);
d) carrying out Fischer indole cyclization reaction on the compound of the formula (3) to obtain a compound of a formula (2);
e) the compound of formula (2) undergoes decarboxylation to produce the compound of formula (1).
Wherein the terms "acylation reaction", "amine aldehyde condensation cyclization reaction", "catalytic nitrile group hydrogenation reduction", "diazotization reaction", "amine aldehyde condensation reaction", "fischer indole cyclization reaction", "decarboxylation reaction" and the later mentioned "hydrolysis reaction" are to be understood as meaning that the corresponding chemical combination reaction with its name takes place using reagents and conditions well known in the art.
In another aspect of the present invention, there is provided a second preparation method for preparing the pyrazine compound of formula (1) above, which is a preferred synthetic method using 1, 4-dicyano-2, 3-diamino-2-butene as a raw material, and is not used to limit the pyrazine compound of formula (1) of the present invention, and the synthetic process is as shown in the following scheme 2:
firstly, 1, 4-dinitrile-2, 3-diamino-2-butene in a formula (6) is taken as an initial raw material to synthesize a compound in a formula (5); further synthesizing a compound of formula (4) from the compound of formula (5) synthesized above; further synthesizing a compound of formula (3) from the compound of formula (4) synthesized above; further synthesizing a compound of formula (2) from the compound of formula (3) synthesized above; in contrast to the former preparation method, the present method is most characterized by further synthesizing the compound of formula (7) from the compound of formula (2) synthesized above, and finally further synthesizing the target compound of formula (1) from the compound of formula (7) synthesized above. The former preparation method has a short preparation path and a simpler operation process, but the required reaction temperature is higher, and the method synthesizes the compound of the formula (7) on the basis of the intermediate compound (2) and then synthesizes the target compound (1), so that the reaction conditions are mild, and the controllability is higher.
The method specifically comprises the following steps:
a) carrying out acylation reaction and amine aldehyde condensation cyclization reaction on 1, 4-dinitrile-2, 3-diamino-2-butene in a formula (6) to obtain a compound in a formula (5);
b) the compound of the formula (5) is subjected to a nitrile group catalytic hydrogenation reduction amino reaction to obtain a compound of a formula (4);
c) carrying out diazotization reaction and amine-aldehyde condensation reaction on the compound of the formula (4) to obtain a compound of a formula (3);
d) carrying out Fischer indole cyclization reaction on the compound of the formula (3) to obtain a compound of a formula (2);
f) carrying out hydrolysis reaction on the compound of the formula (2) to obtain a compound of a formula (7);
g) the compound of formula (7) undergoes decarboxylation to produce the compound of formula (1).
The first embodiment is as follows:
step a): the 1, 4-dinitrile-2, 3-diamino-2-butene in the formula (6) is subjected to acylation reaction and amine aldehyde condensation cyclization reaction to obtain a compound in the formula (5): slowly adding concentrated sulfuric acid into water at the temperature of 0 ℃, adding 1, 4-dicyanyl-2, 3-diamino-2-butene after dropwise adding, slowly heating, continuously and slowly dropwise adding a water solution of glyoxylic acid, continuously heating to reflux reaction, slowly cooling to 0 ℃, adding glacial ethanol into the reaction liquid, stirring and filtering the reaction liquid to obtain the compound shown in the formula (5). Wherein the acylation reaction and the amine aldehyde condensation cyclization reaction occur simultaneously in the reaction system; the reagents other than the raw materials for the acylation reaction include, but are not limited to, concentrated sulfuric acid, perchloric acid, tetrafluoroboric acid, hydrogen chloride gas and other inorganic acids, and benzene sulfonic acid, p-toluene sulfonic acid and other organic acids. The reagent for the amine aldehyde condensation cyclization reaction comprises various acids, bases or can be catalyzed by a metal catalyst, and is not limited to the glyoxylic acid in the embodiment.
In particular toThe following steps: slowly dripping 18g (0.18mol) of concentrated sulfuric acid into 1000mL of water in a reaction bottle at the temperature of 0 ℃, adding 244g (1.8mol) of 1, 4-dicyan-2, 3-diamino-2-butene after dripping, slowly heating to 50 ℃, slowly dripping 270g (the mass concentration is 50 percent and 1.8mol) of aqueous solution of glyoxylic acid, continuously heating to reflux after dripping for about 1h, slowly cooling to 0 ℃ after reacting for 5h, separating out a large amount of white solid in the cooling process, adding 500mL of glacial ethanol into the reaction liquid, stirring for 10min, and filtering the reaction liquid to obtain the product
260g, yield 83%.
Step b): the compound of the formula (5) is subjected to catalytic nitrile hydrogenation to reduce amino to obtain a compound of a formula (4): adding absolute ethyl alcohol, the compound shown in the formula (5) and a nickel catalyst into a high-pressure reaction kettle, sealing the high-pressure reaction kettle, adding hydrogen gas, pressurizing, slowly heating to react, cooling to room temperature, adding a dilute acid solution, filtering the reaction solution, and concentrating the filtrate to obtain the compound shown in the formula (4). The catalyst used therein includes, but is not limited to, nickel, raney nickel, palladium, platinum, etc., and the reaction is carried out under high pressure.
Concretely, 500mL of absolute ethyl alcohol is added into a high-pressure reaction kettle, and then the absolute ethyl alcohol is added
17g (0.1mol), adding 3g of Raney nickel, sealing the reaction kettle, replacing gas twice with nitrogen, introducing hydrogen to ensure that the pressure in the kettle reaches 0.2MPa, slowly heating to 60 ℃, leading the reaction in the kettle to be violent due to the rising of the reaction temperature, increasing the pressure to 0.4MPa, reducing the pressure to 0.3MPa after reacting for 30min, leading most of the reaction liquid to be a single reduction product, continuously supplementing hydrogen to ensure that the pressure reaches 0.4MPa, cooling to room temperature after reacting for 2h, adding a certain amount of dilute hydrochloric acid solution, carrying out suction filtration on the reaction liquid, and concentrating filtrate to obtain the product
22g of hydrochloride, 88% yield.
Step c): carrying out diazotization reaction and amine-aldehyde condensation reaction on the compound of the formula (4) to obtain a compound of a formula (3): adding the compound of the formula (4) into a mixed solution of water and hydrochloric acid, uniformly stirring, cooling to 0 ℃, dropwise adding an aqueous solution in which sodium nitrite is dissolved under the stirring condition, and uniformly mixing to obtain a solution A; preparing an aqueous solution dissolved with potassium hydroxide, slowly dropwise adding ethanol dissolved with ethyl acetoacetate at 0 ℃, and uniformly stirring after dropwise adding to prepare a solution B; slowly dripping the solution B into the solution A at the temperature of 0 ℃, heating for reaction after dripping, extracting the reaction solution by using ether, combining organic phases, drying by using anhydrous magnesium sulfate, concentrating, and separating by silica gel column chromatography to obtain the compound shown in the formula (3). Reagents required for the diazotization reaction to take place include, but are not limited to, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, fluoroboric acid, and sodium nitrite; the reagent for the amine-aldehyde condensation reaction includes various acids, bases, or may be catalyzed by a metal catalyst, and is not limited to potassium hydroxide in this embodiment.
In particular, in the reaction bottle, the handle
Adding 55g (0.3mol) of the aqueous solution into 3000mL of mixed solution of water and 2000mL of hydrochloric acid, uniformly stirring, cooling to 0 ℃, dropwise adding 1000mL of aqueous solution dissolved with 24g (0.34mol) of sodium nitrite under the stirring condition, and uniformly mixing after dropwise adding to obtain solution A; preparing 3000mL of aqueous solution in which 156g (2.8mol) of potassium hydroxide is dissolved in another reaction bottle, slowly dropwise adding 250mL of ethanol in which 60g (0.46mol) of ethyl acetoacetate is dissolved at 0 ℃, and uniformly stirring after dropwise adding to prepare solution B; slowly adding the solution A into the solution B at 0 ℃, heating to 40 ℃ after dropwise adding, reacting for 10min, extracting the reaction solution for three times by using 1000mL of diethyl ether, combining organic phases, drying by using anhydrous magnesium sulfate, concentrating, and separating by silica gel column chromatography (PE: EA is 9:1) to obtain the compound
95g, yield 78%.
Step d): performing Fischer indole cyclization reaction on the compound of the formula (3) to obtain a compound of a formula (2), adding the compound of the formula (3) and polyphosphoric acid into toluene, heating and stirring for reaction, removing the toluene in vacuum, adding ice water, stirring, filtering reaction liquid, and performing silica gel column chromatography separation on a filter cake to obtain the compound of the formula (2). Reagents in which the fischer indole ring-closure reaction occurs include, but are not limited to, protonic acids such as hydrochloric acid, sulfuric acid, polyphosphoric acid, p-toluenesulfonic acid, and lewis acids such as zinc chloride, ferric chloride, aluminum chloride, boron trifluoride.
In particular, in the reaction bottle, the handle
Adding 111g (0.273mol) and 500g polyphosphoric acid into 1000mL of toluene, heating to 45 ℃, stirring for reaction for 1h, then starting vacuum, removing toluene, adding 2000mL of ice water, stirring for 10min, then filtering the reaction solution, and separating the filter cake by silica gel column chromatography (PE: EA is 9:1) to obtain the product
87g, yield 85%.
Step e): the compound of formula (2) is subjected to decarboxylation reaction to generate the compound of formula (1); adding the compound of the formula (2) into a hydrochloric acid solution, heating to reflux reaction, cooling to room temperature, carrying out suction filtration on the reaction solution, and drying a filter cake to obtain the compound of the formula (1).
In particular, in the reaction bottle, the handle
Adding 37g (0.1M) of the reaction solution into 500mL of 2M HCl, heating to reflux, reacting for 15 hours, cooling to room temperature, filtering the reaction solution, and drying a filter cake to obtain the product
11g, yield 79%; 1HNMR (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.231.27for C12H14N 4O),[M+H]+)
example two:
steps a) to d) in the present embodiment are similar to steps a) to d) in the first embodiment, and the description in this embodiment is not repeated;
step e): the compound of formula (2) is subjected to decarboxylation reaction to generate the compound of formula (1); adding the compound of the formula (2) into a boric acid solution, heating to reflux reaction, cooling to room temperature, carrying out suction filtration on the reaction solution, and drying a filter cake to obtain the compound of the formula (1).
In particular, in the reaction bottle, the handle
Adding 37g (0.1m) of the mixed solution into a saturated aqueous solution of boric acid, heating to reflux, reacting for 30 hours, cooling to room temperature, filtering the reaction solution, and drying a filter cake to obtain the boric acid-containing reaction product
16g, yield 70%; 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.231.27for C12H14N4O, [ M + H + ESI 3.11: -HRMS) (+) -ESI M/z ═ 231.2776 (calcd.231.2712H 14N 4)]+)
Example three:
steps a) to d) in the present embodiment are similar to steps a) to d) in the first embodiment, and the description in this embodiment is not repeated;
step e): the compound of formula (2) is subjected to decarboxylation reaction to generate the compound of formula (1); adding the compound of the formula (2) into a lithium chloride solution, heating to reflux reaction, cooling to room temperature, carrying out suction filtration on the reaction solution, and drying a filter cake to obtain the compound of the formula (1).
In particular, in the reaction bottle, the handle
37g (0.1mol) and 8.5g (0.2mol) of lithium chloride were added to 200mL of DMSO, the mixture was heated to 180 ℃ and reacted for 10 hours, then the reaction mixture was poured into ice water,after stirring, a large amount of solid is separated out, reaction liquid is filtered, and a filter cake is dried to obtain
17g, 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), 13CNMR (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.231.27for C12H14N4O, [ M + H + 12H ], (M + ESI 12H): 12H)]+)
Example four:
steps a) to d) in the present embodiment are similar to steps a) to d) in the first embodiment, and the description in this embodiment is not repeated;
step e): the compound of formula (2) is subjected to decarboxylation reaction to generate the compound of formula (1); adding the compound of the formula (2) into a lithium chloride solution, heating to reflux reaction, cooling to room temperature, carrying out suction filtration on the reaction solution, and drying a filter cake to obtain the compound of the formula (1).
In the reaction flask, handle
Adding 37g (0.1mol) and 4.8g (0.2mol) of lithium hydroxide into DMSO200mL, heating to 180 ℃, reacting for 10h, pouring the reaction solution into ice water, stirring, precipitating a large amount of solid, filtering the reaction solution, and drying the filter cake to obtain the final product
18g, yield 78%; 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), 13CNMR (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.231.27for C12H14N4O, [ M + H + 12H ], (M + ESI 12H): 12H)]+)
Example five:
steps a) to d) in the present embodiment are similar to steps a) to d) in the first embodiment, and the description in this embodiment is not repeated;
for the second route, step f): preparing a compound of formula (7): carrying out hydrolysis reaction on the compound of the formula (2) to obtain a compound of a formula (7); adding the compound of the formula (2) into a dilute acid solution, heating for reaction, cooling to room temperature, carrying out suction filtration on the reaction solution, and drying a filter cake to obtain a compound of the formula (7); the dilute acids in which the hydrolysis reaction occurs include, but are not limited to: dilute hydrochloric acid, dilute sulfuric acid, dilute nitric acid, and the like.
In particular, in the reaction bottle, the handle
Adding 37g (0.1mol) of the mixture into 200mL of dilute hydrochloric acid, heating to 60 ℃, reacting for 5 hours, cooling to room temperature, filtering the reaction solution, and drying a filter cake to obtain the product
30g, yield 94%; 1HNMR (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): δ 169.93,168.45,153.32,146.50,141.22,141.05,127.81,118.34,102.85,58.31,43.61,43.16,41.29, 40.26.
Step g) of: compound of formula (7) preparation of target compound a compound of formula (1): the compound of formula (7) is subjected to decarboxylation reaction to generate the compound of formula (1), the compound of formula (7) is added into pyrazine, then basic copper carbonate is added, heating reaction is carried out, reaction liquid is filtered after complete reaction, a certain amount of dichloromethane is added, washing and concentrating are carried out, and the compound of formula (1) is obtained through column chromatography separation.
In particular, in the reaction bottle, the handle
Adding 32g (0.1mol) of pyrazine into 200mL, adding 3.2g of basic copper carbonate, heating at 120 ℃ for reaction for 1h, monitoring the reaction completion of raw materials by TLC, filtering the reaction solution, adding a certain amount of dichloromethane, washing with water, concentrating, and finally performing column chromatography separation to obtain the product
21g, yield 91%; 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.231.27for C12H14N4O, [ M + H + ESI 3.11: -HRMS) (+) -ESI M/z ═ 231.2776 (calcd.231.2712H 14N 4)]+)。
Example six:
additionally, the present embodiments provide a pharmaceutical composition comprising: a compound of formula (1), and pharmaceutically acceptable salts thereof, or mixtures thereof;
the pharmaceutical composition may further comprise one or more agents selected from the group consisting of: monoglyceride, IPP, white vaseline, propyl hydroxybenzoate, propylene glycol, methyl hydroxybenzoate, glycerol, MAP emulsifier, essence, oleum Menthae Dementholatum and water. Wherein the compound of formula (1)
The weight ratio of the pure soybean oil to the monoglyceride, IPP, white vaseline, propyl hydroxybenzoate, propylene glycol, methyl hydroxybenzoate, glycerol, MAP emulsifier, essence, peppermint oil and water is as follows: 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: 1-2.5: 35-45.
Preferably, the compounds of formula (1) in this example
The weight ratio of the pure soybean oil to the monoglyceride, IPP, white vaseline, propyl hydroxybenzoate, propylene glycol, methyl hydroxybenzoate, glycerol, MAP emulsifier, essence, peppermint oil and water is as follows: 5:4:12:4:0.5:20:1.5:5:3:3:2:40.
The pharmaceutical composition provided by the invention is a pharmaceutical ointment.
Specifically, the preparation method of the medicinal ointment of the medicinal composition comprises the following steps: at 10 ℃,40 g of water and 20g of propylene glycol are added into a stirring container, and 5g of glycerol and2g of peppermint oil, stirring and adding the compound of formula (1)
5g, then adding 4g of monoglyceride, 12g of IPP, 4g of white vaseline, 0.5g of propylparaben, 1.5g of methyl paraben, 3g of MAP emulsifier and 3g of essence in sequence, and stirring for 2 hours at the temperature of 10 ℃ to obtain the medicinal ointment.
Example seven:
the compound of this example is (1)
The antibacterial test of (1). Bacillus anthracis and staphylococcus aureus are selected as the test objects of antibacterial activity. Firstly, preparing a liquid culture medium (1 g of peptone, 0.5g of yeast extract, 1g of sodium chloride and 100mL of distilled water are placed in a 250mL conical flask and are placed on an electric furnace to be heated while stirring, when the peptone, the yeast extract, the sodium chloride and the distilled water are mixed and clarified uniformly, the heating is stopped, and the bottleneck is sequentially sealed by gauze and kraft paper for standby) and a solid culture medium (1 g of peptone, 0.5g of yeast extract, 1g of sodium chloride, 2g of agar and 100mL of distilled water are placed in a 250mL conical flask and are placed on an electric furnace to be heated while stirring, when the peptone, the yeast extract, the agar and the distilled water are mixed and clarified uniformly, the heating is stopped, and the bottleneck is sequentially sealed by gauze and; then the culture medium is sterilized by an autoclave. Secondly, preparing bacterial liquid, namely activating escherichia coli and staphylococcus aureus strains, transferring 100 mu L of activated bacterial liquid by using a liquid transfer gun, and putting the activated bacterial liquid into sterilized 100mL of distilled water for uniformly mixing. And finally, sterilizing the flat plate by an ultraviolet lamp, quickly pouring the culture medium into the flat plate while the culture medium is hot, uniformly paving the flat plate with the thickness of about 0.15cm, standing the flat plate, slowly solidifying the flat plate, and putting the solidified flat plate into an incubator at 37 ℃ for culturing for one day for carrying out non-impurity bacteria detection.
The target compound and the control compound solutions are prepared respectively with DMF and placed in volumetric flasks for later use. Punching a hole on the filter paper by using a puncher, wherein the hole diameter is 5mm, and then sterilizing the filter paper sheet and soaking the filter paper sheet in a sample solution with the concentration of 0.1mg/mL for later use.
On a clean bench, an alcohol lamp was lit, and 10. mu.L of diluted culture solution was applied to the surface of the solid medium with a pipette and spread uniformly. The soaked round filter paper sheet was spread on the surface of the medium with sterile forceps. 4 plates were placed on each plate and 3 replicates were run, one of which was blank controlled. The plate with the tablets was incubated at 37 ℃ for 24h and observed for signs. The transparent circular rings-bacteriostatic rings with different sizes are respectively arranged on the agar culture medium, and the bacteriostatic activity of each sample can be seen by measuring the diameters of the bacteriostatic rings.
It can be found that the compound of the formula (1) provided by the invention has good antibacterial and bactericidal effects, and particularly has good activity inhibition on bacillus anthracis and staphylococcus aureus.
Example eight:
this example is a clinical trial example and is the application of a pharmaceutical ointment, which is a pharmaceutical composition, to the care of outer skin ulcers caused by gastrointestinal disorders.
Liu Jie, male, 43 years old, was admitted to hospital for 2 years after discontinuation of mucopurulent bloody stool accompanied by skin ulcer in the extremities due to ulcerative colitis. The patient has no obvious reason to have mucus, bloody stool 2 years before admission, the red spots appear on the skin of four limbs and are rapidly developed into abscess and ulcer 3-4 times per day, the skin of the chest can be affected occasionally mainly by two lower limbs, the symptoms of fever, cough and expectoration are accompanied, and the body temperature can reach more than 39 ℃ at most.
Admission to the examinee: the anemic appearance is characterized in that auscultation and breath sounds of the two lungs are thickened, bowel sounds are active, skin abscess can be seen on the nearly naked parts of the two lower limbs to heal, the maximum ulcer area is 3.0cm multiplied by 4.5cm, the minimum ulcer area is 1.5cm multiplied by 1.5cm, the depth is 0.1-0.5 cm, and the base part of ulcer has suppuration or purulent blood secretion with different degrees.
The conventional iodophor disinfection is firstly carried out, for example, wound infection is caused, the concentrated secretion is cleaned by 3 wt% of hydrogen peroxide and then debridement is carried out according to the procedure, and a small amount of debridement methods for many times are preferably adopted for wound surfaces with excessive necrotic tissues. The treatment group is applied on wound surface by medical care personnel, covered with sterile gauze, fixed, changed every two days, and changed every day for severe infected patients until healing. The blank control group was prepared by soaking 1 wt% gentamicin in vaseline oil gauze, and dressing change once a day.
The treatment effect is seen by the healing speed of the ulcer surface, and the healing speed of the balance of the treatment group 7 is (0.37 +/-0.12) cm 2/day, which is obviously faster than that of the blank control group (0.33 +/-0.15) cm 2/day.
The composition is a new medicine composition for nursing the external skin ulcer caused by ulcerative colitis, and in clinical nursing experiments, the cure speed of the skin ulcer of a patient is higher than that of a control group, so that the cure time is obviously shortened.
In particular, the pharmaceutical composition is used for nursing skin ulcer caused by bacillus anthracis or/and staphylococcus aureus. The composition prepared from the pyrazine compound shown in the formula (1) has good activity inhibition on bacillus anthracis and staphylococcus aureus which are easy to cause skin ulcer, and has a good effect on curing most of external skin ulcer caused by ulcerative colitis.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A pyrazine drug, characterized in that it has the following formula:
2. a method of preparing a pyrazine drug of claim 1, comprising the steps of:
a) carrying out acylation reaction and amine aldehyde condensation cyclization reaction on 1, 4-dinitrile-2, 3-diamino-2-butene in a formula (6) to obtain a compound in a formula (5);
b) the compound of the formula (5) is subjected to a nitrile group catalytic hydrogenation reduction amino reaction to obtain a compound of a formula (4);
c) carrying out diazotization reaction and amine-aldehyde condensation reaction on the compound of the formula (4) to obtain a compound of a formula (3);
d) carrying out Fischer indole cyclization reaction on the compound of the formula (3) to obtain a compound of a formula (2);
e) the compound of formula (2) undergoes decarboxylation to produce the compound of formula (1).
3. A method for preparing a pyrazine drug according to claim 2, wherein in the step a), concentrated sulfuric acid is slowly added into water at 0 ℃,1, 4-dicyano-2, 3-diamino-2-butene is added after dropwise addition, then the temperature is slowly raised, an aqueous solution of glyoxylic acid is continuously and slowly added dropwise, the temperature is continuously raised to reflux reaction, then the reaction solution is slowly cooled to 0 ℃, glacial ethanol is added into the reaction solution, and the reaction solution is stirred and filtered to obtain the compound of formula (5).
4. A process for preparing a pyrazine drug according to claim 2, wherein in step b), absolute ethyl alcohol, the compound of formula (5) and a nickel catalyst are added into a high pressure reactor, the reaction is performed under sealed hydrogen gas pressure and slowly heated, then a diluted acid solution is added after cooling to room temperature, the reaction solution is filtered, and the filtrate is concentrated to obtain the compound of formula (4).
5. A process for preparing a pyrazine drug according to claim 2, wherein in the step c), the compound of formula (4) is added into a mixed solution of water and hydrochloric acid, the temperature is reduced to 0 ℃ after uniform stirring, an aqueous solution dissolved with sodium nitrite is added dropwise under the condition of stirring, and the mixture is uniformly mixed to obtain a solution a; preparing an aqueous solution dissolved with potassium hydroxide, slowly dropwise adding ethanol dissolved with ethyl acetoacetate at 0 ℃, and uniformly stirring after dropwise adding to prepare a solution B; slowly dripping the solution B into the solution A at the temperature of 0 ℃, heating for reaction after dripping, extracting the reaction solution by using ether, combining organic phases, drying by using anhydrous magnesium sulfate, concentrating, and separating by silica gel column chromatography to obtain the compound shown in the formula (3).
6. A process for preparing a pyrazine drug according to claim 2, wherein in step d), the compound of formula (3) and polyphosphoric acid are added to toluene, the mixture is heated and stirred for reaction, the toluene is removed by vacuum evaporation, ice water is added and stirred, the reaction solution is filtered, and the filter cake is separated by silica gel column chromatography to obtain the compound of formula (2).
7. A method for preparing a pyrazine drug according to claim 2, wherein in step e), the compound of formula (2) is added into an acid solution or a lithium salt solution, heated to reflux reaction, cooled to room temperature, filtered, and dried to obtain the compound of formula (1).
8. A pharmaceutical composition, comprising: a compound of formula (1) according to claim 1, and pharmaceutically acceptable salts thereof, or mixtures thereof;
and one or more agents selected from the group consisting of: monoglyceride, IPP, white vaseline, propyl hydroxybenzoate, propylene glycol, methyl hydroxybenzoate, glycerol, MAP emulsifier, essence, oleum Menthae Dementholatum and water.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is a pharmaceutical ointment.
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Non-Patent Citations (2)
| Title |
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| A Family of Pyrazinone Natural Products;Michael Zimmermann等;《Chemistry & Biology》;20100924;第17卷(第9期);第925-930页 * |
| Butrepyrazinone, a New Pyrazinone with an Unusual Methylation Pattern from a Ghanaian Verrucosispora sp. K51G;Kwaku Kyeremeh等;《Marine drugs》;20141016;第12卷(第10期);第5197-5208页 * |
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