CN110452224B - Pyrimidineazolol compound and preparation method and application thereof - Google Patents
Pyrimidineazolol compound and preparation method and application thereof Download PDFInfo
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- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention relates to a pyrimidinol compound and a preparation method and application thereof, belonging to the technical field of chemical synthesis, wherein the pyrimidinol compound is shown as a general formula I-II, has certain inhibitory activity on one or more of gram-positive bacteria, gram-negative bacteria and fungi, and can be used for preparing antibacterial and/or antifungal medicaments, so that more efficient and safe candidate medicaments are provided for clinical antimicrobial treatment, and the clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly-appeared harmful microorganisms and the like are solved. The preparation raw materials are simple, cheap and easy to obtain, the synthetic route is short, and the application in the aspect of infection resistance is of great significance.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a pyrimidineol compound and a preparation method and application thereof.
Background
Pyrimidine has a unique double-nitrogen aromatic structure, so that the pyrimidine is easy to interact with various biological molecules such as deoxyribonucleic acid, ribonucleic acid, enzyme, receptor and the like through intermolecular supramolecular interaction, and has high affinity, thereby being widely applied to design of biological or drug molecules. In addition, researches show that the pyrimidine derivatives not only can inhibit dihydrofolate reductase, but also play an important role in DNA synthesis so as to show high-efficiency antibacterial activity; and are capable of hybridizing with the active structural fragments to render these hybrid products membrane active. Therefore, structural modification of pyrimidines is expected to result in more effective antibacterial agents.
Azoles are aromatic heterocyclic compounds widely existing in natural products and synthetic molecules, and have good electrical richness due to unique structural characteristics, so that supramolecular drugs are easily formed through hydrogen bonds, coordination bonds, van der waals force, pi-pi interaction and the like, and the physicochemical and pharmacokinetic properties of drug molecules are improved; can also be combined with various action targets such as various enzymes and receptors in organisms through various non-covalent bond forces to show various biological activities. Therefore, the compound plays an important role in the development of medicine and is widely applied to one of the hot spots of the design and development of medicines. Based on the method, the pyrimidine and the azole are combined to obtain high-activity drug molecules, so that the drug resistance of bacteria is overcome, the antibacterial spectrum is widened, and a new candidate drug is provided for clinic.
Disclosure of Invention
In view of the above, one of the purposes of the present invention is to introduce an azole ring into pyrimidine, and provide a pyrimidineazolol compound and its pharmaceutically acceptable salts, which have broad development prospects, high safety, low drug resistance, and good bioavailability; the second purpose of the invention is to provide a preparation method of the pyrimidineol compound and the medicinal salt thereof; the third purpose of the invention is to provide the application of the pyrimidineol compound and the medicinal salt thereof in preparing antibacterial and/or antifungal medicaments; the fourth purpose of the invention is to provide a preparation containing the pyrimidineol compound and the pharmaceutically acceptable salts thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the structure of the pyrimidineol compound and the pharmaceutically acceptable salts thereof is shown as the general formula I-II:
in the formula (I), the compound is shown in the specification,
R1、R2、R3、R4、R5and R6Is hydrogen, halogen, aryl, alkyl, nitro, hydroxyalkyl, trifluoromethyl, formyl, carboxyl, cyano or amino;
x, Y and Z is carbon or nitrogen.
Preferably, the first and second liquid crystal materials are,
R1is hydrogen, methyl, propyl or phenyl;
R2is hydrogen, methyl or nitro;
R3is hydrogen or nitro;
R4is hydrogen or methyl;
R5is hydrogen;
R6is hydrogen or nitro;
x, Y and Z is carbon or nitrogen.
Preferably, it is any one of the following compounds:
preferably, the pharmaceutically acceptable salt is hydrochloride, nitrate or acetate.
2. The preparation method of the pyrimidineol compound and the pharmaceutically acceptable salt thereof comprises the following steps:
a. preparing intermediates III-1-9: 2, 4-dichloropyrimidine and azole compounds are used as starting materials, and are subjected to substitution reaction under the action of alkali to obtain intermediates III-1-9;
b. preparing an intermediate IV-1-4: 2, 4-dichloropyrimidine and azole compounds are used as starting materials, and an intermediate IV-1-4 is obtained through substitution reaction under the action of alkali;
c. preparation of pyrimidineol compounds represented by general formula I: carrying out nucleophilic substitution reaction on the intermediate III-1-9 and diethanol amine to obtain a pyrimidinazolol compound shown in the general formula I;
d. preparation of pyrimidineol compounds of formula II: and carrying out nucleophilic substitution reaction on the intermediate IV-1-4 and diethanol amine to obtain the pyrimidineol compound shown in the general formula II.
Preferably, the first and second liquid crystal materials are,
in the step a, the molar ratio of the 2, 4-dichloropyrimidine to the azole compound to the base is 1:1.2: 1.5; the alkali is potassium carbonate; the substitution reaction is carried out for 11 hours at 50 ℃ by taking acetonitrile as a solvent;
in the step b, the molar ratio of the 2, 4-dichloropyrimidine to the azole compound to the alkali is 1:1.2: 1.5; the alkali is potassium carbonate; the substitution reaction is carried out for 11 hours at 50 ℃ by taking acetonitrile as a solvent;
in the step c, the molar ratio of the intermediate III-1-9 to diethanolamine is 1: 1.5; the nucleophilic substitution reaction is carried out for 5 hours at 80 ℃ by taking acetonitrile as a solvent;
the molar ratio of the intermediate IV to the diethanol amine in the step d is 1: 1.5; the nucleophilic substitution reaction is carried out for 5 hours at 80 ℃ by taking acetonitrile as a solvent.
3. The pyriconazole compound and the medicinal salt thereof are applied to the preparation of antibacterial and/or antifungal medicaments.
Preferably, the bacteria is one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC 25923, staphylococcus aureus ATCC 29213, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC 27853, escherichia coli ATCC 25922 or acinetobacter baumannii; the fungi is one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC 90023 or Candida parapsilosis ATCC 22019.
4. A preparation containing the pyrimethanil alcohol compound and the medicinal salt thereof.
Preferably, the preparation is one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols.
The invention has the beneficial effects that: the invention provides a pyrimidineol compound and a preparation method and application thereof, the invention utilizes the drug design split principle, introduces an azole ring on pyrimidine, designs and synthesizes a series of novel pyrimidineol compounds, the compounds have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC 25923 and staphylococcus aureus ATCC 29213), gram-negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC 27853, escherichia coli ATCC 25922 and acinetobacter baumannii) and fungi (candida albicans, candida tropicalis, aspergillus fumigatus, candida albicans ATCC 90023 and candida parapsilosis ATCC 22019) through in-vitro antimicrobial activity detection, and can be used for preparing antibacterial and/or antifungal drugs, therefore, more efficient and safe candidate drugs are provided for clinical antimicrobial treatment, and the clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly appeared harmful microorganisms and the like are solved. The preparation raw materials are simple, cheap and easy to obtain, the synthetic route is short, and the application in the aspect of infection resistance is of great significance.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objectives and other advantages of the invention may be realized and attained by the means of the instrumentalities and combinations particularly pointed out hereinafter.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Example 1 preparation of intermediate III-1
2, 4-dichloropyrimidine (3.000g,20.2mmol), imidazole (1.646g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were added to acetonitrile (30mL) and reacted at 50 ℃ for 11 hours. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give intermediate III-1(574mg) as a white solid in a yield of 15.8%.
Example 2 preparation of intermediate III-2
2, 4-dichloropyrimidine (3.000g,20.2mmol), 2-methyl-5-nitroimidazole (3.073g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged into a round-bottomed flask (100mL), and reacted at 50 ℃ for 11 hours using acetonitrile (40mL) as a solvent. The reaction was followed by thin layer chromatography until completion, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give intermediate III-2(685mg) as a white solid in 14.2% yield.
Example 3 preparation of intermediate III-3
2, 4-dichloropyrimidine (3.000g,20.2mmol), 4-nitroimidazole (2.735g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged into a round-bottomed flask (100mL), and reacted at 50 ℃ for 11 hours with acetonitrile (40mL) as a solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give intermediate III-3(932mg) as a white solid with a yield of 20.5%.
Example 4 preparation of intermediate III-4
2-phenylimidazole (3.000g,20.2mmol), 2-phenylimidazole (3.845g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged in a round-bottomed flask (100mL) and reacted at 50 ℃ for 11 hours with acetonitrile (40mL) as a solvent. The reaction was followed by thin layer chromatography to completion, and purified by distillation under reduced pressure and column chromatography to give intermediate III-4(538mg), yield: 10.4 percent; a colorless oil.
Example 5 preparation of intermediate III-5
2, 4-dichloropyrimidine (3.000g,20.2mmol), 4-methylimidazole (2.735g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged into a round-bottomed flask (100mL), and reacted at 50 ℃ for 11 hours with acetonitrile (40mL) as a solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give intermediate III-5(600mg) as a white solid with a yield of 15.3%.
Example 6 preparation of intermediate III-6
2, 4-dichloropyrimidine (3.000g,20.2mmol), 2, 4-dimethylimidazole (1.939g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged into a round-bottomed flask (100mL), and reacted at 50 ℃ for 11 hours with acetonitrile (40mL) as a solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give intermediate III-6(1.395g) as a white solid with a yield of 33.2%.
Example 7 preparation of intermediate III-7
2, 4-dichloropyrimidine (3.000g,20.2mmol), 2-propylimidazole (2.662g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged into a round-bottomed flask (100mL), and reacted at 50 ℃ for 11 hours with acetonitrile (40mL) as a solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give intermediate III-7(1.453g) as a white solid with a yield of 32.4%.
EXAMPLE 8 preparation of intermediate III-8
2, 4-dichloropyrimidine (3.000g,20.2mmol), 1,3, 4-triazole (1.669g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged into a round-bottomed flask (100mL), and reacted at 50 ℃ for 11 hours using acetonitrile (40mL) as a solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give intermediate III-8(826mg) as a white solid with a yield of 17.1%.
EXAMPLE 9 preparation of intermediate III-9
2, 4-dichloropyrimidine (3.000g,20.2mmol), 1,2,3, 4-tetrazole (1.694g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged into a round-bottomed flask (100mL), and reacted at 50 ℃ for 11 hours using acetonitrile (40mL) as a solvent. The reaction was followed by thin layer chromatography until completion, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give intermediate III-9(588mg) as a white solid in 16.0% yield.
Experimental example 10
Preparation of intermediate IV-1
2, 4-dichloropyrimidine (3.000g,20.2mmol), imidazole (1.646g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were added to acetonitrile (30mL) and reacted at 50 ℃ for 11 hours. The reaction was followed by thin layer chromatography to completion, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give intermediate IV-1(447mg) as a white solid in a yield of 12.3%.
Experimental example 11
Preparation of intermediate IV-2
2, 4-dichloropyrimidine (3.000g,20.2mmol), 2-methyl-5-nitroimidazole (3.073g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged into a round-bottomed flask (100mL), and reacted at 50 ℃ for 11 hours using acetonitrile (40mL) as a solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give intermediate IV-2(826mg) as a white solid with a yield of 17.1%.
Experimental example 12
Preparation of intermediate IV-3
2, 4-dichloropyrimidine (3.000g,20.2mmol), 2-methylimidazole (1.984g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged into a round-bottomed flask (100mL), and reacted at 50 ℃ for 11 hours with acetonitrile (40mL) as a solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give intermediate IV-3(1.031g) as a white solid with a yield of 26.3%.
Experimental example 13
Preparation of intermediate IV-4
2, 4-dichloropyrimidine (3.000g,20.2mmol), 1,2,3, 4-tetrazole (1.694g,24.2mmol) and potassium carbonate (4.168g,30.3mmol) were charged into a round-bottomed flask (100mL), and reacted at 50 ℃ for 11 hours using acetonitrile (40mL) as a solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give intermediate IV-4(404mg) as a white solid in a yield of 11.0%.
Experimental example 14
Preparation of Compound I-1
Intermediate III-1(200mg,1.11mmol) and diethanolamine (175 mg)1.67mmol) was added to a round bottom flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was followed by thin layer chromatography to completion, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give compound I-1(234mg) in 84.6% yield. White solid, melting point 155-;1H NMR(400MHz,DMSO-d6)δ8.63(s,1H,Im-5-H),8.44(d,J＝5.4Hz,1H,pyrimidine-6-H),7.97(s,1H,Im-2-H),7.14(s,1H,Im-4-H),6.99(d,J＝5.4Hz,1H,pyrimidine-5-H),4.79(bs,2H,OH),3.69(bs,8H,N(CH2CH2OH)2)ppm.
experimental example 15
Preparation of Compound I-2
Intermediate III-2(200mg,0.84mmol) and diethanolamine (132mg,1.26mmol) were added to a round-bottomed flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was followed by thin layer chromatography until completion, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give compound I-2(166mg) in 64.1% yield. White solid, melting point 150-;1H NMR(400MHz,DMSO-d6)δ8.85(s,1H,Im-4-H),8.55(d,J＝5.3Hz,1H,pyrimidine-6-H),7.03(d,J＝5.3Hz,1H,pyrimidine-5-H),4.80(bs,2H,OH),3.71(bs,4H,N(CH2CH2OH)2),3.62(bs,4H,N(CH2CH2OH)2),2.67(s,3H,CH3)ppm.
experimental example 16
Preparation of Compound I-3
Intermediate III-3(200mg,0.89mmol) and diethanolamine (140mg,1.34mmol) were added to a round-bottomed flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. Tracking by thin layer chromatography until the reaction is completed, cooling to room temperature, and purifying by reduced pressure distillation and column chromatographyCompound I-3(92mg) was obtained in 35.3% yield. White solid, melting point 205-;1H NMR(600MHz,DMSO-d6)δ9.11(s,1H,Im-5-H),8.80(s,1H,Im-2-H),8.55(d,J＝5.2Hz,1H,pyrimidine-6-H),7.19(d,J＝5.3Hz,1H,pyrimidine-5-H),4.79(bs,2H,OH),3.77(bs,4H,N(CH2CH2OH)2),3.66(bs,4H,N(CH2CH2OH)2)ppm.
experimental example 17
Preparation of Compound I-4
Intermediate III-4(200mg,0.78mmol) and diethanolamine (123mg,1.17mmol) were added to a round-bottomed flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give compound I-4(47mg) in 18.4% yield. White solid, melting point 220-;1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝6.2Hz,1H,pyrimidine-6-H),7.74(s,1H,Im-5-H),7.35(bs,5H,phenyl-2,3,4,5,6-H),7.11(s,1H,Im-4-H),6.65(d,J＝6.2Hz,1H,pyrimidine-5-H),4.70(bs,2H,OH),3.52(bs,4H,N(CH2CH2OH)2),3.26(bs,4H,N(CH2CH2OH)2)ppm.
experimental example 18
Preparation of Compound I-5
Intermediate III-5(200mg,1.03mmol) and diethanolamine (163mg,1.55mmol) were added to a round bottom flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was followed by thin layer chromatography to completion, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give compound I-5(66mg) in 18.4% yield. White solid with melting point of 168-170 ℃;1H NMR(400MHz,DMSO-d6)δ8.50(s,1H,Im-5-H),8.39(d,J＝5.4Hz,1H,pyrimidine-6-H),7.65(s,1H,Im-2-H),6.90(d,J＝5.4Hz,1H,pyrimidine-5-H),4.78(bs,2H,OH),3.70(bs,4H,N(CH2CH2OH)2),3.61(bs,4H,N(CH2CH2OH)2),2.17(s,3H,CH3)ppm.
experimental example 19
Preparation of Compound I-6
Intermediate III-6(200mg,0.96mmol) and diethanolamine (151mg,1.44mmol) were added to a round-bottomed flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give compound I-6(137mg) in 51.5% yield. A colorless oily liquid;1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝5.4Hz,1H,pyrimidine-6-H),7.38(s,1H,Im-5-H),6.75(d,J＝5.4Hz,1H,pyrimidine-5-H),4.81(bs,2H,OH),3.66(bs,8H,N(CH2CH2OH)2),2.59(s,3H,Im-2-CH3),2.09(s,3H,Im-4-CH3)ppm.
experimental example 20
Preparation of Compound I-7
Intermediate III-7(200mg,0.90mmol) and diethanolamine (142mg,1.35mmol) were added to a round bottom flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was followed by thin layer chromatography to completion, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give compound I-7(207mg) in 79.2% yield. White solid with a melting point of 92-94 ℃;1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝5.4Hz,1H,pyrimidine-6-H),7.63(d,J＝1.3Hz,1H,Im-5-H),6.95(d,J＝1.3Hz,1H,Im-4-H),6.79(d,J＝5.4Hz,1H,pyrimidine-6-H),4.80(bs,2H,OH),3.67(bs,8H,N(CH2CH2OH)2),3.02(t,J＝7.6Hz,2H,CH2CH2CH3),1.75–1.62(m,2H,CH2CH2CH3),0.92(t,J＝7.4Hz,3H,CH2CH2CH3)ppm.
experimental example 21
Preparation of Compound I-8
Intermediate III-8(200mg,1.10mmol) and diethanolamine (173mg,1.65mmol) were added to a round-bottomed flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give compound I-8(98mg) in 35.6% yield. White solid, melting point 119-120 ℃;1H NMR(600MHz,CDCl3)δ9.07(s,1H,1,2,4-triazole-5-H),8.42(d,J＝5.3Hz,1H,pyrimidine-6-H),8.08(s,1H,1,2,4-triazole-3-H),7.07(d,J＝5.3Hz,1H,pyrimidine-5-H),4.81(bs,2H,OH),4.00–3.95(bs,4H,N(CH2CH2OH)2),3.90(bs,4H,N(CH2CH2OH)2)ppm.
experimental example 22
Preparation of Compound I-9
Intermediate III-9(200mg,1.10mmol) and diethanolamine (173mg,1.65mmol) were added to a round-bottomed flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give compound I-9(89mg) in 32.1% yield. White solid, melting point 137-138 ℃;1H NMR(400MHz,DMSO-d6)δ10.22(d,J＝1.8Hz,1H,tetrazole-5-H),8.62(d,J＝5.1,1.3Hz,1H,pyrimidine-6-H),7.16(d,J＝5.1,1.8Hz,1H,pyrimidine-5-H),3.75(bs,5H,CH2CH2OH),3.67(bs,5H,CH2CH2OH)ppm.
experimental example 23
Preparation of Compound II-1
Intermediate IV-1(200mg,1.11mmol) and diethanolamine (175mg,1.67mmol) were added to a round-bottomed flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give compound II-1(219mg) in 79.2% yield. White solid, melting point 140-142 ℃;1H NMR(400MHz,DMSO-d6)δ8.52(s,1H,Im-5-H),8.14(d,J＝6.2Hz,1H,pyrimidine-6-H),7.87(s,1H,Im-2-H),7.08(s,1H,Im-4-H),6.66(d,J＝6.2Hz,1H,pyrimidine-5-H),4.85(bs,2H,OH),3.66(bs,8H,N(CH2CH2OH)2)ppm.
experimental example 24
Preparation of Compound II-2
Intermediate IV-2(200mg,0.84mmol) and diethanolamine (132mg,1.26mmol) were added to a round-bottomed flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give compound II-2(114mg) in 43.9% yield. White solid, melting point 164-166 ℃;1H NMR(400MHz,DMSO-d6)δ8.67(s,1H,Im-4-H),8.21(d,J＝6.3Hz,1H,pyrimidine-6-H),6.79(d,J＝6.3Hz,1H,pyrimidine-5-H),4.85(bs,2H,OH),3.68(bs,8H,N(CH2CH2OH)2),2.73(s,3H,CH3)ppm.
experimental example 25
Preparation of Compound II-3
Intermediate IV-3(200mg,1.03mmol) and diethanolamine (163mg,1.55mmol) were added to a round-bottomed flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by distillation under reduced pressure and column chromatography to give compound II-3(129mg) in 47.8% yield. White solid, melting point 127-;1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝6.2Hz,1H,pyrimidine-6-H),7.78(d,J＝1.2Hz,1H,Im-5-H),6.84(d,J＝1.2Hz,1H,Im-4-H),6.64(d,J＝6.2Hz,1H,pyrimidine-5-H),4.85(bs,2H,OH),3.68(bs,8H,N(CH2CH2OH)2)ppm.
experimental example 26
Preparation of Compound II-4
Intermediate IV-4(200mg,1.10mmol) and diethanolamine (173mg,1.65mmol) were added to a round bottom flask (50mL) and stirred at 80 ℃ for 5 hours with acetonitrile (20mL) as solvent. The reaction was completed by thin layer chromatography, cooled to room temperature, and purified by reduced pressure distillation and column chromatography to give compound II-4(8.8mg) in 3.2% yield. White solid, melting point 143-144 ℃;1H NMR(400MHz,DMSO-d6)δ9.32(s,1H,tetrazole-5-H),8.67(d,J＝5.1Hz,1H,pyrimidine-6-H),7.24(d,J＝5.1Hz,1H,pyrimidine-5-H),4.81(bs,2H,OH),3.72(bs,8H,N(CH2CH2OH)2)ppm.
example 27 in vitro antimicrobial Activity of Pyrimidineol Compounds
The Minimalist Inhibitory Concentrations (MIC) of the pyrimidinol compounds prepared in examples 14 to 26 against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213), gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC 90023, Candida parapsilosis ATCC 22019) were determined by a 96-well microdilution method in accordance with the Clinical Laboratory Standards Institute (CLSI) set by the American national Committee, and the test compounds were dissolved in a small amount of dimethyl sulfoxide and diluted with water to a concentration of 1.28mg/mL, then, the culture medium was diluted to 128. mu.g/mL, cultured at 35 ℃ for 24 to 72 hours, and after the plate was sufficiently shaken on a shaker, MIC was measured at a wavelength of 490nm, and the results are shown in tables 1 to 3.
TABLE 1 in vitro gram-positive activity data (MIC, μ g/mL) for pyrimidinol compounds prepared in examples 14 to 26
TABLE 2 in vitro gram-negative activity data (MIC, μ g/mL) of pyrimidineol compounds prepared in examples 14 to 26
As can be seen from tables 1 and 2, the pyrimidineol compounds prepared in examples 14 to 26 of the present invention exhibit certain inhibitory effects on the tested bacteria, and in particular, the triazole-modified pyrimidineol compound I-8 has better antibacterial activity on both gram-negative bacteria and gram-positive bacteria, and especially has better antibacterial activity on escherichia coli ATCC 25922, acinetobacter baumannii and enterococcus faecalis than that of the reference drug norfloxacin.
TABLE 3 in vitro antifungal Activity data (MIC, μ g/mL) of Pyrimidineol Compounds prepared in examples 14 to 26
As can be seen from Table 3, the pyrimidineol compounds prepared in examples 14-26 of the present invention showed certain inhibitory effect on the tested fungi, and in particular, the minimum inhibitory concentration of triazole modified pyrimidineol compound I-8 on Candida albicans ATCC 90023 was 1 μ g/mL, and the activity was better than that of the reference drug fluconazole.
Example 27 pharmaceutical use of Pyrimidineol Compounds
According to the antimicrobial activity detection result, the pyrimethanil alcohol compound has better antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicines for clinical use. The medicines can be single-ingredient preparations, for example, the medicines are prepared from pyrimidineol compounds with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the compound is prepared by the pyrimidinol compounds with one structure, the existing antibacterial and antifungal active ingredients (such as sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole and the like) and pharmaceutically acceptable auxiliary materials, or the compound is prepared by a plurality of pyrimidinol compounds with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include, but are not limited to, tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches and other dosage forms, and various sustained-release and controlled-release preparations and nano preparations.
1. Preparation of Compound I-5 tablets
Prescription: the tablet is prepared from compound I-510 g, corn starch 50g, lactose 187g, magnesium stearate 3.0g, and ethanol solution with volume percentage concentration of 70% in a proper amount, and is prepared into 1000 tablets.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-5 with lactose and corn starch, making soft mass with 70% ethanol solution, sieving to obtain wet granule, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10 mg.
2. Preparation of Compound II-4 Capsule
Prescription: compound II-425 g, modified starch (120 meshes) 12.5g, microcrystalline cellulose (100 meshes) 7.5g, low-substituted hydroxypropyl cellulose (100 meshes) 2.5g, talcum powder (100 meshes) 2.0g, sweetening agent 1.25g, orange essence 0.25g, proper amount of pigment and water, and prepared into 1000 granules.
The preparation method comprises the following steps: micronizing compound II-4 into superfine powder, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment, making into soft material with water, granulating with 12-14 mesh sieve, drying at 40-50 deg.C, sieving, grading, and making into capsule; each tablet weighs 50mg, and the content of active ingredient is 25 mg.
3. Preparation of Compound I-8 granules
Prescription: compound I-826 g, dextrin 120g and sucrose 280 g.
The preparation method comprises the following steps: mixing compound I-8, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of Compound II-2 injection
Prescription: 1000mL of the total of the compound II-210 g, 500mL of propylene glycol and 500mL of water for injection was prepared.
The preparation method comprises the following steps: weighing the compound II-2, adding propylene glycol and injection water, stirring for dissolving, adding 1g of activated carbon, fully stirring, standing for 15 minutes, filtering with a 5-micron titanium rod for decarbonization, sequentially fine-filtering with microporous filter membranes with the pore diameters of 0.45 micron and 0.22 micron, finally encapsulating in a 10mL ampoule, and sterilizing with 100 ℃ circulating steam for 45 minutes to obtain the compound II-2.
5. Preparation of compound II-1 powder injection
The preparation method comprises the following steps: and subpackaging the compound II-1 sterile powder under the aseptic condition to obtain the compound II-1.
6. Preparation of Compound I-6 eye drops
Prescription: compound I-63.78 g, sodium chloride 0.9g, appropriate amount of boric acid buffer solution, and distilled water to 1000 mL.
The preparation method comprises the following steps: weighing the compound I-6 and sodium chloride, adding into 500mL of distilled water, dissolving completely, adjusting pH to 6.5 with boric acid buffer solution, adding distilled water to 1000mL, stirring well, filtering with microporous membrane, bottling, sealing, and sterilizing with 100 deg.C flowing steam for 1 hr.
7. Preparation of compound II-3 liniment
Prescription: compound II-34 g, potassium soap 7.5g, camphor 5g, distilled water to 100 mL.
The preparation method comprises the following steps: dissolving camphor with 95 percent ethanol solution by volume percentage for later use; heating potassium soap to liquefy, weighing compound II-3, adding potassium soap solution and Camphora ethanol solution under stirring, gradually adding distilled water, emulsifying completely, and adding distilled water to full volume.
8. Preparation of suppository of compound I-5
Prescription: compound I-54 g, gelatin 14g, glycerol 70g, distilled water to 100mL, metric 100.
The preparation method comprises the following steps: weighing gelatin and glycerol, adding distilled water to 100mL, heating in water bath at 60 deg.C to melt into paste, adding compound I-5, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling for solidification.
9. Preparation of Compound I-4 ointment
Prescription: 40.5-2 g of compound I, 6-8 g of hexadecanol, 8-10 g of white vaseline, 8-19 g of liquid paraffin, 2-5 g of monoglyceride, 2-5 g of polyoxyethylene (40) stearate, 5-10 g of glycerol, 0.1g of ethylparaben and distilled water added to 100 g.
The preparation method comprises the following steps: heating cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to completely dissolve, mixing, and keeping the temperature at 80 deg.C to obtain oil phase; adding ethylparaben into glycerol and distilled water, heating to 85 deg.C for dissolving, adding oil phase under stirring, emulsifying, adding compound I-4, stirring, and cooling.
10. Preparation of compound I-3 and fluconazole compound powder injection
Prescription: 100 bottles of compound I-350 g, fluconazole 50g and sodium benzoate 1 g.
The preparation method comprises the following steps: taking the compound I-3, the fluconazole and the sodium benzoate according to the prescription amount, uniformly mixing in a sterile state, and subpackaging 100 bottles to obtain the compound I-3.
11. Preparation of Compound I-8 Aerosol
Prescription: 82.5 g of compound I, Span 203 g, 4g of talcum powder (100 meshes) and trichlorofluoromethane added to a proper amount.
The preparation method comprises the following steps: respectively drying the compound I-8, the Span20 and the talcum powder in a vacuum drying oven for several hours, cooling in a drier to room temperature, crushing into micro powder by using an air flow crusher, uniformly mixing according to the formula amount, filling into a closed container, and adding trichloromonofluoromethane to a specified amount to obtain the trichloromonofluoromethane.
Finally, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.
Claims (9)
1. The pyriconazole alcohol compound and the medicinal salt thereof are characterized in that the structure is shown as general formulas I-II:
in the formula (I), the compound is shown in the specification,
R1is hydrogen, methyl, propyl or phenyl;
R2is hydrogen, methyl or nitro;
R3is hydrogen or nitro;
R4is hydrogen or methyl;
R5is hydrogen;
R6is hydrogen or nitro;
x, Y and Z is carbon or nitrogen.
2. The pyrimidineazolol compound and the pharmaceutically acceptable salt thereof according to claim 1, which is any one of the following compounds:
3. the pyrisoxazole alcohol compounds and their pharmaceutically acceptable salts according to claim 1, which are hydrochloride, nitrate or acetate salts.
4. A process for producing pyrimidineazolol compounds and pharmaceutically acceptable salts thereof according to any of claims 1 to 3, which comprises the steps of:
a. preparing intermediates III-1-9: 2, 4-dichloropyrimidine and azole compounds are used as starting materials, and are subjected to substitution reaction under the action of alkali to obtain intermediates III-1-9;
b. preparing an intermediate IV-1-4: 2, 4-dichloropyrimidine and azole compounds are used as starting materials, and an intermediate IV-1-4 is obtained through substitution reaction under the action of alkali;
c. preparation of pyrimidineol compounds represented by general formula I: carrying out nucleophilic substitution reaction on the intermediate III-1-9 and diethanol amine to obtain a pyrimidinazolol compound shown in the general formula I;
d. preparation of pyrimidineol compounds of formula II: and carrying out nucleophilic substitution reaction on the intermediate IV-1-4 and diethanol amine to obtain the pyrimidineol compound shown in the general formula II.
5. The method of claim 4,
in the step a, the molar ratio of the 2, 4-dichloropyrimidine to the azole compound to the base is 1:1.2: 1.5; the alkali is potassium carbonate; the substitution reaction is carried out for 11 hours at 50 ℃ by taking acetonitrile as a solvent;
in the step b, the molar ratio of the 2, 4-dichloropyrimidine to the azole compound to the alkali is 1:1.2: 1.5; the alkali is potassium carbonate; the substitution reaction is carried out for 11 hours at 50 ℃ by taking acetonitrile as a solvent;
in the step c, the molar ratio of the intermediate III-1-9 to diethanolamine is 1: 1.5; the nucleophilic substitution reaction is carried out for 5 hours at 80 ℃ by taking acetonitrile as a solvent;
the molar ratio of the intermediate IV to the diethanol amine in the step d is 1: 1.5; the nucleophilic substitution reaction is carried out for 5 hours at 80 ℃ by taking acetonitrile as a solvent.
6. Use of the pyrimidineazolol compounds according to any of claims 1 to 3 and their pharmaceutically acceptable salts for the preparation of antibacterial and/or antifungal medicaments.
7. The use of claim 6, wherein the bacteria is one or more of enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa or acinetobacter baumannii; the fungi is one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 22019.
8. A preparation comprising the pyrimidineol compound according to any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof.
9. The preparation of claim 8, wherein the preparation is one of a tablet, a capsule, a granule, an injection, a powder injection, an eye drop, a liniment, a suppository, an ointment or an aerosol.
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|---|---|---|---|---|
| DE2202385A1 (en) * | 1972-01-19 | 1973-07-26 | Boehringer Mannheim Gmbh | Nitrofuryl-pyrimidines and -1,2,4-thiadiazoles - - with antimicrobial activity |
| WO2003101442A1 (en) * | 2002-05-31 | 2003-12-11 | Smithkline Beecham Corporation | Peptide deformylase inhibitors |
| CN1633294A (en) * | 2001-08-13 | 2005-06-29 | 詹森药业有限公司 | 2,4,5-trisubstituded thiazolyl derivatives and their antiinflammatory activity |
| CN109851611A (en) * | 2018-12-29 | 2019-06-07 | 西南大学 | Sulphadiazine class compound and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2202385A1 (en) * | 1972-01-19 | 1973-07-26 | Boehringer Mannheim Gmbh | Nitrofuryl-pyrimidines and -1,2,4-thiadiazoles - - with antimicrobial activity |
| CN1633294A (en) * | 2001-08-13 | 2005-06-29 | 詹森药业有限公司 | 2,4,5-trisubstituded thiazolyl derivatives and their antiinflammatory activity |
| WO2003101442A1 (en) * | 2002-05-31 | 2003-12-11 | Smithkline Beecham Corporation | Peptide deformylase inhibitors |
| CN109851611A (en) * | 2018-12-29 | 2019-06-07 | 西南大学 | Sulphadiazine class compound and its preparation method and application |
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