CN110013483A - Thiazole simultaneously [3,2-a] pyrimidine -6- 6-carbonitrile derivatives be used for antibacterial purposes - Google Patents

Thiazole simultaneously [3,2-a] pyrimidine -6- 6-carbonitrile derivatives be used for antibacterial purposes Download PDF

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CN110013483A
CN110013483A CN201910392457.4A CN201910392457A CN110013483A CN 110013483 A CN110013483 A CN 110013483A CN 201910392457 A CN201910392457 A CN 201910392457A CN 110013483 A CN110013483 A CN 110013483A
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amino
pyrimidine
infection
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CN110013483B (en
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苑睿
任璇璇
张鹏
陈雯
周杭
宛瑜
吴翚
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Jiangsu Normal University
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Abstract

The invention belongs to medical fields, more particularly to compound of formula I, simultaneously [3,2-a] pyrimidine -6- 6-carbonitrile derivatives are used for the purposes of antibacterial to thiazole, compound provided by the invention has bacteriostasis to methicillin-resistant staphylococcus aureus, and the compound has inhibiting effect to five kinds of cell strains；

Description

Thiazole simultaneously [3,2-a] pyrimidine -6- 6-carbonitrile derivatives be used for antibacterial purposes
Technical field
The invention belongs to medical fields, and in particular to thiazole simultaneously [3,2-a] pyrimidine -6- 6-carbonitrile derivatives be used for antibacterial use On the way.
Background technique
Gram positive bacterial infection is common disease and frequently-occurring disease, endangers human health, in recent years gram-positive bacteria sense Increasing day by day is contaminated, methicillin-resistant staphylococcus aureus (MRSA) recall rate rises, penicillin resistance pneumococcus (PRSP) It is propagated in many countries and regions, the vancomycin-resistant enterococcus (VRE) of resistance to glycopeptide and other Multiple Classes of Antibiotics occurs, and also indicates The last line of defense of antibacterials be broken, therefore, the newtype drug of research and development treatment gram positive bacteria infection is As the task of top priority.
Summary of the invention
The purpose of the present invention is to provide a kind of thiazole simultaneously [3,2-a] pyrimidine -6- 6-carbonitrile derivatives be used for antibacterial purposes.
The present invention provides Formulas I compound represented and its pharmaceutically acceptable salt in the drug of preparation treatment antibacterial agent Application:
Wherein, R1For halogen, nitro, cyano is replaced or unsubstituted C by one or more halogens, hydroxyl, amino1-5 Alkyl, replaced or unsubstituted C by one or more halogens, hydroxyl, amino1-5Alkoxy；
R2For halogen, cyano is replaced or unsubstituted C by one or more halogens, hydroxyl, amino1-5Alkyl, quilt One or more halogens, hydroxyl, amino replaces or unsubstituted C1-5Alkoxy.
In the compound shown in above-mentioned Formulas I, wherein the C1-5Alkyl be selected from methyl, ethyl, propyl, butyl or penta Base；The C1-5Alkoxy be selected from methoxyl group, ethyoxyl, propoxyl group, butoxy or amoxy.
In the compound shown in above-mentioned Formulas I, wherein the halogen is selected from fluorine, chlorine, bromine or iodine.
In the compound shown in above-mentioned Formulas I, wherein the R1For methyl, chlorine, cyano, bromine, nitro, methoxyl group；R1For Methyl, chlorine, cyano, bromine, methoxyl group.
In the further preferred example scheme of the present invention, the C1-5Alkyl be selected from n-propyl (n-Pr ,- CH2CH2CH3) or isopropyl ((i-Pr ,-CH (CH3)2)；The butyl is selected from normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl Base (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3) or tert-butyl (t-Bu ,-C (CH3)3)；Described penta Base is selected from n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- Methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1-butyl (- CH2CH2CH(CH3)2) or 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3)。
In the further preferred example scheme of the present invention, the C1-5Alkoxy be selected from methoxyl group (MeO ,-OCH3)、 Ethyoxyl (EtO ,-OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (the third oxygen of i-PrO, i- Base ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- Butoxy ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t-BuO, t- butoxy ,-OC (CH3)3), 1- amoxy (n- amoxy ,-OCH2CH2CH2CH2CH3), 2- amoxy (- OCH (CH3)CH2CH2CH3), 3- amoxy (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl- 2- butoxy (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3)。
In the preferred example scheme of the present invention, the C1-5Alkyl preferably be selected from C1-3Alkyl, the C1-3Alkyl Selected from methyl, ethyl, n-propyl (n-Pr ,-CH2CH2CH3) or isopropyl ((i-Pr ,-CH (CH3)2)。
In the preferred example scheme of the present invention, the C1-5Alkoxy preferably be selected from C1-3Alkoxy, the C1-3's Alkoxy is selected from methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,-OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,- OCH2CH2CH3) or 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2)。
In currently preferred other embodiments scheme, the example compound of the Formulas I compound represented is as follows:
The present invention further provides the pharmaceutical salt of Formulas I compound represented, enantiomter, the pharmaceutical salt Selected from hydrochloride, hydrobromate, hydriodate, nitrate, sulfate, disulfate, phosphate, acid phosphate, acetate, Lactate, citrate, tartrate, maleate, fumarate, mesylate, gluconate, saccharate, benzoic acid Salt, esilate, benzene sulfonate or tosilate.
In addition, it includes therapeutically effective amount that the present invention, which provides a kind of pharmaceutical composition, such as any one of claim 1- institute Formulas I compound represented, enantiomter or its pharmaceutical salt for stating and medically acceptable carrier.
In preferred embodiment of the invention scheme, pharmaceutical composition can use one or more pharmaceutical carriers according to Conventional mode is prepared.Therefore, reactive compound of the invention can be formulated into oral, buccal administration, it is intranasal, The dosage form of parenteral (such as intravenous, intramuscular or subcutaneous) or rectally, or suitable for by sucking or being blown into administration Dosage form.The compound of the present invention can also be formulated into the dosage form of sustained release.
In preferred embodiment of the invention scheme, the compounds of this invention of effective dose can with such as inert diluent or certain Carrier takes orally together.According to some embodiments of the present invention, the compound of the present invention can be wrapped in gelatine capsule or is suppressed In flakes.For the purpose of oral medication, the compounds of this invention can be used together with excipient and with tablet, pastille, capsule, suspension The forms such as agent, syrup use.According to an embodiment of the invention, above-mentioned preparation should contain the of the invention of at least 0.5% (w/w) Reactive compound, but can be changed according to specific dosage form, wherein it is convenient for accounting for the 4% to about 70% of Unit Weight.In this way Pharmaceutical composition in the amount of reactive compound should reach dosage appropriate.
Formulas I compound represented, enantiomter or its pharmaceutical salt provided by the invention or the pharmaceutical composition Purposes of the object in preparation treatment antibacterials.
On the other hand, the present invention provides a kind of preparation formula I compound represented, enantiomter or its pharmaceutical salt Preparation method, this method comprises: alpha-brominated acetophenone is reacted with the addition of thiocarbamide, malononitrile, aromatic aldehyde, catalyst 2a and ethyl alcohol In container, sufficiently react at 80 DEG C to complete, preparation of compounds of formula I；Reaction equation is as follows:
The beneficial technical effect of the present invention
Compound provided by the invention has bacteriostasis to methicillin-resistant staphylococcus aureus, and the compound is to five Kind cell strain has inhibiting effect, wherein 22 pairs of methicillin-resistant staphylococcus aureus have good inhibiting effect, especially There is extraordinary inhibitory effect to 18H6,18I1, MIC, if continuing to study its antimicrobial mechanism, is expected to it in 5 μ g/mL Development is the novel drugs of methicillin-resistant staphylococcus aureus.
Embodiment
The embodiment of the present invention is described below in detail.The embodiments described below is exemplary, and is only used for explaining this hair It is bright, and be not considered as limiting the invention.Unless otherwise specified, ratio as referred to herein, percentage etc. are by weight.
Embodiment 1:5,12- dimethyl -3,10- diphenyl-dimethyl -1H- pyrazolo [b, f] [4,5] -1,5- phenodiazine Miscellaneous two rings [3.3.1] -2,6- octadiene (1)
In dry 250mL three-neck flask be added pyridine (0.5mol, 39.5g), n-butyl bromide (0.55mol, 68g) and 60mL methylene chloride is first heated to 60 DEG C, and boiling lifts, and raises the temperature to 80 after preventing bumping, solution from not boiling℃, heating Flow back 5~6 hours until the reaction is complete.Then sodium tetrafluoroborate (0.5mol, 55g) is added in the system, exchanges anion, It is heated to reflux at a temperature of 80 DEG C 12 hours, filters, washed with methylene chloride, filtrate decompression is distilled, remove methylene chloride, Golden yellow ionic liquid [Bpy] BF can be obtained4。
1mL ionic liquid [Bpy] BF is added in 25mL round-bottomed flask4, 1mmol3- methyl-1-phenyl-1H- pyrazoles-5- Amine, 0.5mL formalin (30%) and 1mL trifluoroacetic acid stir 5~7 hours at room temperature, after reaction terminates (TLC tracking) 10mL distilled water is added, mixture is filtered, washs, it is dry, crude product is obtained, after weighing and calculating yield, with dehydrated alcohol weight Crystallization obtains pure product 2a: white solid, fusing point: 266-267 DEG C of1H NMR(400MHz,CDCl3)δ7.95-7.97(d, J=8.4Hz, 4H) .7.49-7.53 (m, 4H), 7.30-7.32 (t, J=8.0Hz, 2H), 4.24-4.32 (t, J=7.2Hz, 4H), 3.59 (d, J=15.6Hz, 2H), 1.97 (s, 6H)13C NMR(100MHz,CDCl3)δ145.4,145.1,139.4, 129.2,125.9,120.8,104.3,68.5,48.1,12.5.HRMS(ESI)m/z[M+H]+Calculated value C23H22N6: 383.1984；Experiment value: 383.1969.
Embodiment 2,5- amino -3- (4- methoxyphenyl) -7- (p- tolyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- Formonitrile HCN (2)
Reaction equation (1)
By 4- methoxyl group-bromoacetophenone (1mmol), thiocarbamide (1.5mmol), malononitrile (2mmol), p-tolyl aldehyde (1mmol), catalyst 2a (20mmol%) and ethyl alcohol (5mL) sequentially add in 50mL round-bottomed flask, sufficiently reacted at 80 DEG C to (TLC tracking and monitoring) completely.It is cooled to room temperature, is extracted with dichloromethane, collect organic phase, through anhydrous Na2SO4Dry, decompression is steamed It evaporates, the product (V of column chromatographic purifyingMethylene chloride: VMethanol=80:1).Obtain target product 5- amino -3- (4- methoxyphenyl) -7- (p- tolyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN: white solid .108.6-109.4 DEG C of fusing point,1H NMR (400MHz, DMSO) δ 7.43-7.30 (m, 4H), 7.25 (d, J=8.1Hz, 4H), 6.97 (t, J=12.3Hz, 2H), 5.64 (d, J=8.0Hz, 1H), 5.06 (d, J=8.0Hz, 1H), 3.74 (s, J=35.8Hz, 3H), 2.31 (s, 3H)13C NMR (101MHz,)δ167.39,159.45,150.22,138.09,135.60,130.30,130.14,127.96,127.58, (115.09,114.35,55.66,44.25,30.74,21.16.HRMS ESI) m/z: calculated value C21H19N4OS[M+H]+: 375.1280；Experiment value: 375.7574
Embodiment 3,5- amino -7- (4- chlorphenyl) -3- (4- methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- Formonitrile HCN (3)
P-tolyl aldehyde is replaced with 4- chlorobenzaldehyde, prepares target compound 5- amino -7- as described in Example 1 (4- chlorphenyl) -3- (4- methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (3).
Gray solid, fusing point: 103.2-104.5 DEG C,1H NMR (400MHz, DMSO) δ 7.51 (dd, J=26.8, 8.0Hz, 4H), 7.33 (d, J=6.2Hz, 4H), 6.99 (d, J=8.2Hz, 2H), 5.68 (d, J=7.9Hz, 1H), 5.17 (d, J=16.1Hz, 1H), 3.78 (s, 3H)13C NMR(101MHz,)δ167.52,159.51,150.71,137.60,133.48, 130.31,130.06,129.62,127.45,114.38,114.18,113.75,113.59,55.66,43.81, 30.69.HRMS (ESI) m/z: calculated value C20H15ClN4OS[M+H]+:395.0733；Experiment value: 395.0728.
Embodiment 4,5- amino -7- (4- cyano-phenyl) -3- (4- methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine - 6- formonitrile HCN (4)
P-tolyl aldehyde is replaced with to cyanobenzaldehyde, prepares target compound 5- amino -7- as described in Example 1 (4- cyano-phenyl) -3- (4- methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (4)
Yellow solid, fusing point: 112.4-113.2 DEG C,1H NMR(400MHz,CDCl3) δ 7.69 (d, J=7.9Hz, 2H), 7.47 (d, J=7.8Hz, 2H), 7.23 (d, J=8.2Hz, 2H), 6.90 (d, J=7.8Hz, 2H), 5.28 (s, 2H), 4.89 (d, J=8.2Hz, 1H), 4.13 (d, J=7.6Hz, 1H), 3.79 (s, 3H)13C NMR(101MHz,DMSO)δ167.64, 159.52,143.73,133.51,130.30,129.14,127.02,118.82,114.34,113.76,113.54,113.34, (111.58,55.61,55.35,44.08,30.27.HRMS ESI) m/z: calculated value C21H15N5OS[M+H]+:386.1076；It is real Test value: 386.1072
Bis- (4- the methoxyphenyl) -7H- thiazoles of embodiment 5,5- amino -3,7- simultaneously use by [3,2-a] pyrimidine -6- formonitrile HCN (5) P-methoxybenzal-dehyde replaces p-tolyl aldehyde, prepares the bis- (4- of target compound 5- amino -3,7- as described in Example 1 Methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (5)
Yellow solid, fusing point: 99.6-100.5 DEG C,1H NMR(400MHz,CDCl3)δ7.36–7.23(m,4H),6.90 (m, J=6.3Hz, 4H), 5.48 (s, 2H), 4.80 (d, J=8.0Hz, 1H), 4.08 (d, J=7.8Hz, 1H), 3.78 (d, J= 10.8Hz,6H).13C NMR(101MHz,DMSO)δ167.23,159.35,149.95,130.37,130.20,129.27, 127.51,115.17,114.83,114.27,113.86,113.71,55.63,55.59,43.80,30.85.HRMS(ESI)m/ Z: calculated value C21H18N4O2S[M-NH2]-:375.1041；Experiment value: 375.1208
Embodiment 6,5- amino -7- (4- bromophenyl) -3- (4- methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- Formonitrile HCN (6)
P-tolyl aldehyde is replaced with 4- bromobenzaldehyde, prepares target compound 5- amino -7- as described in Example 1 (4- bromophenyl) -3- (4- methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (6)
Gray solid, fusing point: 132.5-133.6 DEG C,1H NMR(400MHz,CDCl3) δ 7.50 (d, J=7.9Hz, 2H), 7.24 (d, J=7.6Hz, 2H), 7.20 (d, J=7.7Hz, 2H), 6.89 (d, J=8.0Hz, 2H), 5.32 (s, J=73.8Hz, 2H), 4.79 (d, J=7.8Hz, 1H), 4.08 (d, J=7.8Hz, 1H), 3.78 (s, 3H)13C NMR(101MHz,)δ 166.41,160.11,151.46,135.77,132.85,130.19,129.30,126.21,115.68,114.37,111.38, (111.27,55.47,45.22,30.66.HRMS ESI) m/z: calculated value C20H15BrN4OS[M+H]+:439.0228；Experiment value: 439.0217
Embodiment 7,5- amino -7- (4- chlorphenyl) -3- (p-methylphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (7)
4- methoxyl group-bromoacetophenone is replaced with 4- methyl-bromoacetophenone, is replaced with 4- chlorobenzaldehyde to methylbenzene first Aldehyde, prepare as described in Example 1 target compound 5- amino -7- (4- chlorphenyl) -3- (p-methylphenyl) -7H- thiazole simultaneously [3, 2-a] pyrimidine -6- formonitrile HCN (7)
Gray solid, fusing point: 114.8-115.6 DEG C,1H NMR(400MHz,CDCl3) δ 7.42 (d, J=7.5Hz, 2H), 7.34 (d, J=7.5Hz, 2H), 7.26 (dd, J=12.6,8.2Hz, 4H), 5.49 (s, 2H), 4.89 (d, J=7.5Hz, 1H), 4.14 (d, J=7.2Hz, 1H), 2.39 (d, J=15.5Hz, 3H)13C NMR(101MHz,)δ166.49,139.03, 135.23,135.20,129.88,129.65,129.03,128.77,116.21,111.36,111.26,45.08,30.73, 21.43.HRMS (ESI) m/z: calculated value C20H15ClN4S[M+H]+:379.0784；Experiment value: 379.0784
Embodiment 8,5- amino -7- (4- cyano-phenyl) -3- (p-methylphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- first Nitrile (8)
4- methoxyl group-bromoacetophenone is replaced with 4- methyl-bromoacetophenone, is replaced with 4- cyanobenzaldehyde to methylbenzene Formaldehyde prepares target compound 5- amino -7- (4- cyano-phenyl) -3- (p-methylphenyl) -7H- thiazole as described in Example 1 And [3,2-a] pyrimidine -6- formonitrile HCN (8)
Yellow solid, fusing point: 182.3-183.4 DEG C,1H NMR(400MHz,CDCl3) δ 7.68 (d, J=7.7Hz, 2H), 7.46 (d, J=7.4Hz, 2H), 7.19 (s, 4H), 5.40 (s, 2H), 4.90 (d, J=7.5Hz, 1H), 4.17 (d, J= 7.1Hz,1H),2.34(s,3H).13C NMR(101MHz,)δ167.81,143.84,137.97,133.59,129.58, 129.20,128.98,118.90,113.99,113.62,113.41,111.64,44.10,30.37,21.36.HRMS(ESI) M/z: calculated value C21H15N5S[M+H]+:370.1125；Experiment value: 370.1132
Embodiment 9,5- amino -7- (4- bromophenyl) -3- (p-methylphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (9)
4- methoxyl group-bromoacetophenone is replaced with 4- methyl-bromoacetophenone, is replaced with 4- bromobenzaldehyde to methylbenzene first Aldehyde, prepare as described in Example 1 target compound 5- amino -7- (4- bromophenyl) -3- (p-methylphenyl) -7H- thiazole simultaneously [3, 2-a] pyrimidine -6- formonitrile HCN (9)
Gray solid, fusing point: 102.5-102.9 DEG C,1H NMR(400MHz,CDCl3) δ 7.51 (d, J=7.9Hz, 2H), 7.20 (dd, J=14.1,9.1Hz, 6H), 5.21 (s, 2H), 4.81 (d, J=7.6Hz, 1H), 4.06 (d, J=7.7Hz, 1H), 2.34(s,3H).13C NMR(101MHz,)δ166.52,151.75,139.02,135.75,132.83,130.94,129.65, .44.HRMS 129.30,128.76,123.34,116.08,111.35,111.25,45.15,30.64,21 (ESI) m/z: calculating Value C20H15BrN4S[M+H]+:423.0279；Experiment value: 423.0257
Embodiment 10,5- amino -7- (3- chlorphenyl) -3- (4- chlorphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (10)
4- methoxyl group-bromoacetophenone is replaced with the chloro- bromoacetophenone of 4-, is replaced with 3- chlorobenzaldehyde to methylbenzene first Aldehyde, prepare as described in Example 1 target compound 5- amino -7- (3- chlorphenyl) -3- (4- chlorphenyl) -7H- thiazole simultaneously [3, 2-a] pyrimidine -6- formonitrile HCN (10)
Gray solid, fusing point: 113.5-114.1 DEG C,1HNMR(400MHz,CDCl3)δ7.40–7.31(m,6H),7.28 (d, J=8.5Hz, 2H), 5.34 (s, 1H), 4.75 (d, J=7.7Hz, 1H), 4.12 (d, J=7.8Hz, 1H) .HRMS (ESI) M/z: calculated value C31H31N6[M+H]+:383.0051；Experiment value: 384.3076.
Bis- (4- the chlorphenyl) -7H- thiazoles of embodiment 11,5- amino -3,7- simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (11)
4- methoxyl group-bromoacetophenone is replaced with the chloro- bromoacetophenone of 4-, is replaced with 4- chlorobenzaldehyde to methylbenzene first Aldehyde prepares bis- (4- the chlorphenyl) -7H- thiazoles of target compound 5- amino -3,7- simultaneously [3,2-a] pyrimidine-as described in Example 1 6- formonitrile HCN (11)
Yellow solid, fusing point: 92.7-94.2 DEG C,1H NMR(400MHz,CDCl3) δ 7.52 (d, J=7.7Hz, 2H), 7.35 (d, J=7.4Hz, 2H), 7.26 (d, J=7.0Hz, 2H), 7.09 (d, J=8.7Hz, 2H), 5.20 (s, 2H), 4.75 (d, J=8.2Hz, 1H), 4.08 (d, J=7.3Hz, 1H)13C NMR(101MHz,)δ166.39,135.44,135.14, 134.88,132.23,130.24,130.02,129.21,128.94,117.13,111.21,111.05,45.15,30.87, 27.00.HRMS (ESI) m/z: calculated value C16H11N6O2S[M+H]+:384.3081；Experiment value: 374.3076
Embodiment 12,5- amino -7- (4- bromophenyl) -3- (4- chlorphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (12)
4- methoxyl group-bromoacetophenone is replaced with the chloro- bromoacetophenone of 4-, is replaced with 4- bromobenzaldehyde to methylbenzene first Aldehyde, prepare as described in Example 1 target compound 5- amino -7- (4- bromophenyl) -3- (4- chlorphenyl) -7H- thiazole simultaneously [3, 2-a] pyrimidine -6- formonitrile HCN (12)
Gray solid, fusing point: 121.7-122.1 DEG C,1H NMR(400MHz,CDCl3) δ 7.70 (d, J=7.7Hz, 2H), 7.45 (d, J=7.8Hz, 2H), 7.37 (d, J=7.6Hz, 2H), 7.25 (d, J=7.8Hz, 2H), 5.22 (s, 2H), 4.84 (d, J=7.7Hz, 1H), 4.13 (d, J=7.7Hz, 1H)13C NMR(101MHz,)δ167.88,149.60,137.78, 133.84,133.19,132.57,130.85,130.36,129.06,127.75,122.17,115.94,43.58, 30.55.HRMS (ESI) m/z: calculated value C17H13N6O2S[M+H]+:442.9733；Experiment value: 442.9725
Embodiment 13,5- amino -3- (4- chlorphenyl) -7- (4- cyano-phenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- first Nitrile (13)
4- methoxyl group-bromoacetophenone is replaced with the chloro- bromoacetophenone of 4-, is replaced with 4- cyanobenzaldehyde to methylbenzene first Aldehyde, preparing target compound 5- amino -3- (4- chlorphenyl) -7- (4- cyano-phenyl) as described in Example 1, -7H- thiazole is simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (13)
Yellow solid, fusing point: 196.8-198.0 DEG C,1H NMR(400MHz,CDCl3) δ 7.70 (d, J=7.5Hz, 2H), 7.45 (d, J=7.7Hz, 2H), 7.36 (d, J=7.5Hz, 2H), 7.29-7.21 (m, 2H), 5.20 (s, 2H), 4.84 (d, J= 7.1Hz, 1H), 4.13 (d, J=7.6Hz, 1H)13C NMR(101MHz,DMSO)δ167.95,149.99,143.56, 133.65,133.54,133.16,130.82,129.14,129.00,118.81,115.13,113.52,113.29,111.62, 43.80,30.22.HRMS (ESI) m/z: calculated value C20H12ClN5S[M-H]-:388.0424；Experiment value: 388.0499
Embodiment 14,5- amino -7- (4- chlorphenyl) -3- (4- cyano-phenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- first Nitrile (14)
4- methoxyl group-bromoacetophenone is replaced with 4- cyano-bromoacetophenone, is replaced with 4- chlorobenzaldehyde to methylbenzene first Aldehyde, preparing target compound 5- amino -7- (4- chlorphenyl) -3- (4- cyano-phenyl) as described in Example 1, -7H- thiazole is simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (14)
Yellow solid, fusing point: 158.7-159.5 DEG C,1H NMR(400MHz,CDCl3) δ 7.67 (d, J=7.4Hz, 2H), 7.46 (d, J=7.6Hz, 2H), 7.39 (d, J=7.5Hz, 2H), 7.27 (d, J=7.7Hz, 2H), 5.17 (s, 2H), 4.76 (d, J=7.5Hz, 1H), 4.10 (d, J=8.0Hz, 1H) .HRMS (ESI) m/z: calculated value C20H12ClN5S[M-H]-: 388.0424；Experiment value: 388.0492
Embodiment 15,5- amino -7- (3- chlorphenyl) -3- (4- methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- Formonitrile HCN (15)
P-tolyl aldehyde is replaced with 3- chlorobenzaldehyde, prepares target compound 5- amino -7- as described in Example 1 (3- chlorphenyl) -3- (4- methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (15)
Yellow solid, fusing point: 126.1-126.5 DEG C,1H NMR(400MHz,DMSO)δ7.66(s,1H),7.58(s, 1H), 7.43 (s, 2H), 7.32 (d, J=9.0Hz, 4H), 6.99 (d, J=7.8Hz, 2H), 5.71 (d, J=8.0Hz, 1H), 5.20 (d, J=7.9Hz, 1H), 3.79 (s, 3H)13C NMR(101MHz,DMSO)δ167.07,158.91,150.35, 140.41,133.57,130.85,129.75,128.22,127.33,126.52,113.56,113.27,55.06,48.65, 43.27,30.02.HRMS (ESI) m/z: calculated value C20H15ClN4OS[M+H]+:395.0720；Experiment value: 395.0733.
Embodiment 16,5- amino -7- (3- bromophenyl) -3- (4- methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- Formonitrile HCN (16)
P-tolyl aldehyde is replaced with 3- bromobenzaldehyde, prepares target compound 5- amino -7- as described in Example 1 (3- bromophenyl) -3- (4- methoxyphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (16)
Gray solid, fusing point: 163.4-164.8 DEG C,1H NMR(400MHz,DMSO)δ7.66(s,1H),7.58(s, 1H), 7.43 (s, 2H), 7.32 (d, J=9.0Hz, 4H), 6.99 (d, J=7.8Hz, 2H), 5.71 (d, J=8.0Hz, 1H), 5.20 (d, J=7.9Hz, 1H), 3.79 (s, 3H)13C NMR(101MHz,DMSO)δ167.49,160.29,159.45, 150.75,141.08,131.72,131.65,130.62,130.25,127.37,127.27,122.66,114.32,113.84, 55.61,43.78,30.50.HRMS (ESI) m/z: calculated value C20H15BrN4OS[M+H]+:439.0228；Experiment value: 439.0217。
Embodiment 17,5- amino -7- (3- nitrobenzophenone) -3- (p-methylphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- first Nitrile (17)
4- methoxyl group-bromoacetophenone is replaced with 4- methyl-bromoacetophenone, is replaced with 3- nitrobenzaldehyde to methylbenzene Formaldehyde prepares target compound 5- amino -7- (3- nitrobenzophenone) -3- (p-methylphenyl) -7H- thiazole as described in Example 1 And [3,2-a] pyrimidine -6- formonitrile HCN (17)
Yellow solid, fusing point: 199.6-200.3 DEG C,1H NMR (400MHz, DMSO) δ 8.35 (s, 1H), 8.25 (d, J= 7.8Hz, 1H), 7.90 (d, J=7.4Hz, 1H), 7.77 (t, J=7.8Hz, 1H), 7.37 (s, 2H), 7.25 (dd, J=14.3, 7.4Hz, 4H), 5.79 (d, J=7.8Hz, 1H), 5.40 (d, J=7.7Hz, 1H), 2.34 (s, 3H)13C NMR(101MHz, DMSO it) δ 168.05,158.47,149.62,127.79,126.78,113.76,99.29,55.02.HR MS (ESI) m/z: calculates Value C20H15N5O2S[M-H]-:388.0868；Experiment value: 388.0753.
Embodiment 18,5- amino -3- (4- methoxyphenyl) -7- (3- nitrobenzophenone) -7H- thiazole simultaneously [3,2-a] pyrimidine - 6- formonitrile HCN (18)
P-tolyl aldehyde is replaced with 3- nitrobenzaldehyde, prepares target compound 5- amino -3- as described in Example 1 (4- methoxyphenyl) -7- (3- nitrobenzophenone) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (18)
Yellow solid, fusing point: 132.9-133.2 DEG C,1H NMR (400MHz, DMSO) δ 8.36 (s, 1H), 8.25 (d, J= 7.8Hz 1H), 7.90 (d, J=7.1Hz, 1H), 7.78 (t, J=7.9Hz, 1H), 7.35 (s, 2H), 7.31 (d, J=7.4Hz, 2H), 6.98 (d, J=7.5Hz, 2H), 5.80 (d, J=7.7Hz, 1H), 5.41 (d, J=7.7Hz, 1H), 3.78 (s, 3H)13C NMR(101MHz,DMSO)δ172.70,167.61,159.52,148.53,147.39,140.53,135.01,131.64, 131.25,130.29,123.77,122.82,114.34,113.56,113.17,55.62,43.63,30.60.HRMS(ESI) M/z: calculated value C20H15N5O3S[M+H]+:406.0974；Experiment value: 406.0972.
Embodiment 19,5- amino -3- (4- chlorphenyl) -7- (3- nitrobenzophenone) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- first Nitrile (19)
4- methoxyl group-bromoacetophenone is replaced with the chloro- bromoacetophenone of 4-, is replaced with 3- nitrobenzaldehyde to methylbenzene first Aldehyde, preparing target compound 5- amino -3- (4- chlorphenyl) -7- (3- nitrobenzophenone) as described in Example 1, -7H- thiazole is simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (19)
Yellow solid, fusing point: 189.3-190.5 DEG C,1H NMR(400MHz,DMSO)δ8.42–7.99(m,6H),7.80 (dd, J=20.0,12.2Hz, 2H), 7.70 (d, J=7.0Hz, 2H), 5.72 (d, J=11.1Hz, 1H), 4.53 (d, J= 11.4Hz,1H).13C NMR(101MHz,DMSO)δ167.98,150.09,148.53,140.29,135.02,133.59, 133.23,131.26,130.82,130.00,129.00,128.65,123.82,122.82,114.97,113.50,113.25, 43.44,30.54,14.33,11.23.HRMS (ESI) m/z: calculated value C20H16ClN5O2S[M+H]+:410.0478；Experiment value: 410.0472。
Embodiment 20,5- amino -7- (4- nitrobenzophenone) -3- (p-methylphenyl) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- first Nitrile (20)
4- methoxyl group-bromoacetophenone is replaced with 4- methyl-bromoacetophenone, is replaced with 4- nitrobenzaldehyde to methylbenzene Formaldehyde prepares target compound 5- amino -7- (4- nitrobenzophenone) -3- (p-methylphenyl) -7H- thiazole as described in Example 1 And [3,2-a] pyrimidine -6- formonitrile HCN (20)
Yellow solid, fusing point: 203.4-204.2 DEG C,1H NMR (400MHz, DMSO) δ 8.32 (d, J=7.5Hz, 2H), 7.71 (d, J=7.9Hz, 2H), 7.36 (s, 2H), 7.25 (d, J=8.4Hz, 4H), 5.77 (d, J=7.1Hz, 1H), 5.37 (d, J=7.9Hz, 1H), 2.34 (s, 3H)13C NMR(101MHz,DMSO)δ167.77,151.51,147.67,145.63, 137.92,132.01,129.56,129.51,128.90,124.71,113.80,113.52,113.31,43.85,30.39, 21.29.HRMS (ESI) m/z: calculated value C20H15N5O2S[M+H]+:390.1025；
Experiment value 390.1018.
Embodiment 21,5- amino -3- (4- methoxyphenyl) -7- (4- nitrobenzophenone) -7H- thiazole simultaneously [3,2-a] pyrimidine - 6- formonitrile HCN (21)
P-tolyl aldehyde is replaced with 4- nitrobenzaldehyde, prepares target compound 5- amino -3- as described in Example 1 (4- methoxyphenyl) -7- (4- nitrobenzophenone) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (21)
Yellow solid, fusing point: 205.7-206.3 DEG C,1H NMR (400MHz, DMSO) δ 8.39 (d, J=7.8Hz, 2H), 7.78 (d, J=8.5Hz, 2H), 7.44 (s, 2H), 7.38 (d, J=7.4Hz, 2H), 7.05 (d, J=7.7Hz, 2H), 5.84 (d, J=7.6Hz, 1H), 5.44 (d, J=7.6Hz, 1H), 3.85 (s, 3H)13C NMR(101MHz,DMSO)δ167.64, 159.48,151.23,147.66,145.70,130.26,129.58,127.24,124.71,114.32,113.55,113.35, (113.18,55.61,43.88,30.40.HRMS ESI) m/z: calculated value C20H15N5O3S[M+H]+:406.0974；Experiment value: 406.0972。
Embodiment 22,5- amino -3- (4- chlorphenyl) -7- (4- nitrobenzophenone) -7H- thiazole simultaneously [3,2-a] pyrimidine -6- first Nitrile (22)
4- methoxyl group-bromoacetophenone is replaced with the chloro- bromoacetophenone of 4-, is replaced with 4- nitrobenzaldehyde to methylbenzene first Aldehyde, preparing target compound-amino -3- (4- chlorphenyl) -7- (4- nitrobenzophenone) as described in Example 1, -7H- thiazole is simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (22)
Yellow solid, fusing point: 206.3-207.5 DEG C,1H NMR (400MHz, DMSO) δ 8.39 (d, J=7.5Hz, 2H), 7.77 (d, J=7.8Hz, 2H), 7.56 (d, J=7.1Hz, 4H), 7.46 (d, J=7.3Hz, 2H), 5.87 (d, J=8.1Hz, 1H), 5.49 (d, J=7.4Hz, 1H)13C NMR(101MHz,DMSO)δ167.47,149.50,147.26,133.08, (132.60,130.37,129.11,128.46,124.16,43.47,29.53.HRMS ESI) m/z: calculated value C20H16ClN5O2S [M+H]+:410.0478；Experiment value 410.0472.
23 5- amino -7- (4- chlorphenyl) -3- (p-methylphenyl) -7H- thiazole of embodiment simultaneously [3,2-a] pyrimidine -6- formonitrile HCN (23)
4- methoxyl group-bromoacetophenone is replaced with 4- methyl-bromoacetophenone, is replaced with 4- chlorobenzaldehyde to methylbenzene first Aldehyde, prepare as described in Example 1 target compound 5- amino -7- (4- chlorphenyl) -3- (p-methylphenyl) -7H- thiazole simultaneously [3, 2-a] pyrimidine -6- formonitrile HCN (23)
White solid, fusing point: 92.7-94.2oC.1H NMR (400MHz, DMSO) δ 7.50 (d, J=8.1Hz, 2H), 7.41 (d, J=8.3Hz, 2H), 7.37-7.28 (m, 4H), 7.25 (d, J=7.6Hz, 2H), 5.65 (d, J=8.3Hz, 1H), 5.11 (d, J=8.1Hz, 1H), 2.31 (s, 3H) .13C NMR (101MHz) δ 167.71,149.09,138.15,135.40, 134.00,133.06,130.82,130.16,129.03,127.94,116.92,113.88,113.69,43.90,30.69, (ESI) m/z: calculated value C20H15BrN4S [M+H] 21.17.HRMS+: 379.0784；Experiment value: 379.0713.
It is embodiment 23, novel containing polysubstituted 5- amino -3,7- diphenyl -7H- thiazole simultaneously [3,2-a] pyrimidine -6- formonitrile HCN Derivative antibacterial activity test:
The antibacterial activity of product is screened by the methicillin-resistant staphylococcus aureus being clinically separated, it is specific real Test that steps are as follows:
Product is configured to 10mg/Ml solution with methanol, 6 μ L are sucked out to new centrifuge tube, volatilizes and is left quantitatively to methanol Solid product 6 μ L DMSO and 294 μ LLuria-Bertani (LB) solution be added (guarantee the DMSO solution in final 96 orifice plate Less than 2%), the sample that product is made into 200 μ g/mL is thus diluted to 20 μ g/mL, 2 μ g/mL with LB solution again in proportion, The drug solution that 50 μ L concentration are 200 μ g/mL is added in each hole of the first row of 96 orifice plates, each hole of second row is added 50 μ L solubility and is The drug solution of 20 μ g/mL, third arrange each hole and the drug solution that 50 μ L solubility are 2 μ g/mL are added.The 50 single bacterium solutions of μ L are drawn to arrive In each hole and mix medical fluid and bacterium solution.Only add bacterium solution in one piece of 96 new orifice plate, as negative control BO；Meropenem is added With bacterium solution mixed liquor as positive control.96 orifice plates equipped with drug solution and bacterium solution are placed under microplate reader and surveys its absorbance value and is B1, put it into 37 DEG C of incubator culture 18-20h later, after survey its absorbance value B2, and calculate its inhibiting rate.
Inhibiting rate (%)=[1- (sample OD600Incrementss (B2-B1)/negative control OD600Incrementss (B2-B1))] × 100%
Minimum inhibitory concentration (MIC, μ g/mL) of 2 compound 6 of table to five kinds of bacterial strainsa
aThe label that minimum inhibitory concentration is greater than percent 50% is.
Being greater than 50% according to minimum inhibitory concentration is invalid principle, and seven compounds (4,6,9,10,12,16,22) are to resistance to Methicillin staphylococcus aureus has bacteriostasis, and seven compounds have inhibiting effect to five kinds of cell strains, wherein 22 pairs of methicillin-resistant staphylococcus aureus have good inhibiting effect, especially have extraordinary suppression to 18H6,18I1 Effect processed, MIC is in 5 μ g/mL, if continuing to study its antimicrobial mechanism, is expected to be developed as methicillin-resistant staphylococcus Portugal The novel drugs of grape coccus.

Claims (6)

1. the application of Formulas I compound represented and its pharmaceutically acceptable salt in the drug of preparation treatment antibacterial agent:
Wherein, R1For halogen, nitro, cyano is replaced or unsubstituted C by one or more halogens, hydroxyl, amino1-5Alkane Base is replaced or unsubstituted C by one or more halogens, hydroxyl, amino1-5Alkoxy；
R2For halogen, cyano is replaced or unsubstituted C by one or more halogens, hydroxyl, amino1-5Alkyl, by one or Multiple halogens, hydroxyl, amino replaces or unsubstituted C1-5Alkoxy.
2. application according to claim 1, which is characterized in that the C1-5Alkyl be selected from methyl, ethyl, propyl, butyl Or amyl；The C1-5Alkoxy be selected from methoxyl group, ethyoxyl, propoxyl group, butoxy or amoxy.
3. application according to claim 1, which is characterized in that the halogen is selected from fluorine, chlorine, bromine or iodine.
4. application according to claim 1, it is characterised in that the R1For methyl, chlorine, cyano, bromine, nitro, methoxyl group； R1For methyl, chlorine, cyano, bromine, methoxyl group.
5. application according to claim 1, which is characterized in that the Formulas I compound represented is selected from:
6. application according to claim 1 is selected from skin infection, mucous membrane sense wherein the antibacterial agent is used for bacterium infection Dye, gynecological infection, respiratory tract infection (RTI), CNS infection, alimentary infection, infection of bone, cardiovascular infections, the infection to spread through sex intercourse or Urethral infection.
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Cited By (2)

* Cited by examiner, † Cited by third party
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CN110041348A (en) * 2019-05-10 2019-07-23 江苏师范大学 Simultaneously [3,2-a] pyrimidine -6- 6-carbonitrile derivatives and its application of 5- amino -3,7- diphenyl -7H- thiazole
CN114853782A (en) * 2022-06-27 2022-08-05 潍坊医学院 Pleuromutilin derivative with pyrimidine side chain and preparation method and application thereof

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