CN104788473B - A kind of compound with antibacterial ability and preparation method thereof and purposes - Google Patents
A kind of compound with antibacterial ability and preparation method thereof and purposes Download PDFInfo
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- CN104788473B CN104788473B CN201510132552.2A CN201510132552A CN104788473B CN 104788473 B CN104788473 B CN 104788473B CN 201510132552 A CN201510132552 A CN 201510132552A CN 104788473 B CN104788473 B CN 104788473B
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses 3 aryl, the 6 aryl 7H thiazoles simultaneously application of [3,2 b] 1,2,4 triazine, 7 ketones derivant in antibacterials of formula I：Wherein R1, R2Independently for methyl, halogen, hydroxyl, methoxyl group, acetyl group, propiono, formylphenyl, benzamido group formyl ylmethoxy, 4 toluidine formyl ylmethoxies or 4 chloroanilino formyl ylmethoxies.The compound of the present invention has obvious inhibitory action to various bacterias such as methicillin-resistant Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosas, can be used to prepare antibacterials.
Description
Technical field
The present invention relates to chemical pharmaceutical technical field, more particularly to 3- aryl-6s-aryl -7H- thiazoles simultaneously [3,2-b] -1,
2,4- triazine -7- ketones derivants and their applications in antibacterials are prepared.
Background technology
Since the forties in 20th century, penicillin was applied to clinic, antibiotic has saved the life of countless people, penicillin
Also therefore become 20th century mankind greatest find one of, and started antibiotic research new era, emerged in large numbers cephalo bacterium
Polytype antibiotic such as element, quinolones, macrolides, aminoglycoside.Really we to have species so numerous
Many antimicrobials, but the abuse with antibiotic, the resistance problems of bacterium also become increasingly conspicuous.In fact, nearly all antibiotic
The challenge of corresponding antibody-resistant bacterium has all been met with.There are to penicillin the pneumonia streptococcus of drug resistance from New Grinea discoveries in 1967
Since bacterium, multiple drug-resistant bacteria is clinically had discovered that, including methicillin-resistant staphylococcus aureus, super wide spectrum beta-lactam
Enzyme producing strains, vancomycin-resistant enterococcus, AmpC enzymes and metallo-β-lactamase producing strains and multiple drug resistant M bacillus
Deng.The particularly discovery of superbacteria NDM-1 in 2010, allows drug-resistant bacteria to cause the shock of global range again and fear
Unbearably.The appearance of these antibody-resistant bacterium makes the effective clinical application of existing antibacterials occur in that crisis.Therefore, in order to ensure from now on
Still there are operational effective antibacterials, especially for the active drug of antibody-resistant bacterium, explore and have new, activity is more
High antibacterials are significant.
Content of the invention
It is an object of the invention to provide a kind of 3- aryl-6s-aryl -7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7-
The application of ketones derivant, the especially compound on antibacterials are prepared.
The above-mentioned purpose of the present invention is achieved by the following technical solution：
A kind of compound with antibacterial ability, the compound be 3- aryl-6s-aryl -7H- thiazoles with formula I simultaneously
[3,2-b] -1,2,4- triazine -7- ketones derivants or its pharmaceutically acceptable hydrate, salt, including its stereoisomer or mutually
Tautomeric；
R in Formulas I1, R2Independently for methyl, halogen, hydroxyl, methoxyl group, acetyl group, propiono, formylphenyl,
Benzamido group formyl ylmethoxy, 4- toluidine formyl ylmethoxies or 4- chloroanilino formyl ylmethoxies.
As a preferred technical solution of the present invention, R1For hydroxyl.
As a preferred technical solution of the present invention, R2For acetyl group.
As a preferred technical solution of the present invention, R2For propiono.
As a preferred technical solution of the present invention, R2For formylphenyl.
As a preferred technical solution of the present invention, R2For benzamido group formyl ylmethoxy.
Present invention also offers above-claimed cpd is used for the purposes for preparing antibacterials.
" pharmaceutically acceptable salt " refers to the biopotency and property for remaining type I compound, and with suitable non-toxic
Conventional acid addition salts or base addition salts that organic or inorganic acid or organic or inorganic alkali are formed.The example of acid-addition salts includes acetic acid
Salt, adipate, alginates, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphor
Hydrochlorate, camsilate, cipionate, digluconate, lauryl sulfate, esilate, fumarate, Portugal heptan
Sugar lime, glycerophosphate, Hemisulphate, enanthate, caproate, hydrogen chlorate, hydrobromate, hydriodate, 2- hydroxyl second
Sulfonate, lactate, maleate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oxalates, pamoate, pectin ester
Hydrochlorate, persulfate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfate, tartrate,
Rhodanate, toluene fulfonate and undecylate.Alkali salt includes ammonium salt, alkali metal salt, such as sodium and sylvite, alkali salt,
Such as calcium and magnesium salts, the such as salt of organic base, dicyclohexyl amine salt, N- methyl-D-glucamine salts, and the salt of amino acid, such as essence
Propylhomoserin, lysine etc., and, Basic nitrogen-containing groups can be quaternized with such reagent, such as elementary alkyl halide, such as first
The chlorine of base, ethyl, propyl group and butyl, bromine and iodide；Dialkyl sulfate, such as dimethyl suflfate, diethylester, dibutyl ester and two
Pentyl ester；The chlorine of long chain halide, such as decyl, lauryl, myristyl and stearyl, bromine and iodide；Aralkyl halide,
Such as bromide of benzyl and phenethyl etc..The acid for being preferred for generating acid-addition salts includes hydrochloric acid and acetic acid.
Present invention also offers the preparation method of above-mentioned compound of Formula I, the method sees below formula.
Present invention also offers application of the above-mentioned compound of Formula I in antibacterials are prepared.
Structure and the preparation of above-claimed cpd are studied and illustrated to present system, especially ground-breaking explore its
Purposes in terms of preparation antibacterials, provides brand-new direction and wide platform for developing novel antibacterial medicine.
Specific embodiment
Embodiment 1
The preparation of 2- methyl -4- (4- acetoxyl group benzals) oxazolone
By 0.1 mol of parahydroxyben-zaldehyde, 0.13 mol of acetoglycocoll, 50 g of anhydrous sodium acetate 0.12mol and aceticanhydride
It is added sequentially in the three-necked bottle of 100 mL, 90 DEG C of temperature control, 5 h of stirring reaction, after being cooled to room temperature, solution becomes solid, suction filtration,
Filter cake is washed with cold water, obtains 24.5 g of yellow powder, yield 100%, ESI-MS (m/z) after filtration cakes torrefaction: 246.2.
Embodiment 2
Thio -1,2,4- the triazines -5 (2 of 3,4- dihydro -6- (4- hydroxybenzyls) -3-H) -one preparation
By 2- methyl -4- (4- acetoxyl group benzals) oxazolone（0.1mol, 24.5g）, KOH (11.2g) is mixed in
In 500ml water, heating water bath makes its 6 hour that flow back, reactant liquor become limpid, be subsequently adding thiosemicarbazides（0.12mol,
9g）, mixture reacts 4.5h, and reactant liquor adjusts acid-base value with acetic acid afterwards so as to which pH is 4, separates out solid, and suction filtration is yellowly dry
15.7 grams of color powder, yield 66.8%, ESI-MS (m/z): 236.1 (M+H)+.
Embodiment 3
3- (4- acetylphenyls) -6- (4- hydroxybenzyls) -7H- thiazole simultaneously [3,2-b] -1,2,4- triazines -7- ketone (L1)
Preparation
By thio for 3,4- dihydro -6- (4- hydroxybenzyls) -3- -1,2,4- triazines -5 (2H) 0.01 mol of -one, 4- acetyl
0.01 mol of base-alpha-chloro acetophenone adds 50 mL glacial acetic acid, stirring 26 h of lower back flow reaction, TLC to monitor after the completion of reacting,
It is cooled to room temperature, reactant liquor separates out solid gradually, suction filtration, and after water washing, ethyl alcohol recrystallization obtains 2.12 grams of white crystal, receives
Rate 56.23%,
1H-NMR (600 MHz, DMSO-d 6 ): δ 10.01 (1H, s), 7.48 (2H, d,J= 8.4Hz),
7.33 (1H, s), 7.21 (2H, d,J= 8.4Hz), 6.87 (2H, d,J= 8.4Hz), 6.80 (2H, d,J= 8.4Hz), 3.91 (2H, s), 2.76 (3H, s); ESI-MS (m/z): 378.0 (M+H)+.
Embodiment 4
3- (4- propionylphenyls) -6- (4- hydroxybenzyls) -7H- thiazole simultaneously [3,2-b] -1,2,4- triazines -7- ketone (L2)
Preparation
By thio for 3,4- dihydro -6- (4- hydroxybenzyls) -3- -1,2,4- triazines -5 (2H) 0.01 mol of -one, 4- propionyl
0.01 mol of base-alpha-chloro acetophenone adds 50 mL glacial acetic acid, stirring 26 h of lower back flow reaction, TLC to monitor after the completion of reacting,
It is cooled to room temperature, reactant liquor separates out solid gradually, suction filtration, and after water washing, ethyl alcohol recrystallization obtains 2.43 grams of white crystal, receives
Rate 62.15%.
1H-NMR (600 MHz, DMSO-d 6 ): δ 9.98 (1H, s), 7.47 (2H, d,J= 8.4Hz),
7.32 (1H, s), 7.22 (2H, d,J= 8.4Hz), 6.89 (2H, d,J= 8.4Hz), 6.82 (2H, d,J= 8.4Hz), 3.90 (2H, s), 3.54 (2H, m), 1.18 (3H, t); ESI-MS (m/z): 392.0 (M+
H)+.
Embodiment 5
3- (4- benzoylphenyls) -6- (4- hydroxybenzyls) -7H- thiazole simultaneously [3,2-b] -1,2,4- triazine -7- ketone
(L3) preparation
By thio for 3,4- dihydro -6- (4- hydroxybenzyls) -3- -1,2,4- triazines -5 (2H) 0.01 mol of -one, 4- benzoyls
0.01 mol of base-alpha-chloro acetophenone adds 50 mL glacial acetic acid, stirring 26 h of lower back flow reaction, TLC to monitor after the completion of reacting,
It is cooled to room temperature, reactant liquor separates out solid gradually, suction filtration, and after water washing, ethyl alcohol recrystallization obtains 3.21 grams of white crystal, receives
Rate 73.12%.
1H-NMR (600 MHz, DMSO-d 6 ): δ 9.80 (1H, s), 7.33-7.58 (7H, m), 7.30
(1H, s), 7.21 (2H, d,J= 8.4Hz), 6.87 (2H, d,J= 8.4Hz), 6.81 (2H, d,J=
8.4Hz), 3.90 (2H, s); ESI-MS (m/z): 440.2 (M+H)+.
Embodiment 6
3- (4- benzamido group formoxyl methoxyphenyls) -6- (4- hydroxybenzyls) -7H- thiazole simultaneously [3,2-b] -1,2,4- three
The preparation of piperazine -7- ketone (L4)
By thio for 3,4- dihydro -6- (4- hydroxybenzyls) -3- -1,2,4- triazines -5 (2H) 0.01 mol of -one, 4- benzamido groups
Formyl ylmethoxy -0.01 mol of alpha-chloro acetophenone adds 50 mL glacial acetic acid, and lower 26 h of back flow reaction of stirring, TLC monitorings are anti-
Should after the completion of, be cooled to room temperature, reactant liquor separates out solid gradually, suction filtration, and after water washing, ethyl alcohol recrystallization obtains white crystal
3.02 grams, yield 62.40%.1H-NMR (600 MHz, DMSO-d 6 ):δ 9.80 (1H, s), 8.72 (1H, t), 7.61
(2H, d,J=8.4Hz), 7.42 (1H, s), 7.22 ~ 7.32 (5H, s), 7.21 (2H, d,J= 8.4Hz),
7.03 (2H, d,J= 9.0Hz), 6.86 (2H, d,J= 9.0Hz), , .64 (2H, s), 4.36 (2H,
d), 3.89 (2H, s)；ESI-MS (m/z): 485.3.
Embodiment 7
3- [4- (4- toluidines) formoxyl methoxyphenyl] -6- (4- hydroxybenzyls) -7H- thiazole simultaneously [3,2-b]-
The preparation of 1,2,4- triazines -7- ketone (L5)
By thio for 3,4- dihydro -6- (4- hydroxybenzyls) -3- -1,2,4- triazines -5 (2H) 0.01 mol of -one, 4- (4- first
Base anilino-) formyl ylmethoxy -0.01 mol of alpha-chloro acetophenone, 50 mL glacial acetic acid of addition, stirring 26 h of lower back flow reaction,
After the completion of TLC monitoring reactions, room temperature is cooled to, reactant liquor separates out solid gradually, suction filtration, and after water washing, ethyl alcohol recrystallization is obtained
3.22 grams of white crystal, yield 66.53%.1H-NMR (600 MHz, DMSO-d 6 ): δ 10.06 (1H, s), 9.80
(1H, s), 7.61 (2H, d,J= 8.4Hz), 7.53 (2H, d,J= 8.4Hz ), 7.42 (1H, s), 7.40
(2H, d,J= 8.4Hz), 7.13 (2H, d,J= 8.4Hz), 7.05 (2H, d,J= 8.4Hz), 6.86
(2H, d,J= 8.4Hz) , 4.77 (2H, s), 3.89 (2H, s), 2.26 (3H, s); ESI-MS (m/z):
485.3 (M+H)+.
Embodiment 8
3- [4- (4- chloroanilinos) formoxyl methoxyphenyl] -6- (4- hydroxybenzyls) -7H- thiazole simultaneously [3,2-b]-
The preparation of 1,2,4- triazines -7- ketone (L6)
By thio for 3,4- dihydro -6- (4- hydroxybenzyls) -3- -1,2,4- triazines -5 (2H) 0.01 mol of -one, 4- (4- chlorine
Anilino-) formyl ylmethoxy -0.01 mol of alpha-chloro acetophenone, 50 mL glacial acetic acid of addition, stirring 26 h of lower back flow reaction,
After the completion of TLC monitoring reactions, room temperature is cooled to, reactant liquor separates out solid gradually, suction filtration, and after water washing, ethyl alcohol recrystallization is obtained
3.47 grams of white crystal, yield 68.85%.1H-NMR (600 MHz, DMSO-d 6 ): δ 10.30 (1H, s), 10.01
(1H, s), 7.69 (2H, d,J= 8.4Hz), 7.62 (2H, d,J= 8.4Hz ), 7.42 (1H, s), 7.40
(2H, d,J= 8.4Hz), 7.20 (2H, d,J= 8.4Hz), 7.05 (2H, d,J= 8.4Hz), 6.86
(2H, d,J= 8.4Hz) , 4.80 (2H, s), 3.90 (2H, s); ESI-MS (m/z): 505.2 (M+H)+.
Embodiment 9
Minimal inhibitory concentration（MIC）Experiment
Method：Testing compound is dissolved in dimethyl sulfoxide (DMSO), in 96 hole microtiter plates, adds appropriate meat soup
Nutrient solution, takes appropriate compound DMSO solution and is added drop-wise to 96 hole microtiter plates, to produce from the 64 μ g/ of μ g/mL to 0.0625
The concentration range of mL, is finally inoculated with a certain amount of bacterium solution (bacterial turbidity is 0.5 Maxwell), through 37 DEG C of incubated 22h, determines and inhale
Luminosity, reads the minimum inhibitory concentration (MIC) of compound.
As a result：Experiment shows that the above-claimed cpd L1 of the present invention, L2, L3, L4, L5 and L6 are respectively provided with good antibacterial and live
Property, the minimal inhibitory concentration data to different bacterium are as shown in the table：
Claims (2)
1. a kind of compound with antibacterial ability, it is characterised in that：The compound is the 3- aryl-6-aryl-with formula I
7H- thiazoles simultaneously [3,2-b] -1,2,4- triazine -7- ketones derivants；
R in Formulas I1For hydroxyl, R2For acetyl group, propiono, benzoyl or benzamido group formyl ylmethoxy.
2. the compound described in claim 1 is used for the purposes for preparing antibacterials.
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| CN105622637B (en) * | 2016-03-10 | 2018-09-25 | 沈阳药科大学 | Thiazole simultaneously [3,2-b] -1,2,4- triazine -2- carboxylic acid derivates and its preparation method and application |
| CN105601649B (en) * | 2016-03-10 | 2018-09-28 | 沈阳药科大学 | Thiazole simultaneously [3,2-b] -1,2,4- triazine -3- acetogenins and its application |
| CN105884802B (en) * | 2016-03-10 | 2017-12-15 | 沈阳药科大学 | Thiazole simultaneously [3,2 b] 1,2,4 triazine derivatives and its application |
| CN115197244B (en) * | 2022-09-03 | 2023-07-07 | 石家庄学院 | [1,2,4] triazino [3,2-b ] [1,3,5] thiadiazine derivatives and application thereof |
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| NZ186511A (en) * | 1977-03-19 | 1980-11-14 | Smith Kline French Lab | 3-substituted alkylamino-6-substituted alkyl-1,2,4-triazin-5-ones and pharmaceutical compositions 3-substituted thio-1,2,4-triazin-5-ones |
| JP2011522024A (en) * | 2008-06-04 | 2011-07-28 | アストラゼネカ アクチボラグ | Thiazolo [5,4-B] pyridine and oxazolo [5,4-B] pyridine derivatives as antibacterial agents |
| CN101503414B (en) * | 2009-03-04 | 2013-10-30 | 沈阳药科大学 | Thiazolo[3,2-b]-1,2,4-triazine derivative and use thereof |
| CN103012438B (en) * | 2012-11-15 | 2015-10-14 | 沈阳药科大学 | The thiazole that alkoxyl group replaces is [3,2-b]-1,2,4-pyrrolotriazine derivatives and application thereof also |
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