CN102267987A - Novel fluorine-containing antibacterial compound - Google Patents

Abstract

The invention discloses a compound with a remarkable antibacterial activity. The structure of the compound is shown as a formula I. The compound plays a good role in resisting methicillin-resistant staphylococcus aureus (MRSA) and methicillin sensitive staphylococcus aureus (MSSA).

Description

A kind of fluorine-containing antibiotic compound

Technical field:

The present invention relates to a kind of compound that is used for anti-microbial effect, this compound has the excellent antibiotic activity to MRSA, MSSA.

Background technology:

In recent years, along with antibiotic widespread use (comprising humans and animals), glucocorticosteroid and the increase of immunosuppressor application and increasing of gerontal patient, lung's drug-fast bacteria infection problem becomes increasingly conspicuous.These resistant organisms are common penicillin resistant streptococcus pneumoniae, methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), produce extended spectrum (ESBL) gram-negative bacteria etc.Relevant methicillin-resistant staphylococcus aureus also is the comparison stubborn problem, year surplus since the strain MRSA that confesses one's crime detects 40, MRSA infects in rising trend always all over the world, American National ward infection monitoring (NNIS) report, 182 MRSA of hospital in 1975 account for the bacterium infection of golden Portugal and rose to 24.8% in total 2.4%, 1997 year.Ground large hospital MRSA separation rates such as capital, Shanghai all infect more than 50% of sum above golden Portugal bacterium after the domestic nineties.MRSA has multi-drug resistant, to all beta-lactam class microbiotic (comprising enzyme-containing inhibitor) resistances, and often to resistances such as quinolones, aminoglycoside, macrolide antibiotics and clindamycins.Clinical confirmation, glycopeptide antibiotics (vancomycin, Norvancomycin, teicoplanin) has become choice drug clinically at present to the MRSA sensitivity.Japan found the streptococcus aureus (VISA) to the vancomycin medium sensitivity in 1997, and the U.S. in 2002 find the streptococcus aureus (VRSA) of vancomycin resistance, and up to now, the case that many cases VISA and 2 routine VRSA infect has been reported in the whole world.VISA infects can select glycopeptide class and other microbiotic combination therapys for use, as Rifampin, amikacin/Arbekacin etc., also can select new antibiotic for use, as Quinupristin/dalfopristin (quinupristin/dolfopristin), Linezolid (linezolid) etc., VRSA infects can select new antibiotic for use.Yet these medicines have all produced resistance in various degree after clinical application for some time, and therefore the new antibiotic of probing at resistant organism becomes necessity.

Summary of the invention

We provide a kind of new compound, this new compound as shown in the figure:

R=-CH wherein ₃-CF ₃

This compound is remarkable to the fungistatic effect of methicillin-resistant gold Portugal bacterium (MRSA), methicillin-sensitivity gold Portugal bacterium (MSSA), and this compound can be obtained by following reaction scheme.

Wherein, compound a is R=-CH ₃, compound b is R=-CF ₃

1,2,3,7 have compound 1a, 1b respectively among the figure, 2a and 2b, and 3a and 3b, 7a and 7b, during for a, R=--CH ₃, during for b, R=-CF ₃, as: 1a, R=-CH ₃, 1b, R=-CF ₃

Specific embodiment:

Embodiment 1: the preparation of formula 1 compound

1, compound 2a, 2b's is synthetic

Accurately take by weighing 4.26 gram raw material a and be dissolved among the THF of 20.0mL, add the anhydrous of .4 gram

Change lithium, under 0 ℃, add 1.0 gram sodium borohydrides in batches, then reaction solution is moved in the oil bath and refluxed 3 hours, stop heating, cool to room temperature, 20.0mL is saturated in adding

Change ammonium solution, tell organic layer, underpressure distillation removes and desolvates, and obtains the 3.5 thick products that digest compound 2a after the vacuum-drying, and productive rate is 95%, and crude product is not made purification process, is directly used in next step reaction.MS(m/z)：185.05。

Use raw material b to obtain 4.6 with method and digest compound 2b, productive rate is 96%, MS (m/z): 240.12.

2, compound 3a, 3b's is synthetic

The thick product 2a of previous step is dissolved among the THF of 20.0mL, under 0 ℃, adds 1.44 gram sodium hydrides in batches, finish, continue to stir 10 minutes, slowly drip 4.2 gram tolysulfonyl THF (20.0mL) solution, dropwised in 10 minutes, reaction solution is moved in the oil bath refluxed 3 hours, stop heating, cool to room temperature, it is saturated to add 20.0mL

Change ammonium solution, separatory is got organic phase, and underpressure distillation removes and desolvates, and vacuum-drying obtains the 6.3 thick products that digest compound 3a, and productive rate is 93%, MS (m/z): 440.34.

Use raw material 2b to obtain the 7.5 thick products that digest compound 3b with method, productive rate is 95%, MS (m/z): 394.31.

3, compound 4 is synthetic

2-thiophene ethanol 5g is dissolved among the THF of 20.0mL, adds 1.44 gram sodium hydrides under 0 ℃ in batches, finishes, and continues to stir 10 minutes, slowly drips 4.2 gram tolysulfonyl

THF (20.0mL) solution, dropwised in 10 minutes, reaction solution is moved in the oil bath refluxed 3 hours, stop heating, cool to room temperature, it is saturated to add 20.0mL

Change ammonium solution, separatory is got organic phase, and underpressure distillation removes and desolvates, and vacuum-drying obtains 6.3 and digests compound 4, and the productive rate of thick product is 90.1%, MS (m/z): 283.38.

4, compound 5 is synthetic

Accurately take by weighing 3.66 gram 4-pyridone-N-oxide compounds and be dissolved among the THF of 50.0mL, under ice bath, add 2.40 gram sodium hydrides in batches, continue to stir 20 minutes, THF (10.0mL) solution of compound 4 is digested in dropping 8.46, finish, reaction solution is moved to continue reaction 5 hours, stopped reaction in 50 ℃ the oil bath, add 20.0mL water, get organic layer behind the separatory, underpressure distillation removes desolvates, and obtains the 5.46 thick products that digest compound 5 after the vacuum-drying, productive rate is 81%, MS (m/z): 222.28.

5, compound 6 is synthetic

Digesting compound 5 with 5.46 is dissolved in the 50.0mL aceticanhydride, reaction is 5 hours in 110 ℃ oil bath, and stopped reaction is cooled to room temperature, reaction solution is poured in the trash ice of 50.0mL, ammoniacal liquor with 10% is regulated pH=8.0, filters filter cake vacuum-drying, obtain 4.82 with ethyl alcohol recrystallization and digest compound 6, productive rate is 88%, HNMR (400Hz, CDCl ₃): 8.05 (s, 1H), 7.28 (d, J=8.4Hz, 1H), 6.92 (m, 1H), 6.71 (m, 1H), 6.61 (m, 1H), 5.76 (d, J=8.4Hz, 1H), 5.35 (s, 1H), 4.28 (m, 2H), 2.93 (m, 2H); MS (m/z): 222.28.

6, compound 7a, 7b's is synthetic

The compound 6 of 2.21 grams is dissolved in the THF solution of 10.0mL, add 0.72 gram sodium hydride in batches under ice bath, continue to stir 20 minutes, THF (10.0mL) solution of compound 3a is digested in dropping 3.39, after dropwising, reaction solution moved in 60 ℃ the oil bath and continue reaction 3 hours, stopped reaction adds 20.0mL water, organic layer is through underpressure distillation, obtain 3.2 after the vacuum-drying and digest compound 7a, productive rate is 86%, MS (m/z): 389.43.

Use raw material 3b can obtain 3.1 with method and digest compound 7b, productive rate is 84%, MS (m/z): 443.37.

7, compound 1a, 1b's is synthetic

The compound 7a of 3.2 grams is dissolved in the methyl alcohol of 20.0mL, the palladium carbon that adds 160 milligram 10%, with the air in the hydrogen exchange reaction flask three times, logical hydrogen reaction spends the night under the room temperature, stopped reaction, reaction solution except that after desolvating, digests compound 1a with obtaining 2.1 behind the ethyl alcohol recrystallization through underpressure distillation, and productive rate is 70%.HNMR(400Hz，CDCl ₃)：7.28(d，J＝8.4Hz，1H)，6.92(m，1H)，6.71(m，1H)，6.61(m，1H)，6.01(d，J＝1.2Hz，1H)，5.86(d，J＝1.2Hz，1H)，5.76(d，J＝8.4Hz，1H)，5.35(s，1H)，4.28(m，2H)，4.22(s，2H)，4.01(s，2H)，2.93(m，2H)，2.35(s，3H)；MS(m/z)：359.41。

Obtain 1.9 with method and digest compound 1b, productive rate is 65%.HNMR(400Hz，CDCl ₃)：7.28(d，J＝8.4Hz，1H)，6.92(m，1H)，6.71(m，1H)，6.61(m，1H)，6.06(m，J＝1.2Hz，1H)，5.91(m，J＝1.2Hz，1H)，5.76(d，J＝8.4Hz，1H)，5.35(s，1H)，4.28(m，2H)，4.22(s，2H)，4.02(s，2H)，2.93(m，2H)；MS(m/z)：413.40。

Embodiment 2: the anti-microbial activity research of formula 1 compound

2.1 materials and methods

Antibacterials: compound 1a (formula 1 compound R=-CH ₃) Guangdong Zonk Drug R ﹠ D Limited is synthetic

The contrast medicine: hydrochloric acid demethyl vancomycin is available from North China pharmacy group

Tested bacterial strain: 101 strain MRSA and 105 strain MSSA all receive the pharmaceutical college in Zhongshan University, determine by the NCCLS standard after identifying.

Substratum: available from French Biomerieux SA, lot number: 811813401.

Method: adopt two times of agar dilutions measure compound 1a (formula 1 compound R=-CH ₃) and hydrochloric acid demethyl vancomycin to the minimum inhibitory concentration (MIC) of all bacterial strains.Promptly earlier two kinds of microbiotic are become 12 concentration with the sterile phosphate damping fluid doubling dilution of different concns PH respectively, each 10ml of soup with each concentration, join respectively and dissolved and be chilled in the M-H agar about 50 ℃, pour plate immediately makes that the microbiotic ultimate density of substratum is followed successively by 0.0625,0.125,0.25-128mg/L.Inoculate instrument with 10 with micro-multiple spot ⁸-10 ⁹The CFU/ml bacterial suspension inoculation is put 35 ℃ and is cultivated the 24h observations to containing the antibiotic above-mentioned agar plate surface of different concns, is defined as MIC with the minimum antibiotic concentration that suppresses the bacterium sound field.Add up MIC scope, MIC50, MIC90 respectively, and, calculate responsive rate, describe concentration simultaneously and accumulate antibacterial percentage curves bacterium according to the threshold concentration of antibacterials sensitivity.

2.2 result

Compound 1a (formula 1 compound, R=-CH ₃) and hydrochloric acid demethyl vancomycin antibacterial effect relatively as table 1 (MIC, mg/L):

The anti-microbial activity of formula 1 compound is better than the anti-microbial activity of hydrochloric acid demethyl vancomycin, and the responsive rate of MRSA, MSSA has also been embodied formula compound 1a (formula 1 compound, R=-CH ₃) for the advantage of salt demethyl vancomycin.

Claims (3)

1. the compound shown in the formula I and at the salt and the hydrate of pharmaceutically acceptable acid:

Wherein: R=-CH3;-CF3.

2. the pharmaceutical composition that contains the described formula I compound of claim 1 and form at the salt of pharmaceutically acceptable acid and hydrate and other pharmaceutical excipient.

3. be used for anti-microbial effect as claim 1 and 2 described materials or composition.