CN102827187A - Fluoroquinolone acetal isoniazone, and preparation method and application thereof - Google Patents
Fluoroquinolone acetal isoniazone, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a fluoroquinolone acetal isoniazone, of which the chemical structure general formula is disclosed as Formula I, wherein R1 is hydrogen atom or methyl group; R2 is hydrogen atom or amino group; R3 is hydrogen atom, methyl group, ethyl group, formacyl group, acetyl group, aroyl group or sulfonyl group; R4 is hydrogen atom or methyl group; and X is oxygen atom or sulfur atom. The fluoroquinolone isoniazone disclosed by the invention implements complementarity between the two anti-tuberculosis medicines fluoroquinolone and the isoniazide, lowers the toxic and side effect of the fluoroquinolone and the isoniazide, reduces the generation probability of drug resistance of Mycobacterium tuberculosis for the double-effect antimicrobial agent, and can be used as an anti-Mycobacterium tuberculosis medicine for brand-new structure development of medicinal active substances.
Description
Technical field
The present invention relates to a kind of fluoroquinolone derivative compound, be specifically related to a kind of fluoroquinolone aldehyde Vanizide that contracts, also relate to fluoroquinolone aldehyde the contract preparation method of Vanizide and the application in antitubercular agent simultaneously.
Background technology
White plaque is that one of human health threatens greatly, and the whole world infects white plaque above 1,000 ten thousand people at present, has 1,500,000 people to die from tuberculosis infection approximately.At present, white plaque is except that AIDS, the infection that mortality ratio is the highest.Because the clinical development process of antitubercular agent is very long, find activated new compound and develop into clinical antitubercular agent difficulty likely big, go back the none novel cpd and be used for antituberculosis therapy from come out so far 40 years of Rifampin.In addition, resistant tuberculosis, the especially multidrug resistance the incidence of infection lungy that thoroughly do not make of non-rational use of drug and treatment constantly rises, and therefore, it is extremely urgent to study new (or act on novel targets) antitubercular agent.
FQNS is one type and acts on DNA of bacteria gyrase (Gry) and topoisomerase I V (TopIV) synthetic antibacterial drug; Tubercule bacillus there are good inhibition and killing action; Simultaneously, owing to having not crossing drug resistant of such medicine and existing antitubercular agent, do not suppress the activity of other drug; Untoward reaction is few; Advantages such as taking orally, some kind (like CIPROFLOXACIN USP 24, Gatifloxacin, Ofloxacine USP 23 etc.) has been used as the two wires antitubercular agent, is used to treat many resistant tuberculosis (MDR-TB) and to the patient's that can not tolerate a line antitubercular agent treatment.But because the cartilage development of FQNS (FQs) drug influence animal; Phototoxicity is arranged; And a line antitubercular agent also classical not as good as vazadrine (INH), Rifampin (RFP) etc. to curative effect lungy, so such medicine exists certain defective to treatment lungy.Yet the vazadrine has a kind of antitubercular agent of extremely strong lethal effect to Mycobacterium tuberculosis, but himself exists certain liver toxicity.
Summary of the invention
The purpose of this invention is to provide a kind of new compound, promptly the fluoroquinolone aldehyde Vanizide that contracts has antiphthisic effect and effect, the preparation method who provides fluoroquinolone aldehyde to contract Vanizide simultaneously.
In order to realize above purpose, the technical scheme that the present invention adopted is: a kind of fluoroquinolone aldehyde Vanizide that contracts, adopt as shown in the formula the I chemical structure of general formula:
R among the formula I
1Be Wasserstoffatoms or methyl;
R among the formula I
2Be Wasserstoffatoms or amino;
R among the formula I
3Be Wasserstoffatoms, methyl, ethyl, formyl radical, ethanoyl, aroyl or alkylsulfonyl;
R among the formula I
4Be the substituting group on the carbon atom that is connected piperazine ring, be chosen as Wasserstoffatoms or methyl;
X is Sauerstoffatom or sulphur atom among the formula I.
As further improvement, the fluoroquinolone aldehyde of this law Vanizide that contracts is specially the compound of following chemical structure:
The contract preparation method of Vanizide of fluoroquinolone aldehyde of the present invention is that feedstock production forms with the fluoroquinolone carboxylic shown in the formula II,
Concrete preparation process is following:
1) fluoroquinolone carboxylic shown in the formula II is processed the fluoroquinolone C-3 formaldehyde shown in the formula III through reduction, formylation, oxidation successively;
Step 1) can reference literature (Kondo H; Sakamoto F; Et al.Studies on prodrugs.7.Synthesis and antimicrobial activity of 3-formylquinolone derivatives, J.Med.Chem.1988,31; 221-225. the research of prodrug (7): method the preparation synthetic and antimicrobial acivity of quinolone-3-aldehyde derivatives), it is following specifically to prepare process:
2) with the fluoroquinolone C-3 formaldehyde shown in the formula III and vazadrine in absolute ethyl alcohol, in acidic conditions refluxed reaction 3～6 hours, placing response filtered, and made the Vanizide that contracts of the fluoroquinolone aldehyde shown in the formula I;
R in said formula I, formula II, the formula III
1Be Wasserstoffatoms or methyl;
R in said formula I, formula II, the formula III
2Be Wasserstoffatoms or amino;
R in said formula I, formula II, the formula III
3Be Wasserstoffatoms, methyl, ethyl, formyl radical, ethanoyl, aroyl or alkylsulfonyl;
R in said formula I, formula II, the formula III
4Be the substituting group on the carbon atom that is connected piperazine ring, be chosen as Wasserstoffatoms or methyl;
X is Sauerstoffatom or sulphur atom in said formula I, formula II, the formula III.
As further improvement, the mol ratio of fluoroquinolone C-3 formaldehyde shown in the formula III and vazadrine is 1:1.
Fluoroquinolone aldehyde of the present invention contracts Vanizide based on goldenrain tree medicine design theory; Convert the C-3 carboxyl of FQNS (FQs) medicine into formyl radical; Obtain one type of new fluoroquinolone aldehyde Vanizide analog derivative that contracts with the vazadrine condensation again; Realized the complementarity of two types of anti-tuberculosis drugs of fluoroquinolone and vazadrine; Reduce the toxic side effect of the two, reduce the resistance generation probability of tubercule bacillus, can be used as the anti-mycobacterium tuberculosis medicine of pharmaceutically active substance exploitation brand new economic benefits and social benefits effect antiseptic-germicide.
Embodiment
Embodiment 1
The fluoroquinolone aldehyde of the present embodiment Vanizide that contracts is (S)-N '-[6-fluoro-7-(4-N-METHYL PIPERAZINE-1-yl)-1,8-(2,1-oxygen propyl group)-quinoline (1H)-4-ketone-3-methylene radical] Vanizide, and its chemical structural formula is:
Be R among the formula I
1Be methyl (S), R
2Be Wasserstoffatoms, R
3Be methyl, R
4Be Wasserstoffatoms, X is a Sauerstoffatom.
The contract preparation method of Vanizide of the fluoroquinolone aldehyde of present embodiment is: get (S)-6-fluoro-1; 8-(2; 1-oxygen propyl group)-and 7-(4-N-METHYL PIPERAZINE-1-yl)-3-formyl radical-4 (1H)-quinolinone 0.35g (1mmol), absolute ethyl alcohol 12ml is heated to dissolving; Add vazadrine 0.14g (1mmol) again, backflow 3h.Placement is spent the night, the solid that filter collection generates, and absolute ethanol washing, drying obtains the embodiment 1 fluoroquinolone aldehyde Vanizide compound 0.37g that contracts, productive rate 81%, m.p.211.9～214.3 ℃.
1HNMR(DMSO-d
6，400MHz)δ:11.98(s，1H，CONH)，8.76～8.78(m，3H，C
2-Handpyridine-H)，8.56(s，1H，N=CH)，7.84(d，J＝6.1Hz，2H，pyridine-H)，7.45(d，J＝12.5Hz，1H，C
5-H)，4.32～4.87(m，3H，-OCH
2-CHN-)，2.44～3.25(m，8H，piperizine-H)，2.24(s，3H，NCH
3)，1.42(d，J＝6.7Hz，3H，CH
3)。
Embodiment 2
The fluoroquinolone aldehyde of the present embodiment Vanizide that contracts is N '-[6-fluoro-7-(4-N-METHYL PIPERAZINE-1 base)-1,8-(2,1-oxygen propyl group)-quinoline (1H)-4-ketone-3-methylene radical] Vanizide, and its chemical structural formula is:
Be R among the formula I
1Be methyl, R
2Be Wasserstoffatoms, R
3Be methyl, R
4Be Wasserstoffatoms, X is a Sauerstoffatom.
The contract preparation method of Vanizide of the fluoroquinolone aldehyde of present embodiment is: get 6-fluoro-1,8-(2,1-oxygen propyl group)-7-(4-N-METHYL PIPERAZINE-1-yl)-3-formyl radical-4 (1H)-quinolinone 0.35g (1mmol); Absolute ethyl alcohol 15ml; Be heated to dissolving, add vazadrine 0.14g (1mmol) again, backflow 3h.Placement is spent the night, the solid that filter collection generates, and absolute ethanol washing, drying obtains the embodiment 2 fluoroquinolone aldehyde Vanizide compound 0.38g that contracts, productive rate 83%, m.p.293.5～295.6 ℃.
1HNMR(DMSO-d
6，400MHz)δ:11.97(s，1H，CONH)，8.76～8.78(m，3H，C
2-Handpyridine-H)，8.55(s，1H，N=CH)，7.84(d，J＝5.8Hz，2H，pyridine-H)，7.45(d，J＝12.5Hz，1H，C
5-H)，4.32～4.87(m，3H，-OCH
2-CHN-)，2.43～3.25(m，8H，piperizine-H)，2.23(s，3H，NCH
3)，1.42(d，J＝6.7Hz，3H，CH
3)。
Embodiment 3
The fluoroquinolone aldehyde of the present embodiment Vanizide that contracts is (S)-N '-[6-fluoro-7-piperazine-1-base-1,8-(2,1-oxygen propyl group)-quinoline (1H)-4-ketone-3-methylene radical] Vanizide, and its chemical structural formula is:
Be R among the formula I
1Be methyl (S), R
2Be Wasserstoffatoms, R
3Be Wasserstoffatoms, R
4Be Wasserstoffatoms, X is a Sauerstoffatom.
The contract preparation method of Vanizide of the fluoroquinolone aldehyde of present embodiment is: get (S)-6-fluoro-1; 8-(2-methyl inferior ethoxyl)-7-(piperazine-1-yl)-3-formyl radical-4 (1H)-quinolinone 0.33g (1mmol); Absolute ethyl alcohol 12ml; Be heated to dissolving, add vazadrine 0.14g (1mmol) again, reflux 3h.Placement is spent the night, and the solid that filter collection generates, absolute ethanol washing, drying obtains the embodiment 3 fluoroquinolone aldehyde Vanizide compound 0.34g that contracts, productive rate 76%, m.p.>300 ℃.
1HNMR(CD
3CO
2D，400MHz)δ:8.76～8.78(m，3H，C
2-Handpyridine-H)，8.56(s，1H，N=CH)，7.84(d，J＝6.1Hz，2H，pyridine-H)，7.45(d，J＝12.5Hz，1H，C
5-H)，4.32～4.87(m，3H，-OCH
2-CHN-)，2.44～3.25(m，8H，piperizine-H)，1.42(d，J＝6.7Hz，3H，CH
3)。
Embodiment 4
The fluoroquinolone aldehyde of the present embodiment Vanizide that contracts is N '-[6-fluoro-7-(4-N-METHYL PIPERAZINE-1-yl)-1,8-(2,1-sulphur ethyl)-quinoline (1H)-4-ketone-3-methylene radical] Vanizide, and its chemical structural formula is:
Be R among the formula I
1Be Wasserstoffatoms, R
2Be Wasserstoffatoms, R
3Be methyl, R
4Be Wasserstoffatoms, X is a sulphur atom.
The contract preparation method of Vanizide of the fluoroquinolone aldehyde of present embodiment is: get 1,8-(2,1-sulphur ethyl)-6-fluoro-7-(4-N-METHYL PIPERAZINE-1-yl)-3-formyl radical-4 (1H)-quinolinone 0.35g (1mmol); Absolute ethyl alcohol 15ml; Be heated to dissolving, add vazadrine 0.14g (1mmol) again, backflow 3h.Placement is spent the night, the solid that filter collection generates, and absolute ethanol washing, drying obtains the embodiment 4 fluoroquinolone aldehyde Vanizide compound 0.4g that contracts, productive rate 85%, m.p.231.2～233.5 ℃;
1HNMR (DMSO-d6,400MHz) δ: 11.98 (s, 1H, CONH), 8.75～8.78 (m, 3H, C
2-Handpyridine-H), 8.57 (s, 1H, N=CH), 7.85 (d, J=5.4Hz, 2H, pyridine-H), 7.45 (d, J=12.5Hz, 1H, C
5-H), 4.42～4.92 (m, 3H ,-SCH
2-CHN-), 2.43～3.25 (m, 8H, piperizine-H), 2.23 (s, 3H, NCH
3), 1.45 (d, J=6.7Hz, 3H, CH
3).
Experimental example
One, the contract Tuberculosis in vitro nuclear activity of vazadrine compound of the fluoroquinolone aldehyde that provides of embodiment 1-4 is measured
1, test reagent
The vazadrine (isoniazid, INH), (ofloxacin is OFX) available from Nat'l Pharmaceutical & Biological Products Control Institute for Ofloxacine USP 23; Under aseptic condition, 4 compounds that embodiment 1-4 provided with DMSO are made into the solution of 4mg/ml, and fully the dissolving back is with 0.22 μ m membrane filtration, put-20 ℃ of preservations (during use, avoid the influence of DMSO, the concentration of DMSO in nutrient solution < 0.5%); The 7H9 liquid medium is available from U.S. Difco company.
2, bacterial strain
Mycobacterium tuberculosis type strain H
37Ra (ATCC25177), H
37Rv (ATCC27294); The clinical isolating resistance Mycobacterium tuberculosis H6 of 3 strains, H7, (disease prevention and control center, Henan Province provides H10; Wherein, H6, H7 are to vazadrine, Rifampin, Tibutol, Streptomycin sulphate, Ofloxacine USP 23 multiple antibiotic resistant strain, and H10 is to vazadrine, Rifampin Resistant strain).
3, experimental technique
1) preparation of bacterial suspension: the tubercule bacillus that will cultivate 2～3 all cell ages is taken out in the access sterilization bottle with transfering loop; Mixing is to becoming emulsus, the saline water dilution, through with NO.1 Maxwell standard opacity tube than turbid; Bacterium liquid is configured to the bacterium liquid of 1mg/ml, is diluted to 1 * 10 with saline water again
5CFU is subsequent use.
2) on 96 well culture plates, add the testing compound solution (with aseptic 7H9 liquid medium dilution testing compound to 100 μ g/ml) of 200 μ L suitable concns, again testing compound is diluted (doubling dilution to 50,25 as required then; 12.5,6.25,3.125,1.56; 0.78,0.39,0.195,0.097; 0.048,0.024,0.012 μ g/ml), and be provided with no medicine control wells.The bacterium liquid that dilution is good joins all and detects in holes and do not have in the medicine control wells, and as in the constant temperature incubator, every plate is at 37 ℃ with these plates, 5%CO
2Cultivated 21 days under the condition.40 * microscopic examination, naked eyes do not see that the lowest drug concentration of bacterial growth is the minimum inhibitory concentration of this medicine (MIC).Simultaneously, with vazadrine, the positive contrast of Ofloxacine USP 23, with DMSO and the culture bacteria liquid that does not add any compound as negative control.Experimental result is seen shown in the table 1.
Table 1 respectively supplies the Tuberculosis in vitro nuclear activity (MIC) of test agent
Can find out that from table 1 compound that embodiment 1-4 provides is to Mycobacterium tuberculosis type strain H
37Ra, H
37Rv is external to have the good restraining activity.
Two, the contract vitro cytotoxicity of vazadrine compound of the fluoroquinolone aldehyde that provides of embodiment 1-4 is measured
1, test reagent
The vazadrine (isoniazid, INH), (ofloxacin is OFX) available from Nat'l Pharmaceutical & Biological Products Control Institute for Ofloxacine USP 23; Under aseptic condition, 4 compounds that embodiment 1-4 provided with DMSO are made into the solution of 4mg/ml, and fully-20 ℃ of preservations are put with 0.22 μ m membrane filtration in the dissolving back.The RPMI-1640 nutrient solution, trypsin TRGPSIN); Foetal calf serum (Hangzhou Sijiqing Biological Engineering Material Co., Ltd.); Tetrazole pulvis (BIOSAIL); Bromination-(4,5)-dimethyl--2-thiazolyl-2,5-phenylbenzene tetrazole (MTT, AMRESCO packing); Sodium lauryl sulphate (SDS), Sodium phosphate, dibasic (Tianjin section close europeanized reagent development centre); EDTA Disodium (EDTA); DMSO 99.8MIN. (Tianjin moral grace chemical reagent ltd).
2, cell strain
VEROcells purchases the Shanghai cell bank in the Chinese Academy of Sciences.
3, experimental technique (mtt assay)
With cell with 10
6Cells/ml is laid in the 96 porocyte culture plates, 37 ℃, 5%CO
2Cultivate in the constant temperature incubator, behind the 24h, add the medicine nutrient solution of different concns, the medicine starting point concentration is 10mmol/L, and to be diluted to final concentration successively be 10,5,2.5,1.25,0.625 μ mol/L, and each concentration repeats 3 times; Simultaneously, be the property contrast with vazadrine, Ofloxacine USP 23; DMSO organizes the DMSO of parallel adding and medicine equal volume, and every hole adds 20 μ LMTT behind the 48h, and 37 ℃ are continued to hatch 4h; The buckle method is taken out nutrient solution; Every hole adds the DMSO of 200 μ L, and vibration 10min dissolves until blue crystallisate fully, detects OD with full-automatic ELIASA immediately
570Value.Cell proliferation inhibition rate by formula calculates sees formula:
With each drug level logarithmic value the inhibiting rate under each concentration is done linear regression then, go out the half-inhibition concentration (IC of each test compound experimental cell from gained docs-effect Equation for Calculating
50).Experimental result is seen shown in the table 2.
Table 2 respectively supplies the vitro cytotoxicity of test agent to measure (IC
50)
| Supply test agent | VERO cells cytotoxicity (IC 50) |
| Embodiment 1 | >;100 |
| Embodiment 2 | >;100 |
| Embodiment 3 | >;100 |
| Embodiment 4 | >;100 |
| The vazadrine | >;100 |
| Levofloxacin | 75 |
In sum, the compound that embodiment 1-4 provides is external, and all to show good tuberculosis active, and most compounds does not have significant cytotoxicity, is expected to develop the antitubercular agent of one type of efficient, low toxicity.
Claims (7)
1. fluoroquinolone aldehyde Vanizide that contracts, adopt as shown in the formula the I chemical structure of general formula:
R among the formula I
1Be Wasserstoffatoms or methyl;
R among the formula I
2Be Wasserstoffatoms or amino;
R among the formula I
3Be Wasserstoffatoms, methyl, ethyl, formyl radical, ethanoyl, aroyl or alkylsulfonyl;
R among the formula I
4Be Wasserstoffatoms or methyl;
X is Sauerstoffatom or sulphur atom among the formula I.
2. according to the said fluoroquinolone aldehyde of claim 1 Vanizide that contracts, it is characterized in that: the compound that is specially following chemical structure:
3. the fluoroquinolone aldehyde preparation method of Vanizide that contracts, it is characterized in that: with the fluoroquinolone carboxylic shown in the formula II is that feedstock production forms,
Concrete preparation process is following:
1) fluoroquinolone carboxylic shown in the formula II is processed the fluoroquinolone C-3 formaldehyde shown in the formula III through reduction, formylation, oxidation successively;
2) with the fluoroquinolone C-3 formaldehyde shown in the formula III and vazadrine in absolute ethyl alcohol, in acidic conditions refluxed reaction 3～6 hours, placing response filtered, and made the Vanizide that contracts of the fluoroquinolone aldehyde shown in the formula I;
R in said formula I, formula II, the formula III
1Be Wasserstoffatoms or methyl;
R in said formula I, formula II, the formula III
2Be Wasserstoffatoms or amino;
R in said formula I, formula II, the formula III
3Be Wasserstoffatoms, methyl, ethyl, formyl radical, ethanoyl, aroyl or alkylsulfonyl;
R in said formula I, formula II, the formula III
4Be Wasserstoffatoms or methyl;
X is Sauerstoffatom or sulphur atom in said formula I, formula II, the formula III.
4. preparation method according to claim 3 is characterized in that: the mol ratio of fluoroquinolone C-3 formaldehyde shown in the said formula III and vazadrine is 1:1.
One kind according to claim 1 or claim 2 fluoroquinolone aldehyde contract Vanizide in the application of preparation in the antitubercular agent.
6. according to the said application of claim 5, it is characterized in that: the fluoroquinolone aldehyde Vanizide that contracts suppresses the application in the Mycobacterium tuberculosis medicine in preparation.
7. according to the said application of claim 6, it is characterized in that: said Mycobacterium tuberculosis is H
37Ra or H
37Rv.
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| CN104844619A (en) * | 2015-03-30 | 2015-08-19 | 河南大学 | Ofloxacin (rhodanine unsaturated ketone) amide derivative and preparation method and application thereof |
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| CN106854214A (en) * | 2016-12-26 | 2017-06-16 | 郑州工业应用技术学院 | Ofloxacin aldehyde 4 arylamino thiourea derivatives of contracting and its preparation method and application |
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| GB2496972A (en) * | 2011-11-18 | 2013-05-29 | Redx Pharma Ltd | Oxime and hydrazone derivatives of fluoroquinolone antibacterial drugs |
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