CN103405435A - Application of clinafloxacin amino derivatives and medicinal salts thereof in preparing antitubercular medicaments - Google Patents
Application of clinafloxacin amino derivatives and medicinal salts thereof in preparing antitubercular medicaments Download PDFInfo
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Abstract
The invention discloses an application of clinafloxacin amino derivatives and medicinal salts thereof in preparing antitubercular medicaments. In the structural general formula of the clinafloxacin amino derivatives, R is -(CH2)nNR<1>R<2>, -CH(CH2CH2XCH3)NH2, 2-pyrrolidyl or -OR3; n is 0 or 1; R1 and R2 are separately hydrogen, methyl, 2-hydroxyethyl, (R)-1-ethyl-2-hydroxyethyl, 2-aminoethyl, 3-(dimethylamino)propyl, hydroxyl, amino, methylamino, methoxyl or thiourea group; X is S or SO2; R3 is methyl or isobutyl; the compounds have certain inhibitory effect on standard sensitive strains, clinically isolated sensitive strains and clinically isolated drug-resistant strains of mycobacterium tuberculosis, the antitubercular activity of a part of compounds is stronger than that of ofloxacin and clinafloxacin and weaker than that of moxifloxacin, thus providing a new research direction for the antitubercular medicaments, and being beneficial to clinical treatment of tuberculosis.
Description
Technical field
The invention belongs to chemical field, relate to the new purposes of compound at pharmaceutical field.
Background technology
The tuberculosis caused by mycobacterium is a kind of chronic disease of hyperinfection, and its crowd infection rate is always high since ancient times.China is that 22 tuberculosis height are born one of country in the world, and patient's number is only second to India and occupies global second.The reason of some areas tuberculosis Re-emergence is many-sided, have that the recurrent population increases suddenly, the odjective causes such as double infection of the spreading of Resistance Mycobacterium Tuberculosis, tulase and HIV (human immunodeficiency virus), main is, generally Tuberculosis Health Education is paid attention to not, the relevant knowledge of tuberculosis prevention and treatment is not universal etc.At present, common first-line treatment medicine lungy, as rifampicin (RFP), isoniazid (INH), pyrazinamide (PZA), ethambutol (EMB) and streptomycin (SM), although can effectively treat common tuberculosis, be accompanied by treatment poor, cycle of compliance long, certain shortcomings such as toxic and side effects are arranged; And anti-multiple medicines tuberculosis (MDR-TB) and extensive resistant tuberculosis (XDR TB) become increasingly complex the tuberculotherapy problem.In nearly 50 years in the past, the prevention that neither one is new and treatment tuberculosis are introduced to the market.Find or synthetic safe and effective, treatment cycle is short, the antimycobacterial compounds compatible with inverase is extremely urgent.
Clinafloxacin (CF) was once the star molecule that has " super wide spectrum " character in the antibiotic new varieties of the 4th generation quinolones.A large amount of in vitro and in vivo research finds, CF not only has superpower inhibition killing action, show simultaneously that bioavailability is high, tissue penetration by force, safety and better tolerance, the pharmaceutical properties such as serum half-life is long and pharmacokinetic property is good.It is clinical that the research and development unit once pushed clinafloxacin to for three phases, yet the intrinsic untoward reaction such as phototoxicity, cardiac toxicity and hypoglycemia incidence rate of clinafloxacin have hindered its application for quotation.In addition, in experimentation, find that the former medicine dissolubility of CF is less, the stability in aqueous solution is inadequate, may be also the major reason that affects its patent medicine.
Clinafloxacin derivative, the strategy of simple possible are exactly the precursor structure that retains clinafloxacin, its non-pharmacophoric group are carried out to structural modification.And numerous research shows, 7 bit substituents of quinolinones can affect the enzymatic synthesis of DNA topoisomerase and cell permeability to a great extent, and finally affect its biological activity, antimicrobial spectrum, dissolubility and pharmacokinetics.The inventor modifies derivative to 3-amino on 7 pyrrole rings of clinafloxacin, synthesized more than 200 Clinafloxacin amino derivatives, be included in amino upper introduce five yuan or hexa-member heterocycle, urea and amine etc., therefrom obtained antibiotic active molecular (the Chinese patent application 201010523646x that toxicity reduction, increased activity, dissolubility raising and stability of molecule increase, 201210483417.9,201210086238.1,201310349071.8).But whether these derivants, except antibacterial activity, also have new pharmacologically active, it be not immediately clear, remain further to be studied.
Summary of the invention
In view of this, the object of the invention is to the selected part bacteriostatic activity preferably Clinafloxacin amino derivatives carry out the tuberculosis screening active ingredients, the expectation to new direction of anti-tuberculosis drugs.
After deliberation, the invention provides following technical scheme:
1. the application of Clinafloxacin amino derivatives in preparing anti-tuberculosis drugs, described Clinafloxacin amino derivatives has following general structure:
In formula, R is-(CH
2) nNR
1R
2,-CH (CH
2CH
2XCH
3) NH
2, the 2-pyrrolidinyl or-OR
3
N is 0 or 1; R
1And R
2Be hydrogen, methyl, 2-hydroxyethyl, (R)-1-ethyl-2-hydroxyethyl, 2-amino-ethyl, 3-(dimethylamino) propyl group, hydroxyl, amino, methylamino, methoxyl group or ghiourea group independently;
X is S or SO
2
R
3For methyl or isobutyl group.
Further, n is 0, R
1And R
2Be hydrogen, methyl, 2-hydroxyethyl, hydroxyl, amino, methylamino or methoxyl group independently; N is 1, R
1And R
2Be hydrogen, methyl, 2-hydroxyethyl, (R)-1-ethyl-2-hydroxyethyl, 2-amino-ethyl, 3-(dimethylamino) propyl group, hydroxyl, amino or ghiourea group independently.
Further, R is-(CH
2) nNR
1R
2,-CH (CH
2CH
2XCH
3) NH
2, the 2-pyrrolidinyl or-OCH
3N is 0, R
1And R
2Be hydrogen, methyl, hydroxyl or amino independently; N is 1, R
1And R
2Be hydrogen, methyl, 2-hydroxyethyl, (R)-1-ethyl-2-hydroxyethyl, 2-amino-ethyl, hydroxyl, amino or ghiourea group independently; X is S or SO
2.
Further, R is-CH
2NR
1R
2R
1For hydrogen, R
2For ghiourea group; R
1For methyl or 2-hydroxyethyl, R
2For the 2-hydroxyethyl.
Beneficial effect of the present invention is: the present invention has filtered out the compound with tuberculosis activity Clinafloxacin amino derivatives preferably from the part bacteriostatic activity, these compounds all have certain inhibition to mycobacterium tuberculosis standard sensitive strain, clinical separation sensitive strain and the clinical persister that separates, wherein the tuberculosis activity of part of compounds is better than ofloxacin and clinafloxacin and slightly is weaker than Moxifloxacin, thereby to antituberculotics, provide a new research direction, helped clinical treatment lungy.
The specific embodiment
In order to make purpose of the present invention, technical scheme and beneficial effect clearer, below the preferred embodiments of the present invention are described in detail.
Embodiment 1, compound TM1's is synthetic
In reaction bulb, add clinafloxacin (CF), K
2CO
3And appropriate dichloromethane (DCM), the DCM solution of dropping chloracetyl chloride under ice bath, CF, K
2CO
3With the molar ratio of chloracetyl chloride be 10:25:15～25, drip to finish stirring reaction under ice bath, TLC (thin layer chromatography) monitoring reaction process.React complete, obtain the yellow green turbid solution, sucking filtration, filter cake washs with DCM, and washing liquid and filtrate merge, and revolve and steam to dry, obtain intermediate compound I M1.
In reaction bulb, add amine component, K
2CO
3And the KI of catalytic amount and appropriate solvent, stirring at room adds intermediate compound I M1, IM1, K after 30 minutes
2CO
3With the molar ratio of amine component be 1:3:2, the reaction of 30-45 ℃ of temperature control, TLC monitoring reaction process.React complete, by following several modes, carry out post processing respectively as the case may be: (1), if product is dissolved in organic solvent, adds water, with 2N HCl, adjust pH to 6-7, with the DCM extraction, collect organic facies, revolve and steam to obtain crude product, with dichloromethane-petroleum ether (DCM-PE) recrystallization; (2) if product is water-soluble, adjust pH to neutral, stratification, collect water, continues to adjust pH to 4～5, cold preservation crystallize, sucking filtration, filter cake 90% ethyl alcohol recrystallization; (3) if reaction system has solid to produce, sucking filtration, filter cake adds water, adjusts pH to 4～5, cold preservation crystallize with 2N HCl; (4) if product both had been dissolved in organic solvent, water-soluble again, first revolve to steam and remove organic facies, then adjust pH to 4～5 with 2N HCl, the cold preservation crystallize, obtain compound TM1.Synthesize and the results are shown in Table 1.
Table 1 compound TM1 synthesizes result
TM1-17-(3-(2-(azanol base) acetamido)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: light yellow solid, m.p.223.2～224.1 ℃;
1H NMR (600MHz, DMSO-d
6) δ: 14.50 (s, 1H, H-11), 8.82 (s, 1H; H-2), 7.91 (d, 1H, J=12.0Hz; H-5), 4.41-4.36 (m, 1H, H-12); (3.80-3.58 m, 5H, H-16, H-20and H-17), 3.38-3.33 (m; 4H, H-14and H-15), 1.21-1.17 (m, 2H; H-13), 1.01-0.98 (m, 2H, H-13);
13C NMR (151MHz, DMSO-d
6) δ: 176.07,166.73,165.06, (156.30; 154.64), 152.79, (143.59,143.50); 137.95, (122.83,122.78), (119.48; 119.45), (110.63,110.47), 107.63; 62.64,51.05,50.66,45.97; 41.94,41.56,10.84 (2 * C);
(c=1.5mg/mL, DMF).
TM1-27-(3-(2-((R)-1-hydroxyl butanols-2-amido) acetamido)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: light yellow solid, m.p.233.7～235.5 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.52 (s, 1H, H-11), 8.86 (s, 1H, H-2), (8.68 s, 1H, CONH), 7.99 (d, 1H, J=11.4Hz, H-5), 5.41 (s, 1H, H-24), 4.43-4.39 (m, 1H, H-12), 4.17 (s, 2H, H-20), 3.73-3.60 (m, 6H, H-16, H-17, H-14and H-23), 3.39-3.34 (m, 3H, H-14and H-15), 3.08-3.06 (m, 1H, H-22), 1.69-1.53 (m, 2H, CH
3 CH 2 ), 1.20-1.18 (m, 2H, H-13), 1.01-0.91 (m, 5H, H-13and
CH 3 CH
2);
13C NMR (75MHz, DMSO-d
6) δ: 176.17,165.14,164.35, (157.30,153.97); 152.92, (143.43,143.24), 137.92, (123.20; 123.09), 119.88, (110.81,110.50), 107.68; 60.60,58.22,50.74,50.38;, 45.11,44.70,42.37; 41.65,20.28,10.92,9.99; HR MS:C
23H
28ClFN
4O
5[M+H]
+Value of calculation is 495.1805, and measured value is 495.1809;
(c=1.5mg/mL, H
2O).
TM1-37-(3-(2-(ethoxy amido) acetamido)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: faint yellow solid, m.p.239.5-240.2 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.50 (s, 1H, H-11), 8.93 (s, 1H; H-18), 8.84 (s, 1H, H-2), 7.97 (d; 2H, J=12Hz, H-5), 5.26 (s, 1H;-OH), 4.33-4.26 (m, 1H, H-12); (4.15 s, 2H, H-20), 3.71-3.68 (m; 3H, H-16and H-17), 3.58-3.55 (m, 2H; H-23), 3.38-3.31 (m, 4H, H-14and H-15); (3.01-2.99 m, 2H, H-22), 2.87-2.78 (m; 2H, H-21), 1.21-1.18 (m, 2H; H-13), 1.03-0.99 (m, 2H, H-13);
13C NMR (75MHz, DMSO-d
6) δ: 176.52,165.46,164.43, (157.42,154.27), 153.27,143.61,138.27; 123.56,120.34, (111.15,110.85), 108.07,50.97,49.16,48.31; 45.54,42.56,42.02,30.41,29.37,11.56,11.37; HR MS:C
21H
24ClFN
4O
5[M+Na]
+Value of calculation is 489.1311, and measured value is 489.1315;
(c=1.0mg/mL, CHCl
3).
TM1-47-(3-(2-(N-methyl-ethoxy amido) acetamido)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: faint yellow solid, m.p.130.7-131.4 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.55 (s, 1H, H-11), 9.59 (s, 1H, H-18), (8.88 s, 1H, H-2), 8.00 (d, 2H, J=12.0Hz, H-5), 5.40 (s, 1H ,-OH), 4.50-4.39 (m, 3H, H-12and H-20), 3.88-3.66 (m, 4H, H-16, H-17and H-14), 3.56-3.53 (m, 2H, H-22), 3.42-3.39 (m, 3H, H-14and H-15), 3.25-3.18 (m, 2H, H-21), 2.92 (s, 3H, CH
3), 1.22-1.19 (m, 2H, H-13), 1.02-0.93 (m, 2H, H-13);
13C NMR (75MHz, DMSO) δ: 176.52,165.46,164.43, (157.43; 154.58), 153.27, (143.61,143.45), 138.27; 123.56,120.34, (111.15,110.85), 108.07; 62.86,61.19,58.34,50.97; 49.72,48.31,45.54,42.56; 42.02,30.41,11.53,11.34; HR MS:C
22H
26ClFN
4O
5[M+Na]
+Value of calculation is 503.1468, and measured value is 503.1465;
(c=1.0mg/mL, CHCl
3).
TM1-57-(3-(2-(dihydroxy ethyl amido) acetamido)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: faint yellow solid, m.p.242.3-242.8 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.48 (s, 1H, H-11), 9.64 (s, 1H; H-18), 8.84 (s, 1H, H-2); (7.98 d, 2H, J=12Hz, H-5); (5.21 s, 2H, OH), 4.56-4.40 (m; 1H, H-12), 4.16 (s, 2H; H-20), 3.82-3.74 (m, 3H, H-16and H-17); (3.64 t, 4H, J=6.0Hz, H-22); (3.59-3.48 m, 6H, H-14and H-23), 3.00-2.98 (m; 2H, H-15), 1.22-1.19 (m, 2H; H-13), 1.04-1.00 (m, 2H, H-13);
13C NMR (75MHz, DMSO-d
6) δ: 176.04,168.24,164.98, (156.32,154.66); 152.82, (143.29,143.20), 137.82; (123.02,122.97), (119.71,119.68); (110.62,110.46), 107.58,55.12 (2 * C); 54.69 (2 * C), 50.65,50.45,49.79; 45.48,41.77,41.46,10.73 (2 * C); HR MS:C
23H
28ClFN
4O
6[M+Na]
+Value of calculation is 533.1574, and measured value is 533.1576;
(c=1.0mg/mL, CHCl
3).
TM1-67-(3-(2-(2-aminoethyl amido) acetamido)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: light yellow solid, m.p.241.2～242.3 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.50 (s, 1H, H-11), 8.85 (s, 1H; H-2), 7.97 (d, 1H, J=11.7Hz, H-5); (4.43-4.39 m, 1H, H-12), 4.27 (s, 2H; H-20), 3.72-3.58 (m, 4H, H-16, H-17and H-14), 3.40-3.27 (m; 7H, H-14, H-22, H-23and H-15), 1.22-1.19 (m, 2H; H-13), 1.02-0.99 (m, 2H, H-13);
13C NMR (75MHz, DMSO-d
6) δ: 176.09,165.08,163.93, (157.26,153.94); 152.86, (143.42,143.22), 137.89; (123.13,123.03), (119.93,119.86); (110.75,110.44), 107.64,50.89; 50.60,47.23,45.12,44.16; 42.21,41.64,35.00,10.92 (2 * C); HRMS:C
21H
25ClFN
5O
4[M+H]
+Value of calculation is 466.1652, and measured value is 466.1658;
(c=1.5mg/mL, H
2O).
TM1-77-(3-(2-((3-dimethylamino-propyl) amido) acetamido)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: light yellow solid, m.p.181.8～183.6 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.47 (s, 1H, H-11), 8.84 (s, 1H, H-2), (8.64 s, 1H, H-18), 7.94 (d, 1H, J=11.7Hz, H-5), 4.44-4.39 (m, 1H, H-12), 4.22 (s, 2H, H-20), 3.71-3.61 (m, 4H, H-16, H-17and H-14), 3.42-3.33 (m, 3H, H-14andH-15), 3.21-3.07 (m, 4H, H-22and H-24), 2.89 (d, 1H, J=7.5Hz, H-21), 2.76 (s, 6H, CH
3), 2.22-2.18 (m, 2H, H-23), 1.24-1.19 (m, 2H, H-13), 1.04-1.01 (m, 2H, H-13);
13C NMR (75MHz, DMSO-d
6) δ: 176.03,165.06,164.05, (157.20,153.88); 152.80, (143.41,143.22), 137.86, (123.07; 122.96), 119.80, (110.71,110.40); 107.61,53.37,51.45,50.58; 46.86,45.15,44.18,41.91 (2 * C); 41.65,36.11,20.43,10.93 (2 * C); HR MS:C
24H
31ClFN
5O
4[M+H]
+Value of calculation is 508.2121, and measured value is 508.2129;
(c=1.5mg/mL, H
2O).
TM1-87-(3-(2-(diazanyl) acetamido)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: yellow solid, m.p.164.6～166.2 ℃;
1H NMR (600MHz, DMSO-d
6) δ: 14.51 (s, 1H, H-11), 8.84 (s, 1H, H-2); (7.94 d, 1H, J=12.0Hz, H-5), 4.43-4.39 (m; 1H, H-12), 3.96 (s, 2H, H-20); (3.73-3.64 m, 3H, H-16and H-17), 3.58-3.56 (m, 2H; H-22), 3.38-3.33 (m, 4H, H-14and H-15), 1.21-1.19 (m; 2H, H-13), 1.02-0.97 (m, 2H, H-13);
13C NMR (151MHz, DMSO-d
6) δ: 176.13,165.12 (2 * C), (156.84,154.34); 152.92, (143.43,143.29), 137.93; (123.13,123.05), (119.87,119.82); (110.76,110.53), 107.67,50.78; 50.62,49.45,45.01; 42.03,41.64,10.91 (2 * C); HR MS:C
28H
35ClFN
5O
6[M+H]
+Value of calculation is 438.1339, and measured value is 438.1340;
(c=1.5mg/mL, DMF).
TM1-97-(3-(2-(1-methyl diazanyl) acetamido)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: yellow solid, m.p.157.1～158.7 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.52 (s, 1H, H-11), 8.86 (s, 1H, H-2), 7.97 (d, 1H, J=11.7Hz, H-5), 4.43-4.39 (m, 1H, H-12), (3.94 s, 2H, H-20), 3.68-3.61 (m, 4H, H-16, H-17and H-14), 3.38-3.33 (m, 3H, H-14and H-15), 3.47 (s, 3H, CH
3), 1.22-1.19 (m, 2H, H-13), 1.02-0.99 (m, 2H, H-13);
13C NMR (75MHz, DMSO-d
6) δ: 176.09,166.40,165.08, (157.23; 153.91), 152.84, (143.45,143.26); 137.91, (123.08,122.97), 119.76; (110.74,110.44), 107.65,56.97; 50.84,50.57,45.51,43.35; 41.90,41.63,10.90 (2 * C); HR MS:C
20H
23ClFN
5O
4[M+H]
+Value of calculation is 452.1495, and measured value is 452.1504;
(c=1.0mg/mL, DMF).
TM1-107-(3-(2-(sulfo-urea groups amido) acetamido)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: khaki solid, m.p.287.5～289.2 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 8.86 (s, 1H, H-2), 8.01 (d, 1H; J=11.7Hz, H-5), 6.01 (s, 2H; H-20), 4.43-4.38 (m, 1H, H-12); (3.56-3.50 m, 5H, H-20, H-16and H-17), 3.27-3.20 (m; 4H, H-14and H-17), 1.20-1.18 (m, 2H; H-13), 1.03-1.00 (m, 2H, H-13);
(c=1.5mg/mL, H
2O).
Embodiment 2, compound TM2's is synthetic
In reaction bulb, add CF and appropriate chloroform, after stirring, slowly drip the chloroformic solution of two (trichloromethyl) carbonic ester (BTC), dropwise, under ice bath, the vigorous stirring reaction is 7 hours, more slowly drips triethylamine (TEA), the molar ratio of CF, BTC and TEA is 17:6:10, dropwise, react under room temperature, TLC monitoring reaction process.React complete, sucking filtration, filter cake washs with DCM, and washing liquid and filtrate merge, and add water, with 2N HCl, adjust pH to 4～5, then, with DCM extraction 2 times, collect organic facies, with saturated common salt water washing 2 times, anhydrous sodium sulfate drying, filter, the filtrate concentrated by rotary evaporation, rapid column chromatography method purification, obtain intermediate compound I M2.
In reaction bulb, add chloroform, amine component and K
2CO
3, stirring at room, after 0.5 hour, adds intermediate compound I M2, amine component, K
2CO
3With the molar ratio of IM2 be 1.5:2:1, temperature control reaction, TLC monitoring reaction process.React complete, by following several modes, carry out post processing respectively as the case may be: (1) is for the poor product of water solublity, sucking filtration, filter cake, with after the DCM washing, adds water, adjusts pH to faintly acid, with the DCM extraction, collect organic facies, with DCM-PE (petroleum ether) recrystallization; (2) for water solublity product preferably, adjust pH to faintly acid, add solid Sal to saturated, then, with the DCM extraction, collect organic facies, with DCM-PE (petroleum ether) recrystallization; Perhaps, adjust pH to faintly acid, add solid Sal to saturated, put refrigerator and cooled and hide crystallize, next day, sucking filtration, obtained compound TM2.Synthesize and the results are shown in Table 2.
Table 2 compound TM2 synthesizes result
TM2-17-(3-urea-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: m.p.253.7-254.9 ℃
1H NMR (600MHz, DMSO-d
6) δ: 14.34 (s, 1H, H-11), 8.83 (s, 1H, H-2); (7.92 d, 1H, J=12Hz, H-5), 6.12 (s; 2H, H-20), 5.76 (m, 1H, H-18); (4.41-4.38 m, 1H, H-12), 3.48-3.43 (m, 3H; H-14, H-15and H-17), 3.30-3.27 (m, 4H, H-14, H-15, H-16and H-17), 1.22-1.19 (m; 2H, H-13), 1.01-0.99 (m, 2H, H-13);
13C NMR (151MHz, DMSO-d
6) δ: (176.55,176.53), (165.51,158.56); 156.83,155.16,155.22, (144.12; 144.02), 138.38, (123.28,123.23); (120.03,120.00), (111.06,110.91); 108.06,51.21,51.18; 44.63 (2 * C), 42.02,11.27 (2 * C); HR MS C
18H
18ClFN
4NaO
4Value of calculation is 431.0893, and measured value is 431.0896;
(c=1mg/mL, DMF).
TM2-27-(3-(3-MU)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: m.p.212.9-215.8 ℃;
1H NMR (300MHz, CDCl
3) δ: 14.26 (s, 1H, H-11), 8.93 (s, 1H, H-2); (8.05 d, 1H, J=9Hz, H-5), 5.30 (s, 1H; H-18), 4.61-4.59 (m, 1H, H-20), 4.40-4.33 (m; 1H, H-12), 3.93-3.85 (m, 4H, H-14, H-15, H-16and H-17); (3.43-3.42 m, 3H, H-14, H-15and H-17), 3.37-3.28 (d, 3H; J=9Hz, H-21), 1.36-0.96 (m, 4H, H-13);
13C NMR (75MHz, CDCl
3) δ: 176.63,165.82,158.05,154.72; 148.58, (143.52,143.26), 137.72; (124.63,124.48), (120.74,120.59); (112.12,111.81), 108.53,50.93; 50.44,49.11,46.62; 41.35,35.76,11.43 (2 * C); HR MS:C
19H
21ClFN
4O
4Value of calculation is 423.1230, and measured value is 423.1236;
(c=1mg/mL, DCM).
TM2-37-(3-diazanyl Methanamide-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: m.p.221.2.1-223.7 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.52 (s, 1H, H-11), 8.83 (s, 1H; H-2), 7.94 (d, 1H, J=12Hz; H-5), 5.75 (m, 1H, H-18); (4.42-4.34 m, 1H, H-20), 3.48-3.43 (m; 4H, H-12, H-14, H-15and H-17), 3.35-3.30 (m, 4H; H-14, H-15, H-16and H-17), 1.18-0.98 (m, 4H, H-13);
13CNMR (75MHz, DMSO-d
6) δ: (176.65,176.62), 165.84,157.88; 154.53,151.97, (144.21,144.01); 137.87, (123.78,123.67), (120.05; 119.99), (111.80,111.48); 108.43,51.18,51.04; 44.48 (2 * C), 41.98,11.25 (2 * C); HR MS:C
18H
20ClFN
5O
4Value of calculation is 424.1182, and measured value is 424.1185;
(c=1mg/mL, DMF).
TM2-47-(3-(1-methyl diazanyl Methanamide-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid hydrochloride: m.p.266.7-269.3 ℃,
1H NMR (600MHz, DMSO-d
6) δ: 14.34 (s, 1H, H-11), 10.15 (s; 3H, H-22and H-23), 8.86 (s, 1H; H-2), 7.98 (d, 1H, J=12Hz; H-5), 5.76 (s, 1H, H-18); (4.43-4.40 m, 1H, H-12); (3.39-3.36 m, 3H, H-14, H-15and H-17); (3.37-3.34 m, 4H, H-14, H-15, H-16and H-17); (3.07 s, 3H, H-21); (1.22-1.19 m, 2H, H-13); (1.02-0.99 m, 2H, H-13);
13C NMR (151MHz, DMSO-d
6) δ: 176.60,165.51,161.67, (156.91; 155.23), 153.39, (143.72,143.62); 138.34, (123.72,123.67), (120.44; 120.41), (111.20,111.04), 108.14; 50.92,50.89,46.32 (2 * C); 42.02,41.36,11.29 (2 * C); HR MS C
19H
22ClFN
5O
4Value of calculation is 438.1339, and measured value is 438.1336;
(c=1mg/mL, DMF).
TM2-57-(3-(3-hydroxyurea)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: m.p.219.3-222.0 ℃,
1H NMR (600MHz, DMSO-d
6) δ: 14.34 (s, 1H, H-11), 9.20 (s; 1H, H-21), 8.83 (s, 1H; H-2), 8.13 (s, 1H, H-20); (7.92 d, 1H, J=12Hz, H-5); (5.76 s, 1H, H-18); (4.40-4.38 m, 1H, H-12); (3.48-3.44 m, 3H, H-14, H-15and H-17); (3.30-3.27 m, 4H, H-14, H-15, H-16and H-17); (1.22-1.19 m, 2H, H-13); (1.02-0.99 m, 2H, H-13);
13C NMR (151MHz, DMSO-d
6) δ: 176.53,165.52,160.13, (156.84; 155.18), 153.25, (143.99,143.90); 138.35, (123.42,123.37), (120.17; 120.14), (111.09,110.93); 108.12,51.07,51.04; 44.40 (2 * C), 42.00,11.27 (2 * C); HR MS C
18H
19ClFN
4O
5Value of calculation is 425.1022, and measured value is 425.1027;
(c=1mg/mL, DMF).
TM2-67-(3-(3-methoxyl group urea)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: m.p.252.0-257.0 ℃,
1H NMR (600MHz, CDCl
3) δ: 14.32 (s, 1H, H-11), 8.92 (s, 1H, H-2); (8.06 d, 1H, J=12Hz, H-5), 5.30 (s; 1H, H-18), 4.36-4.34 (m, 1H, H-12); (3.78 s, 3H, H-21), 3.66-3.64 (m, 3H; H-14, H-15and H-17), 3.41-3.39 (m, 4H, H-14, H-15, H-16and H-17), 1.34-1.32 (m; 2H, H-13), 0.99-0.97 (m, 2H, H-13);
13C NMR (151MHz, CDCl
3) δ: 176.77,165.93,157.18,155.50; 152.16, (143.89,143.80), 137.85; (124.30,124.24), (120.41,120.39); (112.06,111.91), 108.74,64.29; 50.90,47.33,44.49; 41.30,29.70,11.49 (2 * C); HR MS C
19H
21ClFN
4O
5Value of calculation is 439.1179, and measured value is 439.1175;
(c=1mg/mL, DMF).
TM2-77-(3-(3,3-bis-(2-ethoxy) urea)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: m.p.218.1-219.4 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.53 (s, 1H, H-11), 8.82 (s, 1H; H-2), 7.93 (d, 1H, J=12Hz, H-5); (6.63 t, 2H, J=6Hz, H-22), 4.73 (m; 1H, H-18), 4.39-4.37 (m, 1H, H-12); (3.53-3.48 m, 4H, H-21), 3.33-3.25 (m, 11H; H-14, H-15, H-16, H-17and H-20), 1.21-0.98 (m, 4H, H-13);
13C NMR (75MHz, DMSO-d
6) δ: (176.41,176.37), 165.43,164.41,157.50; (154.17,153.04), (144.17,143.97); (138.35,138.33), (123.03,122.93); (119.75,119.68), (111.02,110.70); 107.98,59.16,51.03,50.99; 50.47,47.9 (2 * C) 6,43.44,11.26 (2 * C); HR MS:C
22H
26ClFN
4NaO
6Value of calculation is 519.1417, and measured value is 519.1419;
(c=1mg/mL, DCM).
Embodiment 3, compound TM3's is synthetic
In reaction bulb, add amino aminoacid Boc-AA-OH 12mmol and the DCM 20mL protected by tertbutyloxycarbonyl (Boc); stir 1min; under ice bath, add 1-hydroxy benzo triazole (HOBt) 12mmol and dicyclohexyl carbodiimide (DCC) 15mmol; stir 1min; drip again TEA 1mL; stir about 30min under ice bath; after to raw material, all generating Acibenzolar; sucking filtration; filter cake washs with DCM, and washing liquid and filtrate merge, and add clinafloxacin 10mmol; the stirring at normal temperature reaction, TLC monitoring reaction process.React complete, sucking filtration, filter cake washs with DCM, and washing liquid and filtrate merge, and use respectively 10% (w/w) citric acid solution, 0.5mol/L NaHCO
3Solution, saturated NaCl solution washing, collect organic facies, anhydrous Na
2SO
4Drying, revolve steaming, and column chromatography purification obtains intermediate compound I M3.
In reaction bulb, add intermediate compound I M3 and appropriate DCM, stirring at room is dissolved, and under ice bath, drips TFA (V
TFA: V
DCM=1:3), stirring at room reaction, TLC monitoring reaction process.React complete, in fume hood, take out TFA30min, then revolve to steam as far as possible and remove TFA, reactant liquor is slowly joined in freezing ether to separate out product, centrifugal, solid is with chilled ethyl ether (15mL * 2) washing again, drying, be dissolved in a small amount of ethanol, adds 10% (w/w) Na
2CO
3Frozen water solution, stir, standing, filter to obtain solid, then be dissolved in dehydrated alcohol, add HCl, stir, standing, sucking filtration, washing, drying, obtain compound TM4.Synthesize and the results are shown in Table 3.
Table 3 compound TM3 synthesizes result
TM3-17-(3-(2-glycyl amino)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid hydrochloride: m.p.223.1-225.6 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.48 (s, 1H, H-11), 8.85 (s, 1H; H-2), 8.08 (s, 3H, H-21), 7.97 (d; 1H, J=11.7Hz, H-5), 4.34-4.45 (m, 1H; H-12), 3.96 (s, 2H, H-20), 3.49-3.79 (m; 5H, H-14, H-16and H-17), 1.71-2.14 (m, 2H; H-15), 0.97-1.22 (m, 4H, H-13);
13CNMR (75MHz, DMSO-d
6) δ: 11.28,39.64,39.81,40.18,40.46,42.01,51.02,108.13,111.12,120.38,123.42,133.68,138.25,143.81,153.27,165.41,167.63,176.54; HR MS:C
19H
20ClFN
4O
4[M+H]
+Value of calculation is 423.1230, and measured value is 423.1232.
TM3-27-(3-(2-pyrrolidinyl formamido group)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid hydrochloride: m.p.196.8-199.8 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.47 (s, 1H, H-11), 8.85 (s; 1H, H-2), 8.14 (s, 2H; H-24), 7.97 (d, 1H; J=11.7Hz, H-5), 4.32-4.50 (m, 2H; H-12and H-20), 3.60-3.80 (m, 6H, H-14; H-17and H-23), 3.38-3.53 (m, 1H, H-16); (2.04-2.17 m, 2H, H-21); (1.68-2.00 m, 2H, H-15); (1.33-1.35 m, 2H, H-22); (0.88-1.31 m, 4H, H-13);
13C NMR (75MHz, DMSO-d
6) δ: 11.27,24.25,28.76,33.54,39.64,40.47,41.88,46.72,51.34,62.04,108.09,111.20,123.64,128.36,133.80,138.28,143.70,153.28,165.48,168.69,176.64; HR MS:C
22H
24ClFN
4O
4[M+H]
+Value of calculation is 463.1543, and measured value is 463.1540.
TM3-37-(3-(2-amino-4-(methyl mercapto) butyrylamino)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid hydrochloride: m.p.244.7-247.6 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.27 (s, 1H, H-11), 8.92 (s, 1H; H-2), 8.76 (s, 3H, H-24), 8.06 (d; 1H, J=11.1Hz, H-5), 5.47 (t; 1H, J=9Hz, H-20), 4.31-4.39 (m; 1H, H-12), 4.03 (t, 2H; J=9Hz, H-22), 3.52-3.92 (m, 4H; H-14and H-17), 3.44-3.53 (m, 1H, H-16); (2.43 s, 3H, H-23), 2.17-2.21 (m; 2H, H-21), 1.68-2.03 (m, 2H; H-15), 0.91-1.36 (m, 4H, H-13);
13C NMR (75MHz, DMSO-d
6) δ: 11.41,15.19,28.39,33.89,34.39,41.29,43.10,48.82,49.20,51.13,107.96,111.19,123.24,125.48,134.66,138.42,143.79,153.26,165.47,167.63,176.54.
Embodiment 4, compound TM4's is synthetic
In reaction bulb, add successively Boc-Met-OH, HOBt and appropriate THF, be stirred to dissolve, ice bath is cooling, add DCC and diisopropyl ethylenediamine (DIPEA), ice bath stirred 30 minutes, added CF and added appropriate THF, and the molar ratio of CF, Boc-Met-OH, HOBt, DCC and DIPEA is 10:14:12-15:12-15:15-20, the stirring at room reaction, TLC monitoring reaction process.React complete, by reactant liquor in 4 ℃ of hold over night, sucking filtration, filter cake washs with DCM, washing liquid and filtrate merge, distilling under reduced pressure is except desolventizing, residue is used 0.5mol/L NaHCO after with DCM, dissolving successively
3Solution, 10% (w/w) citric acid solution and saturated common salt water washing, collect organic facies, anhydrous Na
2SO
4Drying, filter, and the filtrate decompression distillation, except desolventizing, with DCM-petroleum ether mixed solvent recrystallization, obtains intermediate compound I M4-1.
In reaction bulb, add intermediate compound I M4-11mmol, more progressively add DCM4mL, ice bath is cooling, adds metachloroperbenzoic acid (mCPBA) 2.1mmol, 0 ℃ of stirring reaction, TLC monitoring reaction process.React complete, if obtained faint yellow turbid solution, add appropriate DCM solid is dissolved fully; If obtained supernatant liquid, do not need to add DCM; Then use successively 5% (w/w) Na
2CO
3Solution and saturated common salt water washing, anhydrous Na
2SO
4Drying, filter, and the filtrate decompression distillation, except desolventizing, with DCM-PE mixed solvent recrystallization, obtains intermediate compound I M4-2.
In reaction bulb, add intermediate compound I M4-21mmol and DCM3～6mL, stirring and dissolving, ice bath is cooling, slowly drips TFA1～3mL, ice bath stirring reaction, TLC monitoring reaction process.React complete, TFA is removed in distilling under reduced pressure, and residual liquid slowly adds in freezing ether, stirs, and refrigerator and cooled is hidden crystallize, inhales and abandons ether, and solid washs with chilled ethyl ether, and drying slowly drips saturated K under room temperature
2CO
3Solution 15～25mL (fully dissolve and be as the criterion with raw material), regulate pH to 3～4 with dilute hydrochloric acid, if any solid, separates out, and sucking filtration, a small amount of water washing of filter cake, obtain crude product; If without solid, separated out, in solution, add solid Sal to reaching capacity, then put refrigerator and cooled and hide crystallize, a small amount of water washing of sucking filtration, filter cake, obtain crude product.Crude product is disperseed with 92% (v/v) ethanol, sucking filtration, drying, obtain compound TM4.
TM47-(3-(2-amino-4-mesyl) butyrylamino)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-the dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid hydrochloride: m.p.222.9-225.5 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 14.35 (s, 1H, H-11), 8.85 (s; 1H, H-2), 8.55 (s, 3H; H-24), 7.98 (d, 1H, J=11.4Hz; H-5), 4.60-4.63 (m, 1H, H-16); (4.40-4.43 m, 1H, H-12), 3.64-3.81 (m; 4H, H-14and H-17), 3.56 (m, 1H; H-20), 3.36-3.37 (m, 2H, H-22); (3.33-3.35 m, 2H, H-21), 3.05 (s; 3H, H-23), 2.19-2.21 (m, 2H; H-15), 0.98-1.21 (m, 4H, H-13);
13C NMR (75MHz, DMSO-d
6) δ: 11.32 (2 * C), 24.31,40.72,42.01,42.99,46.24,48.48,49.58,50.81,51.26,107.96,110.85,120.13,123.27,138.23,143.58,143.77,153.11,165.38,166.99,176.47; HR MS:C
22H
27ClFN
4O
6S[M+H]
+Value of calculation is 529.1318, and measured value is 529.1314;
(c=1mg/mL, H
2O).
Embodiment 5, compound TM5's is synthetic
In reaction bulb, add 5mL alcohol and enough na sheet, stirring at room, when without bubble, producing, take out unnecessary sodium sheet, adds appropriate correspondent alcohol and compd A 1mmol according to the state of sodium alkoxide, continues the stirring at room reaction, TLC monitoring reaction process.React complete, adjust pH=4～5 with 3N HCl, add 10mL DCM extraction, organic facies water (2 * 10mL) washings, anhydrous Na
2SO
4Dry.For the lower alcohol of boiling point, revolve and steam to obtain crude product; The alcohol high for boiling point, that water solublity is bad, concentrated by rotary evaporation is removed DCM, adds ether, often has a large amount of solids to separate out, sucking filtration, filter cake washs with ether, obtains crude product.The crude product column chromatography purification, obtain compound TM5.
Table 4 compound TM5 synthesizes result
TM5-17-(3-((methoxycarbonyl group) amino)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: m.p.205.6-208.2 ℃,
1H NMR (600MHz, CDCl
3) δ: 14.34 (s, 1H, H-11), 8.92 (s, 1H, H-2); (8.05 d, 1H, J=12Hz, H-5), 5.30 (s; 1H, H-18), 4.38-4.34 (m, 1H, H-12); (3.76 s, 3H, H-20), 3.69-3.67 (m, 3H; H-14, H-15and H-17), 3.34-3.32 (m, 4H, H-14, H-15, H-16and H-17), 1.33-1.25 (m; 2H, H-13), 1.00-0.97 (m, 2H, H-13);
13C NMR (151MHz, CDCl
3) δ: (176.78,176.75), 165.93,157.59; (155.94,155.07), 152.07, (144.21; 144.07), 137.86, (124.10,124.02); (120.24,120.19), (112.01,111.17); 108.68,52.84,51.04,51.00; 44.39,41.27,29.68,11.45 (2 * C); HR MS calcd for C
19H
19ClFN
3O
5[M-H]
-422.0925, found422.0928;
(c=1mg/mL, DCM).
TM5-27-(3-((isopropyl oxygen carbonyl) amino)-1-pyrrolidinyl)-chloro-Isosorbide-5-Nitrae-dihydro of the fluoro-8-of 1-cyclopropyl-6--4-oxo-3-quinoline carboxylic acid: m.p.191.8-193.3 ℃,
1H NMR (600MHz, CDCl
3) δ: 14.34 (s, 1H, H-11), 8.91 (s; 1H, H-2), 8.04 (d, 1H; J=12Hz, H-5), 5.30 (s, 1H; H-18), 5.01-4.95 (m, 1H, H-20); (4.37-4.35 m, 1H, H-12), 3.69-3.67 (m; 3H, H-14, H-15and H-17), 3.36-3.34 (m, 4H; H-14, H-15, H-16and H-17), 1.34-1.30 (m, 2H, H-13); (1.29 s, 3H, H-21); (1.28 s, 3H, H-21); (0.99-0.96 m, 2H, H-13);
13C NMR (151MHz, CDCl
3) δ: (176.77,176.75), 165.95,157.56, (155.19; 155.04), 152.03, (144.30,144.16); 137.87, (124.00,123.96), (120.11; 120.06), (111.99,111.76), 108.67; 69.03,51.09,51.05,44.28; 44.19,41.26,22.24 (2 * C), 11.44 (2 * C); HR MS calcd for C
21H
23ClFN
3O
5[M-H]
-450.1238, found450.1378;
(c=1mg/mL, DCM).
Embodiment 6, synthetic compound are measured the minimum inhibitory concentration (MIC) of mycobacterium tuberculosis
Picking goes down to posterity in modified Russell medium 2 weeks, well-grown bacterial strains were appropriate afterwards, ground to form bacteria suspension with bacteria grinder, and by turbidimetry, regulating concentration is 1mg/mL, then uses general enriched medium stepwise dilution to 1 * 10
-3Mg/mL and 5 * 10
-4The working concentration of mg/mL.Testing compound is dissolved in to the storing solution of making 5mg/mL in dimethyl sulfoxine (DMSO) ,-20 ℃ of preservations; With general enriched medium dilution, be the basal liquid of 42 μ g/mL before use, then basal liquid is diluted to different experimental concentration (4,2,1,0.5,0.25,0.125,0.0625,0.0313,0.0156 μ g/mL) with general enriched medium.In 96 orifice plates, by 10 μ L/ holes, add respectively the testing compound of variable concentrations, with ofloxacin and the positive medicine contrast of Moxifloxacin, the growth control hole adds general enriched medium, again the bacteria suspension of variable concentrations is inoculated in each hole with 200 μ L/ holes respectively, strain class and bacteria concentration in each hole of same plate are identical, and establish 1 compound plate, and then with adhesive tape, 96 orifice plate lids are sealed, hatch for 37 ℃.Hatch approximately after 7 days, be that the growth control hole has a large amount of bacteria growings and the antibacterial gradient of positive drug when obvious, every hole adds the mixed liquor of 20 μ L Alamar blue solution and the aseptic 5%Tween80 solution of 50 μ L, hatches 24 hours for 37 ℃, records each hole color: blue Kong Weiwu growth; The pink hole is for there being growth; The aubergine hole continues at 37 ℃ again and cultivated 24 hours, does not become pink, and adjacent blue hole be still blueness, has been recorded as growth.MIC the results are shown in Table 5 and table 6.
The MIC (μ g/mL) of table 5 synthetic compound to mycobacterium tuberculosis standard sensitive strain
Annotate: "-" means undetermined.
As can be seen from Table 5, on the whole, test-compound all has certain inhibition to mycobacterium tuberculosis standard sensitive strain, wherein, the bacteriostatic activity of compound TM1-4 and TM1-10 is the strongest, suitable with clinafloxacin, is better than ofloxacin and slightly is weaker than Moxifloxacin; Bacteriostatic activity and the ofloxacin of TM1-5 are suitable; The bacteriostatic activity of TM1-3 and TM1-9 slightly is weaker than ofloxacin.In addition, the fungistatic effect of compound substantially can be along with bacterial strain concentration increases and changes.
The MIC (μ g/mL) of table 6 partial synthesis compound to the different clinical separation strains of mycobacterium tuberculosis
Annotate: "-" means undetermined.
As can be seen from Table 6, on the whole, test-compound all has certain inhibition to the clinical separation sensitive strain of mycobacterium tuberculosis with the clinical persister that separates, wherein, the bacteriostatic activity of compound TM1-4 is the strongest, bacteriostatic activity to clinical separation sensitive strain is better than ofloxacin and slightly is weaker than Moxifloxacin, and high 2～4 times than clinafloxacin, and clinical separation persister is also shown to stronger bacteriostatic activity No. 1288; The bacteriostatic activity of TM1-5 and TM1-10 takes second place.
Finally explanation is, above preferred embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is described in detail by above preferred embodiment, but those skilled in the art are to be understood that, can to it, make various changes in the form and details, and not depart from the claims in the present invention book limited range.
Claims (4)
1. Clinafloxacin amino derivatives and officinal salt thereof the application in preparing antituberculotics, described Clinafloxacin amino derivatives has following general structure:
In formula, R is-(CH
2) nNR
1R
2,-CH (CH
2CH
2XCH
3) NH
2, the 2-pyrrolidinyl or-OR
3
N is 0 or 1; R
1And R
2Be hydrogen, methyl, 2-hydroxyethyl, (R)-1-ethyl-2-hydroxyethyl, 2-amino-ethyl, 3-(dimethylamino) propyl group, hydroxyl, amino, methylamino, methoxyl group or ghiourea group independently;
X is S or SO
2
R
3For methyl or isobutyl group.
2. Clinafloxacin amino derivatives according to claim 1 and officinal salt thereof the application in preparing antituberculotics, is characterized in that, n is 0, R
1And R
2Be hydrogen, methyl, 2-hydroxyethyl, hydroxyl, amino, methylamino or methoxyl group independently; N is 1, R
1And R
2Be hydrogen, methyl, 2-hydroxyethyl, (R)-1-ethyl-2-hydroxyethyl, 2-amino-ethyl, 3-(dimethylamino) propyl group, hydroxyl, amino or ghiourea group independently.
3. Clinafloxacin amino derivatives according to claim 2 and officinal salt thereof the application in preparing antituberculotics is characterized in that R is-(CH
2) nNR
1R
2,-CH (CH
2CH
2XCH
3) NH
2, the 2-pyrrolidinyl or-OCH
3N is 0, R
1And R
2Be hydrogen, methyl, hydroxyl or amino independently; N is 1, R
1And R
2Be hydrogen, methyl, 2-hydroxyethyl, (R)-1-ethyl-2-hydroxyethyl, 2-amino-ethyl, hydroxyl, amino or ghiourea group independently; X is S or SO
2.
4. Clinafloxacin amino derivatives according to claim 3 and officinal salt thereof the application in preparing antituberculotics is characterized in that R is-CH
2NR
1R
2R
1For hydrogen, R
2For ghiourea group; R
1For methyl or 2-hydroxyethyl, R
2For the 2-hydroxyethyl.
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| CN111087390A (en) * | 2017-11-10 | 2020-05-01 | 西南大学 | Fluoroquinolone amino derivative and application thereof |
| CN112159390A (en) * | 2020-09-25 | 2021-01-01 | 西南大学 | Synephrine fluoroquinolone derivative and preparation method and application thereof |
| CN113480519A (en) * | 2021-07-23 | 2021-10-08 | 西南大学 | Oxacycloxacin derivative and preparation method and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| DE102017218114A1 (en) | 2017-10-11 | 2019-04-11 | Leuphana Universität Lüneburg Stiftung Öffentlichen Rechts | Biodegradable quinolone antibiotics |
| WO2019072907A1 (en) | 2017-10-11 | 2019-04-18 | Leuphana Universitaet Lueneburg Stiftung Oeffentlichen Rechts | Biodegradable quinolone antibiotics |
| CN111087390A (en) * | 2017-11-10 | 2020-05-01 | 西南大学 | Fluoroquinolone amino derivative and application thereof |
| CN111087390B (en) * | 2017-11-10 | 2022-07-05 | 西南大学 | Fluoroquinolone amino derivative and application thereof |
| CN112159390A (en) * | 2020-09-25 | 2021-01-01 | 西南大学 | Synephrine fluoroquinolone derivative and preparation method and application thereof |
| CN112159390B (en) * | 2020-09-25 | 2022-07-19 | 西南大学 | Synephrine fluoroquinolone derivative and preparation method and application thereof |
| CN113480519A (en) * | 2021-07-23 | 2021-10-08 | 西南大学 | Oxacycloxacin derivative and preparation method and application thereof |
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