CN107459507B - Clinafloxacin oxazolidinyl derivative and preparation method and application thereof - Google Patents

Clinafloxacin oxazolidinyl derivative and preparation method and application thereof Download PDF

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CN107459507B
CN107459507B CN201610390274.5A CN201610390274A CN107459507B CN 107459507 B CN107459507 B CN 107459507B CN 201610390274 A CN201610390274 A CN 201610390274A CN 107459507 B CN107459507 B CN 107459507B
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CN107459507A (en
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杨大成
任正红
范莉
蔚建勇
徐兴然
陈力
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Southwest University
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract

The invention discloses a clinafloxacin oxazolidinyl derivative which has the following structural formula, clinafloxacin is used as a substrate, the basic skeleton of the clinafloxacin is reserved, an azole structural unit is introduced at a 3-amino position of a pyrrole ring through a Linker, the derivative is a double-drug-effect group molecule which contains a fluoroquinolone mother nucleus and the azole structural unit, and experiments prove that the derivative has good antibacterial activity, particularly good activity of mycobacterium tuberculosis, low toxicity, good water solubility and good stability, can be used for preparing antibacterial drugs, and has potential application prospects in the field of antibacterial therapy, particularly tuberculosis treatment drugs.

Description

Clinafloxacin oxazolidinyl derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a novel clinafloxacin derivative, a preparation method thereof and application thereof in pharmacy.
Background
Quinolones (Quinolones) are high-efficiency, low-toxicity, good-selectivity drugs without cross-resistance with antibiotics, and are long-term used as first-line antibacterial drugs for clinical application. Clinafloxacin (CF) is an 'ultra-broad-spectrum' candidate molecule in fourth-generation quinolone antibacterial drugs, has already completed phase III clinical evaluation abroad, but is not applied for marketing finally due to obvious phototoxicity and the like. In addition, clinafloxacin has poor water solubility and insufficient stability of aqueous solution, and may also be an important factor influencing the patent medicine of clinafloxacin. The structural modification is carried out on the clinafloxacin, and a reasonable structural unit is introduced through reasonable drug design, so that a lead molecule with enhanced activity, reduced toxicity, improved water solubility and increased molecule stability can be obtained.
Azole molecules have a wide range of biological activities. In recent years, monoazazoles such as oxazole, carbazole, thiazole; bis-azoles such as pyrazole, imidazole, benzimidazole; triazole, such as triazole, benzotriazole, and tetrazole, such as tetrazole, etc., have been studied exceptionally widely and many have been applied to the fields of medicine, agriculture, and the like.
Disclosure of Invention
In view of the above, the invention aims to design and synthesize a novel molecule containing clinafloxacin and azoles double pharmacophores, and research the biological activity of the novel molecule, so as to obtain a lead molecule with better biological activity, lower toxicity, better water solubility and stability, and provide a new variety for pharmaceutical research.
Through research, the invention provides the following technical scheme:
1. clinafloxacin oxazolidinyl derivatives having the following structural formula:
Figure BDA0001009109690000011
wherein n is 1 or 2;
y is 1-hydro-imidazol-1-yl, 2-methyl-1-hydro-imidazol-1-yl, 4-methyl-1-hydro-imidazol-1-yl, 1-hydro-benzoimidazol-2-mercapto, 1-hydro-pyrazol-1-yl, 3, 5-dimethyl-1-hydro-pyrazol-1-yl, 3-amino-1-hydro-pyrazol-1-yl, 1-hydro-1, 2, 4-triazol-1-yl, 3-amino-1-hydro-1, 2, 4-triazol-5-mercapto, or mixtures thereof, 1-hydro-1, 2, 3-triazol-1-yl, 2-hydro-1, 2, 3-triazol-2-yl, 1-hydro-tetrazol-1-yl, 2-hydro-tetrazol-2-yl, 5-methyl-1-hydro-tetrazol-1-yl, 5-methyl-2-hydro-tetrazol-2-yl, 5-amino-2-hydro-tetrazol-2-yl, 5-methylmercapto-2-hydro-tetrazol-2-yl, 5-amino-1, 3, 4-thiadiazole-2-mercapto, 5-methoxy-1-hydro-benzimidazol-2-mercapto or 1-hydro-benzotriazol-1-yl.
Preferably, n is 1, Y is 1-hydro-imidazol-1-yl, 2-methyl-1-hydro-imidazol-1-yl, 4-methyl-1-hydro-imidazol-1-yl, 1-hydro-benzimidazol-2-mercapto, 1-hydro-pyrazol-1-yl, 3, 5-dimethyl-1-hydro-pyrazol-1-yl, 3-amino-1-hydro-pyrazol-1-yl, 1-hydro-1, 2, 4-triazol-1-yl, 3-amino-1-hydro-1, 2, 4-triazol-5-mercapto, or mixtures thereof, 1-hydro-1, 2, 3-triazol-1-yl, 2-hydro-1, 2, 3-triazol-2-yl, 1-hydro-tetrazol-1-yl, 2-hydro-tetrazol-2-yl, 5-methyl-1-hydro-tetrazol-1-yl, 5-methyl-2-hydro-tetrazol-2-yl, 5-amino-2-hydro-tetrazol-2-yl, 5-methylmercapto-2-hydro-tetrazol-2-yl, 5-amino-1, 3, 4-thiadiazole-2-mercapto, 5-methoxy-1-hydro-benzimidazol-2-mercapto or 1-hydro-benzotriazol-1-yl;
n is 2; y is 1-hydro-imidazol-1-yl, 2-methyl-1-hydro-imidazol-1-yl, 4-methyl-1-hydro-imidazol-1-yl, 1-hydro-benzimidazol-1-yl, 1-hydro-pyrazol-1-yl, 3, 5-dimethyl-1-hydro-pyrazol-1-yl, 1-hydro-1, 2, 4-triazol-1-yl, 1-hydro-1, 2, 3-triazol-1-yl, 2-hydro-1, 2, 3-triazol-2-yl, 5-methyl-1-hydro-tetrazol-1-yl, methyl-1-hydro-imidazol-1-yl, methyl-1-hydroxy-pyrazol-1-yl, methyl-1-hydroxy, 5-methyl-2-hydro-tetrazol-2-yl, 5-amino-1, 3, 4-thiadiazole-2-mercapto.
2. The preparation method of the clinafloxacin oxazolidinyl derivative comprises the step of reacting a compound IM with an azole compound YH in a solvent under the action of alkali at 25-85 ℃ to prepare the clinafloxacin oxazolidinyl derivative, wherein the solvent is Dichloromethane (DCM), Dimethylformamide (DMF), water or a dimethylformamide-water mixed solution, and the alkali is potassium carbonate (K)2CO3) Or sodium hydride (NaH); the chemical reaction formula is as follows:
Figure BDA0001009109690000021
the definition of n in the structural formula of the compound IM is the same as that of n in the structural formula of the clinafloxacin oxazolidinyl derivative; the definition of Y in the structural formula of the azole compound YH is the same as that of Y in the structural formula of the clinafloxacin oxazolidinyl derivative.
3. Use of the clinafloxacin oxazolidinyl derivative of claim 1 or 2 for the preparation of antibacterial medicaments.
Preferably, the antibacterial drug is a drug against any one or more of pseudomonas aeruginosa, salmonella, staphylococcus aureus, escherichia coli and mycobacterium tuberculosis.
The invention has the beneficial effects that: based on the active fragment drug design idea, clinafloxacin is used as a substrate, the idea of 'reserving clinafloxacin basic skeleton and deriving pyrrole ring 3-amino' is adopted, and an azole structural unit is introduced by means of a Linker, so that the clinafloxacin oxazolidinyl derivatives with novel structures are synthesized, and the derivatives are double-drug-effect group molecules containing fluoroquinolone mother nuclei and the azole structural unit.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, preferred embodiments of the present invention will be described in detail below.
The raw material compounds IM1 and IM2 are prepared according to the synthesis method described in Chinese patent CN 103396396A "amino alkanoyl clinafloxacin and its application".
EXAMPLE 1 Synthesis of the object Compound TM3/TM4
Figure BDA0001009109690000031
Adding the azole compound YH, a solvent and a base into a 100mL round-bottom flask in sequence, stirring for 30min, adding the compound IM1 or IM2, stirring at a controlled temperature for reaction, and monitoring the reaction progress by thin-layer chromatography (TLC). After the reaction is finished, adding 10mL of NaCl aqueous solution, adjusting the pH to 6-7 with 2N HCl solution, refrigerating at 2-8 ℃, filtering, fully washing a filter cake with saturated salt solution, washing with water, drying, and using EtOH-H with different proportions2Recrystallizing or dispersing the O solution to obtain crude product or pure product, and purifying the crude product by column chromatography to obtain target compound TM3 or TM 4. Specific preparation conditions and experimental results are shown in table 1. The structure of the product is measured by physical constants,1H NMR、13C NMR and HR-MS.
TABLE 1 preparation conditions and experimental results for the target compound TM3/TM4
Figure BDA0001009109690000032
Figure BDA0001009109690000041
Figure BDA0001009109690000051
Note: indicates that no product was obtained.
The 1,2, 3-triazole and the tetrazole compound have the following interconversion structures:
Figure BDA0001009109690000052
thus, when it is used as a reaction raw material, two products may be produced: 1-substitution product a 'and 2-substitution product b'. However, depending on the reactants, the amount of isomers is small, and separation and purification are difficult.
The structural identification data of the target compound TM3/TM4 are as follows:
Figure BDA0001009109690000053
(7- (3- (2- (1-hydro-imidazol-1-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-1): a light yellow solid, m.p.258.3-260.1 ℃;1H NMR(300MHz,DMSO-d6)δ:14.52(s,1H,H-11),9.06(s,1H,H-21),8.86(s,1H,H-2),7.99(d,1H,J＝11.7Hz,H-5),7.67(s,2H,H-22and H-23),5.46(s,2H,H-20),4.46-4.38(m,1H,H-12),3.71-3.67(m,3H,H-16and H-17),3.50-3.43(m,2H,H-14),3.38-3.35(m,2H,H-15),1.23-1.19(m,2H,H-13),1.04-1.00(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.15,165.14,164.34,(157.31,153.99),152.96,(143.43,143.24),137.94,136.82,123.52,(123.24,123.12),119.91,119.63,(110.86,110.54),107.69,50.62,50.55,49.78,45.14,42.55,41.66,10.92(2×C)；HR MS:C22H21ClFN5O4[M+H]+calculated value is 474.1344, found value is474.1346.
(7- (3- (2- (2-methyl-1-hydro-imidazol-1-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-2): a light yellow solid, m.p. 269.3-270.6 ℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),8.86(s,1H,H-2),7.99(d,1H,J＝11.7Hz,H-5),7.56(d,2H,J＝9.9Hz,H-21and H-22),5.41(s,2H,H-20),4.45-4.38(m,1H,H-12),3.70-3.64(m,3H,H-16and H-17),3.50-3.45(m,2H,H-14),3.38-3.34(m,2H,H-15),2.50(s,3H,H-23),1.22-1.18(m,2H,H-13),1.03-0.99(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.13,165.12,163.84,(157.23,153.90),152.90,145.57,(143.48,143.29),137.95,123.27,(123.10,123.00),119.83,117.43,(110.80,110.49),107.66,50.67,50.62,48.49,45.22,42.57,41.65,10.93,10.33(2×C)；HR MS:C23H23ClFN5O4[M+H]+the calculated value was 488.1501, found 488.1503.
(7- (3- (2- (4-methyl-1-hydro-imidazol-1-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-3): a light yellow solid, m.p.265.5-266.7 ℃;1H NMR(300MHz,DMSO-d6)δ:14.52(s,1H,H-11),8.97(s,1H,H-21),8.86(s,1H,H-2),7.99(d,1H,J＝11.7Hz,H-5),7.37(s,1H,H-22),5.40(s,2H,H-20),4.46-4.38(m,1H,H-12),3.70-3.64(m,3H,H-16and H-17),3.49-3.43(m,2H,H-14),3.37-3.31(m,2H,H-15),2.31(s,3H,H-23),1.23-1.19(m,2H,H-13),1.03-0.99(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.09,165.12,164.36,(157.24,153.85),152.89,(143.44,143.26),137.92,135.76,128.78,(123.15,123.05),120.12,(119.84,119.67),(110.79,110.48),107.67,50.87,50.58,49.80,45.15,42.57,41.66,10.94,9.65,8.60；HR MS:C23H23ClFN5O4[M+H]+the calculated value was 488.1501, found 488.1503.
Figure BDA0001009109690000061
(7- (3- (2- (1-hydro-benzimidazol-1-yl) acetamido) -1-pyri-dinePyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (TM 3-4): creamy yellow solid, m.p.272.4-273.8 ℃;1H NMR(300MHz,DMSO-d6)δ:14.55(s,1H,H-11),8.86(s,1H,H-2),8.59(s,1H,H-21),7.99(d,1H,J＝11.7Hz,H-5),7.76-7.68(m,2H,H-22),7.39-7.30(m,2H,H-23),5.53(s,2H,H-20),4.46-4.39(m,1H,H-12),3.80-3.69(m,3H,H-16and H-17),3.54-3.51(m,2H,H-14),3.38-3.34(m,2H,H-15),1.24-1.18(m,2H,H-13),1.05-1.01(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.16,165.20,165.14,(157.25,153.93),152.89,(143.53,143.34),137.94,124.45,123.20(2×C),122.98,122.64,119.82,118.13,114.79,111.48,(110.81,110.50),107.67,50.79,50.69,46.13,45.25,42.45,41.65,10.92(2×C)；HR MS:C26H23ClFN5O4[M+H]+the calculated value was 524.1501, found 524.1505.
(7- (3- (2- (1-hydro-benzoimidazol-2-mercapto) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-5): a creamy yellow solid, m.p.214.7-216.1 ℃;1H NMR(300MHz,DMSO-d6)δ:14.27(s,1H,H-11),8.75(s,1H,H-2),7.95(s,1H,H-21),7.99(d,1H,J＝12.0Hz,H-5),7.47-7.44(m,2H,H-22),7.13-7.09(m,2H,H-23),4.52(s,2H,H-20),4.33-4.26(m,1H,H-12),3.75-3.67(m,3H,H-16and H-17),3.35-3.33(m,2H,H-14),3.28-3.25(m,2H,H-15),1.19-1.13(m,2H,H-13),0.93-0.87(m,2H,H-13)；HR MS:C26H23ClFN5O4S[M+H]+the calculated value was 556.1222, found 556.1219.
Figure BDA0001009109690000071
(7- (3- (2- (1-hydro-pyrazol-1-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-6): a light yellow solid, m.p.258.2-259.1 ℃;1H NMR(300MHz,DMSO-d6)δ:14.54(s,1H,H-11),8.86(s,1H,H-2),7.97(d,1H,J＝11.7Hz,H-5),7.68(d,1H,J＝2.1Hz,H-21),7.45(d,1H,J＝1.5Hz,H-23),6.28(t,1H,J＝1.8Hz,H-22),5.22(s,2H,H-20),4.43-4.38(m,1H,H-12),3.70-3.66(m,3H,H-16and H-17),3.58-3.54(m,4H,H-14and H-15),1.22-1.18(m,2H,H-13),1.03-0.99(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.18,165.84,165.15,(157.27,153.94),152.90,(143.54,143.35),138.64,137.97,131.49,(123.09,122.98),119.82,(110.81,110.50),107.67,105.41,52.68,50.84,50.68,45.24,42.25,41.65,10.91(2×C)；HR MS:C22H21ClFN5O4[M+Na]+the calculated value was 496.1164, found 496.1162.
(7- (3- (2- (3, 5-dimethyl-1-hydro-pyrazol-1-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-7): a light pink solid, m.p.290.2-291.6 ℃;1H NMR(300MHz,DMSO-d6)δ:14.56(s,1H,H-11),8.86(s,1H,H-2),7.99(d,1H,J＝11.4Hz,H-5),5.81(s,1H,H-21),5.04(s,2H,H-20),4.44-4.40(m,1H,H-12),3.71-3.67(m,3H,H-16and H-17),3.40-3.32(m,4H,H-14and H-15),2.13(s,3H,H-23),2.07(s,3H,H-22),1.23-1.19(m,2H,H-13),1.03-0.99(m,2H,H-13)；HR MS:C24H25ClFN5O4[M+Na]+the calculated value was 524.1477, found 524.1476.
(7- (3- (2- (3-amino-1-hydro-pyrazol-1-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-8): orange solid, m.p. 155.9-157.1 ℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),8.86(s,1H,H-2),7.97(d,1H,J＝11.7Hz,H-5),7.70(d,1H,J＝2.4Hz,H-22),5.74(d,1H,J＝2.7Hz,H-21),4.44-4.37(m,1H,H-12),4.11(s,2H,H-20),3.68-3.61(m,3H,H-16and H-17),3.40-3.32(m,4H,H-14and H-15),1.23-1.18(m,2H,H-13),1.03-0.99(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.15,167.73,165.15,(157.23,153.40),152.87,143.40,137.94,132.99,122.93,119.76,115.29,(110.78,110.49),107.66,58.72,50.86,50.77,45.48,42.84,41.67,10.94(2×C)；HR MS:C22H22ClFN6O4[M+H]+the calculated value was 489.1453, found 489.1452.
Figure BDA0001009109690000072
(7- (3- (2- (1-hydro-1, 2, 4-triazol-1-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-10): a light yellow solid, m.p.208.6-209.9 ℃;1H NMR(300MHz,DMSO-d6)δ:14.54(s,1H,H-11),8.86(s,1H,H-2),8.47(s,1H,H-21),7.98(s,1H,H-22),7.97(d,1H,J＝11.7Hz,H-5),5.38(s,2H,H-20),4.44-4.38(m,1H,H-12),3.72-3.68(m,3H,H-16and H-17),3.43-3.41(m,2H,H-14),3.36-3.33(m,2H,H-15),1.22-1.17(m,2H,H-13),1.05-1.00(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.50,165.84,165.33,(157.00,154.30),153.23,151.32,145.97,(143.87,142.75),138.27,(123.77,123.31),(120.19,119.81),(111.45,111.13),107.92,51.00,50.89,50.49,45.56,42.69,42.04,11.25(2×C)；HR MS:C21H20ClFN6O4[M+H]+the calculated value was 475.1297, found 475.1296.
(7- (3- (2- (3-amino-1-hydro-1, 2, 4-triazole-5-mercapto) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-11): a light yellow solid, m.p.268.9-270.3 ℃;1H NMR(300MHz,DMSO-d6)δ:14.55(s,1H,H-11),12.02(s,1H,H-21),8.85(s,1H,H-2),7.97(d,1H,J＝11.7Hz,H-5),6.11(s,2H,H-22),4.43-4.38(m,1H,H-12),4.10(s,2H,H-20),3.70-3.64(m,3H,H-16and H-17),3.37-3.30(m,4H,H-14and H-15),1.24-1.18(m,2H,H-13),1.03-0.98(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.16,166.57,165.16,(157.23,153.90),152.87,(143.54,143.35),137.95,(123.03,122.95),119.76,(110.78,110.47),107.66,50.91,50.69,46.44,42.24,41.66,34.25,10.92；HR MS:C21H21ClFN7O4S[M+H]+the calculated value was 522.1127, found 522.1122.
Figure BDA0001009109690000081
(7- (3- (2- (1-hydro-1, 2, 3-triazol-1-yl) acetamido) -1-pyri-dinePyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (TM 3-12): a light yellow solid, m.p. 290.3-290.5 ℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),8.86(s,1H,H-2),8.06(d,1H,J＝0.9Hz,H-22),8.00(d,1H,J＝12.0Hz,H-5),7.76(d,1H,J＝0.9Hz,H-21),5.59(s,2H,H-20),4.44-4.37(m,1H,H-12),3.75-3.69(m,3H,H-16and H-17),3.47-3.43(m,2H,H-14),3.38-3.33(m,2H,H-15),1.22-1.17(m,2H,H-13),1.05-1.00(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.20,165.16,164.77,(157.27,153.96),152.92,(143.54,143.34),137.98,134.75,126.62,(123.14,123.10),119.76,(110.82,110.51),107.68,55.59,50.82,50.59,45.22,42.24,41.66,10.92(2×C)；HR MS:C21H20ClFN6O4[M+Na]+the calculated value was 497.1116, found 497.1118.
(7- (3- (2- (2-hydro-1, 2, 3-triazol-2-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-13): a light yellow solid, m.p.254.3-255.2 ℃;1H NMR(300MHz,DMSO-d6)δ:14.54(s,1H,H-11),8.86(s,1H,H-2),7.98(d,1H,J＝11.7Hz,H-5),7.83(s,2H,H-21),5.63(s,2H,H-20),4.44-4.37(m,1H,H-12),3.71-3.65(m,3H,H-16and H-17),3.44-3.39(m,2H,H-14),3.37-3.33(m,2H,H-15),1.22-1.17(m,2H,H-13),1.03-0.99(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.11,176.07,165.11,164.76,164.70,(157.23,153.91),152.83,(143.50,143.31),137.90,133.11(2×C),(123.07,122.96),119.75,(110.77,110.46),107.68,50.81,50.74,50.59,45.19,42.37,41.64,10.93(2×C)；HR MS:C21H20ClFN6O4[M+Na]+the calculated value was 497.1116, found 497.1118.
Figure BDA0001009109690000091
(7- (3- (2- (1-hydro-tetrazol-1-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-14): a light yellow solid, m.p.289.2-289.7 ℃;1H NMR(300MHz,DMSO-d6)δ:14.54(s,1H,H-11),9.03(s,1H,H-21),8.86(s,1H,H-2),7.98(d,1H,J＝12.0Hz,H-5),6.05(s,2H,H-20),4.45-4.38(m,1H,H-12),3.73-3.68(m,3H,H-16and H-17),3.49-3.45(m,2H,H-14),3.38-3.34(m,2H,H-15),1.23-1.17(m,2H,H-13),1.04-1.00(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.18,165.17,163.53,(157.29,153.96),153.28,152.95,143.31,137.97,123.05,(119.49,119.03),110.84,107.69,53.79,50.66,50.54,45.28,42.38,41.65,10.91(2×C)；HR MS:C20H19ClFN7O4[M+H]+the calculated value was 476.1249, found 476.1247.
(7- (3- (2- (2-hydro-tetrazol-2-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-15): a yellowish crystalline lens, m.p.290.0-290.4 ℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),9.35(s,1H,H-21),8.86(s,1H,H-2),7.98(d,1H,J＝11.7Hz,H-5),5.75(s,2H,H-20),4.45-4.38(m,1H,H-12),3.73-3.68(m,3H,H-16and H-17),3.49-3.45(m,2H,H-14),3.38-3.34(m,2H,H-15),1.24-1.15(m,2H,H-13),1.05-0.99(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.23,165.18,163.86,(157.32,154.00),152.99,145.42,(143.48,143.30),137.99,(123.23,123.12),(119.95,119.88),(110.87,110.57),107.71,50.72,50.58,48.91,45.19,42.53,41.66,10.92(2×C)；HR MS:C20H19ClFN7O4[M+Na]+the calculated value was 498.1069, found 498.1068.
Figure BDA0001009109690000092
(7- (3- (2- (5-methyl-1-hydro-tetrazol-1-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-16): a yellowish crystalline lens, m.p.272.1-272.9 ℃;1H NMR(300MHz,DMSO-d6)δ:14.54(s,1H,H-11),8.86(s,1H,H-2),7.98(d,1H,J＝11.7Hz,H-5),5.92(s,2H,H-20),4.45-4.38(m,1H,H-12),3.72-3.66(m,3H,H-16and H-17),3.48-3.43(m,2H,H-14),3.38-3.34(m,2H,H-15),2.48(s,3H,H-21),1.24-1.17(m,2H,H-13),1.04-0.99(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.19,165.17,163.62,162.18,(157.29,153.97,152.96,143.51,(137.99,137.96),(123.17,123.06),(119.88,119.81),(110.85,110.54),107.70,53.58,50.75,50.59,45.64,42.37,41.66,10.91(2×C),10.47；HR MS:C21H21ClFN7O4[M+H]+the calculated value was 490.1406, found 490.1408.
(7- (3- (2- (5-methyl-2-hydro-tetrazol-2-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-17): a light yellow solid, m.p.290.2-290.7 ℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),8.86(s,1H,H-2),7.98(d,1H,J＝11.7Hz,H-5),5.69(s,2H,H-20),4.45-4.38(m,1H,H-12),3.73-3.68(m,3H,H-16and H-17),3.51-3.45(m,2H,H-14),3.38-3.34(m,2H,H-15),2.45(s,3H,H-21),1.24-1.17(m,2H,H-13),1.04-0.98(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.16,165.13,163.56,(157.24,153.92),153.56,152.89,(143.51,143.32),137.96,123.09,119.81,(110.81,110.50),107.66,50.72,50.65,47.89,45.20,42.46,41.65,10.92(2×C),8.35；HR MS:C21H21ClFN7O4[M+H]+the calculated value was 490.1406, found 490.1404.
Figure BDA0001009109690000101
(7- (3- (2- (5-amino-2-hydro-tetrazol-2-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-18): creamy yellow solid, m.p.256.4-257.6 ℃;1H NMR(300MHz,DMSO-d6)δ:14.54(s,1H,H-11),8.86(s,1H,H-2),7.98(d,1H,J＝12.0Hz,H-5),6.70(s,2H,H-21),5.25(s,2H,H-20),4.45-4.38(m,1H,H-12),3.69-3.63(m,3H,H-16and H-17),3.49-3.43(m,2H,H-14),3.38-3.33(m,2H,H-15),1.23-1.17(m,2H,H-13),1.03-0.95(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.13,165.12,163.91,(157.25,153.93),156.46,152.89,(143.53,143.34),137.94,(123.09,122.99),(119.81,119.74),(110.81,110.50),107.67,50.63,50.57,46.32,45.02,42.35,41.64,10.90(2×C)；HR MS:C21H21ClFN7O4[M+H]+the calculated value was 491.1358, found 491.1359.
(7- (3- (2- (5-methylmercapto-2-hydro-tetrazol-2-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-19): a creamy yellow solid, m.p.296.3-297.2 ℃; HR MS: C21H21ClFN7O4S[M+Na]+The calculated value was 544.0946, found 544.0945.
(7- (3- (2- (5-amino-1, 3, 4-thiadiazole-2-mercapto) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-20): creamy yellow solid, m.p.277.8-278.9 ℃;1H NMR(300MHz,DMSO-d6)δ:14.56(s,1H,H-11),8.85(s,1H,H-2),7.96(d,1H,J＝11.7Hz,H-5),7.33(s,2H,H-21),4.43-4.36(m,1H,H-12),4.26(s,2H,H-20),3.70-3.64(m,3H,H-16and H-17),3.37-3.31(m,4H,H-14and H-15),1.22-1.17(m,2H,H-13),1.02-0.98(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.16,170.05,165.77,165.18,(157.23,153.91),152.90,149.36,(143.48,143.31),137.96,123.04,(119.79,119.72),111.06,(110.82,110.51),50.83,50.67,46.36,42.36,41.62,37.55,10.92(2×C)；HR MS:C21H20ClFN6O4S2[M+H]+the calculated value was 539.0738, found 539.0736.
Figure BDA0001009109690000111
(7- (3- (2- (5-methoxy-1-hydro-benzoimidazole-2-mercapto) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-21): light pink solid, m.p.193.5-200.9 ℃;1H NMR(600MHz,DMSO-d6)δ:12.73(s,1H,H-11),8.74(s,1H,H-2),7.88(d,1H,J＝9.6Hz,H-5),7.33-7.31(m,1H,H-23),6.99-6.95(m,1H,H-22),6.73-6.71(m,1H,H-24),4.46(s,2H,H-20),4.35-4.29(m,1H,H-12),3.77-3.74(m,3H,H-16、H-22and H-17),3.34-3.32(m,2H,H-14),3.28-3.25(m,2H,H-15),1.19-1.13(m,2H,H-13),0.94-0.90(m,2H,H-13).
(7- (3- (2- (1-hydro-benzotriazol-1-yl) acetamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 3-22): creamy yellow solid, m.p.270.3-272.1 ℃;1H NMR(600MHz,DMSO-d6)δ:14.60(s,1H,H-11),8.75(s,1H,H-2),8.05(d,1H,J＝8.4Hz,H-24),7.90(d,1H,J＝9.6Hz,H-5),7.79(d,1H,J＝8.4Hz,H-21),7.55(t,1H,J＝7.8Hz,H-23),7.41(t,1H,J＝7.8Hz,H-22),5.94(s,2H,H-20),4.36-4.30(m,1H,H-12),3.83-3.79(m,3H,H-16、H-22and H-17),3.48-3.44(m,2H,H-14),3.34-3.32(m,2H,H-15),1.20-1.15(m,2H,H-13),0.95-0.91(m,2H,H-13).
Figure BDA0001009109690000112
(7- (3- (2- (1-hydro-imidazol-1-yl) propionamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-1): light yellow emulsion, m.p.179.6-181.1 ℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),8.85(s,1H,H-2),8.58(s,1H,H-22),7.95(d,1H,J＝11.7Hz,H-5),7.58(s,1H,H-23),7.36(s,1H,H-24),4.43-4.37(m,1H,H-12),4.36(t,1H,J＝6.6Hz,H-21),3.63-3.59(m,3H,H-16and H-17),3.34-3.31(m,2H,H-14),3.29-3.26(m,2H,H-15),3.04(t,1H,J＝6.6Hz,H-20),1.19(q,2H,J＝6.6Hz,H-13),1.02-0.98(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.09,168.26,165.05,(157.24,153.91),152.83,(143.46,143.27),137.91,136.35,(123.10,122.99),122.87,121.14,(119.81,119.75),(110.74,110.43),107.66,50.81,50.58,45.52,43.79,41.82,41.57,33.03,10.84(2×C).
(7- (3- (2- (2-methyl-1-hydro-imidazol-1-yl) propionamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-2): brown solid, m.p.235.8-237.2 ℃;1H NMR(300MHz,DMSO-d6)δ:14.52(s,1H,H-11),8.85(s,1H,H-2),7.96(d,1H,J＝11.7Hz,H-5),7.67(d,1H,J＝2.1Hz,H-23),7.55(d,1H,J＝2.1Hz,H-24),4.44-4.37(m,1H,H-12),4.31(d,1H,J＝6.6Hz,H-21),3.63-3.60(m,3H,H-16and H-17),3.34-3.27(m,2H,H-14and H-15),3.07(d,1H,J＝6.6Hz,H-20),2.68(s,3H,H-22),1.19(q,2H,J＝6.6Hz,H-13),1.03-0.97(m,2H,H-13)；13C NMR(151MHz,DMSO-d6)δ:176.05,168.05,164.93,(156.41,154.73),152.71,144.28,(143.32,143.23),137.82,123.09,121.65,119.83,117.65,(110.59,110.43),107.65,50.73,50.52,45.48,42.76,41.77,41.47,32.02,10.76(2×C),10.27.
(7- (3- (2- (4-methyl-1-hydro-imidazol-1-yl) propionamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-3): yellow solid, m.p.175.9-176.8 ℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),9.08(s,1H,H-22),8.85(s,1H,H-2),7.97(d,1H,J＝11.7Hz,H-5),7.43(s,1H,H-23),4.44-4.37(m,1H,H-12),4.37-4.33(m,2H,H-21),3.64-3.60(m,3H,H-16and H-17),3.42-3.39(m,2H,H-14),3.30-3.26(m,2H,H-15),3.09(d,2H,J＝6.3Hz,H-20),2.28(s,3H,H-24),1.23-1.17(m,2H,H-13),1.03-0.97(m,2H,H-13)；13C NMR(151MHz,DMSO-d6)δ:176.03,168.01,164.94,(156.39,154.73),152.71,(143.34,143.24),137.83,134.51,130.46,123.04,119.80,118.63,(110.58,110.42),107.64,50.74,50.49,45.46,44.60,41.76,41.48,32.46,10.76(2×C),9.46.
Figure BDA0001009109690000121
(7- (3- (2- (1-hydro-benzoimidazol-1-yl) propionamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-4): off-white solid, m.p.259.2-261.7 ℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),8.84(s,1H,H-2),8.24(s,1H,H-22),7.94(d,1H,J＝11.7Hz,H-5),7.64(d,2H,J＝7.5Hz,H-23),7.29-7.17(m,2H,H-24),4.52(t,2H,J＝5.7Hz,H-21),4.42-4.35(m,1H,H-12),3.63-3.53(m,3H,H-16and H-17),3.24-3.16(m,4H,H-14and H-15),3.09(t,2H,J＝5.7Hz,H-20),1.21-1.15(m,2H,H-13),1.01-0.96(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.08,168.69,165.03,(157.15,153.83),152.79,144.28,(143.37,143.18),137.85,133.68,(123.13,123.01),122.15,121.35(2×C),(119.71,119.64),119.32(2×C),(110.70,110.44),110.39,50.73,50.47,45.49,41.76,41.46,40.46,32.49,10.78(2×C).
(7- (3- (2- (1-hydro-pyrazol-1-yl) propanamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-6): a pale pink solid, m.p.211.8-220.1 ℃;1H NMR(300MHz,DMSO-d6)δ:14.54(s,1H,H-11),8.85(s,1H,H-2),7.96(d,1H,J＝11.7Hz,H-5),7.73(s,1H,H-22),7.44(s,1H,H-24),6.22(s,1H,H-23),4.41-4.38(m,1H,H-12),4.37(t,2H,J＝6.6Hz,H-21),3.61-3.66(m,3H,H-16and H-17),3.31-3.27(m,4H,H-14and H-15),2.96(t,2H,J＝6.6Hz,H-20),1.19(q,2H,J＝6.3Hz,H-13),1.02-0.98(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.18,168.62,165.08,(157.24,153.92),152.87,(143.49,143.30),138.52,137.93,130.10,(123.11,123.10),119.72,(110.77,110.46),107.67,104.84,50.89,50.64,47.41,45.57,41.79,41.56,33.02,10.82(2×C).
(7- (3- (2- (3, 5-dimethyl-1-hydro-pyrazol-1-yl) propanamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-7): white emulsion, m.p.212.1-213.9 ℃;1H NMR(300MHz,DMSO-d6)δ:14.54(s,1H,H-11),8.85(s,1H,H-2),7.96(d,1H,J＝12.0Hz,H-5),5.76(s,1H,H-23),4.43-4.36(m,1H,H-12),4.14(t,2H,J＝6.3Hz,H-21),3.63-3.56(m,3H,H-16and H-17),3.28-3.22(m,4H,H-14and H-15),2.88(t,2H,J＝6.6Hz,H-20),2.23(s,3H,H-22),2.08(s,3H,H-24),1.23-1.16(m,2H,H-13),1.03-0.97(m,2H,H-13)；13C NMR(151MHz,DMSO-d6)δ:176.06,168.81,164.92,(156.36,154.71),152.68,145.72,(143.37,143.27),138.61,137.84,123.02,119.72,(110.57,110.42),107.64,104.27,50.72,50.53,45.62,43.95,41.72,41.45,32.56,13.25,10.73(2×C),10.38.
Figure BDA0001009109690000131
(7- (3- (2- (1-hydro-1, 2, 4-triazol-1-yl) propanamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-10): yellowish emulsion with m.p.229.5-231.2 deg.C;1H NMR(300MHz,DMSO-d6)δ:14.54(s,1H,H-11),8.85(s,1H,H-2),8.51(s,1H,H-22),7.96(s,1H,H-23),7.96(d,1H,J＝11.7Hz,H-5),4.44(t,2H,J＝6.6Hz,H-21),4.43-4.37(m,1H,H-12),3.64-3.58(m,3H,H-16and H-17),3.31-3.27(m,4H,H-14and H-15),1.19((q,2H,J＝6.3Hz,H-13),1.03-0.97(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.14,168.26,165.06,(157.22,153.93),152.87,151.22,144.28,(143.48,143.26),137.92,122.46,119.59,110.99,107.68,50.82,50.56,45.48,44.93,41.79,41.55,32.22,10.81(2×C).
(7- (3- (2- (2-hydro-1, 2, 3-triazol-2-yl) propanamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-12): a light yellow solid, m.p.185.7-187.2 ℃;1H NMR(300MHz,CDCl3)δ:14.30(s,1H,H-11),8.92(s,1H,H-2),7.98(d,1H,J＝11.4Hz,H-5),7.62(s,2H,H-22),4.86(t,2H,J＝7.2Hz,H-21),4.39-4.32(m,1H,H-12),3.85-3.64(m,3H,H-16and H-17),3.37-3.32(m,4H,H-14and H-15),3.11(t,2H,J＝7.2Hz,H-20),1.32(q,2H,J＝6.9Hz,H-13),1.01-0.95(m,2H,H-13)；13C NMR(151MHz,CDCl3)δ:176.78,168.42,165.81,(157.32,155.64),152.17,(143.88,143.79),(137.91,137.90),134.26(2×C),(124.37,124.32),(120.63,120.60),(111.98,111.82),108.73,51.10,51.07,50.75,46.22,42,42,41.41,32.69,11.52(2×C).
(7- (3- (2- (1-hydro-1, 2, 3-triazol-1-yl) propanamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-13): a light yellow solid, m.p.206.3-208.1 ℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),8.85(s,1H,H-2),8.13(s,1H,H-23),7.95(d,1H,J＝11.7Hz,H-5),7.71(s,1H,H-22),4.63(t,2H,J＝6.6Hz,H-21),4.43-4.37(m,1H,H-12),3.64-3.58(m,3H,H-16and H-17),3.32-3.27(m,4H,H-14and H-15),3.08(t,2H,J＝6.6Hz,H-20),1.19(q,2H,J＝6.6Hz,H-13),1.03-0.97(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.06,168.19,165.09,(157.19,153.88),152.84,(143.44,143.26),137.89,133.04,125.14,(123.15,123.01),(119.75,119.68),(110.74,110.43),50.88,50.66,45.50(2×C),41.84,41.54,32.80,10.85(2×C).
Figure BDA0001009109690000141
(7- (3- (2- (5-methyl-2-hydro-tetrazol-2-yl) propionamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-16): a light yellow solid, m.p. 203.4-204.9 ℃;1H NMR(300MHz,CDCl3)δ:14.29(s,1H,H-11),8.93(s,1H,H-2),7.98(d,1H,J＝11.4Hz,H-5),4.96(t,2H,J＝7.2Hz,H-21),4.40-4.32(m,1H,H-12),3.85-3.66(m,3H,H-16and H-17),3.38-3.34(m,4H,H-14and H-15),3.17(t,2H,J＝7.2Hz,H-20),2.55(s,3H,H-22),1.33(q,2H,J＝7.2Hz,H-13),1.01-0.96(m,2H,H-13)；13C NMR(75MHz,CDCl3)δ:176.83,167.58,165.92,163.04,(158.13,154.78),152.25,(143.86,143.66),(137.90,137.88),(124.46,124.36),(120.66,120.59),(112.16,111.85),108.74,51.15,51.08,48.83,46.18,42.45,41.43,32.23,11.57,10.97(2×C).
(7- (3- (2- (5-methyl-1-hydro-tetrazol-1-yl) propionamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-17): a yellowish crystalline lens, m.p.207.3-208.7 ℃;1H NMR(300MHz,CDCl3)δ:14.33(s,1H,H-11),8.92(s,1H,H-2),8.05(d,1H,J＝11.4Hz,H-5),4.60(t,2H,J＝6.3Hz,H-21),4.40-4.33(m,1H,H-12),3.76-3.65(m,3H,H-16and H-17),3.37-3.35(m,2H,H-14),3.32-3.30(m,2H,H-15),3.16(t,2H,J＝6.3Hz,H-20),2.55(s,3H,H-22),1.33(q,2H,J＝6.9Hz,H-13),1.01-0.96(m,2H,H-13)；13C NMR(75MHz,CDCl3)δ:176.86,167.63,166.15,(158.18,154.81),152.52,152.31,(143.83,143.64),137.90,(124.54,124.46),(120.75,120.70),(112.21,111.90),108.74,51.15,50.99,46.18,42.80,42.56,41.48,32.58,11.60,9.08,9.05.
(7- (3- (2- (5-amino-2-hydro-tetrazol-2-yl) propionamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-18): pale yellow opal, m.p.>300℃；1H NMR(300MHz,DMSO-d6)δ:14.51(s,1H,H-11),8.85(s,1H,H-2),7.97(d,1H,J＝11.7Hz,H-5),6.69(s,2H,H-22),4.44-4.38(m,1H,H-12),4.30(t,2H,J＝6.9Hz,H-21),3.65-3.60(m,3H,H-16and H-17),3.33-3.28(m,2H,H-14and H-15),2.99(t,2H,J＝6.9Hz,H-20),1.19(q,2H,J＝6.6Hz,H-13),1.03-0.97(m,2H,H-13)；13C NMR(151MHz,DMSO-d6)δ:176.09,168.28,164.95,155.42,(156.40,154.73),152.73,143.35,137.85,(123.10,123.04),(119.80,119.77),(110.61,110.45),107.65,50.74,50.50,45.49,41.81,41.46,40.89,31.56,10.73(2×C).
Figure BDA0001009109690000142
(7- (3- (2- (5-amino-1, 3, 4-thiadiazole-2-mercapto) propionamido) -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid) (TM 4-20): yellowish emulsion, m.p.260.9-262.3 ℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),8.85(s,1H,H-2),7.97(d,1H,J＝12.0Hz,H-5),7.28(s,2H,H-22),4.42-4.37(m,1H,H-12),4.26(s,2H,H-20),3.66-3.61(m,3H,H-16and H-17),3.33-3.26(m,6H,H-21、H-14and H-15),2.84(t,2H,J＝6.6Hz,H-20),1.20(q,2H,J＝6.6Hz,H-13),1.02-0.97(m,2H,H-13)；13C NMR(75MHz,DMSO-d6)δ:176.15,169.39,168.98,165.12,163.98,(157.28,153.92),152.87,143.53,137.96,123.12,119.68,(110.75,110.48),107.70,50.92,50.61,45.53,41.89,41.52,32.78,29.96,10.85(2×C).
EXAMPLE 2 agar bacteriostatic Activity test of the object Compound TM3/TM4 against a part of gram bacteria
The test takes staphylococcus aureus ATCC29213, pseudomonas aeruginosa PS1.0050, salmonella S1.1152 and duck source escherichia coli clinical isolates as indicator bacteria, and adopts a perforation method in an agar diffusion method to carry out antibacterial activity detection on a target compound TM3/TM 4. The method is characterized in that the inhibition effect of a test sample on an indicator bacterium is detected by comparing the size of an inhibition zone of the test sample and clinafloxacin on the indicator bacterium by utilizing the diffusion principle of a medicament in an agar culture medium.
The specific test method is as follows: dissolving the sample with dimethyl sulfoxide (DMSO) or sterile water to obtain 2mg/mL mother solution, and diluting with sterile water or 1M phosphate buffer (pH7.2) before useThe resulting solution was diluted to 2. mu.g/25. mu.L. Inoculating indicator bacteria in a common liquid culture medium (beef extract 0.3%, peptone 1%, sodium chloride 0.5%, pH value adjusted to 7.0-7.2), performing shake culture at 37 deg.C for 24 hr, and diluting with normal saline to 10%8CFU/mL of bacterial suspension. Heating beef extract peptone culture medium to melt, maintaining temperature in 55 deg.C water bath, adding bacterial suspension (inoculum size is about 10%) at 1% volume ratio6CFU/mL), shaking up, placing 25mL into a sterile culture dish to prepare a bacterial plate, standing, after the plate is cooled and solidified, uniformly punching the plate by using a punching tube with the diameter of 4mm, then adding 25 mu L of sample solution to be tested (equivalent to that each hole contains 2 mu g of medicine), culturing for 18 hours at 37 ℃, and measuring the diameter of a bacteriostatic circle. Each test sample was run against 3 replicates of each indicator strain, along with control of clinafloxacin and solvent.
The diameter (mm) of the inhibition zone of the target compound TM3 to the indicator bacteria is shown in Table 2, and the TM3 series of compounds have certain antibacterial activity to staphylococcus aureus, salmonella, pseudomonas aeruginosa and escherichia coli.
TABLE 2 inhibition zone diameter (mm) of the target compound TM3 for part of gram bacteria
Figure BDA0001009109690000151
Figure BDA0001009109690000161
The diameter (mm) of a bacteriostasis zone of a target compound TM4 to indicator bacteria is shown in a table 3, the water solubility of the TM4 series compound is better than that of the TM3 series compound, but the series compound has an unobvious bacteriostasis effect on salmonella and Escherichia coli with the increase of a Linker carbon chain.
TABLE 3 inhibition zone diameter (mm) of the target compound TM4 for part of gram bacteria
Figure BDA0001009109690000162
Note: negative is indicated.
Example 3 Minimal Inhibitory Concentration (MIC) test of the Compound of interest TM3 against a portion of gram bacteria
In the test, staphylococcus aureus ATCC29213, pseudomonas aeruginosa PS1.0050, salmonella S1.1152 and duck source escherichia coli clinical isolates are used as indicator bacteria, a trace broth dilution method recommended by NCCLS is adopted to detect the MIC of a target compound TM3, and the MIC is compared with norfloxacin and clinafloxacin.
The specific test method is as follows: in a 96-well plate, 200. mu.L of M-H broth containing 32mg/L of the test sample was added to well 1, and 100. mu.L of blank medium was added to the remaining 11 wells; sucking 100 mu L from the 1 st hole to the 2 nd hole, sucking 100 mu L from the 2 nd hole to the 3 rd hole after mixing, and the like till the 10 th hole, sucking 100 mu L after mixing and discarding, wherein the sample concentration from the 1 st hole to the 10 th hole is 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 and 0.0625mg/L in sequence; no test sample was added to wells 11 and 12 as bacterial growth controls and negative controls, respectively. Then 10 is added into the 1 st to 11 th holes respectively8CFU/mL of bacterial suspension 0.5. mu.L (inoculum size about 10)5CFU/mL), culturing for 16-20 hours at 37 ℃, and observing the growth condition of bacteria in the holes by naked eyes, wherein the lowest sample concentration of the bacteria-free growth hole is the MIC of the sample to the bacteria. Each strain was tested in 3 replicates simultaneously. The test sample for the test is a solution which is dissolved by sterile water (the sample which is insoluble in water or insoluble in water is dissolved by a proper amount of DMSO) and is stored for 120 days at room temperature in a dark place.
The results are shown in table 4, after the TM3 series compounds are dissolved for 120 days, the compounds still have different degrees of bacteriostatic activity on staphylococcus aureus, pseudomonas aeruginosa and salmonella, which indicates that the aqueous solution has better stability.
TABLE 4 MIC of the object Compound TM3 for a portion of gram bacteria (. mu.g/mL)
Figure BDA0001009109690000171
Figure BDA0001009109690000181
EXAMPLE 4 test of inhibitory Activity of the object Compound TM3 against Mycobacterium tuberculosis
The objective compound TM3 was tested for inhibitory activity against Mycobacterium tuberculosis (H37Rv standard strain). The testing work was done by the Open Innovation Drug Discovery (OIDD) and the American Infectious Disease Research Institute (IDRI) Research team of the American Gift pharmaceutical group (Eli Lilly and Company). Single concentration (SP) inhibitory activity test (inhibition rate of 20. mu.M) and multiple concentration (CRC) inhibitory activity test (MIC) were performed, respectively, and employed
Figure BDA0001009109690000182
Luminescent Cell Viability Assay(
Figure BDA0001009109690000183
Luminescence method cell viability detection kit) test the cytotoxicity (20 mu M percent inhibition rate, half inhibition concentration IC) of the test sample on Hela cells50)。
The specific results are shown in Table 5.
TABLE 5 test results of antitubercular activity of the target compounds TM3 and TM4
Figure BDA0001009109690000184
Figure BDA0001009109690000191
Note: and/means not determined.
As seen from Table 5, all compounds showed strong inhibitory activity against Mycobacterium tuberculosis H37Rv when tested at a single concentration of 20. mu.M; MIC values for 14 compounds were below 2 μ M; HeLa cell viability assay showed that all compounds were very low in cytotoxicity at the 20. mu.M assay concentration. Therefore, the TM3 and TM4 series compounds have stronger anti-mycobacterium tuberculosis activity and lower cytotoxicity.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims (5)

1. Clinafloxacin oxazolidinyl derivative, which is characterized in that: has the following structural formula:
Figure FDA0002757054280000011
wherein n is 1, Y is 1-hydro-imidazol-1-yl, 2-methyl-1-hydro-imidazol-1-yl, 4-methyl-1-hydro-imidazol-1-yl, 1-hydro-benzimidazol-2-mercapto, 1-hydro-pyrazol-1-yl, 3, 5-dimethyl-1-hydro-pyrazol-1-yl, 3-amino-1-hydro-pyrazol-1-yl, 1-hydro-1, 2, 4-triazol-1-yl, 3-amino-1-hydro-1, 2, 4-triazol-5-mercapto, or mixtures thereof, 1-hydro-1, 2, 3-triazol-1-yl, 2-hydro-1, 2, 3-triazol-2-yl, 1-hydro-tetrazol-1-yl, 2-hydro-tetrazol-2-yl, 5-methyl-1-hydro-tetrazol-1-yl, 5-amino-2-hydro-tetrazol-2-yl;
n is 2; y is 1-hydro-imidazol-1-yl, 1-hydro-pyrazol-1-yl, 2-hydro-1, 2, 3-triazol-2-yl, 5-methyl-2-hydro-tetrazol-2-yl.
2. A method for producing an oxazolidinyl clinafloxacin derivative as claimed in claim 1, characterized in that: reacting a compound IM with an azole compound YH in a solvent at 25-85 ℃ under the action of alkali to obtain a clinafloxacin oxazolidinyl derivative, wherein the solvent is dichloromethane, dimethylformamide, water or a dimethylformamide-water mixed solution, and the alkali is potassium carbonate or sodium hydride; the chemical reaction formula is as follows:
Figure FDA0002757054280000012
the definition of n in the structural formula of the compound IM is the same as that of n in the structural formula of the clinafloxacin oxazolidinyl derivative in the claim 1; the definition of Y in the structural formula of the azole compound YH is the same as that of Y in the structural formula of the clinafloxacin oxazolidinyl derivative in the claim 1.
3. The use of the azolidinoyl derivatives of clinafloxacin with n of 1 as defined in claim 1 for the preparation of antibacterial medicaments.
4. Use of the azolidinoyl derivative of clinafloxacin as claimed in claim 3 for the preparation of an antibacterial medicament against any one or more of pseudomonas aeruginosa, salmonella, staphylococcus aureus, escherichia coli and mycobacterium tuberculosis.
5. The use of the clinafloxacin oxazolidinyl derivative with n being 2 as claimed in claim 1 for preparing an antibacterial medicament, wherein the antibacterial medicament is one or two of pseudomonas aeruginosa and staphylococcus aureus.
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