CN109369676B - Bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative and preparation method and application thereof - Google Patents
Bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative, a preparation method and application thereof, wherein the general formula of the chemical structure is shown as the following formula:
in the formula, R is ethyl, cyclopropyl, fluoroethyl, an oxazine ring formed by C-8 position or a thiazine ring formed by C-8 position; wherein L is independent chlorine atom, fluorine atom, 1-piperazinyl, substituted piperazin-1-yl or nitrogen-fused heterocycle; x is-CH (hydrocarbon), N (nitrogen), -CF (fluorine-substituted carbon atom) or-COCH3(methoxy-substituted carbon atom). The bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative realizes organic combination of a bis-fluoroquinolone skeleton, an oxadiazole heterocycle and functional ureas, further realizes migration and superposition of different pharmacophores, and increases the antitumor activity and selectivity of fluoroquinoloneThe compound can reduce the toxic and side effects on normal cells, and can be used as an anti-tumor active substance to develop an anti-tumor drug with a brand new structure.
Description
Technical Field
The invention belongs to the technical field of medicament innovation research, relates to a complex and hard intelligence creation process, and particularly relates to a design of a bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative, a preparation method of the derivative, and application of the derivative in antitumor medicaments.
Background
The research and development of new drugs originate from the discovery of leads, and the structural optimization of the leads is a key link for promoting the development of the leads to patent drugs. Based on a rational drug design strategy of a structure or a mechanism, a novel small molecule primer which has the functions of treating and regulating serious diseases such as malignant tumor is created by utilizing the dominant skeleton or pharmacophore fragment of the existing drug, and the strategy is the most economical and effective strategy for developing new drugs. Based on the above, on one hand, the Fluoroquinolone (FQs) is considered as a class of antibacterial drugs widely used in clinic, the antibacterial dominant pharmacophore skeleton of the Fluoroquinolone (FQs) is quinoline (naphthyridine) -4-ketone-3-carboxylic acid, and as the action target of the Fluoroquinolone (FQs), Topoisomerase (TOPO) is also an important target enzyme of the antitumor drugs, the antibacterial activity of the fluoroquinolone can be converted into the antitumor activity through a structural modification strategy, and then the antitumor fluoroquinolone guide with a new structure is discovered. Meanwhile, the structure-activity relationship research finds that fluoroquinolone C-3 carboxyl is not a pharmacophore necessary for anti-tumor activity although necessary for anti-bacterial activity, and the heterocyclic ring or the fused heterocyclic ring is used as an isostere of the C-3 carboxyl to obviously improve the anti-tumor activity, so that a new thought is provided for converting an anti-bacterial fluoroquinolone medicament into an anti-tumor FQ molecule. However, the problem is that selecting what structure type of carboxyl isostere and how to link with the fluoroquinolone skeleton is beneficial to the discovery of targeting small molecule leads, and the discovery of further innovating and driving targeting anti-tumor fluoroquinolone drugs is still a problem to be solved at present. On the other hand, targeted antitumor drug molecules constructed based on Protein Tyrosine Kinase (PTK) targets have made great progress, and numerous small molecule Protein Tyrosine Kinase Inhibitors (PTKIs) enter clinical targeted therapy of tumors, thereby stimulating discovery and research and development of targeted therapeutic drugs. Meanwhile, the structures of the marketed targeting PTKIs molecules are analyzed, and the structures can be divided into four structure types (Fig 1) such as arylaminopyrimidines such as imatinib (A), arylaminoquinazolines such as gefitinib (B), diarylureas such as regorafenib (C) and alpha, beta-unsaturated ketones such as sunitinib (D). Therefore, 2 quinolone skeleton structural units are constructed into the bis-fluoroquinolone oxadiazole urea derivatives by taking oxadiazole urea as a connecting chain of the quinolone skeleton structural units by fully utilizing the structural characteristics of targeted PTKIs molecules, so that the structural characteristics of the antitumor fluoroquinolone are reserved, the urea structural characteristics of the targeted PTKIs molecules are reflected, a novel fluoroquinolone antitumor lead compound can be found, and a new thought is provided for the development of targeted tumor treatment medicines.
Disclosure of Invention
The invention aims to provide a compound with a novel structure, namely a bis-fluoroquinolone ring-substituted oxadiazole urea N-acetylnorfloxacin derivative with anti-tumor effect and effect, and a preparation method of the bis-fluoroquinolone ring oxadiazole urea N-acetylnorfloxacin derivative.
In order to achieve the above object, the technical scheme adopted by the invention is as follows:
a bis-fluoroquinolone cyclo-oxadiazole urea N-acetyl norfloxacin derivative has a chemical structural formula shown in a general formula I:
in the formula I, R is ethyl, cyclopropyl, fluoroethyl, an oxazine ring formed by the C-8 position or a thiazine ring formed by the C-8 position;
in the formula I, L is independent chlorine atom, fluorine atom, 1-piperazinyl, substituted piperazin-1-yl or nitrogen-fused heterocycle;
x is-CH (hydrocarbon), N (nitrogen), -CF (fluorine-substituted carbon atom) or-COCH3(methoxy-substituted carbon atom).
Further preferably, the above bis-fluoroquinolone cyclo-oxadiazole urea N-acetylnorfloxacin derivative is a compound represented by the following formulae I-1 to I-18:
the preparation method of the bis-fluoroquinolone cyclo-oxadiazole urea N-acetyl norfloxacin derivative specifically comprises the following preparation steps:
1) the N-acetyl norfloxacin C-3 oxadiazolamine intermediate II can be prepared by taking N-acetyl norfloxacin (7) as a raw material and condensing the N-acetyl norfloxacin (7) with semicarbazide in polyphosphoric acid (PPA) and carrying out post-treatment, and the synthetic preparation route is as follows:
2) respectively condensing fluoroquinolone carboxylic acid series compounds (FQ-COOH) shown in formulas 1-18 with carbonyl diimidazole CDI in DMF to generate corresponding fluoroquinolone carboxylic acid imidazole amide series compounds 1 '-18'; then directly reacting the prepared fluoroquinolone carboxylic acid imidazole amide series compounds 1 'to 18' with hydroxylamine hydrochloride in pyridine Py without purification to prepare corresponding fluoroquinolone hydroxamic acid series compounds 1 'to 18'; the fluoroquinolone hydroxamic acid series compounds 1 '-18' are rearranged into fluoroquinolone isocyanate through Lossen under the auxiliary catalysis of carbonyl diimidazole CDI, directly carry out condensation reaction with the N-acetyl norfloxacin C-3 oxadiazolamide intermediate II obtained in the step 1) without separation, and obtain the compounds shown in the formulas I-1 to I-18 after post treatment; the synthetic route is shown below.
Wherein the fluoroquinolone carboxylic acid series compounds (FQ-COOH) shown in formulas 1-18 comprise: the ofloxacin injection comprises ofloxacin (1), levofloxacin (2), ofloxacin (3), levofloxacin carboxylic acid (4), norfloxacin (5), pefloxacin (6), N-acetylnorfloxacin (7), ciprofloxacin (8), N-methyl ciprofloxacin (9), N-acetylciprofloxacin (10), enoxacin (11), N-methyl enoxacin (12), N-acetylenoxacin (13), fleroxacin (14), N-methyl lomefloxacin (15), N-methyl gatifloxacin (16), N-methyl moxifloxacin (17) and rufloxacin (18), and the structural formulas are shown as follows.
The fluoroquinolone carboxylic acid imidazole amide series compounds 1 'to 18' prepared correspondingly are: ofloxacin imidazole amide (1 '), levofloxacin imidazole amide (2'), ofloxacin imidazole amide (3 '), levofloxacin imidazole amide (4'), norfluorocarboxylic acid imidazole amide (5 '), pefloxacin imidazole amide (6'), N-acetylnorfloxacin imidazole amide (7 '), cyclopropanecarboxylic acid imidazole amide (8'), N-methylcyclofloxacin imidazole amide (9 '), N-acetylciprofloxacin imidazole amide (10'), enoxacarboxylic acid imidazole amide (11 '), N-methylenoxacin imidazole amide (12'), N-acetylenoxacin imidazole amide (13 '), fleroxacin imidazole amide (14'), N-methyllomefloxacin imidazole amide (15 '), N-methylglucfloxacin imidazole amide (16'), N-methylmoxifloxacin imidazole amide (17 ') and rufloxacin imidazole amide (18'), the structure is as follows.
The corresponding fluoroquinolone hydroxamic acid series compounds 1 'to 18': ofloxacin hydroxamic acid (1 '), levofloxacin hydroxamic acid (2'), ofloxacin hydroxamic acid (3 '), levofloxacin hydroxamic acid (4'), norfloxacin hydroxamic acid (5 '), pefloxacin hydroxamic acid (6'), N-acetylnorfloxacin hydroxamic acid (7 '), ciprofloxacin hydroxamic acid (8'), N-methylcyclociprofloxacin hydroxamic acid (9 '), N-acetylciprofloxacin hydroxamic acid (10'), enoxacarboxylic acid (11 '), N-methylenoxacillin hydroxamic acid (12'), N-acetylenoxacin hydroxamic acid (13 '), fleroxacin hydroxamic acid (14'), N-methyllomefloxacin hydroxamic acid (15 '), N-methylgatifloxacin hydroxamic acid (16'), N-methylmoxifloxacin hydroxamic acid (17 '), and norfloxacin hydroxamic acid (18'), the structure is as follows.
In the method for producing a bis-fluoroquinolone oxadiazolyl urea N-acetylnorfloxacin derivative, the molar ratio of the fluoroquinolone carboxylic acid series compound represented by formula 1 to formula 18 to carbonyldiimidazole is more preferably 1:1.0 to 2.0.
In the preparation method of the bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative, the molar ratio of 1 'to 18' of the fluoroquinolone carboxylic acid imidazole amide series compound to hydroxylamine hydrochloride is preferably 1:1.0 to 5.0.
In the preparation method of the bis-fluoroquinolone oxadiazole urea N-acetylnorfloxacin derivative, the molar ratio of 1 'to 18' of the fluoroquinolone hydroxamic acid series compounds to carbonyldiimidazole is preferably 1: 1.0-2.0, and the molar ratio of 1 'to 18' of the fluoroquinolone hydroxamic acid series compounds to the N-acetylnorfloxacin C-3 oxadiazolidine intermediate II is preferably 1:1.
The invention also provides application of the bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative in preparation of antitumor drugs.
Preferably, the anti-tumor drug is a drug for treating lung cancer, liver cancer, stomach cancer, pancreatic cancer, skin melanoma, leukemia or gefitinib-resistant cancer.
The bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative is based on a ureido pharmacophore structure segment of a targeted tyrosine kinase inhibitor and an effective bioisostere oxadiazole heterocycle of a fluoroquinolone C-3 carboxyl, utilizes a pharmacophore mosaic drug molecule design principle, takes oxadiazole urea as a connecting chain to connect a bis-fluoroquinolone framework, and further designs and synthesizes the bis-fluoroquinolone urea derivative, realizes the migration and complementation of dominant pharmacophore structures among different action mechanisms, innovates the structure of a drug molecule, achieves the effects of synergy and toxicity reduction, and can be developed as an anti-tumor drug with a brand new structure.
Detailed Description
The technical solution of the present invention will be described in detail by the following specific examples.
In the following examples, unless otherwise specified, the volume ratio of DMF to ethanol in a DMF-ethanol mixed solvent was 1: 5.
The preparation process of the N-acetyl norfloxacin C-3 oxadiazolamine intermediate II is given by taking N-acetyl norfloxacin as a raw material, and the synthetic route is shown as follows;
the preparation method of the intermediate N-acetyl norfloxacin C-3 oxadiazolamine (II) comprises the following steps: 10.0g (27.7mmol) of N-acetylnorfloxacin (7) and 3.0g (40.0mmol) of thiosemicarbazide are uniformly mixed and added into 150g of PPA, and the mixture is stirred and reacted for 12 hours at 140 ℃ in an oil bath. The reaction mixture was cooled to 80 deg.C, 350mL of water was slowly added dropwise, refluxed for 2 hours, cooled to 0 deg.C, adjusted to pH 10.0 with concentrated ammonia water, and left overnight. The resulting solid was filtered and collected, washed to neutrality with water and dried. Recrystallizing the crude product by using an ethanol-DMF mixed solvent to obtain 6.8g of an analytically pure intermediate II with m.p.236-238 ℃.
In the invention, fluoroquinolone carboxylic acid series compounds 1-18 (FQ-COOH) are used as raw materials and are respectively condensed with carbonyl diimidazole CDI in DMF to generate corresponding fluoroquinolone carboxylic acid imidazole amide series compounds 1 '-18'; then directly reacting the prepared fluoroquinolone carboxylic acid imidazole amide series compounds 1 'to 18' with hydroxylamine hydrochloride in pyridine Py without purification to prepare corresponding fluoroquinolone hydroxamic acid series compounds 1 'to 18'; the fluoroquinolone hydroxamic acid series compounds 1 '-18' are rearranged into fluoroquinolone isocyanate through Lossen under the auxiliary catalysis of carbonyl diimidazole CDI, directly carry out condensation reaction with the N-acetyl norfloxacin C-3 oxadiazolamide intermediate II obtained in the step 1) without separation, and obtain the compounds shown in the formulas I-1 to I-18 after post treatment; the synthetic route is shown below.
The general preparation methods of the fluoroquinolone carboxylic acid imidazole amide series compounds 1 'to 18' and the fluoroquinolone hydroxamic acid series compounds 1 'to 18' are given below.
1) Preparation of fluoroquinolone carboxylic acid imidazole amides (1 'to 18') the procedure is general: 1-18 (0.10mol) fluoroquinolone carboxylic acid series compounds are respectively dissolved in anhydrous N, N-dimethyl amide (DMF) (500mL), 16.2-32.4 g (0.10-0.20 mol) of Carbonyl Diimidazole (CDI) is added, and the mixture is stirred and reacted for 10.0-24.0 hours in a water bath at the temperature of 80-90 ℃. The solvent was evaporated under reduced pressure, ethyl acetate-free (500mL) was added, the solid was stirred well, filtered, washed with ethyl acetate, dried and used in the next reaction without purification.
The commercially available fluoroquinolone carboxylic acid series compounds 1 to 18(FQ-COOH) are respectively: ofloxacin (1), levofloxacin (2), ofloxacin (3), levofloxacin carboxylic acid (4), norfloxacin carboxylic acid (5), pefloxacin (6), N-acetylnorfloxacin (7), ciprofloxacin (8), N-methylcyclociprofloxacin (9), N-acetylciprofloxacin (10), enoxacid (11), N-methylenoxacin (12), N-acetylenoxacin (13), fleroxacin (14), N-methyllomefloxacin (15), N-methylgentifloxacin (16), N-methylmoxifloxacin (17) and rufloxacin (18).
The fluoroquinolone carboxylic acid imidazole amide (1 'to 18') prepared correspondingly is respectively as follows: ofloxacin imidazole amide (1 '), levofloxacin imidazole amide (2 '), ofloxacin imidazole amide (3 '), levofloxacin imidazole amide (4 '), norfluorocarboxylic acid imidazole amide (5 '), pefloxacin imidazole amide (6 '), N-acetylnorfloxacin imidazole amide (7 '), cyclopropanecarboxylic acid imidazole amide (8 '), N-methylcyclofloxacin imidazole amide (9 '), n-acetylciprofloxacin imidazole amide (10 '), enoxacarboxylic acid imidazole amide (11 '), N-methylenoxacin imidazole amide (12 '), N-acetylenoxacin imidazole amide (13 '), fleroxacin imidazole amide (14 '), N-methyllomefloxacin imidazole amide (15 '), N-methylgentifloxacin imidazole amide (16 '), N-methylmoxifloxacin imidazole amide (17 ') and rufloxacin imidazole amide (18 ').
2) Preparation of fluoroquinolone hydroxamic acid (1 "-18") the general procedure was as follows: suspending the crude product (1 '-18') (0.10mol) of the fluoroquinolone carboxylic acid imidazole amide prepared in the above step in pyridine (By) (500mL), adding 13.8g (0.20mol) of hydroxylamine hydrochloride, and stirring in a water bath at 60-75 ℃ for reaction for 8.0-24.0 hours. Cooling to room temperature, filtering, washing the solid with pyridine, and vacuum drying at 60-70 ℃. Suspending the crude product in a saturated sodium bicarbonate solution (500mL), and stirring in a water bath at 50-65 ℃ for 3-5 hours. Filtered, washed with deionized water to pH 7.0 and dried. Recrystallizing with absolute ethyl alcohol (or absolute ethyl alcohol-DMF mixed solvent) to obtain analytically pure crystalline fluoroquinolone hydroximic acid (1 '-18').
The fluoroquinolone hydroxamic acid (1 '-18') prepared accordingly is: ofloxacin hydroxamic acid (1 '), levofloxacin hydroxamic acid (2 '), ofloxacin hydroxamic acid (3 '), levofloxacin hydroxamic acid (4 '), norfloxacin hydroxamic acid (5 '), pefloxacin hydroxamic acid (6 '), N-acetyl norfloxacin hydroxamic acid (7 '), ciprofloxacin hydroxamic acid (8 '), N-methyl ciprofloxacin hydroxamic acid (9 '), n-acetyl ciprofloxacin hydroximic acid (10 '), enoxacid hydroximic acid (11 '), N-methyl enoxacin hydroximic acid (12 '), N-acetyl enoxacin hydroximic acid (13 '), fleroxacin hydroximic acid (14 '), N-methyl lomefloxacin hydroximic acid (15 '), N-methyl gatifloxacin hydroximic acid (16 '), N-methyl moxifloxacin hydroximic acid (17 ') and rufloxacin hydroximic acid (18 ').
General method for preparing the target compound bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative:
1.0g of fluoroquinolone hydroxamic acid (1 '-18') is suspended in a proper amount of acetonitrile, 1.0-2.0 times of carbonyldiimidazole is added, the mixture is stirred and dissolved at normal temperature, then N-acetylnorfloxacin C-3 oxadiazolamine intermediate II (1.0 times of the mixture) is added, and the mixture is stirred in a water bath at the temperature of 55-60 ℃ for 10-24 hours. Standing overnight, filtering and collecting the resultant solid, and recrystallizing with an appropriate solvent to obtain the bis-fluoroquinolone oxadiazole urea N-acetylnorfloxacin derivatives represented by formulas I-1 to I-18.
The following examples 1 to 18, starting with fluoroquinolone hydroxamic acid (1 "-18"), respectively, give detailed preparations of the target compounds.
Example 1
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 6-fluoro-7- (4-methylpiperazin-1-yl) -8,1- (1, 3-oxopropyl) -quinolin-4 (1H) -one-3-yl ] -urea (I-1) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: after 1.0g (2.7mmol) of ofloxacin hydroxamic acid (1') was suspended in 25mL of acetonitrile, 0.67g (4.1mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the material was dissolved. Then, 1.08g (2.7mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 16 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-1) with the yield of 61 percent and m.p.225-227 ℃.1H NMR(400MHz,DMSO-d6)δ:11.57(brs,1H,NH),9.48(s,1H,NH),9.20,8.98(2s,2H,2×2′-H),8.36,8.17(2d,2H,2×5′-H),7.54(d,1H,8′-H),4.92～4.82(m,3H,OCH2CHN),4.47(q,2H,NCH2) 3.62 to 3.47(m,8H,2 XPiperazine-H), 2.63 to 2.38(m,14H,2 XPiperazine-H, NCH)3 and Ac),1.61～1.45(m,6H,2×CH3)；MS(m/z):759[M+H]+Calculating the value: 758.79.
example 2
(S) -1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 6-fluoro-7- (4-methylpiperazin-1-yl) -8,1- (1, 3-oxopropyl) -quinolin-4 (1H) -one-3-yl ] -urea (I-1) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.7mmol) of levofloxacin hydroxamic acid (2') is suspended in 25mL of acetonitrile, 0.60g (3.7mmol) of Carbonyldiimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.08g (2.7mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 10 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. The crude product was recrystallized from ethanol to give a pale yellow crystal (I-2) with a yield of 50%, m.p.213～215℃。1H NMR(400MHz,DMSO-d6) Delta 11.57(brs,1H, NH),9.46(s,1H, NH),9.20,9.03(2s,2H, 2X 2 ' -H), 8.42-7.55 (m, 2X 5 ' -H and 8 ' -H), 4.93-4.84 (m,3H, OCH)2CHN),4.48(q,2H,NCH2) 3.62 to 3.45(m,8H,2 XPiperazine-H), 2.66 to 3.36(m,14H,2 XPiperazine-H and NCH)3 and Ac),1.62～1.45(m,6H,2×CH3)；MS(m/z):759[M+H]+Calculating the value: 758.79.
example 3
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [6, 7-difluoro-1, 8- (1, 3-oxopropyl) -quinolin-4 (1H) -one-3-yl ] -urea (I-3) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: after 1.0g (3.4mmol) of oxyfluorocarboxylic acid hydroxamic acid (3') was suspended in 25mL of acetonitrile, 0.82g (5.1mmol) of Carbonyldiimidazole (CDI) was added thereto, and the mixture was stirred at ordinary temperature until the materials were dissolved. Then, 1.36g (3.4mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 24 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-3), wherein the yield is 65 percent, and the m.p.222-224 ℃.1H NMR(400MHz,DMSO-d6)δ:11.56(brs,1H,NH),9.47(s,1H,NH),9.16,8.92(2s,2H,2×2′-H),8.34～7.42(m,3H,2×5′-H and 8′-H),4.93～4.81(m,3H,OCH2CHN),4.45(q,2H,NCH2) 3.62 to 3.47(m,4H, piperazine-H), 2.60 to 2.36(m,10H, piperazine-H, NCH)3And Ac) 1.62 to 1.46(m,6H,2 XCH)3)；MS(m/z):679[M+H]+Calculating the value: 678.63.
example 4
(S) -1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [6, 7-difluoro-8, 1- (1, 3-oxopropyl) -quinolin-4 (1H) -one-3-yl ] -urea (I-3) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (3.4mmol) of levofloxacin hydroxamic acid (4') was suspended in 25mL of acetonitrile, 0.82g (5.1mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the material was dissolved. Then, 1.36g (3.4mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 18 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-4), wherein the yield is 62%, and the m.p.215-217 ℃.1H NMR(400MHz,DMSO-d6)δ:11.56(brs,1H,NH),9.45(s,1H,NH),9.15,8.93(2s,2H,2×2′-H),8.36～7.47(m,3H,2×5′-H and 8′-H),4.92～4.82(m,3H,OCH2CHN),4.46(q,2H,NCH2) 3.65 to 3.43(m,4H, piperazine-H), 2.62 to 2.37(m,10H, piperazine-H, NCH)3 and Ac),1.62～1.45(m,6H,2×CH3)；MS(m/z):679[M+H]+Calculating the value: 678.63.
example 5
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-ethyl-6-fluoro-7-chloro-quinolin-4 (1H) -one-3-yl ] -urea (I-5) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (3.5mmol) of norfluorocarboxylic acid hydroxamic acid (5') was suspended in 25mL of acetonitrile, 0.98g (6.0mmol) of Carbonyldiimidazole (CDI) was added thereto, and the mixture was stirred at room temperature until the materials were dissolved. Then, 1.40g (3.5mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 24 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-5) with the yield of 63 percent and the m.p.225-227 ℃.1H NMR(400MHz,DMSO-d6) Δ:11.52(brs,1H, NH),9.43(s,1H, NH),9.14,8.96(2s,2H, 2X 2 ' -H),8.34 to 7.35(m,4H, 2X 5 ' -H and 2X 8 ' -H),4.46,4.38(2q,4H, 2X NCH)2) 3.57 to 3.42(m,4H, piperazine-H), 2.58 to 2.38(m,7H, piperazine-H and Ac),1.62 to 1.35(m,6H,2 XCH)3)；MS(m/z):667[M+H]+(35Cl), calculated: 666.08.
example 6
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-ethyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -urea (I-6) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.9mmol) of pefloxacin hydroxamic acid (6') was suspended in 25mL of acetonitrile, 0.61g (3.7mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the material was dissolved. Then, 1.16g (2.9mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 20 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-6) with the yield of 56 percent and the m.p.223-225 ℃.1H NMR(400MHz,DMSO-d6) Δ:11.57(brs,1H, NH),9.46(s,1H, NH),9.22,9.08(2s,2H, 2X 2 ' -H),8.45 to 7.42(m,4H, 2X 5 ' -H and 2X 8 ' -H),4.48,4.42(2q,4H, 2X NCH)2) 3.63 to 3.45(m,8H,2 XPiperazine-H), 2.62 to 2.38(m,14H,2 XPiperazine-H, NCH)3And Ac),1.65 to 1.44(m,6H,2 XCH)3)；MS(m/z):731[M+H]+Calculating the value: 730.78.
example 7
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -urea (I-7) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.7mmol) of N-acetylnorfloxacin hydroxamic acid (7') was suspended in 25mL of acetonitrile, 0.69g (4.3mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the material was dissolved. Then, 1.08g (2.7mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 22 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-7) with the yield of 57 percent and m.p.228-230 ℃.1H NMR(400MHz,DMSO-d6) Δ:11.62(brs,1H, NH),9.53(s,1H, NH),9.24,9.11(2s,2H, 2X 2 ' -H),8.46 to 7.63(m,4H, 2X 5 ' -H and 2X 8 ' -H),4.54,4.46(2q,4H, 2X NCH)2) 3.65 to 3.47(m,8H,2 XPiperazine-H), 2.66 to 2.37(m,12H,2 XPiperazine-H, NCH)3And Ac),1.66 to 1.42(m,6H,2 XCH)3)；MS(m/z):759[M+H]+Calculating the value: 758.79.
example 8
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-cyclopropyl-6-fluoro-7-chloro-quinolin-4 (1H) -one-3-yl ] -urea (I-8) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (3.4mmol) of cyclopropyl carboxylic acid hydroxamic acid (8') was suspended in 25mL of acetonitrile, 0.82g (5.1mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the materials were dissolved. Then, 1.36g (3.4mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 24 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-8) with the yield of 60 percent and m.p. 226-228 ℃.1H NMR(400MHz,DMSO-d6)δ:11.53(brs,1H,NH),9.42(s,1H,NH),9.17,9.06(2s,2H,2×2′-H),8.34～7.45(m,4H, 2X 5 '-H and 2X 8' -H), 4.54-4.42 (m,5H, CH and 2X NCH)2) 3.57 to 3.43(m,4H, piperazine-H), 2.65 to 2.37(m,7H, piperazine-H and Ac),1.68(d,3H, CH)3),1.25～0.96(m,4H,CH2CH2)；MS(m/z):679[M+H]+(35Cl), calculated: 678.09.
example 9
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -urea (I-9) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.8mmol) of N-methyl ciprofloxacin hydroxamic acid (9') is suspended in 25mL of acetonitrile, 0.73g (4.5mmol) of Carbonyl Diimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.12g (2.8mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 16 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-9) with the yield of 55 percent and the m.p. of 230-232 ℃.1H NMR(400MHz,DMSO-d6) Delta.11.58 (brs,1H, NH),9.46(s,1H, NH),9.23,9.12(2s,2H, 2X 2 ' -H), 8.46-7.68 (m,4H, 2X 5 ' -H and 2X 8 ' -H), 4.65-4.47 (m,5H, CH and 2X NCH)2) 3.64 to 3.45(m,8H,2 XPiperazine-H), 2.63 to 2.37(m,14H,2 XPiperazine-H, NCH)3 and Ac),1.66(d,3H,CH3),1.35～1.15(m,4H,CH2CH2)；MS(m/z):743[M+H]+Calculating the value: 742.79.
example 10
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -urea (I-10) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.6mmol) of N-acetyl ciprofloxacin hydroxamic acid (10') is suspended in 25mL of acetonitrile, 0.75g (4.6mmol) of Carbonyl Diimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.04g (2.6mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 22 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-10), wherein the yield is 65 percent, and the m.p.223-225 ℃.1H NMR(400MHz,DMSO-d6) Δ:11.62(brs,1H, NH),9.47(s,1H, NH),9.25,9.13(2s,2H, 2X 2 ' -H),8.46 to 7.68(m,4H, 2X 5 ' -H and 2X 8 ' -H),4.72 to 4.53(m,5H, CH and 2X NCH)2) 3.67 to 3.45(m,8H,2 XPiperazine-H), 2.68 to 2.36(m,14H,2 XPiperazine-H and 2 XPac), 1.72(d,3H, CH)3),1.41～1.27(m,4H,CH2CH2)；MS(m/z):771[M+H]+Calculating the value: 770.80.
example 11
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-ethyl-6-fluoro-7-chloro- [1,8] naphthyridin-4 (1H) -one-3-yl ] -urea (I-11) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (3.5mmol) of enoxohydroxamic acid (11') was suspended in 25mL of acetonitrile, 0.81g (5.0mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the material was dissolved. Then, 1.40g (3.5mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 24 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal target product (I-11), wherein the yield is 64 percent, and m.p.227-229 ℃.1H NMR(400MHz,DMSO-d6)δ:11.54(brs,1H, NH),9.46(s,1H, NH),9.25,9.12(2s,2H, 2X 2 ' -H),8.87 to 7.72(m,3H, 2X 5 ' -H and 8 ' -H),4.82,4.42(2q,4H, 2X NCH)2) 3.63 to 3.42(m,4H, piperazine-H), 2.65 to 2.37(m,7H, piperazine-H and Ac),1.72 to 1.46(m,6H,2 XCH)3)；MS(m/z):668[M+H]+(35Cl), calculated: 668.06.
example 12
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-ethyl-6-fluoro-7- (4-methylpiperazin-1-yl) - [1,8] naphthyridin-4 (1H) -one-3-yl ] -urea (I-12) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.9mmol) of N-methylenoxacin hydroximic acid (12') is suspended in 25mL of acetonitrile, 0.65g (4.0mmol) of Carbonyldiimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.16g (2.9mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 18 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a golden yellow crystal target (I-12) with the yield of 60 percent and the m.p.222-224 ℃.1H NMR(400MHz,DMSO-d6) Δ:11.58(brs,1H, NH),9.46(s,1H, NH),9.32,9.13(2s,2H, 2X 2 ' -H), 8.94-7.86 (m,3H, 2X 5 ' -H and 8 ' -H),4.86,4.45(2q,4H, 2X NCH)2) 3.67 to 3.46(m,8H,2 XPiperazine-H), 2.67 to 2.38(m,14H,2 XPiperazine-H, NCH)3 and Ac),1.74～1.46(m,6H,2×CH3)；MS(m/z):732[M+H]+Calculating the value: 731.77.
example 13
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) - [1,8] naphthyridin-4 (1H) -one-3-yl ] -urea (I-13) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.7mmol) of N-acetyl enoxacin hydroximic acid (13') is suspended in 25mL of acetonitrile, 0.58g (3.6mmol) of Carbonyl Diimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.08g (2.7mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 22 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a golden yellow crystal target product (I-13), wherein the yield is 66%, and m.p.227-229 ℃.1H NMR(400MHz,DMSO-d6) Δ:11.62(brs,1H, NH),9.51(s,1H, NH),9.35,9.23(2s,2H, 2X 2 ' -H),8.94 to 7.88(m,3H, 2X 5 ' -H and 8 ' -H),4.88,4.50(2q,4H, 2X NCH)2) 3.67 to 3.46(m,8H,2 XPiperazine-H), 2.63 to 2.37(m,14H,2 XPiperazine-H and 2 XPac), 1.75 to 1.47(m,6H,2 XPCH)3)；MS(m/z):760[M+H]+Calculating the value: 759.78.
example 14
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [1- (2-fluoroethyl) -6, 8-difluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -urea (I-14) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.6mmol) of fleroxacin hydroxamic acid (14') is suspended in 25mL of acetonitrile, 0.52g (3.2mmol) of Carbonyl Diimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.04g (2.6mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 16 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a golden yellow crystal target product (I-14), wherein the yield is 61%, and m.p.225-227 ℃.1H NMR(400MHz,DMSO-d6)δ:11.63(brs,1H,NH),9.52(s,1H,NH),9.37,9.26(2s,2H, 2X 2 ' -H), 9.16-7.65 (m,3H, 2X 5 ' -H and 8 ' -H), 4.94-4.52 (m,6H, FCH)2CH2And NCH2) 3.68 to 3.46(m,8H,2 XPiperazine-H), 2.65 to 2.38(m,14H,2 XPiperazine-H, NCH)3And Ac),1.47(d,3H, CH)3)；MS(m/z):767[M+H]+Calculating the value: 766.76.
example 15
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-ethyl-6, 8-difluoro-7- (3, 4-dimethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -urea (I-15) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.6mmol) of N-methyl lomefloxacin hydroxamic acid (15') is suspended in 25mL of acetonitrile, 0.55g (3.4mmol) of Carbonyl Diimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.04g (2.6mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 15 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a golden yellow crystal target (I-15), wherein the yield is 45%, and the m.p.214-216 ℃.1H NMR(400MHz,DMSO-d6) Delta.11.55 (brs,1H, NH),9.42(s,1H, NH),9.16,8.95(2s,2H, 2X 2 ' -H), 8.72-7.56 (m,3H, 2X 5 ' -H and 8 ' -H),4.56,4.46(2q,4H, 2X CH)2) 3.63 to 3.46(m,8H,2 XPiperazine-H), 2.64 to 2.37(m,13H,2 XPiperazine-H, NCH)3And Ac) 1.45 to 1.37(m,9H,3 XCH)3)；MS(m/z):763[M+H]+Calculating the value: 762.80.
example 16
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (3, 4-dimethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -urea (I-16) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.5mmol) of N-methyl gatifloxacin hydroxamic acid (16') is suspended in 25mL of acetonitrile, 0.55g (3.4mmol) of Carbonyldiimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.00g (2.5mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 18 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a golden yellow crystal target (I-16) with the yield of 42 percent and m.p. 214-216 ℃.1H NMR(400MHz,DMSO-d6) Delta 11.58(brs,1H, NH),9.47(s,1H, NH),9.25,9.16(2s,2H, 2X 2 ' -H), 8.56-7.548.72-7.56 (m,3H, 2X 5 ' -H and 8 ' -H), 4.66-4.45 (m,3H, CH and NCH)2),3.89(s,3H,OCH3) 3.58 to 3.45(m,8H,2 XPiperazine-H), 2.57 to 2.36(m,13H,2 XPiperazine-H, NCH)3And Ac) 1.47 to 1.16(m,10H,2 XCH)3and CH2CH2)；MS(m/z):787[M+H]+Calculating the value: 786.85.
example 17
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-yl) -quinolin-4 (1H) -one-3-yl ] -urea (I-17) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.3mmol) of N-methylmoxifloxacin hydroximic acid (17') is suspended in 25mL of acetonitrile, 0.52g (3.2mmol) of Carbonyldiimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 0.92g (2.5mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 16 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product with DMF-ethanol mixed solvent to obtain light yellow crystalThe target (I-17) was obtained in 51% yield, m.p.210-212 ℃.1H NMR(400MHz,DMSO-d6) Delta 11.57(brs,1H, NH),9.45(s,1H, NH),9.26,9.17(2s,2H, 2X 2 ' -H),8.53 to 7.57(m,3H, 2X 5 ' -H and 8 ' -H),4.62 to 4.45(m,3H, CH and NCH)2),3.87(s,3H,OCH3) 3.64 to 3.16(m,8H, piperazine-H and pyrrolidine ring-H), 2.58 to 2.27(m,13H, piperazine-H, piperidine ring-H, NCH)3 and Ac),1.95～1.23(m,12H,CH3cyclopropyl-H and piperidine ring-H); MS (M/z) 813[ M + H]+Calculating the value: 812.88.
example 18
1- {2- [ 1-ethyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 6-fluoro-8, 1-thienylethyl-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-yl ] -urea (I-18) having the chemical formula:
the preparation method of bis-fluoroquinolone oxadiazole urea in this example is as follows: 1.0g (2.6mmol) of rufloxacin hydroxamic acid (18') was suspended in 25mL of acetonitrile, 0.52g (3.2mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the material was dissolved. Then, 1.04g (2.6mmol) of the intermediate II of N-acetyl norfloxacin C-3 oxadiazolamine is added, and the mixture is stirred for 15 hours in a water bath at the temperature of 55-60 ℃. Left overnight, filtered and the resulting solid collected and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal target product (I-18), wherein the yield is 57 percent, and m.p.227-229 ℃.1H NMR(400MHz,DMSO-d6)δ:11.55(brs,1H,NH),9.46(s,1H,NH),9.16,9.10(2s,2H,2×2′-H),8.54,8.13(2d,2H,2×5′-H),7.68(d,1H,8′-H),4.45(d,2H,NCH2),3.88～3.43(m,124H,SCH2CH2And 2 XPiperazine-H), 2.66 to 2.37(m,14H,2 XPiperazine-H, NCH)3 and Ac),1.43(d,3H,CH3)；MS(m/z):761[M+H]+Calculating the value: 760.83.
test examples
In one embodiment, examples 1 to 18 provide an in vitro antitumor activity assay of bis-fluoroquinolone oxadiazolyl urea N-acetylnorfloxacin derivatives
1. Test sample
Using 18 novel bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivatives provided in examples 1-18, as well as classical antitumor topoisomerase inhibitor 10-Hydroxycamptothecin (HC), urea tyrosine kinase inhibitor Regorafenib (RRF), Cabozantinib (CZT), and parent compound N-acetyl norfloxacin (MNF) as test samples, 22 samples were used, wherein HC, RRF, CZT and MNF are positive control test groups, and examples 1-18 are test groups;
thiazole blue (MTT), HC, RRF, CZT and MNF are all products of Sigma company; the RPMI-1640 culture solution is a product of GIBCO company; other used reagents are all domestic analytical pure reagents.
The experimental cancer cell strains are respectively a human non-small cell lung cancer cell strain A549, a human liver cancer cell strain SMCC-7721, a human gastric cancer cell strain HGC27, a human pancreatic cancer cell strain Capan-1, a human skin melanoma cell strain A375 and a human leukemia cell strain HL60 which are purchased from a Shanghai cell bank of Chinese academy of sciences; gefitinib-resistant cell strain K562G was purchased from Tianjin hematopathy researchers; normal cells were VerO cells, which were obtained from Shanghai city, park, Inc.
2. Measurement method
The determination method comprises the following specific steps:
(1) firstly, the 22 samples were dissolved in dimethyl sulfoxide (DMSO) to prepare 1.0X 10- 4mol·L-1Stock solution of concentration, then using RPMI-1640 culture solution containing 10% (mass percentage concentration) calf serum to dilute the stock solution into working solution with 5 concentration gradients (50, 10, 5, 1.0 and 0.1 mu M) according to a 10-fold dilution method;
the first set of experiments: taking cancer cell strains HL60, Capan-1 and K562G in logarithmic growth phase, inoculating 5000 cells per well into a 96-well plate, culturing overnight, respectively adding working solution with 5 concentration gradients, discarding culture medium after 48 hours, adding 1 g.L per well–1MTT solution 100. mu.L, then culture was continued for 4 hours and supernatant was discarded, 150. mu.L of DMSO was added to each wellGently shaking for 30 minutes, and then measuring the absorbance (OD) value at a wavelength of 570nm with a microplate reader;
the second set of experiments: taking cancer cell strains A549, SMCC-7721, HGC27, VERO and A375 in logarithmic growth phase, inoculating 7000 cells per well into a 96-well plate, respectively adding working solution with 5 concentration gradients, and adding 5 g.L per well after 48 hours–110 mu L of MTT solution is continuously cultured for 4 hours, then 100 mu L of Sodium Dodecyl Sulfate (SDS) solution with the mass percentage concentration of 10 percent is added for culture overnight, and then an OD value is measured at the wavelength of 570nm by using an enzyme-labeling instrument;
(2) calculating the inhibition rate of the test samples with different concentrations on the experimental cancer cells according to the formula shown below,
the cancer cell inhibition rate is [1- (experimental group OD value/control group OD value) ] × 100%,
then, linear regression is carried out on the cancer cell inhibition rate corresponding to each concentration by the pair value of each concentration of the test sample to obtain a dose-effect equation, and the half Inhibition Concentration (IC) of each test sample to the experimental cancer cell is calculated from the obtained dose-effect equation50) (ii) a Each data was measured in parallel five times and averaged, the results are shown in Table 1.
TABLE 1 antitumor Activity (IC) of the test samples50)
As can be seen from table 1, the bis-fluoroquinolone oxadiazolyl urea N-acetylnorfloxacin derivatives provided in examples 1 to 18 all have significant proliferation inhibitory activity on 7 experimental cancer cell lines, and particularly show higher activity on human non-small cell lung cancer cell line a549, human pancreatic cancer cell line Capan-1 and human skin melanoma cell line a375, which is significantly stronger than the activity of the parent compound N-acetylnorfloxacin, and at the same time stronger than the activity of the control topoisomerase inhibitor Hydroxycamptothecin (HC), and the activity of most compounds is also stronger than the activity of the control tyrosine kinase inhibitors regorafenib (RRF) and Cabozantinib (CZT). More significantly, the compounds provided in examples 1-18 also showed very strong sensitivity to gefitinib resistant cell line K562G, while showing low toxicity to normal cell IIERO cells, with the property of being druggable. Therefore, according to the general approach of drug development, the conventional antitumor in vitro screening is carried out, and then the targeted research is carried out, so that the compound has strong antitumor and anti-drug resistance activity and lower toxicity, and can be used for preparing antitumor drugs by salifying with acid acceptable for human bodies or mixing with medicinal carriers.
Claims (7)
1. A bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative is characterized by being a compound shown in the following formulas I-1 to I-18:
2. the process for preparing bis-fluoroquinolone oxadiazolyl urea N-acetylnorfloxacin derivative according to claim 1, which comprises the following steps:
1) the N-acetyl norfloxacin C-3 oxadiazolamine intermediate II can be prepared by taking N-acetyl norfloxacin as a raw material and condensing the N-acetyl norfloxacin with semicarbazide in PPA (polyphosphoric acid) and carrying out post-treatment, and the synthetic preparation route is as follows:
2) respectively condensing fluoroquinolone carboxylic acid series compounds shown in formulas 1-18 with carbonyl diimidazole CDI in DMF to generate corresponding fluoroquinolone carboxylic acid imidazole amide series compounds 1 '-18'; then, respectively reacting the prepared fluoroquinolone carboxylic acid imidazole amide series compounds 1 'to 18' with hydroxylamine hydrochloride in pyridine Py to prepare corresponding fluoroquinolone hydroxamic acid series compounds 1 'to 18'; the fluoroquinolone hydroxamic acid series compounds 1 '-18' are rearranged into fluoroquinolone isocyanate under the auxiliary catalysis of carbonyl diimidazole CDI through Lossen, directly carry out condensation reaction with the N-acetyl norfloxacin C-3 oxadiazolamide intermediate II obtained in the step 1) without separation, and are obtained after post-treatment; the synthetic route is as follows:
the structural formulas of the fluoroquinolone carboxylic acid series compounds shown in formulas 1-18 are respectively as follows:
3. the method for producing a bis-fluoroquinolone oxadiazolyl urea N-acetylnorfloxacin derivative according to claim 2, wherein the molar ratio of the fluoroquinolone carboxylic acid series compound represented by formula 1 to 18 to carbonyldiimidazole is 1:1.0 to 2.0.
4. The method for preparing the bis-fluoroquinolone oxadiazole urea N-acetylnorfloxacin derivative according to claim 2, wherein the molar ratio of the fluoroquinolone carboxylic acid imidazole amide series compounds 1 'to 18' to hydroxylamine hydrochloride is 1: 1.0-5.0.
5. The process for preparing bis-fluoroquinolone oxadiazolyl ureas N-acetylnorfloxacin derivatives according to claim 2, wherein the molar ratio of fluoroquinolone hydroxamic acid series compounds 1 "-18" to carbonyldiimidazole is 1: 1.0-2.0, and the molar ratio of fluoroquinolone hydroxamic acid series compounds 1 "-18" to N-acetylnorfloxacin C-3 oxadiazolidine intermediate II is 1:1.
6. Use of the bis-fluoroquinolone oxadiazolyl urea N-acetylnorfloxacin derivative according to claim 1 for the preparation of antitumor medicaments.
7. The use of the bis-fluoroquinolone oxadiazolyl urea N-acetylnorfloxacin derivative according to claim 6 for preparing an antitumor medicament, wherein the antitumor medicament is a medicament for treating lung cancer, liver cancer, stomach cancer, pancreatic cancer, cutaneous melanoma, leukemia or gefitinib-resistant cancer.
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| CN108191854A (en) * | 2018-01-11 | 2018-06-22 | 河南大学 | Fluoro- 7- piperazines-nalidixic acid compounds of 1- (N- Ciprofloxacins amide groups) -6- and its preparation method and application |
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