CN109438481B

CN109438481B - Bis-fluoroquinolone oxadiazole urea derivative containing N-methylmoxifloxacin and preparation method and application thereof

Info

Publication number: CN109438481B
Application number: CN201811425124.9A
Authority: CN
Inventors: 岑世宏; 耿胜男; 杨莉; 胡国强
Original assignee: Zhengzhou University of Industrial Technology
Current assignee: Zhengzhou University of Industrial Technology
Priority date: 2018-11-27
Filing date: 2018-11-27
Publication date: 2021-07-06
Anticipated expiration: 2038-11-27
Also published as: CN109438481A

Abstract

The invention discloses a bis-fluoroquinolone oxadiazole urea derivative containing N-methylmoxifloxacin, a preparation method and application thereof, wherein the general formula of the chemical structure is shown as the following formula I:

in the general formula I, R is-CH₂‑CH₃Cyclopropyl or-CH₂‑CH₂F; l is-Cl, -F, 1-piperazinyl, substituted piperazin-1-yl, or a nitrogen-containing fused heterocycle; x is-CH, -N, -CF or-COCH₃(ii) a Or R and X together form an oxazine ring or a thiazine ring. The bis-fluoroquinolone oxadiazole urea derivative provided by the invention realizes organic combination of a bis-fluoroquinolone skeleton, an oxadiazole heterocycle and functional ureas, further realizes migration and superposition of different pharmacophores, increases antitumor activity and selectivity of fluoroquinolone, reduces toxic and side effects on normal cells, and can be used as an antitumor active substance to develop an antitumor drug with a brand new structure.

Description

Bis-fluoroquinolone oxadiazole urea derivative containing N-methylmoxifloxacin and preparation method and application thereof

Technical Field

The invention belongs to the technical field of new drug discovery and innovative drug synthesis, and particularly relates to a bis-fluoroquinolone oxadiazole urea derivative containing N-methylmoxifloxacin, a preparation method of the derivative, and application of the derivative in antitumor drugs.

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 structural types (shown as follows) of arylaminopyrimidines such as imatinib (a), arylaminoquinazolines such as gefitinib (B), diarylureas such as regorafenib (C), and α, β -unsaturated ketones such as sunitinib (D):

if the fluoroquinolone can be combined with the targeting PTKIs molecules, the structural characteristics of the antitumor fluoroquinolone are reserved, and the urea structural characteristics of the targeting PTKIs molecules are reflected, so that a new thought is provided for the development of the targeting tumor treatment medicine.

Disclosure of Invention

The invention provides a bis-fluoroquinolone oxadiazole urea derivative containing N-methylmoxifloxacin, aiming at the technical problem of combining fluoroquinolone with targeted PTKIs molecules, and the prepared derivative has the effects of synergism and toxicity reduction and can be developed as an anti-tumor medicament with a brand new structure.

In order to achieve the above object, the technical scheme adopted by the invention is as follows: the bis-fluoroquinolone oxadiazole urea derivative containing N-methylmoxifloxacin has a structural general formula shown as the following formula I:

in the general formula I, R is-CH₂-CH₃Cyclopropyl or-CH₂-CH₂F；

L is-Cl, -F, 1-piperazinyl, substituted piperazin-1-yl, or a nitrogen-containing fused heterocycle;

x is-CH, -N, -CF or-COCH 3;

or R and X together form an oxazine ring or a thiazine ring.

Preferably, the bis-fluoroquinolone oxadiazole urea derivative containing N-methylmoxifloxacin is a compound with a structure shown in the following formulas I-1 to I-18:

the preparation method of the bis-fluoroquinolone oxadiazole urea derivative containing N-methylmoxifloxacin comprises the following specific preparation processes:

1) n-methyl moxifloxacin (17) is used as a raw material, condensed with semicarbazide hydrochloride in polyphosphoric acid (PPA), and subjected to post-treatment to prepare an N-methyl moxifloxacin C-3 oxadiazolidine intermediate II, wherein the synthetic preparation route is as follows:

2) carrying out condensation reaction on fluoroquinolone carboxylic acid (marked as FQ-COOH) shown in formulas 1-18 and N ', N-carbonyl diimidazole (marked as CDI) in N, N-Dimethylformamide (DMF) respectively to prepare corresponding fluoroquinolone carboxylic acid imidazole amide (shown in formulas 1 ' -18 '); the obtained fluoroquinolone carboxylic acid imidazole amide (1 'to 18') is respectively reacted with hydroxylamine hydrochloride in pyridine (By) to conveniently prepare corresponding fluoroquinolone hydroximic acid (1 'to 18');

wherein the molar ratio of the fluoroquinolone carboxylic acid shown in the formulas 1-18 to the N, N' -carbonyldiimidazole is 1: 1.0-2.0;

the molar ratio of the fluoroquinolone carboxylic acid imidazole amide shown in the formula 1 'to 18' to hydroxylamine hydrochloride is 1: 1.0-5.0.

3) Fluoroquinolone hydroxamic acid (1 ' -18 ') is rearranged into fluoroquinolone isocyanate under the auxiliary catalysis of N ', N-carbonyl diimidazole through Lossen, directly undergoes condensation reaction with N-methyl moxifloxacin C-3 oxadiazomide intermediate II without separation, and is subjected to post treatment to prepare the bis-fluoroquinolone oxadiazole urea derivative containing N-methyl moxifloxacin shown in formulas I-1 to I-18, wherein the synthetic route is as follows:

wherein the molar ratio of the fluoroquinolone hydroximic acid shown in the formula 1 ' to 18 ' to the N, N ' -carbonyldiimidazole is 1: 1.0-2.0, and the molar ratio of the fluoroquinolone hydroximic acid shown in the formula 1 ' to 18 ' to the N-methylmoxifloxacin C-3 oxadiazolamide intermediate II is 1:1.

Wherein the fluoroquinolone carboxylic acid (FQ-COOH) comprises: the ofloxacin injection comprises ofloxacin (1), levofloxacin (2), ofloxacin (3), levofloxacin (4), norfloxacin (5), pefloxacin (6), N-acetylnorfloxacin (7), ciprofloxacin (8), N-methylcyclociprofloxacin (9), N-acetylciprofloxacin (10), enoxacin (11), N-methylenoxacin (12), N-acetylenoxacin (13), fleroxacin (14), N-methyllomefloxacin (15), N-methylgatifloxacin (16), N-methylmoxifloxacin (17) and rufloxacin (18), and the structures are shown as follows.

The corresponding fluoroquinolone carboxylic acid imidazolamides (1 'to 18') 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 (1 "-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:

the bis-fluoroquinolone oxadiazole urea derivative containing N-methyl moxifloxacin is applied to preparation of antitumor drugs.

Specifically, the anti-tumor drug is a drug for treating lung cancer, liver cancer, stomach cancer, pancreatic cancer, skin melanoma or leukemia and treating gefitinib-resistant cancer cells.

The invention is based on an effective bioisostere oxadiazole heterocycle of a pharmacophore urea structural fragment of a targeted tyrosine kinase inhibitor and a fluoroquinolone C-3 carboxyl, designs and synthesizes a 'bis-fluoroquinolone urea derivative' by utilizing a pharmacophore mosaic drug molecule design principle and taking oxadiazole urea as a connecting chain to connect a bis-fluoroquinolone framework, realizes the migration and complementation of superior pharmacophore structures among drugs with different action mechanisms, further innovates a new 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 preparation method of the N-methylmoxifloxacin-containing bis-fluoroquinolone oxadiazole urea derivative comprises the following specific preparation processes:

the preparation operation steps of the N-methyl moxifloxacin C-3 oxadiazomide II intermediate are as follows: 10.0 g (24.1mmol) of N-methylmoxifloxacin (17) and 2.5g (33.0mmol) of semicarbazide hydrochloride 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 collected by filtration, neutralized with water and dried. Recrystallizing the crude product with ethanol-DMF (volume ratio of 5:1) to obtain analytically pure intermediate II 6.6g, m.p.223-225 deg.C

the general method for preparing fluoroquinolone carboxylic acid imidazole amide (1 'to 18') is as follows: dissolving fluoroquinolone carboxylic acid FQ-COOH (0.10mol) in anhydrous N, N-diformylamide (500mL), adding 16.2-32.4 g (0.10-0.20 mol) of CDI, stirring and reacting for 10.0-24.0 hours in a water bath at 80-90 ℃, after the reaction is finished, evaporating the solvent under reduced pressure, adding ethyl acetate (500mL), fully stirring and dispersing the solid, filtering and collecting the solid, washing with ethyl acetate, and drying to obtain a fluoroquinolone carboxylic acid imidazole amide crude product, wherein the fluoroquinolone carboxylic acid imidazole amide crude product is directly used for the next reaction without purification.

The fluoroquinolone hydroxamic acid (1 "-18") is prepared by the general method as follows: suspending the crude fluoroquinolone carboxylic acid imidazole amide (0.10mol) in 500mL of pyridine, adding 7.0-35.0 g (0.1-0.5 mol) of hydroxylamine hydrochloride, stirring in a water bath at 60-75 ℃ for 8.0-24.0 hours for reaction, cooling to room temperature, filtering to collect a solid, washing the obtained solid with pyridine, drying in vacuum at 60-70 ℃, dispersing in a saturated sodium bicarbonate solution (500mL) again, stirring in a water bath at 50-65 ℃ for 3-5 hours, filtering to collect the solid, washing with deionized water until the pH value is 7.0, drying to obtain a crude product, recrystallizing the obtained crude product with absolute ethyl alcohol (or an absolute ethyl alcohol-DMF mixed solvent with the volume ratio of 5:1) to obtain analytically pure crystalline fluoroquinolone hydroxamic acid (1 '-18').

The general preparation method of the target compound of the bis-fluoroquinolone oxadiazole urea derivative containing N-methylmoxifloxacin comprises the following steps: 1.0g of each fluoroquinolone hydroxamic acid (1 '-18') is suspended in an appropriate amount of acetonitrile, CDI (the molar weight of CDI is 1.0-2.0 times that of fluoroquinolone hydroxamic acid) is added, the mixture is stirred and dissolved at normal temperature, an N-methylmoxifloxacin C-3 oxadiazolamine II intermediate (the molar weight of CDI is 1.0 time that of fluoroquinolone hydroxamic acid) is added, the mixture is stirred in a water bath at 55-60 ℃ for 10-24 hours, the mixture is cooled to room temperature, the generated solid is collected through filtration, and the target compound is obtained through recrystallization by using an appropriate solvent.

The preparation of the object compounds of the formulae I-1 to I-18 according to the invention is illustrated in detail below by means of 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.

Example 1

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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 structure:

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, 0.79g (4.9mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the material was dissolved. Then, 1.23g (2.7mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 16 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 56 percent and m.p.212-214 ℃.¹H NMR(400MHz,DMSO-d₆)δ:11.63 (brs,1H,NH),9.52(s,1H,NH),9.23,9.12(2s,2H,2×2′-H),8.86,8.62(2d,2H,2×5′-H), 5.16～4.64(m,4H,OCH₂CHN and CH),3.93(s,3H,OCH₃) 3.68 to 3.37(m,8H, piperazine-H and pyrrole-H), 2.86 to 2.37(m,13H, piperazine-H, piperidine-H and 2 XNCH)₃) 1.86-1.17 (m,12H, piperidine-H, CH)₃And CH₂CH₂)；MS(m/z):813[M+H]⁺Calculating the value: 812.88[ M ]]⁺。

Example 2

(S) -1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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, 0.70g (4.3mmol) of Carbonyldiimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.23g (2.7mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 10 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration and washed with acetonitrile. Recrystallizing the crude product by using ethanol to obtain a light yellow crystal (I-2) with the yield of 46 percent and m.p.206-208 ℃.¹H NMR(400MHz,DMSO-d₆)δ:11.64(brs,1H,NH), 9.55(s,1H,NH),9.26,9.15(2s,2H,2×2′-H),8.88,8.64(2d,2H,2×5′-H),5.17～4.62(m,4H, OCH₂CHN and CH),3.92(s,3H,OCH₃) 3.67 to 3.37(m,8H, piperazine-H and pyrrole-H), 2.86 to 2.36(m,13H, piperazine-H, piperidine-H and 2 XNCH)₃) 1.87 to 1.15(m,12H, piperidine-H, CH)₃And CH₂CH₂)；MS(m/z): 813[M+H]⁺Calculating the value: 812.88[ M ]]⁺。

Example 3

(1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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: 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, 1.54g (3.4mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 24 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 57 percent, and the m.p.213-215 ℃.¹H NMR(400MHz,DMSO-d₆)δ:11.58 (brs,1H,NH),9.47(s,1H,NH),9.13,8.94(2s,2H,2×2′-H),8.68,8.36(2d,2H,2×5′-H), 5.10～4.63(m,4H,OCH₂CHN and CH),3.89(s,3H,OCH₃) 3.65 to 3.28(m,4H, pyrrole-H), 2.86 to 2.37(m,6H, piperidine-H and NCH)₃) 1.86 to 1.15(m,12H, piperidine-H, CH)₃And CH₂CH₂)；MS(m/z): 733[M+H]⁺Calculating the value: 732.73[ M ]]⁺。

Example 4

S) -1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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, 1.54g (3.4mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 20 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 52 percent, and the m.p. is 205-207 ℃.¹H NMR(400MHz,DMSO-d₆)δ:11.57 (brs,1H,NH),9.46(s,1H,NH),9.10,8.92(2s,2H,2×2′-H),8.66,8.35(2d,2H,2×5′-H), 5.07～4.60(m,4H,OCH₂CHN and CH),3.88(s,3H,OCH₃) 3.63 to 3.25(m,4H, pyrrole-H), 2.84 to 2.37(m,6H, piperidine-H and NCH)₃) 1.85 to 1.15(m,12H, piperidine-H, CH)₃And CH₂CH₂)；MS(m/z): 733[M+H]⁺Calculating the value: 732.73[ M ]]⁺。

Example 5

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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, 1.59g (3.5mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 24 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 60 percent and the m.p.215-217 ℃.¹H NMR(400MHz,DMSO-d₆) Delta.11.55 (brs,1H, NH),9.46(s,1H, NH),9.15,8.87(2s,2H, 2X 2 ' -H), 8.64-7.52 (m,3H, 2X 5 ' -H and 8 ' -H), 4.58-4.36 (m,3H, CH and NCH)₂),3.88(s,3H,OCH₃) 3.67 to 3.36(m,4H, pyrrole-H), 2.87 to 2.36(m, 6H, piperidine-H and NCH)₃) 1.84-1.08 (m,12H, piperidine-H, CH)₃And CH₂CH₂)；MS(m/z):721 [M+H]⁺(³⁵Cl), calculated: 721.17[ M ]]⁺。

Example 6

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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 adding 1.32g (2.9mmol) of N-methylmoxifloxacin C-3 oxadiazolidine II intermediate, stirring in a water bath at 55-60 ℃ for 16And (4) hours. After standing overnight, the resulting solid was collected by filtration 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 57 percent and m.p. 216-218 ℃.¹H NMR(400MHz,DMSO-d₆)δ:11.65 (brs,1H,NH),9.52(s,1H,NH),9.22,9.05(2s,2H,2×2′-H),8.72～7.58(m,3H,2×5′-H and 8′-H),4.66～4.38(m,3H,CH and NCH₂),3.88(s,3H,OCH₃) 3.76 to 3.42(m,8H, piperazine-H and pyrrole-H), 2.87 to 2.37(m,13H, piperazine-H, 2 XNCH)₃And piperidine-H), 1.93-1.17 (m,12H, CH)₃piperidine-H and CH₂CH₂)；MS(m/z):785[M+H]⁺Calculating the value: 784.87[ M ]]⁺。

Example 7

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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-acetyl norfloxacin hydroxamic acid (7') was suspended in 25mL of acetonitrile, 0.75g (5.4mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the material was dissolved. Then, 1.23g (2.7mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 20 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 55 percent and the m.p.223-225 ℃.¹H NMR(400MHz,DMSO-d₆)δ:11.67 (brs,1H,NH),9.55(s,1H,NH),9.28,9.12(2s,2H,2×2′-H),8.78～7.67(m,3H,2×5′-H and 8′-H),4.68～4.42(m,3H,CH and NCH₂),3.92(s,3H,OCH₃) 3.78 to 3.38(m,8H, piperazine-H and pyrrole-H), 2.96 to 2.37(m,13H, piperazine-H, Ac, NCH)₃And piperidine-H), 1.97 to 1.26(m,12H, CH)₃piperidine-H and CH₂CH₂)；MS(m/z):813[M+H]⁺Calculating the value: 812.88[ M ]]⁺。

Example 8

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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, 0.97g (6.0mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the materials were dissolved. Then, 1.54g (3.4mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 24 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-8), wherein the yield is 58 percent, and the m.p.225-227 ℃.¹H NMR(400MHz,DMSO-d₆)δ:11.58 (brs,1H,NH),9.52(s,1H,NH),9.22,9.04(2s,2H,2×2′-H),8.87～7.63(m,3H,2×5′-H and 8′-H),4.66～4.58(m,2H,2×CH),3.92(s,3H,OCH₃) 3.72 to 3.37(m,4H, pyrrole-H), 2.88 to 2.36(m, 6H, piperidine-H and NCH)₃) 1.96-1.15 (m,13H, piperidine-H and 2 XCH)₂CH₂)；MS(m/z):733[M+H]⁺ (³⁵Cl), calculated: 733.18[ M ]]⁺。

Example 9

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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 structure:

bis-fluoroquinolones of this exampleThe preparation method of the ketooxadiazole urea comprises the following steps: 1.0g (2.8mmol) of N-methyl ciprofloxacin hydroxamic acid (9') is suspended in 25mL of acetonitrile, 0.81g (5.0mmol) of Carbonyl Diimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.27g (2.8mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 16 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 52 percent and m.p. 226-228 ℃.¹H NMR(400MHz,DMSO-d₆)δ:11.65 (brs,1H,NH),9.53(s,1H,NH),9.26,9.07(2s,2H,2×2′-H),8.92～7.72(m,3H,2×5′-H and 8′-H),4.72～4.66(m,2H,2×CH),3.93(s,3H,OCH₃) 3.76 to 3.45(m,8H, pyrrole-H and piperazine-H), 2.96 to 2.43(m,13H, piperidine-H, piperazine-H and 2 XNCH)₃) 2.07 to 1.26(m,13H, piperidine-H and 2 XCH)₂CH₂)； MS(m/z):797[M+H]⁺Calculating the value: 796.88[ M ]]⁺。

Example 10

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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 structure:

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, 1.18g (2.6mmol) of the N-methylmoxifloxacin C-3 oxadiazolamine II intermediate is added, and the mixture is stirred for 20 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 58 percent, and the m.p.223-225 ℃.¹H NMR(400MHz,DMSO-d₆)δ11.68 (brs,1H,NH),9.56(s,1H,NH),9.32,9.14(2s,2H,2×2′-H),8.95～7.78(m,3H,2×5′-H and 8′-H),4.75～4.68(m,2H,2×CH),3.93(s,3H,OCH₃) 3.78 to 3.44(m,8H, pyrrole-H and piperazine-H), 3.12 to 2.36(m,13H, piperidine-H, piperazine-H, Ac and NCH)₃) 2.17 to 1.33(m,13H, piperidine-H and 2 XCH)₂CH₂)； MS(m/z):825[M+H]⁺Calculating the value: 824.90[ M ]]⁺。

Example 11

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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 structure:

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, 1.13g (7.0mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the material was dissolved. Then, 1.59g (3.5mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 24 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 62%, and the m.p.231-233 ℃.¹H NMR(400MHz,DMSO-d₆)δ: 11.64(brs,1H,NH),9.52(s,1H,NH),9.25,8.97(2s,2H,2×2′-H),8.88～7.52(m,2H,2×5′-H), 4.67～4.62(m,3H,NCH₂And CH),3.88(s,3H, OCH)₃) 3.76 to 3.44(m,4H, pyrrole-H), 2.98 to 2.37(m,6H, piperidine-H and NCH)₃) 2.04 to 1.16(m,12H, piperidine-H, CH)₃And CH₂CH₂)；MS(m/z):722[M+H]⁺ (³⁵Cl), calculated: 722.16[ M ]]⁺。

Example 12

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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 structure:

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, 1.32g (2.9mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 20 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 56 percent and the m.p.221-223 ℃.¹H NMR(400MHz,DMSO-d₆)δ: 11.66(brs,1H,NH),9.57(s,1H,NH),9.32,9.13(2s,2H,2×2′-H),8.94～7.76(m,2H,2×5′-H), 4.68～4.62(m,3H,NCH₂And CH),3.95(s,3H, OCH)₃) 3.78 to 3.36(m,8H, pyrrole-H and piperazine-H), 2.96 to 2.36(m,13H, piperidine-H, piperazine-H and 2 XNCH)₃) 2.15 to 1.27(m,13H, piperidine-H and 2 XCH)₂CH₂)； MS(m/z):786[M+H]⁺Calculating the value: 785.86[ M ]]⁺。

Example 13

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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, 0.84g (5.2mmol) of Carbonyl Diimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.23g (2.7mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 20 hours in a water bath at the temperature of 55-60 ℃. Standing overnight, and filteringThe resulting solid, acetonitrile was washed. 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 62%, and m.p.227-229 ℃.¹H NMR(400MHz,DMSO-d₆)δ: 11.68(brs,1H,NH),9.57(s,1H,NH),9.36,9.18(2s,2H,2×2′-H),8.96～7.84(m,2H,2×5′-H), 4.72～4.66(m,3H,NCH₂And CH),3.95(s,3H, OCH)₃) 3.75 to 3.38(m,8H, pyrrole-H and piperazine-H), 2.95 to 2.36(m,13H, piperidine-H, piperazine-H, Ac and NCH)₃) 2.23 to 1.28(m,13H, piperidine-H and 2 XCH)₂CH₂)； MS(m/z):814[M+H]⁺Calculating the value: 813.87[ M ]]⁺。

Example 14

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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 structure:

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, 0.62g (3.8mmol) of Carbonyl Diimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.18g (2.6mmol) of the N-methylmoxifloxacin C-3 oxadiazolamine II intermediate is added, and the mixture is stirred for 18 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a golden yellow crystal target (I-14) with the yield of 60 percent and the m.p. of 218-220 ℃.¹H NMR(400MHz,DMSO-d₆)δ: 11.67(brs,1H,NH),9.58(s,1H,NH),9.36,9.25(2s,2H,2×2′-H),8.97～7.86(m,2H,2×5′-H), 4.96～4.68(m,5H,NCH₂CH₂F and CH),3.94(s,3H, OCH)₃) 3.87 to 3.45(m,8H, pyrrole-H and piperazine-H), 3.16 to 2.37(m,13H, piperidine-H, piperazine-H and 2 XNCH)₃) 2.17 to 1.26(m,9H, piperidine-H and CH)₂CH₂)；MS(m/z):821[M+H]⁺Calculating the value: 820.85[ M ]]⁺。

Example 15

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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 structure:

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, 1.18g (2.6mmol) of the N-methylmoxifloxacin C-3 oxadiazolamine II intermediate is added, and the mixture is stirred for 16 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 52%, and the m.p.212-214 ℃.¹H NMR(400MHz,DMSO-d₆) Delta.11.65 (brs,1H, NH),9.54(s,1H, NH),9.18,8.97(2s,2H, 2X 2 '-H), 8.82,8.34(2d,2H, 2X 5' -H), 4.62-4.45 (m,3H, CH and NCH)₂),3.88(s,3H,OCH₃) 3.62 to 3.37(m,8H, pyrrole-H and piperazine-H), 2.96 to 2.37(m,12H, piperidine-H, piperazine-H and 2 XNCH)₃) 2.07 to 1.18(m,15H, piperidine-H, 2 XCH)₃And CH₂CH₂)；MS(m/z):817[M+H]⁺Calculating the value: 816.89[ M ]]⁺。

Example 16

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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 structure:

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, 0.75g (4.6mmol) of Carbonyldiimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.14g (2.5mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 20 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 46 percent and m.p.208-210 ℃.¹H NMR(400MHz,DMSO-d₆)δ: 11.67(brs,1H,NH),9.56(s,1H,NH),9.28,9.16(2s,2H,2×2′-H),8.97,8.56(2d,2H,2×5′-H), 4.66～4.62(m,2H,2×CH),3.88,3.94(2s,6H,2×OCH₃) 3.64 to 3.43(m,8H, pyrrole-H and piperazine-H), 2.95 to 2.37(m,12H, piperidine-H, piperazine-H and 2 XNCH)₃) 1.95-1.16 (m,16H, piperidine-H, CH)₃And 2 XCH₂CH₂)；MS(m/z):841[M+H]⁺Calculating the value: 840.94[ M ]]⁺。

Example 17

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-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 of the 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, 0.65g (4.0mmol) of Carbonyldiimidazole (CDI) is added, and the mixture is stirred at normal temperature until the materials are dissolved. Then, 1.04g (2.3mmol) of the intermediate of N-methylmoxifloxacin C-3 oxadiazolamine II is added, and the mixture is stirred for 18 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration and washed with acetonitrile. Recrystallizing the crude product by using a DMF-ethanol mixed solvent to obtain a light yellow crystal target product (I-17), wherein the yield is 463%, and the m.p. is 205-207 ℃.¹H NMR(400MHz,DMSO-d₆)δ: 11.66(brs,1H,NH),9.57(s,1H,NH),9.34,9.24(2s,2H,2×2′-H),8.974,8.58(2d,2H,2×5′-H), 4.66～4.62(m,2H,2×CH),3.89,3.94(2s,6H,2×OCH₃) 3.68 to 3.26(m,8H,2 XPyrrole-H), 2.93 to 2.37(m,12H,2 XPiperidine-H and 2 XPNCH)₃) 1.82 to 1.16(m,18H,2 × piperidine-H and 2 × CH)₂CH₂)；MS (m/z):867[M+H]⁺Calculating the value: 866.98[ M ]]⁺。

Example 18

1- {2- [ 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methyl-octahydropyrrolo [3,4-b ] pyridin-6-yl) -quinolin-4 (1H) -one-3-yl ] -1,3, 4-oxadiazol-5-yl } -3- [ 6-fluoro-8, 1-thienyloxy-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, 0.72g (4.4mmol) of Carbonyldiimidazole (CDI) was added, and the mixture was stirred at room temperature until the material was dissolved. Then, 1.18g (2.6mmol) of the N-methylmoxifloxacin C-3 oxadiazolamine II intermediate is added, and the mixture is stirred for 18 hours in a water bath at the temperature of 55-60 ℃. After standing overnight, the resulting solid was collected by filtration 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 54 percent, and the m.p.223-225 ℃.¹H NMR(400MHz,DMSO-d₆)δ:

11.62(brs,1H,NH),9.47(s,1H,NH),9.16,8.96(2s,2H,2×2′-H),8.83,8.56(2d,2H, 2×5′-H),4.64～3.36(m,13H,CH、SCH₂CHN, piperazine-H and pyrrole-H), 3.89(s,3H, OCH₃) 2.82 to 2.37(m,13H, piperazine-H, piperidine-H and 2 XNCH)₃) 1.86-1.17 (m,9H, piperidine-H and CH)₂CH₂)；MS(m/z):815 [M+H]⁺Calculating the value: 814.92[ M ]]⁺。

Test examples

In vitro antitumor Activity assay of bis-fluoroquinolone oxadiazolyl Urea derivatives prepared in examples 1-18

1. Test sample

Using 18 new bis-fluoroquinolone oxadiazole urea derivatives provided in examples 1-18 and the classical antitumor topoisomerase inhibitor 10-Hydroxycamptothecin (HC), the urea tyrosine kinase inhibitor Regorafenib (RRF), Cabozantinib (CZT), and the parent compound N-methylmoxifloxacin (MMF) as test samples, 22 samples, wherein HC, RRF, CZT, and MMF are positive control test groups, and examples 1-18 are sample test groups;

3- (4, 5-dimethyl-2-thiazole) -2, 5-diphenyl tetrazolium bromide (MTT), HC, RRF, CZT and MMF 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 institute; 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^-1The stock solution was diluted to 5 concentration gradients (50, 10, 5, 1.0, 0.1. mu. mol. L) by 10-fold dilution method using 10% by mass of calf serum RPMI-1640 culture solution^-1) The working fluid of (1);

the first set of experiments: inoculating 5000 cells per well of cancer cell strains HL60, Capan-1 and K562G in logarithmic growth phase to 96-well plate, culturing overnight, adding working solution with 5 concentration gradients, discarding culture medium after 48 hr, adding 1 g.L per well^–13- (4, 5-dimethyl-2-thiazole) -2, 5-diphenyl tetrazolium bromide (MTT) solution 100. mu.L, followed byAfter culturing for 4 hours, removing the supernatant, adding 150 mu L of DMSO into each well, slightly shaking for 30 minutes, and then measuring the absorbance (OD) value at the wavelength of 570nm by using 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) the inhibition rate of the test samples with different concentrations on the experimental cancer cells is calculated according to the following formula:

the cancer cell inhibition rate ═ 1 [ (experimental OD value)/control 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.

As can be seen from table 1, the bis-fluoroquinolone oxadiazolyl urea N-methylmoxifloxacin derivatives provided in examples 1 to 18 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 that of the parent compound N-methylmoxifloxacin, and stronger than that of the control topoisomerase inhibitor Hydroxycamptothecin (HC), and the activity of most compounds is also stronger than that 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 VERO 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.

TABLE 1 antitumor Activity (IC) of the test samples₅₀)

Claims

1. A bis-fluoroquinolone oxadiazole urea derivative containing N-methylmoxifloxacin is characterized by being a compound with a structure shown in formulas I-1 to I-18 as follows:

2. the method for preparing the bis-fluoroquinolone-based oxadiazole urea derivatives containing N-methylmoxifloxacin as claimed in claim 1, which comprises the following specific steps:

1) condensing N-methyl moxifloxacin and semicarbazide hydrochloride in polyphosphoric acid, and performing post-treatment to obtain an N-methyl moxifloxacin C-3 oxadiazolamide intermediate II, wherein the structural formula of the intermediate II is as follows:

2) the fluoroquinolone carboxylic acid series with the structural formula shown as 1-18 are respectively subjected to condensation reaction with N, N ' -carbonyldiimidazole to generate corresponding fluoroquinolone carboxylic acid imidazole amide series with the structural formula shown as 1 ' -18 '; the fluoroquinolone carboxylic acid imidazole amide series obtained by the preparation respectively reacts with hydroxylamine hydrochloride to obtain corresponding fluoroquinolone hydroximic acid series, and the structural formula is shown as 1 'to 18';

formulas 1 to 18:

formulas 1 'to 18':

formulas 1 'to 18':

3) the fluoroquinolone hydroxamic acid series prepared in the step 2) are rearranged into corresponding fluoroquinolone isocyanate series through Lossen under the auxiliary catalysis of N, N' -carbonyldiimidazole, the condensation reaction is directly carried out with the N-methylmoxifloxacin C-3 oxadiazolamide intermediate II prepared in the step 1) without treatment, and the target compounds shown in the formulas I-1 to I-18 can be prepared through post treatment.

3. The method for preparing an N-methylmoxifloxacin-containing bis-fluoroquinolone oxadiazole urea derivative as claimed in claim 2, wherein the molar ratio of the fluoroquinolone carboxylic acid represented by formula 1 to 18 to N, N' -carbonyldiimidazole in step 2) is 1:1.0 to 2.0.

4. The method for preparing a bis-fluoroquinolone-based oxadiazole urea derivative containing N-methylmoxifloxacin according to claim 2, wherein in step 2), the molar ratio of the fluoroquinolone carboxylic acid imidazole amide represented by formulae 1 'to 18' to hydroxylamine hydrochloride is 1:1.0 to 5.0.

5. The method for preparing bis-fluoroquinolone-based oxadiazole urea derivatives containing N-methylmoxifloxacin as claimed in claim 2, wherein in step 3), the molar ratio of fluoroquinolone hydroxamic acid represented by formulas 1 "to 18" to N, N' -carbonyldiimidazole is 1:1.0 to 2.0, and the molar ratio of fluoroquinolone hydroxamic acid represented by formulas 1 "to 18" to N-methylmoxifloxacin C-3 oxadiazolamide intermediate II is 1:1.

6. The use of bis-fluoroquinolone-based oxadiazole urea derivatives containing N-methylmoxifloxacin as claimed in claim 1 for preparing antitumor drugs.

7. The application of the bis-fluoroquinolone oxadiazole urea derivatives containing N-methylmoxifloxacin as claimed in claim 6 in preparation of antitumor drugs, wherein the antitumor drugs are drugs for treating lung cancer, liver cancer, gastric cancer, pancreatic cancer, skin melanoma, leukemia or gefitinib resistant cancer.