CN109369676A - A kind of pair-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives and its preparation method and application - Google Patents

A kind of pair-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives and its preparation method and application Download PDF

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CN109369676A
CN109369676A CN201811425174.7A CN201811425174A CN109369676A CN 109369676 A CN109369676 A CN 109369676A CN 201811425174 A CN201811425174 A CN 201811425174A CN 109369676 A CN109369676 A CN 109369676A
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fluoquinolone
acetyl
oxadiazoles
double
carboxylic acid
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CN109369676B (en
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姜亚玲
刘秋伟
邵香敏
胡国强
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Zhengzhou University of Industrial Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

The invention discloses a kind of double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives and its preparation method and application, and general formula of the chemical structure is shown below:R is ethyl, cyclopropyl, fluoro ethyl, the oxazines ring constituted with C-8 or the thiazine ring constituted with C-8 in formula；L is independent chlorine atom, fluorine atom, 1- piperazinyl, substituted piperazine -1- base or nitrogen condensed hetero ring in formula；X is that-CH(is hydrocarbon), N(nitrogen-atoms), the fluorine-substituted carbon atom of-CF() or-COCH3(methoxy-substituted carbon atom).Double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives of the invention, realize organic split of double-fluoquinolone skeleton and oxadiazoles heterocycle and function base ureas, and then realize different pharmacophores move more be superimposed, increase the anti-tumor activity and selectivity of fluoquinolone, the toxic side effect to normal cell is reduced, can be used as the anti-tumor drug of anti-tumor active substance exploitation brand new.

Description

A kind of pair-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives and its system Preparation Method and application
Technical field
The present invention is New drug discovery studying technological domain, is the intellectual creation process of a complicated hardships, and in particular to one The design of kind pair-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives, also relates to the preparation of the analog derivative Method and its application in anti-tumor drug.
Background technique
New drug development originates from the discovery of primer, and is the pass for promoting it to develop to patent medicine to the structure optimization of primer Key link.Rational drug layout strategy based on structure or mechanism utilizes the advantage skeleton or pharmacophore segment of existing drug, wound Building there is the new small molecule primer for the treatment of and function controlling, which to be that new drug development is most economical, the major diseases such as malignant tumour has The strategy of effect.Based on this, on the one hand in view of fluoquinolone (FQs) is as a kind of clinical widely used antimicrobial, antibacterial Advantage pharmacophore skeleton is " quinoline (naphthyridines) -4- ketone -3- carboxylic acid ", because its action target-topoisomerase (TOPO) is also anti- The important target enzyme of tumour medicine can convert anti-tumor activity for its antibacterial activity by the strategy of structural modification, and then find The antitumor fluoquinolone primer of new construction.At the same time, though structure activity study discovery fluoquinolone C-3 carboxyl is antibacterial Necessary to activity, but not be pharmacophore necessary to anti-tumor activity, use heterocycle or condensed hetero ring as C-3 carboxyl etc. arrange Body is remarkably improved its anti-tumor activity, this provides new think of how to convert antibacterial fluoroquinolone drug to antitumor FQ molecule Road.However, problem be select how the carboxyl isostere of structure type, and take and what kind of connection type of fluoquinolone skeleton It is beneficial to the discovery of targeting small molecule primer, the further discovery of innovation driving targeting anti-tumor flouroquinolone drugs is still Urgently project to be resolved at present.On the other hand, the targeting anti-tumor medicine constructed based on protein tyrosine kinase (PTK) target spot Object molecule has made substantial progress, and the clinic for having numerous small molecular protein tyrosine kinase inhibitors (PTKIs) to enter tumour Targeted therapy, and then excite the discovery and research and development of target therapeutic agent.Meanwhile to the knot of the targeting PTKIs molecule listed Structure is dissected, structure can be divided into fragrant amino miazines such as Imatinib (A), fragrant amino quinazoline ditosylate salt such as Gefitinib (B), Substituted bisarylurea such as Rui Gefeini (C) and α, four kinds of structure types (Fig 1) such as beta-unsaturated ketone such as Sutent (D).For This, makes full use of the structure feature of targeting PTKIs molecule, and 2 carbostyril skeleton structural units are connected by oxadiazoles urea for it Chain link constructs in pairs-fluoquinolone oxadiazoles carbamide derivative, has not only remained the design feature of antitumor fluoquinolone, but also embody The urea structure characteristic of PTKIs molecule is targeted out, it is possible to find the antitumor lead compound of novel fluoroquinolones is target tumor The development of therapeutic agent provides new approaches.
Summary of the invention
The object of the present invention is to provide a kind of compounds of new construction, i.e., containing double-cyclosubstituted oxadiazoles urea of fluoquinolone Class N- acetyl norfloxacin derivatives, have an antitumor effect and efficacy, while providing a kind of double-fluoquinolone ring oxadiazoles The preparation method of ureas N- acetyl norfloxacin derivatives.
In order to realize the above target, the technical scheme adopted by the invention is that:
A kind of double-fluoquinolone ring oxadiazoles ureas N- acetyl norfloxacin derivatives, chemical structural formula such as general formula I institute Show:
R is ethyl, cyclopropyl, fluoro ethyl, the oxazines ring constituted with C-8 or the thiazine ring constituted with C-8 in Formulas I；
L is independent chlorine atom, fluorine atom, 1- piperazinyl, substituted piperazine -1- base or nitrogen condensed hetero ring in Formulas I；
X is-CH (hydrocarbon), N (nitrogen-atoms) ,-CF (fluorine-substituted carbon atom) or-COCH3(methoxy-substituted carbon is former Son).
It is further preferred that above-mentioned double-fluoquinolone ring oxadiazoles ureas N- acetyl norfloxacin derivatives, are following Formulas I -1 is to I-18 compound represented:
The preparation method of above-mentioned double-fluoquinolone ring oxadiazoles ureas N- acetyl norfloxacin derivatives, specifically includes Following preparation step:
1) with N- acetyl Norfloxacin (7) for raw material, the condensation in the polyphosphoric acids (PPA) with semicarbazides, it is post-treated can N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II is made, it is as follows to be synthetically prepared route:
2) fluoroquinolone carboxylic acid series compound (FQ-COOH) shown in formula 1~18 is existed with carbonyl dimidazoles CDI respectively Condensation generates corresponding fluoroquinolone carboxylic acid Orazamide series compound 1 '~18 ' in DMF；Then the fluorine quinoline that will be prepared Promise keto carboxylic acid Orazamide series compound 1 '~18 ' directly reacts in pyridine Py with hydroxylamine hydrochloride respectively without further purification to be made Corresponding fluoquinolone hydroximic acid series compound 1 "~18 "；Fluoquinolone hydroximic acid series compound 1 "~18 " is in carbonyl two Fluoquinolone isocyanates is rearranged to by Lossen under the auxiliary catalysis of imidazoles CDI, without isolation directly and obtained by step 1) Condensation reaction occurs for N- acetyl group Norfloxacin C-3 oxadiazoles amine intermediate II, post-treated to change up to shown in Formulas I -1 to I-18 Close object；Synthetic route is as follows.
Wherein, fluoroquinolone carboxylic acid series compound (FQ-COOH) shown in formula 1~18 includes: Ofloxacin (1), a left side Ofloxacin (2), oxygen carboxylic acid fluoride (3), levofloxacin carboxylic acid (4), promise carboxylic acid fluoride (5), pefloxacin (6), N- acetyl Norfloxacin (7), cyclopropyl carboxylic acid (8), N- methyl Ciprofloxacin (9), N- acetyl Ciprofloxacin (10), according to promise carboxylic acid (11), N- methyl according to promise Sha Xing (12), N- acetyl Enoxacin (13), fleraxacin (14), N- methyl Lomefloxacin (15), N- methyl gatifloxacin (16), N- methyl Moxifloxacin (17) and Rufloxacin (18), structural formula is as follows.
The fluoroquinolone carboxylic acid Orazamide series compound 1 '~18 ' being accordingly prepared are as follows: Ofloxacin imidazoles acyl Amine (1 '), lavo-ofloxacin Orazamide (2 '), oxygen carboxylic acid fluoride Orazamide (3 '), levofloxacin carboxylic acid Orazamide (4 '), promise Carboxylic acid fluoride Orazamide (5 '), pefloxacin Orazamide (6 '), N- acetyl Norfloxacin Orazamide (7 '), cyclopropyl carboxylic acid miaow Azoles amide (8 '), N- methyl Ciprofloxacin Orazamide (9 '), N- acetyl Ciprofloxacin Orazamide (10 '), according to promise carboxylic acid miaow Azoles amide (11 '), N- methyl Enoxacin Orazamide (12 '), N- acetyl Enoxacin Orazamide (13 '), fleraxacin Orazamide (14 '), N- methyl Lomefloxacin Orazamide (15 '), N- methyl gatifloxacin Orazamide (16 '), N- methyl Moxifloxacin Orazamide (17 ') and Rufloxacin Orazamide (18 '), structure are as follows.
Corresponding fluoquinolone hydroximic acid series compound 1 "~18 ": Ofloxacin hydroximic acid (1 "), lavo-ofloxacin hydroxyl Oxime acid (2 "), oxygen carboxylic acid fluoride hydroximic acid (3 "), levofloxacin carboxylic acid hydroximic acid (4 "), promise carboxylic acid fluoride hydroximic acid (5 "), pefloxacin Hydroximic acid (6 "), N- acetyl Norfloxacin hydroximic acid (7 "), cyclopropyl carboxylic acid hydroximic acid (8 "), N- methyl Ciprofloxacin hydroximic acid (9 "), N- acetyl Ciprofloxacin hydroximic acid (10 "), according to promise carboxylic acid hydroximic acid (11 "), N- methyl Enoxacin hydroximic acid (12 "), N- acetyl Enoxacin hydroximic acid (13 "), fleraxacin hydroximic acid (14 "), N- methyl Lomefloxacin hydroximic acid (15 "), N- first Base gatifloxacin hydroximic acid (16 "), N- methyl Moxifloxacin hydroximic acid (17 ") and Rufloxacin hydroximic acid (18 "), structure is such as Shown in lower.
The preparation method of above-mentioned double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives, it is further preferred that The molar ratio of fluoroquinolone carboxylic acid series compound and carbonyl dimidazoles shown in formula 1~18 is 1:1.0~2.0.
The preparation method of above-mentioned double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives, it is further preferred that The molar ratio of fluoroquinolone carboxylic acid Orazamide series compound 1 '~18 ' and hydroxylamine hydrochloride is 1:1.0~5.0.
The preparation method of above-mentioned double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives, it is further preferred that The molar ratio of fluoquinolone hydroximic acid series compound 1 "~18 " and carbonyl dimidazoles is 1:1.0~2.0, fluoquinolone hydroxyl oxime The molar ratio of sour series compound 1 "~18 " and N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II is 1:1.
It is anti-swollen in preparation that the present invention also provides above-mentioned double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives Application in tumor medicine.
It is further preferred that the anti-tumor drug be treatment lung cancer, liver cancer, gastric cancer, cancer of pancreas, cutaneous melanoma, The drug of leukaemia or resistance to Gefitinib cancer.
Double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives of the invention, based on targeting tyrosine kinase suppression The urea groups structural pharmacophore segment of preparation and effective biological isostere oxadiazoles heterocycle of fluoquinolone C-3 carboxyl, and utilize medicine Effect group split drug molecule design principle is connected double-fluoquinolone skeleton using oxadiazoles urea as connection chain, and then designs and close At " double-afloqualone ureas " derivative, realize advantage structural pharmacophore between different role mechanism drug move more with it is complementary, The structure for having innovated drug molecule, achieves synergistic and detoxifying effects, and can be used as the anti-tumor drug exploitation of brand new.
Specific embodiment
Technical solution of the present invention is described in detail by following specific embodiments.
In following embodiments, unless otherwise specified, in DMF- alcohol mixed solvent, DMF, ethyl alcohol volume ratio are 1:5.
Below using N- acetyl Norfloxacin as raw material, N- acetyl group Norfloxacin C-3 oxadiazoles amine intermediate II is given Preparation process, synthetic route is as follows；
The preparation method of intermediate N acetyl Norfloxacin C-3 oxadiazoles amine (II): N- acetyl Norfloxacin (7) 10.0g (27.7mmol) and thiosemicarbazides 3.0g (40.0mmol) is added to after mixing in 150g PPA, and 140 DEG C of oil bath stirrings are anti- It answers 12 hours.Reaction mixture is cooled to 80 DEG C, and 350mL water is slowly added dropwise, and flows back 2 hours, 0 DEG C is cooled to, with concentrated ammonia liquor tune PH 10.0, stands overnight.The solid for filtering and collecting generation is washed to neutrality, dry.Crude product ethyl alcohol-DMF mixed solvent Recrystallization, must analyze pure intermediate II 6.8g, m.p.236~238 DEG C.
In the present invention, with fluoroquinolone carboxylic acid series compound 1~18 (FQ-COOH) be raw material, respectively with two miaow of carbonyl Azoles CDI is condensed in DMF generates corresponding fluoroquinolone carboxylic acid Orazamide series compound 1 '~18 '；Then it will be prepared into To fluoroquinolone carboxylic acid Orazamide series compound 1 '~18 ' without further purification directly respectively with hydroxylamine hydrochloride in pyridine Py Corresponding fluoquinolone hydroximic acid series compound 1 "~18 " is made in reaction；Fluoquinolone hydroximic acid series compound 1 "~18 " Fluoquinolone isocyanates is rearranged to by Lossen under the auxiliary catalysis of carbonyl dimidazoles CDI, without isolation directly with step Condensation reaction occurs for rapid 1) gained N- acetyl group Norfloxacin C-3 oxadiazoles amine intermediate II, post-treated up to Formulas I -1 to I- Compound shown in 18；Synthetic route is as follows.
Following present fluoroquinolone carboxylic acid Orazamide series compounds 1 '~18 ', fluoquinolone hydroximic acid seriation Method is led in the preparation for closing object 1 "~18 ".
1) the preparation manipulation step of fluoroquinolone carboxylic acid Orazamide (1 '~18 ') leads to method: taking fluoroquinolone carboxylic acid serial Compound 1~18 (0.10mol), is dissolved in anhydrous N respectively, and in N- diformamide (DMF) (500mL), carbonyl dimidazoles are added (CDI) 16.2g~32.4g (0.10~0.20mol), 80~90 DEG C of water-bath are stirred to react 10.0~24.0 hours.It removes under reduced pressure Solvent is added without ethyl acetate (500mL), dispersing solid is sufficiently stirred, and filters, ethyl acetate washing, dry, without further purification directly It connects for the next step.
Above-mentioned commercially available fluoroquinolone carboxylic acid series compound 1~18 (FQ-COOH) be respectively as follows: Ofloxacin (1), Lavo-ofloxacin (2), oxygen carboxylic acid fluoride (3), levofloxacin carboxylic acid (4), promise carboxylic acid fluoride (5), pefloxacin (6), N- acetyl promise fluorine are husky Star (7), cyclopropyl carboxylic acid (8), N- methyl Ciprofloxacin (9), N- acetyl Ciprofloxacin (10), according to promise carboxylic acid (11), N- methyl according to Promise sand star (12), N- acetyl Enoxacin (13), fleraxacin (14), N- methyl Lomefloxacin (15), N- methyl gatifloxacin (16), N- methyl Moxifloxacin (17) and Rufloxacin (18).
The fluoroquinolone carboxylic acid Orazamide (1 '~18 ') being accordingly prepared is respectively as follows: Ofloxacin Orazamide (1 '), lavo-ofloxacin Orazamide (2 '), oxygen carboxylic acid fluoride Orazamide (3 '), levofloxacin carboxylic acid Orazamide (4 '), promise fluorine Carboxylic acid Orazamide (5 '), pefloxacin Orazamide (6 '), N- acetyl Norfloxacin Orazamide (7 '), cyclopropyl carboxylic acid imidazoles Amide (8 '), N- methyl Ciprofloxacin Orazamide (9 '), N- acetyl Ciprofloxacin Orazamide (10 '), according to promise carboxylic acid imidazoles Amide (11 '), N- methyl Enoxacin Orazamide (12 '), N- acetyl Enoxacin Orazamide (13 '), fleraxacin miaow Azoles amide (14 '), N- methyl Lomefloxacin Orazamide (15 '), N- methyl gatifloxacin Orazamide (16 '), N- methyl are not Xisha star Orazamide (17 ') and Rufloxacin Orazamide (18 ').
2) the preparation manipulation step of fluoquinolone hydroximic acid (1 "~18 ") leads to method: taking and above-mentioned fluoquinolone carboxylic is prepared Imidazole acid crude amide (1 '~18 ') (0.10mol) is suspended in pyridine (By) (500mL), and hydroxylamine hydrochloride 13.8g is added (0.20mol), 60~75 DEG C of stirring in water bath are reacted 8.0~24.0 hours.It being cooled to room temperature, filters, solid is washed with pyridine, and 60 ~70 DEG C of vacuum drying.Crude product is suspended in saturated sodium bicarbonate solution (500mL), 50~65 DEG C stirring in water bath 3~5 hours. Filtering, deionized water is washed to pH 7.0, dry.It is recrystallized with dehydrated alcohol (or dehydrated alcohol-DMF mixed solvent), score Analyse pure lenticular fluoquinolone hydroximic acid (1 "~18 ").
The fluoquinolone hydroximic acid (1 "~18 ") being accordingly prepared is respectively as follows: Ofloxacin hydroximic acid (1 "), left oxygen fluorine Husky star hydroximic acid (2 "), oxygen carboxylic acid fluoride hydroximic acid (3 "), levofloxacin carboxylic acid hydroximic acid (4 "), promise carboxylic acid fluoride hydroximic acid (5 "), training Flucloxacillin hydroximic acid (6 "), N- acetyl Norfloxacin hydroximic acid (7 "), cyclopropyl carboxylic acid hydroximic acid (8 "), N- methyl Ciprofloxacin hydroxyl Oxime acid (9 "), N- acetyl Ciprofloxacin hydroximic acid (10 "), according to promise carboxylic acid hydroximic acid (11 "), N- methyl Enoxacin hydroximic acid (12 "), N- acetyl Enoxacin hydroximic acid (13 "), fleraxacin 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″)。
Method is led in the preparation of target compound pair-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives:
Fluoquinolone hydroximic acid (1 "~18 ") each 1.0g is suspended in suitable acetonitrile, addition carbonyl dimidazoles (1.0~ 2.0 times of amounts), after stirring at normal temperature dissolution, it is added N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II (1.0 times of amounts), 55~60 DEG C stirring in water bath 10~24 hours.It stands overnight, filters and collect the solid of generation, recrystallized with solvent appropriate, formula is made Double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives shown in I-1 to I-18.
Following example 1, respectively with fluoquinolone hydroximic acid (1 "~18 ") for raw material, it is detailed to give target compound to 18 Thin preparation process.
Embodiment 1
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [the fluoro- 7- of 6- (4- methylpiperazine-1-yl) -8,1- (1,3- oxygen propyl group)-quinoline -4 (1H) -one -3- base] - Urea (I-1), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking Ofloxacin hydroximic acid (1 ") 1.0g (2.7mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.67g (4.1mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.08g (2.7mmol) is added, 55~60 DEG C of water-bath stirrings 16 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-1), yield 61%, m.p.225~227 DEG C.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 (- the H of d, 1H, 8 '), 4.92~4.82 (m, 3H, OCH2CHN),4.47(q,2H,NCH2), 3.62~3.47 (m, 8H, 2 × piperazines- ), H 2.63~2.38 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.61~1.45 (m, 6H, 2 × CH3)；MS(m/z):759 [M+H]+, calculated value: 758.79.
Embodiment 2
(S) -1- 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3, 4- oxadiazoles -5- base } -3- [the fluoro- 7- of 6- (4- methylpiperazine-1-yl) -8,1- (1,3- oxygen propyl group)-quinoline -4 (1H) -one -3- Base]-urea (I-1), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking lavo-ofloxacin hydroximic acid (2 ") 1.0g (2.7mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.60g (3.7mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.08g (2.7mmol) is added, 55~60 DEG C of water-bath stirrings 10 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product ethyl alcohol recrystallization obtains pale yellow crystals object (I-2), yield 50%, m.p.213~215 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.57(brs,1H,NH),9.46(s, 1H, NH), the 9.20,9.03 (- H of 2s, 2H, 2 × 2 '), 8.42~7.55 (m, 2 × 5 '-H and 8 '-H), 4.93~4.84 (m, 3H, OCH2CHN),4.48(q,2H,NCH2), 3.62~3.45 (m, 8H, 2 × piperazine-H), 2.66~3.36 (m, 14H, 2 × piperazine-H And NCH3And Ac), 1.62~1.45 (m, 6H, 2 × CH3)；MS(m/z):759[M+H]+, calculated value: 758.79.
Embodiment 3
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [6,7- bis- fluoro- 1,8- (1,3- oxygen propyl group)-quinoline -4 (1H) -one -3- base]-urea (I-3), chemistry knot Structure formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking oxygen carboxylic acid fluoride hydroximic acid (3 ") 1.0g (3.4mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.82g (5.1mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.36g (3.4mmol) is added, 55~60 DEG C of water-bath stirrings 24 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-3), yield 65%, m.p.222~224 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.56(brs, 1H, NH), 9.47 (s, 1H, NH), the 9.16,8.92 (- H of 2s, 2H, 2 × 2 '), 8.34~the 7.42 (- H of m, 3H, 2 × 5 ' and 8 '- ), H 4.93~4.81 (m, 3H, OCH2CHN),4.45(q,2H,NCH2), 3.62~3.47 (m, 4H, piperazine-H), 2.60~2.36 (m, 10H, piperazine-H, NCH3And Ac), 1.62~1.46 (m, 6H, 2 × CH3)；MS(m/z):679[M+H]+, calculated value: 678.63。
Embodiment 4
(S) -1- 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3, 4- oxadiazoles -5- base } -3- [6,7- bis- fluoro- 8,1- (1,3- oxygen propyl group)-quinoline -4 (1H) -one -3- base]-urea (I-3), change Learn structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking levofloxacin carboxylic acid hydroximic acid (4 ") 1.0g (3.4mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.82g (5.1mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.36g (3.4mmol) is added, 55~60 DEG C of water-bath stirrings 18 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-4), yield 62%, m.p.215~217 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.56(brs, 1H, NH), 9.45 (s, 1H, NH), the 9.15,8.93 (- H of 2s, 2H, 2 × 2 '), 8.36~the 7.47 (- H of m, 3H, 2 × 5 ' and 8 '- ), H 4.92~4.82 (m, 3H, OCH2CHN),4.46(q,2H,NCH2), 3.65~3.43 (m, 4H, piperazine-H), 2.62~2.37 (m, 10H, piperazine-H, NCH3And Ac), 1.62~1.45 (m, 6H, 2 × CH3)；MS(m/z):679[M+H]+, calculated value: 678.63。
Embodiment 5
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [fluoro- 7- chlorine-quinoline -4 (1H) -one -3- base of 1- ethyl -6-]-urea (I-5), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking promise carboxylic acid fluoride hydroximic acid (5 ") 1.0g (3.5mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.98g (6.0mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.40g (3.5mmol) is added, 55~60 DEG C of water-bath stirrings 24 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-5), yield 63%, m.p.225~227 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.52(brs, 1H, NH), 9.43 (s, 1H, NH), the 9.14,8.96 (- H of 2s, 2H, 2 × 2 '), 8.34~the 7.35 (- H of m, 4H, 2 × 5 ' and 2 × 8 '- H),4.46,4.38(2q,4H,2×NCH2), 3.57~3.42 (m, 4H, piperazine-H), 2.58~2.38 (m, 7H, piperazine-H and ), Ac 1.62~1.35 (m, 6H, 2 × CH3)；MS(m/z):667[M+H]+(35), Cl calculated value: 666.08.
Embodiment 6
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base]-urea (I-6), Chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking pefloxacin hydroximic acid (6 ") 1.0g (2.9mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.61g (3.7mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.16g (2.9mmol) is added, 55~60 DEG C of water-bath stirrings 20 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-6), yield 56%, m.p.223~225 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.57(brs, 1H, NH), 9.46 (s, 1H, NH), the 9.22,9.08 (- H of 2s, 2H, 2 × 2 '), 8.45~the 7.42 (- H of m, 4H, 2 × 5 ' and 2 × 8 '- H),4.48,4.42(2q,4H,2×NCH2), 3.63~3.45 (m, 8H, 2 × piperazine-H), 2.62~2.38 (m, 14H, 2 × piperazines Piperazine-H, NCH3And Ac), 1.65~1.44 (m, 6H, 2 × CH3)；MS(m/z):731[M+H]+, calculated value: 730.78.
Embodiment 7
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base]-urea (I-7), Its chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- acetyl Norfloxacin hydroximic acid (7 ") 1.0g (2.7mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.69g (4.3mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.08g (2.7mmol) is added, 55~60 DEG C of water-bath Stirring 22 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is tied again with DMF- alcohol mixed solvent Crystalline substance obtains pale yellow crystals object (I-7), yield 57%, m.p.228~230 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.62 (brs, 1H, NH), 9.53 (s, 1H, NH), the 9.24,9.11 (- H of 2s, 2H, 2 × 2 '), 8.46~the 7.63 (- H of m, 4H, 2 × 5 ' and 2 ×8′-H),4.54,4.46(2q,4H,2×NCH2), 3.65~3.47 (m, 8H, 2 × piperazine-H), 2.66~2.37 (m, 12H, 2 × piperazine-H, NCH3And Ac), 1.66~1.42 (m, 6H, 2 × CH3)；MS(m/z):759[M+H]+, calculated value: 758.79.
Embodiment 8
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [fluoro- 7- chlorine-quinoline -4 (1H) -one -3- base of 1- cyclopropyl -6-]-urea (I-8), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking cyclopropyl carboxylic acid hydroximic acid (8 ") 1.0g (3.4mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.82g (5.1mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.36g (3.4mmol) is added, 55~60 DEG C of water-bath stirrings 24 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-8), yield 60%, m.p.226~228 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.53(brs, 1H, NH), 9.42 (s, 1H, NH), the 9.17,9.06 (- H of 2s, 2H, 2 × 2 '), 8.34~the 7.45 (- H of m, 4H, 2 × 5 ' and 2 × 8 '- ), H 4.54~4.42 (m, 5H, CH and 2 × NCH2), 3.57~3.43 (m, 4H, piperazine-H), 2.65~2.37 (m, 7H, piperazines- H and Ac), 1.68 (d, 3H, CH3), 1.25~0.96 (m, 4H, CH2CH2)；MS(m/z):679[M+H]+(35), Cl calculated value: 678.09。
Embodiment 9
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base]-urea (I-9), Its chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- methyl Ciprofloxacin hydroximic acid (9 ") 1.0g (2.8mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.73g (4.5mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.12g (2.8mmol) is added, 55~60 DEG C of water-bath Stirring 16 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is tied again with DMF- alcohol mixed solvent Crystalline substance obtains pale yellow crystals object (I-9), yield 55%, m.p.230~232 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.58 (brs, 1H, NH), 9.46 (s, 1H, NH), the 9.23,9.12 (- H of 2s, 2H, 2 × 2 '), 8.46~the 7.68 (- H of m, 4H, 2 × 5 ' and 2 × 8 '-H), 4.65~4.47 (m, 5H, CH and 2 × NCH2), 3.64~3.45 (m, 8H, 2 × piperazine-H), 2.63~2.37 (m, 14H, 2 × piperazine-H, NCH3 and Ac),1.66(d,3H,CH3), 1.35~1.15 (m, 4H, CH2CH2)；MS(m/z):743 [M+H]+, calculated value: 742.79.
Embodiment 10
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base]-urea (I- 10), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- acetyl group Ciprofloxacin hydroximic acid (10 ") 1.0g (2.6mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.75g (4.6mmol), stirring at normal temperature is added To material dissolution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.04g (2.6mmol) is added, water-bath 55~ 60 DEG C are stirred 22 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product DMF- alcohol mixed solvent Recrystallization, obtains pale yellow crystals object (I-10), yield 65%, m.p.223~225 DEG C.1H NMR(400MHz,DMSO-d6)δ: 11.62 (brs, 1H, NH), 9.47 (s, 1H, NH), the 9.25,9.13 (- H of 2s, 2H, 2 × 2 '), 8.46~7.68 (m, 4H, 2 × 5 '-H and 2 × 8 '-H), 4.72~4.53 (m, 5H, CH and 2 × NCH2), 3.67~3.45 (m, 8H, 2 × piperazine-H), 2.68~ 2.36 (m, 14H, 2 × piperazine-H and 2 × Ac), 1.72 (d, 3H, CH3), 1.41~1.27 (m, 4H, CH2CH2)；MS(m/z): 771[M+H]+, calculated value: 770.80.
Embodiment 11
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [chloro- [1,8] naphthyridines -4 (1H) -one -3- base of the fluoro- 7- of 1- ethyl -6-]-urea (I-11), chemical structural formula Are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking according to promise carboxylic acid hydroximic acid (11 ") 1.0g (3.5mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.81g (5.0mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.40g (3.5mmol) is added, 55~60 DEG C of water-bath stirrings 24 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-11), yield 64%, m.p.227~229 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.54 (brs, 1H, NH), 9.46 (s, 1H, NH), the 9.25,9.12 (- H of 2s, 2H, 2 × 2 '), 8.87~7.72 (- the H of m, 3H, 2 × 5 ' and 8′-H),4.82,4.42(2q,4H,2×NCH2), 3.63~3.42 (m, 4H, piperazine-H), 2.65~2.37 (m, 7H, piperazine-H And Ac), 1.72~1.46 (m, 6H, 2 × CH3)；MS(m/z):668[M+H]+(35), Cl calculated value: 668.06.
Embodiment 12
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-[1,8] naphthyridines -4 (1H) -one -3- base]-urea (I- 12), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- methyl Enoxacin hydroximic acid (12 ") 1.0g (2.9mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.65g (4.0mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.16g (2.9mmol) is added, 55~60 DEG C of water-bath Stirring 18 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is tied again with DMF- alcohol mixed solvent Crystalline substance obtains golden yellow crystallization object (I-12), yield 60%, m.p.222~224 DEG C.1H NMR(400MHz,DMSO-d6)δ: 11.58 (brs, 1H, NH), 9.46 (s, 1H, NH), the 9.32,9.13 (- H of 2s, 2H, 2 × 2 '), 8.94~7.86 (m, 3H, 2 × 5 '-H and 8 '-H), 4.86,4.45 (2q, 4H, 2 × NCH2), 3.67~3.46 (m, 8H, 2 × piperazine-H), 2.67~2.38 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.74~1.46 (m, 6H, 2 × CH3)；MS(m/z):732[M+H]+, calculated value: 731.77。
Embodiment 13
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [the fluoro- 7- of 1- ethyl -6- (4- acetylpiperazine -1- base)-[1,8] naphthyridines -4 (1H) -one -3- base]-urea (I- 13), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- acetyl Enoxacin hydroximic acid (13 ") 1.0g (2.7mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.58g (3.6mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.08g (2.7mmol) is added, 55~60 DEG C of water-bath Stirring 22 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is tied again with DMF- alcohol mixed solvent Crystalline substance obtains golden yellow crystallization object (I-13), yield 66%, m.p.227~229 DEG C.1H NMR(400MHz,DMSO-d6)δ: 11.62 (brs, 1H, NH), 9.51 (s, 1H, NH), the 9.35,9.23 (- H of 2s, 2H, 2 × 2 '), 8.94~7.88 (m, 3H, 2 × 5 '-H and 8 '-H), 4.88,4.50 (2q, 4H, 2 × NCH2), 3.67~3.46 (m, 8H, 2 × piperazine-H), 2.63~2.37 (m, 14H, 2 × piperazine-H and 2 × Ac), 1.75~1.47 (m, 6H, 2 × CH3)；MS(m/z):760[M+H]+, calculated value: 759.78.
Embodiment 14
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] - Urea (I-14), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking fleraxacin hydroximic acid (14 ") 1.0g (2.6mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.52g (3.2mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.04g (2.6mmol) is added, 55~60 DEG C of water-bath stirrings 16 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Golden yellow crystallization object (I-14), yield 61%, m.p.225~227 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.63 (brs, 1H, NH), 9.52 (s, 1H, NH), the 9.37,9.26 (- H of 2s, 2H, 2 × 2 '), 9.16~7.65 (- the H of m, 3H, 2 × 5 ' and 8 '-H), 4.94~4.52 (m, 6H, FCH2CH2And NCH2), 3.68~3.46 (m, 8H, 2 × piperazine-H), 2.65~2.38 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.47 (d, 3H, CH3)；MS(m/z):767[M+H]+, calculated value: 766.76.
Embodiment 15
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [the fluoro- 7- of 1- ethyl -6,8- two (3,4- lupetazin -1- base)-quinoline -4 (1H) -one -3- base]-urea (I-15), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- methyl Lomefloxacin hydroximic acid (15 ") 1.0g (2.6mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.55g (3.4mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.04g (2.6mmol) is added, 55~60 DEG C of water-bath Stirring 15 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is tied again with DMF- alcohol mixed solvent Crystalline substance obtains golden yellow crystallization object (I-15), yield 45%, m.p.214~216 DEG C.1H NMR(400MHz,DMSO-d6)δ: 11.55 (brs, 1H, NH), 9.42 (s, 1H, NH), the 9.16,8.95 (- H of 2s, 2H, 2 × 2 '), 8.72~7.56 (m, 3H, 2 × 5 '-H and 8 '-H), 4.56,4.46 (2q, 4H, 2 × CH2), 3.63~3.46 (m, 8H, 2 × piperazine-H), 2.64~2.37 (m, 13H, 2 × piperazine-H, NCH3And Ac), 1.45~1.37 (m, 9H, 3 × CH3)；MS(m/z):763[M+H]+, calculated value: 762.80。
Embodiment 16
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [the fluoro- 8- methoxyl group -7- of 1- cyclopropyl -6- (3,4- lupetazin -1- base)-quinoline -4 (1H) -one -3- Base]-urea (I-16), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- methyl gatifloxacin hydroximic acid (16 ") 1.0g (2.5mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.55g (3.4mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.00g (2.5mmol) is added, 55~60 DEG C of water-bath Stirring 18 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is tied again with DMF- alcohol mixed solvent Crystalline substance obtains golden yellow crystallization object (I-16), yield 42%, m.p.214~216 DEG C.1H NMR(400MHz,DMSO-d6)δ: (11.58 brs, 1H, NH), 9.47 (s, 1H, NH), the 9.25,9.16 (- H of 2s, 2H, 2 × 2 '), 8.56~7.548.72~7.56 (- the H of m, 3H, 2 × 5 ' and 8 '-H), 4.66~4.45 (m, 3H, CH and NCH2),3.89(s,3H,OCH3), 3.58~3.45 (m, 8H, 2 × piperazine-H), 2.57~2.36 (m, 13H, 2 × piperazine-H, NCH3And Ac), 1.47~1.16 (m, 10H, 2 × CH3 and CH2CH2)；MS(m/z):787[M+H]+, calculated value: 786.85.
Embodiment 17
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [the fluoro- 8- methoxyl group -7- of 1- cyclopropyl -6- (1- methyl-octahydro pyrrolo- [3,4-b] pyridine -6- base)-quinoline Quinoline -4 (1H) -one -3- base]-urea (I-17), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- methyl Moxifloxacin hydroximic acid (17 ") 1.0g (2.3mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.52g (3.2mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 0.92g (2.5mmol) is added, 55~60 DEG C of water-bath Stirring 16 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is tied again with DMF- alcohol mixed solvent Crystalline substance obtains pale yellow crystals object (I-17), yield 51%, m.p.210~212 DEG C.1H NMR(400MHz,DMSO-d6)δ: 11.57 (brs, 1H, NH), 9.45 (s, 1H, NH), the 9.26,9.17 (- H of 2s, 2H, 2 × 2 '), 8.53~7.57 (m, 3H, 2 × 5 '-H and 8 '-H), 4.62~4.45 (m, 3H, CH and NCH2),3.87(s,3H,OCH3), 3.64~3.16 (m, 8H, piperazines- H and pyrrolidine ring-H), 2.58~2.27 (m, 13H, piperazine-H, piperidine ring-H, NCH3And Ac), 1.95~1.23 (m, 12H,CH3, cyclopropyl-H and piperidine ring-H)；MS(m/z):813[M+H]+, calculated value: 812.88.
Embodiment 18
{ 2- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- is disliked 1- Diazole -5- base } -3- [6- fluoro- 8,1- sulphur ethylene group -7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base]-urea (I- 18), chemical structural formula are as follows:
Double-fluoquinolone oxadiazoles urea of the present embodiment the preparation method comprises the following steps: taking Rufloxacin hydroximic acid (18 ") 1.0g (2.6mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.52g (3.2mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II 1.04g (2.6mmol) is added, 55~60 DEG C of water-bath stirrings 15 hours.It stands overnight, filters and collect the solid of generation, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-18), yield 57%, m.p.227~229 DEG C.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, SCH2CH2With 2 × piperazine-H), 2.66~ 2.37 (m, 14H, 2 × piperazine-H, NCH3 and Ac),1.43(d,3H,CH3)；MS(m/z):761[M+H]+, calculated value: 760.83。
Test example
One, one kind pair-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives body that embodiment 1-18 is provided Outer antitumor cytolytic activity
1, test sample
With the embodiment 1-18 18 new double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives provided and warp The antitumor topoisomerase enzyme inhibitor 10-hydroxycamptothecine (Hydroxycamptothecin, HC) of allusion quotation, ureas tyrosine kinase Inhibitor Rui Gefeini (Regorafenib, RRF) and card are rich for Buddhist nun (Cabozantinib, CZT) and parent compound N- acetyl Norfloxacin (MNF) is test sample, and totally 22 kinds, wherein HC, RRF, CZT and MNF are positive control experiment group, embodiment 1-18 Sample is experimental group；
Thiazolyl blue (MTT), HC, RRF, CZT and MNF are Sigma Products；RPMI-1640 culture solution is GIBCO public Take charge of product；Reagent used in other is domestic analytical reagents.
Experimental cancer cell line is respectively Non-small cell lung carcinoma cell line A549, human hepatoma cell strain SMCC-7721, people's stomach Cancer cell line HGC27, human pancreas cancer cell strain Capan-1, Human skin melanoma cell strain A375, human leukemia cell line HL60 is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences；The cell cycling inhibiting of resistance to Gefitinib G is purchased from Tianjin blood disease postgraduate；Just Normal cell uses African green monkey kidney cell VERO cell, buys in Shanghai Tongtong Biological Technology Co., Ltd..
2, measuring method
The specific steps of measuring method are as follows:
(1) it uses dimethyl sulfoxide (DMSO) to dissolve respectively above-mentioned 22 kinds of test samples first, is configured to 1.0 × 10- 4mol·L-1Then the stock solution of concentration is pressed with the RPMI-1640 culture solution containing 10% (mass percent concentration) calf serum Stock solution is diluted to the working solution with 5 concentration gradients (50,10,5,1.0,0.1 μM) by 10 times of dilution methods；
First group of experiment: cancer cell line HL60, Capan-1 and K562G of logarithmic growth phase, with 5000, every hole cell 96 orifice plates are inoculated in be separately added into the working solution with 5 concentration gradients after culture is overnight, culture medium is discarded after 48 hours, often 1gL is added in hole–1100 μ L of MTT solution discards supernatant liquid after then proceeding to culture 4 hours, the DMSO of 150 μ L is added in every hole, gently Light oscillation 30 minutes, measures absorbance (OD) value with microplate reader later at 570nm wavelength；
Second group of experiment: cancer cell line A549, SMCC-7721, HGC27, VERO and A375 of logarithmic growth phase, with every 7000, hole cell inoculation is then separately added into the working solution with 5 concentration gradients in 96 orifice plates, and every hole is added after 48 hours 5g·L–1The dodecyl sulphate that 100 μ L mass percent concentrations are 10% is added in 10 μ L of MTT solution after continuing culture 4 hours Sodium (SDS) hydroponics are overnight, and OD value is then measured at 570nm wavelength with microplate reader；
(2) inhibiting rate of the test sample to experiment cancer cell of various concentration is calculated by using the formula shown below,
Cancer inhibition rate=[1- (experimental group OD value/control group OD value)] × 100%,
Then linear regression is made to the corresponding cancer inhibition rate of each concentration with the logarithm of each concentration of test sample, obtained To dose-effect equation, each test sample is calculated to the half-inhibitory concentration of experiment cancer cell from gained dose-effect equation (IC50)；Each data are measured in parallel five times, are averaged, the results are shown in Table 1.
Anti-tumor activity (the IC of each test sample of table 150)
As it can be seen from table 1 double-fluoquinolone oxadiazoles ureas N- acetyl Norfloxacin that embodiment 1-18 is provided is derivative Object all has significant proliferation inhibition activity to 7 kinds of experimental cancer cell lines, especially to Non-small cell lung carcinoma cell line A549, people Pancreas cancer cell strain Capan-1 and Human skin melanoma cell strain A375 show higher activity, are not only significantly stronger than parent Compound N-acetyl Norfloxacin activity, while being better than the activity of control topoisomerase enzyme inhibitor Hydroxycamptothecin (HC), it is more The activity of number compound is also better than control tyrosine kinase inhibitor Rui Gefeini (RRF) and the rich activity for Buddhist nun (CZT) of card.More Significantly, the compound that embodiment 1-18 is provided also shows extremely strong sensibility to the cell cycling inhibiting of resistance to Gefitinib G, together When normal cell IIERO cell is shown low toxicity, with druggability attribute.Therefore, according to the one of drug development As approach be first to carry out conventional antitumor in-vitro screening, then targetedly studied, thus the compound of the present invention have There are strong antitumor anti-drug-resistance activity and lower toxicity, it can be by being mixed with acid human-acceptable at salt or with pharmaceutical carrier Prepare anti-tumor drug.

Claims (8)

1. a kind of double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives, general formula of the chemical structure are as follows:
In formula, R is ethyl, cyclopropyl, fluoro ethyl, the oxazines ring constituted with C-8 or the thiazine ring constituted with C-8；
L is independent chlorine atom, fluorine atom, 1- piperazinyl, substituted piperazine -1- base or nitrogen condensed hetero ring；
X is-CH ,-N ,-CF or-COCH3。
2. double according to claim 1-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives, which is characterized in that For following formula I-1 to I-18 compound represented:
3. the preparation method of double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives, feature described in claim 2 It is, specifically includes following preparation step:
1) it using N- acetyl Norfloxacin as raw material, is condensed in polyphosphoric acids PPA with semicarbazides, it is post-treated that N- acetyl is made Norfloxacin C-3 oxadiazoles amine intermediate II, it is as follows to be synthetically prepared route:
2) fluoroquinolone carboxylic acid series compound shown in formula 1~18 is condensed generation with carbonyl dimidazoles CDI in DMF respectively Corresponding fluoroquinolone carboxylic acid Orazamide series compound 1 '~18 '；Then the fluoroquinolone carboxylic acid imidazoles that will be prepared Amide series compound 1 '~18 ' reacts in pyridine Py with hydroxylamine hydrochloride respectively is made corresponding fluoquinolone hydroximic acid series Compound 1 "~18 "；Fluoquinolone hydroximic acid series compound 1 "~18 " passes through under the auxiliary catalysis of carbonyl dimidazoles CDI Lossen is rearranged to fluoquinolone isocyanates, directly dislikes two with N- acetyl group Norfloxacin C-3 obtained by step 1) without isolation Azoles amine intermediate II occur condensation reaction, it is post-treated to obtain the final product；Synthetic route is as follows:
The difference of fluoroquinolone carboxylic acid series compound structural formula shown in formula 1~18 is as follows:
4. the preparation method of double according to claim 3-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives, It is characterized in that, the molar ratio of fluoroquinolone carboxylic acid series compound and carbonyl dimidazoles shown in formula 1~18 is 1:1.0~2.0.
5. the preparation method of double according to claim 3-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives, It is characterized in that, the molar ratio of fluoroquinolone carboxylic acid Orazamide series compound 1 '~18 ' and hydroxylamine hydrochloride is 1:1.0~5.0.
6. the preparation method of double according to claim 3-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives, It is characterized in that, the molar ratio of fluoquinolone hydroximic acid series compound 1 "~18 " and carbonyl dimidazoles is 1:1.0~2.0, fluorine quinoline The molar ratio of promise ketone hydroximic acid series compound 1 "~18 " and N- acetyl Norfloxacin C-3 oxadiazoles amine intermediate II is 1:1.
7. double-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives described in claim 1 are preparing anti-tumor drug In application.
8. double according to claim 7-fluoquinolone oxadiazoles ureas N- acetyl norfloxacin derivatives prepare it is antitumor Application in drug, which is characterized in that the anti-tumor drug is treatment lung cancer, liver cancer, gastric cancer, cancer of pancreas, dermal melanin The drug of tumor, leukaemia or resistance to Gefitinib cancer.
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