CN109761999A - The preparation and application of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives - Google Patents

The preparation and application of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives Download PDF

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CN109761999A
CN109761999A CN201811343703.9A CN201811343703A CN109761999A CN 109761999 A CN109761999 A CN 109761999A CN 201811343703 A CN201811343703 A CN 201811343703A CN 109761999 A CN109761999 A CN 109761999A
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acetyl group
fluoquinolone
thiadiazoles
double
ciprofloxacin
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胡国强
张呈霞
孙姣姣
王娜
沈睿智
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Henan University
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Henan University
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Abstract

The invention discloses a kind of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives and its preparation method and application, and general formula of the chemical structure is as shown in following formula I:In Formulas I R be ethyl or cyclopropyl or fluoro ethyl or with C-8 constitute oxazines ring or with C-8 composition thiazine rings, L is independent chlorine atom or fluorine atom or 1- piperazinyl or substituted piperazine -1- base or nitrogen condensed hetero ring, X are hydrocarbon (CH) or nitrogen-atoms or fluorine-substituted carbon atom (F-C) or methoxy-substituted carbon atom (CH3O-C).Double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives of the invention; realize organic split of double-fluoquinolone skeleton and thiadiazoles 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

The preparation of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives and Using
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 thiadiazoles ureas N- acetyl group ciprofloxacin derivatives, also relates to the system of the analog derivative Preparation 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, using the advantage skeleton or pharmacophore segment of existing drug, The new small molecule primer that creating has treatment and function controlling to major diseases such as malignant tumours is that new drug development is most economical Effective strategy.Based on this, on the one hand in view of fluoquinolone (FQs) is as a kind of clinical widely used antimicrobial, resist Bacterium advantage pharmacophore skeleton is " quinoline (naphthyridines) -4- ketone -3- carboxylic acid ", because of its action target-topoisomerase (TOPO) It is the important target enzyme of anti-tumor drug, anti-tumor activity can be converted by its antibacterial activity by the strategy of structural modification, in turn It was found that the antitumor fluoquinolone primer of new construction.At the same time, though structure activity study finds fluoquinolone C-3 carboxyl It is necessary to antibacterial activity, but is not pharmacophore necessary to anti-tumor activity, uses heterocycle or condensed hetero ring as C-3 carboxylic The isostere of base is remarkably improved its anti-tumor activity, this is how to convert antibacterial fluoroquinolone drug to antitumor FQ molecule Provide new approaches.However, problem be select how the carboxyl isostere of structure type, and take with fluoquinolone skeleton why The connection type of sample is beneficial to the discovery of targeting small molecule primer, further innovation driving targeting anti-tumor fluoquinolone The discovery of drug is still urgently project to be resolved at present.On the other hand, the structure based on protein tyrosine kinase (PTK) target spot The anti-tumor drugs targeting molecule built has made substantial progress, and has numerous small molecular protein tyrosine kinase inhibitors (PTKIs) enter the clinical targeted therapy of tumour, and then excite the discovery and research and development of target therapeutic agent.Meanwhile on The structure of the targeting PTKIs molecule in city is dissected, and 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, beta-unsaturated ketone such as Sutent (D) etc. Four kinds of structure types.For this purpose, making full use of the structure feature of targeting PTKIs molecule, 2 carbostyril skeleton structural units are led to Crossing thiadiazoles urea is that its connection chain constructs in pairs-fluoquinolone thiadiazoles carbamide derivative, has both remained antitumor fluoquinolone Design feature, and embody targeting PTKIs molecule urea structure characteristic, it is possible to find the antitumor elder generation of novel fluoroquinolones Compound is led, the development for targeting therapy for tumor drug 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 thiadiazoles urea of fluoquinolone Class N- acetyl group ciprofloxacin derivatives, have an antitumor effect and efficacy, while providing a kind of double-fluoquinolone ring thiophene The preparation method of diazole ureas N- acetyl group ciprofloxacin derivatives.
In order to realize the above target, the technical scheme adopted by the invention is that: a kind of double-fluoquinolone ring thiadiazoles urea Class N- acetyl group ciprofloxacin derivatives, chemical structural formula is as shown in general formula I:
R is ethyl or cyclopropyl or fluoro ethyl or the oxazines ring constituted with C-8 or the thiazine constituted with C-8 in Formulas I Ring；
L is independent chlorine atom or fluorine atom or 1- piperazinyl or substituted piperazine -1- base or nitrogen condensed hetero ring in Formulas I；
X is hydrocarbon (CH) or nitrogen-atoms or fluorine-substituted carbon atom (F-C) or methoxy-substituted carbon atom (CH3O-C)。
One kind pair-fluoquinolone ring thiadiazoles ureas N- acetyl group ciprofloxacin derivatives preparation method of the invention, It include: to generate N- acetyl Jino fluorine under the action of potassium carbonate with iodomethane 1) with N- acetyl group Ciprofloxacin (10) for raw material Husky star methyl esters (II) is prepared into N- acetyl group Ciprofloxacin hydrazide compound shown in formula (III) through hydrazinolysis reaction；Then formula III and potassium rhodanide occur condensation reaction in the aqueous solution of dilute hydrochloric acid and N- acetyl group Ciprofloxacin acyl shown in formula (IV) are made Amido thiourea compound；Last formula IV intramolecular cyclisation occurs in concentrated sulfuric acid, N- acetyl group Ciprofloxacin is prepared C-3 thiadiazoles amine intermediate (V) is synthetically prepared shown in route sees below.
The preparation method of intermediate N acetyl group Ciprofloxacin C-3 thiadiazoles amine (V):
A) N- acetyl group Ciprofloxacin (10) 37.3g (0.10mol) is dissolved in 500mL DMF, and Anhydrous potassium carbonate is added 21.1g (0.15mol), 90 DEG C are stirred to react 2.0 hours, are cooled to room temperature.It is added iodomethane 21.3g (0.15 mol), heating It is stirred to react 6.0 hours to 90 DEG C.Evaporating solvent under reduced pressure is added 500mL ice water, dispersing solid is sufficiently stirred, and filters, washing. Dry, dehydrated alcohol recrystallization obtains colorless solid N- acetyl group Ciprofloxacin methyl esters (II), 32.4g, m.p.224~226 DEG C.
B) N- acetyl group Ciprofloxacin methyl esters (II) 20.0g (51.7mmol) is added to 500mL dehydrated alcohol and quality point The in the mixed solvent of the hydrazine hydrate 10.0g (0.16mol) of number 80% is stirred at reflux reaction 24 hours.The solid generated is filtered, It is recrystallized with dehydrated alcohol, obtains colorless crystalline solid N- acetyl group Ciprofloxacin hydrazides (III), 18.5 g, m.p.226~228 ℃。
C) N- acetyl group Ciprofloxacin hydrazides (III) 15.0g (38.8mmol) is mixed with 200mL water, sequentially adds sulphur cyanogen Sour potassium 15.0g (155.0mmol) and concentrated hydrochloric acid 13.0mL, reaction mixture, which is stirred at reflux, to react 8 hours, cooling room temperature, and use is dense Ammonium hydroxide tune pH 8.0 flows back 2 hours, and heat filtering washes solid.It is dry, it is recrystallized, is obtained colourless with DMF- alcohol mixed solvent Solid N- acetyl group Ciprofloxacin amidoamino thiocarbamide (IV), 15.2 g, m.p.215~217 DEG C.
D) N- acetyl group Ciprofloxacin amidoamino thiocarbamide (IV) 10.0g (22.4mmol) is slowly added to stirring It is warming up to 70~80 DEG C in the 150mL concentrated sulfuric acid, after material dissolution to be stirred to react 12 hours, slowly pours into the trash ice of 1500g, With concentrated ammonia liquor tune pH 10.0.It stands overnight, filter collection solid is washed to neutrality, dry.Crude product DMF- alcohol mixed solvent weight Crystallization, obtains pale yellow crystals N- acetyl group Ciprofloxacin C-3 thiadiazoles amine
2) it is anti-that fluoroquinolone carboxylic acid (FQ-COOH, 1~18) in DMF to that condensation occur with carbonyl dimidazoles (CDI) respectively Corresponding fluoroquinolone carboxylic acid Orazamide (1 '~18 ') should be prepared；The fluoroquinolone carboxylic acid Orazamide being prepared (1 '~18 ') directly corresponding fluoquinolone hydroximic acid can be conveniently made in reaction in pyridine (Py) with hydroxylamine hydrochloride without further purification (1 "~18 ")；Fluoquinolone hydroximic acid (1 "~18 ") is reset under the auxiliary catalysis of carbonyl dimidazoles (CDI) by Lossen For fluoquinolone isocyanates, condensation reaction occurs with N- acetyl group Ciprofloxacin C-3 thiadiazoles amine intermediate V without isolation, It is post-treated that one kind shown in claim 1 pair-fluoquinolone thiadiazoles ureas N- acetyl group Norfloxacin is prepared Derivative (Formulas I -1~I-18), synthetic route is as follows.
Wherein fluoroquinolone carboxylic acid (FQ-COOH) include: Ofloxacin (1), lavo-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 ring Third husky star (9), N- acetyl Ciprofloxacin (10), according to promise carboxylic acid (11), N- methyl Enoxacin (12), N- acetyl Enoxacin (13), fleraxacin (14), N- methyl Lomefloxacin (15), N- methyl gatifloxacin (16), N- methyl Moxifloxacin (17) and Rufloxacin (18), structure see below shown.
The fluoroquinolone carboxylic acid Orazamide (1 '~18 ') being accordingly prepared are as follows: Ofloxacin Orazamide (1 '), a left side Ofloxacin Orazamide (2 '), oxygen carboxylic acid fluoride Orazamide (3 '), levofloxacin carboxylic acid Orazamide (4 '), promise carboxylic acid fluoride miaow Azoles amide (5 '), pefloxacin Orazamide (6 '), N- acetyl Norfloxacin Orazamide (7 '), cyclopropyl carboxylic acid Orazamide (8 '), N- methyl Ciprofloxacin Orazamide (9 '), N- acetyl Ciprofloxacin Orazamide (10 '), according to promise carboxylic acid Orazamide (11 '), N- methyl Enoxacin Orazamide (12 '), N- acetyl Enoxacin Orazamide (13 '), fleraxacin imidazoles acyl Amine (14 '), N- methyl Lomefloxacin Orazamide (15 '), N- methyl gatifloxacin Orazamide (16 '), N- methyl Moses are husky Star Orazamide (17 ') and Rufloxacin Orazamide (18 '), structure see below shown.
The preparation manipulation step of fluoroquinolone carboxylic acid Orazamide (1 '~18 ') leads to method: taking fluoquinolone as shown above Carboxylic acid (0.10mol) is dissolved in anhydrous N, in N- diformamide (DMF) (500mL), be added carbonyl dimidazoles (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.Nothing is added in evaporating solvent under reduced pressure Ethyl acetate (500mL), is sufficiently stirred dispersing solid, filtering, ethyl acetate washing, dry, is directly used in lower step without further purification Reaction.
Corresponding fluoquinolone hydroximic acid (1 "~18 "): Ofloxacin hydroximic acid (1 "), lavo-ofloxacin hydroximic acid (2 "), oxygen carboxylic acid fluoride hydroximic acid (3 "), levofloxacin carboxylic acid hydroximic acid (4 "), promise carboxylic acid fluoride hydroximic acid (5 "), pefloxacin hydroxyl oxime Sour (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- second Acyl Enoxacin hydroximic acid (13 "), fleraxacin hydroximic acid (14 "), N- methyl Lomefloxacin hydroximic acid (15 "), N- methyl add For husky star hydroximic acid (16 "), N- methyl Moxifloxacin hydroximic acid (17 ") and Rufloxacin hydroximic acid (18 "), structure is seen below It is shown.
The preparation manipulation step of fluoquinolone hydroximic acid (1 "~18 "): fluoroquinolone carboxylic acid imidazoles acyl as shown above is taken Amine crude product (0.10mol) is suspended in pyridine (By) (500mL), is added hydroxylamine hydrochloride 13.8g (0.20mol), 60~75 DEG C of water Bath is stirred to react 8.0~24.0 hours.It is cooled to room temperature, filters, solid is washed with pyridine, 60~70 DEG C of vacuum drying.Crude product Be suspended in saturated sodium bicarbonate solution (500mL), 50~65 DEG C stirring in water bath 3~5 hours.Filtering, deionized water wash to PH 7.0 is dry.It is recrystallized with dehydrated alcohol (or dehydrated alcohol-DMF mixed solvent), pure lenticular fluoquinolone must be analyzed Hydroximic acid (1 "~18 ").
Method: fluorine quinoline is led in the preparation of target compound pair-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives Promise ketone hydroximic acid (1 "~18 ") each 1.0g is suspended in suitable acetonitrile, carbonyl dimidazoles (1.0~2.0 times of amounts) is added, often After warm stirring and dissolving, N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate (1.0 times of amounts) is added, 55~60 DEG C of water-baths are stirred It mixes 10~24 hours.Room temperature is placed, the solid that filter collection generates is recrystallized with solvent appropriate, is made shown in claim 1 Double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives.
One kind pair-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives of the invention, based on targeting junket ammonia The pharmacophore urea structure segment of acid kinase inhibitor and effective biological isostere thiadiazoles heterocycle of fluoquinolone C-3 carboxyl, and Using pharmacophore split drug molecule design principle, double-fluoquinolone skeleton is connected using thiadiazoles urea as connection chain, into And design and synthesized " double-afloqualone ureas " derivative, realize moving for advantage structural pharmacophore between different role mechanism drug More with it is complementary, innovated the structure of drug molecule, achieved synergistic and detoxifying effects, can be used as the antineoplastic of brand new Object exploitation.
Specific embodiment
Technical solution of the present invention is described in detail by following specific embodiments.
Embodiment 1
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -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 thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking Ofloxacin hydroximic acid (1 ") 1.0g (2.7 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.79g (4.9mmol), stirring at normal temperature to material is added Dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.16g (2.7 mmol) is added, 55~60 DEG C of water-bath are stirred It mixes 16 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained light Yellow crystal object (I-1), yield 65%, 225~227 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.54(brs,1H, NH),9.42(s,1H,NH), 9.17,9.04(2s,2H,2×2′-H),8.42,8.18(2d,2H,2×5′-H),7.53(d, 1H, 8 '-H), 4.96~4.58 (m, 4H, OCH2CHN and CH), 3.47~3.36 (m, 8H, 2 × piperazine-H), 2.55~ 2.37 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.58~1.05 (m, 7H, CH3and CH2CH2)；MS(m/z):787 [M+H]+, calculated value: 786.87 [M]+。
Embodiment 2
(S) -1- 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1, 3,4- thiadiazoles -5- base } -3- [the fluoro- 7- of 6- (4- methylpiperazine-1-yl) -8,1- (1,3- oxygen propyl group)-quinoline -4 (1H) -one - 3- yl]-urea (I-1), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles 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) 0.70g (4.3mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.16g (2.7 mmol) is added, 55~60 DEG C of water-bath stirrings 12 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product ethyl alcohol recrystallization obtains pale yellow crystals object (I- 2), yield 52%, m.p.220~222 DEG C.1H NMR(400 MHz,DMSO-d6)δ:1H NMR(400MHz,DMSO-d6)δ: 11.53(brs,1H,NH),9.40(s, 1H,NH),9.17,8.97(2s,2H,2×2′-H),8.43,8.17(2d,2H,2× 5 '-H), the 7.56 (- H of d, 1H, 8 '), 4.97~4.57 (m, 4H, OCH2CHN and CH), 3.46~3.36 (m, 8H, 2 × piperazines Piperazine-H), 2.56~2.37 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.56~1.06 (m, 7H, CH3and CH2CH2)； MS(m/z):787 [M+H]+, calculated value: 786.87 [M]+。
Embodiment 3
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -5- base } -3- [6,7- bis- fluoro- 1,8- (1,3- oxygen propyl group)-quinoline -4 (1H) -one -3- base]-urea (I-3), chemistry Structural formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking oxygen carboxylic acid fluoride hydroximic acid (3 ") 1.0g (3.4 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.82g (5.1mmol), stirring at normal temperature to material is added Dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.46g (3.4 mmol) is added, 55~60 DEG C of water-bath are stirred It mixes 24 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained light Yellow crystal object (I-3), yield 72%, 231~233 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.48(brs,1H, NH),9.37(s,1H,NH), 9.13,8.96(2s,2H,2×2′-H),8.38,8.14(2d,2H,2×5′-H),7.48(d, 1H, 8 '-H), 4.94~4.56 (m, 4H, OCH2CHN and CH), 3.45~3.35 (m, 4H, piperazine-H), 2.46~2.25 (m, 7H, piperazine-H and Ac), 1.56~0.96 (m, 7H, CH3and CH2CH2)；MS(m/z):707[M+H]+, calculated value: 706.71[M]+。
Embodiment 4
(S) -1- 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1, 3,4- thiadiazoles -5- bases } -3- [6,7- bis- fluoro- 8,1- (1,3- oxygen propyl group)-quinoline -4 (1H) -one -3- base]-urea (I-3), Chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles 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 group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.46g (3.4 mmol) is added, 55~60 DEG C of water-bath stirrings 22 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained yellowish Color crystal (I-4), yield 61%, 215~217 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.47(brs,1H, NH),9.38(s,1H,NH), 9.15,8.97(2s,2H,2×2′-H),8.37,8.15(2d,2H,2×5′-H),7.50(d, 1H, 8 '-H), 4.96~4.56 (m, 4H, OCH2CHN and CH), 3.45~3.35 (m, 4H, piperazine-H), 2.45~2.27 (m, 7H, piperazine-H and Ac), 1.57~0.98 (m, 7H, CH3and CH2CH2)；MS(m/z):707[M+H]+, calculated value: 706.71[M]+。
Embodiment 5
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -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 thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking fluorine chlorine quinolone 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 group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.50g (3.5 mmol) is added, 55~60 DEG C of water-bath stirrings 24 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained yellowish Color crystal (I-5), yield 75%, 226~228 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.46(brs,1H, ), NH 9.36 (s, 1H, NH), the 8.97,8.86 (- H of 2s, 2H, 2 × 2 '), 8.24~the 7.78 (- H of m, 2H, 2 × 5 '), 7.36~ 7.26(m,2H,2×8′-H), 4.56(m,1H,CH),4.27(q,2H,NCH2), 3.45~3.35 (m, 4H, piperazine-H), 2.46~2.35 (m, 7H, piperazine-H and Ac), 1.38~1.02 (m, 7H, CH3and CH2CH2)；MS(m/z):695 [M+ H]+(35), Cl calculated value: 695.15 [M]+。
Embodiment 6
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -5- base } -3- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base]-urea (I-6), Its chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking pefloxacin hydroximic acid (6 ") 1.0g (2.9 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.61g (3.7mmol), stirring at normal temperature to material is added Dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.24g (2.9 mmol) is added, 55~60 DEG C of water-bath are stirred It mixes 20 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained light Yellow crystal object (I-6), yield 58%, 224~226 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.48(brs,1H, ), NH 9.38 (s, 1H, NH), the 9.15,9.04 (- H of 2s, 2H, 2 × 2 '), 8.36~the 8.17 (- H of m, 2H, 2 × 5 '), 7.84~ The 7.52 (- H of m, 2H, 2 × 8 '), 4.58~4.42 (m, 3H, NCH2And CH), 3.57~3.36 (m, 8H, 2 × piperazine-H), 2.47~2.35 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.38~1.12 (m, 7H, CH3and CH2CH2)；MS(m/ z):759 [M+H]+, calculated value: 758.86 [M]+。
Embodiment 7
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -5- base } -3- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base]-urea (I- 7), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- acetyl group Norfloxacin hydroximic acid (7 ") 1.0g (2.7mmol) is suspended in 25mL acetonitrile, carbonyl dimidazoles (CDI) 0.75g (5.4mmol) is added, room temperature stirs It mixes to material dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.16g (2.7mmol) is added, water-bath 55 ~60 DEG C are stirred 22 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is tied again with DMF- alcohol mixed solvent Crystalline substance obtains pale yellow crystals object (I-7), yield 58%, and 228~230 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.52 (brs, 1H, NH), 9.44 (s, 1H, NH), the 9.23,9.14 (- H of 2s, 2H, 2 × 2 '), 8.38~the 8.26 (- H of m, 2H, 2 × 5 '), 7.77~the 7.53 (- H of m, 2H, 2 × 8 '), 4.56~4.32 (m, 3H, NCH2And CH), 3.56~3.37 (m, 8H, 2 × piperazines Piperazine-H), 2.53~2.38 (m, 11H, 2 × piperazine-H and Ac), 1.36~1.02 (m, 7H, CH3and CH2CH2)；MS(m/ z):787[M+H]+, calculated value: 786.87 [M]+。
Embodiment 8
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -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 thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking cyclopropyl fluorine chlorine quinolone hydroximic acid (8 ") 1.0g (3.4mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.97g (6.0mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.46g (3.4mmol) is added, 55~60 DEG C of water-bath Stirring 24 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-8), yield 75%, 245~247 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.46(brs, 1H, NH), 9.35 (s, 1H, NH), the 9.06,8.87 (- H of 2s, 2H, 2 × 2 '), 8.27~the 7.68 (- H of m, 2H, 2 × 5 '), 7.67 ~the 7.46 (- H of m, 2H, 2 × 8 '), 4.58~4.47 (m, 2H, 2 × CH), 3.46~3.37 (m, 4H, piperazine-H), 2.53~ 2.34 (m, 7H, piperazine-H and Ac), 1.24~0.87 (m, 8H, 2 × CH2CH2)；MS(m/z):707[M+H]+(35), Cl it counts Calculation value: 707.16 [M]+。
Embodiment 9
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -5- base } -3- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base]-urea (I- 9), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles 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) 0.81g (5.0mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.20g (2.8mmol) is added, 55~60 DEG C of water-bath Stirring 18 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-9), yield 68%, 223~225 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.52(brs, 1H, NH), 9.43 (s, 1H, NH), the 9.16,9.04 (- H of 2s, 2H, 2 × 2 '), 8.35~the 8.26 (- H of m, 2H, 2 × 5 '), 8.15 ~the 7.68 (- H of m, 2H, 2 × 8 '), 4.56~4.28 (m, 2H, 2 × CH), 3.46~3.33 (m, 8H, 2 × piperazine-H), 2.55 ~2.35 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.21~0.95 (m, 8H, 2 × CH2CH2)；MS(m/z):771[M+ H]+, calculated value: 770.87 [M]+。
Embodiment 10
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -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 thiadiazoles 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, is added carbonyl dimidazoles (CDI) 0.75g (4.6 mmol), room temperature stirs It mixes to material dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.11g (2.6mmol) is added, water-bath 55 ~60 DEG C are stirred 23 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is tied again with DMF- alcohol mixed solvent Crystalline substance obtains pale yellow crystals object (I-10), yield 66%, m.p.232~234 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.56 (brs, 1H, NH), 9.45 (s, 1H, NH), the 9.23,9.12 (- H of 2s, 2H, 2 × 2 '), 8.56~the 8.37 (- H of m, 2H, 2 × 5 '), 8.25~the 7.75 (- H of m, 2H, 2 × 8 '), 4.66~4.58 (m, 2H, 2 × CH), 3.56~3.37 (m, 8H, 2 × piperazine-H), 2.57~2.36 (m, 14H, 2 × 2 × Ac of piperazine-H and), 1.27~1.12 (m, 8H, 2 × CH2CH2)；MS(m/z):799 [M+H]+, calculated value: 798.88 [M]+。
Embodiment 11
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -5- base } -3- [chloro- [1,8] naphthyridines -4 (1H) -one -3- base of the fluoro- 7- of 1- ethyl -6-]-urea (I-11), chemistry knot Structure formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking ethyl fluoride chlorine naphthyridones hydroximic acid (11 ") 1.0g (3.5mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 1.13g (7.0mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.50g (3.5mmol) is added, 55~60 DEG C of water-bath Stirring 24 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-11), yield 70%, 227~229 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.55 (brs, 1H, NH), 9.47 (s, 1H, NH), the 9.26,9.11 (- H of 2s, 2H, 2 × 2 '), 8.78~the 8.36 (- H of m, 2H, 2 × 5 '), The 7.72 (- H of d, 1H, 8 '), 4.86~4.58 (m, 3H, NCH2And CH), 3.46~3.37 (m, 4H, piperazine-H), 2.55~ 2.38 (m, 7H, piperazine-H and Ac), 1.62~1.13 (m, 7H, CH3and CH2CH2)；MS(m/z):696[M+H]+ (35), Cl calculated value: 696.14 [M]+。
Embodiment 12
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -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 thiadiazoles 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 group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.24g (2.9mmol) is added, 55~60 DEG C of water-bath Stirring 20 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Golden yellow crystallization object (I-12), yield 67%, 226~228 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.55 (brs,1H,NH),9.46(s,1H,NH), 9.31,9.14(2s,2H,2×2′-H),8.86,8.35(2d,2H,2×5′-H), The 7.68 (- H of d, 1H, 8 '), 4.87~4.56 (m, 3H, NCH2And CH), 3.56~3.35 (m, 8H, 2 × piperazine-H), 2.55 ~2.40 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.68~1.15 (m, 7H, CH3and CH2CH2)；MS(m/z):760 [M+H]+, calculated value: 759.84 [M]+。
Embodiment 13
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -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 thiadiazoles 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) 0.84g (5.2mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.16g (2.7mmol) is added, 55~60 DEG C of water-bath Stirring 22 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Golden yellow crystallization object (I-13), yield 65%, 234~236 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.58 (brs,1H,NH),9.47(s,1H,NH), 9.34,9.18(2s,2H,2×2′-H),8.92,8.43(2d,2H,2×5′-H), The 7.86 (- H of d, 1H, 8 '), 4.88~4.57 (m, 3H, NCH2And CH), 3.55~3.36 (m, 8H, 2 × piperazine-H), 2.55 ~2.38 (m, 14H, 2 × 2 × Ac of piperazine-H and), 1.65~1.15 (m, 7H, CH3and CH2CH2)；MS(m/z):788 [M+H]+, calculated value: 787.85 [M]+。
Embodiment 14
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -5- base } -3- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- of 1- (2- fluoro ethyl) -6,8- Base]-urea (I-14), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles 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) 0.62g (3.8mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.11g (2.6 mmol) is added, 55~60 DEG C of water-bath stirrings 18 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained golden yellow Color crystallizes object (I-14), yield 62%, and 225~227 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.53(brs, 1H,NH),9.41(s,1H,NH), 9.30,9.13(2s,2H,2×2′-H),9.15,8.62(2d,2H,2×5′-H),7.86 (d,1H,8′-H),4.96, 4.78(2t,4H,FCH2and NCH2), 4.58 (m, 1H, CH), 3.56~3.41 (m, 8H, 2 × piperazines Piperazine-H), 2.56~2.36 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.25~1.13 (m, 4H, CH2CH2)；MS (m/ z):795[M+H]+, calculated value: 794.84 [M]+。
Embodiment 15
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -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 thiadiazoles 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 group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.11g (2.6mmol) is added, 55~60 DEG C of water-bath Stirring 16 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Golden yellow crystallization object (I-15), yield 58%, 217~219 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.51 (brs,1H,NH),9.38(s,1H,NH), 9.13,8.94(2s,2H,2×2′-H),8.68,8.32(2d,2H,2×5′-H), The 7.56 (- H of d, 1H, 8 '), 4.57~4.34 (m, 3H, CH2And CH), 3.47~3.36 (m, 8H, 2 × piperazine-H), 2.53~ 2.37 (m, 13H, 2 × piperazine-H, NCH3And Ac), 1.46~1.07 (m, 10H, 2 × CH3and CH2CH2)；MS(m/z): 791[M+H]+, calculated value: 790.87 [M]+。
Embodiment 16
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -5- base } -3- [the fluoro- 8- methoxyl group -7- of 1- cyclopropyl -6- (3,4- lupetazin -1- base)-quinoline -4 (1H) - Ketone -3- base]-urea (I-16), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles 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) 0.75g (4.6mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.07g (2.5mmol) is added, 55~60 DEG C of water-bath Stirring 20 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Golden yellow crystallization object (I-16), yield 64%, 223~227 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.55 (brs, 1H, NH), 9.42 (s, 1H, NH), the 9.23,9.13 (- H of 2s, 2H, 2 × 2 '), 8.42~the 7.56 (- H of m, 3H, 2 × 5 ' 8 '-H of and), 4.58~4.55 (m, 2H, 2 × CH), 3.87 (s, 3H, OCH3), 3.47~3.36 (m, 8H, 2 × piperazine-H), 2.55~2.36 (m, 13H, 2 × piperazine-H, NCH3And Ac), 1.46~1.12 (m, 11H, CH3and 2×CH2CH2)；MS (m/z):815 [M+H]+, calculated value: 814.92 [M]+。
Embodiment 17
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -5- base } -3- [the fluoro- 8- methoxyl group -7- of 1- cyclopropyl -6- (1- methyl-octahydro pyrrolo- [3,4-b] pyridine -6- Base)-quinoline -4 (1H) -one -3- base]-urea (I-17), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles 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) 0.65g (4.0mmol), stirring at normal temperature to object is added Material dissolution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 0.98g (2.3mmol) is added, 55~60 DEG C of water-bath Stirring 16 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained Pale yellow crystals object (I-17), yield 47%, 213~215 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.57 (brs, 1H, NH), 9.46 (s, 1H, NH), the 9.26,9.17 (- H of 2s, 2H, 2 × 2 '), 8.56~the 7.63 (- H of m, 3H, 2 × 5 ' 8 '-H of and), 4.63~4.58 (m, 2H, 2 × CH), 3.88 (s, 3H, OCH3), 3.47~3.18 (m, 8H, piperazine-H and pyrroles Cough up alkane ring-H), 2.56~2.27 (m, 13H, piperazine-H and piperidine ring-H, NCH3And Ac), 2.14~1.06 (m, 13H, 2 × CH2CH2With piperidine ring-H)；MS(m/z):841[M+H]+, calculated value: 840.96 [M]+。
Embodiment 18
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -1,3,4- Thiadiazoles -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 thiadiazoles 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) 0.62g (3.8mmol) is added, and stirring at normal temperature is molten to material Solution.Then N- acetyl group Ciprofloxacin C-3 thiadiazoles amine V intermediate 1.11g (2.6 mmol) is added, 55~60 DEG C of water-bath stirrings 18 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained yellowish Color crystallizes object (I-18), yield 60%, and 226~228 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.53(brs, 1H,NH),9.46(s,1H,NH), 9.17,9.03(2s,2H,2×2′-H),8.56,8.17(2d,2H,2×5′-H),7.76 (- the H of d, 1H, 8 '), 4.57 (m, 1H, CH), 3.87~3.56 (m, 4H, SCH2CH2), 3.46~3.32 (m, 8H, 2 × piperazines- ), H 2.56~2.28 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.26~1.13 (m, 4H, CH2CH2)；MS(m/z):789 [M+H]+, calculated value: 788.90 [M]+。
Test example
One, one kind pair-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives that embodiment 1-18 is provided In vitro antitumor activity assay
1, test sample
The 18 new double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives provided with embodiment 1-18 With classical antitumor topoisomerase enzyme inhibitor 10-hydroxycamptothecine (Hydroxycamptothecin, HC), ureas tyrosine Kinase inhibitor Rui Gefeini (Regorafenib, RRF) and card are rich for Buddhist nun (Cabozantinib, CZT) and parent compound N- acetyl group Ciprofloxacin (ACF) is test sample, and totally 22 kinds, wherein HC, RRF, CZT and LOF are control group, embodiment 1- 18 samples are experimental group；
Thiazolyl blue (MTT), HC, RRF, CZT are Sigma Products；RPMI-1640 culture solution is the production of GIBCO company 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 Stomach cancer cell line HGC27, human pancreas cancer cell strain Capan-1, Human skin melanoma cell strain A375, human leukemia cell Strain 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 research It is raw；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 × 10-4 mol·L-1The RPMI-1640 culture solution of the stock solution of concentration, the calf serum for being later 10% with mass percent concentration is pressed Stock solution is diluted to the working solution with 5 concentration gradients by 10 times of dilution methods；
First group of experiment: cancer cell line HL60, Capan-1 and K562G of logarithmic growth phase are 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, discard culture medium after 48 hours, 1gL is added in every hole–1Bromination tetrazole 100 μ L of blue (MTT) solution, discards supernatant liquid, every hole after then proceeding to culture 4 hours The DMSO of 150 μ L is added, gently vibrates 30 minutes, measures absorbance (OD) value at 570nm wavelength with microplate reader later；
Second group of experiment: cancer cell line A549, SMCC-7721, HGC27, VERO and A375 of logarithmic growth phase are with every 7000, hole cell inoculation is then separately added into the working solution with 5 concentration gradients, every hole adds after 48 hours in 96 orifice plates Enter 5gL–1The dodecyl sulphur that 100 μ L mass percent concentrations are 10% is added in 10 μ L of MTT solution after continuing culture 4 hours Sour 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 from gained dose-effect equation, dense is inhibited to the half of experiment cancer cell Spend (IC50)；Each data are measured in parallel 5 times, are averaged, the results are shown in Table 1.
As it can be seen from table 1 double-fluoquinolone thiadiazoles ureas N- acetyl group Ciprofloxacin that embodiment 1-18 is provided Derivative, in addition to embodiment 3,4,5,8,11, remaining all has significant proliferation inhibition activity to 7 kinds of experimental cancer cell lines, especially It is to Non-small cell lung carcinoma cell line A549, human pancreas cancer cell strain Capan-1 and Human skin melanoma cell strain A375 It shows higher activity, is not only significantly stronger than the activity of parent compound N- acetyl group Ciprofloxacin, while being better than control topology The activity of isomerase inhibitors Hydroxycamptothecin (HC), it is auspicious that the activity of most compounds is also better than control tyrosine kinase inhibitor Ge Feini (RRF) and the rich activity for Buddhist nun (CZT) of card.What makes more sense is that the compound that embodiment 1-18 is provided is to Nai Jifei Extremely strong sensibility is also shown for Buddhist nun's cell cycling inhibiting G, while normal cell VERO cell is shown low toxicity, is had There is the attribute of druggability.It therefore, is first to carry out conventional antitumor in-vitro screening according to the general way of drug development, then It is targetedly studied, so the compound of the present invention has strong antitumor anti-drug-resistance activity and lower toxicity, can be led to It crosses with acid human-acceptable at salt or is mixed with anti-tumor drug with pharmaceutical carrier.
Anti-tumor activity (the IC of 1 test sample of table50)

Claims (7)

1. a kind of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives, are typically characterized by as following knot The typical compound (I-1~I-18) of structure:
。
2. a kind of system of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives according to claim 1 Preparation Method, which is characterized in that specifically preparation step includes:
1) with N- acetyl group Ciprofloxacin (10) for raw material, it is husky that N- acetyl group cyclopropyl is generated under the action of potassium carbonate with iodomethane Star (II) is prepared into N- acetyl group Ciprofloxacin compound shown in formula III through hydrazinolysis reaction；Then formula III and potassium rhodanide Condensation reaction occurs in the aqueous solution of dilute hydrochloric acid, N- acetyl group Ciprofloxacin amide groups thiourea compound shown in formula IV is made；Most Formula IV intramolecular cyclisation occurs in concentrated sulfuric acid N- acetyl group Ciprofloxacin C-3 thiadiazoles amine intermediate V is prepared afterwards. Intermediate target compound (V) is synthetically prepared route as shown in synthetic route one.
One the third husky star thiadiazoles amine (V) of intermediate ring N- acetyl group of synthetic route is synthetically prepared route
2) it is corresponding that fluoroquinolone carboxylic acid (FQ-COOH, 1~18) is condensed to generation with carbonyl dimidazoles (CDI) in DMF respectively Fluoroquinolone carboxylic acid Orazamide (1 '~18 ')；The fluoroquinolone carboxylic acid Orazamide (1 '~18 ') being prepared respectively with salt Corresponding fluoquinolone hydroximic acid (1 "~18 ") can be conveniently made in the reaction in pyridine (Py) of sour azanol；Fluoquinolone hydroximic acid (1 "~18 ") are rearranged to fluoquinolone isocyanates by Lossen under the auxiliary catalysis of carbonyl dimidazoles (CDI), without point Condensation reaction occurs from N- acetyl group Ciprofloxacin C-3 thiadiazoles amine intermediate V, it is post-treated that claim is prepared One kind shown in 1 pair-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives (Formulas I -1~I-18) synthesizes road Line is as shown in synthetic route two.
Fluoroquinolone carboxylic acid (FQ-COOH): Ofloxacin (1), lavo-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 Enoxacin (12), N- acetyl Enoxacin (13), fluorine Luo Sha Star (14), N- methyl Lomefloxacin (15), N- methyl gatifloxacin (16), N- methyl Moxifloxacin (17) and Rufloxacin (18)
Synthetic route two target compound pair-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives (I-1~I- 18) it is synthetically prepared route.
3. a kind of system of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives according to claim 2 Preparation Method, which is characterized in that fluoroquinolone carboxylic acid shown in the formula 1~18 and the molar ratio of carbonyl dimidazoles be 1:1.0~ 2.0。
4. a kind of system of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives according to claim 3 Preparation Method, which is characterized in that the molar ratio of fluoroquinolone carboxylic acid Orazamide shown in the formula 1 '~18 ' and hydroxylamine hydrochloride is 1:1.0~5.0.
5. a kind of system of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives according to claim 4 Preparation Method, which is characterized in that the molar ratio of fluoquinolone hydroximic acid shown in the formula 1 "~18 " and carbonyl dimidazoles is 1: It 1.0~2.0, is 1:1 with the molar ratio of N- acetyl group Ciprofloxacin C-3 thiadiazoles amine intermediate V.
6. prepared by a kind of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives as described in claim 1 Application in anti-tumor drug.
7. a kind of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives according to claim 6 are being made Application in standby anti-tumor drug, which is characterized in that the anti-tumor drug be treatment Non-small cell lung carcinoma, liver cancer, gastric cancer, Human pancreas cancer, Human skin melanoma or human leukemia, while the treatment to the cancer cell of resistance to Gefitinib.
CN201811343703.9A 2018-11-13 2018-11-13 The preparation and application of double-fluoquinolone thiadiazoles ureas N- acetyl group ciprofloxacin derivatives Pending CN109761999A (en)

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