CN109678884A - The preparation and application of double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative - Google Patents
The preparation and application of double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative Download PDFInfo
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- CN109678884A CN109678884A CN201811284357.1A CN201811284357A CN109678884A CN 109678884 A CN109678884 A CN 109678884A CN 201811284357 A CN201811284357 A CN 201811284357A CN 109678884 A CN109678884 A CN 109678884A
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- C07—ORGANIC CHEMISTRY
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- 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
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- 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
- C07D513/06—Peri-condensed systems
Abstract
The invention discloses a kind of double-fluoquinolone thiadiazoles ureas N- methyl 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- methyl Ciprofloxacin derivative 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
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- methyl Ciprofloxacin derivative, 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 thiadiazoles urea for it
Chain link constructs in pairs-fluoquinolone thiadiazoles 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 thiadiazoles urea of fluoquinolone
Class N- methyl Ciprofloxacin derivative, has an antitumor effect and efficacy, while providing a kind of double-fluoquinolone ring thiadiazoles
The preparation method of ureas N- methyl Ciprofloxacin derivative.
In order to realize the above target, the technical scheme adopted by the invention is that: a kind of double-fluoquinolone ring thiadiazoles ureas
N- methyl Ciprofloxacin derivative, 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- methyl Ciprofloxacin derivative preparation method of the invention, packet
It includes: 1) being that raw material is prepared into N- methyl Ciprofloxacin hydrazides shown in formula (II) through hydrazinolysis reaction with N- methyl Ciprofloxacin (9)
Compound；Then Formula II and potassium rhodanide the N- methyl shown in the aqueous solution generation condensation reaction obtained formula (III) of dilute hydrochloric acid
Ciprofloxacin amide groups thiourea compound；Last formula III intramolecular cyclisation occurs in concentrated sulfuric acid, N- methyl is prepared
Ciprofloxacin C-3 thiadiazoles amine intermediate (IV) is synthetically prepared route as shown in Fig 2.
The preparation method of intermediate N methyl Ciprofloxacin C-3 thiadiazoles amine (V):
A) N- methyl Ciprofloxacin (9) is stirred at reflux with the hydrazine hydrate of mass fraction 80% reacts to obtain colorless crystalline solid
N- methyl Ciprofloxacin hydrazides (II), detailed operating procedure can refer to document, and (Hu Guoqiang waits fluoquinolone C-3 jeterocyclic chemistry
Design, synthesis and the antitumor activity of conjunction object: Ciprofloxacin pair-oxadiazoles methyl sulfide derivative, Acta Pharmaceutica Sinica, 2012,
47 (8): 1017-1022.) method.
B) N- methyl Ciprofloxacin hydrazides (II) 15.0g (41.8mmol) is mixed with 150mL water, sequentially adds potassium rhodanide
15.0g (155.0mmol) and concentrated hydrochloric acid 13.0mL, reaction mixture are stirred at reflux reaction 10 hours, and cooling room temperature uses concentrated ammonia liquor
PH 8.0 is adjusted, is flowed back 2 hours, heat filtering washes solid.It is dry, it is recrystallized with DMF- water mixed solvent, obtains colorless solid N-
Methyl Ciprofloxacin amidoamino thiocarbamide (III), 12.8g, m.p.232~234 DEG C.
C) N- methyl Ciprofloxacin amidoamino thiocarbamide (III) 10.0g (24.0mmol) is slowly added to the 150 of stirring
It is warming up to 70~80 DEG C in the mL concentrated sulfuric acid, after material dissolution to be stirred to react 12 hours, slowly pours into the trash ice of 1500g, use is dense
Ammonium hydroxide tune pH 10.0.It stands overnight, filter collection solid is washed to neutrality, dry.Crude product is recrystallized with DMF- alcohol mixed solvent,
Obtain pale yellow crystals N- methyl Ciprofloxacin C-3 thiadiazoles amine intermediate (IV), 7.6g, m.p.232~234 DEG C.
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 compound IV without isolation,
Post-treated one kind shown in the claim 1 pair-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin that is prepared is spread out
Biological (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 imidazoles
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.Evaporating solvent under reduced pressure is added without second
Acetoacetic ester (500mL), is sufficiently stirred dispersing solid, filtering, ethyl acetate washing, dry, and it is anti-to be directly used in lower step without further purification
It answers.
Fluoquinolone hydroximic acid (1 "~18 "): Ofloxacin hydroximic acid (1 "), lavo-ofloxacin hydroximic acid (2 "), oxygen fluorine
Carboxylic acid 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 ring
Third husky star hydroximic acid (10 "), according to promise carboxylic acid hydroximic acid (11 "), N- methyl Enoxacin hydroximic acid (12 "), N- acetyl Yi Nuosha
Star hydroximic acid (13 "), fleraxacin hydroximic acid (14 "), N- methyl Lomefloxacin hydroximic acid (15 "), N- methyl gatifloxacin hydroxyl
Oxime acid (16 "), N- methyl Moxifloxacin hydroximic acid (17 ") and Rufloxacin hydroximic acid (18 "), structure see below 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 hydroxyl must be analyzed
Oxime acid (1 "~18 ").
Method: fluorine quinoline promise is led in the preparation of target compound pair-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative
Ketone hydroximic acid (1 "~18 ") each 1.0g is suspended in suitable acetonitrile, carbonyl dimidazoles (1.0~2.0 times of amounts) is added, room temperature stirs
After mixing dissolution, it is added N- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate (1.0 times of amounts), 55~60 DEG C of stirring in water bath 10~
24 hours.Room temperature is placed, the solid that filter collection generates is recrystallized with solvent appropriate, and double-fluorine quinoline shown in claim 1 is made
Promise ketone thiadiazoles ureas N- methyl Ciprofloxacin derivative.
One kind pair-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative of the invention, based on targeting tyrosine
The urea structure pharmacophore urea segment of 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, in turn
Design has synthesized " double-afloqualone ureas " derivative, realizes moving more for advantage structural pharmacophore between different role mechanism drug
With it is complementary, innovated the structure of drug molecule, achieved synergistic and detoxifying effects, the anti-tumor drug that can be used as brand new is opened
Hair.
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- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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) 0.84g (5.2mmol) is added, and stirring at normal temperature is molten to material
Solution.Then N- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.08g (2.7mmol) is added, 55~60 DEG C of water-bath stirrings 16
Hour.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained faint yellow
Crystal (I-1), yield 58%, m.p.224~226 DEG C.1H NMR (400MHz,DMSO-d6)δ:11.47(brs,1H,NH),
9.38(s,1H,NH),9.18,8.96(2s,2H, 2×2′-H),8.36,8.12(2d,2H,2×5′-H),7.46(d,1H,
8 '-H), 4.94~4.57 (m, 4H, OCH2CHN and CH), 3.55~3.36 (m, 8H, 2 × piperazine-H), 2.55~2.32
(m, 14H, 2 × 2 × NCH of piperazine-H and3), 1.57~1.03 (m, 7H, CH3and CH2CH2)；MS(m/z):759[M+H]+,
Calculated value: 758.86 [M]+。
Embodiment 2
(S) -1- 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.08g (2.7 mmol) is added, 55~60 DEG C of water-bath stirrings
10 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 54%, m.p.214~216 DEG C.1H NMR(400 MHz,DMSO-d6)δ:11.46(brs,1H,NH),9.37(s,1H,
), NH the 9.16,8.94 (- H of 2s, 2H, 2 × 2 '), the 8.35,8.17 (- H of 2d, 2H, 2 × 5 '), the 7.52 (- H of d, 1H, 8 '), 4.96~
4.57(m,4H, OCH2CHN and CH), 3.57~3.46 (m, 8H, 2 × piperazine-H), 2.55~2.37 (m, 14H, 2 × piperazines
2 × NCH of piperazine-H and3), 1.57~1.06 (m, 7H, CH3and CH2CH2)；MS(m/z):759[M+H]+, calculated value:
758.86[M]+。
Embodiment 3
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
Diazole -5- base } -3- [6,7- bis- fluoro- 8,1- (1,3- oxygen propyl group)-quinoline -4 (1H) -one -3- base]-urea (I-3), chemistry knot
Structure 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) is added, and stirring at normal temperature is molten to material
Solution.Then N- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.36g (3.4mmol) is added, 55~60 DEG C of water-bath stirrings 24
Hour.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained faint yellow
Crystal (I-3), yield 64%, m.p.235~237 DEG C.1H NMR (400MHz,DMSO-d6)δ:11.45(brs,1H,NH),
9.38(s,1H,NH),9.06,8.87(2s,2H, 2×2′-H),8.35,8.10(2d,2H,2×5′-H),7.42(d,1H,
8 '-H), 4.95~4.56 (m, 4H, OCH2CHN and CH), 3.55~3.37 (m, 4H, piperazine-H), 2.57~2.26 (m,
7H, piperazine-H and CH3), 1.56~0.87 (m, 7H, CH3and CH2CH2)；MS(m/z):679[M+H]+, calculated value:
678.70[M]+。
Embodiment 4
(S) -1- 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,
4- thiadiazoles -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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.36g (3.4 mmol) is added, 55~60 DEG C of water-bath stirrings
20 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained faint yellow
Crystal (I-4), yield 62%, 230~232 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.37(brs,1H,NH),
9.36(s,1H,NH), 9.06,8.92(2s,2H,2×2′-H),8.35,8.10(2d,2H,2×5′-H),7.43(d,1H,
8 '-H), 4.92~4.55 (m, 4H, OCH2CHN and CH), 3.46~3.37 (m, 4H, piperazine-H), 2.53~2.34 (m,
7H, piperazine-H and CH3), 1.57~0.96 (m, 7H, CH3and CH2CH2)；MS(m/z):679[M+H]+, calculated value:
678.70[M]+。
Embodiment 5
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.40g (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 faint yellow
Crystal (I-5), yield 71%, 234~236 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.38(brs,1H,NH),
9.35 (s, 1H, NH), the 8.97,8.86 (- H of 2s, 2H, 2 × 2 '), 8.26~the 7.78 (- H of m, 2H, 2 × 5 '), 7.35~7.22
(m,2H,2×8′-H), 4.56(m,1H,CH),4.26(q,2H,NCH2), 3.55~3.38 (m, 4H, piperazine-H), 2.54~
2.32 (m, 7H, piperazine-H and CH3), 1.42~1.02 (m, 7H, CH3and CH2CH2)；MS(m/z):667 [M+H]+
(35), Cl calculated value: 667.14 [M]+。
Embodiment 6
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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) is added, and stirring at normal temperature is molten to material
Solution.Then N- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.16g (2.9mmol) is added, 55~60 DEG C of water-bath stirrings 20
Hour.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained faint yellow
Crystal (I-6), yield 56%, m.p.225~227 DEG C.1H NMR (400MHz,DMSO-d6)δ:11.48(brs,1H,NH),
9.35 (s, 1H, NH), the 9.15,9.06 (- H of 2s, 2H, 2 × 2 '), 8.47~the 8.16 (- H of m, 2H, 2 × 5 '), 7.86~7.50
(- the H of m, 2H, 2 × 8 '), 4.58~4.46 (m, 3H, NCH2And CH), 3.57~3.36 (m, 8H, 2 × piperazine-H), 2.54~
2.36 (m, 14H, 2 × 2 × NCH of piperazine-H and3), 1.37~1.08 (m, 7H, CH3and CH2CH2)；MS(m/z):731[M
+H]+, calculated value: 730.85 [M]+。
Embodiment 7
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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, and carbonyl dimidazoles (CDI) 0.75g (5.4mmol), stirring at normal temperature is added
To material dissolution.Then N- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.08g (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 recrystallized with DMF- alcohol mixed solvent,
It obtains pale yellow crystals object (I-7), yield 60%, 230~232 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.52
(brs, 1H, NH), 9.43 (s, 1H, NH), the 9.23,9.12 (- H of 2s, 2H, 2 × 2 '), 8.36~the 8.25 (- H of m, 2H, 2 × 5 '),
7.76~the 7.56 (- H of m, 2H, 2 × 8 '), 4.58~4.46 (m, 3H, NCH2And CH), 3.56~3.42 (m, 8H, 2 × piperazines
Piperazine-H), 2.55~2.36 (m, 11H, 2 × piperazine-H and CH3), 1.38~1.05 (m, 7H, CH3and CH2CH2)；MS
(m/z):759[M+H]+, calculated value: 758.86 [M]+。
Embodiment 8
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV 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 light
Yellow crystal object (I-8), yield 72%, 245~247 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.52(brs,1H,
), NH 9.42 (s, 1H, NH), the 9.07,8.93 (- H of 2s, 2H, 2 × 2 '), 8.26~the 7.68 (- H of m, 2H, 2 × 5 '), 7.86~
The 7.47 (- H of m, 2H, 2 × 8 '), 4.57~4.54 (m, 2H, 2 × CH), 3.56~3.37 (m, 4H, piperazine-H), 2.55~2.34
(m, 7H, piperazine-H and CH3), 1.22~0.85 (m, 8H, 2 × CH2CH2)；MS(m/z):679[M+H]+(35), Cl it calculates
Value: 679.15 [M]+。
Embodiment 9
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.12g (2.8mmol) 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 light
Yellow crystal object (I-9), yield 66%, 236~238 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.52(brs,1H,
), NH 9.43 (s, 1H, NH), the 9.16,9.05 (- H of 2s, 2H, 2 × 2 '), 8.34~the 8.18 (- H of m, 2H, 2 × 5 '), 8.05~
The 7.76 (- H of m, 2H, 2 × 8 '), 4.56~4.53 (m, 2H, 2 × CH), 3.56~3.37 (m, 8H, 2 × piperazine-H), 2.55~
2.36 (m, 14H, 2 × 2 × NCH of piperazine-H and3), 1.26~0.97 (m, 8H, 2 × CH2CH2)；MS(m/z):743[M+H]+, meter
Calculation value: 742.86 [M]+。
Embodiment 10
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.04g (2.6mmol) 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 recrystallized with DMF- alcohol mixed solvent,
It obtains pale yellow crystals object (I-10), yield 68%, m.p.234~236 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.53
(brs, 1H, NH), 9.45 (s, 1H, NH), the 9.23,9.15 (- H of 2s, 2H, 2 × 2 '), 8.57~the 8.36 (- H of m, 2H, 2 × 5 '),
8.32~the 7.78 (- H of m, 2H, 2 × 8 '), 4.64~4.57 (m, 2H, 2 × CH), 3.56~3.37 (m, 8H, 2 × piperazine-H),
2.57~2.38 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.24~1.11 (m, 8H, 2 × CH2CH2)；MS(m/z):771
[M+H]+, calculated value: 770.87 [M]+。
Embodiment 11
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.40g (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 light
Yellow crystal object (I-11), yield 74%, 243~245 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.53
(brs,1H,NH),9.46(s,1H,NH), 9.28,9.16(2s,2H,2×2′-H),8.85,8.35(2d,2H,2×5′-H),
The 7.76 (- H of d, 1H, 8 '), 4.87~4.56 (m, 3H, NCH2And CH), 3.56~3.45 (m, 4H, piperazine-H), 2.56~
2.40 (m, 7H, piperazine-H and NCH3), 1.38~1.07 (m, 7H, CH3and CH2CH2)；MS(m/z):668[M+H]+
(35), Cl calculated value: 668.13 [M]+。
Embodiment 12
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.16g (2.9mmol) 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 crystal object (I-12), yield 62%, 232~234 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.55
(brs,1H,NH),9.46(s,1H,NH), 9.33,9.16(2s,2H,2×2′-H),8.85,8.34(2d,2H,2×5′-H),
The 7.66 (- H of d, 1H, 8 '), 4.86~4.58 (m, 3H, NCH2And CH), 3.55~3.45 (m, 8H, 2 × piperazine-H), 2.55
~2.36 (m, 14H, 2 × 2 × NCH of piperazine-H and3), 1.37~1.10 (m, 7H, CH3and CH2CH2)；MS(m/z):
732[M+H]+, calculated value: 731.83 [M]+。
Embodiment 13
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.08g (2.7mmol) 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 crystal object (I-13), yield 60%, 226~228 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.56
(brs,1H,NH),9.45(s,1H,NH), 9.26,9.15(2s,2H,2×2′-H),8.92,8.43(2d,2H,2×5′-H),
The 7.86 (- H of d, 1H, 8 '), 4.86~4.56 (m, 3H, NCH2And CH), 3.56~3.36 (m, 8H, 2 × piperazine-H), 2.55
~2.35 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.38~1.14 (m, 7H, CH3and CH2CH2)；MS(m/z):760
[M+H]+, calculated value: 759.84 [M]+。
Embodiment 14
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.04g (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
It crystallizes object (I-14), yield 62%, 230~232 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.56(brs,
1H,NH),9.47(s,1H,NH), 9.27,9.15(2s,2H,2×2′-H),9.07,8.52(2d,2H,2×5′-H),7.76
(d,1H,8′-H),4.87(t, 2H,FCH2),4.76(t,2H,NCH2), 4.56 (m, 1H, CH), 3.56~3.45 (m, 8H, 2 ×
Piperazine-H), 2.56~2.36 (m, 14H, 2 × 2 × NCH of piperazine-H and3), 1.23~1.12 (m, 4H, CH2CH2)；MS(m/
z): 767[M+H]+, calculated value: 766.83 [M]+。
Embodiment 15
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.04g (2.6mmol) is added, 55~60 DEG C of water-bath
Stirring 15 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 crystal object (I-15), yield 54%, 226~228 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.47
(brs,1H,NH),9.36(s,1H,NH), 9.13,8.92(2s,2H,2×2′-H),8.68,8.25(2d,2H,2×5′-H),
The 7.53 (- H of d, 1H, 8 '), 4.56~4.34 (m, 3H, NCH2And CH), 3.56~3.43 (m, 8H, 2 × piperazine-H), 2.55
~2.36 (m, 13H, 2 × 2 × NCH of piperazine-H and3), 1.46~1.06 (m, 10H, 2 × CH3and CH2CH2)；MS(m/
z):763[M+H]+, calculated value: 762.86 [M]+。
Embodiment 16
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
Diazole -5- base } -3- [the fluoro- 8- methoxyl group -7- of 1- cyclopropyl -6- (3,4- lupetazin -1- base)-quinoline -4 (1H) -one -
3- yl]-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- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.00g (2.5mmol) 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 crystal object (I-16), yield 50%, 223~225 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.55
(brs,1H,NH),9.47(s,1H,NH), 9.25,9.14(2s,2H,2×2′-H),8.63,7.76(2d,2H,2×5′-H),
The 7.46 (- H of d, 1H, 8 '), 4.62~4.57 (m, 2H, 2 × CH), 3.87 (s, 3H, OCH3), 3.55~3.42 (m, 8H, 2 × piperazines
Piperazine-H), 2.57~2.36 (m, 13H, 2 × 2 × NCH of piperazine-H and3), 1.47~1.05 (m, 11H, CH3and 2×
CH2CH2)；MS(m/z): 787[M+H]+, calculated value: 786.91 [M]+。。
Embodiment 17
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 -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- methyl Ciprofloxacin C-3 thiadiazoles amine V intermediate 0.92g (2.3mmol) 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 yellowish
Color crystallizes object (I-17), yield 48%, and 216~218 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.55(brs,
1H,NH),9.43(s,1H,NH), 9.08,8.87(2s,2H,2×2′-H),8.46,7.62(2d,2H,2×5′-H),7.53
(- the H of d, 1H, 8 '), 4.62~5.53 (m, 2H, 2 × CH), 3.88 (s, 3H, OCH3), 3.56~3.16 (m, 8H, piperazine-H and
Pyrrolidine ring-H), 2.55~2.24 (m, 13H, 2 × NCH of piperazine-H and piperidine ring-H and3), 2.16~1.03 (m, 13H,
2×CH2CH2With piperidine ring-H)；MS(m/z):813[M+H]+, calculated value: 812.95 [M]+。
Embodiment 18
1- { 2- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene
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 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) 0.72g (4.4mmol) is added, and stirring at normal temperature is molten to material
Solution.Then N- methyl Ciprofloxacin C-3 thiadiazoles amine IV intermediate 1.04g (2.6 mmol) is added, 55~60 DEG C of water-bath stirrings
15 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained faint yellow
It crystallizes object (I-18), yield 62%, 234~236 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.54(brs,
1H,NH),9.42(s,1H,NH), 9.10,8.92(2s,2H,2×2′-H),8.47,8.03(2d,2H,2×5′-H),7.62
(- the H of d, 1H, 8 '), 4.58 (m, 1H, CH), 3.86~3.34 (m, 12H, SCH2CH22 × piperazine of and-H), 2.56~2.25
(m, 14H, 2 × 2 × NCH of piperazine-H and3), 1.23~1.07 (m, 4H, CH2CH2)；MS(m/z):761[M+H]+, calculate
Value: 760.89 [M]+。
Test example
One, one kind pair-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative body that embodiment 1-18 is provided
Outer antitumor cytolytic activity
1, test sample
With the embodiment 1-18 18 new double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin 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- methyl
Ciprofloxacin (MCF) is test sample, and totally 22 kinds, wherein HC, RRF, CZT and LOF are control group, and embodiment 1-18 sample is
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'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；
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 after then proceeding to culture 4 hours, every hole adds
Enter the DMSO of 150 μ L, gently vibrates 30 minutes, measure 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 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.
As it can be seen from table 1 double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin 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
The activity of compound N-methy Ciprofloxacin, 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 VERO 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.
Anti tumor activity in vitro (the IC of 1 test sample of table50)
Claims (7)
1. a kind of double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative, is typically characterized by as with flowering structure
Typical compound (I-1~I-18):
2. a kind of preparation of double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative according to claim 1
Method, which is characterized in that specifically preparation step includes:
1) with N- methyl Ciprofloxacin (9) for raw material, N- methyl Ciprofloxacin hydrazides shown in Formula II is prepared into through hydrazinolysis reaction；
Then Formula II and potassium rhodanide the N- methyl Ciprofloxacin acyl shown in the obtained formula III of aqueous solution generation condensation reaction of dilute hydrochloric acid
Amido thiourea compound；Last formula III intramolecular cyclisation occurs in concentrated sulfuric acid, N- methyl Ciprofloxacin C-3 is prepared
Thiadiazoles amine IV intermediate.Intermediate target compound (IV) is synthetically prepared route as shown in synthetic route one.
One intermediate N methyl Ciprofloxacin thiadiazoles amine (IV) 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- methyl Ciprofloxacin C-3 thiadiazoles amine intermediate compound IV, it is post-treated that claim 1 is prepared
Shown in one kind it is double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative (Formulas I -1~I-18), synthetic route is such 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- methyl Ciprofloxacin derivative (I-1~I-18)
It is synthetically prepared route.
3. a kind of preparation of double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative according to claim 2
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 preparation of double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative according to claim 3
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 preparation of double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative according to claim 4
Method, which is characterized in that the molar ratio of fluoquinolone hydroximic acid shown in the formula 1 "~18 " and carbonyl dimidazoles is 1:1.0
It~2.0, is 1:1 with the molar ratio of N- methyl Ciprofloxacin C-3 thiadiazoles amine intermediate compound IV.
6. a kind of double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative as described in claim 1 is anti-in preparation
Application in tumour medicine.
7. prepared by a kind of double-fluoquinolone thiadiazoles ureas N- methyl Ciprofloxacin derivative according to claim 6
Application in anti-tumor drug, which is characterized in that the anti-tumor drug is treatment Non-small cell lung carcinoma, liver cancer, gastric cancer, people
Cancer of pancreas, Human skin melanoma or human leukemia, while the treatment to the cancer cell of resistance to Gefitinib.
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| CN112824396A (en) * | 2019-11-20 | 2021-05-21 | 河南大学 | N-acetyl lomefloxacin allyl ketone derivative and preparation method and application thereof |
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