CN109678882A - The preparation and application of double-fluoquinolone thiadiazoles ureas pefloxacin derivative - Google Patents

The preparation and application of double-fluoquinolone thiadiazoles ureas pefloxacin derivative Download PDF

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CN109678882A
CN109678882A CN201811284149.1A CN201811284149A CN109678882A CN 109678882 A CN109678882 A CN 109678882A CN 201811284149 A CN201811284149 A CN 201811284149A CN 109678882 A CN109678882 A CN 109678882A
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pefloxacin
fluoquinolone
double
thiadiazoles
carboxylic acid
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胡国强
孙姣姣
张呈霞
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 pefloxacin 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 of the invention trains fluorine Flucloxacillin derivative, realize organic split of double-fluoquinolone skeleton and thiadiazoles heterocycle and function base ureas pharmacophore, and then realize different pharmacophores move more be superimposed, the new construction of drug molecule is innovated, and then 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 and application of double-fluoquinolone thiadiazoles ureas pefloxacin derivative
Technical field
The present invention is New drug discovery research, and in particular to a kind of double-fluoquinolone thiadiazoles ureas pefloxacin is derivative Object also relates to the preparation method and its application in anti-tumor drug of the analog derivative.
Background technique
New drug development originates from the discovery of primer, and is that it is promoted 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 piece of existing drug Section, create to the major diseases such as malignant tumour have treatment and function controlling new small molecule primer be new drug development most Cost-effective strategy.Based on this, on the one hand in view of fluoquinolone (FQs) is used as a kind of clinical widely used antimicrobial, Its antibacterial advantage pharmacophore skeleton is " quinoline (naphthyridines) -4- ketone -3- carboxylic acid ", because of its action target-topoisomerase (TOPO) be also anti-tumor drug important target enzyme, can be converted its antibacterial activity to by the strategy of structural modification antitumor Activity, and then find the antitumor fluoquinolone primer of new construction.At the same time, structure activity study finds fluoquinolone It is not pharmacophore necessary to anti-tumor activity, with heterocycle or condensed hetero ring though C-3 carboxyl is necessary to antibacterial activity Isostere as C-3 carboxyl is remarkably improved its anti-tumor activity, this swells how to convert antibacterial fluoroquinolone drug to anti- Tumor FQ molecule provides new approaches.However, problem be select how the carboxyl isostere of structure type, and take and fluorine quinoline promise What kind of connection type of ketone skeleton is beneficial to the discovery of targeting small molecule primer, further innovation driving targeting anti-tumor The discovery of flouroquinolone drugs is still urgently project to be resolved at present.On the other hand, it is based on protein tyrosine kinase (PTK) Target spot and the anti-tumor drugs targeting molecule constructed has made substantial progress, and there are numerous small molecular protein tyrosine kinase to press down Preparation (PTKIs) enters the clinical targeted therapy of tumour, and then excites the discovery and research and development of target therapeutic agent.Meanwhile it is right The structure of the targeting PTKIs molecule listed is dissected, and structure can be divided into fragrant amino miazines such as Imatinib (A), virtue Amino-quinazoline such as Gefitinib (B), substituted bisarylurea such as Rui Gefeini (C) and α, beta-unsaturated ketone such as Sutent (D) four kinds of structure types (Fig 1) such as.For this purpose, the structure feature of targeting PTKIs molecule is made full use of, 2 quinolone bones Frame structural unit is that its connection chain constructs in pairs-fluoquinolone thiadiazoles carbamide derivative by thiadiazoles urea, has both been remained anti- The design feature of tumour fluoquinolone, and embody the urea structure characteristic of targeting PTKIs molecule, it is possible to find novel fluorine quinoline promise The antitumor lead compound of ketone, the development for targeting therapy for tumor drug provide new approaches.
Summary of the invention
The object of the present invention is to provide a kind of compounds of new construction, i.e., the thiadiazoles replaced containing double-fluoquinolone skeleton Ureas pefloxacin derivative, has an antitumor effect and efficacy, while providing a kind of double-fluoquinolone thiadiazoles ureas The preparation method of pefloxacin derivative.
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 pefloxacin 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 pefloxacin derivative preparation method of the invention, comprising: 1) With pefloxacin (5) be raw material, through hydrazinolysis reaction be prepared into pefloxacin hydrazide compound shown in Formula II, then Formula II with Potassium rhodanide occurs condensation reaction in the aqueous solution of dilute hydrochloric acid and pefloxacin amide groups thiourea compound shown in formula III is made (Xie Yu lock etc., the synthesis of pefloxacin C-3 carboxyl isostere and anti-tumor activity (VIII) triazole sulfide ketone thiosemicarbazones Derivative, China Medicine University's journal, 2015,46 (4): 416-420.)；Molecule inner ring occurs in concentrated sulfuric acid for last formula III It closes reaction and pefloxacin C-3 thiadiazoles amine intermediate compound IV is prepared, be synthetically prepared route as shown in Fig 2.
Pefloxacin intermediate pefloxacin C-3 thiadiazoles amine IV preparation step: pefloxacin amido thiourea (III) 10.0g (24.6mmol) is slowly added in the 150mL concentrated sulfuric acid of stirring, and it is anti-that 70~80 DEG C of stirrings are warming up to after material dissolution It answers 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 Property, it is dry.Crude product is recrystallized with DMF- alcohol mixed solvent, obtains pale yellow crystals pefloxacin C-3 thiadiazoles amine intermediate (IV) 8.2g, m.p.228~230 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 ') are reacted in pyridine with hydroxylamine hydrochloride respectively can conveniently be made corresponding fluoquinolone hydroximic acid (1 "~18 ")；Fluorine It is different that quinolone hydroximic acid (1 "~18 ") is rearranged to fluoquinolone by Lossen under the auxiliary catalysis of carbonyl dimidazoles (CDI) Condensation reaction occurs with pefloxacin C-3 thiadiazoles amine intermediate compound IV without isolation for cyanate, post-treated to be prepared One kind shown in claim 1 pair-fluoquinolone thiadiazoles ureas pefloxacin derivative (Formulas I -1~I-18) synthesizes road Shown in line is seen below.
Wherein, fluoroquinolone carboxylic acid (FQ-COOH) includes: Ofloxacin (1), pefloxacin (2), oxygen carboxylic acid fluoride (3), a left side Oxygen carboxylic acid fluoride (4), promise carboxylic acid fluoride (5), pefloxacin (6), N- acetyl Norfloxacin (7), cyclopropyl carboxylic acid (8), N- methyl cyclopropyl Sha Xing (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.
Corresponding fluoroquinolone carboxylic acid Orazamide (1 '~18 ') are as follows: Ofloxacin Orazamide (1 '), pefloxacin miaow Azoles amide (2 '), oxygen carboxylic acid fluoride Orazamide (3 '), levofloxacin carboxylic acid Orazamide (4 '), promise carboxylic acid fluoride Orazamide (5 '), Pefloxacin Orazamide (6 '), N- acetyl Norfloxacin Orazamide (7 '), cyclopropyl carboxylic acid Orazamide (8 '), N- methyl Ciprofloxacin Orazamide (9 '), N- acetyl Ciprofloxacin Orazamide (10 '), according to promise carboxylic acid Orazamide (11 '), N- first Base Enoxacin Orazamide (12 '), N- acetyl Enoxacin Orazamide (13 '), fleraxacin Orazamide (14 '), N- Methyl Lomefloxacin Orazamide (15 '), N- methyl gatifloxacin Orazamide (16 '), N- methyl Moxifloxacin Orazamide (17 ') and Rufloxacin Orazamide (18 '), structure 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,N-Dimethylformamide (DMF) (500mL), and carbonyl dimidazoles (CDI) 16.2g is added ~32.4g (0.10~0.20mol), 80~90 DEG C of water-bath are stirred to react 10.0~24.0 hours.Second is added in evaporating solvent under reduced pressure Acetoacetic ester (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 "), pefloxacin hydroximic acid (2 "), Oxygen carboxylic acid fluoride hydroximic acid (3 "), levofloxacin carboxylic acid hydroximic acid (4 "), promise carboxylic acid fluoride hydroximic acid (5 "), pefloxacin hydroximic acid (6 "), N- acetyl Norfloxacin hydroximic acid (7 "), cyclopropyl carboxylic acid hydroximic acid (8 "), N- methyl Ciprofloxacin hydroximic acid (9 "), N- Acetyl Ciprofloxacin hydroximic acid (10 "), according to promise carboxylic acid hydroximic acid (11 "), N- methyl Enoxacin hydroximic acid (12 "), N- acetyl Enoxacin hydroximic acid (13 "), fleraxacin hydroximic acid (14 "), N- methyl Lomefloxacin hydroximic acid (15 "), N- methyl, which add, to be replaced Husky star hydroximic acid (16 "), N- methyl Moxifloxacin hydroximic acid (17 ") and Rufloxacin hydroximic acid (18 "), structure sees below institute Show.
The preparation manipulation step of fluoquinolone hydroximic acid (1 "~18 "): fluoroquinolone carboxylic acid imidazoles acyl shown in Fig 6 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: fluoquinolone hydroxyl oxime is led in the preparation of target compound pair-fluoquinolone thiadiazoles ureas pefloxacin derivative Acid (1 "~18 ") each 1.0g is suspended in suitable acetonitrile, carbonyl dimidazoles (1.0~2.0 times of amounts) is added, stirring at normal temperature is molten Xie Hou is added pefloxacin C-3 thiadiazoles amine IV intermediate (1.0 times amount), 55~60 DEG C stirring in water bath 10~24 hours.It puts Room temperature is set, the solid that filter collection generates is recrystallized with solvent appropriate, and double-fluoquinolone thiophene two shown in claim 1 is made Azoles ureas pefloxacin derivative.
One kind pair-fluoquinolone thiadiazoles ureas pefloxacin derivative of the invention, based on targeting tyrosine kinase suppression The urea groups structural pharmacophore segment of preparation and effective biological isostere thiadiazoles heterocycle of fluoquinolone C-3 carboxyl, and utilize medicine Effect group split drug molecule design principle is connected double-fluoquinolone skeleton using thiadiazoles urea as connection chain, design synthesis " double-afloqualone ureas " derivative, realize advantage structural pharmacophore between different role mechanism drug move more with it is complementary, And then the structure of original new drug molecule, it achieves synergistic and detoxifying effects, can be used as the anti-tumor drug exploitation of brand new.
Specific embodiment
Technical solution of the present invention is described in detail by following specific embodiments.
Embodiment 1
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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) 0.67g (4.1mmol), stirring at normal temperature to material is added Dissolution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 1.05g (2.7mmol) is added, 55~60 DEG C of water-bath stirrings 16 are small When.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, obtains faint yellow knot Brilliant object (I-1), yield 64%, m.p.224~226 DEG C.1H NMR (400MHz,DMSO-d6)δ:11.53(brs,1H,NH), 9.38(s,1H,NH),9.15,8.87(2s,2H, 2×2′-H),8.23,7.64(2d,2H,2×5′-H),7.36(d,1H, 8 '-H), 4.87~4.72 (m, 3H, OCH2CHN),4.46(q,2H,NCH2), 3.56~3.35 (m, 8H, 2 × piperazine-H), 2.55~2.37 (m, 14H, 2 × piperazine-H and 2 × NCH3), 1.57~1.41 (m, 6H, 2 × CH3)；MS(m/z):747[M+H]+, Calculated value: 746.85 [M]+。
Embodiment 2
(S) -1- { 2- [the fluoro- 7- of 1- ethyl -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 pefloxacin hydroximic acid (2 ") 1.0g (2.7 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.60g (3.7mmol), stirring at normal temperature to material is added Dissolution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 1.05g (2.7mmol) is added, 55~60 DEG C of water-bath stirrings 10 are small When.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product ethyl alcohol recrystallization obtains pale yellow crystals object (I-2), produces Rate 52%, m.p.226~228 DEG C.1H NMR(400MHz, DMSO-d6)δ:11.54(brs,1H,NH),9.46(s,1H,NH), 9.13,8.86 (- the H of 2s, 2H, 2 × 2 '), 8.23~the 7.64 (- H of m, 2H, 2 × 5 '), the 7.33 (- H of d, 1H, 8 '), 4.92~4.78 (m,3H,OCH2CHN),4.45(q, 2H,NCH2), 3.55~3.37 (m, 8H, 2 × piperazine-H), 2.56~2.40 (m, 14H, 2 × piperazine-H and 2 × NCH3), 1.57~1.43 (m, 6H, 2 × CH3)；MS(m/z):775[M+H]+, calculated value: 774.86 [M]+。
Embodiment 3
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -5- base } -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 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 pefloxacin C-3 thiadiazoles amine IV intermediate 1.32g (3.4mmol) is added, 55~60 DEG C of water-bath stirrings 15 are small When.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, obtains faint yellow knot Brilliant object (I-3), yield 63%, m.p.232~234 DEG C.1H NMR (400MHz,DMSO-d6)δ:11.48(brs,1H,NH), 9.37 (s, 1H, NH), the 9.12,8.94 (- H of 2s, 2H, 2 × 2 '), 8.25~the 7.58 (- H of m, 2H, 2 × 5 '), 7.26 (d, 1H, 8 '-H), 4.93~4.80 (m, 3H, OCH2CHN),4.38(q,2H,NCH2), 3.54~3.37 (m, 4H, piperazine-H), 2.56~ 2.38 (m, 7H, piperazine-H and NCH3), 1.56~1.41 (m, 6H, 2 × CH3)；MS(m/z):667[M+H]+, calculated value: 666.69[M]+。
Embodiment 4
(S) -1- { 2- [the fluoro- 7- of 1- ethyl -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), 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 pefloxacin C-3 thiadiazoles amine IV intermediate 1.32g (3.4mmol) is added, 55~60 DEG C of water-bath are stirred 12 hours. It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, obtains pale yellow crystals object (I-4), yield 54%, m.p.224~226 DEG C.1H NMR (400MHz,DMSO-d6)δ:11.48(brs,1H,NH),9.36 (s, 1H, NH), the 9.15,8.95 (- H of 2s, 2H, 2 × 2 '), 8.26~the 7.62 (- H of m, 2H, 2 × 5 '), the 7.30 (- H of d, 1H, 8 '), 4.92~4.83 (m, 3H, OCH2CHN),4.40(q,2H,NCH2), 3.56~3.37 (m, 4H, piperazine-H), 2.53~2.37 (m, 7H, piperazine-H and NCH3), 1.56~1.42 (m, 6H, 2 × CH3)；MS(m/z):667[M+H]+, calculated value: 666.69 [M]+。
Embodiment 5
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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 pefloxacin C-3 thiadiazoles amine IV intermediate 1.36g (3.5mmol) is added, 55~60 DEG C of water-bath are stirred 24 hours. It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, obtains pale yellow crystals object (I-5), yield 65%, m.p.218~220 DEG C.1H NMR (400MHz,DMSO-d6)δ:11.46(brs,1H,NH),9.37 (s, 1H, NH), the 8.91,8.86 (- H of 2s, 2H, 2 × 2 '), 8.24~the 7.68 (- H of m, 2H, 2 × 5 '), 7.35~7.16 (m, 2H, 2×8′-H),4.42,4.26(2q,4H, 2×NCH2), 3.56~3.35 (m, 4H, piperazine-H), 2.52~2.38 (m, 7H, piperazines Piperazine-H and NCH3), 1.43~1.35 (m, 6H, 2 × CH3)；MS(m/z):655[M+H]+(35), Cl calculated value: 655.13 [M]+。
Embodiment 6
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -5- base } -3- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base]-urea (I-6), change Learn 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 pefloxacin C-3 thiadiazoles amine IV intermediate 1.20g (2.9mmol) is added, 55~60 DEG C of water-bath stirrings 18 are small When.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, obtains faint yellow knot Brilliant object (I-6), yield 62%, m.p.225~227 DEG C.1H NMR (400MHz,DMSO-d6)δ:11.54(brs,1H,NH), 9.42 (s, 1H, NH), the 9.15,8.97 (- H of 2s, 2H, 2 × 2 '), 8.36~the 8.23 (- H of m, 2H, 2 × 5 '), 7.56~7.47 (m,2H,2×8′-H),4.46,4.43(2q,4H, 2×NCH2), 3.56~3.37 (m, 8H, 2 × piperazine-H), 2.56~ 2.38 (m, 14H, 2 × piperazine-H and 2 × NCH3), 1.46~1.44 (m, 6H, 2 × CH3)；MS(m/z):719[M+H]+, calculate Value: 718.84 [M]+。
Embodiment 7
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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) 0.69g (4.3mmol) is added, room temperature stirs It mixes to material dissolution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 1.05g (2.7 mmol) 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-7), yield 64%, 231~233 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.55(brs, 1H, NH), 9.43 (s, 1H, NH), the 9.18,8.96 (- H of 2s, 2H, 2 × 2 '), 8.36~the 8.06 (- H of m, 2H, 2 × 5 '), 7.66 ~the 7.46 (- H of m, 2H, 2 × 8 '), 4.48,4.40 (2q, 4H, 2 × NCH2), 3.57~3.36 (m, 8H, 2 × piperazine-H), 2.55~2.34 (m, 14H, 2 × piperazine-H, 2NCH3And Ac), 1.46~1.42 (m, 6H, 2 × CH3)；MS(m/z):747[M+ H]+, calculated value: 746.85 [M]+。
Embodiment 8
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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) 0.82g (5.1mmol), stirring at normal temperature to object is added Material dissolution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 1.32g (3.4 mmol) 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-8), yield 62%, 236~238 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.52(brs,1H,NH), 9.44 (s, 1H, NH), the 9.12,8.87 (- H of 2s, 2H, 2 × 2 '), 8.26~the 7.88 (- H of m, 2H, 2 × 5 '), 7.66~7.53 (- the H of m, 2H, 2 × 8 '), 4.56~4.46 (m, 5H, CH and 2 × NCH2), 3.53~3.37 (m, 4H, piperazine-H), 2.55~ 2.36 (m, 7H, piperazine-H and NCH3), 1.45~0.87 (m, 7H, CH3And CH2CH2)；MS(m/z):667[M+H]+(35Cl), Calculated value: 667.14 [M]+。
Embodiment 9
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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) 0.73g (4.5mmol), stirring at normal temperature to object is added Material dissolution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 1.09g (2.8 mmol) 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-9), yield 61%, 226~228 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.54(brs,1H,NH), 9.46 (s, 1H, NH), the 9.15,8.94 (- H of 2s, 2H, 2 × 2 '), 8.36~the 7.86 (- H of m, 2H, 2 × 5 '), 7.74~7.50 (- the H of m, 2H, 2 × 8 '), 4.62~4.48 (m, 5H, CH and 2 × NCH2), 3.57~3.42 (m, 8H, 2 × piperazine-H), 2.55 ~2.36 (m, 14H, 2 × piperazine-H and 2 × NCH3),1.46(d,3H,CH3), 1.25~0.93 (m, 4H, CH2CH2)；MS (m/z):731[M+H]+, calculated value: 730.85 [M]+。
Embodiment 10
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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 pefloxacin C-3 thiadiazoles amine IV intermediate 1.01g (2.6mmol) 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-10), yield 68%, 232~234 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.56(brs, 1H, NH), 9.43 (s, 1H, NH), the 9.15,8.96 (- H of 2s, 2H, 2 × 2 '), 8.36~the 8.21 (- H of m, 2H, 2 × 5 '), 7.78 ~the 7.64 (- H of m, 2H, 2 × 8 '), 4.64~4.48 (m, 5H, CH and 2 × NCH2), 3.57~3.45 (m, 8H, 2 × piperazines- ), H 2.57~2.36 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.47 (d, 3H, CH3), 1.26~1.13 (m, 4H, CH2CH2)；MS (m/z):759[M+H]+, calculated value: 758.86 [M]+。
Embodiment 11
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -5- base } -3- [chloro- [1,8] naphthyridines -4 (1H) -one -3- base of the fluoro- 7- of 1- ethyl -6-]-urea (I-11), chemical structural formula Are as follows:
Double-fluoquinolone 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) 0.81g (5.0mmol), stirring at normal temperature to object is added Material dissolution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 1.36g (3.5 mmol) 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 It crystallizes object (I-11), yield 72%, 230~232 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.48(brs, 1H,NH),9.42(s,1H,NH), 9.21,9.16(2s,2H,2×2′-H),8.67,8.26(2d,2H,2×5′-H),7.62 (d,1H,8′-H),4.74,4.48 (2q,4H,2×NCH2), 3.56~3.42 (m, 4H, piperazine-H), 2.55~2.40 (m, 7H, piperazine-H and NCH3), 1.57~1.42 (m, 6H, 2 × CH3)；MS(m/z):656[M+H]+(35), Cl calculated value: 656.12 [M]+。
Embodiment 12
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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 pefloxacin C-3 thiadiazoles amine IV intermediate 1.13g (2.9 mmol) is added, 55~60 DEG C of water-bath stirrings 18 Hour.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-12), yield 64%, 224~226 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.54(brs, 1H,NH),9.45(s,1H,NH), 9.26,9.05(2s,2H,2×2′-H),8.76,8.28(2d,2H,2×5′-H),7.74 (d,1H,8′-H),4.82,4.46 (2q,4H,2×NCH2), 3.57~3.46 (m, 8H, 2 × piperazine-H), 2.57~2.40 (m, 14H, 2 × piperazine-H and 2 × NCH3), 1.58~1.42 (m, 6H, 2 × CH3)；MS(m/z):720[M+H]+, calculated value: 719.82[M]+。
Embodiment 13
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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) 0.58g (3.6mmol), stirring at normal temperature to object is added Material dissolution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 1.05g (2.7 mmol) 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 golden yellow It crystallizes object (I-13), yield 67%, 232~234 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.57(brs, 1H,NH),9.48(s,1H,NH), 9.26,9.10(2s,2H,2×2′-H),8.76,8.33(2d,2H,2×5′-H),7.76 (d,1H,8′-H),4.88,4.46 (2q,4H,2×NCH2), 3.56~3.46 (m, 8H, 2 × piperazine-H), 2.57~2.37 (m, 14H, 2 × piperazine-H, NCH3), Ac 1.62~1.48 (m, 6H, 2 × CH3)；MS(m/z):748[M+H]+, calculated value: 747.83[M]+。
Embodiment 14
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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) 0.52g (3.2mmol) is added, and stirring at normal temperature is molten to material Solution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 1.01g (2.6mmol) is added, 55~60 DEG C of water-bath are stirred 17 hours. It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, obtains golden yellow crystallization mesh It marks object (I-14), yield 64%, m.p.232~234 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.57(brs,1H,NH), 9.53(s,1H,NH),9.31,9.14 (2s,2H,2×2′-H),8.87,8.46(2d,2H,2×5′-H),7.78(d,1H, 8 '-H), 4.88~4.46 (m, 6H, FCH2CH2And NCH2), 3.57~3.42 (m, 8H, 2 × piperazine-H), 2.56~2.41 (m, 14H, 2 × piperazine-H and 2 × NCH3),1.45(d,3H,CH3)；MS(m/z):755[M+H]+, calculated value: 754.82 [M]+。
Embodiment 15
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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 pefloxacin C-3 thiadiazoles amine IV intermediate 1.01g (2.6 mmol) 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 golden yellow It crystallizes object (I-15), yield 52%, 214~216 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.53(brs, 1H, NH), 9.46 (s, 1H, NH), the 9.14,8.93 (- H of 2s, 2H, 2 × 2 '), 8.62~the 7.48 (- H of m, 3H, 2 × 5 ' and 8 '- H),4.46,4.42(2q,4H, 2×CH2), 3.57~3.42 (m, 8H, 2 × piperazine-H), 2.57~2.38 (m, 13H, 2 × piperazines Piperazine-H and 2 × NCH3), 1.56~1.42 (m, 9H, 3 × CH3)；MS(m/z):751[M+H]+, calculated value: 750.85 [M]+。
Embodiment 16
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -5- base } -3- [the fluoro- 8- methoxyl group -7- of 1- cyclopropyl -6- (3,4- lupetazin -1- base)-quinoline -4 (1H) -one -3- Base]-urea (I-16), chemical structural formula are as follows:
Double-fluoquinolone 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) 0.55g (3.4mmol), stirring at normal temperature to object is added Material dissolution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 0.97g (2.5 mmol) 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 golden yellow It crystallizes object (I-16), yield 42%, 227~229 DEG C of m.p..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 '), 8.46~the 7.56 (- H of m, 3H, 2 × 5 ' and 8 '- ), H 4.62~4.46 (m, 3H, CH and NCH2),3.87(s,3H,OCH3), 3.56~3.36 (m, 8H, 2 × piperazine-H), 2.55~2.37 (m, 13H, 2 × piperazine-H and 2 × NCH3), 1.46~1.07 (m, 10H, 2 × CH3and CH2CH2)；MS(m/ z): 774[M+H]+, calculated value: 774.90 [M]+。
Embodiment 17
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -5- base } -3- [the fluoro- 8- methoxyl group -7- of 1- cyclopropyl -6- (1- methyl-octahydro pyrrolo- [3,4-b] pyridine -6- base)-quinoline Quinoline -4 (1H) -one -3- base]-urea (I-17), chemical structural formula are as follows:
Double-fluoquinolone 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) 0.52g (3.2mmol), stirring at normal temperature to object is added Material dissolution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 0.97g (2.5 mmol) is added, 55~60 DEG C of water-bath stirrings 17 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 It crystallizes object (I-17), yield 52%, 224~226 DEG C of m.p..1H NMR(400MHz,DMSO-d6)δ:11.56(brs, 1H, NH), 9.46 (s, 1H, NH), the 9.22,9.15 (- H of 2s, 2H, 2 × 2 '), 8.45~the 7.62 (- H of m, 3H, 2 × 5 ' and 8 '- ), H 4.66~4.46 (m, 3H, CH and NCH2),3.87(s,3H,OCH3), 3.56~3.12 (m, 8H, piperazine-H and pyrroles Alkane ring-H), 2.56~2.25 (m, 13H, piperazine-H, piperidine ring-H and 2 × NCH3), 1.75~1.13 (m, 12H, CH3, cyclopropyl Base-H and piperidine ring-H)；MS(m/z):801[M+H]+, calculated value: 800.94 [M]+。
Embodiment 18
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -1,3,4- thiophene two Azoles -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) 0.52g (3.2mmol) is added, and stirring at normal temperature is molten to material Solution.Then pefloxacin C-3 thiadiazoles amine IV intermediate 1.01g (2.6mmol) is added, 55~60 DEG C of water-bath are stirred 18 hours. It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, obtains pale yellow crystals mesh It marks object (I-18), yield 55%, m.p.232~234 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.54(brs,1H,NH), 9.42 (s, 1H, NH), the 9.23,9.15 (- H of 2s, 2H, 2 × 2 '), 8.53~the 7.60 (- H of d, 3H, 2 × 5 ' and 8 '-H), 4.42 (d,2H,NCH2), 3.87~3.36 (m, 12H, SCH2CH2With 2 × piperazine-H), 2.62~2.40 (m, 14H, 2 × piperazine-H and 2×NCH3),1.46 (d,3H,CH3)；MS(m/z):749[M+H]+, calculated value: 748.88 [M]+。
Test example
One, one kind pair-fluoquinolone thiadiazoles ureas pefloxacin derivative that embodiment 1-18 is provided is external anti-swollen Tumor activity measurement
1, test sample
It is anti-with the embodiment 1-18 18 new double-fluoquinolone thiadiazoles ureas pefloxacin derivatives provided and classics Tumor topoisomerase inhibitor 10-hydroxycamptothecine (Hydroxycamptothecin, HC), ureas tyrosine kinase inhibit Agent Rui Gefeini (Regorafenib, RRF) and card are rich for Buddhist nun (Cabozantinib, CZT) and parent compound pefloxacin It (PF) is test sample, totally 22 kinds, wherein HC, RRF, CZT and LOF are control group,
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 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 five times, are averaged, the results are shown in Table 1.
The anti tumor activity in vitro of table 1 pair-fluoquinolone thiadiazoles ureas pefloxacin derivative (I-1~I-18)
As it can be seen from table 1 double-fluoquinolone thiadiazoles ureas pefloxacin derivative that embodiment 1-18 is provided is to 7 Kind experimental cancer cell line all has significant proliferation inhibition activity, especially to Non-small cell lung carcinoma cell line A549, human pancreas Cancer cell line Capan-1 and Human skin melanoma cell strain A375 show higher activity, are not only significantly stronger than parent chemical combination The activity of object pefloxacin, while being better than the activity of control topoisomerase enzyme inhibitor Hydroxycamptothecin (HC), most compounds Activity is also better than control tyrosine kinase inhibitor Rui Gefeini (RRF) and the rich activity for Buddhist nun (CZT) of card.More meaningful It is that the compound that embodiment 1-18 is provided also shows extremely strong sensibility to the cell cycling inhibiting of resistance to Gefitinib G, while to just Normal cell VERO cell is shown low toxicity, the attribute with druggability.Therefore, according to the general way of drug development It is first to carry out conventional antitumor in-vitro screening, is then targetedly studied, so the compound of the present invention has strong Antitumor anti-drug-resistance activity and lower toxicity, can be by being mixed with acid human-acceptable at salt or with pharmaceutical carrier Anti-tumor drug.

Claims (7)

1. a kind of double-fluoquinolone thiadiazoles ureas pefloxacin derivative, is typically characterized by as with the typical case of flowering structure Compound (I-1~I-18):
2. a kind of preparation method of double-fluoquinolone thiadiazoles ureas pefloxacin derivative according to claim 1, It is characterized in that, specific preparation step includes:
1) with pefloxacin (6) for raw material, pefloxacin hydrazide compound shown in Formula II is prepared into through hydrazinolysis reaction；Then formula II and potassium rhodanide occur condensation reaction in the aqueous solution of dilute hydrochloric acid and pefloxacin amide groups thiocarbamide chemical combination shown in formula III are made Object；Last formula III intramolecular cyclisation occurs in concentrated sulfuric acid, pefloxacin C-3 thiadiazoles amine intermediate compound IV is prepared. Intermediate target compound (IV) is synthetically prepared route as shown in synthetic route one.
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 pefloxacin C-3 thiadiazoles amine intermediate compound IV, it is post-treated that the shown of claim 1 is prepared One kind it is double-fluoquinolone thiadiazoles ureas pefloxacin derivative (Formulas I -1~I-18), synthetic route is shown in two institute of synthetic route Show.
One intermediate pefloxacin thiadiazoles amine (IV) of synthetic route is synthetically prepared route
Fluoroquinolone carboxylic acid (FQ-COOH): Ofloxacin (1), pefloxacin (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- second Acyl 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)
Synthetic route two target compound pair-fluoquinolone thiadiazoles ureas pefloxacin derivative (I-1~I-18) synthesis system Standby route.
3. a kind of preparation method of double-fluoquinolone thiadiazoles ureas pefloxacin derivative according to claim 2, It is characterized in that, fluoroquinolone carboxylic acid shown in the 1~formula of formula 18 and the molar ratio of carbonyl dimidazoles are 1:1.0~2.0.
4. a kind of preparation method of double-fluoquinolone thiadiazoles ureas pefloxacin derivative according to claim 3, Be characterized in that, the molar ratio of fluoroquinolone carboxylic acid Orazamide shown in the formula 1 '~18 ' and hydroxylamine hydrochloride be 1:1.0~ 5.0。
5. a kind of preparation method of double-fluoquinolone thiadiazoles ureas pefloxacin derivative according to claim 4, Be characterized in that, the molar ratios of fluoquinolone hydroximic acid shown in the formula 1 "~18 " and carbonyl dimidazoles be 1:1.0~2.0, with The molar ratio of pefloxacin C-3 thiadiazoles amine intermediate compound IV is 1:1.
6. a kind of double-fluoquinolone thiadiazoles ureas pefloxacin derivative as described in claim 1 is preparing antineoplastic Application in object.
7. a kind of double-fluoquinolone thiadiazoles ureas pefloxacin derivative according to claim 6 prepare it is antitumor Application in drug, which is characterized in that the anti-tumor drug is 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.
CN201811284149.1A 2018-10-31 2018-10-31 The preparation and application of double-fluoquinolone thiadiazoles ureas pefloxacin derivative Pending CN109678882A (en)

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