CN109761998A - The preparation and application of double-fluoquinolone thiadiazoles ureas fleraxacin derivative - Google Patents
The preparation and application of double-fluoquinolone thiadiazoles ureas fleraxacin derivative Download PDFInfo
- Publication number
- CN109761998A CN109761998A CN201811343694.3A CN201811343694A CN109761998A CN 109761998 A CN109761998 A CN 109761998A CN 201811343694 A CN201811343694 A CN 201811343694A CN 109761998 A CN109761998 A CN 109761998A
- Authority
- CN
- China
- Prior art keywords
- fleraxacin
- fluoquinolone
- thiadiazoles
- double
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 50
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 26
- RAZMBRTXTADRMQ-UHFFFAOYSA-N (4-carbamoyl-1h-imidazol-5-yl)azanium;2,4-dioxo-1h-pyrimidine-6-carboxylate;dihydrate Chemical compound O.O.NC(=O)C=1NC=NC=1N.OC(=O)C1=CC(=O)NC(=O)N1 RAZMBRTXTADRMQ-UHFFFAOYSA-N 0.000 claims description 23
- 229950010911 orazamide Drugs 0.000 claims description 23
- XNXHTLMYBNXMJK-UHFFFAOYSA-N 4-fluoro-2-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2NC(=O)C(C(=O)O)=C(F)C2=C1 XNXHTLMYBNXMJK-UHFFFAOYSA-N 0.000 claims description 13
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- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003235 pyrrolidines Chemical group 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of double-fluoquinolone thiadiazoles ureas fleraxacin derivatives and its preparation method and application, and general formula of the chemical structure is as shown in following formula I:R is ethyl or cyclopropyl or fluoro ethyl or the oxazines ring constituted with C-8 or the thiazine ring constituted with C-8 in Formulas I;L is independent chlorine atom or fluorine atom or 1- piperazinyl or substituted piperazine -1- base or nitrogen condensed hetero ring;X is hydrocarbon (CH) or nitrogen-atoms or fluorine-substituted carbon atom (F-C) or methoxy-substituted carbon atom (CH3O-C).Double-fluoquinolone thiadiazoles ureas fleraxacin derivative of the invention, realize organic split of double-fluoquinolone skeleton and thiadiazoles heterocycle and function base ureas pharmacophore, 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 fleraxacin derivative, also relates to the preparation method of the analog derivative,
And its application in anti-tumor drug.
Background technique
New drug development originates from the discovery of primer, and is the pass for promoting it to develop to patent medicine to the structure optimization of primer
Key link.Rational drug layout strategy based on structure or mechanism, using the advantage skeleton or pharmacophore segment of existing drug,
The new small molecule primer that creating has treatment and function controlling to major diseases such as malignant tumours is that new drug development is most economical
Effective strategy.Based on this, on the one hand in view of fluoquinolone (FQs) is as a kind of clinical widely used antimicrobial, resist
Bacterium advantage pharmacophore skeleton is " quinoline (naphthyridines) -4- ketone -3- carboxylic acid ", because of its action target-topoisomerase (TOPO)
It is the important target enzyme of anti-tumor drug, anti-tumor activity can be converted by its antibacterial activity by the strategy of structural modification, in turn
It was found that the antitumor fluoquinolone primer of new construction.At the same time, though structure activity study finds fluoquinolone C-3 carboxyl
It is necessary to antibacterial activity, but is not pharmacophore necessary to anti-tumor activity, uses heterocycle or condensed hetero ring as C-3 carboxylic
The isostere of base is remarkably improved its anti-tumor activity, this is how to convert antibacterial fluoroquinolone drug to antitumor FQ molecule
Provide new approaches.However, problem be select how the carboxyl isostere of structure type, and take with fluoquinolone skeleton why
The connection type of sample is beneficial to the discovery of targeting small molecule primer, further innovation driving targeting anti-tumor fluoquinolone
The discovery of drug is still urgently project to be resolved at present.On the other hand, the structure based on protein tyrosine kinase (PTK) target spot
The anti-tumor drugs targeting molecule built has made substantial progress, and has numerous small molecular protein tyrosine kinase inhibitors
(PTKIs) enter the clinical targeted therapy of tumour, and then excite the discovery and research and development of target therapeutic agent.Meanwhile on
The structure of the targeting PTKIs molecule in city is dissected, and structure can be divided into fragrant amino miazines such as Imatinib (A), fragrant amino
Quinazoline ditosylate salt such as Gefitinib (B), substituted bisarylurea such as Rui Gefeini (C) and α, beta-unsaturated ketone such as Sutent (D) etc.
Four kinds of structure types.For this purpose, making full use of the structure feature of targeting PTKIs molecule, 2 carbostyril skeleton structural units are led to
Crossing thiadiazoles urea is that its connection chain constructs in pairs-fluoquinolone thiadiazoles carbamide derivative, has both remained antitumor fluoquinolone
Design feature, and embody targeting PTKIs molecule urea structure characteristic, it is possible to find the antitumor elder generation of novel fluoroquinolones
Compound is led, the development for targeting therapy for tumor drug provides new approaches.
Summary of the invention
The object of the present invention is to provide a kind of compounds of new construction, i.e., containing double-cyclosubstituted thiadiazoles urea of fluoquinolone
Class fleraxacin derivative, has an antitumor effect and efficacy, while providing a kind of double-fluoquinolone ring thiadiazoles ureas
The preparation method of fleraxacin 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
Fleraxacin 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 of the invention is double-preparation method of fluoquinolone ring thiadiazoles ureas fleraxacin derivative, comprising: 1) with
Fleraxacin (14) is raw material through reacting fleraxacin hydrazides chemical combination shown in the formula of being prepared into (II) with hydrazine hydrate generation hydrazinolysis
Object;Then Formula II and potassium rhodanide the fleraxacin acyl shown in the aqueous solution generation condensation reaction obtained formula (III) of dilute hydrochloric acid
Amido thiourea compound;Last formula III intramolecular cyclisation occurs in concentrated sulfuric acid, fleraxacin C-3 thiophene two is prepared
Azoles amine (IV) intermediate is synthetically prepared shown in route sees below.
The preparation method of intermediate fleraxacin C-3 thiadiazoles amine (IV):
A) fleraxacin (14) 25g (67.8mmol) is stirred at reflux with the hydrazine hydrate 300mL of mass fraction 80% reacts 15
Hour, it stands overnight.Filter solid is crossed, is recrystallized with water, golden yellow crystalline solid fleraxacin hydrazides (II) 16.4g, m.p. are obtained
236~238 DEG C.
B) fleraxacin hydrazides (II) 15.0g (39.2mmol) 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, cooling room temperature, with concentrated ammonia liquor tune pH
8.0, it flows back 2 hours, heat filtering washes solid.It is dry, it is recrystallized with DMF- water mixed solvent, obtains faint yellow solid fluorine Luo Sha
Star amido thiourea (III), 10.6g, m.p.224~226 DEG C.
C) fleraxacin amido thiourea (III) 10.0g (24.6mmol) is slowly added to the 150mL concentrated sulfuric acid of stirring
In, it is warming up to 70~80 DEG C after material dissolution and is stirred to react 12 hours, slowly pours into the trash ice of 1500g, with concentrated ammonia liquor tune pH
10.0.It stands overnight, filter collection solid is washed to neutrality, dry.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained faint yellow
Crystallize fleraxacin C-3 thiadiazoles amine intermediate (IV) 8.7g, m.p.227~229 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 fleraxacin C-3 thiadiazoles amine intermediate compound IV without isolation, after
Reason can be prepared one kind shown in claim 1 pair-fluoquinolone thiadiazoles ureas fleraxacin derivative (Formulas I -1~
I-18), synthetic route is as follows.
Wherein fluoroquinolone carboxylic acid (FQ-COOH) include: Ofloxacin (1), lavo-ofloxacin (2), oxygen carboxylic acid fluoride (3),
Levofloxacin carboxylic acid (4), promise carboxylic acid fluoride (5), pefloxacin (6), N- acetyl Norfloxacin (7), cyclopropyl carboxylic acid (8), N- methyl ring
Third husky star (9), N- acetyl Ciprofloxacin (10), according to promise carboxylic acid (11), N- methyl Enoxacin (12), N- acetyl Enoxacin
(13), fleraxacin (14), N- methyl Lomefloxacin (15), N- methyl gatifloxacin (16), N- methyl Moxifloxacin (17) and
Rufloxacin (18), structure see below shown.
The fluoroquinolone carboxylic acid Orazamide (1 '~18 ') being accordingly prepared are as follows: Ofloxacin Orazamide (1 '), a left side
Ofloxacin Orazamide (2 '), oxygen carboxylic acid fluoride Orazamide (3 '), levofloxacin carboxylic acid Orazamide (4 '), promise carboxylic acid fluoride miaow
Azoles amide (5 '), pefloxacin Orazamide (6 '), N- acetyl Norfloxacin Orazamide (7 '), cyclopropyl carboxylic acid Orazamide
(8 '), N- methyl Ciprofloxacin Orazamide (9 '), N- acetyl Ciprofloxacin Orazamide (10 '), according to promise carboxylic acid Orazamide
(11 '), N- methyl Enoxacin Orazamide (12 '), N- acetyl Enoxacin Orazamide (13 '), fleraxacin imidazoles acyl
Amine (14 '), N- methyl Lomefloxacin Orazamide (15 '), N- methyl gatifloxacin Orazamide (16 '), N- methyl Moses are husky
Star Orazamide (17 ') and Rufloxacin Orazamide (18 '), structure see below shown.
The preparation manipulation step of fluoroquinolone carboxylic acid Orazamide (1 '~18 ') leads to method: taking fluoquinolone as shown above
Carboxylic acid (0.10mol) is dissolved in anhydrous N, in N- diformamide (DMF) (500mL), be added carbonyl dimidazoles (CDI) 16.2g~
32.4g (0.10~0.20mol), 80~90 DEG C of water-bath are stirred to react 10.0~24.0 hours.Nothing is added in evaporating solvent under reduced pressure
Ethyl acetate (500mL), is sufficiently stirred dispersing solid, filtering, ethyl acetate washing, dry, is directly used in lower step without further purification
Reaction.Fluoquinolone hydroximic acid (1 "~18 "): Ofloxacin hydroximic acid (1 "), lavo-ofloxacin hydroximic acid (2 "), oxygen fluorine carboxylic
Sour hydroximic acid (3 "), levofloxacin carboxylic acid hydroximic acid (4 "), promise carboxylic acid fluoride hydroximic acid (5 "), pefloxacin hydroximic acid (6 "), N- second
Acyl Norfloxacin hydroximic acid (7 "), cyclopropyl carboxylic acid hydroximic acid (8 "), N- methyl Ciprofloxacin hydroximic acid (9 "), N- acetyl cyclopropyl
Husky star hydroximic acid (10 "), according to promise carboxylic acid hydroximic acid (11 "), N- methyl Enoxacin hydroximic acid (12 "), N- acetyl Enoxacin
Hydroximic acid (13 "), fleraxacin hydroximic acid (14 "), N- methyl Lomefloxacin hydroximic acid (15 "), N- methyl gatifloxacin hydroxyl oxime
Sour (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 must be analyzed
Hydroximic acid (1 "~18 ").
Method: fluoquinolone hydroxyl oxime is led in the preparation of target compound pair-fluoquinolone thiadiazoles ureas fleraxacin 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 fleraxacin 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 fleraxacin derivative.
One kind pair-fluoquinolone thiadiazoles ureas fleraxacin derivative of the invention, based on targeting tyrosine kinase suppression
The urea structure pharmacophore segment of preparation and effective biological isostere thiadiazoles heterocycle of fluoquinolone C-3 carboxyl, and utilize drug effect
Group's split drug design principle is connected double-fluoquinolone skeleton using thiadiazoles urea as connection chain, and then constructs and synthesize
" double-afloqualone ureas " derivative, realize advantage structural pharmacophore between different role mechanism drug move more with complementary, wound
The new structure of drug molecule, achieves synergistic and detoxifying effects, can be used as the anti-tumor drug exploitation of brand new.
Specific embodiment
The technical scheme of the invention is described in detail through specific implementation examples.
Embodiment 1
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
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) -
Ketone -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 (II-1 ") 1.0g
(2.7 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.79g (4.9mmol) is added, and stirring at normal temperature is molten to material
Solution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.14g (2.7mmol) is added, 55~60 DEG C of water-bath are stirred 15 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-1), yield 67%, m.p.226~228 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.57(brs,1H, NH),9.45
(s, 1H, NH), the 9.23,8.94 (- H of 2s, 2H, 2 × 2 '), the 8.64,8.15 (- H of 2d, 2H, 2 × 5 '), 4.94~4.67 (m, 7H,
OCH2CHN and FCH2CH2), 3.57~3.46 (m, 8H, 2 × piperazine-H), 2.56~2.36 (m, 14H, 2 × piperazine-H and
2×NCH3),1.58(d,3H,CH3);MS(m/z):783[M+H]+, calculated value: 782.83.
Embodiment 2
(S) -1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- of 1- (2- fluoro ethyl) -6,8-
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 (II-2 ")
1.0g (2.7 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.70g (4.3mmol), stirring at normal temperature to object is added
Material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.14g (2.7mmol) is added, 55~60 DEG C of water-bath stirrings 10
Hour.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product ethyl alcohol recrystallization obtains pale yellow crystals object (I-2),
Yield 46%, m.p.214~216 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.53(brs,1H,NH),9.56(s,1H,
), NH the 9.23,9.16 (- H of 2s, 2H, 2 × 2 '), the 8.67,8.15 (- H of 2d, 2H, 2 × 5 '), 4.96~4.68 (m, 7H, OCH2CHN
and FCH2CH2), 3.57~3.45 (m, 8H, 2 × piperazine-H), 2.56~2.35 (m, 14H, 2 × piperazine-H and 2 ×
NCH3),1.57(d, 3H,CH3);MS(m/z):783[M+H]+, calculated value: 782.83.
Embodiment 3
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
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),
Its 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 (II-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 fleraxacin C-3 thiadiazoles amine IV intermediate 1.44g (3.4mmol) is added, 55~60 DEG C of water-bath are stirred 20 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-3), yield 67%, m.p.225~227 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.53(brs,1H, NH),9.41
(s, 1H, NH), the 9.16,9.03 (- H of 2s, 2H, 2 × 2 '), the 8.64,8.15 (- H of 2d, 2H, 2 × 5 '), 4.92~4.66 (m, 7H,
OCH2CHN and FCH2CH2), 3.56~3.42 (m, 4H, piperazine-H), 2.56~2.34 (m, 7H, 2 × piperazine-H and
NCH3),1.56(d,3H,CH3);MS(m/z):702[M+H]+, calculated value: 703.67.
Embodiment 4
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
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),
Its 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 (II-4 ")
1.0g (3.4 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.82g (5.1mmol), stirring at normal temperature to object is added
Material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.44g (3.4mmol) 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-4), yield 54%m.p.216~218 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.51(brs,1H, NH),
9.42 (s, 1H, NH), the 9.18,9.06 (- H of 2s, 2H, 2 × 2 '), the 8.67,8.17 (- H of 2d, 2H, 2 × 5 '), 4.92~4.67 (m,
7H,OCH2CHN and FCH2CH2), 3.57~3.44 (m, 4H, piperazine-H), 2.56~2.38 (m, 7H, piperazine-H and
NCH3),1.56(d,3H,CH3);MS(m/z):702[M+H]+, calculated value: 703.67.
Embodiment 5
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-[1,8] naphthyridines -4 (1H) -one -3- base] -1,3,4-
Thiadiazoles -5- base } -3- [fluoro- 7- chlorine-quinoline -4 (1H) -one -3- base of 1- ethyl -6-]-urea (I-5), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking fluorine chlorine quinolone hydroximic acid (II-5 ")
1.0g (3.5 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.98g (6.0mmol), stirring at normal temperature to object is added
Material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.48g (3.5mmol) 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-5), yield 74%, m.p.232~234 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.48(brs,1H, NH),
9.35 (s, 1H, NH), the 9.12,8.95 (- H of 2s, 2H, 2 × 2 '), 8.58~the 8.13 (- H of m, 2H, 2 × 5 '), 7.45 (d, 1H,
8 '-H), 4.87~4.74 (m, 4H, FCH2CH2),4.27(q,2H,NCH2), 3.55~3.41 (m, 4H, piperazine-H), 2.56~
2.36 (m, 7H, piperazine-H and NCH3),1.37(t,3H,CH3);MS(m/z):691[M+H]+(35), Cl calculated value:
691.11。
Embodiment 6
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3--[the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base] -
Urea (I-6), 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 (II-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 fleraxacin C-3 thiadiazoles amine IV intermediate 1.23g (2.9mmol) is added, 55~60 DEG C of water-bath are stirred 20 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-6), yield 60%, m.p.223~225 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.55(brs,1H, NH),9.43
(s, 1H, NH), the 9.16,9.03 (- H of 2s, 2H, 2 × 2 '), 8.62~the 8.13 (- H of m, 2H, 2 × 5 '), the 7.56 (- H of d, 1H, 8 '),
4.88~4.76 (m, 4H, FCH2CH2),4.36(q,2H,NCH2), 3.55~3.45 (m, 8H, 2 × piperazine-H), 2.57~
2.34 (m, 14H, 2 × 2 × NCH of piperazine-H and3),1.42(t,3H,CH3);MS(m/z):755[M+H]+, calculated value:
754.82。
Embodiment 7
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3- [the fluoro- 7- of 1- ethyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3- base] -
Urea (I-7), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- acetyl group Norfloxacin hydroximic acid
(II-7 ") 1.0g (2.7mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.75g (5.4mmol), room temperature is added
It stirs to material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.14g (2.7mmol) is added, water-bath 55~60
DEG C stirring 18 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 65%, m.p.231~233 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.55
(brs, 1H, NH), 9.47 (s, 1H, NH), the 9.26,9.15 (- H of 2s, 2H, 2 × 2 '), 8.68~the 8.23 (- H of m, 2H, 2 × 5 '),
The 7.64 (- H of d, 1H, 8 '), 4.91~4.78 (m, 4H, FCH2CH2),4.42(q,2H,NCH2), 3.57~3.42 (m, 8H, 2 ×
Piperazine-H), 2.57~2.36 (m, 14H, 2 × piperazine-H, NCH3and Ac),1.44(t,3H,CH3);MS(m/z):783[M+
H]+, calculated value: 782.83.
Embodiment 8
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3- [fluoro- 7- chlorine-quinoline -4 (1H) -one -3- base of 1- cyclopropyl -6-]-urea (I-8), chemistry
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 (II-
8 ") 1.0g (3.4mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.97g (6.0mmol), stirring at normal temperature is added
To material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.44g (3.4mmol) is added, 55~60 DEG C of water-bath are stirred
It mixes 24 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained light
Yellow crystal object (I-8), yield 68%, m.p.234~236 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.56(brs, 1H,
), NH 9.46 (s, 1H, NH), the 9.27,9.16 (- H of 2s, 2H, 2 × 2 '), 8.72~7.53 (the 8 '-H of-H of m, 3H, 2 × 5 ' and),
4.93~4.78 (m, 4H, FCH2CH2), 4.56~4.67 (m, 1H, CH), 3.55~3.43 (m, 4H, piperazine-H), 2.55~
2.36 (m, 7H, piperazine-H and NCH3), 1.18~0.86 (m, 4H, CH2CH2);MS(m/z):703[M+H]+(35), Cl it counts
Calculation value: 703.12.
Embodiment 9
1- { 2- [the fluoro- 7- of 1- ethyl -6- (4- methylpiperazine-1-yl)-[1,8] naphthyridines -4 (1H) -one -3- base] -1,3,4-
Thiadiazoles -5- base } -3- [the fluoro- 7- of 1- cyclopropyl -6- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base]-urea (I-
9), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- methyl Ciprofloxacin hydroximic acid (II-
9 ") 1.0g (2.8mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.81g (5.0mmol), stirring at normal temperature is added
To material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.19g (2.8mmol) is added, 55~60 DEG C of water-bath are stirred
It mixes 12 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 57%, m.p.226~228 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.53(brs, 1H,
), NH 9.45 (s, 1H, NH), the 9.16,9.02 (- H of 2s, 2H, 2 × 2 '), 8.37~the 8.26 (- H of m, 2H, 2 × 5 '), 7.57 (d,
1H, 8 '-H), 4.96~4.62 (m, 5H, FCH2CH2And CH), 3.53~3.38 (m, 8H, 2 × piperazine-H), 2.57~2.37
(m, 14H, 2 × 2 × NCH of piperazine-H and3), 1.23~1.12 (m, 4H, CH2CH2);MS(m/z):767[M+H]+, calculate
Value: 766.83.
Embodiment 10
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3- [the fluoro- 7- of 1- cyclopropyl -6- (4- Acetylpiperazine -1- base)-quinoline -4 (1H) -one -3-
Base]-urea (I-10), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- acetyl group Ciprofloxacin hydroximic acid
(II-10 ") 1.0g (2.6mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.75g (4.6mmol), room temperature is added
It stirs to material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.10g (2.6mmol) is added, water-bath 55~60
DEG C stirring 20 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 65%, m.p.234~236 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.56
(brs, 1H, NH), 9.46 (s, 1H, NH), the 9.23,9.05 (- H of 2s, 2H, 2 × 2 '), 8.38~the 8.26 (- H of m, 2H, 2 × 5 '),
The 7.56 (- H of d, 1H, 8 '), 4.98~4.57 (m, 5H, FCH2CH2And CH), 3.55~3.44 (m, 8H, 2 × piperazine-H),
2.57~2.40 (m, 14H, 2 × piperazine-H, NCH3And Ac), 1.26~1.14 (m, 4H, CH2CH2);MS(m/z):795[M+
H]+, calculated value: 794.84.
Embodiment 11
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3- [chloro- [1,8] naphthyridines -4 (1H) -one -3- base of the fluoro- 7- of 1- ethyl -6-]-urea (I-11),
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 (II-
11 ") 1.0 g (3.5mmol) are suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 1.13g (7.0mmol), stirring at normal temperature is added
To material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.48g (3.5mmol) is added, 55~60 DEG C of water-bath are stirred
It mixes 24 hours.It stands overnight, the solid that filter collection generates, acetonitrile washing.Crude product is recrystallized with DMF- alcohol mixed solvent, is obtained light
Yellow crystal object (I-11), yield 72%, m.p.236~238 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.53
(brs,1H,NH),9.42(s,1H,NH),9.26,9.15(2s,2H,2×2′-H),8.86(d,1H,5′-H),8.37(d,1H,
5 '-H), 4.93~4.82 (m, 4H, FCH2CH2),4.38(q,2H,NCH2), 3.54~3.42 (m, 4H, piperazine-H), 2.55~
2.28 (m, 7H, piperazine-H and NCH3),1.38(t,3H,CH3);MS(m/z):691[M+H]+(35), Cl calculated value:
691.10。
Embodiment 12
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles-5- base }-3- [the fluoro- 7- of 1- ethyl-6- (4- methylpiperazine-1-yl)-[1,8] (1H) -one of naphthyridines-4-3-
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 fleraxacin hydroximic acid (II-12 ")
1.0g (2.9 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.65g (4.0mmol), stirring at normal temperature to object is added
Material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.23g (2.9mmol) 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 57%, m.p.223~225 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.56(brs,
1H, NH), 9.46 (s, 1H, NH), the 9.32,9.17 (- H of 2s, 2H, 2 × 2 '), 8.86~the 8.46 (- H of m, 2H, 2 × 5 '), 4.95~
4.86 (m,4H,FCH2CH2),4.46(q,2H,NCH2), 3.57~3.45 (m, 8H, 2 × piperazine-H), 2.57~2.38 (m,
2 × NCH of 14H, 2 × piperazine-H and3),1.42(t,3H,CH3);MS (m/z): 756 [M+H], calculated value: 755.80.
Embodiment 13
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3- [the fluoro- 7- of 1- ethyl -6- (4- acetylpiperazine -1- base)-[1,8] naphthyridines -4 (1H) -one -3-
Base]-urea (I-13), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking N- acetyl Enoxacin hydroximic acid (II-
13 ") 1.0 g (2.7mmol) are suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.84g (5.2mmol), stirring at normal temperature is added
To material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.14g (2.7mmol) is added, 55~60 DEG C of water-bath are stirred
It mixes 23 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 67%, m.p.235~237 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.58
(brs, 1H, NH), 9.47 (s, 1H, NH), the 9.35,9.18 (- H of 2s, 2H, 2 × 2 '), 8.92~the 8.48 (- H of m, 2H, 2 × 5 '),
4.97~4.86 (m, 4H, FCH2CH2),4.42(q,2H,NCH2), 3.53~3.46 (m, 8H, 2 × piperazine-H), 2.56~2.38
(m, 14H, 2 × piperazine-H, Ac and NCH3),1.44(t,3H,CH3);MS (m/z): 784 [M+H], calculated value: 783.81.
Embodiment 14
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3- [1- (2- fluoro ethyl) -6,8- two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -
Ketone -3- base]-urea (I-14), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking fleraxacin hydroximic acid (II-14 ")
1.0g (2.6 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.62g (3.8mmol), stirring at normal temperature to object is added
Material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.10g (2.6mmol) 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-14), yield 63%, m.p.224~226 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.62(brs,
1H, NH), 9.53 (s, 1H, NH), the 9.37,9.21 (- H of 2s, 2H, 2 × 2 '), 8.96~the 8.53 (- H of m, 2H, 2 × 5 '), 5.12~
4.87 (m,8H,2×FCH2CH2), 3.57~3.45 (m, 8H, 2 × piperazine-H), 2.63~2.40 (m, 14H, 2 × piperazine-H
and 2×NCH3);MS (m/z): 791 [M+H], calculated value: 790.80.
Embodiment 15
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3- [the fluoro- 7- of 1- ethyl -6,8- two (3,4- lupetazin -1- base)-quinoline -4 (1H) -one -
3- yl]-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 (II-
15 ") 1.0 g (2.6mmol) are suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.55g (3.4mmol), stirring at normal temperature is added
To material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.10g (2.6mmol) is added, 55~60 DEG C of water-bath are stirred
It mixes 17 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 55%, m.p.214~216 DEG C.1H NMR(400MHz,DMSO-d6)δ: 11.53
(brs, 1H, NH), 9.42 (s, 1H, NH), the 9.05,8.87 (- H of 2s, 2H, 2 × 2 '), 8.84~the 8.16 (- H of m, 2H, 2 × 5 '),
4.92~4.78 (m, 4H, FCH2CH2),4.45(q,2H,NCH2), 3.56~3.43 (m, 8H, 2 × piperazine-H), 2.57~2.36
(m, 13H, 2 × 2 × NCH of piperazine-H and3), 1.46~1.35 (m, 6H, 2 × CH3);MS (m/z): 787 [M+H], it calculates
Value: 786.83.
Embodiment 16
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3- [the fluoro- 8- methoxyl group -7- of 1- cyclopropyl -6- (3,4- lupetazin -1- base)-quinoline -4
(1H) -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 (II-
16 ") 1.0 g (2.5mmol) are suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.75g (4.6mmol), stirring at normal temperature is added
To material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.06g (2.5mmol) is added, 55~60 DEG C of water-bath are stirred
It mixes 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%, m.p.226~228 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.55
(brs, 1H, NH), 9.46 (s, 1H, NH), the 9.16,8.97 (- H of 2s, 2H, 2 × 2 '), 8.86~the 7.84 (- H of m, 2H, 2 × 5 '),
4.87~4.56 (m, 5H, FCH2CH2and CH),3.88(s,3H,OCH3), 3.56~3.40 (m, 8H, 2 × piperazine-H),
2.55~2.36 (m, 13H, 2 × 2 × NCH of piperazine-H and3), 1.65~1.14 (m, 7H, CH3and CH2CH2);MS(m/
Z): 811 [M+H], calculated value: 810.88.
Embodiment 17
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3- [the fluoro- 8- methoxyl group -7- of 1- cyclopropyl -6- (1- methyl-octahydro pyrrolo- [3,4-b] pyrrole
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 (II-
17 ") 1.0 g (2.3mmol) are suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.65g (4.0mmol), stirring at normal temperature is added
To material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 0.98g (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 light
Yellow crystal object (I-17), yield 48%, m.p.213~215 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.57
(brs, 1H, NH), 9.46 (s, 1H, NH), the 9.37,9.16 (- H of 2s, 2H, 2 × 2 '), 8.76~the 8.32 (- H of m, 2H, 2 × 5 '),
4.94~4.68 (m, 5H, FCH2CH2and CH),3.87(s,3H,OCH3), 3.56~3.23 (m, 8H, piperazine-H and pyrrolidines
Ring-H), 2.64~2.28 (m, 13H, 2 × NCH of piperazine-H and piperidine ring-H and3), 2.16~1.14 (m, 9H, piperidine ring-H
and CH2CH2);MS(m/z):837[M+H]+, calculated value: 836.92.
Embodiment 18
1- { 2- [two fluoro- 7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3- base of 1- (2- fluoro ethyl) -6,8-] -
1,3,4- thiadiazoles -5- base } -3- [6- fluoro- 8,1- sulphur ethylene group -7- (4- methylpiperazine-1-yl)-quinoline -4 (1H) -one -3-
Base]-urea (I-18), chemical structural formula are as follows:
Double-fluoquinolone thiadiazoles urea of the present embodiment the preparation method comprises the following steps: taking Rufloxacin hydroximic acid (II-18 ")
1.0g (2.6 mmol) is suspended in 25mL acetonitrile, and carbonyl dimidazoles (CDI) 0.72g (4.4mmol), stirring at normal temperature to object is added
Material dissolution.Then fleraxacin C-3 thiadiazoles amine IV intermediate 1.10g (2.6mmol) 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-18), yield 57%, m.p.234~236 DEG C.1H NMR(400MHz,DMSO-d6)δ:11.53(brs,
1H, NH), 9.41 (s, 1H, NH), the 9.15,9.06 (- H of 2s, 2H, 2 × 2 '), the 8.85,8.36 (- H of 2d, 2H, 2 × 5 '), 4.88~
4.76 (m,4H,FCH2CH2), 4.24~3.38 (m, 12H, SCH2CH2) 2 × piperazine of and-H), 2.56~2.38 (m, 14H, 2
2 × NCH of × piperazine-H and3);MS(m/z):785[M+H]+, calculated value: 784.86.
Test example
One, one kind pair-fluoquinolone thiadiazoles ureas fleraxacin derivative that embodiment 1-18 is provided is external anti-swollen
Tumor activity measurement
1, test sample
It is anti-swollen with embodiment 1-18 18 new double-fluoquinolone thiadiazoles ureas fleraxacin derivatives provided and classics
Tumor topoisomerase enzyme inhibitor 10-hydroxycamptothecine (Hydroxycamptothecin, HC), ureas tyrosine kinase inhibitor
Rui Gefeini (Regorafenib, RRF) and card are rich for Buddhist nun (Cabozantinib, CZT) and parent compound fleraxacin
It (FL) is test sample, 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, 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 dosage-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.
Anti-tumor activity (the IC of each test sample of table 150)
As it can be seen from table 1 double-fluoquinolone thiadiazoles ureas fleraxacin 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 fleraxacin (LF), while being better than the activity of control topoisomerase enzyme inhibitor Hydroxycamptothecin (HC), most chemical combination
The activity of object is also better than control tyrosine kinase inhibitor Rui Gefeini (RRF) and the rich activity for Buddhist nun (CZT) of card.It is more meaningful
, the compound that embodiment 1-18 is provided also shows extremely strong sensibility to the cell cycling inhibiting of resistance to Gefitinib G, while right
Normal cell VERO cell is shown low toxicity, the attribute with druggability.Therefore, according to the general way of drug development
Diameter is first to carry out conventional antitumor in-vitro screening, is then targetedly studied, so the compound of the present invention has by force
Antitumor anti-drug-resistance activity and lower toxicity, can be by mixing system at salt or with pharmaceutical carrier with acid human-acceptable
Standby anti-tumor drug.
Claims (7)
1. a kind of double-fluoquinolone thiadiazoles ureas fleraxacin 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 fleraxacin derivative according to claim 1,
It is characterized in that, specific preparation step includes:
1) with fleraxacin (14) for raw material, fleraxacin acyl shown in Formula II can be prepared into through reacting with hydrazine hydrate generation hydrazinolysis
Hydrazine;Then Formula II and potassium rhodanide the fleraxacin amide shown in the obtained formula III of aqueous solution generation condensation reaction of dilute hydrochloric acid
Base thiourea compound;Last formula III intramolecular cyclisation occurs in concentrated sulfuric acid, fleraxacin C-3 thiadiazoles amine is prepared
Intermediate compound IV.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 fleraxacin 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 fleraxacin derivative (Formulas I -1~I-18), synthetic route such as two institute of synthetic route
Show.
One intermediate fleraxacin thiadiazoles amine (IV) of synthetic route is synthetically prepared route
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 fleraxacin derivative (I-1~I-18) synthesis system
Standby route.
3. a kind of preparation method of double-fluoquinolone thiadiazoles ureas fleraxacin derivative according to claim 2,
It is characterized in that, fluoroquinolone carboxylic acid shown in the formula 1~18 and the molar ratio of carbonyl dimidazoles are 1:1.0~2.0.
4. a kind of preparation method of double-fluoquinolone thiadiazoles ureas fleraxacin 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 fleraxacin 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 fleraxacin C-3 thiadiazoles amine intermediate V is 1:1.
6. a kind of double-fluoquinolone thiadiazoles ureas fleraxacin derivative as described in claim 1 is preparing antineoplastic
Application in object.
7. a kind of double-fluoquinolone thiadiazoles ureas fleraxacin 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.
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