CN102653521B - Piperazine thiocarbohydrazide derivate of indole-2-ketone and preparation method and application of piperazine thiocarbohydrazide derivate - Google Patents
Piperazine thiocarbohydrazide derivate of indole-2-ketone and preparation method and application of piperazine thiocarbohydrazide derivate Download PDFInfo
- Publication number
- CN102653521B CN102653521B CN201210128476.4A CN201210128476A CN102653521B CN 102653521 B CN102653521 B CN 102653521B CN 201210128476 A CN201210128476 A CN 201210128476A CN 102653521 B CN102653521 B CN 102653521B
- Authority
- CN
- China
- Prior art keywords
- sulfo
- piperazine
- subunit
- indoles
- formyl hydrazine
- 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.)
- Expired - Fee Related
Links
- 0 CC(C[C@]1C2=NNC(NCCNc3c(*)c(*)c(*)c(*)c3*)=S)=CC=C1NC2=O Chemical compound CC(C[C@]1C2=NNC(NCCNc3c(*)c(*)c(*)c(*)c3*)=S)=CC=C1NC2=O 0.000 description 1
- UJGXTMZILSGDLG-LGMDPLHJSA-N CCN(CC)CCNC(c1c(C)[nH]c(/C=C(/c(cccc2)c2N2)\C2=O)c1C)=O Chemical compound CCN(CC)CCNC(c1c(C)[nH]c(/C=C(/c(cccc2)c2N2)\C2=O)c1C)=O UJGXTMZILSGDLG-LGMDPLHJSA-N 0.000 description 1
- WUWDLXZGHZSWQZ-WQLSENKSSA-N Cc1c(/C=C(/c(cccc2)c2N2)\C2=O)[nH]c(C)c1 Chemical compound Cc1c(/C=C(/c(cccc2)c2N2)\C2=O)[nH]c(C)c1 WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 1
- NHFDRBXTEDBWCZ-ZROIWOOFSA-N Cc1c(/C=C(/c(cccc2)c2N2)\C2=O)[nH]c(C)c1CCC(O)=O Chemical compound Cc1c(/C=C(/c(cccc2)c2N2)\C2=O)[nH]c(C)c1CCC(O)=O NHFDRBXTEDBWCZ-ZROIWOOFSA-N 0.000 description 1
Abstract
The invention discloses a piperazine thiocarbohydrazide derivate of indole-2-ketone, which is represented by the general formula (I), wherein the definitions of R4, R5, R6, R7, R11, R12, R13, R14 and R15 can be found in the specification in detail. The invention also discloses a preparation method for the compound and a medicinal compound of the piperazine thiocarbohydrazide derivate. The compound represented by the general formula (I) has an effect of suppressing multiplication of cells of human lung cancer (A-549), human breast cancer (MFC-7) and human colorectal cancer (HCT-116) and can be used as an anticancer medicine.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, more particularly, relate to piperazine sulfo-formyl hydrazine derivative of indol-2-one and preparation method thereof and antiproliferative purposes.
Background technology
1H-Indole-2,3-dione (isatin, isatin) and derivative thereof are the important heterogeneous ring compounds of a class, and its C3 position is subject to the attack of nucleophilic reagent, thereby form indol-2-one derivates [Vine, K.L. that various 3-replaces; Cytotoxic and anticancer activities of isatin and itsderivatives:a comprehensive review from 2000-2008.Anti-cancer agents Med.Chem.2009,9 (4), 397-414].Some indol-2-one derivates have demonstrated good anti-tumor activity, for example, and compound S U-5416 (Semaxanib) [Abadi, A.H. taking indol-2-one as skeleton; Abou-Seri, S.M.; Abdel-Rahman, D.E.; Klein, C.; Lozach, O.; Meijer, L.Synthesis of 3-substituted-2-oxoindole analogues and their evaluation as kinaseinhibitors, anticancer and antiangiogenic agents.Eur.J.Med.Chem.2006,41,296-305.] can be used as vascular endothelial growth factor receptor (Vascular endothelial growthfactor receptor, VEGFR) kinase inhibitor, the propagation of inhibition tumor cell, has entered the II clinical trial phase stage at present.SU-11248 (Sunitinib) is a multiple receptor tyrosine kinases inhibitor, can produce specific inhibitory effect to VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β and other Tyrosylprotein kinases, be used for the treatment of imatinib mesylate treatment failure or not tolerant gastrointestinal stromal tumor and advanced renal cell cancer [Maskell, L. in 2006 by U.S. FDA approval; Blanche, E.A.; Colucci, M.A.; Whatmorea, J.L.; Moody, C.J.Synthesis andevaluation of prodrugs for anti-angiogenic pyrrolylmethylidenyl oxindoles.Bioorg.Med.Chem.Lett.2007,17,1575-1578)].And can be used as platelet-derived growth factor acceptor (Plateletderived growth factor receptor with the compound S U-6668 of SU-5416 and SU-11248 similar, PDGFR) tyrosine kinase inhibitor (Kammasud, N.; Boonyarat, C.; Tsunoda, S.; Sakurai, H.; Saiki, I.; Griersond, D.S.; Vajraguptaa, O.Novel inhibitor for fibroblast growth factor receptor tyrosine kinase.Bioorg.Med.Chem.Lett, 2007,17,4812-4818).In addition document (Vine, K.L..; Locke, J.M..; Ranson, M.; Pyne, S.G.and Bremner, J.B.In vitro cytotoxicity evaluationof some substituted isatin derivatives.Bioorg.Med.Chem.2007,15,931-938) report, the cytotoxic activity of indol-2-one derivates is different with the change of structure.
On the other hand, thiosemicarbazone structure fragment is a known antitumor drug effect group.For example, Trianpine (3-AP) is a ribonucleotide reductase (Ribonucleotide reductase) inhibitor, carrying out comprising for several malignant tumours II clinical trial phase [Zeglis, the B.M. of nonsmall-cell lung cancer and kidney; Divilov, V.; Lewis, J.S.Roleof metalation in the topoisomerase IIr inhibition and antiproliferation activityof a series of r-heterocyclic-N4-substituted thiosemicarbazones and their Cu (II) Complexes.J.Med.Chem.2011,54,2391-2398.].Karal1[Karal1, N.Synthesisand primary cytotoxicity evaluation of new 5-nitroindole-2,3-dione derivatives.Eur.J.Med.Chem.2002,37,909-918.] synthesize 5-nitroindoline-2-ketone-3-(thiosemicarbazone) compound and carried out anti tumor activity in vitro test, result shows the multi-form substituting group of the upper introducing of N4 in thiosemicarbazone, and its anti-tumor activity is had a great impact.2006, [Hu, the W.X such as Hu; Zhou, W; Xia, C.N.; Wen, X.Synthesis and anticancer activity ofthiosemicarbazones.Bioorg.Med.Chem.Lett.2006,16,2213-2218.] taking hydrazine hydrate, dithiocarbonic anhydride and substituted-piperazinyl as raw material, through reactions such as nucleophilic addition(Adn), condensation and nucleophilic substitution, a series of thiosemicarbazone compounds containing piperazine ring are synthesized, and adopt MTT colorimetry and sulphonyl rhodamine protein staining method (Sulforhodamine B, SRB) carry out Anticancer Activity in vitro test, the IC of compound wherein to SGC-7901gastriccarcinomacellline
50can reach 0.032 μ M.
Summary of the invention
The present invention is on the basis of this study group previous work, successfully synthesize the piperazine sulfo-formyl hydrazine derivative of the brand-new indol-2-one of a class, this compound is inhibited to the propagation of the cancer cells such as people's lung cancer, human breast carcinoma and human colon carcinoma, can be used as antitumor drug.
The object of this invention is to provide a kind of piperazine sulfo-formyl hydrazine derivative of indol-2-one.
Another object of the present invention is to provide the preparation method of the piperazine sulfo-formyl hydrazine derivative of above-mentioned indol-2-one.
Another object of the present invention is to provide the medicinal compositions of the piperazine sulfo-formyl hydrazine derivative that comprises above-mentioned indol-2-one.
Another object of the present invention has been to provide the piperazine sulfo-formyl hydrazine derivative of above-mentioned indol-2-one in the purposes of preparing in cancer therapy drug.
Specifically, the invention provides the piperazine sulfo-formyl hydrazine derivative suc as formula the indol-2-one shown in (I):
Wherein, R
4, R
5, R
6and R
7be selected from independently of one another hydrogen, halogen (for example, fluorine, chlorine, bromine or iodine), nitro, hydroxyl, C1-C4 alkyl or C1-C4 alkoxyl group;
R
11, R
12, R
13, R
14and R
15be selected from independently of one another C1-C4 alkyl or the C1-C4 alkoxyl group of hydrogen, halogen (for example, fluorine, chlorine, bromine or iodine), nitro, hydroxyl, C1-C4 alkyl, replacement.
In embodiments of the invention, described halogen refers to fluorine, chlorine, bromine or iodine.Described C1-C4 alkyl refers to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl.Described C1-C4 alkoxyl group refers to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy.The C1-C4 alkyl of described replacement refers to that C1-C4 alkyl for example, by replacements such as more than one halogen (, fluorine, chlorine, bromine or iodine), hydroxyl or nitros, for example, and trifluoromethyl.
In embodiment provided by the invention, preferably, the invention provides suc as formula the compound shown in (I), wherein, R
4, R
5, R
6and R
7be selected from independently of one another hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, methyl or methoxyl group.
In embodiment provided by the invention, preferably, the invention provides suc as formula the compound shown in (I), wherein, R
11, R
12, R
13, R
14and R
15be selected from independently of one another hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, trifluoromethyl or methoxyl group.
In embodiment provided by the invention, more preferably, the invention provides suc as formula the compound shown in (I), wherein, R
4, R
5, R
6and R
7be selected from independently of one another hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, methyl or methoxyl group; R
11, R
12, R
13, R
14and R
15be selected from independently of one another hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, trifluoromethyl or methoxyl group.
In embodiment provided by the invention, preferably, the invention provides suc as formula the compound shown in (IV),
Wherein, R
4, R
5, R
6and R
7definition is suc as formula defined in (I) compound.
In embodiment provided by the invention, preferably, the invention provides the compound as shown in formula V,
Wherein, R
11, R
12, R
13, R
14and R
15definition is suc as formula defined in (I) compound.
In embodiment provided by the invention, particularly preferably, the invention provides following compounds:
N '-(2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 1);
N '-(5-methyl-2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 2);
N '-(the bromo-2-oxindole-3-of 5-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 3);
N '-(the bromo-2-oxindole-3-of 5,7-bis-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 4);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 5);
N '-(the fluoro-2-oxindole-3-of 5-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 6);
N '-(5-nitro-2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 7);
N '-(the bromo-2-oxindole-3-of 4-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 8);
N '-(4-chloro-2-oxo indoles-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 9);
N '-(the bromo-2-oxindole-3-of 6-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 10);
N '-(6-chloro-2-oxo indoles-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 11);
N '-(5-methoxyl group-2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 12);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-p-methoxy-phenyl) piperazine-1-sulfo-formyl hydrazine (compound 13);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-aminomethyl phenyl) piperazine-1-sulfo-formyl hydrazine (compound 14);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-aminomethyl phenyl) piperazine-1-sulfo-formyl hydrazine (compound 15);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2,4-3,5-dimethylphenyl) piperazine-1-sulfo-formyl hydrazine (compound 16);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-chloro-phenyl-) piperazine-1-sulfo-formyl hydrazine (compound 17);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-chloro-phenyl-) piperazine-1-sulfo-formyl hydrazine (compound 18);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2,4 dichloro benzene base) piperazine-1-sulfo-formyl hydrazine (compound 19);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-fluorophenyl) piperazine-1-sulfo-formyl hydrazine (compound 20);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-fluorophenyl) piperazine-1-sulfo-formyl hydrazine (compound 21);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2,4 difluorobenzene base) piperazine-1-sulfo-formyl hydrazine (compound 22);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-nitrophenyl) piperazine-1-sulfo-formyl hydrazine (compound 23);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-nitrophenyl) piperazine-1-sulfo-formyl hydrazine (compound 24);
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-trifluoromethyl) phenyl) piperazine-1-sulfo-formyl hydrazine (compound 25).
On the other hand, the invention provides the preparation method of the piperazine sulfo-formyl hydrazine derivative of the indol-2-one as shown in general formula (I), comprise the steps:
Formula (II) compound reacts in ethanol with formula (III) compound, obtains formula (I) compound:
Here each substituent definition cotype (I) compound of formula (II) compound and formula (III) compound.
Provided by the invention as shown in general formula (I) preparation method of the piperazine sulfo-formyl hydrazine derivative of indol-2-one, wherein, formula (II) compound is (for example,, as R in formula (II) compound
11, R
12, R
13, R
14, R
15during for hydrogen) can prepare by following technique:
The synthesis technique of midbody compound (II)
Reagent and reaction conditions: a. dithiocarbonic anhydride, methyl iodide, Virahol, water; 0 DEG C, 2 hours; B.1-phenylpiperazine or 1-substituted phenylpiperazine, dehydrated alcohol, refluxes, 10-22 hour.
Taking hydrazine hydrate (VI) as starting raw material, according to document [Klayman, D.L.; Bartosevich, J.F.; Griffin, T.S.; Mason, C.J.; Scovill, J.P.2-Acetylpyridine thiosemicarbazones.1.A new class of potential antimalarial agents.J.Med.Chem.1979,22 (7), 855-862.] report method, under alkaline condition, react in the mixed solvent of isopropyl alcohol and water with dithiocarbonic anhydride, methyl iodide, obtain Methyl hydrazinecarbodithioate (VII).Reference [Spalinska, K., Foks, H., Kedzia, A., Wierzbowska, M., Kwapisz, E., Gebska, A., Zilkolwska-Klinkosz, M.Synthesis and antibacterial activity of substitutedthiosemicarbazides and of 1, 3, 4-Thiadiazole or 1, 2, 4-Triazole derivatives.Phosphorus, Sulfur Silicon Relat.Elem.2006, 181 (3), 609-625.] method, by Methyl hydrazinecarbodithioate (VII) and 1-php or 1-substituted phenylpiperazine heating reflux reaction in dehydrated alcohol, obtain (replacement) phenylpiperazine-1-sulfo-formyl hydrazine, it is formula (II) compound.
Provided by the invention as shown in general formula (I) preparation method of the piperazine sulfo-formyl hydrazine derivative of indol-2-one, wherein, formula (III) compound is (for example,, as R in formula (III) compound
4, R
6, R
7for hydrogen, R
5during for methyl) can prepare by following technique:
The synthesis technique of midbody compound (IIIb)
Reagent and reaction conditions: a. chloral hydrate, oxammonium hydrochloride, anhydrous sodium sulphate, hydrochloric acid, water, boils, 10 minutes; B. the vitriol oil, 80 DEG C, 10 minutes.
According to document [Lai, Y.S.; Ma, L.; Huang, W.X.; Yu, X.; Zhang, Y.H.; Ji, H.; Tian, J.Synthesis and biological evaluation of 3-[4-(amino/methylsulfonyl) phenyl] methylene-indolin-2-one derivatives as novel COX-1/2and 5-LOXinhibitors.Bioorg.Med.Chem.Lett.2010,20 (24), 7349-7353.] report method by para-totuidine (VIII) and chloral hydrate, anhydrous sodium sulphate, oxammonium hydrochloride, concentrated hydrochloric acid reacts and obtains N-oximido ethanoyl substituted aniline (IX) in distilled water; Then, products therefrom and strong sulfuric acid response are obtained to 5-skatole-2,3-diketone, i.e. formula (IIIb) compound.
Provided by the invention as shown in general formula (I) preparation method of the piperazine sulfo-formyl hydrazine derivative of indol-2-one, wherein, formula (III) compound is (for example,, as R in formula (III) compound
4, R
6for hydrogen, R
5, R
7during for bromine) can prepare by following technique:
The synthesis technique of midbody compound (IIId)
Reagent and reaction conditions: a. bromine, 95% ethanol, 70-75 DEG C, 0.5h.
According to document [Vine, K.L.; Locke, J.M.; Ranson, M.; Pyne, S.G.; Bremner, J.B.; In vitro cytotoxicity evaluation of some substituted isatin derivatives.Bioorg.Med.Chem.2007,15,931-938.] report method, by indoles-2,3-diketone (X) reacts and obtains 5 in 95% ethanol with bromine, 7-dibromo indole-2,3-dione, i.e. formula (IIId) compound.
Provided by the invention as shown in general formula (I) preparation method of the piperazine sulfo-formyl hydrazine derivative of indol-2-one, wherein, formula (III) compound is (for example,, as R in formula (III) compound
4, R
6, R
7for hydrogen, R
5during for nitro) can prepare by following technique:
The synthesis technique of midbody compound (IIIg)
Reagent and reaction conditions: a. saltpetre, the vitriol oil, 0-4 DEG C, 1h.
According to document [Vine, K.L.; Locke, J.M.; Ranson, M.; Pyne, S.G.; Bremner, J.B.; In vitro cytotoxicity evaluation of some substituted isatin derivatives.Bioorg.Med.Chem.2007,15,931-938.] report method, by indoles-2,3-diketone (X) is dissolved in the vitriol oil, then react and obtain 5-nitroindoline-2 with the concentrated sulfuric acid solution of saltpetre, 3-diketone, i.e. formula (IIIg) compound.
The third aspect, the invention provides the medicinal compositions that one comprises the above-mentioned piperazine sulfo-formyl hydrazine derivative suc as formula the indol-2-one shown in (I).This medicinal compositions comprises formula (I) compound and the pharmaceutically acceptable auxiliary material of significant quantity on pharmacology.To those skilled in the art, these auxiliary materials are all known, for example, and physiological saline, gelatin, Sudan Gum-arabic, lactose, Microcrystalline Cellulose, starch, treated starch, Mierocrystalline cellulose, modified-cellulose, hydroxyethanoic acid sodium, secondary calcium phosphate, Magnesium Stearate, talcum, colloid silica etc.In addition, these compositions also can comprise further: stablizer, wetting agent, emulsifying agent, sweeting agent, flavouring agent, buffer reagent etc.
Medicinal compositions of the present invention, as required, can be mixed with solid or liquid form for oral administration, as tablet, pill, oral liquid etc.; For sterile solution, suspension or the emulsion form of parenterai administration, sprays etc.The dosage of medicinal compositions of the present invention is 0.1mg-1000mg/kg body weight, and medical practitioner can, according to the needs of the state of an illness, under instruction of the present invention, formulate suitable dosage.
Fourth aspect, the invention provides formula (I) compound in the application of preparing in antitumor drug.Compound of the present invention can be used for treating lung cancer, mammary cancer, colorectal carcinoma, liver cancer, cancer of the stomach, ovarian cancer, cervical cancer, oral carcinoma, leukemia etc.
Through evidence, the invention provides the piperazine sulfo-formyl hydrazine derivative of the brand-new indol-2-one of a class, this compound is inhibited to the propagation of the cancer cells such as people's lung cancer, human breast carcinoma and human colon carcinoma, can be used as antitumor drug.
Embodiment
Carry out by the following examples exemplary illustration embodiment of the present invention, for the ordinary skill in the art, under instruction of the present invention, according to prior art, the improvement that embodiment of the present invention is carried out, still belongs in protection scope of the present invention.
The source of the raw materials of compound using in embodiment is: indole-2,3-dione (IIIa) is bought in Nanjing Xie Zun Chemical Co., Ltd.; 4-bromo indole-2,3-diketone (IIIh), 4-chloro-indole-2,3-diketone (IIIi), 6-bromo indole-2,3-diketone (IIIj), 6-chloro-indole-2,3-diketone (IIIk) and 5-methoxy-Indole-2,3-diketone (IIIl) is bought the company in TCI.Other raw material is commercially available chemical reagent.
The people's lung cancer (A-549), mammary cancer (MCF-7) and colorectal carcinoma (HCT-116) cell that in embodiment, use are replied key lab of Beijing from Capital Normal University's DNA damage.
Preparation Example
Synthesizing of Methyl hydrazinecarbodithioate (VII)
In 50mL round-bottomed flask, add potassium hydroxide (2.8g, 50mmol), distilled water (100mL), Virahol (3.3mL), under ice-water bath is cooling, add 85% hydrazine hydrate (VI) (2.85mL, 50mmol), stir a moment, obtain colourless transparent solution.Maintain the temperature at below 10 DEG C, dropwise add dithiocarbonic anhydride (3mL, 3.8g, 50mmol).Dropwise, continue to stir 1h, it is faint yellow that reaction solution gradually becomes.Then under ice-water bath is cooling, methyl iodide (3mL, 7.1g, 50mmol) is dropwise added in above-mentioned solution, reaction solution color shoals gradually, produces a large amount of white precipitates.After dropwising, continue to stir 1.5h, filter collection solid, dry, use methylene dichloride recrystallization, obtain white solid 2.75g, yield 45%, m.p.83-85 DEG C. (Lit.m.p.81-83 DEG C)
1h NMR (600MHz, DMSO-d
6) δ: 2.39 (s, 3H, SCH
3), 5.06 (br s, 2H, NH
2), 10.78 (br s, 1H, NH) .EI-MS m/z:122[M
+] .[Klayman, D.L.; Bartosevich, J.F.; Griffin, T.S.; Mason, C.J.; Scovill, J.P.; J.Med.Chem.1979,22 (7), 855-862.]
Synthesizing of formula (II) compound
Methyl hydrazinecarbodithioate (VII) (0.34g, 3mmol) is dissolved in dehydrated alcohol (5mL), adds different 1-substituted phenylpiperazines or 1-php (6mmol).Be heated to reflux, stirring reaction, until moistening Lead acetate paper, in no longer flavescence of reflux condensing tube upper end (10-22h), has solid to separate out in reaction process.Be cooled to room temperature, suction filtration, dry, crude product carries out recrystallization with suitable solvent, obtains formula (II) compound.
4-phenylpiperazine-1-sulfo-formyl hydrazine (IIa)
Yield: 45%, white solid, m.p.189.8-191.3 DEG C (by recrystallizing methanol).
1h NMR (600MHz, DMSO-d
6) δ: 3.15 (t, J=4.8Hz, 4H, piperazine-H), 3.87 (t, J=4.8Hz, 4H, piperazine-H), 4.76 (br s, 2H, NH
2), 6.80 (t, J=7.2Hz, 1H, phenyl 4-H), 6.95 (dJ=8.4Hz, 2H, phenyl 2-H, 6-H), 7.22 (t, J=8.4Hz, 2H, phenyl 3-H, 5-H), 9.18 (br s, 1H, NH). ultimate analysis (C
11h
16n
4s) calculated value: C, 55.90; H, 6.82; N, 23.71, measured value: C, 55.66; H, 6.74; N, 23.85.
4-(4-p-methoxy-phenyl) piperazine-1-sulfo-formyl hydrazine (IIb)
Yield: 51%, yellow solid, m.p.204.0-204.7 DEG C (using DMF recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.00 (t, J=4.8Hz, 4H, piperazine-H), 3.68 (s, 3H, OCH
3), 3.86 (t, J=4.8Hz, 4H, piperazine-H), 4.77 (br s, 2H, NH
2), 6.82 (d, J=9Hz, 2H, phenyl 2-H, 6-H), 6.91 (d, J=9Hz, 2H, phenyl 3-H, 5-H), 9.19 (s, 1H, NH) .ESI-HRMS m/z:C
20h
19n
4oS ([M+H]
+) calculated value: 267.1280, measured value: 267.1274.
4-(4-aminomethyl phenyl) piperazine-1-sulfo-formyl hydrazine (IIc)
Yield: 59%, white solid, m.p.204.0-204.6 DEG C (by recrystallizing methanol).
1h NMR (600MHz, DMSO-d
6) δ: 2.20 (s, 3H, CH
3), 3.07 (t, J=4.8Hz, 4H, piperazine-H), 3.85 (t, J=4.8Hz, 4H, piperazine-H), 4.78 (br s, 2H, NH
2), 6.85 (d, J=7.8Hz, 2H, phenyl 2-H, 6-H), 7.03 (d, J=7.2Hz, 2H, phenyl 3-H, 5-H), 9.18 (br s, 1H, NH) .ESI-HRMS m/z:C
12h
19n
4s ([M+H]
+) calculated value: 251.1330, measured value: 251.1319.
4-(2-aminomethyl phenyl) piperazine-1-sulfo-formyl hydrazine (IId)
Yield: 52%, white solid, m.p.177.6-177.7 DEG C (by recrystallizing methanol).
1h NMR (600MHz, DMSO-d
6) δ: 2.27 (s, 3H, CH
3), 2.81 (t, J=4.8Hz, 4H, piperazine-H), 3.86 (t, J=4.8Hz, 4H, piperazine-H), 4.81 (br s, 2H, NH
2), 6.97 (t, J=7.2Hz, 1H, phenyl 4-H), 7.00 (d, J=7.2Hz, 1H, phenyl 6-H), 7.14 (t, J=7.2Hz, 1H, phenyl 5-H), 7.17 (d, J=7.2Hz, 1H, phenyl 3-H), (9.17 br s, 1H, NH) .ESI-HRMS m/z:C
12h
19n
4s ([M+H]
+) calculated value: 251.1330, measured value: 251.1317.
4-(2,4-3,5-dimethylphenyl) piperazine-1-sulfo-formyl hydrazine (IIe)
Yield: 62%, white solid, m.p.186.7-188.6 DEG C (by recrystallizing methanol).
1h NMR (600MHz, DMSO-d
6) δ: 2.21 (s, 3H, CH
3), 2.23 (s, 3H, CH
3), 2.77 (t, J=4.2Hz, 4H, piperazine-H), 3.84 (br s, 4H, piperazine-H), 4.79 (br s, 2H, NH
2), 6.89 (d, J=8.4Hz, 1H, phenyl 6-H), 6.94 (d, J=8.4Hz, 1H, phenyl 5-H), 6.98 (s, 1H, phenyl 3-H), 9.17 (br s, 1H, NH) .ESI-HRMS m/z:C
13h
21n
4s ([M+H]
+) calculated value: 265.1487, measured value: 265.1480.
4-(4-chloro-phenyl-) piperazine-1-sulfo-formyl hydrazine (IIf)
Yield: 56%, white solid, m.p.202.7-203.1 DEG C (by recrystallizing methanol).
1h NMR (600MHz, DMSO-d
6) δ: 3.16 (t, J=4.8Hz, 4H, piperazine-H), 3.86 (t, J=4.8Hz, 4H, piperazine-H), 4.76 (br s, 2H, NH
2), 6.96 (d, J=9Hz, 2H, phenyl 2-H, 6-H), 7.24 (d, J=9Hz, 2H, phenyl 3-H, 5-H), 9.18 (br s, 1H, NH). ultimate analysis (C
11h
15clN
4s), calculated value: C, 48.79; H, 5.58; N, 20.69. measured value: C, 48.54; H, 5.71; N, 20.44.
4-(2-chloro-phenyl-) piperazine-1-sulfo-formyl hydrazine (IIg)
Yield: 67%, white solid, m.p.188.4-190.3 DEG C (by recrystallizing methanol).
1h NMR (600MHz, DMSO-d
6) δ: 2.96 (t, J=4.8Hz, 4H, piperazine-H), 3.88 (t, J=4.8Hz, 4H, piperazine-H), 4.78 (br s, 2H, NH
2), 7.07 (t, J=7.8Hz, 1H, phenyl 4-H), 7.16 (d, J=8.4Hz, 1H, phenyl 6-H), 7.30 (t, J=7.8Hz, 1H, phenyl 5-H), 7.43 (d, J=7.8Hz, 1H, phenyl 3-H), (9.20 br s, 1H, NH). ultimate analysis (C
11h
15clN
4s) calculated value: C, 48.79; H, 5.58; N, 20.69. measured value: C, 48.78; H, 5.78; N, 20.73.
4-(2,4 dichloro benzene base) piperazine-1-sulfo-formyl hydrazine (IIh)
Yield: 61%, white solid, m.p.189.4-190.6 DEG C (by recrystallizing methanol).
1h NMR (600MHz, DMSO-d
6) δ: 3.23 (t, J=4.8Hz, 4H, piperazine-H), 3.86 (t, J=4.8Hz, 4H, piperazine-H), 4.76 (br s, 2H, NH
2), 6.93 (dd, J=9.0,2.4Hz, 1H, phenyl 5-H), 7.14 (d, J=2.4Hz, 1H, phenyl 3-H), 7.40 (d, J=9.0Hz, 1H, phenyl 6-H), 9.18 (br s, 1H, NH) .ESI-HRMS m/z:C
11h
14c
12n
4s ([M+H]
+) calculated value: 305.0394, measured value: 305.0393.
4-(4-fluorophenyl) piperazine-1-sulfo-formyl hydrazine (IIi)
Yield: 51%, white solid, m.p.186.8-187.0 DEG C (by recrystallizing methanol).
1h NMR (600MHz, DMSO-d
6) δ: 3.08 (t, J=4.8Hz, 4H, piperazine-H), 3.86 (t, J=4.8Hz, 4H, piperazine-H), 4.76 (br s, 2H, NH
2), 6.97 (dd, J=9.0,4.8Hz, 2H, phenyl 2-H, 6-H), 7.06 (t, J=9.0Hz, 2H, phenyl 3-H, 5-H), 9.19 (br s, 1H, NH). ultimate analysis (C
11h
15fN
4s) calculated value: C, 51.95; H, 5.94; N, 22.03. measured value: C, 51.92; H, 6.05; N, 22.16.
4-(2-fluorophenyl) piperazine-1-sulfo-formyl hydrazine (IIj)
Yield: 58%, white solid, m.p.192.3-194.3 DEG C (by recrystallizing methanol).
1h NMR (600MHz, DMSO-d
6) δ: 3.00 (t, J=4.8Hz, 4H, piperazine-H), 3.88 (t, J=4.8Hz, 4H, piperazine-H), 4.77 (s, 2H, NH
2), 7.00 (m, 1H, phenyl 4-H), 7.05 (t, J=8.4Hz, 1H, phenyl 6-H), 7.13 (t, J=8.4Hz, 1H, phenyl 5-H), 7.15 (t, J=8.4Hz, 1H, phenyl 3-H), 9.19 (s, 1H, NH) .ESI-HRMS m/z:C
11h
16fN
4s ([M+H]
+) calculated value: 255.1080, measured value: 255.1078.
4-(2,4 difluorobenzene base) piperazine-1-sulfo-formyl hydrazine (IIk)
Yield: 52%, white solid, m.p.192.2-193.9 DEG C (by recrystallizing methanol).
1h NMR (600MHz, DMSO-d
6) δ: 2.95 (t, J=4.8Hz, 4H, piperazine-H), 3.87 (t, J=4.8Hz, 4H, piperazine-H), 4.79 (br s, 2H, NH
2), 7.00 (td, J=8.4,2.4Hz, 1H, phenyl 3-H), 7.09 (m, 1H, phenyl 6-H), 7.21 (m, 1H, phenyl 5-H), 9.21 (br s, 1H, NH). ultimate analysis (C
11h
14f
2n
4s) calculated value: C, 48.52; H, 5.18; N, 20.57. measured value: C, 58.38; H, 5.30; N, 20.69.
4-(4-nitrophenyl) piperazine-1-sulfo-formyl hydrazine (IIl)
Yield: 60%, yellow solid, m.p.214.8-216.8 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.57 (t, J=5.4Hz, 4H, piperazine-H), 3.91 (t, J=5.4Hz, 4H, piperazine-H), 4.87 (br s, 2H, NH
2), 6.98 (d, J=9.6,4.8Hz, 2H, phenyl 2-H, 6-H), 8.07 (d, J=9.6Hz, 2H, phenyl 3-H, 5-H), 9.12 (br s, 1H, NH) .ESI-HRMS m/z:C
11h
16n
5o
2s ([M+H]
+) calculated value: 282.1025, measured value: 282.1024.
4-(2-nitrophenyl) piperazine-1-sulfo-formyl hydrazine (IIm)
Yield: 45%, yellow solid, m.p.168.6-169.3 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.04 (t, J=4.8Hz, 4H, piperazine-H), 3.84 (t, J=4.8Hz, 4H, piperazine-H), 4.77 (br s, 2H, NH
2), 7.15 (t, J=7.8Hz, 1H, phenyl 4-H), 7.35 (d, J=8.4Hz, 1H, phenyl 6-H), 7.60 (t, J=8.4Hz, 1H, phenyl 5-H), 7.84 (d, J=7.8Hz, 1H, phenyl 3-H), (9.17 br s, 1H, NH). ultimate analysis (C
11h
15n
5o
2s) calculated value: C, 46.96; H, 5.37; N, 24.89. measured value: C, 46.78; H, 5.26; N, 25.09.
4-(4-tri-fluorocarbons phenyl) piperazine-1-sulfo-formyl hydrazine (IIn)
Yield: 47%, white solid, m.p.197.9-198.4 DEG C (by recrystallizing methanol),
1h NMR (600MHz, DMSO-d
6) δ: 3.35 (t, J=5.4Hz, 4H, piperazine-H), 3.89 (t, J=5.4Hz, 4H, piperazine-H), 4.76 (br s, 2H, NH
2), 7.05 (d, J=8.4Hz, 2H, phenyl 2-H, 6-H), 7.51 (d, J=8.4Hz, 1H, phenyl 3-H, 5-H), 9.17 (br s, 1H, NH) .ESI-HRMS m/z:C
12h
16f
3n
4s ([M+H]
+) calculated value: 305.1048, measured value: 305.1034.
Synthesizing of formula (III) compound
IIIb, IIIc, IIIe and IIIf's is synthetic
In reaction flask, add chloral hydrate (6g, 36.3mmol), anhydrous sodium sulphate (40g, 281.6mmol) and distilled water (100mL), stirring and dissolving.Oxammonium hydrochloride (7.4g, 106.5mmol) is dissolved in to distilled water (34mL) simultaneously.Separately aniline (33.6mmol) is mixed with concentrated hydrochloric acid (3.0mL), stir a moment, then add distilled water (20mL).Then, rear two kinds of solution are added in reaction flask successively, be heated to boiling, and keep reaction 10min.Be cooled to room temperature, suction filtration, dry, products therefrom is directly used in next step reaction.
Under stirring, the vitriol oil (6mL) is heated to 50 DEG C, adds in batches respectively above-mentioned reaction product (8.6mmol), control and add speed, temperature is remained between 60-70 DEG C.Finish, be slowly warming up to 80 DEG C, and keep 80 DEG C of reaction 10min.Reaction solution is cooled to room temperature, under agitation, in impouring trash ice, separates out solid, in refrigerator, place and spend the night.The solid that filter collection is separated out, room temperature is dried, and through ethyl alcohol recrystallization, obtains IIIb, IIIc, IIIe and IIIf.
[Lai，Y.S.；Ma，L.；Huang，W.X.；Yu，X.；Zhang，Y.H.；Ji，H；Tian，J.Synthesis and biological evaluation of 3-[4-(amino/methylsulfonyl)phenyl]methylene-indolin-2-one derivatives as novel COX-1/2and 5-LOXinhibitors.Bioorg.Med.Chem.Lett.2010，20(24)，7349-7353]
5-skatole-2,3-diketone (IIIb)
Yield: 65%, red solid, m.p. DEG C of (with first alcohol and water recrystallization) (Lit.m.p.178 DEG C) .[Pawar, V.; Lokwani, D.; Bhandari, S.; Mitra, D.; Sabde, S.; Bothara, K.; Madgulkar, A.Design of potential reverse transcriptase inhibitor containingIsatin nucleus using molecular modeling studies.Bioorg.Med.Chem.2010,18,3198-3211].
1h NMR (600MHz, DMSO-d
6) δ: 2.26 (s, 3H, CH
3), 6.81 (d, J=7.8Hz, 1H, indoles 7-H), 7.32 (s, 1H, indoles 4-H), 7.40 (d, J=7.8Hz, 1H, indoles 6-H), 10.93 (s, 1H, indoles NH) .EI-MS m/z:161[M
+].
5-bromo indole-2,3-diketone (IIIc)
Yield: 70%, yellow solid, m.p.255-258 DEG C (with first alcohol and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 6.87 (d, J=8.4Hz, indoles 7-H), 7.66 (d, J=1.8Hz, indoles 4-H), 7.74 (dd, J=8.4,1.8Hz, 1H, indoles 6-H), 11.13 (s, 1H, indoles NH) .EI-MS m/z:225[M
+].
5-chloro-indole-2,3-diketone (IIIe)
Yield: 57%, yellow solid, m.p.246-247 DEG C (with first alcohol and water recrystallization). (Lit.m.p.248～251 DEG C) .[Gassman, P.G.; Cue, B.W.; Luh, T.Y.A general method for thesynthesis of isatins.J.Org.Chem.1977,42 (8), 1340-1344.]
1h NMR (600MHz, DMSO-d
6) δ: 6.92 (d, J=8.4Hz, indoles 7-H), 7.55 (d, J=1.8Hz, indoles 4-H), 7.61 (dd, J=8.4,1.8Hz, 1H, indoles 6-H), 11.13 (s, 1H, indoles NH) .EI-MS m/z:181[M
+].
5-fluoro indole-2,3-diketone (IIIf)
Yield: 77%, red solid, m.p.227-228 DEG C (with first alcohol and water recrystallization). (Lit.m.p.228-229 DEG C) .[Liu B.; Lin R.; Liao, J.Y.; Li Z.C.; Chen, K.L.Synthesis ofSunitinib.Chin.J.Pharm.2007,38 (8), 539-542.]
1h NMR (600MHz, DMSO-d
6) δ: 6.92 (dd, J=8.4,4.2Hz, 1H, indoles 7-H), 7.40 (dd, J=7.2,2.4Hz, 1H, indoles 4-H), 7.45 (td, J=8.4,2.4Hz, 1H, indoles 6-H), 11.04 (s, 1H, indoles NH) .EI-MS m/z:165[M
+].
5,7-dibromo indole-2,3-dione (IIId)
Bromine (1.63g, 10.2mmol) is added drop-wise in hot ethanol (95%, the 10ml) solution of indole-2,3-dione (X) (0.5g, 3.4mmol), controls rate of addition, make temperature remain on 70-75 DEG C.Then at 70-75 DEG C, reaction 0.5h, is cooled to room temperature by reaction solution, in impouring frozen water, separates out solid.The solid that filter collection is separated out, dries, and through ethyl alcohol recrystallization, obtains orange red solid 0.62g, yield 60%, m.p.248-250 DEG C (Lit.m.p.253-255 DEG C).
1h NMR (600MHz, DMSO-d
6) δ: 7.68 (d, J=1.8Hz, 1H, indoles 4-H), 8.05 (d, J=1.8Hz, 1H, indoles 6-H), 11.44 (s, 1H, indoles NH) .EI-MS m/z:303[M
+] .[Vine, K.L.; Locke, J.M.; RansonM.; Pyne, S.G.; Bremner, J.B.; In vitro cytotoxicity evaluation of somesubstituted isatin derivatives.Bioorg.Med. Chem.2007,15,931-938.]
5-nitroindoline-2,3-diketone (IIIg)
By indoles-2,3-diketone (X) (0.5g, 3.4mmol) be added drop-wise to saltpetre (0.34g with the mixed solution of the vitriol oil (3.2ml), in the vitriol oil (3.8ml) solution 3.4mmol), control rate of addition, make temperature remain on 0-4 DEG C (within 1h, dripping off).Then at 0-4 DEG C, reaction 1h, by reaction solution impouring frozen water, separates out solid.The solid that filter collection is separated out, dries, through silica gel column chromatography purification (elutriant: methylene chloride/methanol=98: 2), obtain yellow look solid 0.26g, yield 40%, m.p.250-252 DEG C of (Lit.
[]m.p.252-254 DEG C).
1h NMR (600MHz, DMSO-d
6) δ: 7.09 (d, J=8.4Hz, 1H, indoles 7-H), 8.21 (d, J=2.4Hz, 1H, indoles 4-H), 8.44 (dd, J=8.4,2.4Hz, 1H, indoles 6-H), 11.67 (s, 1H, indoles NH) .EI-MS m/z:192[M
+] .Vine, K.L.; Locke, J.M.; Ranson, M.; Pyne, S.G.; Bremner, J.B.; In vitro cytotoxicityevaluation of some substituted isatin derivatives.Bioorg.Med.Chem.2007,15,931-938.]
Synthesizing of formula (I) compound of embodiment 1 to 12
By indoles-2 that replace, 3-diketone (III) (1mmol) is dissolved in the anhydrous methanol (20mL) of low-grade fever, add 4-phenylpiperazine-1-sulfo-formyl hydrazine (IIa) (1mmol), be heated to reflux, backflow 8-10h (TLC detection).After reaction finishes, reaction solution is cooled to room temperature, the solid that filter collection is separated out, room temperature is dried, and ethanol or DMF and water recrystallization obtain formula (I) compound.
Embodiment 1
N '-(2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 1)
Yield: 50%, yellow solid, m.p.227-228 DEG C (with ethyl alcohol recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.35 (t, J=4.8Hz, 4H, piperazine-H), 4.15 (br s, 4H, piperazine-H), 6.81 (t, J=7.2Hz, 1H, phenyl 4 '-H), 6.95 (d, J=7.8Hz, 1H, indoles 7-H), 6.98 (d, J=8.4Hz, 2H, phenyl 2 '-H, 6 '-H), 7.10 (t, J=7.8Hz, 1H, indoles 5-H), 7.25 (t, J=7.8Hz, 2H, phenyl 3 '-H, 5 '-H), 7.37 (t, J=7.8Hz, 1H, indoles 6-H), 7.54 (d, J=7.8Hz, 1H, indoles 4-H), 11.30 (s, 1H, indoles NH), 13.22 (s, 1H, NNH). ultimate analysis (C
19h
19n
5o
s), calculated value: C, 62.44, H, 5.24, N, 19.16. measured value: C, 62.50, H, 5.31, N, 19.13.
Embodiment 2
N '-(5-methyl-2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 2)
Yield: 50%, yellow solid, m.p.235-237 DEG C (with ethyl alcohol recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 2.31 (s, 3H, CH
3), 3.35 (t, J=4.8Hz, 4H, piperazine-H), 4.15 (br s, 4H, piperazine-H), 6.81 (t, J=7.2Hz, 1H, phenyl 4 '-H), 6.84 (d, J=7.8Hz, 1H, indoles 7-H), 6.97 (d, J=7.2Hz, 2H, phenyl 2 '-H, 6 '-H), 7.17 (d, J=7.8Hz, 1H, indoles 6-H), 7.25 (t, J=7.2Hz, 2H, phenyl 3 '-H, 5 '-H), 7.37 (s, 1H, indoles 4-H), 11.20 (s, 1H, indoles NH), 13.26 (s, 1H, NNH) .ESI-HRMS m/z:C
20h
22n
5o
s([M+H]
+) calculated value: 380.1545, measured value: 380.1538.
Embodiment 3
N '-(the bromo-2-oxindole-3-of 5-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 3)
Yield: 54%, yellow solid, m.p.231-232 DEG C (with DMF and ethyl alcohol recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.36 (t, J=4.8Hz, 4H, piperazine-H), 4.16 (br s, 4H, piperazine-H), 6.81 (t, J=7.2Hz, 1H, phenyl 4 '-H), 6.92 (d, J=8.4Hz, 1H, indoles 7-H), 6.97 (d, J=8.4Hz, 2H, phenyl 2 '-H, 6 '-H), 7.25 (t, J=8.4Hz, 2H, phenyl 3 '-H, 5 '-H), 7.52 (dd, J=8.4, 1.2Hz, 1H, indoles 6-H), 7.63 (d, J=1.2Hz, 1H, indoles 4-H), 11.11 (s, 1H, indoles NH), 13.12 (s, 1H, NNH). ultimate analysis (C
19h
18brN
5oS) calculated value: C, 51.36, H, 4.08, N, 15.76. measured value: C, 51.55, H, 4,24, N, 15.74.
Embodiment 4
N '-(the bromo-2-oxindole-3-of 5,7-bis-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 4)
Yield: 51%, yellow solid, m.p.229-231 DEG C (with DMF and ethyl alcohol recrystallization).
1h NMR (600MHz, DMSO-d6) δ: 3.36 (t, J=4.8Hz, 4H, piperazine-H), 4.17 (t, J=4.8Hz, 4H, piperazine-H), 6.81 (t, J=7.2Hz, 1H, phenyl 4 '-H), 6.92 (d, J=8.4Hz, 1H, indoles 7-H), 6.97 (d, J=7.8Hz, 2H, phenyl 2 '-H, 6 '-H), 7.25 (t, J=8.4Hz, 2H, phenyl 3 '-H, 5 '-H), 7.65 (d, J=1.2Hz, 1H, indoles 6-H), 7.81 (d, J=1.8Hz, 1H, indoles 4-H), 11.73 (s, 1H, indoles NH), 13.06 (s, 1H, NNH). ultimate analysis (C
19h
17br
2n
5oS) calculated value: C, 43.61, H, 3.27, N, 13.38. measured value: C, 43.77, H, 3.44, N, 13.70.
Embodiment 5
N '-(5-chloro-2-oxo indoles-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 5)
Yield: 52%, yellow solid, m.p.223-224 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.36 (br s, 4H, piperazine-H), 4.16 (t, J=4.8Hz, 4H, piperazine-H), 6.81 (t, J=7.2Hz, 1H, phenyl 4 '-H), 6.97 (d, J=8.4Hz, 2H, phenyl 2 '-H, phenyl 6 '-H), 6.97 (d, J=8.4Hz, 1H, indoles 7-H), 7.25 (t, J=8.4Hz, 2H, phenyl 3 '-H, 5 '-H), 7.40 (dd, J=8.4, 1.8Hz, 1H, indoles 6-H), 7.53 (d, J=1.8Hz, 1H, indoles 4-H), 11.42 (s, 1H, indoles NH), 13.13 (s, 1H, NNH). ultimate analysis (C
19h
18clN
5oS) calculated value: C, 57.07, H, 4.54, N, 17.51. measured value: C, 57.04, H, 4.72, N, 17.50.
Embodiment 6
N '-(the fluoro-2-oxindole-3-of 5-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 6)
Yield: 40%, yellow solid, m.p.213-214 DEG C (with DMF and ethyl alcohol recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.33 (t, J=4.8Hz, 4H, piperazine-H), 4.14 (br s, 4H, piperazine-H), 6.79 (t, J=7.8Hz, 1H, phenyl 4 '-H), 6.94 (m, 3H, phenyl 2 '-H, 6 '-H, indoles 7-H), 7.18 (t, J=8.4Hz, 1H, indoles 6-H), 7.23 (t, J=8.4Hz, 2H, phenyl 3 '-H, 5 '-H), 7.34 (d, J=8.4Hz, 1H, indoles 4-H), (11.29 s, 1H, indoles NH), (13.12 s, 1H, NNH). ultimate analysis (C
19h
18fN
5oS) calculated value: C, 59.51; H, 4.73; N, 18.26. measured value: C, 59.39; H, 4.72; N, 18.25.
Embodiment 7
N '-(5-nitro-2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 7)
Yield: 46%, yellow solid, m.p.217-219 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.37 (t, J=4.8Hz, 4H, piperazine-H), 4.18 (br s, 4H, piperazine-H), 6.82 (t, J=7.8Hz, 1H, phenyl 4 '-H), 6.98 (d, J=8.4Hz, 2H, phenyl 2 '-H, 6 '-H), 7.16 (d, J=8.4Hz, 1H, indoles 7-H), 7.25 (t, J=7.8Hz, 2H, phenyl 3 '-H, 5 '-H), 8.25 (d, J=2.4Hz, 1H, indoles 4-H), 8.29 (dd, J=8.4, 2.4Hz, 1H, indoles 6-H), 11.93 (s, 1H, indoles NH), 13.06 (s, 1H, NNH) .ESI-HRMS m/z:C
19h
19n
6o
3s ([M+H]
+) calculated value: 411.1239, measured value: 411.1240. embodiment 8
N '-(the bromo-2-oxindole-3-of 4-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 8)
Yield: 42%, yellow solid, m.p.177.4-178.6 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.34 (t, J=4.8Hz, 4H, piperazine-H), (4.25 t, J=4.8Hz, 4H, piperazine-H), (6.81 t, J=7.2Hz, 1H, phenyl 4 '-H), 6.96 (d, J=7.8Hz, 1H, indoles 5-H), 6.98 (d, J=8.4Hz, 2H, phenyl 2 '-H, 6 '-H), 7.23-7.29 (m, 4H, indoles 6-H, 7-H, phenyl 3 '-H, 5 '-H), 11.49 (s, 1H, indoles NH), (13.31 s, 1H, NNH) .ESI-HRMS m/z:C
19h
18brN
5oS ([M+H]
+) calculated value: 444.0494, measured value: 444.0487.
Embodiment 9
N '-(4-chloro-2-oxo indoles-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 9)
Yield: 48%, yellow solid, m.p.221.3-223.4 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.34 (t, J=4.8Hz, 4H, piperazine-H), 4.22 (t, J=4.8Hz, 4H, piperazine-H), 6.82 (t, J=7.8Hz, 1H, phenyl 4 '-H), 6.92 (d, J=7.8Hz, 1H, indoles 5-H), 6.97 (d, J=7.8Hz, 2H, phenyl 2 '-H, 6 '-H), 7.12 (d, J=7.8Hz, 1H, indoles 7-H), 7.24 (t, J=7.8Hz, 2H, phenyl 3 '-H, 5 '-H), 7.35 (t, J=7.8Hz, 1H, indoles 6-H), 11.51 (s, 1H, indoles NH), 13.23 (s, 1H, NNH). ultimate analysis (C
19h
18clN
5oS0.7DMF) calculated value: C, 56.18, H, 5.12, N, 17.70. measured value: C, 55.85, H, 4.73, N, 17.77.
Embodiment 10
N '-(the bromo-2-oxindole-3-of 6-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 10)
Yield: 62%, yellow solid, m.p.247.8-248.7 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.35 (t, J=4.8Hz, 4H, piperazine-H), 4.15 (br s, 4H, piperazine-H), 6.81 (t, J=7.2Hz, 1H, phenyl 4 '-H), 6.97 (d, J=7.8Hz, 2H, phenyl 2 '-H, 6 '-H), 7.11 (s, 1H, indoles 7-H), 7.25 (t, J=7.8Hz, 2H, phenyl 3 '-H, 5 '-H), 7.28 (d, J=7.8Hz, 1H, indoles 5-H), 7.47 (d, J=7.8Hz, 1H, indoles 4-H), 11.43 (s, 1H, indoles NH), 13.13 (s, 1H, NNH). ultimate analysis (C
19h
18brN
5oS) calculated value: C, 51.36, H, 4.08, N, 15.76. measured value: C, 51.38, H, 4.23, N, 15.70.
Embodiment 11
N '-(6-chloro-2-oxo indoles-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 11)
Yield: 56%, yellow solid, m.p.238.9-239.6 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.36 (br s, 4H, piperazine-H), 4.15 (brs, 4H, piperazine-H), 6.81 (t, J=7.2Hz, 1H, phenyl 4 '-H), 6.97 (d, J=7.8Hz, 2H, phenyl 2 '-H, 6 '-H), 6.98 (s, 1H, indoles 7-H), 7.13 (d, J=7.8Hz, 1H, indoles 5-H), 7.25 (t, J=7.8Hz, 2H, phenyl 3 '-H, 5 '-H), 7.54 (d, J=7.8Hz, 1H, indoles 4-H), 11.44 (s, 1H, indoles NH), (13.12 s, 1H, NNH). ultimate analysis (C
19h
18clN
5oS) calculated value: C, 57.07; H, 4.54; N, 17.51. measured value: C, 57.02; H, 4.62; N, 17.48.
Embodiment 12
N '-(5-methoxyl group-2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine (compound 12)
Yield: 59%, yellow solid, m.p.192.8-194.2 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.35 (t, J=4.8Hz, 4H, piperazine-H), 3.77 (s, 3H, OCH
3), 4.15 (br s, 4H, piperazine-H), (6.81 t, J=7.8Hz, 1H, phenyl 4 '-H), 6.87 (d, J=8.4Hz, 1H, indoles 7-H), 6.95 (dd, J=8.4,2.4Hz, 1H, indoles 6-H), 6.97 (d, J=7.8Hz, 2H, phenyl 2 '-H, 6 '-H), 7.06 (d, J=2.4Hz, 1H, indoles 4-H), 7.24 (t, J=7.8Hz, 2H, phenyl 3 '-H, 5 '-H), 11.12 (s, 1H, indoles NH), (13.31 s, 1H, NNH). ultimate analysis (C
20h
21n
5o
2s) calculated value: C, 60.74; H, 5.35; N, 17.71. measured value: C, 60.80; H, 5.45; N, 17.72.
Synthesizing of formula (I) compound of embodiment 13 to 25
By 5-chloro-indole-2,3-diketone (IIIe) (0.09g, 0.5mmol) be dissolved in the anhydrous methanol (20mL) of low-grade fever, add respectively different piperazine-1-sulfo-formyl hydrazines (IIb-IIo) (0.5mmol), be heated to reflux, monitor reaction process with TLC, until 5-chloro-indole-2, the spot of 3-diketone disappear (5-10h).After reaction finishes, reaction solution is cooled to room temperature, the solid that filter collection is separated out, room temperature is dried, and DMF and water recrystallization for crude product, obtain formula (I) compound.
Embodiment 13
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-p-methoxy-phenyl) piperazine-1-sulfo-formyl hydrazine (compound 13)
Yield: 59%, yellow solid, m.p.244.7-255.2 DEG C.
1h NMR (600MHz, DMSO-d
6) δ: 3.20 (t, J=4.8Hz, 4H, piperazine-H), 3.70 (s, 3H, OCH
3), 4.15 (br s, 4H, piperazine-H), 6.85 (d, J=8.4Hz, 2H, phenyl 2 '-H, 6 '-H), 6.95 (d, J=8.4Hz, 2H, phenyl 3 '-H, 5 '-H), 6.97 (d, J=8.4Hz, 1H, indoles 7-H), 7.40 (d, J=8.4Hz, 1H, indoles 6-H), 7.51 (s, 1H, indoles 4-H), 11.41 (s, 1H, indoles NH), 13.12 (s, 1H, NNH). and ultimate analysis (C
20h
20clN
5o
2s) calculated value: C, 55.87; H, 4.69; N, 16.29. measured value: C, 53.98; H, 4.64; N, 15.64.
Embodiment 14
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-aminomethyl phenyl) piperazine-1-sulfo-formyl hydrazine (compound 14)
Yield: 61%, yellow solid, m.p.241.6-243.9 DEG C.
1h NMR (600MHz, DMSO-d
6) δ: 2.21 (s, 3H, CH
3), 3.28 (t, J=4.8Hz, 4H, piperazine-H), 4.15 (br s, 4H, piperazine-H), 6.88 (d, J=8.4Hz, 2H, phenyl 2 '-H, 6 '-H), 6.96 (d, J=8.4Hz, 1H, indoles 7-H), 7.06 (d, J=8.4Hz, 2H, phenyl 3 '-H, 5 '-H), 7.40 (dd, J=8.4,1.8Hz, 1H, indoles 6-H), 7.51 (d, J=1.8Hz, 1H, indoles 4-H), 11.41 (s, 1H, indoles NH), (13.12 s, 1H, NNH). ultimate analysis (C
20h
20clN
5oS0.35H
2o) calculated value: C, 57.16; H, 4.96; N, 16.67. measured value: C, 57.49; H, 4.89; N, 16.95.
Embodiment 15
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-aminomethyl phenyl) piperazine-1-sulfo-formyl hydrazine (compound 15)
Yield: 64%, yellow solid, m.p.231.4-233.0 DEG C.
1h NMR (600MHz, DMSO-d
6) δ: 2.32 (s, 3H, CH
3), 3.00 (t, J=4.8Hz, 4H, piperazine-H), 4.16 (br s, 4H, piperazine-H), 6.96 (d, J=8.4Hz, 1H, indoles 7-H), 7.00 (t, J=8.4Hz, 1H, phenyl 4 '-H), 7.07 (d, J=8.4Hz, 1H, phenyl 6 '-H), 7.16 (d, J=8.4Hz, 1H, phenyl 5 '-H), 7.19 (d, J=8.4Hz, 1H, phenyl 3 '-H), 7.40 (d, J=8.4Hz, 1H, indoles 6-H), 7.52 (s, 1H, indoles 4-H), 11.41 (s, 1H, indoles NH), 13.13 (s, 1H, NNH) .ESI-HRMS m/z:C
20h
21clN
5oS ([M+H]
+) calculated value: 414.1155, measured value: 414.1161.
Embodiment 16
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2,4-3,5-dimethylphenyl) piperazine-1-sulfo-formyl hydrazine (compound 16)
Yield: 62%, yellow solid, m.p.226.1-228.3 DEG C.
1h NMR (600MHz, DMSO-d
6) δ: 2.22 (s, 3H, CH
3), 2.27 (s, 3H, CH
3), 2.95 (t, J=4.8Hz, 4H, piperazine-H), 4.14 (br s, 4H, piperazine-H), 6.96 (m, 3H, phenyl 5 '-H, 6 '-H and indoles 7-H), 7.01 (s, 1H, phenyl 3 '-H), (7.40 dd, J=8.4,2.4Hz, 1H, indoles 6-H), 7.52 (d, 1H, J=2.4Hz, indoles 4-H), 11.40 (s, 1H, indoles NH), 13.12 (s, 1H, NNH). and ultimate analysis (C
21h
22clN
5oS0.2DMF) calculated value: C, 58.62; H, 5.33; N, 16.46. measured value: C, 58.36; H, 5.28; N, 16.26.
Embodiment 17
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-chloro-phenyl-) piperazine-1-sulfo-formyl hydrazine (compound 17)
Yield: 57%, yellow solid, m.p.260.1-260.8 DEG C.
1h NMR (600MHz, DMSO-d
6) δ: 3.37 (t, J=4.8Hz, 4H, piperazine-H), (4.16 t, J=4.8Hz, 4H, piperazine-H), 6.96 (d, J=8.4Hz, 1H, indoles 7-H), 6.97 (d, J=8.4Hz, 2H, phenyl 2 '-H, 6 '-H), 7.27 (d, J=8.4Hz, 2H, phenyl 3 '-H, 5 '-H), 7.40 (dd, 1H, J=8.4,1.8Hz, 1H, indoles 6-H), 7.52 (d, J=1.8Hz, 1H, indoles 4-H), 11.41 (s, 1H, indoles NH), (13.12 s, 1H, NNH). ultimate analysis (C
19h
17c
l2n
5oS) calculated value: C, 52.54; H, 3.95; N, 16.12. measured value: C, 52.38; H, 4.06; N, 16.02.
Embodiment 18
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-chloro-phenyl-) piperazine-1-sulfo-formyl hydrazine (compound 18)
Yield: 50%, yellow solid, m.p.236-238 DEG C.
1h NMR (600MHz, DMSO-d
6) δ: 3.15 (t, J=4.8Hz, 4H, piperazine-H), 4.17 (br s, 4H, piperazine-H), 6.96 (d, J=7.8Hz, 1H, indoles 7-H), 7.09 (t, J=7.8Hz, 1H, phenyl 4 '-H), 7.27 (d, J=7.8Hz, 1H, phenyl 6 '-H), 7.33 (t, J=7.8Hz, 1H, phenyl 5 '-H), 7.40 (dd, J=8.4, 1.8Hz, 1H, indoles 6-H), 7.45 (d, J=7.8Hz, 1H, phenyl 3 '-H), 7.54 (d, 1H, J=1.8Hz, indoles 4-H), 11.41 (s, 1H, indoles NH), 13.12 (s, 1H, NNH). ultimate analysis (C
19h
17cl
2n
5oS) calculated value: C, 52.54, H, 3.95, N, 16.12. measured value: C, 52.19, H, 3.95, N, 16.07.
Embodiment 19
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2,4 dichloro benzene base) piperazine-1-sulfo-formyl hydrazine (compound 19)
Yield: 65%, yellow solid, m.p.251.7-253.0 DEG C.
1h NMR (600MHz, DMSO-d
6) δ: 3.45 (t, J=4.8Hz, 4H, piperazine-H), 4.15 (t, J=4.8Hz, 4H, piperazine-H), 6.94 (dd, J=8.4, 2.4Hz, 1H, phenyl 5 '-H), 6.96 (d, J=8.4Hz, 1H, indoles 7-H), 7.15 (d, J=2.4Hz, 1H, phenyl 3 '-H), 7.40 (dd, J=8.4, 1.8Hz, 1H, indoles 6-H), 7.43 (d, J=8.4Hz, 1H, phenyl 6 '-H), 7.53 (d, J=1.8Hz, 1H, indoles 4-H), 11.40 (s, 1H, indoles NH), 13.12 (s, 1H, NNH). ultimate analysis (C
19h
16cl
3n
5oS) calculated value: C, 48.68, H, 3.44, N, 14.94. measured value: C, 48.56, H, 3.54, N, 15.09.
Embodiment 20
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-fluorophenyl) piperazine-1-sulfo-formyl hydrazine (compound 20)
Yield: 60%, yellow solid, m.p.233-234 DEG C.
1h NMR (600MHz, DMSO-d
6) δ: 3.29 (t, J=4.8Hz, 4H, piperazine-H), (4.16 t, J=4.8Hz, 4H, piperazine-H), 6.97 (d, J=8.4Hz, 1H, indoles 7-H), 7.00 (dd, J=8.4,4.8Hz, 2H, phenyl 2 '-H, 6 '-H), 7.09 (t, J=8.4Hz, 2H, phenyl 3 '-H, 5 '-H), 7.40 (dd, J=8.4,2.4Hz, 1H, indoles 6-H), 7.52 (d, J=2.4Hz, 1H, indoles 4-H), 11.41 (s, 1H, indoles NH), (13.12 s, 1H, NNH). ultimate analysis (C
19h
17clFN
5oS) calculated value: C, 54.61; H, 4.10; N, 16.76. measured value: C, 54.84; H, 4.30; N, 16.79.
Embodiment 21
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-fluorophenyl) piperazine-1-sulfo-formyl hydrazine (compound 21)
Yield: 63%, yellow solid, m.p.218-220 DEG C.
1h NMR (600MHz, DMSO-d
6) δ: 3.20 (t, J=4.8Hz, 4H, piperazine-H), 4.18 (br s, 4H, piperazine-H), 6.96 (d, J=8.4Hz, 1H, indoles 7-H), (7.02 m, 1H, phenyl-H), (7.09-7.19 m, 3H, phenyl-H), 7.40 (dd, J=8.4,1.8Hz, 1H, indoles 6-H), 7.54 (d, J=1.8Hz, 1H, indoles 4-H), 11.41 (s, 1H, indoles NH), (13.11 s, 1H, NNH). ultimate analysis (C
19h
17clFN
5oS0.3H
2o) calculated value: C, 53.91; H, 4.19; N, 16.54. measured value: C, 54.05; H, 4.12; N, 16.66.
Embodiment 22
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2,4 difluorobenzene base) piperazine-1-sulfo-formyl hydrazine (compound 22)
Yield: 67%, yellow solid, m.p.235.7-236.6 DEG C.
1h NMR (600MHz, DMSO-d
6) δ: 3.14 (t, J=4.8Hz, 4H, piperazine-H), 4.17 (br s, 4H, piperazine-H), 6.96 (d, J=8.4Hz, 1H, indoles 7-H), 7.03 (td, J=8.4,2.4Hz, 1H, phenyl 3 '-H), 7.15 (m, 1H, phenyl 6 '-H), 7.24 (m, 1H, phenyl 5 '-H), 7.40 (dd, 1H, J=8.4,1.8Hz, indoles 6-H), 7.54 (d, J=1.8Hz, 1H, indoles 4-H), 11.41 (s, 1H, indoles NH), (13.10 s, 1H, NNH). ultimate analysis (C
19h
16clF
2n
5oS0.18DMF) calculated value: C, 51.95; H, 3.89; N, 16.62. measured value: C, 51.60; H, 4.54; N, 16.27.
Embodiment 23
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-nitrophenyl) piperazine-1-sulfo-formyl hydrazine (compound 23)
Yield: 52%, yellow solid, m.p.237.3-239.4 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.76 (t, J=4.8Hz, 4H, piperazine-H), 4.21 (br s, 4H, piperazine-H), 6.96 (d, J=9Hz, 2H, indoles 7-H), 6.96 (d, J=9Hz, 1H, phenyl 2 '-H, 6 '-H), 7.39 (d, J=7.8Hz, 1H, indoles 6-H), 7.55 (s,, 1H, indoles 4-H), 8.10 (d, J=9Hz, 1H, phenyl 3 '-H, 5 '-H), 11.41 (s, 1H, indoles NH), (13.13 s, 1H, NNH) .ESI-HRMS m/z:C
19h
17clN
6o
3s ([M+H]
+) calculated value: 445.0850, measured value: 445.0859.
Embodiment 24
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-nitrophenyl) piperazine-1-sulfo-formyl hydrazine (compound 24)
Yield: 59%, yellow solid, m.p.236.2-237.8 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.26 (t, J=4.8Hz,, 4H, piperazine-H), 4.14 (br s, 4H, piperazine-H), 6.96 (d, J=8.4Hz, 1H, indoles 6-H), (7.15 t, J=7.8Hz, 1H, phenyl 4 '-H), 7.39 (m, 2H, phenyl 6 '-H, indoles 7-H), (7.54 s, 1H, indoles 4-H), 7.62 (t, J=7.8Hz, 1H, phenyl 5 '-H), 7.87 (d, J=7.8Hz, 1H, phenyl 3 '-H), 11.41 (s, 1H, indoles NH), (13.10 s, 1H, NNH). ultimate analysis (C
19h
17clN
6o
3s) calculated value: C, 51.29; H, 3.85; N, 18.89. measured value: C, 51.21; H, 4.01; N, 18.71.
Embodiment 25
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-trifluoromethyl) phenylpiperazine-1-sulfo-formyl hydrazine (compound 25)
Yield: 71%, yellow solid, m.p.238.3-239.3 DEG C (with DMF and water recrystallization).
1h NMR (600MHz, DMSO-d
6) δ: 3.56 (t, J=5.4Hz, 4H, piperazine-H), (4.19 t, J=5.4Hz, 4H, piperazine-H), 6.96 (d, J=8.4Hz, 1H, indoles 6-H), 7.05 (d, J=9.0Hz, 2H, phenyl 2 '-H, 6 '-H), 7.40 (dd, J=8.4, Hz, 1H, indoles 7-H), 7.53 (s, 1H, indoles 4-H), 7.54 (d, J=9.0Hz, 2H, phenyl 3 '-H, 5 '-H), 11.41 (s, 1H, indoles NH), (13.13 s, 1H, NNH) .ESI-HRMS m/z:C
20h
17clF
3n
5oS ([M+H]
+) calculated value: 468.0873, measured value: 468.0860.
Embodiment 26
Tablet formulation:
Preparation method is: supplementary material is crossed to 100 mesh sieves, then mix; Ethanol softwood processed with 90%, granulates, and whole grain, adds Magnesium Stearate to mix, compressing tablet and get final product.
Embodiment 27
Injection formula:
Preparation method:
N.F,USP MANNITOL is added in 1600mL water for injection to stirring and dissolving; Embodiment of the present invention compound is added to above-mentioned solution, stirring and dissolving; 4% disodium phosphate soln adjust pH is 4.15; Inject water to 2000mL, add gac, 50 DEG C of insulated and stirred 20min, filtering decarbonization; With the filtering with microporous membrane of 0.22 μ m, embedding.121 DEG C, 15min high-temperature heat sterilization.
Test example
Antiproliferative activity
Adopt mtt assay to measure the 503nhibiting concentration (IC of target compound to people's lung cancer A549, mammary cancer MCF-7, colorectal carcinoma HCT-116 cell proliferation
50), the results are shown in Table 1,2.With Sutent (Sunitinib) as positive control.
Antiproliferative activity (the IC of table 1. compound 1-12 to A549, MCF-7 and HCT-116 cell
50, μ M)
Antiproliferative activity (the IC of table 2. compound 13-25 to A549, MCF-7 and HCT-116 cell
50, μ M)
Result demonstration, the compound of example of the present invention has significant inhibition to people's lung cancer A549, mammary cancer MCF-7, colorectal carcinoma HCT-116 cell proliferation.
Claims (10)
1. suc as formula the piperazine sulfo-formyl hydrazine derivative of the indol-2-one shown in (I):
Wherein, R
4, R
5, R
6and R
7be selected from independently of one another hydrogen, halogen, nitro, hydroxyl, C1-C4 alkyl or C1-C4 alkoxyl group;
R
11, R
12, R
13, R
14and R
15be selected from independently of one another C1-C4 alkyl or the C1-C4 alkoxyl group of hydrogen, halogen, nitro, hydroxyl, C1-C4 alkyl, replacement;
Here, the C1-C4 alkyl of described replacement refers to that C1-C4 alkyl is replaced by more than one halogen, hydroxyl or nitro.
2. derivative as claimed in claim 1, wherein, R
4, R
5, R
6and R
7, or R
11, R
12, R
13, R
14and R
15described in halogen be selected from fluorine, chlorine, bromine or iodine.
3. derivative as claimed in claim 1, wherein, R
4, R
5, R
6and R
7be selected from independently of one another hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, methyl or methoxyl group.
4. derivative as claimed in claim 1, wherein, R
11, R
12, R
13, R
14and R
15be selected from independently of one another hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, trifluoromethyl or methoxyl group.
5. derivative as claimed in claim 1, formula (I) compound is the compound shown in formula (IV),
Wherein, R
4, R
5, R
6and R
7definition is suc as formula defined in (I) compound.
6. derivative as claimed in claim 1, formula (I) compound is the compound shown in formula (V),
Wherein, R
11, R
12, R
13, R
14and R
15definition is suc as formula defined in (I) compound.
7. derivative as claimed in claim 1, is selected from following compounds:
N '-(2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(5-methyl-2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(the bromo-2-oxindole-3-of 5-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(the bromo-2-oxindole-3-of 5,7-bis-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(the fluoro-2-oxindole-3-of 5-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(5-nitro-2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(the bromo-2-oxindole-3-of 4-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(4-chloro-2-oxo indoles-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(the bromo-2-oxindole-3-of 6-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(6-chloro-2-oxo indoles-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(5-methoxyl group-2-oxindole-3-subunit)-4-phenylpiperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-p-methoxy-phenyl) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-aminomethyl phenyl) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-aminomethyl phenyl) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2,4-3,5-dimethylphenyl) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-chloro-phenyl-) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-chloro-phenyl-) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2,4 dichloro benzene base) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-fluorophenyl) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-fluorophenyl) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2,4 difluorobenzene base) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-nitrophenyl) piperazine-1-sulfo-formyl hydrazine;
N '-(5-chloro-2-oxo indoles-3-subunit)-4-(2-nitrophenyl) piperazine-1-sulfo-formyl hydrazine;
Or N '-(5-chloro-2-oxo indoles-3-subunit)-4-(4-trifluoromethyl) phenyl) piperazine-1-sulfo-formyl hydrazine.
8. the preparation method of the piperazine sulfo-formyl hydrazine derivative of indol-2-one described in any one claim in claim 1 to 7, comprise that formula (II) compound reacts with formula (III) compound, thus the formula of obtaining (I) compound:
Here, each substituent definition cotype (I) compound of formula (II) compound and formula (III) compound, each the substituent definition of formula (I) compound is as defined in any one in claim 1-7.
9. one kind comprises in claim 1 to 7 medicinal compositions of the piperazine sulfo-formyl hydrazine derivative of indol-2-one described in any one claim.
In claim 1 to 7 described in any one claim the piperazine sulfo-formyl hydrazine derivative of indol-2-one in the application of preparing in cancer therapy drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210128476.4A CN102653521B (en) | 2012-04-27 | 2012-04-27 | Piperazine thiocarbohydrazide derivate of indole-2-ketone and preparation method and application of piperazine thiocarbohydrazide derivate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210128476.4A CN102653521B (en) | 2012-04-27 | 2012-04-27 | Piperazine thiocarbohydrazide derivate of indole-2-ketone and preparation method and application of piperazine thiocarbohydrazide derivate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102653521A CN102653521A (en) | 2012-09-05 |
| CN102653521B true CN102653521B (en) | 2014-08-06 |
Family
ID=46729267
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210128476.4A Expired - Fee Related CN102653521B (en) | 2012-04-27 | 2012-04-27 | Piperazine thiocarbohydrazide derivate of indole-2-ketone and preparation method and application of piperazine thiocarbohydrazide derivate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102653521B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311470B (en) * | 2014-09-10 | 2016-08-17 | 首都师范大学 | N-substituted indole-2-ketone-3-S-methyldi-thiocarbazate and its production and use |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1101039A (en) * | 1993-05-14 | 1995-04-05 | 第一制药株式会社 | Piperazine derivatives |
| CN101684119A (en) * | 2008-09-27 | 2010-03-31 | 中国科学院上海药物研究所 | 5,8-disubstituted-1,6-quinazoline-7-amidocarbonylation compound, preparing method, composite and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL114951A (en) * | 1995-08-15 | 1999-08-17 | Hadasit Med Res Service | Quinazolinone-containing pharmaceutical compositions for prevention of neovascularization |
| EP1255752B1 (en) * | 2000-02-15 | 2007-08-08 | Sugen, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
-
2012
- 2012-04-27 CN CN201210128476.4A patent/CN102653521B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1101039A (en) * | 1993-05-14 | 1995-04-05 | 第一制药株式会社 | Piperazine derivatives |
| CN101684119A (en) * | 2008-09-27 | 2010-03-31 | 中国科学院上海药物研究所 | 5,8-disubstituted-1,6-quinazoline-7-amidocarbonylation compound, preparing method, composite and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 刘彪等.舒尼替尼的合成.《中国医药工业杂志》.2007,第38卷(第8期),539-542. |
| 舒尼替尼的合成;刘彪等;《中国医药工业杂志》;20071231;第38卷(第8期);539-542 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102653521A (en) | 2012-09-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Eldehna et al. | Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents | |
| CN102382113B (en) | Comprise the solid form of the compound being used for the treatment of disease or disorder, its composition, and uses thereof | |
| JP6270713B2 (en) | 1- (Allylmethyl) quinazoline-2,4 (1H, 3H) -dione as a PARP inhibitor and uses thereof | |
| CN105492008B (en) | Compounds and compositions for inhibition of FASN | |
| CA2973247C (en) | 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof | |
| CN104513229A (en) | Quinazoline derivatives and preparation method thereof | |
| CN105143228A (en) | [1,2,4]triazol[4,3-a]pyridine derivate, preparation method therefor or medical application thereof | |
| CN101821255A (en) | 2-morpholin-4-yl-pyrimidines as PI3K inhibitors | |
| JP7323896B2 (en) | Casein kinase 1ε inhibitor, pharmaceutical composition and use thereof | |
| CN105722840A (en) | Fused quinoline compunds as PI3K, mTOR inhibitors | |
| CN106831725A (en) | The quinazoline compounds and its application of quinoline containing indoline and similar structures | |
| JP2022547294A (en) | 3,5-disubstituted pyrazole compounds as kinase inhibitors and their applications | |
| CN104277029B (en) | Acridine-1,2,3-triazoles compounds and its preparation method and application | |
| CN102108078B (en) | 1,4-substituted phthalazine compound and preparation method and applications thereof | |
| CN112321604A (en) | Macrocyclic JAK2 inhibitor and application thereof | |
| CN102653521B (en) | Piperazine thiocarbohydrazide derivate of indole-2-ketone and preparation method and application of piperazine thiocarbohydrazide derivate | |
| KR102030886B1 (en) | Novel imidazolyl pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient | |
| CN102321074B (en) | Indole ring-substituted pyrazole hydrazide derivative and preparation method and application thereof | |
| CN103864680B (en) | There is the 7-chloro-4-oxo-quinoline derivative of anti-tumor activity | |
| JP7036798B2 (en) | Quinazoline derivative salt crystals | |
| CA2982862A1 (en) | Preparation and use of kinase inhibitor | |
| CN109988110A (en) | 4- phenoxyquinolines and sulfonyl urea compound, the intermediate for synthesizing the compound and its preparation method and application | |
| CN101759654B (en) | 4-quinazolinone-6-methylamino dithiocarbamate as well as medical composition and application thereof | |
| CN107513040A (en) | Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine | |
| EP3896059B1 (en) | Pan-kit kinase inhibitor having quinoline structure and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140806 Termination date: 20170427 |