CN102898402B - The indole ketone compound that the minaline ester that a kind of Benzisoelenazolone is modified replaces and application thereof - Google Patents
The indole ketone compound that the minaline ester that a kind of Benzisoelenazolone is modified replaces and application thereof Download PDFInfo
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- 0 CCC(C(*C)CC=C1)=C1O Chemical compound CCC(C(*C)CC=C1)=C1O 0.000 description 2
- GONPFFPCDZHBNR-YHYXMXQVSA-N O/N=C\C(Nc1cc(Cl)ccc1)=O Chemical compound O/N=C\C(Nc1cc(Cl)ccc1)=O GONPFFPCDZHBNR-YHYXMXQVSA-N 0.000 description 2
- BOCUEGPAFFXFEK-UHFFFAOYSA-N CCCNC(C)=C Chemical compound CCCNC(C)=C BOCUEGPAFFXFEK-UHFFFAOYSA-N 0.000 description 1
- GDISALBEIGGPER-UHFFFAOYSA-N CCOC(c1c(C)[nH]c(C=O)c1C)=O Chemical compound CCOC(c1c(C)[nH]c(C=O)c1C)=O GDISALBEIGGPER-UHFFFAOYSA-N 0.000 description 1
- YCIHQDVIAISDPS-UHFFFAOYSA-N Cc1c(C=O)[nH]c(C)c1C(O)=O Chemical compound Cc1c(C=O)[nH]c(C)c1C(O)=O YCIHQDVIAISDPS-UHFFFAOYSA-N 0.000 description 1
- RPGKFFKUTVJVPY-UHFFFAOYSA-N Cc1ccc(C(O)=O)c(N)c1 Chemical compound Cc1ccc(C(O)=O)c(N)c1 RPGKFFKUTVJVPY-UHFFFAOYSA-N 0.000 description 1
- RPGKFFKUTVJVPY-UHFFFAOYSA-O Cc1ccc(C(O)=O)c([NH3+])c1 Chemical compound Cc1ccc(C(O)=O)c([NH3+])c1 RPGKFFKUTVJVPY-UHFFFAOYSA-O 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N Nc(cc1)ccc1F Chemical compound Nc(cc1)ccc1F KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N Nc1cc(Cl)ccc1 Chemical compound Nc1cc(Cl)ccc1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- HPTQNIZSFRLFIU-YHYXMXQVSA-N O/N=C\C(Nc(cc1)ccc1Cl)=O Chemical compound O/N=C\C(Nc(cc1)ccc1Cl)=O HPTQNIZSFRLFIU-YHYXMXQVSA-N 0.000 description 1
- DXSBFTGUEOWLSD-YHYXMXQVSA-N O/N=C\C(Nc(cc1)ccc1F)=O Chemical compound O/N=C\C(Nc(cc1)ccc1F)=O DXSBFTGUEOWLSD-YHYXMXQVSA-N 0.000 description 1
- RVXLBLSGEPQBIO-UHFFFAOYSA-N O=C(c(ccc(Cl)c1)c1N1)C1=O Chemical compound O=C(c(ccc(Cl)c1)c1N1)C1=O RVXLBLSGEPQBIO-UHFFFAOYSA-N 0.000 description 1
- XHDJYQWGFIBCEP-UHFFFAOYSA-N O=C(c1cc(Cl)ccc1N1)C1=O Chemical compound O=C(c1cc(Cl)ccc1N1)C1=O XHDJYQWGFIBCEP-UHFFFAOYSA-N 0.000 description 1
- DJHWLHNAWVBDNX-UHFFFAOYSA-N OC(c(ccc(Cl)c1)c1SSc(cc(cc1)Cl)c1C(O)=O)=O Chemical compound OC(c(ccc(Cl)c1)c1SSc(cc(cc1)Cl)c1C(O)=O)=O DJHWLHNAWVBDNX-UHFFFAOYSA-N 0.000 description 1
- FTJQLPXJRKHATE-UHFFFAOYSA-N Oc1c(CC(N2)=O)c2ccc1 Chemical compound Oc1c(CC(N2)=O)c2ccc1 FTJQLPXJRKHATE-UHFFFAOYSA-N 0.000 description 1
Abstract
The application relies on and requires the right of priority of the Chinese patent application 201110105248.0 that on April 26th, 2011 submits to, at this by reference to being incorporated to by its full content herein.The present invention relates to indole ketone compound and the application thereof of the minaline ester replacement that Benzisoelenazolone is modified.The indole ketone compound that the minaline ester that Benzisoelenazolone of the present invention is modified replaces is as shown in general formula I.2-indole ketone compound of the present invention has excellent anti-tumor activity, can be widely used in and prepare antitumor drug.
Description
Technical field
The present invention relates to a kind of 2-indole ketone derivative and its preparation method and application, belong to chemical field.
Background technology
For a long time, oncotherapy is a global difficult problem always, is also the challenge that institute of Pharmaceutical Research faces.All the time, conventional clinically cancer chemotherapeutic drug mainly cytotoxic drug.This kind anti-cancer drugs non-specifically blocks cell fission thus causes necrocytosis, while killing tumour cell, also destroys human normal cell, therefore has the shortcoming such as poor selectivity, strong, the easy generation resistance of toxic side effect.In recent years, along with the develop rapidly of oncobiology and related discipline, people recognize that the essence of cell carcinogenesis is that intracellular signal transduction pathway is lacked of proper care the cell infinite multiplication caused gradually.The focus of research and development transfers to the antitumor drug of new generation for the biological target involved by signal transduction pathway from conventional cell cytotoxic drug.Tyrosylprotein kinase is the key protein matter of intracellular signal transduction pathway, develops closely related with the generation of tumour, thus becomes the important target spot of current Development of New Generation antitumor drug.
Tyrosylprotein kinase is the enzyme of one group of catalytic proteins tyrosine residues phosphorylation, and the phosphate group on energy catalysis ATP is transferred on many important tyrosine residuess, makes its residue phosphorylation.Play a very important role in intracellular signal transduction, it participates in Normocellular adjustment, signal transmission and growth, also closely related with the propagation of tumour cell, differentiation, migration and apoptosis.It is disorderly that the abnormal activation of Tyrosylprotein kinase or overexpression will cause cell proliferation to regulate, and finally lead oncogenic development.Therefore, take Tyrosylprotein kinase as the forward position that exploitation that target spot carries out antitumor drug has become international research.
Sutent (sunitinib, Sutent) is a kind of multiple receptor tyrosine kinases inhibitor developed by Pfizer.Within 2006, obtain FDA approval listing, be used for the treatment for the treatment of with imatinib failure or not tolerant gastrointestinal stromal tumor and advanced renal cell carcinoma.In vitro study shows: the Tyrosylprotein kinase that Sutent can effectively suppress comprises PDGFR-α and PDGFR-β, VEGFR-1, VEGFR-2 and VEGFR-3, C-Kit class FMS Tyrosylprotein kinase-3 (FLT3), colony-stimulating factor 1 acceptor (CSF-1R) and Glial cell derived neurotrophic factor receptor α1 (RET).The propagation of the l cell (NIH-3T3) of the human umbilical vein endothelial cell (HUVECs) that VEGF can be suppressed to induce and PDGF induction.
Sutent shows the effect of Tumor suppression growth and propagation in a lot of cell strain and animal-transplanted tumor model.In the research to HT229 and Colo205 colorectal carcinoma, NCI2H226 nonsmall-cell lung cancer, WM226624 melanoma, 78620 renal cell carcinomas, A431 epidermoid carcinoma transplanted tumor animal model, daily once can make tumor regression, and not produce resistance phenomenon.
The toxicity of Sutent is mainly manifested in following several respects:
(1) dermal toxicity
Dermal toxicity, comprises hand-foot skin reaction (HFSR) and fash and xerosis cutis.HFSR betides the treatment initial stage usually, and generally serious when 2 weeks after medication, after this can alleviate gradually, pain generally even disappears to having significantly to alleviate when 6th ~ 7 weeks in treatment, and along with the prolongation for the treatment of time, HFSR incidence also decreases.The feature of HFSR be insensitive, paresthesia, erythema, oedema, hyperkeratosis, xerosis cutis or chap, harden sample blister, decortication etc.The HFSR incidence of Sutent is 20%
(2) gastrointestinal toxicity
Gastrointestinal symptom may betide any time section of pharmacological agent, comprises diarrhoea, Nausea and vomiting, abdominal distension, pain etc.The diarrhoea that medicine is correlated with often shows as the just rare of number of times increase, instead of watery stool, through suitably processing and can effectively controlling.III phase clinical study results shows, and mild diarrhea incidence is that 53%, 3 ~ 4 grades of Incidence of Diarrheas are respectively 5%.
(3) hematotoxicity
The large multipair blood of anti-angiogenic medicaments based on anti-vegf and hepatic and renal function affect less, but the incidence of Sutent hematotoxicity is 60% ~ 70%, 3 ~ 4 grades of neutrophilic granulocytopenia Sutents are 12%, 3 ~ 4 grades of thrombocytopenia Sutents is 8%.
(4) dysthyroid
The result of study display of U.S. Wong etc., the patient that 89 examples take Sutent treatment receives thyroid function test (TFT).Can accept in the patient assessed in 40 examples, begin treatment is after 5 months, and 21 routine patient (53%) treatments period thyrotropin (TSH) levels raise (meta TSH is 21.4Mu/L).
Rini etc. treat the clinical studies show of 73 routine advanced renal cell cancer patients to Sutent, patient's thyroid function check result of 85% is abnormal, wherein the patient of 84% occurs that first subtracts symptom and (or) sign, 17 routine patients accept substitutional treatment with thyroid hormone, and 9 routine patients symptomatic are improved.
(6) Cardiovascular Toxicity
Wu etc. point out, Sutent mortality of hypertension is 22.5%, and hypertension occurrence risk adds 3.9 times compared with placebo.
The research of American scholar Chu etc. shows, occur together in cardiopathic 75 routine gastrointestinal stromal tumors (GISTs) (GIST) patients in the nothing accepting small molecules, Mutiple Targets TKI antitumor drug Sutent is treated, there is Main adverse cardiovascular event in 8 examples (11%), wherein 6 examples (8%) develop into NYHA3 ~ 4 grade congestive heart failure after meta treats 33.6 weeks.Use in 36 routine patients of granted dosage Sutent and have 10 examples (28%) and 7 examples (19%) LVEF to decrease beyond 10% and 15% respectively.
In February, 2008, Stanford Univ USA investigator reports in ASCO urogenital summit forum, accept in 48 routine patients of Sutent treatment in this College Integrated Cancer center, 12.5% (6/48 example) develops into Symptomatic 3 ~ 4 grades of heart failure, and this result of study is higher than report previously.
Benzisoelenazolone representation compound Ethaselen is a kind of target thioredoxin reductase, organic selenium compounds for antineoplaston, carry out clinical study now, the clinical I phase completed shows, Ethaselen toxicity is low, compared with Sutent toxic manifestations, show good tolerance.Early-stage Study shows (Zhou Haiyan, Peking University Ph.D. Dissertation, 2008), and Benzisoelenazolone structure, can initiative recognition target enzyme active center the targeting embodied tumour and related tissue as the main pharmacodynamics group of this medicine.The internal metabolism research display of medicine, Ethaselen far above Plasma, shows good tumor-targeting in the concentration of tumor tissues.
The present invention be directed to Sutent and introduce Benzisoelenazolone structure in C-4 ' position, obtain a class novel, there is the 3-pyrroles-2-indolone structure of Benzisoelenazolone structure, according to Benzisoelenazolone medicine (Ethaselen) feature, this compounds can target thioredoxin reductase, and there is tumor-targeting, and thioredoxin reductase activity is the important elements of tumor growth, therefore the 3-pyrroles-2-indolone structure of Benzisoelenazolone structure will have Mutiple Targets feature, this class formation is relative to the targeting that improve medicine for Buddhist nun's structure simultaneously, therefore the effect of efficacy enhancing and toxicity reducing can be reached.
Summary of the invention
The object of the invention is to provide a kind of 2-indole ketone derivative based on above theory, and measure its anti-tumor activity by experiment.
The present invention is achieved through the following technical solutions:
The compound of following structure,
General formula I
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9be respectively H, C
1-4alkyl group, C
1-4alkoxy base or halogen.
Wherein, described alkyl group is methyl, ethyl, propyl group or normal-butyl, preferable methyl and ethyl, more preferably methyl.
Wherein, R
1, R
2, R
3, R
4h, C respectively
1-4alkyl group, C
1-4alkoxy base or halogen.
Wherein, described alkyl group is methyl or ethyl, preferable methyl; Described alkoxy base is methoxy or ethoxy, preferred methoxyl group; Described halogen is F, Cl.
Wherein, R
1h, Cl, R
2h, F, methyl or Cl, methoxyl group R
3h, F or Cl; R
4h, methyl or Cl, R
5h, F, R
6h, methyl, F or Cl, R
7h, F or Cl, R
8h.
Described compound is:
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-4-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-4-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-7-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-7-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate preparation,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-4-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[(Z)-4 chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-7-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[(Z)-7 methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-4-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
The preparation of O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5,6-bis-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-methoxyl group-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[(Z)-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5, fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of 6-bis-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
The preparation of O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[(Z)-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5, fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of 6-bis-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate.
Object again of the present invention is to provide a kind of method preparing the above compound, specifically comprises the steps:
(1) compound 1 is prepared
Compound 1
To in the mixed aqueous solution of sodium sulfate and Chloral Hydrate, make
mixed aqueous solution and oxammonium hydrochloride reacting by heating with concentrated hydrochloric acid, obtain white solid; Make gained solid and strong sulfuric acid response in a heated condition, obtain yellow solid; Gained yellow solid is refluxed in hydrazine hydrate, obtains compound 1;
(2) compound 2 is prepared
compound 2
Make under Sodium Nitrite exists
react under ice bath with hydrochloric acid, obtain villaumite, gained villaumite and sodium diselenide are reacted to reaction mixture in alkalescence, gained mixture hcl acidifying is obtained solid, then gained solid is made to reflux in sulfur oxychloride and DMF, obtain residue, react residue obtained with thanomin in methylene dichloride, obtain compound 2;
(3) compound 3 is prepared
compound 3
Methyl aceto acetate and Glacial acetic acid react under Sodium Nitrite and zinc powder exist, and obtain 3,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate, by 3,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate is dissolved in ethanol, reflux in potassium hydroxide aqueous solution, by gained mixture hcl acidifying, obtain white solid, by the melting of gained white solid, use dichloromethane solution, filtration again, obtain garnet crystal, make gained garnet crystal at DMF, POCl
3reflux with in the mixed solution of methylene dichloride, obtain yellow solid, under aqueous sodium hydroxide solution exists, gained yellow solid is refluxed in methyl alcohol, obtain compound 3;
(4) methylene dichloride is as solvent, under EDC and DMAP exists, compound 2 and compound 3 is reacted, obtains intermediate;
(5) under Pyrrolidine exists, the intermediate that step (4) is obtained and compound 1 reflux in dehydrated alcohol, obtain compound of Formula I.
The present invention demonstrates the compounds of this invention by activity experiment and has excellent anti-tumor activity, can be effective to prepare antitumor drug.
Embodiment
Below in conjunction with embodiment, the invention will be further described, it should be understood that these embodiments only for the object of illustration, never limit the scope of the invention.
Below the synthetic route of the compounds of this invention:
The synthesis of compound 1:
Compound 1
The synthesis of compound 2:
2Se+4NaOH+Na
2S
2O
4→Na
2Se
2+2Na
2SO
3+2H
2O
The synthesis of compound 3 and the synthesis of compound of Formula I:
Preparation and the anti-tumor activity of compound of Formula I are described for 37 kinds of compounds below.These 37 kinds of compounds are as shown in table 1.
Table 1
The preparation of embodiment 1N-phenyl-2-oximinoacetamide
Anhydrous sodium sulphate (35g at 40 DEG C, 246mmol) add Chloral Hydrate (5g in batches, after in water (90ml) solution 30.5mmol), instillation aniline (2.57g, 27.6mmol) He 36% concentrated hydrochloric acid (3ml, water (20ml) solution 36mmol), instill oxammonium hydrochloride (6.1g again, water (27.5ml) solution 88.4mmol), drip finish be warming up to 85 DEG C reaction 2h, be cooled to 50 DEG C, suction filtration, cold water washing, the white fluffy solid (3.53g, 78%) that filter cake is dried.
The preparation of embodiment 2 isatin
98% vitriol oil (46ml) is heated to 60 DEG C, add N-phenyl-2-oximinoacetamide (1.8g under stirring in batches, 11mmol), add in 0.5h, finish and be warming up to 80 DEG C of reaction 15min, to be cooled to after room temperature in impouring 250g trash ice, stirring at room temperature 0.5h, suction filtration, frozen water washs, obtain safran solid (1.2g, 75%).
1HNMR(400MHz，DMSO-d
6)：6.89(d，1H)，7.04(m，1H)，7.48(d，1H)，7.57(m，1H)，11.02(s，br，1H)
The preparation of embodiment 31,3-Indolin-2-one
Take isatin (0.8g, 5.4mmol), first will wherein add in 80% hydrazine hydrate (10ml) by 0.3g, be heated to 100 DEG C of backflows, add in remaining 0.5g, 2h in batches and finish, be warming up to 110 DEG C and continue backflow 4h, be cooled to room temperature, drip 36% concentrated hydrochloric acid and be adjusted to pH=3, continue under room temperature to stir 12h, separate out solid, suction filtration, washes with water, obtain brown solid (0.44g, 61%).
1HNMR(400MHz，DMSO-d
6)：3.44(s，2H)，6.79(d，1H)，6.90(t，1H)，7.13(d，1H)，7.18(d，1H)，10.33(s，br，1H)
The preparation of embodiment 4N-(4-fluorophenyl)-2-oximinoacetamide
Obtain this compound in the same manner as example 1.
The preparation of embodiment 55-fluoro indigo red
Obtain this compound in the same way as in example 2.
1HNMR(400MHz，DMSO-d
6)：6.90(dd，1H)，7.38(dd，1H)，7.43(m，1H)，11.02(s，br，1H)
The preparation of fluoro-1, the 3-Indolin-2-one of embodiment 65-
This compound is obtained in the mode identical with embodiment 3.
1HNMR(400MHz，DMSO-d
6)：3.47(s，2H)，6.76(m，1H)，6.97(m，1H)，7.08(m，1H)，10.35(s，br，1H)
The preparation of embodiment 7N-(4-chloro-phenyl-)-2-oximinoacetamide
Obtain this compound in the same manner as example 1.
The preparation of embodiment 85-chlorisatide
Obtain this compound in the same way as in example 2.
1HNMR(400MHz，DMSO-d
6)：6.91(d，1H)，7.53(d，1H)，7.59(dd，1H)，11.11(s，br，1H)
The preparation of chloro-1, the 3-Indolin-2-one of embodiment 95-
This compound is obtained in the mode identical with embodiment 3.
1HNMR(400MHz，DMSO-d
6)：3.48(s，2H)，6.78(d，1H)，7.19(dd，1H)，7.24(d，1H)，10.46(s，br，1H)
The preparation of embodiment 10N-(4-aminomethyl phenyl)-2-oximinoacetamide
Obtain this compound in the same manner as example 1.
The preparation of embodiment 115-methylisatin
Obtain this compound in the same way as in example 2.
1HNMR(400MHz，DMSO-d
6)：2.23(s，3H)，6.78(d，1H)，7.30(s，1H)，7.38(d，1H)，10.92(s，br，1H)
Embodiment 125-methyl isophthalic acid, the preparation of 3-Indolin-2-one
This compound is obtained in the mode identical with embodiment 3.
1HNMR(400MHz，DMSO-d
6)：2.21(s，3H)，3.39(s，2H)，6.67(d，1H)，6.94(d，1H)，6.99(s，1H)，10.23(s，br，1H)
The preparation of embodiment 13N-(3-fluorophenyl)-2-oximinoacetamide
Obtain this compound in the same manner as example 1.
The preparation of embodiment 146-fluoro indigo red
Obtain this compound in the same way as in example 2.
1HNMR(400MHz，DMSO-d
6)：6.72(m，1H)，6.85(m，1H)，7.59(m，1H)，11.17(s，br，1H)
The preparation of fluoro-1, the 3-Indolin-2-one of embodiment 156-
This compound is obtained in the mode identical with embodiment 3.
1HNMR(400MHz，DMSO-d
6)：3.42(s，2H)，6.60(m，1H)，6.69(m，1H)，7.18(m，1H)，10.48(s，br，1H)
The preparation of embodiment 16N-(3-chloro-phenyl-)-2-oximinoacetamide
Obtain this compound in the same manner as example 1.
(400MHz，DMSO-d
6)：6.90(d，1H)，7.09(dd，1H)，7.50(d，1H)，11.16(s，br，1H)
The preparation of embodiment 176-chlorisatide
Obtain the mixture 1.6g of 4-chlorisatide and 6-chlorisatide in the same way as in example 2.Mixture is dissolved in 60ml10%NaOH solution, heating for dissolving in 60 DEG C of oil baths.Filter to obtain clarification dark red solution.Drip 18ml glacial acetic acid, pH=5, stir, suction filtration.Drip concentrated hydrochloric acid 13ml in filtrate, pH=2, stir, suction filtration, dry red solid.
1HNMR(400MHz，DMSO-d
6)：6.90(d，1H)，7.09(dd，1H)，7.50(d，1H)，11.16(s，br，1H)
The preparation of chloro-1, the 3-Indolin-2-one of embodiment 186-
This compound is obtained in the mode identical with embodiment 3.
1HNMR(400MHz，DMSO-d
6)：3.46(s，2H)，6.81(d，1H)，6.96(dd，1H)，7.20(s，1H)，10.49(s，br，1H)
The preparation of embodiment 19N-(3,4-difluorophenyl)-2-oximinoacetamide
Obtain this compound in the same manner as example 1.
The preparation of embodiment 205,6-bis-fluoro indigo red
Obtain this compound in the same way as in example 2.
1HNMR(400MHz，DMSO-d
6)：6.97(dd，1H)，7.70(t，1H)，11.13(s，1H)
The preparation of fluoro-1, the 3-Indolin-2-one of embodiment 215,6-bis-
This compound is obtained in the mode identical with embodiment 3.
1HNMR(400MHz，DMSO-d
6)：3.45(s，2H)，6.79(dd，1H)，7.30(t，1H)，10.44(s，br，1H)
The preparation of embodiment 225-methoxyl group-1,3-Indolin-2-one
This compound is obtained in the mode identical with embodiment 3.
1HNMR(400MHz，DMSO-d
6)：3.41(s，2H)，3.67(s，3H)，6.70(m，2H)，6.84(s，1H)，10.16(s，br，1H)
The preparation of embodiment 234-chlorisatide
Obtain the mixture 1.6g of 4-chlorisatide and 6-chlorisatide in the same way as in example 2.Mixture is dissolved in 60ml10%NaOH solution, heating for dissolving in 60 DEG C of oil baths.Filter to obtain clarification dark red solution.Drip 18ml glacial acetic acid, pH=5, stir, suction filtration.Dry red solid.
The preparation of chloro-1, the 3-Indolin-2-one of embodiment 244-
This compound is obtained in the mode identical with embodiment 3.
1HNMR(400MHz，DMSO-d
6)：3.50(s，2H)，6.78(d，1H)，6.96(dd，1H)，7.20(s，1H)，10.59(s，br，1H)
The preparation of embodiment 25N-(3-chloro-phenyl-)-2-oximinoacetamide
Obtain this compound in the same manner as example 1.
The preparation of embodiment 262-chlorisatide
Obtain this compound in the same way as in example 2.
The preparation of chloro-1, the 3-Indolin-2-one of embodiment 277-
This compound is obtained in the mode identical with embodiment 3.
1HNMR(400MHz，DMSO-d
6)：3.59(s，2H)，6.94(t，1H)，7.17(d，1H)，7.22(d，1H)，10.78(s，br，1H)
The preparation of embodiment 28N-(7-methylphenyl)-2-oximinoacetamide
Obtain this compound in the same manner as example 1.
The preparation of embodiment 292-methylisatin
Obtain this compound in the same way as in example 2.
The preparation of chloro-1, the 3-Indolin-2-one of embodiment 307-
This compound is obtained in the mode identical with embodiment 3.
1HNMR(400MHz，DMSO-d
6)：2.19(s，3H)，3.46(s，2H)，6.83(t，1H)，6.97(d，1H)，7.01(d，1H)，10.40(s，br，1H)
Embodiment 312, the two benzoic preparation of 2 '-two selenizing
2Se+4NaOH+Na
2S
2O
4→Na
2Se
2+2Na
2SO
3+2H
2O
1) anthranilic acid (14.0g) and 1: 1 hydrochloric acid (40ml) are uniformly mixed under ice bath, make < 5 DEG C, slowly instill the solution of the water (20ml) of Sodium Nitrite (9.0g) wherein, drip off and continue reaction 2h, obtain chlorination 2-phenylformic acid diazonium salt.Product is not purified is directly used in next step.
2) add selenium powder (8.8g) and sodium hydroxide (4.4g) in 60ml water, slowly take a policy under stirring powder (8.8g), 50 DEG C of reaction 2h.Obtain sodium diselenide solution, not purified be directly used in next step reaction.
3) solution of chlorination 2-phenylformic acid diazonium salt step 1 obtained under stirring is added drop-wise in the sodium diselenide solution that step 2 obtains, and mixture continues to stir 2h until the nitrogen produced is drained.Litmus paper proves solution alkaline.Reaction mixture hcl acidifying, filtering-depositing solid, washes in rearmounted moisture eliminator dry, obtains product (20.0g, yield 90%).
1HNMR(400MHz，DMSO-d
6)：7.34(t，2H)，7.46(t，2H)，7.67(d，2H)，8.02(d，2H)，13.69(s，br，2H)
The preparation of embodiment 322-selenium chloro-benzoyl chloride
2, two phenylformic acid (the 40.0g of 2 '-two selenizing, 100mmol), sulfur oxychloride (200ml) and DMF (0.15ml, 1.8mmol) stirring and refluxing 3h, revolve and steam the unnecessary thionyl chloride of removing, residue sherwood oil recrystallization, obtains yellow needles (48.5g, 90%).
The preparation of embodiment 332-hydroxyethyl-[1,2-benzisoxa selenazoles-3 (2H)-one]
Thanomin (1.6ml) is dissolved in methylene dichloride (15ml) solution, slowly instill the methylene dichloride (15ml) of 2-selenium chloro-benzoyl chloride (2.7g) wherein, room temperature reaction 2h, suction filtration, obtain white solid (2.2g, 85%).
1HNMR(400MHz，DMSO-d
6)：3.61(q，2H)，3.78(t，2H)，5.08(t，1H)，7.38(m，1H)，7.57(m，1H)，7.80(dd，1H)，8.01(d，1H)
Embodiment 344,4 '-two fluoro-2, the two benzoic preparation of 2 '-two selenizing
2Se+4NaOH+Na
2S
2O
4→Na
2Se
2+2Na
2SO
3+2H
2O
This compound is obtained in the mode identical with embodiment 31.
1HNMR(400MHz，DMSO-d
6)：7.23(m，2H)，7.40(dd，2H)，8.11(m，2H)，13.93(s，br，2H)
The preparation of the chloro-4-fluorobenzoyl chloride of embodiment 352-selenium
This compound is obtained in the mode identical with embodiment 32.
Embodiment 362-hydroxyethyl-[6-fluorine 1,2-benzisoxa selenazoles-3 (2H)-one]
This compound is obtained in the mode identical with embodiment 33.
1HNMR(400MHz，DMSO-d
6)：3.60(q，2H)，3.77(t，2H)，5.13(t，1H)，7.24(m，1H)，7.81(m，2H)
Embodiment 375,5 '-two fluoro-2, the two benzoic preparation of 2 '-two selenizing
2Se+4NaOH+Na
2S
2O
4→Na
2Se
2+2Na
2SO
3+2H
2O
This compound is obtained in the mode identical with embodiment 31.
1HNMR(400MHz，DMSO-d
6)：2.30(s，3H)，7.43(m，2H)，7.66(m，2H)，7.79(dd，2H)，13.50(s，br，2H)
The preparation of the chloro-5-fluorobenzoyl chloride of embodiment 382-selenium
This compound is obtained in the mode identical with embodiment 32.
The preparation of embodiment 392-hydroxyethyl-[5-fluorine 1,2-benzisoxa selenazoles-3 (2H)-one]
This compound is obtained in the mode identical with embodiment 33.
1HNMR(400MHz，DMSO-d
6)：2.69(s，3H)，3.61(q，2H)，3.78(t，2H)，5.12(t，1H)，7.51(m，2H)，8.04(m，1H)
Embodiment 405,5 '-two chloro-2, the two benzoic preparation of 2 '-two selenizing
2Se+4NaOH+Na
2S
2O
4→Na
2Se
2+2Na
2SO
3+2H
2O
This compound is obtained in the mode identical with embodiment 31.
1HNMR(400MHz，DMSO-d
6)：7.59(dd，2H)，7.64(d，2H)，7.99(d，2H)，14.16(s，br，2H)
The preparation of the chloro-5-chloro-benzoyl chloride of embodiment 412-selenium
This compound is obtained in the mode identical with embodiment 32.
The preparation of embodiment 422-hydroxyethyl-[5-chlorine 1,2-benzisoxa selenazoles-3 (2H)-one]
This compound is obtained in the mode identical with embodiment 33.
1HNMR(400MHz，DMSO-d
6)：3.61(q，2H)，3.78(t，2H)，5.11(t，1H)，7.63(dd，1H)，7.75(d，1H)，8.03(d，1H)
Embodiment 435,5 '-two chloro-2, the two benzoic preparation of 2 '-two selenizing
2Se+4NaOH+Na
2S
2O
4→Na
2Se
2+2Na
2SO
3+2H
2O
This compound is obtained in the mode identical with embodiment 31.
1HNMR(400MHz，DMSO-d
6)：7.24(dd，2H)，7.45(d，2H)，7.56(d，2H)，13.87(s，br，2H)
The preparation of the chloro-5-chloro-benzoyl chloride of embodiment 442-selenium
This compound is obtained in the mode identical with embodiment 32.
The preparation of embodiment 452-hydroxyethyl-[5-chlorine 1,2-benzisoxa selenazoles-3 (2H)-one]
This compound is obtained in the mode identical with embodiment 33.
1HNMR(400MHz，DMSO-d
6)：3.61(q，2H)，3.76(t，2H)，5.14(t，1H)，7.15(t，1H)，7.56(d，1H)，7.85(d，1H)
Embodiment 464,4 '-two chloro-2, the two benzoic preparation of 2 '-two selenizing
This compound is obtained in the mode identical with embodiment 31.
1HNMR(400MHz，DMSO-d
6)：7.44(dd，2H)，7.60(d，2H)，8.02(d，2H)，14.01(s，br，2H)
The preparation of the chloro-4-chloro-benzoyl chloride of embodiment 472-selenium
This compound is obtained in the mode identical with embodiment 32.
Embodiment 482-hydroxyethyl-[6-chlorine 1,2-benzisoxa selenazoles-3 (2H)-one]
This compound is obtained in the mode identical with embodiment 33.
1HNMR(400MHz，DMSO-d
6)：3.61(t，2H)，3.78(t，2H)，5.13(t，1H)，7.43(dd，1H)，7.77(d，1H)，8.07(d，1H)
The preparation of embodiment 493,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate
Methyl aceto acetate (15ml, 0.12mol) under ice bath stirs, drip Sodium Nitrite (4.06g with Glacial acetic acid (30ml), water (6ml) solution 0.06mol), drip in 15min and finish, ice bath reaction 2.5h, slowly add zinc powder (7.7g under stirring in batches, 0.12mol), finish in backflow 1h, reaction solution impouring 200ml frozen water and separate out faint yellow solid, suction filtration, filter cake frozen water washs, dehydrated alcohol recrystallization, dries to obtain white solid (8.6g, 61%).
1HNMR(400MHz，DMSO-d
6)：1.26(q，6H)，2.39(s，3H)，2.44(s，3H)，4.19(m，4H)，11.79(s，br，1H)
The preparation of embodiment 503,5-dimethyl-1H-pyrroles-4-ethoxycarbonyl-2-carboxylic acid
3,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate (8.0g, 0.033mol) be dissolved in ethanol (108ml), add water (28ml) solution of potassium hydroxide (2.28g, 0.041mol), backflow 2.5h, is cooled to room temperature, is evaporated to about 40ml, in impouring frozen water (80ml), add 10% hydrochloric acid and be adjusted to pH=4, suction filtration, filter cake washes with water, dry to obtain white solid (6.5g, 92%).
1HNMR(400MHz，DMSO-d
6)：1.25(t，3H)，2.37(s，3H)，2.43(s，3H)，4.15(q，2H)，11.71(s，br，1H)，12.33(s，br，1H)
The preparation of embodiment 512,4-dimethyl-1H-pyrroles-3-carboxylic acid, ethyl ester
3,5-dimethyl-1H-pyrroles-4-ethoxycarbonyl-2-carboxylic acid (9.5g, 0.045mol) is heated to molten state reaction 1.5h, is cooled to room temperature, dissolves with methylene dichloride, filter, filtrate anhydrous sodium sulfate drying, concentrated.Pillar layer separation, with sherwood oil: ethyl acetate=10: 1 (V/V) wash-out, obtains garnet crystal (4.0g, 53%).
1HNMR(400MHz，DMSO-d
6)：1.23(t，3H)，2.09(s，3H)，2.34(s，3H)，4.11(q，2H)，6.36(s，1H)，10.83(s，br，1H)
The preparation of embodiment 522,4-dimethyl-5-formyl radical-1H-pyrroles-3-carboxylic acid, ethyl ester
POCl is dripped in DMF (1.0ml)
3(1.88ml) methylene dichloride (4ml) solution, ice-water bath cooling temperature control is in 5 DEG C, drip to finish and stir 30min, drip 2,4-dimethyl-1H-pyrroles-3-carboxylic acid, ethyl ester (2.0g, methylene dichloride (5ml) solution 12mmol), drips Bi Huiliu 1.5h, is evaporated to dry.Add water (27ml) solution of sodium hydroxide (3.1g), return stirring 0.5h, is cooled to room temperature, and filter, filter cake washes with water, obtains yellow-brown solid (2.25g, 97%).Ethyl alcohol recrystallization, obtains white crystal (1.97g, 84%).
1HNMR(400MHz，DMSO-d
6)：1.26(t，3H)，2.40(s，3H)，2.44(s，3H)，4.17(q，2H)，9.60(s，1H)，12.15(s，br，1H)
The preparation of embodiment 532,4-dimethyl-5-formyl radical-1H-pyrroles-3-formic acid
2; 4-dimethyl-5-formyl radical-1H-pyrroles-3-carboxylic acid, ethyl ester (0.9g; water (8ml) solution of sodium hydroxide (1.0g) is added in methyl alcohol (5ml) solution 4.6mmol); reflux 4h; be cooled to room temperature hypsokinesis in frozen water (16ml); add methylene dichloride (10ml); stratification; collect water layer 10% hydrochloric acid and be adjusted to pH3; filter, filter cake cold water washing, dry; obtain light yellow solid 11 (0.71g, 92%).
1HNMR(400MHz，DMSO-d
6)：2.42(s，3H)，2.52(s，3H)，9.61(s，1H)，12.09(s，br，2H)。
The preparation of embodiment 54O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-2,4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
2, 4-dimethyl-5-formyl radical-1H-pyrroles-3-formic acid (334mg, 2mmol) be dissolved in methylene dichloride (20ml), add EDC (760mg successively, 4mmol), DMAP (293mg, 2.4mmol), 2-hydroxyethyl-[1, 2-benzisoxa selenazoles-3 (2H)-one] (486mg, 2mmol), room temperature reaction 36h, impouring water (60ml) afterwards, extract with methylene dichloride (3 × 20ml), anhydrous sodium sulfate drying, filter, decompression is spin-dried for, column chromatography (methylene dichloride: methyl alcohol=70: 1) be separated to obtain sterling (365mg, 47%).
1HNMR(400MHz，DMSO-d
6)：2.37(s，3H)，2.41(s，3H)，4.08(t，2H)，4.39(t，2H)，7.39(t，1H)，7.58(t，1H)，7.80(d，1H)，8.03(d，1H)，9.59(s，1H)，12.16(s，br，1H)
The preparation of embodiment 55O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-2,4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 54.
1HNMR(400MHz，DMSO-d
6)：2.37(s，3H)，2.41(s，3H)，4.07(t，2H)，4.39(t，2H)，7.25(m，1H)，7.81(m，2H)，9.59(s，1H)，12.16(s，br，1H)
The preparation of embodiment 56O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-2,4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 54.
1HNMR(400MHz，DMSO-d
6)：2.40(s，3H)，2.45(s，3H)，4.06(t，2H)，4.40(t，2H)，7.17(t，1H)，7.58(d，1H)，7.85(d，1H)，9.59(s，1H)，12.16(s，br，1H)
The preparation of embodiment 57O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-2,4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 54.
1HNMR(400MHz，DMSO-d
6)：2.36(s，3H)，2.39(s，3H)，4.08(t，2H)，4.39(t，2H)，7.61(d，1H)，7.74(s，1H)，8.01(d，1H)，9.57(s，1H)，12.14(s，br，1H)
The preparation of embodiment 58O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-2,4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 54.
1HNMR(400MHz，DMSO-d
6)：2.36(s，6H)，2.39(s，3H)，4.08(t，2H)，4.39(t，2H)，7.44(d，1H)，7.65(s，1H)，7.89(d，1H)，9.57(s，1H)，12.14(s，br，1H)
The preparation of embodiment 59O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-2,4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 54.
1HNMR(400MHz，DMSO-d
6)：2.36(s，3H)，2.40(s，3H)，4.07(t，2H)，4.39(t，2H)，7.45(dd，1H)，7.78(d，1H)，8.04(d，1H)，9.59(s，1H)，12.17(s，br，1H)
Embodiment 60O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-4-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[2-(1; 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-2; 4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate (94mg; 0.24mmol) with 4-chloro-1; 3-Indolin-2-one (41mg; 0.24mmol) be dissolved in dehydrated alcohol (10ml), instill 5 Pyrrolidines, backflow 5h.Room temperature to be chilled to, suction filtration, filter cake dehydrated alcohol is washed, dry, obtains yellow solid (102mg, 84%).
1HNMR(400MHz，DMSO-d
6)：2.44(s，3H)，2.49(s，3H)，4.12(t，2H)，4.44(t，2H)，6.89(d，1H)，7.04(d，1H)，7.15(t，1H)，7.43(t，1H)，7.61(t，1H)，7.84(d，1H)，8.03(d，1H)，8.31(s，1H)11.23(s，br，1H)，13.83(s，br，1H)
MS(ES
+)calcdforC
25H
20ClN
3O
4Se
1(MNa
+)，564.02；found，564.06.
Embodiment 61O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.25(s，3H)，2.49(s，3H)，2.52(s，3H)4.13(t，2H)，4.43(t，2H)，6.91(m，1H)，6.97(m，1H)，7.30(t，1H)，7.40(t，1H)，7.63(s，2H)，7.69(m，1H)，8.03(d，1H)，10.97(s，br，1H)，13.94(s，br，1H)
MS(ES
+)calcdforC
26H
23N
3O
4Se
1(MNa
+)，544.08；found，544.14.
Embodiment 62O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-4 chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.53(s，3H)，2.52(s，3H)，3.66(t，2H)，4.36(t，2H)，6.89(d，1H)，7.03(dd，1H)，7.14(d，1H)，7.22(d，1H)，7.39(m，2H)，7.87(m，1H)，8.31(s，1H)，12.89(s，br，1H)，13.87(s，br，1H)
MS(ES
+)calcdforC
25H
19ClFN
3O
4Se
1(MnNa
+)，582.01；found，582.15.
Embodiment 63O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.49(s，3H)，4.11(t，2H)，4.42(t，2H)，6.68(m，1H)，6.80(d，1H)，7.40(d，1H)，7.58(t，1H)，7.76(s，1H)，7.84(m，2H)，7.93(d，1H)，11.38(s，br，1H)，13.83(s，br，1H)
MS(ES
+)calcdforC
25H
19ClFN
3O
4Se
1(MNa
+)，582.01；found，582.09.
Embodiment 64O-[2-(5-methyl 1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.24(s，3H)，2.45(s，3H)，2.50(m，3H)，3.66(s，3H)，4.12(t，2H)，4.44(t，2H)，6.91(d，1H)，6.96(s，1H)，7.43(t，1H)，7.59(m，3H)，7.90(d，1H)，10.97(s，br，1H)，13.92(s，br，1H)
MS(ES
+)calcdforC
27H
25N
3O
4Se
1(MNa
+)，536.11；found，536.24.
Embodiment 65O-[2-(5-methyl 1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.40(s，3H)，2.46(m，6H)，4.11(t，2H)，4.43(t，2H)，7.01(t，1H)，7.20(d，1H)，7.44(d，1H)，7.66(d，1H)，7.72(s，1H)，7.80(d，1H)，7.88(d，1H)，11.36(s，br，1H)，13.81(s，br，1H)
MS(ES
+)calcdforC
26H
22ClN
3O
4Se
1(MH
+)，556.05；found，556.23.
Embodiment 66O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：1.21(m，3H)，2.08(s，3H)，2.40(s，6H)，4.11(t，2H)，4.43(t，2H)，6.91(d，1H)，7.06(d，1H)，7.17(m，1H)，7.44(d，1H)，7.66(s，1H)，7.88(d，1H)，8.35(s，1H)，11.27(s，br，1H)，13.85(s，br，1H)
MS(ES
+)calcdforC
26H
22FN
3O
4Se
1(MH
+)，540.08；found，540.16.
Embodiment 67O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-4-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：1.24(m，3H)2.43(s，3H)，2.49(s，3H)，4.11(t，2H)，4.41(t，2H)，6.90(d，1H)，7.06(t，1H)，7.15(t，1H)，7.48(dd，1H)，7.63(dd，1H)，7.88(d，1H)，8.3(s，1H)，11.25(s，br，1H)，13.85(s，br，1H)
MS(ES
+)calcdforC
26H
22ClN
3O
4Se
1(MH
+)，556.05；found，556.16.
Embodiment 68O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-6-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.40(s，3H)，2.44(m，6H)，4.11(t，2H)，4.42(t，2H)，6.70(d，1H)，6.82(t，1H)，7.43(d，1H)，7.63(m，2H)，7.85(m，2H)，11.09(s，br，1H)，13.73(s，br，1H)
MS(ES
+)calcdforC
26H
22F
1N
3O
4Se
1(MNa
+)，562.07；found，562.17.
Embodiment 69O-[2-(5-chlorine 1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-4-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.49(s，3H)，4.14(t，2H)，4.44(t，2H)，6.89(d，1H)，7.05(m，1H)，7.04(m，1H)，7.65(m，1H)，7.79(s，1H)，8.03(d，1H)，8.30(d，1H)，11.24(s，br，1H)，13.83(s，br，1H)
MS(ES
+)calcdforC
25H
19Cl
2N
3O
4Se
1(MH
+)，576.00；found，576.21.
Embodiment 70O-[2-(5-chloro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.44(s，3H)，2.55(s，3H)，4.13(t，2H)，4.42(t，2H)，7.01(dd，1H)，7.19(t，1H)，7.27(m，1H)，7.65(dd，1H)，7.73(d，1H)，7.86(m，2H)，11.17(s，br，1H)，13.81(s，br，1H)
MS(ES
+)calcdforC
25H
19Cl
2N
3O
4Se
1(MH
+)，576.00；found，576.08.
Embodiment 71O-[2-(5-chloro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.49(s，3H)，4.13(t，2H)，4.45(t，2H)，6.85(m，1H)，6.95(m，1H)，7.66(m，1H)，7.75(s，1H)，7.81(m，2H)，8.04(d，1H)，10.95(s，br，1H)，13.94(s，br，1H)
MS(ES
+)calcdforC
25H
19F
1Cl
1N
3O
4Se
1(MH
+)，560.03；found，560.14.
Embodiment 72O-[2-(5-chloro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl] preparation of-5-[(Z)-7-methyl-2-oxo-3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：1.24(m，3H)，2.43(s，3H)，2.49(s，3H)，4.13(t，2H)，4.43(t，2H)，6.91(m，1H)，6.97(d，1H)，7.65(m，3H)，7.80(s，1H)，8.05(d，1H)，10.97(s，br，1H)，13.95(s，br，1H)
MS(ES
+)calcdforC
26H
22Cl
1N
3O
4Se
1(MH
+)，556.05；found，556.16.
Embodiment 73O-[2-(4-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.48(s，3H)，2.49(s，3H)，4.09(dd，2H)，4.40(dd，2H)，6.85(dd，1H)，6.94(m，1H)，7.18(m，1H)，7.49(m，1H)，7.57(m，1H)，7.74(dd，1H)，7.85(d，1H)，10.95(d，br，1H)，13.91(d，br，1H)
MS(ES
+)calcdforC
25H
19F
2N
3O
4Se
1(MH
+)，544.06；found，544.14.
Embodiment 74O-[2-(4-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-4-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2 ,-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.42(s，3H)，2.48(s，3H)，4.08(t，2H)，4.42(t，2H)，6.89(d，1H)，7.04(t，1H)，7.16(m，2H)，7.58(dd，1H)，7.85(d，1H)，8.28(dd，1H)，11.25(s，br，1H)，13.85(s，br，1H)
MS(ESI
+)calcdforC
25H
19F
1Cl
1N
3O
4Se
1(MH
+)，560.03；found，560.14.
Embodiment 75O-[2-(4-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-6-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.48(s，3H)，2.52(s，3H)，3.68(t，2H)，4.40(t，2H)，6.70(d，1H)，6.81(t，1H)，7.18(t，1H)，7.38(m，1H)，7.49(d，1H)，7.63(s，1H)，7.83(m，1H)，11.08(s，br，1H)，13.70(s，br，1H)
MS(ES
+)calcdforC
25H
19F
2N
3O
4Se
1(MNa
+)，566.04；found，566.15.
Embodiment 76O-[2-(4-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.50(s，3H)，3.67(s，3H)，4.11(t，2H)，4.44(t，2H)，6.91(dd，1H)，6.97(t，1H)，7.18(dd，1H)，7.43(m，1H)，7.62(m，2H)，7.87(d，1H)，10.96(s，br，1H)，13.92(s，br，1H)
MS(ES
+)calcdforC
26H
22F
1N
3O
4Se
1(MNa
+)，562.07；found，562.17.
Embodiment 77O-[2-(4-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-6-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.48(s，3H)，2.53(s，3H)，3.68(t，2H)，4.36(t，2H)，6.89(s，1H)，7.03(d，1H)，7.18(t，1H)，7.38(dd，1H)，7.49(d，1H)，7.69(s，1H)，7.83(d，1H)，11.07(s，br，1H)，13.76(s，br，1H)
MS(ES
+)calcdforC
25H
19Cl
1F
1N
3O
4Se
1(MH
+)，560.03；found，560.21.
The preparation of embodiment 78O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.44(s，3H)，2.49(s，3H)，4.11(t，2H)，4.42(t，2H)，6.87(d，1H)，6.98(t，1H)，7.13(t，1H)，7.40(t，1H)，7.59(t，1H)，7.65(s，1H)，7.80(t，2H)，8.01(d，1H)，10.94(s，br，1H)，13.90(s，br，1H)
HRMS(ESI
+)calcdforC
25H
22N
3O
4Se
1(MH
+)，508.07717；found，508.07817.
Embodiment 79O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.45(s，3H)，2.49(s，3H)，4.11(t，2H)，4.43(t，2H)，6.83(m，1H)，6.92(m，1H)，7.40(t，1H)，7.59(t，1H)，7.72(s，1H)，7.76(m，1H)，7.82(d，1H)，8.01(d，1H)，10.90(s，br，1H)，13.90(s，br，1H)
HRMS(ESI
+)calcdforC
25H
21F
1N
3O
4Se
1(MH
+)，526.06774；found，526.06868.
Embodiment 80O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.45(s，3H)，2.48(s，3H)，4.11(t，2H)，4.43(t，2H)，6.85(d，1H)，7.14(dd，1H)，7.40(t，1H)，7.59(t，1H)，7.78(s，1H)，7.82(d，1H)，8.00(m，2H)，11.02(s，br，1H)，13.86(s，br，1H)
HRMS(ESI
+)calcdforC
25H
21Cl
1N
3O
4Se
1(MH
+)，542.03795；found，542.03860.
Embodiment 81O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.28(s，3H)，2.48(s，3H)，2.52(s，3H)，3.66(t，2H)，4.36(t，2H)，6.74(d，1H)，6.93(d，1H)，7.29(t，1H)，7.36(t，1H)，7.61(m，2H)，7.67(d，1H)，7.79(d，1H)，10.83(s，br，1H)，13.90(s，br，1H)
HRMS(ESI
+)calcdforC
26H
24N
3O
4Se
1(MH
+)，522.09283；found，522.09347.
Embodiment 82O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-6-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.49(s，3H)，4.11(t，2H)，4.42(t，2H)，6.68(m，1H)，6.80(m，1H)，7.40(t，1H)，7.58(t，1H)，7.63(s，1H)，7.82(m，2H)，8.01(d，1H)，11.06(s，br，1H)，13.71(s，br，1H)
HRMS(ESI
+)calcdforC
25H
21F
1N
3O
4Se
1(MH
+)，526.06703；found，526.06661.
Embodiment 83O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-6-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.45(s，3H)，2.50(s，3H)，4.12(t，2H)，4.44(t，2H)，6.89(d，1H)，7.04(dd，1H)，7.42(t，1H)，7.60(t，1H)，7.70(s，1H)，7.84(m，2H)，8.02(d，1H)，11.08(s，br，1H)，13.77(s，br，1H)
HRMS(ESI
+)calcdforC
25H
21Cl
1N
3O
4Se
1(MH
+)，542.03795；found，542.03923.
Embodiment 84O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5, fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of 6-bis-] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.49(s，3H)，4.11(t，2H)，4.43(t，2H)，6.86(m，1H)，7.40(t，1H)，7.59(t，1H)，7.69(s，1H)，7.82(d，1H)，8.00(m，2H)，11.01(s，br，1H)，13.74(s，br，1H)
HRMS(ESI
+)calcdforC
25H
20F
2N
3O
4Se
1(MH
+)，544.05832；found，544.05820.
Embodiment 85O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-methoxyl group-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.45(s，3H)，2.48(s，3H)，3.75(s，3H)，4.11(t，2H)，4.43(t，2H)，6.70(dd，1H)，6.76(d，1H)，7.40(t，1H)，7.50(d，1H)，7.59(m，1H)，7.67(s，1H)，7.82(d，1H)，8.00(d，1H)，10.74(s，br，1H)，13.99(s，br，1H)
HRMS(ESI
+)calcdforC
26H
24N
3O
5Se
1(MH
+)，538.08775；found，538.08839.
Embodiment 86O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.49(s，3H)，4.09(t，2H)，4.42(t，2H)，6.86(d，1H)，6.98(t，1H)，7.13(t，1H)，7.26(m，1H)，7.64(s，1H)，7.79(m，2H)，7.84(m，1H)，10.94(s，br，1H)，13.88(s，br，1H)
HRMS(ESI
+)calcdforC
25H
21F
1N
3O
4Se
1(MH
+)，526.06774；found，526.06878.
Embodiment 87O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.44(s，3H)，2.49(s，3H)，4.09(t，2H)，4.42(t，2H)，6.83(m，1H)，6.93(m，1H)，7.26(m，1H)，7.73(s，1H)，7.78(m，2H)，7.84(m，1H)，10.93(s，br，1H)，13.91(s，br，1H)
HRMS(ESI
+)calcdforC
25H
20F
2N
3O
4Se
1(MH
+)，544.05832；found，544.05765.
Embodiment 88O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-6-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.49(s，3H)，4.09(t，2H)，4.42(t，2H)，6.69(dd，1H)，6.80(m，1H)，7.26(m，1H)，7.64(s，1H)，7.78(dd，2H)，7.83(m，1H)，11.07(s，br，1H)，13.71(s，br，1H)
HRMS(ESI
+)calcdforC
25H
20F
2N
3O
4Se
1(MH
+)，544.05832；found，544.05807.
Embodiment 89O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-6-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.44(s，3H)，2.50(s，3H)，4.11(t，2H)，4.43(t，2H)，6.88(dd，1H)，7.03(dd，1H)，7.27(m，1H)，7.69(s，1H)，7.80(dd，1H)，7.85(m，2H)，11.07(s，br，1H)，13.76(s，br，1H)
HRMS(ESI
+)calcdforC
25H
20Cl
1F
1N
3O
4Se
1(MH
+)，560.02853；found，560.02724.
Embodiment 90O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5, fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of 6-bis-] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.49(s，3H)，4.09(t，2H)，4.42(t，2H)，6.86(m，1H)，7.26(m，1H)，7.69(s，1H)，7.78(dd，1H)，7.84(m，1H)，8.00(m，1H)，11.01(s，br，1H)，13.74(s，br，1H)
HRMS(ESI
+)calcdforC
25H
19F
3N
3O
4Se
1(MH
+)，562.04890；found，562.04769.
Embodiment 91O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.49(s，3H)，4.11(t，2H)，4.43(t，2H)，6.86(d，1H)，6.98(t，1H)，7.13(t，1H)，7.50(t，1H)，7.56(d，1H)，7.65(s，1H)，7.79(d，1H)，8.02(m，1H)，10.94(s，br，1H)，13.89(s，br，1H)
HRMS(ESI
+)calcdforC
25H
21F
1N
3O
4Se
1(MH
+)，526.06703；found，526.06631.
Embodiment 92O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.49(s，3H)，4.10(t，2H)，4.42(t，2H)，6.82(dd，1H)，6.93(m，1H)，7.50(m，1H)，7.56(dd，1H)，7.71(s，1H)，7.77(dd，1H)，8.03(dd，1H)，10.94(s，br，1H)，13.91(s，br，1H)
HRMS(ESI
+)calcdforC
25H
20F
2N
3O
4Se
1(MH
+)，544.05832；found，544.05717.
Embodiment 93O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-6-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.42(s，3H)，2.48(s，3H)，4.10(t，2H)，4.42(t，2H)，6.68(dd，1H)，6.80(t，1H)，7.50(m，1H)，7.56(dd，1H)，7.63(s，1H)，7.83(m，1H)，8.03(dd，1H)，11.06(s，br，1H)，13.71(s，br，1H)
HRMS(ESI
+)calcdforC
25H
20F
2N
3O
4Se
1(MH
+)，544.05761；found，544.05845.
Embodiment 94O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5, fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of 6-bis-] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.42(s，3H)，2.49(s，3H)，4.11(t，2H)，4.42(t，2H)，6.86(dd，1H)，7.50(m，1H)，7.56(dd，1H)，7.68(s，1H)，8.02(m，2H)，11.03(s，br，1H)，13.75(s，br，1H)
HRMS(ESI
+)calcdforC
25H
19F
3N
3O
4Se
1(MH
+)，562.04819；found，562.05031.
Embodiment 95O-[2-(6-chloro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-6-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
1HNMR(400MHz，DMSO-d
6)：2.43(s，3H)，2.50(s，3H)，4.11(t，2H)，4.44(t，2H)，6.70(dd，1H)，6.82(m，1H)，7.47(dd，1H)，7.65(s，1H)，7.83(m，2H)，8.06(d，1H)，11.08(s，br，1H)，13.72(s，br，1H)
HRMS(ESI
+)calcdforC
25H
20Cl
1F
1N
3O
4Se
1(MK
+)，597.98339；found，597.98387.
Embodiment 96O-[2-(5-chloro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-6-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical] preparation of-2,4-dimethyl-1H-pyrroles-3-manthanoate
This compound is obtained in the mode identical with embodiment 60.
The mensuration of the anti tumor activity in vitro of experimental example 37 kinds of compounds
Adopt mtt assay, measure these 37 kinds of compounds to the growth in vitro inhibit activities of Lovo, RKO, Mia-paca2, HpeG-2, acc-m, k562, Panc-1 cell.
Get the RKO being in logarithmic phase, Lovo, Mia-paca2HpeG-2, acc-m, k562, Panc-1 cell is inoculated in 96 orifice plates, and inoculum density is 4 × 10
4individual/ml, 180 μ l/ holes; After cell attachment, every hole adds the liquid of 20 μ l, makes medicine final concentration be respectively 0 μM, 1 μM, 5 μMs, 10 μMs, 20 μMs, 50 μMs, after effect 48h, adds the MTT solution (20 μ l/ hole) of 5mg/ml, puts into CO
2incubator is carefully abandoned supernatant, after residual liquid is air-dry, is added DMSO, 200 μ l/ holes, jolting 0.5-1h on shaking table after cultivating 3 ~ 4h, after dissolving completely to be crystallized, surveys absorbancy OD value in microplate reader 492nm place.The results are shown in Table 2.
Inhibitory rate of cell growth=(negative control OD value-dosing group OD value)/(negative control OD value-blank group OD value) × 100%
Table 2
The experimental result display of table 2, in Lovo clone, has the IC of 8 compounds (being numbered 19,24,27,28,29,30,31,36)
50be worth lower than contrast medicine or with to contrast medicine suitable; In RKO clone, there is the IC of 5 compounds (being numbered 27,29,30,31,36)
50be worth lower than contrast medicine or with to contrast medicine suitable; In Mia-paca2 clone, there is the IC of 8 compounds (being numbered 20,24,27,28,29,30,31,36)
50be worth lower than contrast medicine or with to contrast medicine suitable.Visible, the indole ketone compound that the minaline ester that this class Benzisoelenazolone is modified replaces shows good anti-tumor activity.
The foregoing is only preferred embodiment of the present invention, is only illustrative for the purpose of the present invention, and nonrestrictive.Those skilled in the art is understood, and can carry out many changes in the spirit and scope that the claims in the present invention limit to it, amendment, even equivalence, but all will fall within the scope of protection of the present invention.
Claims (8)
1. the compound of following structure,
Wherein, R
1, R
2, R
3, R
4h, C respectively
1-4alkyl group, C
1-4chain alkoxy group, C
1-4perfluorination alkyl group or perfluorination chain alkoxy group, NO
2, OH or halogen;
R
5, R
6, R
7, R
8be respectively H, C
1-4alkyl group, C
1-4chain alkoxy group, C
1-4acyloxy group, NO
2, OH or halogen.
2. compound according to claim 1, is characterized in that, described C
1-4alkyl group be methyl, ethyl or propyl group; Described C
1-4chain alkoxy group be methoxyl group, oxyethyl group or propoxy-.
3. compound according to claim 1, is characterized in that, perfluorination alkyl group is perfluoro-methyl, and perfluorination chain alkoxy group is perfluoromethoxy.
4. compound according to claim 1, is characterized in that, described halogen is F, Cl or Br.
5. compound according to claim 1, is characterized in that, R
1h, Cl, R
2h, F, methyl or Cl, methoxyl group R
3h, F or Cl; R
4h, methyl or Cl, R
5h, F, R
6h, methyl, F or Cl, R
7h, F or Cl, R
8h.
6. the compound according to any one of claim 1-5, is characterized in that, described compound is
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-4-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-4-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-7-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-7-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-4-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[(Z)-4 chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-7-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[(Z)-7 methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-4-]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 4-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5,6-bis-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-methoxyl group-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[(Z)-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[chloro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5, fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of 6-bis-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[(Z)-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-5-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(fluoro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5, fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of 6-bis-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 6-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(chloro-1,2-benzisoxa selenazoles-3 (2H)-one of 5-) base-ethyl]-5-[fluoro-1, the 2-dihydro-2-oxo--3H-indol-3-yl methylene radical of (Z)-6-]-2,4-dimethyl-1H-pyrroles-3-manthanoate.
7. prepare a method for compound according to any one of claim 1-6, it is characterized in that, comprise the steps:
(1) compound 1 is prepared
To in the mixed aqueous solution of sodium sulfate and Chloral Hydrate, make
mixed aqueous solution and oxammonium hydrochloride reacting by heating with concentrated hydrochloric acid, obtain white solid; Make gained solid and strong sulfuric acid response in a heated condition, obtain yellow solid; Gained yellow solid is refluxed in hydrazine hydrate, obtains compound 1;
(2) compound 2 is prepared
Make under Sodium Nitrite exists
react under ice bath with hydrochloric acid, obtain
make gained
react to reaction mixture with sodium diselenide to be alkalescence, gained mixture hcl acidifying to be obtained solid, then makes gained solid reflux in sulfur oxychloride and DMF, obtain residue, react residue obtained with thanomin in methylene dichloride, obtain compound 2;
(3) compound 3 is prepared
Methyl aceto acetate and Glacial acetic acid react under Sodium Nitrite and zinc powder exist, and obtain 3,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate, by 3,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate is dissolved in ethanol, reflux in potassium hydroxide aqueous solution, by gained mixture hcl acidifying, obtain white solid, by the melting of gained white solid, use dichloromethane solution, filtration again, obtain garnet crystal, make gained garnet crystal at DMF, POCl
3reflux with in the mixed solution of methylene dichloride, obtain yellow solid, under aqueous sodium hydroxide solution exists, gained yellow solid is refluxed in methyl alcohol, obtain compound 3;
(4) methylene dichloride is as solvent, under EDC and DMAP exists, compound 2 and compound 3 is reacted, obtains intermediate; (5) under Pyrrolidine exists, the intermediate that step (4) is obtained and compound 1 reflux in dehydrated alcohol, obtain compound of Formula I.
8. compound according to any one of claim 1-6 is preparing the application in antitumor drug.
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| CN113527301A (en) * | 2020-04-13 | 2021-10-22 | 凯熙医药（武汉）股份有限公司 | Tetrazine substituent-containing aromatic isoselenazole compound and synthetic method and application thereof |
| CN113616642B (en) * | 2020-05-06 | 2023-02-28 | 上海元熙医药科技有限公司 | Use of benzisoselenazole derivatives for preparing anti-coronavirus medicines |
| CN114137128A (en) * | 2021-12-15 | 2022-03-04 | 南京美新诺医药科技有限公司 | Method for detecting esselenoline from blood sample |
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| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| CN1511835A (en) * | 2002-12-27 | 2004-07-14 | 北京大学药学院 | Benzo-isoselenazole derivatives having anti inflammation, anti-tumor and anti-thrumbosis function and its use |
| CN101016319A (en) * | 2007-02-13 | 2007-08-15 | 中国海洋大学 | Benzoisoselenothiazolidone aminosugar derivative, preparing method and application therheof |
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