CN102807574B - New pyridine sulphur nitrogen seven-membered ring derivative as antitumor drug, and its preparation method and application - Google Patents

New pyridine sulphur nitrogen seven-membered ring derivative as antitumor drug, and its preparation method and application Download PDF

Info

Publication number
CN102807574B
CN102807574B CN201110141898.0A CN201110141898A CN102807574B CN 102807574 B CN102807574 B CN 102807574B CN 201110141898 A CN201110141898 A CN 201110141898A CN 102807574 B CN102807574 B CN 102807574B
Authority
CN
China
Prior art keywords
isosorbide
nitrae
benzimidazole thiophanate
sulfone
thiophanate nitrogen
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.)
Active
Application number
CN201110141898.0A
Other languages
Chinese (zh)
Other versions
CN102807574A (en
Inventor
柏旭
闫兵
项金宝
张秋
裴亚中
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CHANGCHUN DISCOVERY SCIENCES Ltd
Original Assignee
CHANGCHUN DISCOVERY SCIENCES Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by CHANGCHUN DISCOVERY SCIENCES Ltd filed Critical CHANGCHUN DISCOVERY SCIENCES Ltd
Priority to CN201110141898.0A priority Critical patent/CN102807574B/en
Priority to PCT/CN2012/075814 priority patent/WO2012163236A1/en
Publication of CN102807574A publication Critical patent/CN102807574A/en
Application granted granted Critical
Publication of CN102807574B publication Critical patent/CN102807574B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

General formula is the polysubstituted pyridine of I-1 and sulphur nitrogen seven-membered ring derivative has anti-tumor activity widely.This compounds reveals good restraining effect to multiple human tumour cell line's list in test cell line in vitro.They comprise human leukemic OP-1, human colon cancer cells's strain HT29, Human Lung Cancer cell strain H460, the kinds of tumor cells series such as the Human Lung Cancer cell strain H460TaxR of resistance to taxol and mankind mastopathy cell's strain MCF-7/Adr of adriamycin-resistant.This compounds can independently, or with other antitumor drugs effective constituent together, in a kind of pharmaceutics be mixed with auxiliary material described in pharmaceutics, said formulation is used for the treatment of various neoplastic conditions.I-1 is compound by having I-2 formula and R 7cOZ (Z=OH, halogen) condensation reoxidizes and obtains.

Description

New pyridine sulphur nitrogen seven-membered ring derivative as antitumor drug, and its preparation method and application
Technical field
The present invention relates to and can be used as a class new pyridine of cancer therapy drug and the low-molecular-weight compound of sulphur nitrogen seven-membered ring and composition thereof, and their preparation.The invention still further relates to treatment, alleviate and control the method for tumor disease, comprise the administering mode of tumour cell accretion inhibitor, separately or with the conbined usage of known therapies.The invention still further relates to and utilize the medicament prepared by these compounds and using dosage and treating the application in a series of disease such as tumor disease, cancer.These preparations also can use to reach result for the treatment of with other treatment method simultaneously.
Background technology
Malignant tumour is one of current harm humans the most serious healthy disease, and its lethality rate is only second to cardiovascular disorder, occupies the
Lung cancer is the malignant tumour that current mortality ratio ascensional range is maximum, mortality ratio is the highest, and the five year survival rate of patient only has 15%.Lung cancer is divided into small cell lung cancer and nonsmall-cell lung cancer, and wherein nonsmall-cell lung cancer (NSCLC) accounts for 85% (http://www.aacr.org/) of whole cases of lung cancer.The histological typing of non-small cell type lung cancer comprises squama cancer, gland cancer and large cell carcinoma.
Mammary cancer is one of modal malignant tumour of women, its sickness rate occupies the first place of female malignant in the world, and with annual 2% speed increase, mortality ratio accounts for 20% (the Giordano C of women because of mortality of malignant tumors total number of persons, Masi A, Pizzini A, Sansone A, Consalvi V, Chiaraluce R, Lucente G.Synthesis and activity of fibrillogenesispeptide inhibitors related to the 17-21beta-amyloid sequence.Eur J Med Chem 2009, 44:179-189) pathogenesis of breast carcinoma is normal relevant with heredity, between 40-60 year, women's sickness rate before and after climacteric is higher.
Colorectal carcinoma is common alimentary system malignant tumour, and its sickness rate has the trend of rising in recent years.Its radical surgery excision latter 5 years survival rates are about 50%.Postoperative recurrence and transfer are the major reasons of its death.The method of current treatment colorectal carcinoma is performed the operation as master and is aided with the complex therapy of chemotherapy, immunotherapy, Chinese medicine and other supportive treatment.Although excision is the Main Means for the treatment of of colon cancer, but local relapse after surgery alone is higher, and most of local recurrence occurs in pelvic cavity, and tumour invades rectum surrounding soft tissue, adopts operation thoroughly to excise.Pelvic cavity chemotherapy removes the effective ways uniquely can for selecting of these cancer cells deposition.
Acute lymphoblastic leukemia is the malignant tumour that in children, sickness rate is the highest.According to statistics, in developed country, the morbidity of children acute lymphoblastic leukaemia has 30-45 example every year up to every 1,1000,000 people.In addition, the survival rate of adult acute lymphoblastic leukemia is at present also lower than 40%.Chemotherapy accounts for critical role in acute lymphoblastic leukemia treatment.Bcr-Abl is the leukemic important molecule target for the treatment of (Baselga J, Aribas J.Treating cancer ' s kinase " addiction " .Nat.Med.2004,10,786-787).Bcr-Abl kinases block polymer is t (9; 22) (q34; Q11) fusion product of gene mutual transposition in hemopoietic stem cell karyomit(e), wherein Abl kinases keeps the conformation that is activated, thus makes it have lasting activity.This lasting Abl activity causes the vicious transformation (Ren R, Mechanism of BCR-ABL in the pathogenesis of chronicmyelogenous leukaemia.Nat.Rev.Cancer, 2005,5,172-183) of cell.Bcr-Abl kinase inhibitor for treating poor effect used at present, the difficult problem recurred after especially can not effectively solving leukemia treating.Imatinib mesylate (Gleevec) has gone on the market to be used for the treatment of the active drug of kinds cancer, and it can allosteric conformational complexing kinase whose with Abl, thus suppresses its tyrosine kinase activity, blocks the signal transduction of cell.But imatinib is bad to most of Patients With Acute Lymphoblastic Leukemia curative effect, even if the effective patient of begin treatment often also can be recurred in 12 months.Research shows, acute lymphoblastic leukemia relapse is because the transgenation of Bcr-Abl causes imatinib to reduce caused (Gorre ME to its knot and power, Ellwood-Yen K, ChiosisG, et al.Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation oramplification.Science, 2001,293,876-880).In addition, other two Bcr-Abl kinase inhibitor, dasatinib and nilotinib (s-generation Bcr-Abl kinase inhibitor) can treat the leukemia that Bcr-Abl causes effectively.But chemotherapy can cause resistance.Research shows that the resistance of cell to s-generation inhibitor is derived from the T315I sudden change of Bcr-Abl, causes medicine not have result for the treatment of to the leukemia cell suddenlyd change containing T315I.Up to the present, many because of Bcr-Abl gene fusion in carcinogenic patient just rear 5 years asymptomatic patient be 37% of patient's sum.Therefore, research and development novel B cr-Abl kinase inhibitor is badly in need of.
In a word, chemotherapy, as systemic treatment means, has operation, the irreplaceable critical role of radiotherapy in treating malignant tumor.The appearance of new chemotherapeutics in recent years greatly improves the prognosis of tumour patient, but the toxicity of chemotherapeutics (KaelinWG.TheConcept of Synthetic Lethality in the Context of Anticancer Therapy.Nat Rev Cancer 2005,5 (9), 689-98) and tumour cell to resistance (the Green DR of medicine, Evan GI.Amatter oflife and death.Cancer Cell2002,1 (1), 19-30.) two hang-ups of puzzlement chemotherapy are just being become.
Most chemotherapeutics, because can not distinguish normal cell and tumour cell, also can produce toxicity to the normal cell of division fast, show as the toxic side effect in treatment clinical course while killing tumor cell.In addition, the final cause of chemotherapy failure is the multidrug resistance (MDR) that produces multi-medicament of cancer cells normally, and it shows the resistance to the very different medicine of number of chemical structure.Numerous clinical data shows that the process LAN of the multidrug resistance of tumour and abc transport carrier is closely related.Abc transport carrier is called as MDR protein family (Gottesman M.M., Pastan I.Biochemistry of multidrug resistancemediated by the multidrug transporter.Annu.Rev.Biochem., 1993,63 (3): 385; Juliano R.L.andLing V.A surface glycoprotein modulating drug permeability in Chinese hamster ovary cellmutants.Biochem.Biophys Acta., 1976,455:152; Kimura Y., Matsuo M., Takahashi K., et al.ATPhydrolysis-dependent multidrug efflux transporter:MDR1/P-glycoprotein.Current DrugMetabolism, 2004,5:1).MDR-1 is the gene of most study in this family, the P glycoprotein (P-glycoprotein, P-gp) of its coding 170kDa.In mdr cell, MDR1 gene amplification causes P-gp overexpression, there is provided energy that Treated with Chemotherapeutic Drugs thing is pumped extracellular fast by ATP and the cytotoxic effect of antitumor drug reduced thus produces resistance (SaunaZ.E.and Ambudkar S.V.Evidence for a requirement for ATP hydrolysis at two distinct stepsdunng a single turnover of the catalytic cycle of human P-gp.Proc.Natl.Acad.Sci., 2000,97 (6): 2515).Research shows that P-gp is a kind of transmembrane glycoprotein, be made up of 1280 amino acid, whole molecule is made up of identical 2 monomers, each monomer has 6 cross-film districts and 1 ATP-binding site, cross-film district is conducive to substance transportation as membrane channel, ATP-binding site and its energy supply relevant (Ruefli A.A., Tainton K.M., Darcy P.K., et al.P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following fas ligation.Cell Death Differ., 2002, 9 (11): 1266).P-gp can utilize ATP be hydrolyzed release energy on one's own initiative by hydrophobic lipophilic drug transport to extracellular, cause drug concentration lower than casualty-producing concentrations; Intracellular drug also can be made to distribute again, cause drug accumulation in the irrelevant organoid of drug effect as in lysosome, reduce the drug level at action target spot position, thus cause resistance.P-gp is very little to the specificity of medicine, can transport the substrate that various structures is different, and therefore MDR cell can produce resistance by the medicine different with mechanism of action to many structures.Current discovery, Treated with Chemotherapeutic Drugs thing such as taxol, vincaleucoblastine, mitomycin, Dx and Etoposide are all substrates of P glycoprotein.
Research in recent years shows, P-gp is except having drug efflux function, the apoptosis of tumor cells that can also cysteine aspartase be suppressed specifically to rely on, postpone apoptosis cascade reaction (Bleiber G., May M., Suarez C., et al.MDR1 geneticpolymorphismdoes not modify either cell permissiveness or disease progresionbefore treatment.J.Inf.Dis., 2004,189:583; Chen B., Jing F., Lu X.L.et al.Effect of PKC Inhibitor on P-gpExpression and drug-resistance in MGC-803 Cells.Chinese Journal of Cancer, 2004,23 (4): 396; Gregory D.L., Tito F.and Susan E.B.The Role of ABC Transporters in Clinical Practice.TheOncologist, 2003,8:411).P-gp is wide expression (Haus C.M. in human normal tissue, Assaraf Y.G., Binyamin L., et al.Disruption of P-glycoprotein anticancer drug efflux activity by a smallrecombinantsingle-chain Fv antibody fragment tragment targeted to anextracellular epitope.Int.J.Cancer, 2004,109 (5): 750; Marzolini C., Paus E., Buclin T.et al.Polymophisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance.Clin.Phamacol.Ther., 2004,75 (1): 13), as epithelial cell, brain, testis, ovary, the adrenal capillary vessel of gi tract, liver, kidney, its function and may be detoxified relevant with the substance transportation of cell, is the basis of resisting adverse factor in spore process.When normal cell develops into malignant cell, still continue to express mdr1 gene, the tumour therefore deriving from these tissues clinically just has resistance to initial chemotherapy.
Research at present about the multidrug resistance reversing P-gp mediation is more, mainly contains several aspects such as concentrating on chemicals reverse, the reverse of MDR1 antisense oligonucleotide, ribozyme reverse.Modal is activity (the Wu H being stoped P-glycoprotein by P-glycoprotein inhibitors, Hait WN, Yang J-M.Small Interfering RNA-induced Suppression of MDR1 (P-Glycoprotein) Restores Sensitivity to Multidrug-resistant Cancer Cells.Cancer Res 2003,63 (7), 1515-1519; Matthes Huesker, Reversal of drug resistance of hepatocellular carcinoma cells byadenoviral delivery of anti-MDR1ribozymes.Hepatology 2002,36 (4), 874-884; Advani R, et al.A Phase I Trial of Doxorubicin, Paclitaxel, and Valspodar (PSC 833), a Modulator of MultidrugResistance.Clin Cancer Res 2001,7 (5), 1221-1229; Samuels BL, et al.Modulation of vinblastineresistance in metastatic renal cell carcinoma with cyclosporine A or tamoxifen:a cancer andleukemia group B study.Clin Cancer Res 1997,3 (11), 1977-1984; Ferry DR, Traunecker H, KerrDJ.Clinical trials of p-glycoprotein reversal in solid tumours.European Journal of Cancer 1996,32 (6), 1070-1081; Cucco C, Calabretta B.In Vitro and in Vivo Reversal ofMultidrug Resistance ina Human Leukemia-resistant Cell Line by mdr1 Antisense Oligodeoxynucleotides.Cancer Res.1996,56 (19), 4332-4337; Bouffard DY, et al.Oligonucleotide modulation of multidrug resistance.European Journal of Cancer 1996,32 (6), 1010-1018).Numerous research display, these inhibitor can not overcome the resistance of tumour to all medicines, as (Samuels BL, et al.Modulation of vinblastine resistance inmetastatic renal cell carcinoma with cyclosporine A or tamoxifen:a cancer and leukemia group Bstudy.Clin Cancer Res such as vincaleucoblastines.November 1，1997，3(11)，1977-1984；Gottesman MM，Fojo T，Bates SE.Multidrug resistance in cancer：role of ATP-dependent transporters.Nat Rev Cancer 2002，2(1)，48-58；Ferry DR，Traunecker H，Kerr DJ.Clinical trials of p-glycoprotein reversal in solidtumours.European Journal of Cancer 1996，32(6)，1070-1081)。And the simple P-gp that suppresses can suppress its normal physiological function, thus produces toxicity.Therefore, the method effectively solving resistance caused by P-gp high expression level is still lacked at present.But these medicines enter clinical after effect mostly barely satisfactory.Therefore, research and development effectively can kill and wound the resistant tumors cell of P-glycoprotein overexpression and the low new type anticancer medicine of toxicity is significant.
This project chooses the H460 of non-small cell lung cancer cell H460 and taxol resistance taxR, the breast cancer cell line MCF-7/ADR of Adriamycin resistant, Colon cancer cell line HT-29, acute leukemia cells system OP-1 is as tumour cell screening model, simultaneously with the people's normal fibroblast grown fast for contrast, screening toxicity is low, anticancer effect is good, and effectively can kill and wound the active compound of drug-resistant cell strain.
H460 taxRclone taxol carries out pressurization screening to non-small cell lung cancer cell H460 and obtains (Teraishi F, et al.P-Glycoprotein-Independent Apoptosis Induction by a Novel Synthetic Compound, MMPT [5-[(4-Methylphenyl) methylene]-2-(phenylamino)-4 (5H)-thiazolone] .J Pharmacol Exp Ther, 2005,314 (1), 355-362).H460 taxRcell transition express P-glycoprotein, thus has resistance to many known cancer therapy drugs.Such as, H460 taxRto the resistibility of taxol higher than H460 at least 80 times.Therefore, H460 is used taxRcell line selection quasi-medicated property small molecule libraries is the effective way finding novel overriding resistance thing.
MCF-7 is mankind mastopathy cell (the Philip J.Vickers multiple cancer therapy drug to resistance, et al, AMultidrug-Resistant MCF-7Human Breast Cancer Cell Line Which Exhibits Cross-Resistance toAntiestrogens and Hormone-Independent Tumor Growth in Vivo, Molecular Endocrinology, 1988,2 (10), 886-892).By contrast, MCF-7/ADR has higher resistance.It is 1000 times of (Wang F of MCF-7 cell to the resistibility of anticancer drugs, doxorubicin, et al, Doxorubicin-gallium-transferrin conjugate overcomesmultidrug resistance:evidence for drug accumulation in the nucleus of drug resistant MCF-7/ADRcells.Anticancer Res.2000,20 (2A), 799-808).Therefore, it is possible to suppress the antitumous effect that the compound of MCF-7/ADR cell enlargement can have.
HT-29 is mankind's secondary colon carcinoma cell line, and much research proves that it can be used for screening novel drugs against colon cancer.OP-1 is the mankind's Type B acute leukemia cells system containing Bcr-Abl kinases block polymer, and it can be used to screening quasi-medicated property micromolecular compound storehouse to research and develop Bcr-Abl kinase inhibitor.
Summary of the invention
The invention discloses the pyrido sulphur nitrogen seven-membered ring derivative that a class has anti-tumor activity.The pyrido sulphur nitrogen seven-membered ring derivative of series of novel has been prepared in the reactions such as the present invention, is substituted for starting raw material with 2-chlorine or the chloro-3-nitropyridine of 4-, nitroreduction, Guan Huan, oxidation, and these compounds have stronger anti-tumor activity.Present invention also offers the preparation method of this compounds and they separately, associating or prepare medicament with other treatment agents and be used for the treatment of kinds of tumors disease.
Therefore, according to an aspect of the present invention, the compounds had represented by general formula I-1 is provided:
And steric isomer, acceptable salt in tautomer, solvate, prodrug and its pharmacodynamics,
Wherein: n=0,1 or 2;
As X=N, Y=CR 8; Work as X=CR 8time, Y=N; Wherein R 8represent hydrogen, halogen group, cyano group, nitro, unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heterocyclic radical with replacing ,-OR 9,-NR 9r 10,-OC (O) R 9,-C (O) OR 9,-C (O) NR 9r 10,-NR 9c (O) R 10,-NR 9sO 2r 10,-SO 2nR 9r 10,-NR 9c (O) NR 10r 11,-NR 9c (NR 10) NR 11r 12, wherein R 9, R 10, R 11, and R 12independently selected from hydrogen, unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heterocyclic radical with replacing;
R 1, R 2, R 3, R 4, R 5, R 6and R 7independently selected from hydrogen, halogen group, cyano group, nitro, unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heterocyclic radical with replacing;-OR 13,-NR 13r 14,-OC (O) R 13,-C (O) OR 13,-C (O) NR 13r 14,-NR 13c (O) R 14,-NR 13sO 2r 14,-SO 2nR 13r 14,-NR 13c (O) NR 14r 15,-NR 13c (NR 14) NR 15r 16, wherein R 13, R 14, R 15, and R 16independently selected from hydrogen, unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heterocyclic radical with replacing; Wherein R 3and R 4together or R 4and R 5together or R 5and R 6together, optional ring system that is unsubstituted or that replace is formed respectively.
The application of the compound 2, represented with general formula I-1 as claimed in claim 1, is characterized in that having the effective ingredient of the antitumor drug suppressing human leukemic OP-1 growth.
The application of the compound 3, represented with general formula I-1 as claimed in claim 1, tool feature is the effective ingredient with the antitumor drug suppressing human colon cancer cells's strain HT29 growth.
The application of the compound 4, represented with general formula I-1 as claimed in claim 1, is characterized in that having the effective ingredient of the antitumor drug suppressing Human Lung Cancer cell strain H460 growth.
The application of the compound 5, represented with general formula I-1 as claimed in claim 1, is characterized in that having the effective ingredient of suppression to the antitumor drug that the Human Lung Cancer cell strain H460TaxR of taxol resistance increases.
The application of the compound 6, represented with general formula I-1 as claimed in claim 1, is characterized in that the effective ingredient of the antitumor drug with the mankind mastopathy cell's strain MCF-7/Adr growth suppressing Adriamycin resistant.
Part of compounds described herein can be used as the intermediate preparing other compounds of the present invention.
Compound of the present invention can prepare by following method:
N, X, Y, R, R 1, R 2, R 3, R 4, R 5, R 6, R 7definition is the same.
In some other embodiments, tumour cell accretion inhibitor can be selected from list I.
List I:
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(3-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-phenyl-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(4-fluorophenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(4-nitrophenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(4-aminomethyl phenyl)-9-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(4-aminomethyl phenyl)-10-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(4-p-methoxy-phenyl)-8-picoline is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(4-aminomethyl phenyl)-8-picoline is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-phenyl-8-picoline is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(4-fluorophenyl)-8-picoline is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(3-nitrophenyl)-8-picoline is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(furans-2-base)-8-picoline also [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(4-p-methoxy-phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(3-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(2-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-phenylpyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(4-fluorophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(4-trifluoromethyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(3-nitrophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(4-nitrophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(3-nitro-4-fluorophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(furans-2-base) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(4-aminomethyl phenyl)-8-fluorine pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-phenyl-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(3-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(3-nitrophenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
6-(4-nitrophenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
8-methyl isophthalic acid 0-(4-p-methoxy-phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
8-methyl isophthalic acid 0-phenylpyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also
8-methyl isophthalic acid 0-(4-nitrophenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen
8-methoxyl group-10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfoxide
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfoxide
6-phenylpyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfoxide
The chloro-10-of 8-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfoxide
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone
6-(4-aminomethyl phenyl)-9-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone
6-(4-aminomethyl phenyl)-10-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone
6-(4-aminomethyl phenyl)-8-picoline is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone
6-(4-p-methoxy-phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(3-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(2-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-phenylpyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone
6-(4-fluorophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(4-trifluoromethyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(furans-2-base) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(4-aminomethyl phenyl)-8-fluorine pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
In yet another aspect, present invention also offers the method that inhibition tumor cell increases.This method comprises the compound or its steric isomer, tautomer, solvate, prodrug or the pharmacy acceptable salt that a cell are exposed to described dosage, effectively can reduce speed and the quantity of tumour cell growth after these materials add.In certain embodiments, tumour cell increases the level at least 10%, at least 30%, at least 50% or at least 90% reduced.In some embodiments of the invention, this method also comprises and adds medication composition (being called composition A after this) described by this patent to cell.
In certain embodiments, compound of the present invention and composition A adopt oral administration.In other embodiments, compound of the present invention and composition A adopt intravenous injection, subcutaneous injection or inhalation.In the embodiment also had, compound of the present invention adopts oral, and composition A adopts intravenous injection, subcutaneous injection or inhalation.As selection, compound of the present invention can adopt intravenous injection, subcutaneous injection or inhalation, and composition A adopts oral administration.
In another aspect, the invention provides a kind of method, by steric isomer, tautomer, solvate, prodrug or the pharmacy acceptable salt of compound of the present invention or wherein any two or more and/or it, combine with one or more compositions A, give the effective dosage of patient that one needs treatment, to increase compared with composition A or to improve validity with being used alone.Wherein, composition A is selected from the reagent of effectively treatment tumor disease.In certain embodiments, validity raising can according to be used alone this Reagent evaluation and embody than the minimizing of one or more compositions A dosage in composition.
In treatment use, the drug regimen of composition A and inclusion compound of the present invention, with the formulation of any routine, in any conventional manner administration, can comprise any approach described herein.Therefore, route of administration to include but not limited in intravenously, intramuscular, subcutaneous, synovia, by inculcating, sublingual, through skin, mouth, local with pass through inhalation.Common administering mode is mouth, epidermis or intravenous administration.
In compound therapy, composition A and compound of the present invention can separate administrable, or with the administration simultaneously of the mode of the combination formula adding other compositions or adjuvant.These other compositions and adjuvant can strengthen the stability of inhibitor, the convenient pharmaceutical composition containing them administration, increase medicine solvability or dispersiveness, increase inhibit activities, assisting therapy is provided, or provide similar advantage.This kind of compound treatment utilizes the conventional treatment agent of lowest dose level usually, avoids when these medicines are as Side effect possible during monotherapy.The drug regimen of composition A and compound of the present invention can form single medicament with conventional treatment agent or other adjuvants.The composition A used and compound of the present invention, as salt, solvate, tautomer and/or prodrug and the mixture as single stereoisomers or steric isomer, can comprise racemic modification.
According to the present invention, the composition A that can combinationally use and the ratio of compound of the present invention are variable.Composition A and compound of the present invention also can the form of their solvates or hydrate exist.According to choosing of composition A and compound of the present invention, the part by weight that can use within the scope of the present invention can change according to the molecular weight of various compound and their different drug effects.Specific composition A and compound of the present invention are depended in the determination of part by weight, and also have in another of the present invention within the scope of art technology, provide a kind of method of Therapeutic cancer, this method comprises needs the effective dosage of the body of compound of the present invention or its pharmacy acceptable salt, solvate or steric isomer.
In specific embodiments more of the present invention, the method for Therapeutic cancer also comprises operative treatment, radiation cure, psychrotherapy, one or more anti-proliferative drugs or a kind of pharmaceutical composition.In the embodiment that some are such, anti-proliferative drugs is alkylide, platinum medicine, metabolic antagonist, Topoisomerase inhibitors, antitumor antibiotics, anti-fissuring agent, aromatase inhibitor, thymidylate synthetase inhibitor, DNA antagonist, Farnesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, inhibitors of metalloproteinase, nucleosides reductase inhibitor, endothelin A receptor antagonist, retinoic acid receptor agonist, immuno modulating agent, hormone or health hormone medicine, photodynamic agents, angiogenesis inhibitor or tyrosine kinase inhibitor.In some such embodiments, alkylide is that busulfan, procarbazine, ifosfamide, altretamine, hexamethylmelamine, estramustine phosphate, thiophene are for group, mustargen, dacarbazine, U-9889, lomustine, Temozolomide, endoxan, semustine or Chlorambucil.The example of platinum medicine comprises Spiroplatin, lobaplatin (Aeterna), four platinum, Satraplatin (JohnsonMatthey), ormaplatin, iproplatin, Miboplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, carboplatin.
In some embodiments of the invention, cancer is osteosarcoma, Kaposi's sarcoma, colorectal carcinoma, the cancer of the brain, the knurl (epithelioma) that epithelial cell causes, rodent cancer (basal cell carcinoma), gland cancer, gastrointestinal cancer, lip cancer, oral carcinoma, the esophageal carcinoma, carcinoma of small intestine, cancer of the stomach (stomach cancer), intestinal cancer (gastric cancer), colorectal carcinoma, liver cancer, bladder cancer, carcinoma of the pancreas, ovarian cancer, cervical cancer, lung cancer, mammary cancer, skin carcinoma, squamous cell cancer, rodent cancer (basal cell cancer), prostate cancer, renal cell carcinoma, leukemia, lymphoma, erythroblastoma, glioblastoma, neurospongioma, meningioma, astrocytoma, myoblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-lymphomas suddenly, or follicular lymphoma.In some such embodiments, cancer is acral lentiginous melanoma, actinic keratosis, gland cancer, adenoid cystic carcinoma, adenoma, sarcoadenoma, adenosquamous carcinoma, astrocytic tumor, bartholin gland carcinoma, rodent cancer (basal cellcarcinoma), bronchial gland carcinoma, capillary lymphan gioma, cancer, sarcocarcinoma, cavernoma, cholangiocarcinoma, chondrosarcoma, papilloma of choroid plexus/cancer, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymary, epithelioid, Ewing sarcoma, Fibrotic, FNH, gastrinoma, germinoma, glioblastoma, glucagonoma, hemangioreticuloma, hemangioendothelioma, hepatic hemangioma, adenoma of liver, adenoma of liver is sick, hepatocellular carcinoma, nesidioblastoma, intraepithelial neoplasia (cin), epithelium woods turns glucagonoma and becomes, vulva squamous cellular infiltration cancer, large cell carcinoma, leiomyosarcoma, element knurl, malignant melanoma, malignant mesothe, medulloblastoma, medullary substance mouth rind gall, melanoma, meninx, mesothelium, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, the smart gland cancer brief summary melanoma of god, oat cell carcinoma, oligodendroglial tumors, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pinealocyte, pituitary tumor, plasmoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, cancer eye, rhabdosarcoma, sarcomata, serous carcinoma, small cell carcinoma, soft tissue cancer, Somatostatin Secretion knurl, squamous cell carcinoma, squamous cell carcinoma, mesothelioma, superficial spreading melanoma, undifferentiated carcinoma, uveal, verrucous carcinoma, lipoma, well-differentiated carcinoma, or embryonal carcinosarcoma.In certain embodiments, cancer is leukemia, erythroblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkin lymphoma or follicular lymphoma.In certain embodiments, cancer is follicular lymphoma, acute myelogenous leukemia, multiple myeloma or non-Hodgkin lymphoma or follicular lymphoma.
In other embodiments, cancer is the cancer of the brain, glioblastoma, meningioma, brain astrocytoma, medulloblastoma, neuroblastoma or cancer eye.In the embodiment that some are such, cancer is neurospongioma or glioblastoma.
In other embodiments also had, cancer is osteosarcoma, Kaposi's sarcoma, chondrosarcoma, Ewing's sarcoma or myoblastoma.In the embodiment that some are such, cancer is osteosarcoma.
In certain embodiments, cancer is the transfer of mammary gland, lung, kidney or prostate cancer.In the embodiment that some are such, tumour is cancer bone metastasis.
Detailed Description Of The Invention
Term below runs through and applies to herein, be defined as follows.
General, when mentioning some element such as hydrogen or H, be intended to comprise all isotropic substances of this element.Such as, if R group is defined as comprising hydrogen or H, it also comprises deuterium and tritium, and therefore, isotope-labeled compound within the scope of the invention.
Say at large, term " replacement ", for an organic chemical groups (such as alkyl), has as given a definition: wherein one or more keys containing hydrogen atom are substituted by the key of not hydrogen atoms or unsubstituted carbon atom.Substituted radical also comprises one or more key be connected with carbon atom or hydrogen atom by one or more key be connected with heteroatoms, comprises double bond and triple bond, substitutes.Therefore, unless outside specifically defined, a group be substituted will containing one or more substituting group.In certain embodiments, a group be substituted, by 1,2,3,4,5, or 6 substituting groups replace.Substituent example comprises halogen (such as, F, Cl, Br, and I), hydroxyl, alkoxyl group, alkenyloxy, alkynyloxy group, aryloxy, aralkoxy, heterocyclic oxy group and heterocyclylalkoxy groups, carbonyl (oxo), carboxyl, ester, urethanes, oxime, azanol, alkoxylamine, mercaptan, sulfide, sulfoxide, sulfone, alkylsulfonyl, sulphonamide, amine, N-oxide compound, hydrazine, hydrazides, hydrazone, trinitride, aminocompound, urea, amidine, guanidine, enamine, imide, isocyanate (or ester), isothiocyanate (or ester), cyanate, thiocyanate-(or ester), imines, nitrile (such as CN) and analogue.
The cycloalkyl that the cyclic group be substituted such as is substituted, aryl, heterocyclic radical and heteroaryl, also comprise ring and and member ring systems, one of them key be connected with hydrogen atom is replaced by the key that is connected with carbon atom.Therefore, the cycloalkyl be substituted, aryl, heterocyclic radical and heteroaryl also can by according to such as undefined that be substituted or unsubstituted alkyl, thiazolinyl and alkynyl substituted.
Alkyl comprises straight chain containing 1 to about 20 carbon atoms and branched-chain alkyl, and typically 1 to 12 carbon or in certain embodiments from 1 to 8,1 to 6, or 1 to 4 carbon atoms.Alkyl also comprises, according to such as undefined cycloalkyl.The example of straight chained alkyl comprises containing the group from 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl.The example of branched-chain alkyl includes but not limited to sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl and 2,2-dimethylbutyl.Typically be substituted alkyl to be replaced 1 time by above-mentioned group or repeatedly.Cycloalkyl is that cyclic alkyl includes, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.In certain embodiments, cycloalkyl comprises 3 to 10 or 3 to 8 rings, and in other embodiments the carbonatoms of ring from 3 to 5,3 to 6 or 3 to 7.Cycloalkyl also comprises monocycle, dicyclo and polycyclic system, bridge ring alkyl such as described below and and ring, include but not limited to naphthane and analogue.In certain embodiments, polycyclic naphthene base contains 3 rings.The cycloalkyl replaced can be replaced one or many by above-mentioned non-hydrogen and non-carbon-based group.But the cycloalkyl of replacement also comprises ring atom and is replaced by the alkyl of straight or branched defined above, alkenyl or alkynyl.Typical substituted cycloalkyl can be monosubstituted or polysubstituted, includes, but are not limited to the cyclohexyl replaced by above-mentioned group 2,2-, 2,3-, 2,4-, 2,5-or 2,6-.
Bridge ring alkyl is the wherein cycloalkyl that replaced by an alkylidene bridge of two or more hydrogen atom, if if can comprise 2 to 6 carbon atoms or this two hydrogen atoms and be positioned at alkylidene bridge on two carbon atoms closed on if these two hydrogen atoms be wherein substituted are positioned at alkylidene bridge on a carbon atom and can comprise 1 to 5 carbon atoms or this two hydrogen atoms and be positioned at alkylidene bridge on the carbon atom that separated by 1 or 2 carbon atoms and can comprise 2 to 4 carbon atoms.Bridge ring alkyl can be two rings, such as, and such as two rings [2.1.1] hexane; Or three ring, such as, such as diamantane.Typical bridge ring alkyl comprises two rings [2.1.1] hexyl, two rings [2.2.1] heptyl, two rings [3.2.1] octyl group, two rings [2.2.2] octyl group, two rings [3.2.2] nonyl, two rings [3.3.1] nonyl, two rings [3.3.2] decyl, adamantyl, noradamantyl, bornyl or norcamphyl.The bridge ring alkyl replaced can by above-mentioned group, comprises the alkyl of side chain or side chain, thiazolinyl, alkynyl substituted 1 time or repeatedly.The bridge ring alkyl that typical case replaces can be monosubstituted or polysubstituted, includes, but are not limited to single, the two or three replacement adamantyls that are replaced by above-mentioned substituting group.
Cycloalkylalkyl is that a hydrogen in above-mentioned definition alkyl or carbon bond are by the alkyl of cycloalkyl substituted defined above.In certain embodiments, cycloalkylalkyl has 4 to 20 carbon atoms, 4 to 16 carbon atoms and typically has 4 to 10 carbon atoms.The cycloalkylalkyl be substituted can be substituted in alkyl, cycloalkyl or be all substituted on both.The cycloalkylalkyl that typical case replaces can be monosubstituted or polysubstituted, includes, but are not limited to by above-mentioned substituting group single group, two or three replacements.
Thiazolinyl comprise straight chain and side chain and and cycloalkyl defined above, but have at least a double bond to be present between two carbon atoms.Therefore, thiazolinyl has 2 to about 20 carbon atoms, typically have 2 to 12 carbon atoms or, in certain embodiments 2 to 8,2 to 6, or 2 to 4 carbon atoms.In certain embodiments, thiazolinyl comprises cycloalkenyl group, has 4 to 20 carbon atoms, 5 to 20 carbon atoms, 5 to 10 carbon atoms, or even 5,6,7 or 8 carbon atoms.Such as include but not limited to vinyl, allyl group ,-CH=CH (CH 3) ,-CH=C (CH 3) 2,-C (CH 3)=CH 2,-C (CH 3)=CH (CH 3) ,-C (CH 2cH 3)=CH 2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl.Typical substituted alkenyl can be monosubstituted or polysubstituted, includes, but are not limited to by above-mentioned substituting group single group, two or three replacements.
Cycloalkenyl alkyl is the alkyl that a hydrogen in above-mentioned definition alkyl or carbon bond are replaced by cycloalkenyl group defined above.The cycloalkenyl alkyl replaced can be substituted at alkyl, cycloalkenyl group or alkyl and cycloalkenyl group are all substituted.The cycloalkenyl alkyl that typical case replaces can be replaced 1 time by above-mentioned group or repeatedly.
Alkynyl comprises straight chain and branched-chain alkyl, but has at least a triple bond to be present between two carbon atoms.Therefore, alkynyl has 2 to about 20 carbon atoms, typically have 2 to 12 carbon or, in certain embodiments, have 2 to 8,2 to 6, or 2 to 4 carbon atoms.Such as include, but are not limited to-C ≡ CH ,-C ≡ C (CH 3) ,-C ≡ C (CH 2cH 3) ,-CH 2c ≡ CH ,-CH 2c ≡ C (CH 3) and-CH 2c ≡ C (CH 7cH 3), inter alia.The alkynyl that typical case replaces can be monosubstituted or polysubstituted, includes, but are not limited to by above-mentioned substituting group single group, two or three replacements.
Aryl is not containing heteroatomic cyclic aromatic compounds.Aryl comprises monocycle, dicyclo and polycyclic system.Therefore, aryl include, but are not limited to phenyl and cycloheptatriene base, xenyl, Dicyclopentadiene (DCPD) phenyl, fluorenyl, phenanthryl, terphenyl, pyrenyl, thick tetraphenyl, base, xenyl, anthryl, indenyl, indanyl, pentalene base and naphthyl.Aryl contains 6 to 14 carbon atoms in certain embodiments, and the part of ring contains 6 to 12 or even 6 to 10 carbon atoms in other embodiments.
" although aryl " one word comprise containing and the group of ring, such as, aromatic ring cycloaliphatic ring system (such as indanyl, tetralyl and analogue), do not comprise containing ring being connected with other groups, the aryl of such as alkyl or halogen atom.To a certain extent, phenmethyl is attributed to the aryl of replacement.Typical substituted aryl can be monosubstituted or polysubstituted.Such as, monosubstituted aryl includes, but are not limited to by the phenyl or naphthyl of above-mentioned substituted radical 2-, 3-, 4-, 5-or 6-replacement.
Aralkyl is the alkyl that a hydrogen in alkyl defined above or carbon bond are replaced by an aryl.In certain embodiments, aralkyl contains 7 to 20 carbon atoms, 7 to 14 carbon atoms or 7 to 10 carbon atoms.The aralkyl replaced can be replace on alkyl, aryl or alkyl and aryl.Typical aralkyl includes but not limited to phenyl, styroyl and and ring (cycloalkylaryl) alkyl, such as 4-ethyl-indanyl.Typical substituted aralkyl can be replaced 1 time by above-mentioned group or repeatedly.
Heterocyclic radical comprises fragrance (also can refer to heteroaryl) and nonaromatic ring compounds, and comprise 3 rings or polynuclear compound, wherein one or more ring memberses are heteroatomss, include but not limited to N, O and S.In certain embodiments, heterocyclic radical comprises 3 to 20 rings, and other similar groups contain 3 to 6,3 to 10,3 to 12 or 3 to 15 rings.Heterocyclylalkyl comprises undersaturated, fractional saturation such as, with saturated ring system, imidazolyl, imidazolinyl and imidazolidyl.Term " Heterocyclylalkyl " comprises and member ring systems comprises those and the fragrance of ring and non-aromatic group, such as, such as, and benzotriazole base, 2,3-dihydrobenzos [Isosorbide-5-Nitrae] dioxin and phendioxin, 3-dioxolyl.Term also comprises containing a heteroatomic bridged ring polycyclic system, includes, but not limited to quinuclidyl.But term does not comprise on ring and is connected with other groups, such as, the heterocyclic radical of alkyl, carbonyl or halogen atom.To a certain extent, these compound definitions are " heterocyclic radical of replacement ".Heterocyclic radical includes, but are not limited to acridyl, azelidinyl, pyrrolidyl, imidazolidyl, pyrazolidyl, thiazolyl, tetrahydrochysene thiophenyl, tetrahydrofuran (THF), 1,3-dioxolyl, furyl, thiophenyl, pyrryl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl group, oxadiazoles base, pyrrolidyl, piperazinyl, morpholinyl, thio-morpholinyl, THP trtrahydropyranyl, tetrahydrochysene thiopyranyl, oxathiane, dioxygen base, sulfinyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridine base, dihydro sulfinyl, single piperazinyl, quinuclidyl, indyl, indoline base, pseudoindoyl, azaindolyl (pyrrolopyridinyl), indazolyl, indoline base, benzotriazole base, benzimidazolyl-, benzofuryl, aisaa benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzimidazole dihydrochloride base, benzothienyl, benzoxathrinyl, benzothiazine base, benzoxazolyl, benzothiazolyl, diazosulfide base, benzo [1,3] dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purine radicals, xenthophylls base, adeninyl, guanyl-, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl, quinazolyl, scold piperazine base, phthalazinyl, naphthyridinyl, pteridyl, thianaphthalenyl, dihydrobenzo thiazinyl, dihydro benzo furyl, indolinyl, dihydrobenzo dioxin, tetrahydro indole base, tetrahydrochysene indazole base, Tetrahydrobenzimidazderivative base, tetrahydro benzo triazolyl, Pyrrolidine pyridyl, tetrahydro-pyrazole pyridyl, imidazolidine pyridyl, tetrahydrochysene Triazolopyridine base and tetrahydric quinoline group.The heterocyclic radical that typical case replaces can be monosubstituted or polysubstituted.Include, but are not limited to be replaced by above-mentioned substituted radical 2-, 3-, 4-, 5-or 6-or Disubstituted pyridine base or morpholine base.
Heteroaryl is wherein one or more ring memberses is that heteroatoms includes but not limited to N, O, and the aromatic compound of 5 rings of S or more ring.Heteroaryl includes but not limited to pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, aisaa benzothiophenyl, furyl, benzofuryl, indyl, assorted azepindole base (pyrrolopyridinyl), indazolyl, benzimidazolyl-, imidazopyridyl (assorted nitrogen benzimidazolyl-), Pyrazolopyridine base, Triazolopyridine base, benzotriazole base, benzoxazolyl, benzothiazolyl, diazosulfide base, imidazopyridyl, isoxzzole pyridyl, thianaphthalenyl, purine radicals, xenthophylls base, adeninyl, guanyl-, quinolyl, isoquinolyl, tetrahydric quinoline group, quinoxalinyl and quinazolyl.Although term " heteroaryl " comprises and cyclic cpds such as indyl and 2,3-indolinyl, term does not comprise other groups, such as alkyl, the heteroaryl that is connected with ring members.To a certain extent, the heteroaryl containing this substitute mode is called " heteroaryl of replacement ".The heteroaryl that typical case replaces can be replaced 1 time by above-mentioned group or repeatedly.
Heterocyclylalkyl refers to previously defined alkyl group, wherein, a hydrogen of alkyl group or carbon bond replace by the key formed with previously defined heterocyclyl groups.The Heterocyclylalkyl replaced can be replace on alkyl, heterocyclic radical or alkyl and heterocyclic radical.Typical Heterocyclylalkyl includes, but not limited to 4-ethyl-morpholine base, 4-ptopylmorphohnyl, furans-2 base, methyl furan-3-ylmethyl pyridine-3 ylmethyl tetrahydrofuran (THF)-2 base ethyl and indoles-2 base propyl group.Typical substituted heterocycle alkyl can be replaced 1 time by above-mentioned group or repeatedly.
Heteroaralkyl refers to previously defined alkyl group, wherein, a hydrogen of alkyl group or carbon bond replace by the key formed with previously defined heteroaryl groups.The heteroaralkyl replaced can be replace on alkyl, heteroaryl or alkyl and heteroaryl.Representational replacement heteroaralkyl can be replaced 1 time by above-mentioned group or repeatedly.
Alkoxyl group refer to the key formed by the carbon atom with previously defined replacement or unsubstituted alkyl group with the key of hydrogen atom in oh group (-OH) replace.The example of linear alkoxide groups includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy and analogue.The example of branched alkoxy include but not limited to isopropoxy, tert.-butoxy, season butoxy, isopentyloxy, different hexyloxy and analogue.The example of cycloalkyloxy includes but not limited to ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy and analogue.Typical substituted alkoxy can be replaced 1 time by above-mentioned group or repeatedly.
Term " aryloxy " and " aralkoxy " refer to respectively, and a replacement and unsubstituted aryl are connected with the group group of Sauerstoffatom and the alkyl of a replacement and unsubstituted aralkyl being connected with Sauerstoffatom.Example includes but not limited to phenoxy group, naphthyloxy and benzyloxy.The aryloxy that typical case replaces and aralkoxy can be replaced 1 time by above-mentioned group or repeatedly.
Alkyl, thiazolinyl, alkynyl group can be unit price or divalence.Alkyl, thiazolinyl, the valency of alkynyl is recognized easily under the background of the art.Such as, the alkyl in aralkyl is divalence.In certain embodiments, divalence can by adding suffix " ene " or " ylene " clearly indicates in term defined here.The alkyl of divalence that what therefore, such as " alkylene " referred to is and alkenylene refers to is the thiazolinyl of divalence.
What term " carboxyl " represented herein is-COOH group.
That term " carboxylicesters " represents herein is-COOR agroup.R asubstituted or unsubstituted alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl, Heterocyclylalkyl or the heterocyclic radical that the present invention defines.
Term " amide group " (or " amido ") comprises the group that C-and N-replaces, and such as, is-C (O) NR respectively br cwith-NR bc (O) R c.R band R cbe the independently hydrogen that defines of the present invention or replacement or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, Heterocyclylalkyl or heterocyclic radical.Amido includes but not limited to formamyl (-C (O) NH 2) and formamido-(-NHC (O) H).Carbamate comprises N-and O-carbamate groups, such as, is-NR respectively ec (O) OR fwith-OC (O) NR er f.R eand R fthe independently hydrogen that defines of the present invention or substituting group or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, Heterocyclylalkyl or heterocyclic radical.
That term " ammonia " (" amino ") represents herein is-NHR gwith-NR gr h, wherein R gand R hthe independently hydrogen that defines of the present invention or substituting group or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, Heterocyclylalkyl or heterocyclic radical.In certain embodiments, amine is NH 2, methylamino-, dimethylamino, ethylamino, diethylin, the third amino, isopropylamino, phenylamino or benzyl be amino.
Term " sulfoamido " comprises S-and N-sulfoamido group, such as, is-SO respectively 2nR ir jwith-NR isO 2r j.R iand R jthe independently hydrogen that defines of the present invention or substituting group or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, Heterocyclylalkyl or heterocyclic radical.Therefore, sulfoamido includes but not limited to sulfahydantoin (-SO 2nH 2).
Term " mercaptan " refers to-SH group, and its medium sulphide content comprises-SR k, sulfoxide comprises-S (O) R k, sulfone comprises-SO 2r k, and alkylsulfonyl comprises-SO 2oR k.R kindependently substituted or unsubstituted alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl that the present invention defines.
That term " urea " refers to is-NR l-C (O)-NR mr ngroup.R l, R mand R nthe independently hydrogen that defines of the present invention or substituting group or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, Heterocyclylalkyl or heterocyclic radical.
It is-C (NR that term " narrows " what refer to o) NR pr qwith-NR oc (NR p) R qgroup, wherein R o, R pand R qthe independently hydrogen that defines of the present invention or substituting group or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, Heterocyclylalkyl or heterocyclic radical.
That term " guanidine " refers to is-NR rc (NR s) NR tr ugroup, wherein R r, R s, R tand R uthe independently hydrogen that defines of the present invention or substituting group or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, Heterocyclylalkyl or heterocyclic radical.
That term " enamine " refers to is-C (R v)=C (R w) NR xr ywith-NR vc (R w)=C (R x) R ygroup, wherein R v, R w, R xand R ybe the present invention define independently hydrogen or substituting group or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, Heterocyclylalkyl or heterocyclic radical.
That term " imide " refers to is-C (O) NR zc (O) R a1group, wherein R zand R a1the independently hydrogen that defines of the present invention or substituting group or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, Heterocyclylalkyl or heterocyclic radical.
That term " imines " refers to is-CR b1(NR c1) and-N (CR b1r c1) group, wherein R b1and R c1be the independently hydrogen that defines of the present invention or substituting group or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, Heterocyclylalkyl or heterocyclic radical, and limit R b1and R c1asynchronously hydrogen.
With oh group, amine groups, the form of these functionality that what the carboxylic group term " protected " relevant with mercapto groups referred to is, they are undertaken protecting in order to avoid suffer adverse effect by protecting group.Blocking group those skilled in the art will know that, can add by known step or remove, such as Organic Synthesis, Greene, T.W.; Wuts, P.G.M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) set forth.The example of protected oh group include but not limited to silyl ether such as those by oh group and following reagent react are obtained, include but not limited to that tert-butyldimethylsilyl chloride is for silane, trimethylchlorosilane, tri isopropyl chlorosilane, chlorotriethyl silane, the methyl replaced and ethyl ether include but not limited to methoxymethyl ether, benzyloxy methyl ether, tert.-butoxy methyl ether, 2-methoxy ethoxy methyl ether, THP trtrahydropyranyl ether, 1-ethoxyethylether, allyl ether, dibenzyl ether, ester includes but not limited to methyl benzoylformate, manthanoate, acetic ester, trichloroacetic esters and trifluoro-acetate.
N blocking group comprises acyl group such as formyl radical, ethanoyl, propionyl, pentanoyl, tertbutylacetyl, 2-chloracetyl, 2-acetyl bromide, trifluoroacetyl group, tribromo-acetyl base, phthalyl base, o-nitrophenoxyacetyl, a-chlorobutyryl, benzene (first) acyl group, 4-chlorobenzene formacyl, 4-benzoyl bromide, 4-nitro benzoyl and analogue.Alkylsulfonyl, such as benzenesulfonyl, to Methyl benzenesulfonyl base and analogue.The group such as carbobenzoxy-(Cbz) that carbamate is formed, to benzyloxycarbonylchloride base, to methbxybenzyl-oxycarbonyl, to nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, to bromo-benzyloxycarbonyl, 3, 4-dimethoxy-benzyloxycarbonyl, 3, 5-dimethoxy-benzyloxycarbonyl, 2, 4-dimethoxy-benzyloxycarbonyl, 4-methbxybenzyl-oxycarbonyl, 2-nitro-4, 5-dimethoxy-benzyloxycarbonyl, 3, 4, 5-trimethoxy carbobenzoxy-(Cbz), 1-(adjacent xenyl)-1-methylethoxy carbonyl, α alpha-alpha-dimethyl-3, 5-dimethoxy-benzyloxycarbonyl, hexichol methoxycarbonyl, tertbutyloxycarbonyl, di-isopropyl methoxycarbonyl, butyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2, 2, 2-trichloro-ethoxycarbonyl, carbobenzoxy, 4-nitro carbobenzoxy, fluorenyl-9-methoxycarbonyl, ring third oxygen carbonyl, Buddha's warrior attendant alkoxy acyl (adamantyloxycarbonyl), cyclohexyl oxygen carbonyl, ring penta oxygen carbonyl, phenyl carbonyl and analogue.Alkyl group is phenyl, trityl, phenoxymethyl and analogue such as.Silyl-group is trimethyl silicon based and analogue such as.Typical N blocking group is formyl radical, ethanoyl, benzoyl, pivaloyl group, tertiary fourth ethanoyl, benzenesulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz).
The example of protected oh group includes but not limited to thioether such as S-benzyl thioether, S-tert-butylsulfide and S-4-picolyl thioether; S-methyl-derivatives such as half sulfenyl (hemithio) replaced, disulfide group and aminothio acetal; And other.
Typical carboxy protective group is C 1to C 8alkyl (such as: methyl, ethyl or the tertiary butyl and analogue); Alkylhalide group, thiazolinyl, cycloalkyl and its substitutive derivative such as cyclohexyl, cyclopentyl and analogue thereof; Cycloalkylalkyl and its substitutive derivative such as methyl cycloalkyl, cyclopentyl-methyl and analogue thereof; Aralkyl, such as, styroyl or benzyl and its substitutive derivative such as alkoxybenzyl, nitrobenzyl and analogue thereof; Arylalkenyl, such as, styryl and analogue thereof; Aryl and its substitutive derivative, such as, 5-indanyl and analogue thereof; Dialkyl aminoalkyl (such as: dimethylaminoethyl and analogue thereof); Alkanoyloxyalkyl (alkanoyloxyalky) group is acetoxy-methyl, butyryl acyloxy methyl such as, pentanoyloxymethyl, isobutyryloxymethyl, isoamyl pivaloyloxymethyl, 1-(propionyloxy)-1-ethyl, 1-(pivaloyl oxygen base)-1-ethyl, 1-methyl isophthalic acid-(propionyloxy)-1-ethyl, pivaloyloxymethyl, propanoyloxymethyl and analogue thereof; Cycloalkanes acyloxyallcyl (cycloalkanoyloxyalkyl) group is ring third carbonyl oxy-methyl such as, ring fourth carbonyl oxy-methyl, ring penta carbonyl oxy-methyl, hexamethylene carbonyl oxy-methyl and analogue thereof; Aroyloxyalkyl, as benzoyloxy group methyl, benzoyloxy group ethyl and analogue thereof; Aralkanoyloxyalkyl, such as benzyl carbonyl oxygen methyl, 2-benzyl carbonyl oxygen ethyl and analogue thereof; Alkoxycarbonyl alkyl, such as methoxycarbonyl-methyl, hexamethylene oxygen carbonvlmethyl, 1-methoxycarbonyl-1-ethyl and analogue thereof; Alcoxyl carbonyl acyloxyallcyl, such as methoxy carbonyl oxygen methyl, tert-butoxycarbonyloxymethyl, 1-ethoxy carbonyl oxygen-1-ethyl, 1-hexamethylene oxygen carbonyl oxygen-1-ethyl etc.; Alkoxycarbonylamino alkyl, such as tertiary butyloxycarbonyl aminoethyl etc.; Alkyl amino carbonyl aminoalkyl, as methylamino carbonyl aminomethyl and analogue; Alkane carbonyl amidoalkyl (alkanuylaminoalkyl), such as acetylamino methyl and analogue thereof; Heterocycle carbonyl acyloxyallcyl, such as 4-methylpiperazine carbonyl pivaloyloxymethyl and analogue thereof; Dialkylaminocarbonylalkyl, such as dimethyl-aminocarbonyl methyl, diethylaminocarbonyl-ethyl and analogue thereof; (5-(alkyl)-2-carbonyl-DOX-4-base) alkyl, such as (the 5-tertiary butyl-2-carbonyl-DOX-4-base) methyl and analogue thereof; (5-phenyl-2-carbonyl-DOX-4-base) alkyl, such as (5-phenyl-2-carbonyl-DOX-4-base) methyl and analogue thereof.
Those skilled in the art will recognize that the compound in invention may exist tautomerism, conformational isomerism, the phenomenon of rotamerism and (or) optical siomerism.Patent specification and the molecular formula drawn by stating can only show wherein a kind of possible tautomerism, conformational isomerism, optical siomerism or rotamerism form, should be understood that this patent comprises and relate to all tautomerisms of the compound with one or more purposes, conformational isomerism, optical siomerism and or rotamerism form, and the mixture of various isomeric form.Term " tautomer " refers to the isomeric forms of the compound of balance mutually.The concentration of each isomeric form will depend on the environment residing for compound, and can be in solid or be in organic or aqueous solution and change to some extent according to compound.Such as, in aqueous solution, may there is following isomeric form in triazole, and this is called as mutual tautomer:
On those skilled in the art institute easy understand ground, many functional groups and other structures can demonstrate tautomerism.The all tautomer of compound of the present invention all within the scope of the invention.
Unless the specific stereochemistry clearly indicated, the steric isomer (also referred to as optical isomer) of compound comprises whole chirality, diastereomeric, racemic isomeric forms.Compound in the present invention is included in the optically active isomer that any one or all asymmetric centers partially or completely split.Racemize and diastereomeric compound, and single optical isomer can be isolated or synthesized, to make to be separated with their enantiomer or diastereomer companion fully, these are also within the scope of the present invention.
The solvate that the present invention uses refers to the polymer of compound molecule described in a this patent and one or more solvent molecule.In the solid state, some compound has the trend in conjunction with certain mol proportion rate solvent.Solvent molecule can with non-solvent molecule by Dipolar cycloadition, and ion dipole interaction, coordinate bond and similar mode interact.When solvent is water, solvate is hydrate.Many organic solvents also can form solvate, comprise, such as, ether as ether and tetrahydrofuran (THF), alcohol as methyl alcohol and ethanol, ketone as acetone, DMF, dimethyl sulfoxide (DMSO), and other solvents.Solvate can be differentiated by the various method of the art.Such as, the solvate containing hydrogen in solvent molecule can be observed by nucleus magnetic resonance.Other effectively identify that the method for solvate has thermogravimetric analysis, dsc, X-ray diffraction analysis, ultimate analysis.Solvate is formed by various ways, such as, compound dissolution is evaporated solvent molecule at large in a kind of solvent, or freeze-drying, or recrystallization.Therefore the formation of solvate is completely within the scope of the art.In fact, compound often needs to remove by careful drying the solvent comprised in solvate.The compound that this patent describes also has and can form solvate, and all solvates all within the scope of the present invention.
Some compound in the scope of the invention is derivative, is called " prodrug "." prodrug " mean it be one known, disease is had to the derivative of the medicine of direct curative effect, such as ester and acid amides, compared with medicine, these derivatives have the administering mode improving medicine, help the effect that it absorbs and improves its curative effect, and it is converted into active medicine by enzyme or chemical process in vivo.See Notari, R.E., " Theory and Practice of Prodrug Kinetics, " Methods in Enzymology/72:309-323 (1985); Bodor, N., " Novel Approaches in Prodrug Design, " Drugs of the Future 6:165-182 (1981); And Bundgaard, H., " Design of Prodrugs:Bioreversible-Derivatives for VariousFunctional Groups and Chemical Entities, " in Design of Prodrugs (H.Bundgaard, ed.), Elsevier, New York (1985), Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int.Ed.1992.Aforementioned reference and all reference listed herein are incorporated to herein by reference to entirety.
Compound pharmacy acceptable salt of the present invention is contemplated within the scope of the present invention, when the compound in the present invention contains basic group, such as, amino group, can with mineral acid (all example hydrochloric acids, boric acid, nitric acid, sulfuric acid and phosphoric acid), organic acid (as formic acid, acetic acid, trifluoroacetic acid, FUMARIC ACID TECH GRADE, oxalic acid, tartrate, lactic acid, toxilic acid, citric acid, succsinic acid, oxysuccinic acid, methylsulfonic acid, Phenylsulfonic acid and toluenesulphonic acids) or acidic amino acid (as aspartic acid and L-glutamic acid) form pharmacy acceptable salt.When the compound in the present invention contains acidic-group, such as such as, a carboxylic group, it can and metal, such as alkali and alkaline earth metal ions is (as Na +, Li +, K +, Ca +, Mg 2+, Zn 2+), ammoniacal liquor, organic amine (such as Trimethylamine 99, triethylamine, pyridine, picoline, thanomin, diethanolamine, trolamine), or basic aminoacids (such as arginine, Methionin, ornithine) forms pharmacy acceptable salt.
Compound in the present invention easily can be synthesized by technology well known to those skilled in the art.
" treatment " in the present invention in scope refers to whole or in part, alleviates the symptom with disease-related, slows down or stop further developing or worsening of these symptoms, or prevent and prevent the morbidity of risk groups.As described herein, " in treatment the effective dose " of compound of the present invention refers to this dosage and can slow down or stop further developing or worsening of these symptoms whole or in part, prevents or prevent the morbidity of risk groups.As is known to those skilled in the art, in the treatment of compound of the present invention, effective dose can change to some extent according to the difference of treated symptom.Such as, be used for the treatment of the effective dose of tumor disease, with treatment other diseases, such as cardiovascular disorder, diabetes, insulin resistance and metabolic syndrome, effective dose compare and be likely different.
On the compounds for treating that the present invention describes, useful main body is any animal, and in certain embodiments, main body refers to Mammals, such as, and people, primate, dog, cat, horse, ox, pig, rodent, such as such as big rat or mouselet.Typical main body is people.
What term " cancer " referred to is take cell proliferation as any different malignant tumour of feature, and this proliferative cell can invade surrounding tissue and shift to new body part.The classification of innocent tumour and malignant tumour all can the type of organ existing for it be determined.Such as, fibroma refers to the tumour of fibrillar connective tissue, and melanoma refers to the misgrowth of pigment (melanochrome) cell.The malignant tumour starting from epithelial cell tissues (such as, skin, segmental bronchus and stomach) is cancer.At breast, the malignant tumour of the epithelial gland such as prostate gland and colon body tissue is referred to as gland cancer.The malignancy of reticular tissue, such as muscle, cartilage, Lymphoid tissue and bone are then referred to as sarcoma.Lymphoma and leukemia belong to the malignant tumour in white corpuscle.
In tumour, when cancer and tumor growth or growth of tumour cell, inhibit activities is by assessing with under type, the delay that primary or secondary tumors occur, slowing down of primary or secondary tumors development, the reduction that primary or secondary tumors occur, the slowing down or reduce of secondary tumors degree, stop tumor growth and tumor regression, etc.In extreme situations, suppression completely here refers to prevention or chemoprophylaxis.In this case, term " prevention " comprise prevent the formation of tumour obvious in clinical completely or prevent clinical before be in the outbreak of the tumour in obvious critical days.This definition also comprises prevention or stops normal cell to the transformation of tumour cell, or stop or reversion cell carcinogenesis process.This comprises the prophylactic treatment that those are in tumor invasion crowd in earlier stage.
The effective dose of compound in the present invention in treatment can change according to route of administration and formulation.The effective dose of the compounds of this invention is usually within the scope of about 0.001 to 100mg/kg/ days.More generally, about 0.05 to 10mg/kg/ days.Usually, the compound in one or more the present invention is selected to be made into the preparation with high therapeutic index.Therapeutic index is the dose ratio between toxic effect and result for the treatment of, and this index can be expressed as LD 50and ED 50between ratio.LD 50the lethal amount of colony of 50%, ED 50be 50% colony have the dosage of result for the treatment of.LD 50and ED 50pharmaceutical procedures by standard in animal cell culture and experimentation on animals measures.
Methods for the treatment of also can comprise to give compound in the present invention or pharmaceutical preparation together with other therapies, and combination treatment of the present invention can be simultaneously, respectively, or administration successively.Such as, compound of the present invention and pharmaceutical preparation can before operative procedure and/or radiation therapy, period or afterwards administration.Determine according to particular case, compound of the present invention also can with other anti-inflammatory agenies described herein, antineoplastic agent and other drug combination medicine-feeding.Inflammation modulators described herein, polytype immunomodulator, immunosuppressor, cytostatic medicine, can use with compound combination described in the invention.
The concrete dosage of active additive is determined according to several factors.These factors comprise used concrete medicament, the type of the disease for the treatment of and maintaining, the severity of disease and stage, and while the dosage of compound of administration and other optional active additives.
In some embodiments of the invention, by specific mode, to a body, particularly human body is given and the one or more compound in the present invention and active additive, administering mode can be in turn and certain hour interval in administration, compared with other administering modes, compound can with other medicament generation combined action, improve result for the treatment of.Such as, active additive can together formulation mode simultaneously administration, order administration successively in administration simultaneously or different interval; But if can not simultaneously administration, the time of their administrations also must be very close to reach required treatment or preventive effect.In certain embodiments, compound and active additive onset time have overlap.Each active additive can with any appropriate form and any approach individually dosed.In some other embodiment, compound before taking active additive, simultaneously or administration afterwards.
In various example, compound and active additive can administrations within the following timed interval, be less than 1 hour, about 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours, 4 hours to 5 hours, 5 hours to 6 hours, 6 hours to 7 hours, 7 hours to 8 hours, 8 hours to 9 hours, 9 hours to 10 hours, 10 hours to 11 hours, 11 hours to 12 hours, be no more than 24 hours or be no more than 48 hours.In some other example, compound and active additive administration simultaneously.In some other embodiments, compound and active additive are with the administration simultaneously of same dosage form.
In some other example, compound and active additive can also administrations within the following timed interval, 2 to 4 days, 4 to 6 days, 1 week, 1 to 2 week, or more than 2 week.
In some example, the compound in the present invention and optional active additive by the mode of rotation to patient's administration.After circulation therapy relates to first medicine for some time of use, then use second or the 3rd preparation medicine for some time, or else disconnected this medication order of repetition.Circulation therapy has a lot of benefit, such as, reduces the probability developed immunity to drugs to one or more therapy, avoids or reduce the side effect of one or more therapy, and/or improves result for the treatment of.
In some other example, the compound in the present invention and optional active additive are with the loop cycle administration being less than 3 weeks, and approximately once every two weeks, every ten days once, once in a week.Circulation can comprise compound in the present invention and optional second active medicine with the form administration of transfusion, and administration time is about one time 90 minutes, one time one hour, one time 45 minutes, one time 30 minutes, one time 15 minutes.Each circulation can comprise at least one week, at least two weeks, the time of having a rest at least three weeks.The number of times of circulation administration is from one to ten two, more typically from two to ten, more typically from two to eight.
Same patient can carry out synchronous therapeutic by the different courses for the treatment of, such as, and the mode administration that each dosage of active additive can also be independent, but in certain time interval, can interact with active additive to make the compound in the present invention.Such as, administration weekly composition can with once every two weeks or other compositions of every three weeks single administrations combine.In other words, even if therapeutic process is not administration simultaneously or is not administration on the same day, dosage regimen also can synchronously be carried out.
Active additive can play additional curative effect, more typically promotes mutually with compound of the present invention the effect reaching attached increasing.In one example in which, the mode administration simultaneously that the compound in the present invention and one or more Equations of The Second Kind activator combine with same agent.In another example, the compound in the present invention and one or more Equations of The Second Kind activator are with the administration simultaneously of the mode of different agents.In another example, the compound in the present invention is prior to or subsequent to the administration of Equations of The Second Kind activator.The present invention considers that compound in the present invention and Equations of The Second Kind activator are with identical or different administration, such as oral or injection.In certain embodiments, when compound and the administration simultaneously of Equations of The Second Kind activator of invention, and Equations of The Second Kind activator has potential side effect, and these side effects include but not limited to toxicity.Like this, the dosage of Equations of The Second Kind activator just can be located at cause side effect dosage under.
Present invention provides pharmaceutical preparation and medicine, this pharmaceutical preparation and medicine can pass through the compound in one or more the present invention, its prodrug, it is acceptable salt pharmaceutically, its steric isomer, its tautomer, its solvate, with pharmaceutically acceptable carrier, vehicle, tackiness agent, thinner or analogue are mixed with and obtain.This pharmaceutical preparation and medicine can be used for that prevention and therapy is various described hereinly produces relevant various diseases with Excessive cytokine, such as, and the disease that inflammation, pain, cancer etc. are involved and the cause of disease.This kind of medicine can be following various forms, e.g., and particle, pulvis, tablet, capsule, syrup, suppository, injection, emulsion, elixir, suspension agent or solution.This medicine preparation can be used for various route of administration, such as, by oral, outside intestines, and skin, rectum, nose, vagina administration, or by implantable container (implanted reservoir) administration.Outer or the systemic applications of intestines includes but not limited to following all kinds of injection system, and as subcutaneous, vein, abdominal cavity, muscle, intraarticular, in synovia, under breastbone, in stndon sheath, in intralesional and head.Formulation below only as example, and does not limit the scope of the invention.
Pulvis, suspension agent, particle, tablet, pill, capsule, granular capsule (gelcaps) and capsule tablets are applicable to oral, the solid dosage of oral cavity and sublingual administration.These formulations can by by the compound in one or more the present invention, or its pharmacy acceptable salt or its tautomer, is mixed with and obtains with at least one additive.Suitable additive comprises sucrose, lactose, cellulose sugar, N.F,USP MANNITOL, maltose alcohol, dextran, starch, agarose, alginates, chitin, chitosan, pectin, tragacanth, gum arabic, gel, collagen, casein, white protein, synthesis or semisynthetic polymkeric substance or glyceryl ester.Also other components can be contained for convenience of drug administration oral administration preparation, the thinner of such as non-activity or lubricant such as Magnesium Stearate, or sanitas such as parabens (paraben) or Sorbic Acid, or antioxidant such as xitix, tocopherol or halfcystine, decomposition agent, tackiness agent, thickening material, buffer reagent, sweeting agent, sweetener or perfume compound.Tablet and pill can further with coating material process known in the art.
Emulsion, syrup, elixir, suspension and solution are the liquid dosage forms being pharmaceutically applicable to oral administration.They can contain the thinner such as water of non-activity.Formula of medicine and medicament can use sterile liquid, include but not limited to oil, water, and the combination of alcohol and these materials, is prepared into liquid suspension or solvent.Pharmaceutically suitable solubility promoter can also be added, suspension agent, emulsifying agent, for oral administration or intestines external administration.
As mentioned above, suspension may comprise oil.This type of oil includes but not limited to peanut oil, sesame oil, Oleum Gossypii semen, Semen Maydis oil and sweet oil.Suspension formulation also can contain the ester of lipid acid, such as ethyl oleate, Isopropyl myristate, glycerol fatty acid ester and acetylated glycerol fatty acid esters.Suspension formulation can comprise alcohols, includes but not limited to ethanol, Virahol, hexadecanol, glycerine and propylene glycol; Ethers, includes but not limited to polyoxyethylene glycol, petroleum hydrocarbon such as mineral oil and paraffin; Water also may be used for suspension formulation.
Injectable dosage formulations generally comprises aqeous suspension, or oil suspension, and it can obtain with suitable dispersion agent or wetting agent and suspension agent preparation.Injectable medicine can be in solution phase (solution phase) or aerosol form, and they can be prepared with solvent or thinner.Acceptable solvent or carrier comprise sterilized water, Ringer ' s solution, or isoosmotic pressure aqueous salt solution.Aseptic oil also can be used as solvent or suspension agent.Usually, oil or lipid acid are nonvolatile, comprise natural or synthesis oil, lipid acid, monoglyceride, triglyceride or triglyceride level.
It can be the powder being applicable to dissolving again for the pharmaceutical preparation injected and medicine.These powder can be include but not limited to cryodesiccated, Rotary drying or spray-dired powder, amorphous powder, particle, throw out or particulate.Injection formulations also can contain stablizer, pH adjusting agent, solubility promoter, the combination of bioavailability modifiers (bioavailability modifiers) or these materials.
Suppository, ointment, enema, tablet or ointment are the pharmaceutical preparation and the medicine that are suitable for rectal administration, for discharging medicine at intestines, sigmoid colon and/or internal rectum.Rectal suppository passes through the compound in one or more the present invention, or the tautomer of pharmacy acceptable salt or compound, with acceptable carrier, such as theobroma oil or polyoxyethylene glycol are mixed with and obtain, they exist with solid phase under normal storage-temp, in vivo, exist so that the release of medicine with liquid phase at the temperature that such as internal rectum is suitable.Oil also may be used for preparation and the suppository of preparing soft gel type.Water, salt solution, may be used for preparing suspension formulation containing dextrose and related sugar solutions and glycerine, this suspension formulation also can comprise suspension agent such as pectin, carbomer, methylcellulose gum, hydroxypropylcellulose and carboxymethyl cellulose, and damping fluid and sanitas.
Compound of the present invention can be sucked lung administration by nose or mouth.The pharmaceutical preparation being suitable for sucking comprises solution, spraying, dry powder and aerosol, they can include but not limited to stablizer, biocide, antioxidant containing any suitable appearance agent and other compounds optional, pH adjusting agent, solubility promoter, the combination of bioavailability modifier and these materials.Preparation for inhalation contains assistant agent, such as lactose, polyoxyethylene-9-12 silica-based ether, glycocholate and deoxycholate salt.Moisture and water-free aerosol is normally used for transmitting compound of the present invention by sucking.
Under normal conditions, aqueous aerosol by by the aqueous solution of compound or suspension formulated together with stablizer with the pharmaceutically acceptable carrier of routine.Carrier and stablizer change along with the demand of specific compound, but generally comprise non-ionic cosolvents (Tweens, Pluronics or polyoxyethylene glycol), nontoxic protein matter is as serum albumin, Isosorbide Dinitrate, oleic acid, Yelkin TTS, amino acid is glycine such as, damping fluid, salt, sugar or sugar alcohol.Aerosol is generally prepared by isotonic solution and obtains, and non-aqueous suspension (such as carbon fluorine propelling agent) also may be used for transmitting compound of the present invention.
Containing the aerosol for the compound in the present invention conventionally by the transmission of use following substances: sucker, spraying gun, compression wrap or atomizer and suitable propelling agent, include but not limited to, the Refrigerant 12 of pressurization, trichlorofluoromethane, dichloro tetrafluoro ethane, nitrogen, air or carbonic acid gas.When these pressurised aerosols, dose unit controls by valve, to transmit specific dosage (metered amount).Containing compound and suitable powder carrier, such as lactose or starch, mixture gel available make capsule in sucker or insufflator and pill.It is feasible for using sonic nebulizer (sonic nebulizers) to transmit aerosol of the present invention, this is because atomizer makes reagent stand minimum shearing force, because shearing force can degradation compound.
For nose administration, pharmaceutical preparation and medicine can be sprayss, nasal drop or aerosol, they contain suitable solvent and other compounds optional, include but not limited to stablizer, biocide, antioxidant, pH adjusting agent, solubility promoter, the combination of bioavailability modifiers and these compounds.For the administration of nasal drop form, compound can be prepared as oily solution or as colloid.For nose aerosol drug delivery, any suitable propelling agent can be used, comprise pressurized air, nitrogen, carbonic acid gas, or lower boiling hydrocarbon polymer.
The formulation that the compounds of this invention is used for skin (comprise oral cavity and sublingual) or wears skin administration comprises powder, spraying, cream, sticks with paste, breast, lotion, glue, solution and paster.Active ingredient can aseptically with pharmaceutically acceptable carrier and assistant agent and mix with required sanitas or damping fluid.Powder and sprays can with assistant agent such as lactose, mica, silicic acid, aluminium hydroxide, the mixture preparation of Calucium Silicate powder and polyamide powder or these materials.Ointment, paste, emulsion and glue also can contain assistant agent, such as animal and plant fat, oil, wax, paraffin, starch, tragacanth, derivatived cellulose, polyoxyethylene glycol, silicone resin, wilkinite, the mixture of mica and zinc oxide or these materials.
Wear the advantage that skin patch has the compound in controlled release the present invention.This kind of formulation can be passed through agent dissolves and be dispersed in suitable medium and prepare.Also absorption enhancer can be added to increase the infiltration of the compounds of this invention to skin.Seepage velocity can control or be dispersed in polymeric matrix and glue by compound and control by Negotiation speed controlling diaphragm.
Ophthalmic preparation, eye ointment, powder, solution and analogue, be also considered within the scope of the invention.Compound of the present invention can be incorporated in various types of ophthalmic preparation, to pass to eyes (in such as surface, anterior eye or by implanting).Compound is incorporated in surperficial ophthalmic preparation usually, to pass to eyes.Compound can sanitas acceptable with ophthalmology, viscosity-increasing agent, penetration enhancers, damping fluid, and sodium-chlor and water combine, and forms moisture, aseptic eye suspension or solution.Ophthalmic solution formulations can by preparing compound dissolution and obtaining in physiologically acceptable isoosmotic pressure water-containing buffering liquid.In addition, ophthalmic solution can comprise acceptable solubility promoter on ophthalmology, to help dissolved compound.In addition, ophthalmic solution can contain reagent, and to increase viscosity, such as Walocel MT 20.000PV, Natvosol, HPMC, methylcellulose gum, polyvinylpyrrolidone or analogue, to increase the retention time of preparation in conjunctival sac.Also can use jelling agent, include but not limited to cold glue and xanthan gum.Compound of the present invention and sanitas can be mixed in suitable carrier, prepare sterile ophthalmic ointment preparation in such as mineral oil, liquid lanolin or white vaseline.According to disclosed similar ophthalmic preparation formula, compound of the present invention can be suspended in hydrophilizing agent and prepare aseptic eye glue preparation, hydrophilizing agent obtains by the combination preparation of Carbopol-974 or analogue.Also sanitas and tonicity agents can be mixed.
Compound can be delivered directly to the regional area of spinal cord by disposable or SE tendon intrathecal drug delivery, such as dorsal horn area, and the subarachnoid space containing CSF (cerebrospinal fluid).
By epidural injection to the spinal cord area outside arachnoid membrane, the object to spinal nerves regional administration can be reached.Use high osmotic pressure solution or add penetration enhancers and can strengthen compound to brain membrane permeability.These penetration enhancers include but not limited to liposomal encapsulated, surfactant or ion-pairing agent.
Except those representational formulations above-mentioned, pharmaceutically acceptable assistant agent and carrier are generally known to those skilled in the art, therefore, are included in the present invention.Assistant agent and carrier have description in the literature, such as " Remingtons PharmaceuticalSciences " Mack Pub Co, and in New Jersey (1991), the document is by reference to being incorporated to herein.
As described below, preparation of the present invention also can be designed to (short-acting) of short-acting type, quick-release (fast-releasing), (long-acting) of long-acting type, (sustained-releasing) of sustained releasing type.Therefore, pharmaceutical preparation also can be mixed with controllable release or slow releasing form.
Preparation in the present invention also can comprise micelle or liposome or some other packing form, or can to extend the form administration of release, to provide storage and/or the releasing effect of prolongation.Therefore, pharmaceutical preparation and medicament can be compressed into ball or cylinder, and are used for support intramuscular or subcutaneous implantation as injection storage thing or graft, and this kind of graft can make of known inert material such as silicone resin and biodegradable polymer.
Concrete dosage can adjust according to disease condition, age, body weight, general health situation, sex, patient diet's custom, spacing of doses, route of administration, discharge rate and these factors of drug regimen.Any above-mentioned formulation containing significant quantity completely within the scope of normal experiment, therefore completely within the scope of the invention.
In cancer therapy, compound described in the invention can be used alone in method and formulation of the present invention, or uses with other therapies or active ingredient and agents thereof.Additional treatment comprises operative treatment, radiation cure, psychrotherapy, and adjunctive drug composition comprises the use of antiproliferative.The object of drug combination is such as, to most of cancer cells, cancer, melanoma, and lymphoma and sarcoma, play cell toxicant synergistic effect, and reduces or eliminate the appearance of mdr cell and reduce each Side effects of pharmaceutical drugs.The determination of the concrete quantity of active additive depends on used particular agent, cancer types, severity and stage, and other active additive dosage of the dosage of compound described herein and administration simultaneously.Can be well known in the art with other additional activity compositions of the compound conbined usage described in this patent.
Generally speaking, operation and radiation cure are mainly used in the crowd of age less than 70 years old as potential radical treatment, and the cancer of these people is local and expectation 10 years alive at least again.
The reagent that term " antiproliferative " comprises prevention Growth of Cells, maturation or spreads, they directly work by toxicity or pass through indirectly to work to the amendment of biomechanism and biological effect.Existing multiple antiproliferative is in Clinical practice, clinical assessment and preclinical development at present, and these compounds are all in the scope of the medicinal composition Therapeutic cancer described in this patent.
Typical antiproliferative can classify as alkylide, platinum medicine, metabolic antagonist, Topoisomerase inhibitors, antitumor antibiotics, anti-fissuring agent, aromatase inhibitor, thymidylate synthetase inhibitor, DNA antagonist, Farnesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, inhibitors of metalloproteinase, nucleosides reductase inhibitor, endothelin A receptor antagonist, retinoic acid receptor agonist, immuno modulating agent, hormone or health hormone medicine, photodynamic agents, angiogenesis inhibitor or tyrosine kinase inhibitor and analogue.Some antiproliferatives work by the mechanism of number of mechanisms or the unknown, therefore can be included in a more than classification.
Can be alkylating drug with a class antiproliferative of the compound conbined usage described by this patent.It is believed that, alkylating drug by other basic sites possible in alkylation and crosslinked guanine and DNA come T suppression cell division.Typical alkylating drug comprises mustargen, azacyclopropane compound, alkyl-sulphate, cis-platinum, and various nitrosourea.The shortcoming of these compounds is that they not only attack tumour cell, also attacks the cell of other proper splittings, such as medullary cell, skin cells, intestinal mucosa cell, and fetal tissue's cell simultaneously.The suitable alkylating drug that may use in this patent includes but not limited to, busulfan, procarbazine, ifosfamide, altretamine, hexamethyl trimeric cyanamide, estramustine phosphate, thiophene are for group, mustargen, dacarbazine, U-9889, lomustine, Temozolomide, endoxan, semustine and Chlorambucil.
Can be platinum medicine with the another kind of antiproliferative of the compound conbined usage described by this patent.The suitable alkylating drug that may use in this patent includes but not limited to Spiroplatin, lobaplatin (Aeterna), four platinum, Satraplatin (Johnson Matthey), ormaplatin, iproplatin, Miboplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, carboplatin.Can be antimetabolic types of drug with the another kind of antiproliferative of the compound conbined usage described by this patent.Antimetabolite is typical reversible or irreversible enzyme inhibitors, or the copying of interfere RNA by other means, the compound translated or transcribe.The suitable antimetabolite that may use in this patent include but not limited to nitrogen cytidine, trimetrexate, floxuridine, deoxycoformycin, 2-chlorodeoxyadenosine, Pentostam, Ismipur, hydroxyurea, 6-thioguanine, West Platform guest (SuperGen), cytosine arabinoside, chlorine cut down and draw shore (Bioenvision), 2-fluorine Deoxyribose cytidine, irofulven (MGI Pharma), methotrexate, Tomudex.Acetylene cytidine (Taiho), fludarabine, gemcitabine, Raltitrexed or capecitabine.
Can be Topoisomerase inhibitors with the another kind of antiproliferative of the compound conbined usage described by this patent.The suitable Topoisomerase inhibitors that may use in this patent includes but not limited to amsacrine, exetecan mesylate (Daiichi), pidorubicin, Azithromycin (ChemGenex), Etoposide, gefitinib (Sigma-Tau), teniposide, mitoxantrone, Diflomotecan (Beaufour-Ipscn), SN38, dexrazoxane (TopoTarget), elsamitrucin (Spectrum), China fir fine jade (NO λ uspharma), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNumerik), BBR-3576 (Novuspharma), Belotecan (Chong Kun Dang), rubitecan (SupeiGen), irinotecan (CPT-11), or topotecan.
Can be antibiotics antiproliferative with the another kind of antiproliferative of this patent conbined usage.The suitable antibiotics antiproliferative that may use in this patent includes but not limited to that daptomycin (dactinomycin), azonafide, valrubicin, anthracene pyrazoles, daunorubicin (daunorubicin), doxantrazole, therarubicin, losoxantrone, darubicin, bleomycin, RBZ, Sha Rou are than star (Menarini)), mithramycin, 1,3-deoxy doxorubicin hydrochloride (Gem Pharmaceuticals), porphyromycin, pidorubicin, mitoxantrone (Nuo Xiaolin) or amonafide.
Can be antimitotic class medicine with the another kind of antiproliferative of this patent conbined usage.The suitable antimitotic class medicine that may use in this patent includes but not limited to colchicine, ABT-751 (Abbott), vinealeucoblastine(VLB), xyotax (CellTherapeutics), desacetyl vinblastine amide, IDN 5109 (Bayer), aplysiatoxin 10 (NCI), A 105972 (Abbott), rhizomycin, A 204197 (Abbott), mivobulin (Warner-Lambert), synthadotin (BASF), Cemadotin (BASF), INN (AS I A.Mcdica), RPR 10988IA (Avcntis), IXD 258 (Avcntis), combretastatin A4 (BMS), epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), Ba Tabulin (Tulank), cryptophycin 52 (Eh Lilly), Vinflunine (Fabre), hydravin (PrescientNeuroPharma), auristatin PE (Teikoku Hormone), Azaepothilone B (BMS), ipsapirone (BMS), tavocept (BioNumenk), BMS 184476 (BMS), Kao Butading A-4 disodic alkaliine (OXiGENE), BMS 188797 (BMS), dolastatin-10 (NIH), taxoprexin (Protarga), cantuzumab mertansine (GlaxoSmithKlinc), Docetaxel, vincristine(VCR).
Can be aromatase inhibitor with the another kind of antiproliferative of this patent conbined usage.The suitable aromatase inhibitor that may use in this patent includes but not limited to aminoglutethimide, Atamestane (BioMedicines), formestane, fadrozole, letrozole, Exemestane or Anastrozole.
Can be thymidylate synthetase inhibitor with the another kind of antiproliferative of this patent conbined usage.The suitable thymidylate synthetase inhibitor that may use in this patent includes but not limited to pemetrexed (Eh Lilly), Nolatrexed (Eximias), ZD-9331 (BTG), doxifluridine (Nippon Roche) or 5,10-CH2-THFA (BioKeys).
Can be DNA antagonist with the another kind of antiproliferative of this patent conbined usage.The suitable DNA antagonist that may use in this patent includes but not limited to trabectedin (PharmaMar), according to peptide of writing music (Novartis), glufosfamide (BaxterInternational), Mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals) or thymectacin (NewBiotics).
Can be Farnesyltransferase inhibitor with the another kind of antiproliferative of this patent conbined usage.The suitable Farnesyltransferase inhibitor that may use in this patent includes but not limited to arglabin (NuOncology Labs), for pyrrole method Buddhist nun (Johnson & Johnson), Luo Nafani (Schcring-Plough), perillyl alcohol (DOR BioPharma) or Xarelto (Bayer).Can be pump inhibitor with the another kind of antiproliferative of this patent conbined usage.The suitable pump inhibitor that may use in this patent includes but not limited to zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex) or MS-209 (Schering AG).
Can be histone acetyltransferase inhibitor with the another kind of antiproliferative of this patent conbined usage.The suitable histone acetyltransferase inhibitor that may use in this patent includes but not limited to tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa) or MS-275 (Schering AG).
Can be inhibitors of metalloproteinase with the another kind of antiproliferative of this patent conbined usage.The suitable inhibitors of metalloproteinase that may use in this patent includes but not limited to Neovastat (Aeterna Laboratories), metastat (CollaGcncx) or Marimastat (British Biotech).
Can be nucleosides reductase inhibitor with the another kind of antiproliferative of this patent conbined usage.The suitable nucleosides reductase inhibitor that may use in this patent includes but not limited to gallium voitol (Titan), tezacitabine (Aventis), triapine (Vion) or didox (Molecules for Health).
Can be endothelin A receptor antagonist with the another kind of antiproliferative of this patent conbined usage.The suitable endothelin A receptor antagonist that may use in this patent includes but not limited to atrasentan (Abbott), bosentan (Roche), An Bosentan (BASF), Si Tashengtan (Encysive), carat raw smooth (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca).
Can be retinoic acid receptor agonists with the another kind of antiproliferative of this patent conbined usage.Retinoic acid receptor agonists comprises natural Vogan-Neu (vitamin A) and the analogue of synthetic, retinoid is combined with one or more retinoid receptor, thus start different process, such as copy, osteoplastic development, cell proliferation and differentiation, apoptosis, hematopoiesis, immunologic function and illusion.Retinoid be maintain nearly all cell normal differentiation and propagation necessary, the effect that it has reversion/suppression canceration is shown in the cancer experimental model of multiple inside and outside, see (Moon et al., Ch.14 Retinoids and cancer.In The Retinoids, Vol.2.Academic Press, Inc.1984).The suitable retinoic acid receptor agonists that may use in this patent includes but not limited to include but not limited to that fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tretinoin (Roche), isotretinoin (Roche), 13-are along vitamin A acid (UCSD) or LGD-1550 (Ligand) with the retinoid receptor activator of combined utilization of the present invention.
Can be immunomodulator with the another kind of antiproliferative of this patent conbined usage.The suitable immunomodulator that may use in this patent includes but not limited to that the antiproliferative that another kind can be combined with the present invention is immunomodulator, and it includes but not limited to Interferon, rabbit, interferon A lfa-2a (Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CDl 54 cell therapy (Tragen), gland cancer vaccine (Biomira), transvax (Intercell), strangle party's alkali (AVI BioPharma), norelin (Biostar), IRX-2 (lmmuno-Rx), BLP-25 liposome bacterin (Biomira), PEP-005 (Peplin Biotech), polyneural joint glycosides fat vaccine (Progenies), synchrovax vaccine (CTL Immuno), β-alethine (Dovetail), melanoma vaccine (CTLImmuno), vasocare (Vasogen), Rituximab (Genentech/Biogen Idec), or p21RAS vaccine (GemVax).
Can be photodynamic agents with the another kind of antiproliferative of this patent conbined usage.The suitable photodynamic agents that may use in this patent includes but not limited to oestrogenic hormon, dexamethasone, conjugated estrogen, prednisone, Ethinylestradiol, prednisolone, Chlortrianisoestrol, prednisolone, Retalon, aminoglutethimide, hydroxyprogesteroni caproas, third Rayleigh, Zytron, Sostatin, testosterone, mitotane, Uniteston, fluoxymesterone, methyltestosterone, 2ME2 (EntreMed), stilboestrol, arzoxifene (Eli Lilly), megestrol, Tamoxifen, bicalutamide, toremifene, flutamide, goserelin, Nilutamide, or Leuprolide.
Can be hormone medicine with the another kind of antiproliferative of this patent conbined usage.The suitable hormone medicine that may use in this patent includes but not limited to talaporfin (Light Sciences), Pd-bacteriopheophorbide (Yeda), theralux (Theratechnologies), lutetium compound (Pharmacyclics), motexafin, gadolinium (Pharmacyclics) or hypericin.
Can be revascularization inhibitor with the another kind of antiproliferative of this patent conbined usage.The suitable revascularization inhibitor that may use in this patent includes but not limited to Neovastat (AEterna Zentaris), ATN-224 (Attenuon), Xarelto (Bayer), tranquilizer, rhuMAb-VEGF (Genentech), ranibizumab (Genentech), benfluralin (Lane Labs), L-651582 (Merck & Co), PTK787 alkali (Novartis) or SU11248 (Pfizer).
Can be tyrosine kinase inhibitor with the another kind of antiproliferative of this patent conbined usage.The suitable tyrosine kinase inhibitor that may use in this patent includes but not limited to imatinib (Novartis), leflunomide (Aventis), kahalide F (PharmaMar) Iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), how card is for Buddhist nun (Pfizer), Tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), the appropriate Supreme Being's that of benzene, SLJ6668 (Pharmacia), Cetuximab (ImClone), rhuMAb-VEGF (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Mcdarcx), PTK787 (Novartis), close Plutarch (Genentech) difficult to understand, lapatimb (GlaxoSmithKline), Victibix (Abgenix), IMC-I Cl1 (ImClone), Xarelto (Bayer) or trastuzumab (Genentech).
Melphalan, carmustine, cis-platinum, 5-fluor-uracil, ametycin, Zorubicin (doxorubicin) can be had in addition with the antiproliferative of conbined usage of the present invention.
Above word describes synoptically to invention has been, and for being easier to understand the present invention, following embodiment is only demonstration, should not be construed as limiting the scope of the invention.
Example: the following abbreviation about the technical term of chemistry is employed in whole patent application:
ML: milliliter
DMSO: dimethyl sulfoxide (DMSO)
M-CPBA: metachloroperbenzoic acid
TLC: tlc
GI 50: half-inhibition concentration
Compound uses name software Autonom 2000 (MDL Information Systems automatically, San Leandro, CA), or Chemdraw Ultra (CambridgeSoft, Cambridge, MA) the automatic name instrument name provided, above-mentioned name software is supported chemical structure generation system title by Cahn-lngold-Prelog rule according to IUPAC rule and stereochemistry.
Embodiment
Illustrate the preparation method of formula I-1 compound of the present invention below by certain embodiments, only the present invention will be described for these examples, instead of limit the invention.
Embodiment 1: polysubstituted pyridine the synthesis of sulphur nitrogen seven-membered ring derivative
Experiment route:
The synthesis of nitrophenylsulfenyl pyridine derivate 2:
40mL dehydrated alcohol is added, sodium (0.92g, 40mmol) with 100mL single port flask, magnetic agitation, after sodium has reacted, ice-water bath has cooled, add thiophenol (40mmol), after it dissolves, add chloro nitropyridine 1 (40mmol) in batches, add rear reaction 20 minutes, suction filtration, water washing, dries, and obtains product 2.
2-(4-Methoxv-phenylsulfanvl)-3-nitropyridine 2.1:mp:140-142 DEG C; 98%; 1h NMR (CDCl 3) δ 8.52-8.47 (m, 2H), 7.47 (d, J=9.0,2H), 7.19-7.14 (m, 1H), 6.98 (d, J=9.0,2H), 3.86 (s, 3H); ES-MS m/z 263.0 [M+H +].
2-(3-Methoxv-phenylsulfanvl)-3-nitropyridine 2.2:mp:84-85 DEG C; 94%; 1h NMR (CDCl 3) δ 8.66-8.39 (m, 2H), 7.41 (q, J=7.5,1H), 7.18 (dd, J=7.6,7.2,1H), 7.14-7.00 (m, 1H), 6.82 (q, J=1.5,1H), 6.78-6.64 (m, 1H), 3.92-3.85 (m, 3H); ES-MS m/z 263.0 [M+H +].
2-(2-Methoxv-phenylsulfanvl)-3-nitropyridine 2.3:mp:85-86 DEG C; 94%; ES-MS m/z 263.3 [M+H +].
2-(4-methylphenyl-sulfanyl)-3-nitropyridine 2.4:mp:92-94 DEG C; 96%; 1h NMR (CDCl 3) δ 8.51-8.47 (m, 2H), 7.43 (d, J=7.8,2H), 7.26 (d, J=7.8,2H), 7.18-7.14 (m, 1H), 2.42 (s, 3H); ES-MS m/z 247.0 [M+H +].
2-benzene sulphur-3-nitropyridine 2.5:mp:105-106 DEG C; 98%; 1H NMR (CDCl 3) δ 8.49 (m, 2H), 7.57-7.54 (m, 2H), 7.47-7.45 (m, 3H), 7.20-7.15 (m, 1H); ES-MS m/z 232.9 [M+H +].
2-(4-chlorophenylthio)-3-nitropyridine 2.6:mp:79-80 DEG C; 80%; 1h NMR (CDCl 3) δ 8.67-8.39 (m, 1H), 7.46-7.37 (m, 1H), 7.24-7.13 (m, 1H); ES-MS m/z 251.0 [M+H +].
2-(4-chlorophenylsulfanyl)-3-nitropyridine 2.7:mp:124-126 DEG C; 82%; 1h NMR (CDCl 3) δ 8.53-8.50 (m, 2H), 7.49 (d, J=8.7,2H), 7.43 (d, J=8.7,2H), 7.21 (dd, J=8.1,4.8,1H); ES-MS m/z 267.0 [M+H +].
3-nitro-4-(4-methylphenyl-sulfanyl) pyridine 2.8:mp:109-111 DEG C; 95%; 1h NMR (CDCl 3) δ 9.34 (s, 1H), 8.34 (d, J=5.4,1H), 7.46 (d, J=8.1,2H), 7.35 (d, J=8.1,2H), 6.70 (d, J=6.0,1H), 2.46 (s, 3H); ES-MS m/z 247.0 [M+H +].
3-nitro-4-thiophenyl pyridine 2.9:92%; ES-MS m/z 233.0 [M+H +].
The synthesis of aminobenzene-thio pyridine derivate 3:
120mL ethanol is added, 30mL water, nitrophenylsulfenyl pyridine 2 (35mmol), reduced iron powder (5.9g, 105mmol), ammonium chloride (1.87g, 35mmol), N with 250mL there-necked flask 2protection, mechanical stirring reflux, reacted after 1 hour, and pad suction filtered through kieselguhr, methanol wash, evaporate to dryness methyl alcohol and ethanol, add saturated NaCl solution 80mL, extraction into ethyl acetate (3 × 40mL), anhydrous Na 2sO 4drying, solvent evaporated petrol ether/ethyl acetate recrystallization obtains target product 3.
2-(4-Methoxv-phenylsulfanvl)-3-aminopyridine 3.1:mp:92-94 DEG C; 84%; 1h NMR (CDCl 3) δ 7.96 (dd, J=4.2,1.5,1H), 7.35 (d, J=6.9,2H), 6.99-6.93 (m, 2H), 6.85 (d, J=6.9,2H), 4.15 (br, 2H), 3.78 (s, 3H); 13c NMR (CDCl 3) δ 159.19,142.80,141.19,140.02,133.09,123.37,123.20,121.63,114.73,55.21; ES-MS m/z233.0 [M+H +].
2-(3-Methoxv-phenylsulfanvl)-3-aminopyridine 3.2:mp:117-118 DEG C; 92%; 1h NMR δ 7.84-7.60 (m, 1H), 7.24-7.05 (m, 2H), 7.00 (q, J=7.4,1H), 6.97-6.78 (m, 1H), 6.78-6.71 (m, 2H), 3.88-3.81 (m, 3H), 3.31-3.24 (m, 2H); ES-MS m/z 233.0 [M+H +].
2-(2-Methoxv-phenylsulfanvl)-3-aminopyridine 3.3:mp:87-88 DEG C; 91%; ES-MS m/z 233.0 [M+H +].
2-(4-methylphenyl-sulfanyl)-3-aminopyridine 3.4:mp:94-96 DEG C; 96%; 1h NMR (CDCl 3) δ 7.99 (dd, J=4.2,1.5,1H), 7.22 (d, J=8.1,2H), 7.08 (d, J=8.1,2H), 7.05-6.95 (m, 2H), 4.18 (br, 2H), 2.30 (s, 3H); 13cNMR (CDCl 3) δ 143.58,140.11,136.86,130.14,129.85,123.76,121.84,21.00; ES-MS m/z 217.0 [M+H +].
2-benzene sulphur-3-aminopyridine 3.5:mp:68-69 DEG C; 92%; 1h NMR (CDCl 3) δ 8.04-8.02 (m, 1H), 7.30-7.18 (m, 5H), 7.10-7.06 (m, 1H), 7.03-7.00 (m, 1H); 13c NMR (CDCl 3) δ 144.17,140.28,138.94,134.04,129.27,129.06,126.60,124.24,122.01; ES-MS m/z 203.0 [M+H +].
2-(4-chlorophenylthio)-3-aminopyridine 3.6:mp:83-84 DEG C; 69%; 1h NMR δ 7.83-7.59 (m, 1H), 7.43-7.36 (m, 3H), 7.23-7.13 (m, 3H), 7.03-6.98 (m, 1H), 6.98-6.74 (m, 2H), 3.30-3.24 (m, 3H); ES-MS m/z 221.0 [M+H +].
2-(4-chlorophenylsulfanyl)-3-aminopyridine 3.7:mp:88-100 DEG C; 74%; 1h NMR (CDCl 3) δ 8.04 (d, J=4.5,1H), 7.26 (d, J=8.5,2H), 7.23 (d, J=8.5,2H), 7.11 (dd, J=8.0,4.5,1H), 7.04 (d, J=8.0,1H), 4.23 (br, 2H); 13c NMR (CDCl 3) δ 144.00,140.29,132.63,132.46,130.71,129.30,129.14,124.33,122.10; ES-MS m/z 237.0 [M+H +].
3-amino-4-(4-methylphenyl-sulfanyl) pyridine 3.8:mp:50-52 DEG C; 95%; 1h NMR (CDCl 3) δ 8.06 (s, 1H), 7.88 (d, J=4.8,1H), 7.24 (d, J=7.8,2H), 7.15 (d, J=7.8,2H), 4.08 (br, 2H), 2.35 (s, 3H); 13c NMR (CDCl 3) δ 139.74,138.19,137.10,131.40,130.31,128.53,128.02,125.47,21.06; ES-MS m/z 217.0 [M+H +].
3-amino-4-thiophenyl pyridine 3.9:86%; ES-MS m/z 203.1 [M+H +].
Pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen the synthesis of 4:
4mL POCl is added in 25mL single port flask 3, magnetic agitation, adds aminobenzene-thio pyridine 3 (2mmol), R successively 7cO 2h (1.5mmol), anhydrous SnCl 4(2mmol), drying tube is connect, reflux, after TLC monitoring has been reacted, be chilled to room temperature, reaction solution poured in frozen water, extraction into ethyl acetate (3 × 20mL), wash twice by 2mol/L NaOH solution, (or by reaction solution to entering in frozen water, 5mol/L NaOH solution adjusts pH value to be 8-9, extraction into ethyl acetate), add the washing of saturated NaCl solution, anhydrous Na 2sO 4drying, column chromatography (petrol ether/ethyl acetate=10/1-5/1), then through petrol ether/ethyl acetate (5/1, v/v) recrystallization, obtain target product 4.
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.1:mp:173-175 DEG C; 23%; 1h NMR (CDCl 3) δ 8.25 (dd, J=4.5,1.0,1H), 7.73 (d, J=8.1,2H), 7.60 (dd, J=7.5,0.9,1H), 7.56 (d, J=9.0,1H), 7.26-7.23 (m, 3H), 6.99 (dd, J=7.5,2.4,1H), 6.75 (d, J=2.4,1H), (3.70 s, 3H), 2.43 (s, 3H); 13c NMR (CDCl 3) δ 169.08,159.13,148.11,146.00,144.80,141.56,137.84,136.80,134.20,132.91,129.90,129.81,129.00,123.66,117.35,115.43,55.47,21.46; ES-MS m/z 333.0 [M+H +].
6-(3-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.2:mp:144-146 DEG C; 25%; 1h NMR (CDCl 3) δ 8.27 (dd, J=4.8,1.5,1H), 7.71 (s, 1H), 7.63 (dd, J=7.8,0.9,1H), 7.58-7.55 (m, 2H), 7.33-7.23 (m, 2H), 7.25 (dd, J=7.8,4.8,1H), 7.00 (dd, J=8.4,3.0,1H), 6.75 (d, J=3.0,1H), (3.70 s, 3H), 2.42 (s, 3H); 13c NMR (CDCl 3) δ 169.49,159.16,148.08,146.14,144.70,139.55,138.05,137.91,134.20,132.97,131.91,130.04,129.87,128.13,127.29,123.67,117.34,115.48,55.50,21.41; ES-MS m/z 333.0 [M+H +].
6-phenyl-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.3:mp:144-145 DEG C; 38%; 1h NMR (CDCl 3) δ 8.27 (d, J=4.5,1H), 7.84 (d, J=7.5,2H), 7.62 (d, J=8.1,1H), 7.57 (d, J=8.4,1H), 7.51 (t, J=7.2,1H), 7.45 (t, J=7.5,2H), 7.27-7.24 (m, 1H), 7.00 (dd, J=8.4,2.4,1H), 6.75 (d, J=2.4,1H), 3.70 (s, 3H); 13c NMR (CDCl 3) δ 169.52,159.44,148.30,146.47,144.95,139.79,138.04,134.51,133.25,131.38,130.19,130.07,128.54,123.96,117.66,115.75,55.75; ES-MS m/z 319.0 [M+H +]; Anal.Calcd for C 19h 14n 2oS:C, 71.67; H, 4.43; N, 8.80; Found:C, 71.65; H, 4.30; N, 8.69.
6-(4-fluorophenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.4:mp:179-181 DEG C; 52%; 1h NMR (CDCl 3) δ 8.28 (dd, J=4.8,1.5,1H), 7.89-7.84 (m, 4H), 7.61 (dd, J=7.5,1.5,1H), 7.58 (d, J=8.7,1H), 7.27 (dd, J=8.1,4.8,1H), 7.14 (t, J=8.7,2H), 7.01 (dd, J=8.7,3.0,1H), 6.73 (d, J=3.0,1H), 3.72 (s, 3H); 13c NMR (CDCl 3) δ 167.92,164.61 (d, J=251.78), 159.22,147.93,146.28,144.55,137.47,135.65,134.36,132.94, (131.93 d, J=9.15), 129.88,123.70,117.42,115.37, (115.32 d, J=21.75), 55.47; ES-MS m/z 337.0 [M+H +].
6-(4-nitrophenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.5:mp:198-200 DEG C; 67%; 1h NMR (CDCl 3) δ 8.34 (dd, J=4.5,1.5,1H), 8.30 (d, J=9.0,2H), 8.03 (d, J=9.0,2H), 7.66 (dd, J=8.1,1.5,1H), 7.59 (d, J=8.5,1H), 7.30 (dd, J=8.1,3.0,1H), 7.04 (dd, J=8.4,3.0,1H), 6.66 (d, J=3.0,1H), 3.72 (s, 3H); 13c NMR (CDCl 3) δ 167.43,159.67,149.43,147.88,147.40,145.35,144.48,137.19,134.93,133.64,130.95,130.28,124.17,123.71,118.03,115.44,55.82; ES-MS m/z 364.0 [M+H +].
6-(4-aminomethyl phenyl)-9-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.6:mp:173-175 DEG C; 70%; 1h NMR (CDCl 3) δ 8.37-8.12 (m, 1H), 7.90-7.66 (m, 2H), 7.67 (s, 1H), 7.67-7.36 (m, 2H), 7.36-7.31 (m, 2H), (7.18 q, J=7.5,1H), 6.95-6.71 (m, 1H), 3.92-3.85 (m, 3H), 2.50-2.43 (m, 3H); MS (ESI): m/z333.0 [M+H +].
6-(4-aminomethyl phenyl)-10-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.7:mp:187-188 DEG C; 60%; 1h NMR (CDCl 3) δ 8.24 (s, 1H), 7.85-7.71 (m, 2H), 7.66 (s, 1H), 7.45-7.30 (m, 2H), 7.20 (d, 2H), 7.12 (s, 1H), 6.91 (s, 1H), 3.87 (s, 3H), 2.47 (s, 3H); ES-MS m/z 333.4 [M+H +].
6-(4-p-methoxy-phenyl)-8-picoline is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.8:mp:179-181 DEG C; 76%; 1h NMR (CDCl 3) δ 8.24 (dd, J=4.2,1.5,1H), 7.78 (d, J=9.0,2H), 7.58 (dd, J=7.8,1.5,1H), 7.54 (d, J=7.8,1H), 7.25-7.21 (m, 2H), 7.06 (s, 1H), 6.95 (d, J=9.0,2H), (3.88 s, 3H), 2.28 (s, 3H); 13c NMR (CDCl 3) δ 168.83,161.95,147.76,145.71,144.88,137.85,136.52,135.39,132.77,132.31,132.19,131.46,130.65,123.57,113.49,55.28,20.96; ES-MS m/z 333.0 [M+H +].
6-(4-aminomethyl phenyl)-8-picoline is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.9:mp:184-186 DEG C; 87%; 1h NMR (CDCl 3) δ 8.26 (dd, J=4.5,1.5,1H), (7.70 d, J=8.4,2H), 7.63 (dd, J=8.1,1.5,1H), 7.27-7.22 (m, 4H), 7.05 (s, 1H), 2.43 (s, 3H), 2.27 (s, 3H); 13c NMR (CDCl 3) δ 169.58,147.83,146.00,144.81,141.41,137.91,137.13,136.66,135.50,132.91,132.80,132.28,130.69,129.78,128.92,123.63,21.43,20.99; ES-MS m/z 317.0 [M+H +].
6-phenyl-8-picoline is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.10:mp:132-134 DEG C; 84%; 1h NMR (CDCl 3) δ 8.28 (dd, J=4.8,1.8,1H), (7.83-7.79 m, 2H), 7.62 (dd, J=7.8,1.8,1H), 7.54 (d, J=8.1,1H), 7.52-7.42 (m, 3H), 7.29-7.23 (m, 2H), 7.04 (d, J=1.5,1H), 2.28 (s, 3H); 13c NMR (CDCl 3) δ 169.72,147.71,146.17,144.66,139.82,137.99,136.57,135.50,132.97,132.82,132.37,130.92,130.63,129.75,128.18,123.64,20.97; ES-MS m/z 303.0 [M+H +]; Anal.Calcd for C 19h 14n 2s:C, 75.47; H, 4.67; N, 9.26; Found:C, 75.44; H, 4.88; N, 9.01.
6-(4-fluorophenyl)-8-picoline is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.11:mp:175-177 DEG C; 88%; 1h NMR (CDCl 3) δ 8.28 (dd, J=4.8,1.8,1H), (7.85-7.80 m, 2H), 7.60 (dd, J=7.8,1.8,1H), 7.55 (d, J=8.1,1H), 7.29-7.23 (m, 2H), 7.13 (t, J=8.4,2H), 7.02 (s, 1H), 2.28 (s, 3H); 13c NMR (CDCl 3) δ 168.45,164.52 (d, J=250.73), 147.57,146.14,144.60,138.11,136.31, (135.94 d, J=3.45), 135.49,132.94,132.53,131.87 (d, J=9.15), 130.48,123.70, (115.23 d, J=21.75), 20.96; ES-MS m/z 321.0 [M+H +]; Anal.Calcd for C 19h 13fN 2s:C, 71.23; H, 4.09; N, 8.74; Found:C, 71.39; H, 3.97; N, 8.77.
6-(3-nitrophenyl)-8-picoline is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.12:mp:208-211 DEG C; 92%; 1h NMR (CDCl 3) δ 8.72 (s, 1H), 8.37-8.33 (m, 2H), (8.11 d, J=7.5,1H), 7.68 (dd, J=8.0,1.5,1H), 7.64 (t, J=8.0,1H), 7.58 (d, J=8.0,1H), 7.34-7.30 (m, 2H), 6.99 (s, 1H), 2.29 (s, 3H); 13c NMR (CDCl 3) δ 167.65,148.62,147.64,147.24,144.53,141.79,138.88,135.99,135.92,135.79,133.69,133.63,133.44,130.36,129.60,125.65,124.68,124.22,21.36; ES-MS m/z 348.0 [M+H +].
6-(furans-2-base)-8-picoline also [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.13:mp:156-158 DEG C; 41%; 1h NMR (CDCl 3) δ 8.26 (dd, J=4.2,1.5,1H), 7.71 (s, 1H), 7.65 (dd, J=8.4,1.5,1H), (7.53 d, J=8.4,1H), 7.34 (s, 1H), 7.30-7.22 (m, 2H), 6.78 (d, J=3.3,1H), 6.57 (dd, J=3.3,1.8,1H), 2.35 (s, 3H); 13c NMR (CDCl 3) δ 158.72,152.70,147.62,146.31,146.23,144.55,138.16,135.78,134.86,133.43,132.89,132.65,130.27,123.83,118.54,112.20,21.08; ES-MS m/z 293.1 [M+H +].
6-(4-p-methoxy-phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.14:mp:148-150 DEG C; 75%; 1h NMR (CDCl 3) δ 8.26 (dd, J=4.8,1.8,1H), 7.77 (d, J=8.7,2H), 7.67 (dd, J=8.7,0.6,1H), 7.61 (dd, J=8.4,1.5,1H), (7.46 td, J=7.5,1.8,1H), 7.32 (td, J=7.8,1.2,1H), 7.28-7.23 (m, 2H), 6.95 (d, J=8.7,2H), 3.88 (s, 3H); 13c NMR (CDCl 3) δ 168.80,162.06,147.47,145.94,144.87,138.75,136.77,133.01,132.92,132.31,131.53,131.33,130.36,127.73,123.73,113.55,55.37; ES-MS m/z 319.0 [M+H +].
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.15:mp:159-161 DEG C; 77%; 1h NMR (CDCl 3) δ 8.27 (dd, J=4.5,1.8,1H), (7.69 d, J=8.4,2H), 7.66-7.61 (m, 2H), 7.45 (td, J=7.5,1.8,1H), 7.34-7.31 (m, 1H), 7.29-7.25 (m, 2H), 7.24 (d, J=8.4,2H), 2.43 (s, 3H); 13c NMR (CDCl 3) δ 169.49,147.47,146.14,144.77,141.51,138.77,137.06,136.84,132.98,131.38,130.37,129.78,128.94,127.75,123.75,21.43; ES-MS m/z 303.0 [M+H +]; Anal.Calcd for C 19h 14n 2s:C, 75.47; H, 4.67; N, 9.26; Found:C, 75.57; H, 4.48; N, 9.21.
6-(3-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.16:mp:133-134 DEG C; 76%; 1h NMR (CDCl 3) δ 8.28 (d, J=4.8,1H), 7.68-7.63 (m, 3H), 7.52-7.44 (m, 2H), 7.34-7.23 (m, 5H), 2.41 (s, 3H); 13cNMR (CDCl 3) δ 169.88,147.42,146.26,144.64,139.78,138.71,137.94,136.88,133.01,132.94,131.81,131.41,130.34,130.04,128.04,127.75,127.18,123.72,21.32; ES-MS m/z 303.0 [M+H +].
6-(2-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.17:61%; ES-MS m/z 303.1 [M+H +].
6-phenylpyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.18:mp:131-133 DEG C; 78%; 1h NMR (CDCl 3) δ 8.28 (dd, J=4.8,1.5,1H), 7.81-7.78 (m, 2H), 7.68-7.62 (m, 2H), 7.51-7.41 (m, 4H), 7.33-7.22 (m, 3H); 13cNMR (CDCl 3) δ 169.64,147.38,146.34,144.64,139.76,138.78,136.77,133.06,133.00,131.47,131.01,130.33,129.76,128.19,127.79,123.76; ES-MS m/z 289.0 [M+H +]; Anal.Calcd forC 18h 12n 2s:C, 74.97; H, 4.19; N, 9.71; Found:C, 74.98; H, 4.20; N, 9.87.
6-(4-fluorophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.19:mp:149-151 DEG C; 80%; 1h NMR (CDCl 3) δ 8.29 (dd, J=4.8,1.5,1H), 7.84-7.79 (m, 2H), 7.68 (dd, J=7.2,0.9,1H), (7.62 dd, J=8.1,1.8,1H), (7.48 td, J=7.2,1.8,1H), (7.33 td, J=7.2,0.9,1H), (7.29-7.22 m, 2H), 7.16-7.10 (m, 2H); 13c NMR (CDCl 3) δ 168.35,164.60 (d, J=250.65), 147.33,146.41,144.57,138.86,136.52, (135.94 d, J=3.45), 133.15,133.04,131.93 (d, J=9.15), 131.64,130.19,127.90,123.83,115.29 (d, J=21.75); ES-MS m/z 307.1 [M+H +].
6-(4-trifluoromethyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.20:mp:136-137 DEG C; 57%; 1h NMR (CDCl 3) δ 8.37-8.12 (m, 1H), 8.01-7.70 (m, 5H), 7.70-7.43 (m, 2H), 7.40-7.32 (m, 1H), 7.28 (dd, J=9.0,1.6,1H), 7.18 (q, J=7.4,1H); ES-MS m/z 357.4 [M+H +].
6-(3-nitrophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.21:mp:222-224 DEG C; 82%; 1h NMR (CDCl 3) δ 8.72 (s, 1H), 8.38-8.35 (m, 2H), (8.12 d, J=8.1,1H), 7.74-7.68 (m, 2H), 7.64 (t, J=8.1,1H), 7.53 (t, J=7.8,1H), 7.40-7.30 (m, 2H), (7.22 d, J=7.8,1H); 13c NMR (CDCl 3) δ 167.13,148.29,147.15,147.02,144.12,141.36,139.01,135.75,135.44,133.47,133.35,132.16,129.72,129.27,128.22,125.37,124.38,123.96; ES-MS m/z 334.0 [M+H +]; Anal.Calcd for C 18h 11n 3o 2s:C, 64.85; H, 3.33; N, 12.60; Found:C, 64.65; H, 3.25; N, 12.58.
6-(4-nitrophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.22:mp:179-181 DEG C; 85%; 1h NMR (CDCl 3) δ 8.36 (dd, J=4.8,1.8,1H), (8.30 d, J=9.0,2H), 7.99 (d, J=9.0,2H), 7.72-7.67 (m, 2H), (7.53 td, J=7.5,1.5,1H), (7.39-7.31 m, 2H), 7.19 (dd, J=7.5,1.5,1H); 13c NMR (CDCl 3) δ 167.54,149.12,147.27,146.98,145.27,144.17,139.03,135.97,133.44,133.40,132.11,130.63,129.81,128.16,123.98,123.37; ES-MS m/z 334.0 [M+H +].
6-(the fluoro-phenyl of 3-nitro-4) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.23:mp:224-226 DEG C; 71%; 1h NMR (CDCl 3) δ 8.57 (dd, J=7.2,2.1,1H), 8.35 (dd, J=4.8,1.8,1H), 8.13-8.08 (m, 1H), (7.72 m, 1H), 7.67 (dd, J=8.1,1.8,1H), 7.54 (dd, J=7.2,1.8,1H), 7.42-7.30 (m, 3H), (7.22 dd, J=7.8,1.5,1H); 13cNMR (CDCl 3) δ 165.97,156.78 (d, J=269.03), 147.25,147.03,144.05,139.13,136.65 (d, J=4.58), 136.40,136.26,135.38,133.65,133.35,132.33,129.59,128.33,127.34,124.02,118.38 (d, J=20.63); ES-MS m/z 352.0 [M+H +].
6-(furans-2-base) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.24:mp:159-161 DEG C; 45%; 1h NMR (CDCl 3) δ 8.28 (dd, J=4.5,1.5,1H), 7.72-7.65 (m, 3H), 7.55 (dd, J=7.8,1.5,1H), 7.49 (td, J=7.5,1.5,1H), 7.41-7.36 (m, 1H), 7.29-7.25 (m, 1H), 6.76 (d, J=3.3,1H), (6.57 dd, J=3.6,1.8,1H); 13c NMR (CDCl 3) δ 158.69,152.72,147.33,146.40,144.55,139.15,135.07,133.52,133.11,131.79,129.87,127.96,123.95,118.59,112.24; ES-MS m/z 279.0 [M+H +].
6-(4-aminomethyl phenyl)-8-fluorine pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.25:mp:145-146 DEG C; 31%; ES-MS m/z 321.4 [M+H +].
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.26:mp:175-176 DEG C; 41%; 1h NMR (CDCl 3) δ 8.28 (dd, J=4.2,1.5,1H), (7.69 d, J=7.8,2H), 7.64-7.58 (m, 2H), 7.42 (dd, J=8.4,2.1,1H), 7.30-7.27 (m, 3H), 7.23 (d, J=2.7,1H), 2.44 (s, 3H); 13c NMR (CDCl 3) δ 168.10,146.99,146.44,141.94,138.11,137.20,136.48,134.23,134.16,133.14,131.49,130.04,129.73,129.18,123.99,21.48; ES-MS m/z 336.9 [M+H +].
6-phenyl-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.27:mp:137-139 DEG C; 63%; 1h NMR (CDCl 3) δ 8.30 (dd, J=4.5,1.5,1H), 7.80 (d, J=6.9,2H), 7.66-7.60 (s, 2H), 7.54-7.42 (m, 4H), 7.30 (dd, J=8.1,4.8,1H), 7.23 (d, J=2.4,1H); 13c NMR (CDCl 3) δ 168.54,147.16,146.91,144.78,139.42,138.27,137.48,134.54,134.49,133.47,131.86,131.64,130.25,129.99,128.72,124.30; ES-MS m/z 322.9 [M+H +].
6-(3-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.28:mp:141-142 DEG C; 40%; 1h NMR (CDCl 3) δ 8.29 (dd, J=4.2,1.5,1H), (7.66-7.59 m, 3H), 7.52-7.49 (m, 1H), (7.43 dd, J=8.4,2.1,1H), (7.35 d, J=4.5,2H), 7.30-7.28 (m, 1H), 7.22 (d, J=2.1,1H), 2.43 (s, 3H); 13c NMR (CDCl 3) δ 168.50,146.92,146.58,144.51,139.18,138.26,138.13,137.10,134.20,134.17,133.17,132.19,131.55,129.98,129.95,128.30,127.18,124.01,21.41; ES-MS m/z 336.9 [M+H +].
6-(3-nitrophenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.29:mp:221-223 DEG C; 75%; 1h NMR (CDCl 3) δ 8.75 (s, 1H), 8.41-8.36 (m, 2H), (8.07 d, J=7.8,1H), 7.72-7.64 (m, 3H), 7.50 (dd, J=7.8,1.8,1H), 7.36 (dd, J=7.8,4.5,1H), (7.19 d, J=2.1,1H); 13c NMR (CDCl 3) δ 165.75,148.41,147.42,147.35,146.48,143.93,140.75,137.35,136.95,135.32,134.69,134.62,133.47,132.24,129.50,129.32,125.64,124.19; ES-MS m/z 367.9 [M+H +].
6-(4-nitrophenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.30:mp:141-143 DEG C; 77%; 1h NMR (CDCl 3) δ 8.37 (dd, J=4.8,1.5,1H), 8.32 (d, J=9.0,2H), 7.99 (d, J=9.0,2H), (7.69 dd, J=8.1,1.8,1H), 7.64 (d, J=8.4,1H), 7.49 (dd, J=8.4,2.4,1H), 7.35 (dd, J=8.1,4.8,1H), 7.16 (d, J=2.4,1H); 13c NMR (CDCl 3) δ 166.19,149.36,147.61,146.51,144.61,144.07,137.42,137.19,134.70,134.66,133.62,132.28,130.63,129.50,124.28,123.65; ES-MS m/z 367.9 [M+H +].
8-methyl isophthalic acid 0-(4-p-methoxy-phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.31:mp:113-116 DEG C; 81%; 1h NMR (CDCl 3) δ 8.56 (s, 1H), 8.23 (d, J=4.8,1H), (7.80 d, J=8.7,2H), 7.41 (d, J=8.1,1H), 7.31 (d, J=4.8,1H), (7.25 d, J=8.1,1H), 7.05 (s, 1H), 6.96 (d, J=8.7,2H), (3.89 s, 3H), 2.28 (s, 3H); 13cNMR (CDCl 3) δ 169.86,162.04,146.87,145.64,145.01,138.42,137.73,136.74,135.70,132.54,132.31,132.22,131.40,131.18,125.87,113.55,55.37,21.08; ES-MS m/z 333.0 [M+H +].
8-methyl isophthalic acid 0-phenylpyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also 4.32:mp:119-121 DEG C; 73%; 1h NMR (CDCl 3) δ 8.59 (s, 1H), 8.26 (d, J=4.8,1H), 7.83 (d, J=6.6,2H), (7.52-7.40 m, 4H), 7.33 (d, J=5.1,1H), 7.25 (d, J=6.6,1H), 7.03 (s, 1H), 2.27 (s, 3H); 13c NMR (CDCl 3) δ 170.68,146.93,146.02,144.78,140.03,138.49,137.82,136.78,135.75,132.38,132.31,131.14,130.98,129.64,128.21,125.90,20.99; ES-MS m/z 303.0 [M+H +].
8-methyl isophthalic acid 0-(4-nitrophenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.33:mp:192-194 DEG C; 86%; 1h NMR (CDCl 3) δ 8.62 (s, 1H), 8.31 (d, J=8.7,3H), 8.02 (d, J=8.7,2H), (7.46 d, J=8.1,1H), 7.37 (d, J=5.1,1H), 7.31 (d, J=8.1,1H), 6.95 (s, 1H), 2.29 (s, 3H); 13c NMR (CDCl 3) δ 168.58,149.09,146.96,146.80,145.51,144.29,138.95,137.79,135.97,135.78,132.98,132.69,130.62,130.48,126.12,123.35,20.99; ES-MS m/z 348.0 [M+H +].
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen 4.34:61%; ES-MS m/z 303.2 [M+H +].
Pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfoxide 5a and pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen the synthesis of sulfone 5b:
With add compound 4 (0.64mmol) and the anhydrous CH of 40mL in 100mL single port flask successively 2cl 2, magnetic agitation, drips the CH of m-CPBA (during n=1 when 0.77mmol, n=2 1.55mmol) under ice-water bath 2cl 2(10mL) solution, drips off rear reaction 20 minutes, uses 5%NaHSO successively 3, saturated NaHCO 3, saturated NaCl solution washing, anhydrous Na 2sO 4drying, evaporated under reduced pressure solvent, silicagel column is separated (petrol ether/ethyl acetate=2: 1 ~ 1: 1, v/v), then through petrol ether/ethyl acetate (5/1, v/v) recrystallization, obtains target product 5.
8-methoxyl group-10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfoxide 5.1a:84%; ES-MS m/z 349.4 [M+H +].
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfoxide 5.2a:mp:175-177 DEG C; 90%; 1h NMR (CDCl 3) δ 8.55 (d, J=4.2,1H), 8.08 (d, J=7.5,1H), (7.89-7.74 m, 3H), 7.67 (d, J=7.8,1H), 7.48 (t, J=7.5,1H), 7.40-7.28 (m, 4H), 2.45 (s, 3H); 13c NMR (CDCl 3) δ 167.09,150.21,147.57,146.87,142.54,138.42,135.47,132.62,132.25,129.90,129.55,129.49,129.15,126.07,125.09,120.39,21.41; ES-MS m/z 319.0 [M+H +].
6-phenylpyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfoxide 5.3a:mp:162-163 DEG C; 87%; 1h NMR (CDCl 3) δ 8.56 (d, J=4.2,1H), 8.09 (d, J=7.8,1H), 7.87 (d, J=6.9,2H), 7.78 (t, J=7.5,1H), 7.69 (d, J=7.8,1H), 7.60-7.47 (m, 4H), 7.42-7.34 (m, 2H); 13c NMR (CDCl 3) δ 167.37,150.25,147.89,147.01,138.34,138.25,132.77,132.46,131.90,129.98,129.58,128.50,128.25,126.08,125.20,120.56; ES-MS m/z 305.1 [M+H +].
The chloro-10-of 8-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfoxide 5.4a:75%; ES-MS m/z 353.8 [M+H +].
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.1b:mp:242-244 DEG C; 43%; 1h NMR (CDCl 3) δ 8.51 (dd, J=4.5,1.5,1H), 8.18 (d, J=8.7,1H), 7.88 (dd, J=8.1,1.4,1H), 7.83-7.75 (m, 2H), 7.55 (dd, J=8.1,4.5,1H), 7.34-7.24 (m, 2H), 7.19 (dd, J=8.7,2.5,1H), 6.95 (d, J=2.4,1H), 3.80 (s, 3H), 2.44 (s, 3H); ES-MS m/z 365.4 [M+H +].
6-(4-aminomethyl phenyl)-9-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.2b:mp:228-229.6 DEG C; 50%; 1hNMR (CDCl 3) δ 8.81-8.56 (m, 1H), 8.10-7.95 (m, 1H), 7.95-7.67 (m, 4H), (7.48 q, J=7.5,1H), 7.44-7.20 (m, 3H), 3.92-3.85 (m, 3H), 2.51-2.44 (m, 3H); ES-MS m/z 365.4 [M+H +].
6-(4-aminomethyl phenyl)-10-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.3b:mp:230-231 DEG C; 50%; 1hNMR (CDCl 3) δ 8.80-8.57 (m, 1H), 8.09-7.83 (m, 1H), 7.83-7.64 (m, 4H), 7.55-7.44 (m, 2H), 7.42-7.27 (m, 2H), 3.94-3.87 (m, 3H), 2.51-2.44 (m, 3H); ES-MS m/z 365.4 [M+H +].
6-(4-aminomethyl phenyl)-8-picoline is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.4b:mp:230-231 DEG C; 97%; ES-MSm/z 349.2 [M+H +].
6-(4-p-methoxy-phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.5b:mp:249-251 DEG C; 90%; ES-MS m/z351.1 [M+H +].
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.6b:mp:236-238 DEG C; 98%; 1h NMR (CDCl 3) δ 8.54 (d, J=4.5,1H), 8.27 (d, J=7.5,1H), 7.90 (d, J=8.1,1H), 7.76-7.73 (m, 3H), 7.69 (t, J=8.1,1H), (7.57 dd, J=8.1,4.5,1H), (7.52 d, J=7.5,1H), 7.28 (d, J=8.1,2H), 2.44 (s, 3H); 13cNMR (CDCl 3) δ 168.50,147.74,146.12,143.44,142.51,141.33,136.62,135.67,133.07,131.64,130.98,130.21,129.27,129.18,127.93,125.64,21.54; ES-MS m/z 335.0 [M+H +].
6-(3-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.7b:mp:221-222 DEG C; 75%; ES-MS m/z 335.1 [M+H +].
6-(2-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.8b:mp:248-250.5 DEG C; 67%; ES-MS m/z 335.1 [M+H +].
6-phenylpyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.9b:mp:214-216 DEG C; 95%; 1h NMR (CDCl 3) δ 8.56 (dd, J=4.5,1.5,1H), (8.29 dd, J=7.5,1.5,1H), 7.94 (dd, J=8.4,1.8,1H), 7.88 (m, 2H), (7.79-7.67 m, 2H), 7.61-7.56 (m, 2H), 7.54-7.46 (m, 4H); 13c NMR (CDCl 3) δ 168.65,146.35,143.47,141.15,139.29,135.72,134.43,133.15,131.76,130.95,130.14,129.21,128.44,127.98,125.64; ES-MS m/z 321.1 [M+H +].
6-(4-fluorophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.10b:mp:263-265 DEG C; 98%; ES-MS m/z 339.1 [M+H +].
6-(4-trifluoromethyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.11b:mp:248-249 DEG C; 63%; 1h NMR (CDCl 3) δ 8.81-8.57 (m, 1H), 8.15-8.08 (m, 1H), 8.0-7.89 (m, 2H), 7.89-7.67 (m, 6H), 7.48 (q, J=7.4,1H); ES-MS m/z 389.0 [M+H +].
6-(furans-2-base) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.12b:mp:257-259 DEG C; 96%; ES-MS m/z 311.0 [M+H +].
6-(4-aminomethyl phenyl)-8-fluorine pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.13b:mp:178-179 DEG C; 85%; 1h NMR δ 8.82-8.57 (m, 1H), 8.18-8.05 (m, 1H), g.02-7.88 (m, 2H), (7.87-7.71 m, 2H), 7.67-7.56 (m, 1H), 7.48 (q, J=7.5,1H), 7.44-7.28 (m, 2H), 2.51-2.44 (m, 3H); ES-MS m/z 353.4 [M+H +].
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.14b:mp:231.5-233 DEG C; 91%; ES-MSm/z369.0 [M+H +].
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.15b:mp:214-216 DEG C; 80%; ES-MS m/z 335.2 [M+H +].
Embodiment 2: the selecting cell oxicity analysis of compound in Human Lung Cancer, mammary cancer, colorectal carcinoma, acute leukemia cells and normal fibroblast model
Test cell used: Non-small cell lung carcinoma cell H460, Non-small cell lung carcinoma cell H460 to taxol resistance taxR; To the human breast cancer cell line Bcap-37/ADR of Adriamycin resistant; Human colon cancer cell HT29; Human leukemia cell OP-1; People's normal fibroblast NHFB.
Experimental technique: Sulforhodamine B (SRB) method (Vanicha Vichail & Kanyawim Kirtikara.SulforhodamineB colorimetric assay for cytotoxicity screening.Nature Protocols 1,2006,1112-1116.)
Get the H460 cell, the H460 that are in logarithmic phase taxRcell, HT-29 cell, MCF-7/ADR cell, OP-1 cell and NHFB cell, be mixed with 3 × 10 4mL -1cell suspension, every hole adds 100 μ L and is inoculated in 96 orifice plates, 5%CO 2, cultivate 24 hours for 37 DEG C, remove supernatant, every hole adds fresh culture (the compound storage liquid of dissolving with DMSO that 200 μ L are with medicine, desired concn is diluted to perfect medium, wherein DMSO final concentration is 0.1%), each concentration establishes 4 multiple holes, and establish blank control wells (acellular, only containing the equal-volume cell culture fluid of 0.1%DMSO) and negative control hole (cell is with the equal-volume cell culture fluid containing 0.1%DMSO), if 4 multiple holes, cultivation is continued 48 hours after dosing, stop cultivating, carefully suck nutrient solution in hole, every hole adds the TCA 200 μ L of 10%, 1 hour is fixed at 4 DEG C, 5 times are rinsed with distilled water, naturally dry rear every hole and add 4mgmL -1sRB solution, dye 15 minutes under room temperature, abandon supernatant, acetic acid with 1% rinses 5 times to remove the dyestuff of non-specific binding, every hole adds the Tris solution 100 μ L of 10mM, measure the light absorption value in each hole in OD490nm place, be calculated as follows the compound effects inhibiting rate of 48 hours, and apply SigmaPlot computed in software half-inhibition concentration (GI 50).Inhibiting rate (%)=(control group OD value-test group OD value)/control group OD value × 100%.Experiment repetition 3 times, data represent with mean value ± sd.Result shows, and compound is at above-mentioned Non-small cell lung carcinoma cell (H460, H460 taxR), human breast cancer cell (MCF-7/ADR), human colon cancer cell (HT29), human leukemia cell (OP-1) have good cytotoxicity, but to the very low (GI of normal cytotoxicity 50> 100 μMs).Specific experiment result is as follows:
Following compounds is to the half-inhibition concentration (GI of OP-1 cell 50) value is 1-10 μM
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.1b
6-(4-aminomethyl phenyl)-10-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.3b
6-(4-aminomethyl phenyl)-8-picoline is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.4b
6-(4-p-methoxy-phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.5b
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.6b
6-phenylpyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.9b
6-(4-aminomethyl phenyl)-8-fluorine pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.13b
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.14b
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.15b
Following compounds is to the half-inhibition concentration (GI of OP-1 cell 50) value is 10-100 μM
6-(4-aminomethyl phenyl)-9-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.2b
6-(3-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.7b
6-(2-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.8b
6-(4-fluorophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.10b
6-(4-trifluoromethyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.11b
6-(furans-2-base) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.12b
Following compounds is to the half-inhibition concentration (GI of HT29 cell 50) value is lower than 1 μM
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.1b
6-(4-aminomethyl phenyl)-10-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.3b
6-(4-aminomethyl phenyl)-8-picoline is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.4b
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.6b
6-(4-aminomethyl phenyl)-8-fluorine pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.13b
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.14b
Following compounds is to the half-inhibition concentration (GI of HT29 cell 50) value is 1-10 μM
6-(4-aminomethyl phenyl)-9-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.2b
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.15b
Following compounds is to the half-inhibition concentration (GI of HT29 cell 50) value is 10-100 μM
6-(4-p-methoxy-phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.5b
6-(3-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.7b
6-(4-fluorophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.10b
6-(4-trifluoromethyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.11b
Following compounds is to the half-inhibition concentration (GI of H460 cell 50) value is lower than 1 μM
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.1b
6-(4-aminomethyl phenyl)-10-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.3b
6-(4-aminomethyl phenyl)-8-picoline is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.4b
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.6b
6-(4-aminomethyl phenyl)-8-fluorine pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.13b
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.14b
Following compounds is to the half-inhibition concentration (GI of H460 cell 50) value is 1-10 μM
6-(4-aminomethyl phenyl)-9-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.2b
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.15b
Following compounds is to H460 taxRhalf-inhibition concentration (the GI of cell 50) value is lower than 1 μM
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.1b
6-(4-aminomethyl phenyl)-10-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.3b
6-(4-aminomethyl phenyl)-8-picoline is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.4b
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.6b
6-(4-aminomethyl phenyl)-8-fluorine pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.13b
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.14b
Following compounds is to H460 taxRhalf-inhibition concentration (the GI of cell 50) value is 1-10 μM
6-(4-aminomethyl phenyl)-9-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.2b
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.15b
Following compounds is to H460 taxRhalf-inhibition concentration (the GI of cell 50) value is 10-100 μM
6-(4-fluorophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.10b
6-(4-trifluoromethyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.11b
Following compounds is to the half-inhibition concentration (GI of MCF-7/ADR cell 50) value is lower than 1 μM
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.1b
6-(4-aminomethyl phenyl)-10-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.3b
6-(4-aminomethyl phenyl)-8-picoline is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.4b
6-(4-aminomethyl phenyl)-8-fluorine pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.13b
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.14b
Following compounds is to the half-inhibition concentration (GI of MCF-7/ADR cell 50) value is 1-10 μM
6-(4-aminomethyl phenyl)-9-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.2b
6-(4-p-methoxy-phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.5b
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.6b
6-(3-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.7b
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.15b
Following compounds is to the half-inhibition concentration (GI of NHFB cell 50) value is higher than 100 μMs
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.1b
6-(4-aminomethyl phenyl)-9-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.2b
6-(4-aminomethyl phenyl)-10-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.3b
6-(4-aminomethyl phenyl)-8-picoline is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.4b
6-(4-p-methoxy-phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.5b
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.6b
6-(3-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.7b
6-(2-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.8b
6-phenylpyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.9b
6-(4-fluorophenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.10b
6-(4-trifluoromethyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.11b
6-(furans-2-base) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.12b
6-(4-aminomethyl phenyl)-8-fluorine pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.13b
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone 5.14b
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone 5.15b

Claims (6)

1. the application of the compound represented by general formula (I-1) in the antitumor drug of preparation suppression human leukemic OP-1 growth;
Wherein:
N=1 or 2;
As X=N, Y=CR 8; Work as X=CR 8time, Y=N; Wherein R 8for hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl group;
R 1, R 2for hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxyl group;
R 3, R 4, R 5, R 6for hydrogen, halogen, C1-C8 alkyl or C1-C8 alkoxyl group;
R 7for phenyl that is unsubstituted or that replace; Wherein said substituting group is selected from halogen, C1-C6 alkoxyl group.
2. the particular compound of the following stated suppresses the application in the antitumor drug of human leukemic OP-1 growth in preparation;
8-methoxyl group-10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfoxide
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfoxide
The chloro-10-of 8-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfoxide
6-(4-aminomethyl phenyl)-8-methoxypyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone
6-(4-aminomethyl phenyl)-9-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone
6-(4-aminomethyl phenyl)-10-methoxypyridine is [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone
6-(4-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(3-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(2-aminomethyl phenyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(4-trifluoromethyl) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(furans-2-base) pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(4-aminomethyl phenyl)-8-fluorine pyrido [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone
6-(4-aminomethyl phenyl)-8-chloropyridine is [2,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen also sulfone
10-(4-aminomethyl phenyl) pyrido [4,3-b] [Isosorbide-5-Nitrae] benzimidazole thiophanate nitrogen sulfone.
3. the compound described in claim 1 or 2 suppresses the application in the antitumor drug of human colon cancer cells's strain HT29 growth in preparation.
4. the compound described in claim 1 or 2 suppresses the application in the antitumor drug of Human Lung Cancer cell strain H460 growth in preparation.
5. the compound described in claim 1 or 2 suppresses the application in the antitumor drug increased the Human Lung Cancer cell strain H460TaxR of taxol resistance in preparation.
6. the compound described in claim 1 or 2 suppresses the application in the antitumor drug of mankind mastopathy cell's strain MCF-7/Adr growth of Adriamycin resistant in preparation.
CN201110141898.0A 2011-05-30 2011-05-30 New pyridine sulphur nitrogen seven-membered ring derivative as antitumor drug, and its preparation method and application Active CN102807574B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201110141898.0A CN102807574B (en) 2011-05-30 2011-05-30 New pyridine sulphur nitrogen seven-membered ring derivative as antitumor drug, and its preparation method and application
PCT/CN2012/075814 WO2012163236A1 (en) 2011-05-30 2012-05-21 Pyridothiazepine derivative, preparation method and uses therefor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201110141898.0A CN102807574B (en) 2011-05-30 2011-05-30 New pyridine sulphur nitrogen seven-membered ring derivative as antitumor drug, and its preparation method and application

Publications (2)

Publication Number Publication Date
CN102807574A CN102807574A (en) 2012-12-05
CN102807574B true CN102807574B (en) 2015-09-02

Family

ID=47231460

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201110141898.0A Active CN102807574B (en) 2011-05-30 2011-05-30 New pyridine sulphur nitrogen seven-membered ring derivative as antitumor drug, and its preparation method and application

Country Status (2)

Country Link
CN (1) CN102807574B (en)
WO (1) WO2012163236A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626761B (en) * 2012-08-24 2015-07-29 上海医药工业研究院 Benazepine compound and the application as antitumor drug thereof
CN110156815A (en) * 2019-06-04 2019-08-23 兰州大学 12a hydrogen-benzo [f] pyridine [1,2-d] [1,4] sulphur nitrogen Zhuo and preparation method thereof
CN112891377B (en) * 2021-03-26 2023-09-19 那生桑 Precious fine Mongolian medicinal powder formula granule and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055525A1 (en) * 2001-01-12 2002-07-18 Institute Of Medicinal Molecular Design. Inc. Retinoid agonists
CN101257948A (en) * 2005-02-18 2008-09-03 阿特努奥恩公司 Pyrimidine-fused diazepine derivatives and indole-fused pteridines

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE1004596A4 (en) * 1990-09-26 1992-12-22 Therabel Res S A N V Methylpiperazinoazepine DERIVATIVES, PREPARATION AND USE.
US5393752A (en) * 1992-05-26 1995-02-28 Therabel Research S.A./N.V. Methylpiperazinoazepine compounds, preparation and use thereof
WO2008048648A2 (en) * 2006-10-17 2008-04-24 Acadia Pharmaceuticals Inc. Cb1-modulating compounds and their use
WO2008118141A2 (en) * 2006-10-17 2008-10-02 Acadia Pharmaceuticals Inc. Use of cannabinoid modulating compounds in combination with other therapeutic compounds for adjunctive therapy

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055525A1 (en) * 2001-01-12 2002-07-18 Institute Of Medicinal Molecular Design. Inc. Retinoid agonists
CN101257948A (en) * 2005-02-18 2008-09-03 阿特努奥恩公司 Pyrimidine-fused diazepine derivatives and indole-fused pteridines

Also Published As

Publication number Publication date
CN102807574A (en) 2012-12-05
WO2012163236A1 (en) 2012-12-06

Similar Documents

Publication Publication Date Title
CN100418971C (en) Heteroryl-fused pyrimidinyl compounds as anticancer agents
ES2339174T3 (en) N- (ARIL- OR HETEROARIL) -PIRAZO (1,5-A) 3-SUBSTITUTED PYRIMIDINS AS KINASE INHIBITORS.
JP2018503648A (en) 4H-pyrrolo [3,2-c] pyridin-4-one derivatives
CN101568529A (en) Heteroaryl-heteroaryl compounds as cdk inhibitors for the treatment of cancer, inflammation and viral infections
TW200908983A (en) Heterocyclic compounds and uses thereof
BRPI1004899B1 (en) 3-KINASE PHOSPHOINOSITIDE INHIBITOR COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF A COMPOUND
WO2008089034A2 (en) Cytokine inhibitors
GB2572305A (en) Heterocyclic urea compound and pharmaceutical composition and application thereof
CN101535280A (en) Arylsulfonamide compounds
US11066370B2 (en) Kinase inhibitor compounds, compositions, and methods of treating cancer
CN105452248A (en) Purine diones as WNT pathway modulators
CN102947290B (en) Sulfonamido derivatives of 3,4-diarylpyrazoles as protein kinase inhibitors
CN107056755B (en) Five-ring heterocycles amides WNT pathway inhibitor
US8389530B2 (en) Substituted quinazoline compounds
WO2014079232A1 (en) 7-oxo-pyridopyrimidine derivatives, pharmaceutical compositions and uses thereof
CN103052627A (en) Pyrimidine derivatives as fak inhibitors
CN101312956A (en) Substituted 5-phenyl-3,6-dihydro-2-oxo-6H-[1,3,4]thiadiazines
CN107698603A (en) Thienopyrimidines, its preparation method, Pharmaceutical composition and its application
CN105705493A (en) Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof
CN102807574B (en) New pyridine sulphur nitrogen seven-membered ring derivative as antitumor drug, and its preparation method and application
ES2893374T3 (en) Antimitotic amides for the treatment of cancer and proliferative disorders
CA3093323C (en) Oxazino-quinazoline and oxazino-quinoline type compound, preparation method and uses thereof
AU2013318672A1 (en) Means and method for treating solid tumours
CN102690278B (en) Novel pyrimidine-fused cyclic compounds as cytokine inhibitors
CN110475771A (en) CK1 and/or IRAK1 inhibitor N1- (4- (5- (Cvclopropvlmethvl) -1- methyl-1 H- pyrazoles -4- base) pyridine -2- base) the cyclohexane-1,4-diamines derivative and related compound for the treatment of cancer

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
DD01 Delivery of document by public notice

Addressee: Changchun Discovery Sciences, Ltd.

Document name: Notification of Publication of the Application for Invention

DD01 Delivery of document by public notice

Addressee: Wang Jun

Document name: Notification of Passing Examination on Formalities

C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant