CN101578279B - Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors - Google Patents

Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors Download PDF

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CN101578279B
CN101578279B CN2008800019265A CN200880001926A CN101578279B CN 101578279 B CN101578279 B CN 101578279B CN 2008800019265 A CN2008800019265 A CN 2008800019265A CN 200880001926 A CN200880001926 A CN 200880001926A CN 101578279 B CN101578279 B CN 101578279B
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piperidines
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CN101578279A (en
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P·琼斯
J·M·安托里亚安托里亚
R·斯卡佩利
C·舒尔茨-费德姆雷希特
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Abstract

The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts, stereoisomers or tautomers thereof which are inhibitors of poly (ADP-ribose) polymerase (PARP) and thus useful for the treatment of cancer, inflammatory diseases, reperfusion injuries, ischemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes, neurodegenerat ive diseases, retroviral infection, retinal damage or skin senescence and UV- induced skin damage, and as chemo- and/or radiosensitizers for cancer treatment.

Description

The indazole replaced as the acid amides that gathers (ADP ribose) polysaccharase (PARP) inhibitor
The present invention relates to the indazole compound that acid amides replaces, they are the inhibitor that before had been called poly-(ADP ribose) polysaccharase (PARP) of poly-(ADP ribose) synthase and poly-(ADP ribosyl) transferring enzyme.Compound of the present invention is used in DNA and repairs the single therapy that has the tumour of specific defects in passage, and for example, as the toughener of some DNA damage agent (anticarcinogen and radiotherapy).In addition, compound of the present invention can be used for reducing necrocytosis (in apoplexy and myocardial infarction), lowers inflammation and tissue injury, treatment retroviral infection and the toxicity that prevents chemotherapy.
Poly-(ADP ribose) polysaccharase (PARP) forms a superfamily (Bioessays (2004) 26:1148) containing 18 kinds of albumen of PARP catalytic domain.These albumen comprise PARP-1, PARP-2, PARP-3, end anchor enzyme-1, end anchor enzyme-2, dome PARP and TiPARP.Its basic element PARP-1 consists of three main territories: containing the amino (N) of two zinc fingerses, holds DNA in conjunction with territory (DBD), automatically modifies territory, and carboxyl (C) end catalytic domain.
PARP is by NAD +cut into niacinamide and ADP ribose, thereby form ribozyme and the kytoplasm enzyme of the ADP ribose polymkeric substance of long and branching on target protein, comprise topoisomerase, histone and PARP itself (Biochem.Biophys.Res.Commun. (1998) 245:1-10).
Poly-(ADP ribosyl) changes the several bioprocesss of participation, comprises that DNA repairs, genetic transcription, cell cycle progression, necrocytosis, chromatin function and genome stability.
Point out, the catalytic activity of PARP-1 and PARP-2 can be excited rapidly by the DNA splitting of chain (seeing Pharmacological Research (2005) 52:25-33).Along with DNA is impaired, PARP-1 is combined with strand and double-stranded DNA breach.Under normal physiological condition, the PARP activity is very little, yet, when DNA damage, the PARP activity is activated immediately until 500 times.PARP-1 and PARP-2 play a part to detect the DNA chain interruption as the breach inductor block, provide fast signal to transcribe and raise as the required enzyme of DNA plerosis at damage location stopping.Because the radiotherapy in cancer therapy and a lot of embolic chemotherapy are to work by radiation-indued DNA damage, so the PARP inhibitor can be used as chemistry and the radiosensitizer of cancer therapy.Reported PARP inhibitor effectively (US 5,032,617, and US 5,215,738 and US5,041,653) aspect radiosensitization anoxic tumour cell.
Most of biological effects of PARP are relevant with following factors: affect the character of target protein and this poly-(ADP ribosyl) change process of function; Give the PAR oligopolymer of special cytosis when cut the albumen of changing from poly-(ADP ribosyl); PARP and nucleoprotein physics associate and form functional complex; With and substrate NAD +cell levels reduce (Nature Review (2005) 4:421-440).
Except relevant with the DNA reparation, PARP can also work as the mesosome of necrocytosis.Its excessive activation under pathological conditions such as local asphyxia and reperfusion injury, can cause intercellular NAD +remarkable shortage, this can cause several NAD +dependency metabolism passage impaired also caused necrocytosis (seeing Pharmacological Research (2005) 52:44-59).Because PARP activates, NAD +level significantly descends.Excessive PARP activates NAD in the cell that causes suffering a large amount of DNA damages +famine.The short half life of poly-(ADP ribose), cause fast turnover ratio, because gather (ADP ribose) once form, just by poly-(ADP ribose) glycosyl hydrolase (PARG) degraded rapidly of constitutive activity.PARP and PARG have formed one by a large amount of NAD +change into the circulation of ADP ribose, cause NAD +be down to below 20% of normal level with ATP.A kind of like this situation is especially harmful between ischemic stage, and now the disappearance of oxygen has seriously jeopardized cellular energy output.Be envisioned for the major cause of tissue injury in the free-radical generating between flush phase more subsequently.In a lot of organs, ATP can occur usually and descend, the NAD that its part may cause with poly-(ADP ribose) conversion during ischemia and reperfusion +lack relevant.Therefore, the inhibition of expection PARP can keep the cellular energy level, thereby strengthens ischemic tissue in injured rear survival.Therefore, as the compound of the inhibitor of PARP, can be used for the illness that treatment is caused by the necrocytosis of PARP mediation, comprise neuropathic conditions, for example apoplexy, wound and Parkinson's disease.
The PARP inhibitor has been proved specific killing (Nature (2005) 434:913-916 and the 917-921 that can be used for BRCA-1 and BRCA-2 defect tumour; And Cancer Biology& Therapy (2005) 4:934-936).
The PARP inhibitor also demonstrates the effect (PharmacologicalResearch (2005) 52:25-33) that strengthens cancer therapy drug, comprise platinic compound, for example cis-platinum and carboplatin (CancerChemother Pharmacol (1993) 33:157-162 and Mol Cancer Ther (2003) 2:371-382).The PARP inhibitor also demonstrates increases the topoisomerase I inhibitor, for example irinotecan and Hycamtin, anti-tumor activity (Mol Cancer Ther (2003) 2:371-382; With Clin Cancer Res (2000) 6:2860-2867), this in vivo in model, be confirmed (JNatl Cancer Inst (2004) 96:56-67).
The PARP inhibitor demonstrates and can recover the cytotoxicity of Temozolomide (TMZ) and the susceptibility of anti-proliferative effect (seeing Curr Med Chem (2002) 9:1285-1301 and Med Chem RevOnline (2004) 1:144-150).This is at some in vitro models (Br J Cancer (1995) 72:849-856; Br J Cancer (1996) 74:1030-1036; Mol Pharmacol (1997) 52:249-258; Leukemia (1999) 13:901-909; Glia (2002) 40:44-54; With ClinCancer Res (2000) 6:2860-2867 and (2004) 10:881-889) and trial model (Blood (2002) 99:2241-2244 in vivo; Clin Cancer Res (2003) 9:5370-5379 and JNatl Cancer Inst (2004) 96:56-67) in be confirmed.The PARP inhibitor also demonstrates and for example can stop, by selective N 3-VITAMIN B4 methylating reagent, MeOSO 2(CH 2)-information is translated the appearance (Pharmacological Research (2005) 52:25-33) of reading the necrocytosis that molecule (Me-Lex) brings out.
The PARP inhibitor demonstrates and plays a part radiosensitizer.Reported that the PARP inhibitor is effective aspect radiosensitization (Hypoxic) tumour cell, and stoped tumour cell lethal (Br.J.Cancer (1984) 49 (Suppl.VI): 34-42 of possibility from radiotherapy; And Int.J.Radiat.Bioi. (1999) 75:91-100) and semilethal (Clin.Oncol. (2004) 16 (1): 29-39) in the DNA damage, the recovery aspect is effective, and estimation is connect and affect several DNA damage signalling channels because they can stop after the DNA splitting of chain.
The PARP inhibitor also demonstrates and can be used for treating acute and chronic myocardosis (seeing Pharmacological Research (2005) 52:34-43).For example, already confirmed, single injection PARP inhibitor can reduce the infarct size that the ischemia and reperfusion of rabbit hearts or skeletal muscle causes.In these researchs, single injection 3-AB (10mg/kg), no matter it is inaccessible last minute, or pour into again last minute, capital causes infarct size to have similarly to reduce (32-42%), and another kind of PARP inhibitor ISQ (1mg/kg) reduces infarct size with close degree (38-48%).These results make and can reasonably infer, the PARP inhibitor can be remedied the reperfusion injury (PNAS (1997) 94:679-683) of ischemic heart or skeletal muscle tissue in advance.Also reported similar discovery for pig (Eur.J.Pharmacol. (1998) 359:143-150 and Ann.Thorac.Surg. (2002) 73:575-581) and dog (Shock. (2004) 21:426-32).
The PARP inhibitor has been proved and has can be used for treating some vascular disease, septic shock, ischemia injury and neurotoxicity (Biochim.Biophys.Acta (1989) 1014:1-7; J.Clin.Invest. (1997) 100:723-735).The oxyradical DNA damage causes the splitting of chain in DNA, it is identified by PARP subsequently, this damage shows as PARP inhibitor institute, is the principal element (J.Neurosci.Res. (1994) 39:38-46 and PNAS (1996) 93:4688-4692) that these morbid states are worked.PARP also is proved in the pathogenesis of hemorrhagic shock play a role (PNAS (2000) 97:10203-10208).
The PARP inhibitor has been proved and has can be used for treating inflammatory diseases (seeing PharmacologicalResearch (2005) 52:72-82 and 83-92).
Also confirm, by suppressing, PARP is active to be blocked the effective retroviral infection of mammalian cell.This inhibition that recombinant retroviral vector infects has demonstrated (J.Virology, (1996) 70 (6): 3992-4000) has occurred in various dissimilar cells.Therefore researched and developed the inhibitor of PARP for antiviral therapy and cancer therapy (WO 91/18591).
Verified in the test in vitro and in vivo, the PARP inhibitor can be used for treating or prevention autoimmune disease, for example type i diabetes and diabetic complication (Pharmacological Research (2005) 52:60-71).
Once inferred that PARP suppressed to have delayed the beginning of aging characteristics in human fibroblast (Biochem.Biophys.Res.Comm. (1994) 201 (2): 665-672 and Pharmacological Research (2005) 52:93-99).This may control with PARP effect relevant (Nature Gen., (1999) 23 (1): 76-80) of whole chain regulator function.
Up to now most PARP inhibitor all are combined territory and are interacted with the niacinamide of enzyme, and with regard to NAD +similarly be competitive inhibitor (Expert Opin.Ther.Patents (2004) 14:1531-1551).The analog of niacinamide, for example benzamide and derivative, belong to first compound as the research of PARP inhibitor.Yet, a little less than the inhibition activity of these molecules, and have and suppress other irrelevant effect of PARP.Therefore, the strong inhibitor of PARP enzyme need to be provided.
The previous existing description about PARP inhibitor relevant on structure.WO 1999/59973 discloses the phenyl ring of the acid amides replacement condensed with 5 yuan of hetero-aromatic rings; WO 2001/85687 discloses the indoles that acid amides replaces; WO 1997/04771, WO 2000/26192, WO 2000/32579, WO 2000/64878, WO 2000/68206, WO 2001/21615, WO 2002/068407, WO 2003/106430 and WO 2004/096793 disclose the benzoglyoxaline that acid amides replaces; WO2000/29384 discloses benzoglyoxaline and indoles that acid amides replaces; EP 0879820 discloses the benzoxazole that acid amides replaces.
Now find unexpectedly, the indazole that acid amides of the present invention replaces shows the active ability of poly-(ADP ribose) polysaccharase (PARP) of extra high inhibition.Therefore the compounds of this invention is particularly suitable as the inhibitor use of PARP-1 and/or PARP-2.They also show particularly preferred cytoactive, show the good anti-proliferative effect to BRCA1 and BRCA2 deficient cells system.
The invention provides formula I compound or its pharmaceutically useful salt, steric isomer or tautomer:
Figure G2008800019265D00051
Wherein:
R 1hydrogen or fluorine; With
R 2hydrogen or fluorine.
In an embodiment, R 1hydrogen.
In another embodiment, R 1it is fluorine.
In an embodiment, R 2hydrogen.
In another embodiment, R 2it is fluorine.
In an embodiment, R 1hydrogen, R 2hydrogen or fluorine.
In another embodiment, R 1fluorine, R 2hydrogen or fluorine.
In another embodiment, R 1hydrogen, R 2hydrogen.
In another embodiment, R 1hydrogen, R 2it is fluorine.
In another embodiment, R 1fluorine, R 2it is fluorine.
In another embodiment, R 1hydrogen or fluorine, R 2hydrogen.
In another embodiment, R 1hydrogen or fluorine, R 2it is fluorine.
The present invention also provides formula II compound or its pharmaceutically useful salt, steric isomer or tautomer:
Figure G2008800019265D00052
R wherein 1and R 2as defined above.
The present invention also provides formula III compound or its pharmaceutically useful salt or tautomer:
Figure G2008800019265D00061
R wherein 1and R 2as defined above.
The present invention also provides formula IV compound or its pharmaceutically useful salt or tautomer:
R wherein 1and R 2as defined above.
Preferred body aspect formula II, III and IV, with previous identical to the definition of formula I, is done on details suitably to revise.
The present invention also comprises the N-oxide compound with above formula I compound in its scope.Usually, these N-oxide compounds can form on any available nitrogen-atoms.The N-oxide compound can form by ordinary method, and for example formula I compound reacts under wet oxidation aluminium exists with oxone.
The present invention comprises the prodrug with above formula I compound in its scope.Usually, these prodrugs should be the functional derivatives of formula I compound, and they easily change into required formula I compound in vivo.The conventional steps of selecting and preparing suitable prodrug derivant for example is described in " Design ofProdrugs " (ed.H.Bundgaard, Elsevier, 1985).
Prodrug can be the derivative of inactivation on the pharmacology of biologically active substance (" parent drug " or " parent molecule "), and it need to transform to discharge active medicine in vivo, and has the improved delivery properties that is better than the parent drug molecule.Transforming in vivo can be the result of some metabolic processes, for example chemical hydrolysis of carboxylic acid, phosphoric acid or sulfuric ester or enzymically hydrolyse, or the oxidation of responsive functional group or reduction.
Scope of the present invention comprises the solvate of formula I compound and salt thereof, for example hydrate.
The compounds of this invention can have asymmetric center, chiral axis and chirality plane (as with described in Publication about Document: E.L.Eliel and S.H.Wilen, Stereochemistry of CarbonCompounds, John Wiley& Sons, New York, 1994, p.1119-1190), and with the form of racemoid, racemic mixture and individual other diastereomer, and all possible isomer and composition thereof, the form that comprises optically active isomer exists, within all these steric isomers all are included in the present invention.In addition, can there be tautomer in compound disclosed herein, and two kinds of tautomeric forms all plan to comprise within the scope of the present invention, even only describe a kind of tautomeric structure.
The compounds of this invention can exist with different isomeric forms, and they are all contained by the present invention.
Can there be multiple different polymorph in the compounds of this invention.
While using in this article, C 1-6alkyl represent is containing the radical of saturated aliphatic alkyl of side chain, straight chain and the annular of 1,2,3,4,5 or 6 carbon atom.For example, " C 1-6alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl etc.Preferred alkyl is methyl and ethyl.
Particular compound in the scope of the invention is:
Chlorination 3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt;
2-{4-[(3R)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide;
2-{4-[(3S)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide;
The fluoro-2H-indazole of trifluoroacetic acid 3-{4-[7-(aminocarboxyl)-5--2-yl] phenyl } piperidinium salt;
The fluoro-2-of trifluoroacetic acid 5-(the fluoro-4-piperidines of 3--3-base phenyl)-2H-indazole-7-methane amide;
Trifluoroacetic acid 3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt;
The fluoro-2-of 5-(4-piperidines-3-base phenyl)-2H-indazole-7-methane amide;
Chlorination (3S)-3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt;
Chlorination (3R)-3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt;
(R) the fluoro-2-of-5-(4-piperidines-3-base phenyl)-2H-indazole-7-methane amide;
(S) the fluoro-2-of-5-(4-piperidines-3-base phenyl)-2H-indazole-7-methane amide;
(R) the fluoro-4-piperidines of the fluoro-2-{3-of-5--3-base phenyl }-2H-indazole-7-methane amide;
(S) the fluoro-4-piperidines of the fluoro-2-{3-of-5--3-base phenyl }-2H-indazole-7-methane amide;
And pharmaceutically useful salt, free alkali or tautomer.The steric isomer of these compounds also is provided.
A kind of particular compound of the present invention is: chlorination 3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt, or its pharmaceutically useful free alkali or tautomer.The steric isomer of this compound also is provided.
A kind of particular compound of the present invention is: 2-{4-[(3R)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide, or its pharmaceutically useful salt, free alkali or tautomer.The steric isomer of this compound also is provided.
A kind of particular compound of the present invention is: 2-{4-[(3S)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide, or its pharmaceutically useful salt, free alkali or tautomer.The steric isomer of this compound also is provided.
A kind of particular compound of the present invention is: the fluoro-2H-indazole of trifluoroacetic acid 3-{4-[7-(aminocarboxyl)-5--2-yl] phenyl } piperidinium salt, or its pharmaceutically useful free alkali or tautomer.The steric isomer of this compound also is provided.
A kind of particular compound of the present invention is: the fluoro-2-of trifluoroacetic acid 5-(the fluoro-4-piperidines of 3--3-base phenyl)-2H-indazole-7-methane amide, or its pharmaceutically useful free alkali or tautomer.The steric isomer of this compound also is provided.
A kind of particular compound of the present invention is: 4-toluene sulfonic acide (3S)-3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt, or its pharmaceutically useful free alkali or tautomer.The steric isomer of this compound also is provided.
The present invention includes free alkali and pharmaceutically useful salt and the steric isomer of formula I compound.The compounds of this invention can, at amine and/or protonated containing the N atom place of N heterocyclic moiety, form salt." free alkali " word refers to the amine compound of salt-independent shape.Included pharmacologically acceptable salt not only comprises for the salt that described particular compound example is enumerated herein, but also comprises all typical pharmacologically acceptable salt of the formula I compound of free alkali form.The free form of described concrete salt formula compound can with technical point known in the art from.For example, this free form can be with box-like dilute alkaline aqueous solution, and for example NaOH, salt of wormwood, ammonia and sodium bicarbonate dilute aqueous soln, process this salt and regenerate.This free form may be for example, slightly different with salt form separately aspect some physical properties (solubleness in polar solvent), but for the present invention, this acid and subsalt are pharmaceutically equivalent in other side with free form separately.
The pharmacologically acceptable salt of the compounds of this invention can be synthetic by conventional chemical process by the compounds of this invention that contains alkalescence or acidic moiety.Generally, prepared by ion exchange chromatography by the salt of basic cpd, or reacts preparation with stoichiometric or excessive required salify mineral acid or organic acid by this free alkali in suitable solvent or all kinds of SOLVENTS mixture.Similarly, acidic cpd reacts preparation by the inorganic or organic bases with suitable.
Therefore, the pharmacologically acceptable salt of the compounds of this invention comprises that logical peralkaline the compounds of this invention reacts the non-toxic salts of the routine of the compounds of this invention formed with inorganic, organic or polymeric acid.For example, conventional non-toxic salts comprises from mineral acid, hydrochloric acid for example, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, sulfurous acid, thionamic acid, phosphoric acid, phosphorous acid, the salt that nitric acid etc. are derivative, and from organic acid, acetic acid for example, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, pamoic acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, Aspirin, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, palmitinic acid, glyconic acid, Aspartic Acid, styracin, pyruvic acid, ethyl sulfonic acid, valeric acid, trifluoroacetic acid etc., the salt prepared.Suitable polysalt comprises by polymeric acid for example tannic acid, the derivative salt of carboxymethyl cellulose.Pharmaceutically useful salt of the present invention preferably contains the inorganic or organic acid of 1 equivalent formula (I) compound and 1,2 or 3 equivalents.In an embodiment, formula (I) compound that pharmaceutically useful salt of the present invention comprises 2 equivalents and the inorganic or organic acid of 1 equivalent.More particularly, pharmaceutically useful salt of the present invention is trifluoroacetate, muriate or tosylate.Particularly, pharmaceutically useful salt of the present invention is trifluoroacetate or chloride salt.In an embodiment, this salt is trifluoroacetate.In another embodiment, this salt is muriate.In another embodiment, this salt is tosylate.
The term toluenesulphonic acids can with 4-toluene sulfonic acide Alternate, and tosylate (toluene sulfonates) also can be called tosilate (tosylate).
When the compounds of this invention is acidic cpd, suitable " pharmacologically acceptable salt " refers to the salt prepared from pharmaceutically useful nontoxicity alkali (comprising mineral alkali and organic bases).By mineral alkali, derivative salt comprises aluminium salt, ammonium salt, calcium salt, mantoquita, molysite, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc.Particularly preferably be ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt.By pharmaceutically useful organic nontoxic alkali, derivative salt comprises the salt of following organic bases: primary amine, secondary amine and tertiary amine, the amine (comprising naturally occurring replacement amine) replaced, cyclammonium and deacidite, for example arginine, Methionin, trimethyl-glycine, caffeine, choline, N, N 1-dibenzyl-ethylenediamin, ethamine, diethylamine, the 2-DEAE diethylaminoethanol, DMAE, thanomin, diethanolamine, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, breathe out amine (hydrabamine), Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol, dicyclohexyl amine, butylamine, benzylamine, phenylbenzylamine etc.
The preparation of above-described and other typical pharmacologically acceptable salt is at (1997) J.Pharm.Sci. such as Berg, and " Pharmaceutical Salts ", have in 66:1-19 mono-literary composition more fully and describe.
Be also pointed out that, the compounds of this invention is likely inner salt or zwitter-ion, for example, because the acidic moiety of compound deprotonation (carboxyl) can be anionic under physiological condition, this elementary charge can for example, be offset by cationic charge protonated or alkylating basic moiety (quaternary nitrogen atoms) in inside.
The compounds of this invention can be used for utilizing the method for therapy for treating human or animal health.
The invention provides the compound that is used for the treatment of or prevents to gather by inhibition the improved illness of (ADP ribose) polysaccharase (PARP) (referring to for example, Nature Review DrugDiscovery (2005) 4:421-440).
Therefore, the invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or prevents to gather by inhibition the improved illness of (ADP ribose) polysaccharase (PARP).
The present invention also provides a kind of method that is used for the treatment of or prevents to gather by inhibition the improved illness of (ADP ribose) polysaccharase (PARP), and the method comprises that the patient to needs are arranged uses the formula I compound of significant quantity or the composition that contains formula I compound.
PARP inhibitor of the present invention can be used for the disease that treatment is lifted in detail in WO 2005/082368.
The compounds of this invention can be used for treatment inflammatory diseases, comprise the illness caused by the organ-graft refection, for example: the chronic inflammatory joint disease comprises sacroiliitis, rheumatoid arthritis, osteoarthritis and increases relevant osteopathy with bone resorption; Inflammatory bowel, for example ileitis, ulcerative colitis, Barrett syndromes and Crohn disease; Inflammatory lung disease, for example asthma, adult respiratory distress syndrome and chronic obstructive airway disease; The inflammatory diseases of eye, comprise cerneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmia and endophthalmitis; The chronic inflammatory gingival disease, comprise oulitis and periodontitis; Tuberculosis; Leprosy; The inflammatory ephrosis, comprise Uremic complications, glomerulonephritis and ephrosis; Inflammatory dermatosis, comprise sclerodermatitis, psoriatic and eczema; The inflammatory diseases of central nervous system, comprise neural chronic demyelinating disease, multiple sclerosis, the neurodegenerative disease relevant with acquired immune deficiency syndrome (AIDS) and alzheimer disease, contagious meningitis, encephalomyelitis, Parkinson's disease, Huntington Chorea, amyotrophic lateral sclerosis and viral or from immune encephalitis; Diabetic complication, include but not limited to, immunocomplex vasculitis, systemic lupus erythematous (SLE); The inflammatory diseases of heart, for example myocardosis, ischemic heart disease, hypercholesterolemia and atherosclerosis; And other various diseases that can there is significant inflammatory component, comprise preeclampsia, chronic liver failure, brain and spinal cord injuries receptor and the bad syndromes of multiple organ dysfunction (MODS) (multiple organ failure (MOF)).Inflammatory diseases can also be the systemic inflammation of health, for example Gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or the shock of bringing out due to cancer chemotherapy response pro-inflammatory cytokine, for example shock relevant with pro-inflammatory cytokine.These shocks can be induced because of the chemotherapeutics of using as cancer therapy.
Therefore, the invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or prevents inflammatory diseases.
The present invention also provides a kind of method that is used for the treatment of or prevents inflammatory diseases, and the method comprises that the patient to needs are arranged uses the formula I compound of significant quantity or the composition that contains formula I compound.
The compounds of this invention also can be used for treatment or prevention by abiogenous outbreak and causes at during surgery reperfusion injury, intestines reperfusion injury for example; Reperfusion injury of cardiac muscle; The reperfusion injury caused by cardiopulmonary bypass surgery, aortic aneurysm prosthesis, carotid endarterectomy or hemorrhagic shock; By the organ transplantation Reoxygenation Injury that for example heart, lung, liver, kidney, pancreas, intestines and corneal transplantation cause.
Therefore, the invention provides a kind of formula I compound of the medicine for the manufacture for the treatment of or prevention reperfusion injury.
The present invention also provides a kind of method for the treatment of and prevention reperfusion injury, and the method comprises to the patient that needs are arranged to be used the formula I compound of significant quantity or contain the composition of formula I compound.
The compounds of this invention also can be used for treatment or prevention ischemic conditionscomprise the ischemic conditions caused by organ transplantation, for example stable angina pectoris, unstable angina pectoris, myocardial ischemia, hepatic ischemia, acute mesenteric artery ischemia, intestinal ischemia, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemic, ischemic nephropathy, ischemia hepatopathy, ischemic retinal are sick, septic shock, and the ischemic disease of central nervous system, for example apoplexy or cerebral ischemia.
Therefore, the invention provides a kind of formula I compound of the medicine for the manufacture for the treatment of or prevention ischemic conditions.
The present invention also provides a kind of method that is used for the treatment of or prevents ischemic conditions, and the method comprises to the patient that needs are arranged uses the formula I compound of significant quantity or the composition that comprises formula I compound.
The invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or preventing apoplectic.
The present invention also provides a kind of and is used for the treatment of or the method for preventing apoplectic, and the method comprises to the patient that needs are arranged uses the formula I compound of significant quantity or the composition that contains formula I compound.
The compounds of this invention also can be used for treatment or prevention chronic or acute renal failure.
Therefore, the invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or prevents renal failure.
The present invention also provides a kind of method for the treatment of or prevention renal failure, and the method comprises to the patient that needs are arranged uses the formula I compound of significant quantity or the composition that comprises formula I compound.
The compounds of this invention also can be used for treatment or prevention the vascular disease of non-cardiovascular disease, for example inaccessible type vasculitis of peripheral arterial occlusion, thrombus, Raynaud disease and Raynaud's phenomenon, flesh end cyanosis, erythromelalgia, venous thrombosis, varix, arterio venous fistula, lymphedema and lipedema.
Therefore, the invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or prevents the vascular disease outside cardiovascular diseases.
The present invention also provides a kind of method that is used for the treatment of or prevents the vascular disease outside cardiovascular diseases, and the method comprises to the patient that needs are arranged uses the formula I compound of significant quantity or the composition that contains formula I compound.
The compounds of this invention also can be used for treatment or prevention cardiovascular diseases, for example chronic heart failure, atherosclerosis, congestive heart failure, cyclical shock, myocardosis, heart transplantation, myocardial infarction, and irregular pulse, for example atrial fibrillation, supraventricular tachycardia, auricular flutter and paroxysmal auricular tachycardia.
Therefore, the invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or prevents cardiovascular diseases.
The present invention also provides a kind of method that is used for the treatment of or prevents cardiovascular diseases, and the method comprises to the patient that needs are arranged uses the formula I compound of significant quantity or the composition that comprises formula I compound.
The compounds of this invention also can be used for treatment and prevention diabetes, comprise type i diabetes (insulin-dependent diabetes), type ii diabetes (non-insulin-dependent diabetes mellitus (NIDDM)), gestational diabetes, for example, from immune diabetes, Insulinopathy, the diabetes that caused by Pancreas Disease, diabetes (Cushing's syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatotropin chalone knurl), A type insulin resistance syndrome, Type B insulin resistance syndrome, the lipotrophy diabetes relevant with other incretopathy and the diabetes of being brought out by the beta cell toxin.The compounds of this invention also can be used for treatment or prevent diabetes complication, diabetic cataract for example, glaucoma, retinopathy, ephrosis (for example microalbuminuria and carrying out property diabetic nephropathy), polyneuropathy, foot gangrene, the atherosclerotic coronary artery disease, peripheral arterial disease, non-ketosis hyperglycemia-hyperosmolar coma, mononeuropathy, autonomic neuropathy, ulcer of foot, the joint problem, skin or mucous membrane complication (for example infect, the shin spot, monilial infection or necrobiosis lipoidica diabeticorum), hyperlipidaemia, hypertension, insulin resistance syndrome, coronary artery disease, retinopathy, diabetic neuropathy, polyneuropathy, mononeuropathy, autonomic neuropathy, ulcer of foot, the joint problem, fungi infestation, bacterium infects and myocardosis.
Therefore, the invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or prevent diabetes.
The present invention also provides a kind of method for the treatment of or prevent diabetes, and the method comprises to the patient that needs are arranged uses the formula I compound of significant quantity or the composition that contains formula I compound.
The compounds of this invention also can be used for treatment or prevention cancer, comprise noumenal tumour, fibrosarcoma for example, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing sarcoma, leiomyosarcoma, rhabdosarcoma, colorectal carcinoma, colorectal carcinoma, kidney, carcinoma of the pancreas, osteocarcinoma, mammary cancer, ovarian cancer, prostate cancer, the esophageal carcinoma, cancer of the stomach, oral carcinoma, rhinocarcinoma, laryngocarcinoma, squamous cell carcinoma, rodent cancer, gland cancer, syringocarcinoma, sebaceous carcinoma, papillary carcinoma, emulsus shape gland cancer, cystadenocarcinoma, medullary carcinoma, segmental bronchus source property cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, the spermatogonium cancer, embryonal carcinoma, wilms' tumor, cervical cancer, uterus carcinoma, carcinoma of testis, small cell lung cancer, bladder cancer, lung cancer, epithelial cancer, skin carcinoma, melanoma, neuroblastoma and retinoblastoma, the haematogenous cancer, acute lymphocytoblast leukemia (" ALL ") for example, acute lymphocytoblast B-chronic myeloid leukemia, acute lymphocytoblast T chronic myeloid leukemia, acute myeloblastic leukemia (" AML "), acute promyelocyte leukemia (" APL "), acute monoblast leukemia, Di Guglielmo syndrome, acute megakaryoblastic leukemia, acute myeloid and monocytic leukemia, acute nonlymphocytic leukemia, acute undifferentiated cell leukemia, chronic myelocytic leukemia (" CML "), chronic lymphocytic leukemia (" CLL "), hairy cell leukemia and multiple myeloma, acute and chronic leukemia, for example lymphocytoblast leukemia, myelocyte derived leukocythemia, Lymphocytic leukemia, myelocytic leukemia, lymphoma, for example Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, waldenstrom macroglobulinemia disease, heavy chain disease and polycythemia, CNS and the cancer of the brain, for example glioma, fibrous astrocytoma, astrocytoma, a modification astrocytoma, glioblastoma multiforme, myeloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic tumor, mesoglioma, meningioma, vestibular schwannomas, adenoma, metastatic brain tumor, meningioma, vertebra knurl and myeloblastoma.
Therefore, the invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or preventing cancer.
The present invention also provides a kind of method for the treatment of or preventing cancer, and the method comprises to the patient that needs are arranged uses the formula I compound of significant quantity or the composition that comprises formula I compound.
The compounds of this invention also can be used for the cancer (seeing WO 2006/021801) that treatment lacks homologous recombination (HR) dependent DNA DSB repairing activity.
HR dependent DNA DSB repairs passage by homologous mechanism DNA plerosis double center chain fracture (DSB), and to recover continuous DNA spiral, (Nat.Genet. (2001) 27 (3): 247-254).The component that HR dependent DNA DSB repairs passage comprises, but be not limited to, ATM (NM-000051), RAD51 (NM-002875), RAD51 L1 (NM-002877), RAD51 C (NM-002876), RAD51L3 (NM-002878), DMC1 (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA-1 (NM-007295), BRCA-2 (NM-000059), RAD5O (NM-005732), MREI 1A (NM-005590), NBS1 (NM-002485), ADPRT (PARP-1), ADPRTL2, (PARP02) CTPS, RPA, RPA1, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51, RAD51p, RAD51C, RAD51D, DMC1, XRCCR, XRCC3, BRCA1, BRCA2, RAD52, RAD54, RAD50, MRE11, NB51, WRN, BLMKU70, RU80, ATM, ATRCHK1, CHK2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RAD1 and RAD9.
Repair at HR dependent DNA DSB the other oroteins related in passage and comprise regulatory factor, for example EMSY (Cell (2003) 115:523-535).
The cancer that lacks HR dependent DNA DSB repairing activity can contain or comprise the cancer cells that one or more are such, with normal cell, compare, they reduce or disappear via the ability of passage DNA plerosis DSB,, in these one or more cancer cells, the activity that HR dependent DNA DSB repairs passage may reduce or disappear.
The patient, lack in one or more cancer cells of individuality of cancer of HR dependent DNA DSB repairing activity, the activity that HR dependent DNA DSB repairs one or more components of passage may disappear.HR dependent DNA DSB repairs the component of passage and is fully confirmed (for example seeing Science (2001) 291:1284-1289) to comprise component listed above in this area.
The invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or prevents to lack the cancer of HR dependent DNA DSB repairing activity.
The present invention also provides a kind for the treatment of or prevention to lack the method for the cancer of HR dependent DNA DSB repairing activity, and the method comprises to the patient that needs are arranged uses the formula I compound of significant quantity or the composition that comprises formula I compound.
In an embodiment, cancer cells lacks the HR dependent DNA DSB repairing activity of one or more phenotypes, described phenotype is selected from: ATM (NM-000051), RAD51 (NM-002875), RAD51 L1 (NM-002877), RAD51 C (NM-002876), RAD51L3 (NM-002878), DMC1 (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA-1 (NM-007295), BRCA-2 (NM-000059), RAD5O (NM-005732), MREI 1A (NM-005590), NBS1 (NM-002485)), ADPRT (PARP-1), ADPRTL2, (PARP02) CTPS, RPA, RPA1, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51, RAD51p, RAD51C, RAD51D, DMC1, XRCCR, XRCC3, BRCA1, BRCA2, RAD52, RAD54, RAD50, MRE11, NB51, WRN, BLMKU70, RU80, ATM, ATRCHK1, CHK2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RAD1 and RAD9.
In another embodiment, cancer cells has a kind of BRCA1 and/or BRCA2 defect phenotype.Cancer cells containing this phenotype may lack BRCA1 and/or BRCA2,, BRCA1 and/or BRCA2 expression and/or the activity in this cancer cells may reduce or disappear, for example, due to the sudden change in coding nucleic acid or polymorphism, or for example, due to amplification, sudden change or polymorphicization (Cell (2003) 115:523-535) of the gene (the EMSY gene of the BRCA2 regulatory factor of encoding) of the coding and regulating factor.
BRCA-1 and BRCA-2 are known tumor inhibitors, and its wild-type allele is usually lost (Oncogene, (2002) 21 (58): 8981-93 in the tumour of heterozygosis carrier; Trends Mol.Med., (2002) 8 (12): 571-6).BRCA-1 and/or BRCA-2 sudden change are fully confirmed (Exp Clin Cancer Res, (2002) 21 (3 Suppl): 9-12) with contacting also of mammary cancer.Also the amplification of the EMSY gene of known coded BRCA-2 binding factor is relevant with mammary gland and ovarian cancer.The carrier of the sudden change in BRCA-1 and/or BRCA-2, the danger of its ovarian cancer, prostate cancer and carcinoma of the pancreas also increases.The detection of the variation in BRCA-1 and BRCA-2 is well known in the art, at for example EP 699 754, EP 705 903, Genet.Test (1992) 1:75-83, Cancer TreatRes (2002) 107:29-59, Neoplasm (2003) 50 (4): 246-50, Ceska Gynekol (2003) 68 (1): explanation is arranged in 11-16.The mensuration of the amplification of BRCA-2 binding factor EMSY is described in Cell115:523-535.Confirmed that the PARP inhibitor can be used for specific killing BRCA-1 and BRCA-2 defect tumour (Nature (2005) 434:913-916 and 917-920).
Therefore, the invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or prevents BRCA-1 or BRCA-2 defect tumour.
The present invention also provides a kind of method that is used for the treatment of or prevents BRCA-1 or BRCA-2 defect tumour, and the method comprises to the patient that needs are arranged uses the formula I compound of significant quantity or the composition that contains formula I compound.
In an embodiment, PARP inhibitor of the present invention can be used for eliminating the prophylactic treatment (seeing Cancer Res. (2005) 65:10145) of BRCA-2 deficient cells.
The compounds of this invention can be used for treatment or prevention neurodegenerative diseasecomprise, neurodegeneration, Huntington Chorea, Kennedy disease, the spinocebellar ataxia relevant with polyglutamyl amine expansion area, repeats of dentatorubropallidolatrophy atrophy (DRPLA), neurodegeneration, Ma-Yue disease, alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis, sponge shape encephalopathic, Protein virus relative disease and the multiple sclerosis (MS) relevant with protein aggregation.
Therefore, the invention provides a kind of compound of the formula I for the manufacture of medicine, this medicine is used for the treatment of or prevents neurodegenerative disease.
The present invention also provides a kind of method that is used for the treatment of or prevents neurodegenerative disease, and the method comprises to the patient that needs are arranged uses the formula I compound of significant quantity or the composition that contains formula I compound.
The compounds of this invention also can be used for treatment or prevention retroviral infection (US 5652260), retina injury (Curr.Eye Res. (2004), 29:403), the skin injury (US 5589483 and Biochem.Pharmacol (2002) 63:921) brought out of skin aging and UV.
The compounds of this invention can be used for the treatment or the prevention presenile aging with delay the cacergastic generation of the cell relevant with the age (Pharmacological Research (2005) 52:93-99).
The compounds of this invention can be according to the pharmaceutical operation of standard, be combined in pharmaceutical composition individually or with pharmaceutically useful carrier, vehicle, thinner, conditioning agent, filler, buffer reagent, stablizer, sanitas, lubricant, be administered to Mammals, the preferred mankind.
The compounds of this invention can be administered to treatment target by any route of administration easily, can be whole body/periphery or use at desirable site of action, include but not limited to, per os (for example ingesting), part (comprises for example transdermal, in nose, eye, cheek contains and hypogloeeis), lung's (for example utilize the suction of aerosol per os or nose or be blown into treatment), rectum, vagina, outer (for example injection of enteron aisle, comprise subcutaneous, intracutaneous, intramuscular, intravenously, intra-arterial, intracardiac, in sheath, in vertebra, in capsule, under capsule, in eye socket, intraperitoneal, in tracheae, under epidermis, intraarticular, under arachnoid membrane and in breastbone), and implant and store storehouse agent (for example subcutaneous or intramuscular is implanted).
Treatment target can be eukaryote, animal, vertebrates, Mammals, rodent (for example cavy, hamster, rat, mouse), murine (for example mouse), Canis animals (for example dog), feline (for example cat), equine species (for example horse), primate, man like ape (as monkey or ape), monkey (as marmoset monkey, baboon), ape (for example gorilla, chimpanzee, orangutan, gibbon) or people.
The present invention also provides the pharmaceutical composition that contains one or more the compounds of this invention and pharmaceutically acceptable carrier.The pharmaceutical composition that contains activeconstituents can be the form that is applicable to orally using, for example, and tablet, lozenge, lozenge, water base or oil base suspensoid, dispersible pulvis or granula, emulsion, hard or soft capsule, or syrup or elixir.The composition of predetermined oral medication can be manufactured according to this area any currently known methods preparation of pharmaceutical composition, and can contain one or more reagent that are selected from sweeting agent, flavour agent, tinting material and sanitas in this based composition, to form pharmaceutically exquisite and good to eat preparation.Contain the activeconstituents with the nontoxic pharmaceutically acceptable mixed with excipients that is applicable to the manufacture tablet in tablet.These vehicle can be, for example, and inert diluent, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example, Microcrystalline Cellulose, crosslinked Xylo-Mucine, W-Gum or alginic acid; Tackiness agent, for example starch, gelatin, polyvinylpyrrolidone or gum arabic; And lubricant, for example Magnesium Stearate, stearic acid or talcum.Tablet can be dressing not, or can use the known technology dressing, with the offending taste that hides medicine or delay disintegration and the absorption in gi tract, thereby provides long continuous action.For example, can use water miscible taste masking material, for example Vltra tears or hydroxypropylcellulose, or use time delay material, for example ethyl cellulose, cellulose acetate butyrate.
Oral preparations also can be made the form of hard gelatin capsule, wherein activeconstituents and a kind of inert solid diluent, for example with calcium carbonate, calcium phosphate or kaolin, mix, or make soft gelatin capsule, wherein activeconstituents for example, for example, mixes with water-soluble carrier (polyoxyethylene glycol) or oil medium (peanut oil, whiteruss or sweet oil).
Water base suspensoid contains the active substance with the mixed with excipients that is applicable to the water base suspensoid of preparation.These vehicle are suspension agents, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; Dispersion agent or wetting agent can be naturally occurring phosphatide, Yelkin TTS for example, or the condensation product of oxyalkylene and lipid acid, polyoxyethylene stearic acid ester for example, or the condensation product of oxyethane and long chain aliphatic, hexadecanol polyoxyethylene (17) ether for example, or oxyethane and derived from the condensation product of the partial ester of lipid acid and hexitol, sorbitol polyoxyethylene monoleate for example, or oxyethane and for example, derived from the condensation product of the partial ester of lipid acid and hexitan, anhydrous sorbitol Aceonon 300 MO.Water base suspensoid also can contain one or more sanitass, for example ethyl p-hydroxybenzoate or n-propyl, one or more tinting materials, one or more flavour agents, and one or more sweeting agents, for example sucrose, asccharin or aspartame.
The oil base suspensoid can for example, by activeconstituents being suspended in vegetables oil (peanut oil, sweet oil, sesame oil or Oleum Cocois), or for example be suspended in, in mineral oil (whiteruss) and prepare.The oil base suspensoid can contain thickening material, for example beeswax, hard wax or hexadecanol.Can add sweeting agent (example described above those) and flavour agent so that good to eat oral preparations to be provided.These compositions can be as anticorrosion as butylated hydroxyanisol or alpha-tocopherol by adding antioxidant.
But be applicable to making dispersion powder and the granula of water base suspensoid by adding water, the activeconstituents mixed with dispersion agent or wetting agent, suspension agent and one or more sanitass is provided.The example of suitable dispersion agent or wetting agent and suspension agent be already mentioned above those.Other vehicle, for example sweeting agent, flavour agent and tinting material, also can exist.These compositions can be for example, by adding antioxidant (xitix) anticorrosion.
Pharmaceutical composition of the present invention can also be the form of oil/water milk sap.Oil phase can be vegetables oil, for example olive cable oil or peanut oil, or mineral oil, for example whiteruss, or these oily mixtures.Suitable emulsifying agent can be naturally occurring phosphatide, soybean phospholipid for example, and for example, by lipid acid and derivative ester or the partial ester of hexitan, sorbitan monooleate, with the condensation product of above-mentioned partial ester and oxyethane, anhydrous sorbitol Aceonon 300 MO for example.Also can contain sweeting agent, correctives, sanitas and antioxidant in emulsion.
Syrup and elixir can be used sweeting agent (for example glycerine, propylene glycol, sorbyl alcohol or sucrose) preparation.This class preparation also can contain analgesic agent, sanitas, correctives, tinting material and antioxidant.
Pharmaceutical composition can be the form of aseptic injectable aqueous solutions.Operable qualified matchmaker's liquid and solvent comprise water, Ringer solution and etc. the sodium chloride solution that oozes.
Aseptic injection formulations can be also aseptic injectable o/w microemulsion, and wherein activeconstituents is dissolved in oil phase.For example, can first activeconstituents be dissolved in the mixture of soybean oil and Yelkin TTS, then this oil solution be added in the mixture of water and glycerine and be processed to form microemulsion.
Injectable solution or microemulsion can utilize part to inject and join in patient's blood flow.Or, use solution or microemulsion may be favourable in the mode of the constant circulation composition that keeps the compounds of this invention.In order to keep a kind of so constant concentration, can use continuous intravenously drug delivery systems.A kind of like this example of device is Deltec CADD-PLUS tM5400 type intravenous injection pumps.
Pharmaceutical composition can be for the sterile water for injection base of intramuscular and subcutaneous administration or oil base suspensoid.This suspensoid can be used those suitable dispersions already mentioned above or wetting agent and suspension agent preparation according to already known processes.Aseptic injection formulations can be also thinner or the aseptic injectable solution in solvent or suspension available outside nontoxic enteron aisle, for example solution in 1,3 butylene glycol.In addition, usually use aseptic nonvolatile oil as solvent or suspension medium.Any bland expressed oil be can use for this reason, synthetic monoglyceride or diester comprised.In addition, lipid acid (as oleic acid) can be used for preparing injection.
Formula I compound also can be used for the form of suppository the rectal administration of medicine.These compositions can be by mixing medicine to prepare with suitable nonirritant excipient, and described vehicle is solid at normal temperatures, but is liquid under rectal temperature, therefore can in rectum, melt, and discharges medicine.This class material comprises the mixture of polyoxyethylene glycol of theobroma oil, glycogelatin, hydrogenated vegetable oil, various molecular weight and the fatty acid ester of polyoxyethylene glycol.
Use for part, adopt emulsifiable paste, ointment, jelly, solution or suspensoid etc. containing formula I compound.(for this purposes, topical application should comprise mouth wash shua and gargarism).
The compounds of this invention can be suitable by topical application intranasal administration mediator and delivery apparatus, use, or by transdermal route the form administration of the transdermal patch that uses those of ordinary skills to know with the intranasal administration form.Will be with the form administration of transdermal delivery system, during therapeutic regimen whole, administration should be continuous rather than intermittently certainly.The compounds of this invention also can utilize such as the mixture of the polyoxyethylene glycol of theobroma oil, glycogelatin, hydrogenated vegetable oil, various molecular weight and the base-materials such as fatty acid ester of polyoxyethylene glycol, with suppository form, sends.
When the compounds of this invention is administered to treatment target, selected dosage level will depend on many factors, include but not limited to the activity of particular compound, the severity of indivedual symptoms, route of administration, administration time, the drainage rate of compound, the time length for the treatment of, the other medicines of associating use, compound and/or material, and patient's age, sex, body weight, situation, general health and previous medical history.Quantity and the route of administration of compound are decided in its sole discretion by the doctor the most at last, but dosage can make the partial concn at site of action place realize desired effect and not produce obvious injury or disadvantageous side reaction usually.
In body, use can be in whole therapeutic process with a dosage continuously or off and on (for example, by appropriate intervals gradation administration) carry out.The method of determining efficient manner and application dosage is well known to those skilled in the art, and will become with preparation, the purpose for the treatment of, the target cell for the treatment of of using in treatment and the object for the treatment of.Can carry out the single or multiple administration, dosage level and pattern are selected by the doctor who is responsible for treatment.
In general, the appropriate dose of active compound be in every kg treatment target body weight every day approximately 100 μ g to about 250mg.At active compound, be the situation of salt, ester, prodrug etc., dosage is calculated on the basis of parent compound, so the actual weight of using increases in proportion.
The compounds of this invention also can be used with cancer therapy drug or chemotherapy drugs in combination.
The compounds of this invention can be used as the chemistry and radiosensitizer for cancer therapy.They can be used for before carrying out or carrying out the mammiferous treatment of cancer therapy.Previous treatment comprises previous chemotherapy, radiotherapy, operation or immunotherapy, for example cancer vaccine.
Therefore, the invention provides the molectron of formula I compound and cancer therapy drug, for while, difference or order administration.
The present invention also provides the molectron of formula I compound, radiotherapy and other chemotherapeutics, for simultaneously, respectively or order use.
The present invention also provides a kind of compound of the formula I for the manufacture of medicine, and this medicine is used as assistant agent in cancer therapy, or by with ionizing rays and other chemotherapy drugs in combination, the effect for strengthening to tumour cell.The present invention also provides the application of formula I compound in manufacturing medicine, and this medicine is used as assistant agent in cancer therapy, or by with ionizing rays and other chemotherapy drugs in combination, strengthen the effect to tumour cell.The compounds of this invention can also be used with ionizing rays and other chemotherapy drugs in combination.
The present invention also provides a kind of method of chemotherapy or radiotherapy, and the method comprises that patient to needs are arranged uses by the formula I compound of significant quantity or containing the composition of formula I compound and ionizing rays or chemotherapy drugs in combination.The compounds of this invention also can be used with ionizing rays and other chemotherapy drugs in combination.
In conjoint therapy, the compounds of this invention can be before the object to needs treatments be used other cancer therapy drug (for example 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, before 8 weeks or 12 weeks), simultaneously, or (for example 5 minutes afterwards, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, after 8 weeks or 12 weeks) use.In embodiment miscellaneous, the compounds of this invention and other cancer therapy drug be separated by 1 minute, 10 minutes, 30 minutes, be less than 1 hour, 1-2 hour, 2-3 hour, 3-4 hour, 4-5 hour, 5-6 hour, 6-7 hour, 7-8 hour, 8-9 hour, 9-10 hour, 10-11 hour, 11-12 hour, be no more than 24 hours, or be no more than administration in 48 hours.
The compounds of this invention and other cancer therapy drug can adduction ground or synergy work.The synergistic combinations of the compounds of this invention and other cancer therapy drug makes the compounds of this invention and one of other cancer therapy drug or the two can use lower dosage and/or less medication number of times, and/or the drug administration of less number of times can reduce and any toxicity relevant to the treatment target drug administration, and do not reduce the effect of medicine in cancer therapy.In addition, synergy can make the effect of these medicines in cancer therapy improve and/or reduce any harmful or bad side effect relevant with any medicine of independent use.
Be used for combining the cancer drug of use with the compounds of this invention or the example of chemotherapeutics can find in following document: Cancer Principles and Practice of Oncology by V.T.Devita and S.Hellman (editors), 6 thedition (February 15,2001), LippincottWilliams& Wilkins Publishers.Those of ordinary skills can judge that the federation of which kind of medicine is useful according to the concrete characteristics of related medicine and cancer.These cancer therapy drugs include, but not limited to following medicine: hdac inhibitor, estrogenic agents, androgen receptor modifier, retinoid receptor modulators, cytotoxicity/cytostatic agent, anti-proliferative agent, prenyl protein transferase inhibitor, HMG-CoA reductase inhibitor, the hiv protease inhibitor, reverse transcriptase inhibitors and other angiogenesis inhibitor, hyperplasia and survival signaling inhibitor, the reagent at apoptosis inducer and the interference cell cycle outpost of the tax office.The compounds of this invention is effective especially when jointly using with radiotherapy.
The example of " hdac inhibitor " comprises Vorinostat (SAHA), LAQ824, LBH589, PXD101, MS275, FK228, valproic acid, butyric acid and CI-994.
Regardless of its mechanism how " estrogenic agents " refers to the compound that disturbs or suppress oestrogenic hormon and receptors bind.The example of estrogenic agents comprises, but be not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(piperidino) oxyethyl group] phenyl]-2H-1-chromene-3-yl] phenyl-2,2-dimethyl propylene acid esters, 4,4'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone, and SH646.
Regardless of its mechanism how " androgen receptor modifier " refers to the compound that disturbs and suppress male sex hormone and receptors bind.The example of androgen receptor modifier comprises finasteride and other 5α-reductase inhibitor, Nilutamide, flutamide, bicalutamide, liarozole and acetic acid Abiraterone.
Regardless of its mechanism how " retinoid receptor modulators " refers to disturb or suppresses the compound of retinoid and receptors bind.The example of this class retinoid receptor modulators comprises bexarotene, tretinoin, isotretinoin, the suitable tretinoin of 9-, alpha-difluoromethyl ornithine, ILX23-7553, trans-N-(4 '-hydroxy phenyl) dimension A acid amides, and N-4-carboxyphenyl dimension A acid amides.
" cytotoxicity/cytostatic agent " refers to mainly the compound that causes necrocytosis or inhibition of cell proliferation by direct interference cells play function or inhibition or interference cell mitotic division, comprise alkylating reagent, tumour necrosis factor, intercalator, the compound that hypoxemia activates, microtubule inhibitors/microtubule stabilizer, mitotic kinesin inhibitors, the kinase inhibitor related in the mitotic division process, metabolic antagonist, the biological response conditioning agent, hormone/hormone antagonist medicine, hemopoieticgrowth factor, the monoclonal antibody targeted drug, topoisomerase enzyme inhibitor, proteasome inhibitor and ubiquitin ligase inhibitor.
The example of cytotoxic agent comprises, but be not limited to, endoxan, Chlorambucil, carmustine (BCNU), lomustine (CCNU), busulfan, Treosulfan, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, mitolactol, ranomustine, fotemustine, naphthalene reaches platinum, aroplatin, oxaliplatin, Temozolomide, methyl mesylate, Procarbazine, Dacarbazine, Eptaplatin, estramustine, the toluenesulphonic acids improsulfan, trofosfamide, nimustine, dibromo spiral shell nitrogen ammonium, pumitepa, lobaplatin, Satraplatin, methylmitomycin, cis-platinum, irofulven, right ifosfamide, cis-amine dichloro (2-picoline) platinum, the benzyl guanine, glufosfamide, GPX100, tetrachloro is (suitable, instead, instead) dimethylene (hexane-1, the 6-diamines) methylene radical [diamines-platinum (II)] two [diamines (chlorine) platinum (II)], two aziridinyl spermine, white arsenic, 1-(11-dodecyl amino-10-hydroxyl undecyl)-3, the 7-dimethyl xanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, Dx, epirubicin, antineoplaston, 3 '-deaminizating-3 '-morpholinyl-13-deoxidation-10-hydroxyl Carubicin, the At mycin, galarubicin, Elinafide, MEN10755 and deaminize-3-of 4-de-methoxy-3-nitrogen heterocyclic propyl group-4-sulfonyloxy methyl daunorubicin (seeing WO 00/50032).Other example comprises Raf kinase inhibitor (for example Bay43-9006) and mTOR inhibitors (for example CCI-779 of Wyeth and Ariad AP23573).Other example is the inhibitor (for example LY294002) of P13K.
In an embodiment, the compounds of this invention can be combined use with alkylating reagent.
The example of alkylating reagent includes, but not limited to mustargen, endoxan, ifosfamide, trofosfamide and Chlorambucil; Nitrosourea: carmustine (BCNU) and lomustine (CCNU); Alkyl sulfonic ester: busulfan and Treosulfan; Triazenes: Dacarbazine, Procarbazine and Temozolomide; Contain platinum complexes: cis-platinum, carboplatin, aroplatin and oxaliplatin.
In an embodiment, alkylating reagent is Dacarbazine.Dacarbazine can be with about 150mg/m 2(body surface area for the treatment of target) is to about 250mg/m 2dosage be administered to treatment target.In another embodiment, Dacarbazine is with about 150-250mg/m 2dosage to the treatment target intravenously, use continuous 5 days once a day.
In an embodiment, alkylating reagent is Procarbazine.Procarbazine can be with about 50mg/m 2(body surface area for the treatment of target) is to about 100mg/m 2dosage be administered to treatment target.In another embodiment, the third carbazine is with about 50-100mg/m 2dosage to the treatment target intravenously, use continuous 5 days once a day.
In an embodiment, alkylating reagent is Temozolomide.Temozolomide can be with about 150-200mg/m 2the dosage of (body surface area for the treatment of target) is administered to treatment target.In another embodiment, Temozolomide is with about 150-200mg/m 2dosage to the animal oral administration continuous 5 days once a day.
The example of anti-mitosis medicine comprises: the isometry colchicine, and halichondrin B, colchicine, colchicine derivative, aplysiatoxin 10, Mei Dengsuo, agile new, thiocolciran alkali and trityl halfcystine.
The example of the compound that hypoxemia activates is Win-59075.
The example of proteasome inhibitor includes but not limited to: lactacystin, Velcade, epoxomicin and peptide aldehyde (for example MG 132, MG 115 and PSI).
The example of microtubule inhibitors/microtubule stabilizer comprises taxol, vindesine sulfate, vincristine(VCR), vinealeucoblastine(VLB), vinorelbine, 3, 4 '-bis-dehydrogenations-4 '-deoxidation-8 '-navelbine, Taxotere, agile new, dolastatin, the mivobulin isethionate, auristatin, Cemadotin, RPR109881, BMS184476, Vinflunine, cryptophycin, 2, 3, 4, 5, the fluoro-N-of 6-five (the fluoro-4-p-methoxy-phenyl of 3-) benzsulfamide, F 81097, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-PROLINE-tert-butylamides, TDX258, esperamicin (is shown in for example US 6, 284, 781 and 6, 288, 237) and BMS188797.
Some examples of topoisomerase enzyme inhibitor are Hycamtins, hycaptamine, irinotecan, rubitecan, exatecan, gefitinib, Diflomotecan, the silyl camptothecine, 9-aminocamptothecin, camptothecine, crisnatol, ametycin, 6-oxyethyl group propionyl-3 ', outside 4 '-O--benzylidene ferment wine rhzomorph, 9-methoxyl group-N, N-dimethyl-5-nitropyrazole also [3, 4, 5-k1] acridine-2-(6H) propylamine, 1-amino-9-ethyl-5-fluoro-2, 3-dihydro-9-hydroxy-4-methyl-1H, 2H-benzo [de] pyrans also [3 ', 4 ': b, 7] indolizine also [1, 2b] quinoline-10, 13 (9H, 15H) diketone, lurtotecan, 7-[2-(N-isopropylamino) ethyl]-(20S) camptothecine, BNP 1350, BNPI1100, BN80915, BN80942, she holds in the palm the pool glycosides phosphoric acid, teniposide, sobuzoxane, she holds in the palm the pool glycosides 2 '-dimethylamino-2 '-deoxidation, GL331, N-[2-(dimethylamino) ethyl]-9-hydroxyl-5, 6-dimethyl-6H-pyrido [4, 3-b] carbazole-1-methane amide, asulacrine, (5a, 5aB, 8aa, 9b)-9-[2-[N-[2-(dimethylamino) ethyl]-the N-methylamino] ethyl]-5-[4-hydroxyl-3, the 5-Dimethoxyphenyl]-5, 5a, 6, 8, 8a, 9-hexahydro furyl also (3 ', 4 ': 6, 7) naphtho-(2, 3-d)-1, 3-dioxole-6-ketone, 2, 3-(inferior methoxyl group)-5-methyl-7-hydroxyl-8-methoxyl group benzo [c]-phenanthridines, 6, 9-bis-[(2-amino-ethyl) amino] benzo [g] isoquinoline 99.9-5, the 10-diketone, 5-(3-aminopropan amino)-7, 10-dihydroxyl-2-(2-hydroxyethyl aminomethyl)-6H-pyrazolo [4, 5, 1-de] acridine-6-ketone, N-[1-[2-(diethylamino) ethylamino]-7-methoxyl group-9-oxo-9H-thioxanthene-4-ylmethyl] methane amide, N-(2-(dimethylamino) ethyl) acridine-4-carboxamide, 6-[[2-(dimethylamino) ethyl] amino]-3-hydroxyl-7H-indeno [2, 1-c] quinoline-7-ketone and dimesna, non-camptothecine topoisomerase-1 inhibitor, for example indolocarbazole, and topoisomerase-1 and II double inhibitor, for example phenonaphthazine, XR20 115761MLN 576 and benzo pyrido indoles.
In an embodiment, topoisomerase enzyme inhibitor is irinotecan.Irinotecan can be with about 50-150mg/m 2the dosage of (experimental subjects body surface area) is administered to treatment target.In another embodiment, irinotecan is with about 50-150mg/m 2dosage at 1-5 days once a day intravenously to treatment target successive administration 5 days, then with about 50-150mg/m 2dosage at 28-32 days continuous 5 days of intravenous administration once a day, and then with about 50-150mg/m 2dosage at 55-59 days continuous 5 days of intravenous administration once a day.
The example of the inhibitor of mitotic kinesins (particularly mankind's mitotic kinesins KSP) has description in following patent documentation: PCT publication WO 01/30768, WO01/98278, WO 02/056880, WO 03/050, 064, WO 03/050, 122, WO03/049, 527, WO 03/049, 679, WO 03/049, 678, WO 03/039460, WO03/079973, WO 03/099211, WO 2004/039774, WO 03/105855, WO03/106417, WO 2004/087050, WO 2004/058700, WO 2004/058148 and WO 2004/037171 and U.S. Patent application US 2004/132830 and US 2004/132719.In an embodiment, the inhibitor of mitotic kinesins comprises but is not limited to: the inhibitor of KSP, the inhibitor of MKLP1, the inhibitor of CENP-E, the inhibitor of MCAK, the inhibitor of Kifl4, the inhibitor of Mphosph1 and the inhibitor of Rab6-KIFL.
" the kinase whose inhibitor related in the mitotic division process " includes, but not limited to the aurora kinase inhibitor, Polo sample kinases (PLK) inhibitor (the particularly inhibitor of PLK-1), bub-1 inhibitor and bub-R1 inhibitor.
" anti-proliferative drug " comprises sense-rna and DNA oligonucleotide, for example G3139, ODN698, RVASKRAS, GEM231 and INX3001, and antimetabolite, for example enocitabine, carmofur, Tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, Galocitabine, octadecyl phosphoric acid cytosine arabinoside, fosteabine sodiumhydrate, Raltitrexed, paltitrexid, emitefur, tiazofurine, Decitabine, Nolatrexed, pemetrexed, naphthalene draws shore, 2 '-deoxidation-2 '-methylene radical cytidine, 2 '-fluorine methylene radical-2 '-Deoxyribose cytidine, N-[5-(2,3-dihydro benzo furyl) sulphonyl]-N '-(3,4-dichlorophenyl) urea, N6-[4-deoxidation-4-[N2-[2 (E), 4 (E)-14 diene acyls] glycyl amino]-L-glycerine-B-L-pyrans mannoheptose base] VITAMIN B4, dehydrogenation film ecteinascidin, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydrochysene-3H-Kui Linpyrimido quinoline [5,4-b] [Isosorbide-5-Nitrae] thiazine-6-base-(S)-ethyl]-2,5-thienyl-Pidolidone, aminopterin, 5 FU 5 fluorouracil, alanosine, 11-acetyl-8-(carbamoyloxy group methyl)-4-formyl-6-methoxyl group-14-oxa--1,11-diaza Fourth Ring (7.4.1.0.0)-14 carbon-2,4,6-triolefin-9-yl acetate, trihydroxyoctahydroindolizidine, lometrexol, dexrazoxane, methioninase, 2 '-cyano group-2 '-'-deoxy-n 4-palmityl-1-B-D-arbinofuranose base cytosine(Cyt) and Trianpine.
The example of monoclonal antibody target therapeutic agent comprises and contains cytotoxic agent or the radioisotopic medicine be attached on the special or monoclonal antibody that target cell is special of cancer cells, and the example comprises Bexxar (tositumomab).
" HMG-CoA reductase inhibitor " refers to the inhibitor of 3-hydroxy-3-methylglutaric acid list acyl coenzyme A reductase enzyme.The example of operable HMG-CoA reductase inhibitor includes but not limited to: lovastatin (
Figure G2008800019265D00251
see US 4,231,938,4,294,926 and 4,319,039), Simvastatin (
Figure G2008800019265D00252
see US 4,444,784,4,820,850 and 4,916,239), Pravastatin (
Figure G2008800019265D00253
see US 4,346,227,4,537,859,4,410,629,5,030,447 and 5,180,589), his spit of fland of fluoro (
Figure G2008800019265D00254
see US 5,354,772,4,911,165,4,929,437,5,189,164,5,118,853,5,290,946 and 5,356,896) and atorvastatin (
Figure G2008800019265D00255
see US 5,273,995,4,681,893,5,489,691 and 5,342,952).The structural formula of these and other HMG-CoA reductase inhibitor that can use in the present invention is described in M.Yalpani, " Cholesterol Lowering Drugs ", Chemistry& Industry, in the 87th page of pp.85-89 (in May, 1996 number) and US 4,782,082 and 4,885,314.(term used herein " HMG-CoA reductase inhibitor " comprises all pharmaceutically useful lactone with HMG-CoA reductase inhibitor activity and open loop acid form, lactonic ring is opened to form free acid), and the salt of these compounds and ester-formin, so the use of these salt, ester, open loop acid and lactone form is included within the scope of the invention.
" prenyl protein transferase inhibitor " refers to suppress the compound of any prenyl protein transferase and any combination thereof, these enzymes comprise farnesyl-protein transferase (FPTase), I type geranyl geranyl protein transferase (GGPTase-I), with II type geranyl geranyl protein transferase (GGPTase-II, also referred to as Rab GGPTase).
The example of prenyl protein transferase inhibitor can find in following publication and patent:
WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S.5, 420, 245, U.S.5, 523, 430, U.S.5, 532, 359, U.S.5, 510, 510, U.S.5, 589, 485, U.S.5, 602, 098, European patent 0 618 221, European patent 0 675 112, European patent 0 604 181, European patent 0 696 593, WO 94/19357, WO 95/08542, WO95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S.5, 661, 152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S.5, 571, 792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO97/26246, WO 97/30053, WO 97/44350, WO 98/02436, and U.S.5, 532, 359.
As the prenyl protein transferase inhibitor to the visible European J.of of the example of the effect of vasculogenesis Cancer (1999), 35 (9): 1394-1401.
" angiogenesis inhibitor " refers to suppress the compound of neovascularization, no matter its mechanism how.The example of angiogenesis inhibitor comprises, but be not limited to, tyrosine kinase inhibitor (for example inhibitor of tyrosine kinase receptor Flt-1 (VEGFR1) and Flt-1/KDR (VEGFR2)), epidermis derives, derivative or the platelet-derived somatomedin of inoblast, MMP (matrix metalloproteinase) inhibitor, the integrin blocker, interferon-' alpha ', IL-12, PPS, cyclooxygenase inhibitors (comprises NSAID (NSAIDs), as Asprin and Ibuprofen BP/EP and selective cyclooxygenase-2 inhibitor, as celecoxib and rofecoxib (PNAS (1992) 89:7384, JNCI (1982) 69:475, Arch.Opthalmol. (1990) 108:573, Anat.Rec. (1994) 238:68, FEBS Letters (1995) 372:83, Clin, Orthop. (1995) 313:76, J.Mol.Endocrinol. (1996) 16:107, Jpn.J.Pharmacol. (1997) 75:105, CancerRes. (1997) 57:1625 (1997), Cell (1998) 93:705, Intl.J.Mol.Med. (1998) 2:715, J.Biol.Chem. (1999) 274:9116)), steroid class antiphlogistic drug (corticosteroid for example, mineralocorticoid, dexamethasone, prednisone, prednisolone, methylprednisolone, Betamethasone Valerate), Carboxyamidotraiazol(, windmill presses down alkali A-4, squalamine, 6-O-chloracetyl carbonyl Fumngillin, Thalidomide, angiostatin, troponin-1, angiotensin-ii antagonist (seeing J.Lab.Clin.Med. (1985) 105:141-145), and the antibody of VEGF (is shown in Nature Biotechnology (1999) 17:963-968, Kim etc. (1993) Nature 362:841-844, WO 00/44777 and WO 00/61186).
Other medicine that can combine with the compounds of this invention the adjusting of use or suppress vasculogenesis comprises the medicine (seeing the commentary in Clin.Chem.La.Med. (2000) 38:679-692) of adjusting or anticoagulant and fibrinolytic system.The exemplary drugs of these adjustings or anticoagulant and fibrinolysis approach comprises, but be not limited to, heparin (seeing Thromb.Haemost. (1998) 80:10-23), low molecular weight heparin and Carboxypeptidase U inhibitor are (also referred to as the activable fibrinolysis inhibitor of active enzyme thrombin [TAFIa] (being shown in Thrombosis Res. (2001) 101:329-354).The TAFIa inhibitor, at PCT publication WO 03/013,526 and US60/349, is reported in 925 (submissions on January 18th, 2002).
" reagent at the interference cell cycle outpost of the tax office " refers to the protein kinase that suppresses transducer cell cycle pass card signal, thereby makes the compound of cancer cells to DNA damage agent sensitization.These reagent comprise the kinase whose inhibitor of ATR, ATM, Chk1 and Chk2, and cdk and cdc kinase inhibitor, and its specific examples is that 7-hydroxyl staurosporin, staurosporin, flavones pyrrole are many, CYC202 (Cyclacel) and BMS-387032.
" inhibitor of hyperplasia and survival signaling passage " refers to the medicine in the signal transduction cascade system downstream that suppresses cell surface receptor and these surface receptors.This class medicine comprises the inhibitor (for example Gefitinib and Tarceva) of EGFR, the inhibitor of ERB-2 (for example Herceptin), the inhibitor of IGFR (for example those disclosed in WO 03/059951), the inhibitor of cytokine receptor, the inhibitor of MET, the inhibitor of P13K (for example LY294002), serine/threonine kinase (includes but not limited to the Akt inhibitor, for example, at WO 03/086404, WO03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO02/083139, described in WO 02/083140 and WO 02/083138), the kinase whose inhibitor of Raf (for example BAY-43-9006), the inhibitor of the inhibitor of MEK (for example CI-1040 and PD-098059) and mTOR (for example Wyeth CCI-779 and Ariad AP23573).These medicines comprise micromolecular inhibitor compound and antibody antagonist.
" tune die inducer " comprises the TNF receptor family member activator of (comprising the TRAIL acceptor).
In an embodiment, the compounds of this invention can be used to and be selected from one or more of Temozolomide, cis-platinum, carboplatin, oxaliplatin, irinotecan and Hycamtin, and particularly a kind of, two or three medicine, combine and be used for the treatment of cancer.
The compounds of this invention can also be combined and be used for the treatment of cancer with one or more following medicines: abarelix Aldesleukin
Figure G2008800019265D00272
Aldesleukin
Figure G2008800019265D00273
A Lun pearl monoclonal antibody
Figure G2008800019265D00274
Alitretinoin
Figure G2008800019265D00275
Other purine Hemel
Figure G2008800019265D00277
Amifostine
Figure G2008800019265D00278
Anastrozole
Figure G2008800019265D00279
Arsenic trioxide
Figure G2008800019265D002710
L-Asparaginasum
Figure G2008800019265D002711
Azacitidine
Figure G2008800019265D002712
Avastin
Figure G2008800019265D002713
The bexarotene capsule
Figure G2008800019265D002714
The bexarotene gel
Figure G2008800019265D002715
Bleomycin
Figure G2008800019265D002716
Bortezomib
Figure G2008800019265D002717
The busulfan intravenous injection
Figure G2008800019265D002718
The busulfan oral agents
Figure G2008800019265D002719
Calusterone
Figure G2008800019265D002720
Capecitabine
Figure G2008800019265D002721
Carboplatin BCNU
Figure G2008800019265D002723
BCNU
Figure G2008800019265D002724
BCNU implant containing Polifeprosan 20
Figure G2008800019265D002725
The Sai Mikao glycosides
Figure G2008800019265D002726
Cetuximab
Figure G2008800019265D002727
Chlorambucil
Figure G2008800019265D002728
Cis-platinum Cladribine Clofarabine
Figure G2008800019265D002731
Endoxan
Figure G2008800019265D002732
Figure G2008800019265D00281
Endoxan
Figure G2008800019265D00282
Endoxan
Figure G2008800019265D00283
Cytarabine
Figure G2008800019265D00284
Cytarabine liposome
Figure G2008800019265D00285
Dacarbazine
Figure G2008800019265D00286
D actinomycin D; Actinomycin D
Figure G2008800019265D00287
Darbepoetin α
Figure G2008800019265D00288
Daunorubicin liposome
Figure G2008800019265D00289
Daunorubicin, daunomycin Daunorubicin, daunomycin
Figure G2008800019265D002811
Denileukin diftitox
Figure G2008800019265D002812
Dexrazoxane
Figure G2008800019265D002813
Docetaxel
Figure G2008800019265D002814
Doxorubicin Doxorubicin
Figure G2008800019265D002816
Doxorubicin
Figure G2008800019265D002817
Mycocet
Figure G2008800019265D002818
Dromostanolone propionate
Figure G2008800019265D002819
Dromostanolone propionate
Figure G2008800019265D002820
Elliott B solution
Figure G2008800019265D002821
Epirubicin
Figure G2008800019265D002822
Epoetin alfa Tarceva
Figure G2008800019265D002824
Estramustine
Figure G2008800019265D002825
Etoposide phosphate Etoposide, VP-16
Figure G2008800019265D002827
Exemestane Filgrastim
Figure G2008800019265D002829
Floxuridine (in artery)
Figure G2008800019265D002830
Fludarabine
Figure G2008800019265D002831
Fluorouracil, 5-FU Fulvestrant
Figure G2008800019265D002833
Gefitinib
Figure G2008800019265D002834
Gemcitabine
Figure G2008800019265D002835
Lucky trastuzumab ozogamicin
Figure G2008800019265D002836
Goserelin acetate
Figure G2008800019265D002837
Goserelin acetate
Figure G2008800019265D002838
Figure G2008800019265D002839
Histrelin acetate
Figure G2008800019265D002840
Hydroxycarbamide Ibritumomab tiuxetan Idarubicin
Figure G2008800019265D002843
Ifosfamide
Figure G2008800019265D002844
Imatinib mesylate
Figure G2008800019265D002845
Intederon Alpha-2a
Figure G2008800019265D002846
Interferon Alpha-2b
Figure G2008800019265D002847
Irinotecan
Figure G2008800019265D002848
Lenalidomide
Figure G2008800019265D002849
Letrozole Folinic acid
Figure G2008800019265D002851
The acetic acid leuproside
Figure G2008800019265D002852
Levamisol Lomustine, CCNU
Figure G2008800019265D002854
Meclorethamine, mustargen Megestrol acetate Melphalan, L-PAM
Figure G2008800019265D002857
Purinethol, 6-MP
Figure G2008800019265D002858
Mesna Mesna
Figure G2008800019265D002860
Methotrexate (MTX)
Figure G2008800019265D002861
Methoxsalen
Figure G2008800019265D002862
Mitomycin C
Figure G2008800019265D002863
Mitotane
Figure G2008800019265D002864
Mitoxantrone
Figure G2008800019265D002865
Nandrolone Phenpropionate Nelarabine
Figure G2008800019265D002867
Promise is monoclonal antibody not
Figure G2008800019265D002868
Oprelvekin
Figure G2008800019265D002869
Oxaliplatin
Figure G2008800019265D002870
Taxol Taxol
Figure G2008800019265D002872
Taxol protein combination particle
Figure G2008800019265D002873
Pa Lifuming
Figure G2008800019265D002874
Pamidronic Acid
Figure G2008800019265D002875
Pegademase
Figure G2008800019265D002876
Pegaspargase
Figure G2008800019265D002877
The Pei Feisi booth
Figure G2008800019265D002878
Pemetrexed disodium
Figure G2008800019265D002879
Pentostatin
Figure G2008800019265D00291
Pipobroman
Figure G2008800019265D00292
Plicamycin, mithramycin
Figure G2008800019265D00293
Porfimer Sodium
Figure G2008800019265D00294
Procarbazine
Figure G2008800019265D00295
The quina Kelin Rasburicase Rituximab
Figure G2008800019265D00298
Sargramostim
Figure G2008800019265D00299
Sargramostim
Figure G2008800019265D002910
Sorafenib Streptozotocin
Figure G2008800019265D002912
The Sutent maleate
Figure G2008800019265D002913
Talcum
Figure G2008800019265D002914
TAM
Figure G2008800019265D002915
Temozolomide
Figure G2008800019265D002916
Teniposide, VM-26
Figure G2008800019265D002917
Testolactone
Figure G2008800019265D002918
Thioguanine, 6-TG
Figure G2008800019265D002919
Phosphinothioylidynetrisaziridine
Figure G2008800019265D002920
Hycamtin
Figure G2008800019265D002921
Toremifene
Figure G2008800019265D002922
Tositumomab
Figure G2008800019265D002923
Tositumomab/[ 131I] tositumomab Herceptin Tretinoin, ATRA
Figure G2008800019265D002926
Uracil mastard
Figure G2008800019265D002927
Valrubicin
Figure G2008800019265D002928
Vincaleukoblastinum Vincristine Vinorelbine
Figure G2008800019265D002931
SAHA
Figure G2008800019265D002932
Zoledronate
Figure G2008800019265D002933
AMN107
Figure G2008800019265D002934
And Dasatinib
Figure G2008800019265D002935
The present invention also comprises with the NSAID that belongs to selective COX-2-2 inhibitor and combining.For this manual, the NSAID that belongs to selective COX-2-2 inhibitor is according to cell or microsome test, by measuring the IC for COX-2 50with the IC for COX-1 50ratio, determine and to suppress specifically those NSAID that COX-2 surpasses at least 100 times of COX-1.These compounds include, but not limited to disclosed compound: US 5,474,995,5,861,419,6,001 in following patent documentation, 843,6,020,343,5,409,944,5,436,265,5,536,752,5,550,142,5,604,260,5,698,584,5,710,140, WO 94/15932, and US 5,344, and 991,5,134,142,5,380,738,5,393,790,5,466,823,5,633,272 and 5,932,598, they all are incorporated to this paper in the mode of incorporated by reference.
In methods for the treatment of of the present invention, useful especially cox 2 inhibitor is the chloro-3-of 5-(4-methyl sulphonyl) phenyl-2-(2-methyl-5-pyridyl) pyridine, or its pharmaceutically useful salt.
As the COX-2 specific inhibitor, described and therefore can be used for compound of the present invention and included but not limited to: parecoxib, with
Figure G2008800019265D002937
or its pharmaceutically useful salt.
Other example of angiogenesis inhibitor comprises, but be not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxyl group-4-[2-methyl-3-(3-methyl-2-butene base) epoxy ethyl]-1-oxaspiro [2, 5] suffering-6-base (chloracetyl) carbamate, Tacedinaline, 5-amino-1-[[3, the chloro-4-of 5-bis-(4-chlorobenzoyl) phenyl] methyl]-1H-1, 2, 3-triazole-4-methane amide, CM101, squalamine, windmill presses down alkali, RPI4610, NX31838, sulfation sweet dew pentose phosphate ester, 7, 7-(two [imino--N-methyl-4 of carbonyl, 2-pyrrolylcarbonyl imino-[N-methyl-4, 2-pyrroles] the carbonyl imino-] two-(1, the 3-napadisilate) and 3-[(2, 4-dimethyl pyrrole-5-yl) methylene radical]-2-indolinone (SU5416).
" integrin blocker " word of above use, refer to selectivity antagonism, inhibition or resist physiology part and α vβ 3the compound of integrin combination, selectivity antagonism, inhibition or resistance physiology part and α vβ 5the compound of integrin combination, antagonism, inhibition or resistance physiology part and α vβ 3integrin and α vβ 5the compound of these two combination of integrin, and the compound of the activity of antagonism, inhibition or the special integrin of resistance expression on the capillary endotheliocyte.This noun also refers to α vβ 6, α vβ 8, α 1β 1, α 2β 1, α 5β 1, α 6β 1and α 6β 4the antagonist of integrin.This noun also refers to α vβ 3, α vβ 5, α vβ 6, α vβ 8, α 1β 1, α 2β 1, β 5α 1, α 6β 1and α 6β 4the antagonist of any combination of integrin.
Some specific exampless of tyrosine kinase inhibitor comprise N-(trifluoromethyl)-5-methyl-isoxazole-4-methane amide, 3-[(2, 4-dimethyl pyrrole-5-yl) methylene radical] indole-2-ketone, 17-(allyl amido)-17-demethoxylation geldanamycin, 4-(the chloro-4-fluorophenyl of 3-amino)-7-methoxyl group-6-[3-(4-morpholinyl) propoxy-] quinazoline, N-(3-ethynyl phenyl)-6, 7-bis-(2-methoxy ethoxy)-4-quinazoline amine, BIBX1382, 2, 3, 9, 10, 11, 12-six hydrogen-10-(methylol)-10-hydroxyl-9-methyl-9, 12-epoxy-1H-bis-indoles also [1, 2, 3-fg:3 ', 2 ', 1 '-kl] pyrrolo-[3, 4-i] [1, 6] tetraene between benzodiazepine heterocycle suffering-1-ketone, SH268, tri hydroxy isoflavone, STI571, CEP2563, 4-(3-chloro-phenyl-amino)-5, 6-dimethyl-7H-pyrrolo-[2, 3-d] the pyrimidine methane sulfonates, 4-(the bromo-4-hydroxyphenyl of 3-) amino-6, the 7-dimethoxyquinazoline, 4-(4 '-hydroxyphenyl) amino-6, 7 dimethoxyquinazolines, SU6668, STI571A, N-4-chloro-phenyl--4-(4-picolyl)-1-phthalazines amine, with EMD 121974.
In an embodiment, the compounds of this invention can be used for treatment or prevention by selective N 3-VITAMIN B4 methylating reagent MeOSO for example 2(CH 2the appearance of the necrocytosis that)-lexitropsin (Me-Lex) brings out.
With the combining of compound that is not anticancer compound, also be included in the methods of the invention, for example, the compounds of this invention and PPAR-γ (that is, PPAR-gamma) agonist and PPAR-δ (that is, PPAR-delta) combination medicine of agonist can be used for treating some cancer.PPAR-γ and PPAR-δ are core peroxisome proliferation-activated receptors γ and δ.Expression and the participation in vascularization thereof of PPAR-γ on endotheliocyte has been reported in the literature (sees J.Cardiovasc.Phormacol. (1998) 31:909-913; J.Biol.Chem. (1999) 274:9116-9121; Invest.Ophthalmol Vis.Sci. (2000) 41:2309-2317).Recently, pointed out that the PPAR-gamma agonist suppresses the vasculogenesis response to VEGF in testing in vitro, troglitazone and rosiglitazone maleate all suppress the development that in mouse, the retina neovascularity generates.(Arch.Ophthamol. (2001) 119:709-717).The example of PPAR-γ and PPAR-γ/alfa agonists comprises, but be not limited to, thiazolidinedione (DRF2725 for example, CS-011, troglitazone, rosiglitazone and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5, 7-dipropyl-3-Trifluoromethyl-1, 2-benzoisoxazole-6-yl) oxygen]-2 Methylpropionic acid (is disclosed in USSN 09/782, 856) and 2 (R)-7-(3-(the chloro-4-of 2-(4-fluorophenoxy) phenoxy group) propoxy-)-2-ethyl coumaran-2-carboxylic acid (is disclosed in USSN 60/235, 708 and 60/244, 697).
Another embodiment of the present invention is that compound disclosed by the invention and antiviral drug (for example nucleoside analog, comprise ganciclovir) are combined and be used for the treatment of cancer.Referring to WO 98/04290.
Another embodiment of the present invention is that compound disclosed by the invention is combined and is used for the treatment of cancer with gene therapy.About the genetic method for the treatment of cancer referring to (Am J Hum Genet (1997) 61:785-789 and the Kufe etc. (Cancer Medicine, the 5th edition, pp 876-889, BCDecker, Hamilton 2000) such as Hall.Gene therapy can be used to send any tumor suppressor gene.The example of this genoid comprises, but be not limited to, p53 (send by the transgenosis that it can mediate by recombinant virus, for example see US 6,069,134), uPA/uPAR antagonist (" Adenovirus-MediatedDelivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-DependentTumor Growth and Dissemination in Mice ", Gene Therapy, August (1998) 5 (8): 1105-13), and interferon-gamma (J Immunol (2000) 164:217-222).
The compounds of this invention can also with intrinsic multi-medicine resistance (MDR), particularly the inhibitor of the MDR relevant with the high level expression of translocator is co-administered.This MDR inhibitor comprises the inhibitor of p-glycoprotein (P-gp), for example LY335979, XR9576, OC144-093, R101922, VX853, verapamil and PSC833 (valspodar).
Compound of the present invention can be combined use with antiemetic, and the n or V for the treatment of because separately using or use the compounds of this invention to cause together with radiotherapy comprises that acute, Delayed onset, later stage and early onset vomit.For prevention or treatment vomiting, the compounds of this invention can be combined use with other antiemetic, antagonists of neurokinine-1 receptor especially, 5HT3 receptor antagonist (as ondansetron, granisetron, tropisetron and zatisetron), GABA breceptor stimulant (for example baclofen), corticosteroid (as Decadron (dexamethasone), healthy and free from worry pleasure, Aristocort, nose pine, Preferid, Benecorten or at US 2,789,118,2,990,401,3,048,581,3,126,375,3,929,768,3,996,359,3,928,326 and 3,749, those disclosed in 712), the dopamine antagonist medicine, for example, as thiodiphenylamine (prochlorperazine, Fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.In an embodiment, a kind of antiemetic that is selected from antagonists of neurokinine-1 receptor, 5HT3 Receptor antagonist and reflunomide is used as assistant agent, is used for treating or prevents to take the vomiting that the compounds of this invention may cause.
The neurokinine-1 receptor antagonist of combining use with the compounds of this invention has sufficient description: U.S.5,162,339,5,232,929,5,242,930,5 in for example with Publication about Document, 373,003,5,387,595,5,459,270,5,494,926,5,496,833,5,637,699,5,719,147, EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514274, 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913, 0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0709 375, 0 709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893, PCT patent publications WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702, with English Patent 2266529,2268931,2269170,2269590,2271774,2292144,2293168,2293169, and 2302689.
In above-mentioned patent and publication, have the absolutely proving of the preparation of this compounds, they are incorporated to this paper in the mode with reference to quoting.
An embodiment, the antagonists of neurokinine-1 receptor of combining use with the compounds of this invention is selected from: 2-(R)-(1-(R)-(3,5-bis-(trifluoromethyl) phenyl) oxyethyl group)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo) methyl) morpholine, or its pharmaceutically useful salt, this compound is described in US 5,719, in 147.
The compounds of this invention also can be used together with the medicine that is used for treating anaemia.This treatment for anemia agent is that for example a kind of continuous red corpuscle (eythropoiesis) generates receptor activators (for example Epoetin α).
The compounds of this invention also can be used for treating the medicine that neutrophilic leukocyte reduces together with use.It is for example to regulate the production of neutrophilic granulocyte and the hemopoieticgrowth factor of function that a kind of like this neutrophilic leukocyte reduces medicine, human myelomonocyte colony-stimulating factor (G-CSF) for example, and the example of G-CSF comprises filgrastim.
The compounds of this invention can also be taken together with medicament for immunity enhancement, for example LEVAMISOLE HCL, isoprinosine and Zadaxin (Zadaxin).
The compounds of this invention also can with diphosphonate (comprising bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).The example of diphosphate includes but not limited to: etidronate (Didronel), Pamidronate Disodium (Aredia), alendronate sodium (Fosamax), profit plug phosphoric acid salt (Actonel), zoledronate (Zometa), her spot phosphonate (Boniva), incadronate or BP, clodronate, EB-1053, YM 529, neridronic acid salt, NE 97221 and Tiludronate, comprise their all pharmaceutically useful salt, derivative, hydrate and mixture.
Therefore, scope of the present invention comprises that the compounds of this invention and ionizing rays and the second compound are co-administered, this the second compound is selected from: hdac inhibitor, estrogenic agents, androgen receptor modifier, the retinoid receptor modulators, cytotoxicity/cytostatic agent, anti-proliferative agent, the prenyl protein transferase inhibitor, the HMG-CoA reductase inhibitor, angiogenesis inhibitor, the PPAR-gamma agonist, the PPAR-delta agonists, antiviral drug, the inhibitor of intrinsic multiple medicines patience, antiemetic, the medicine that is used for the treatment of anaemia, be used for the treatment of the medicine that neutrophilic leukocyte reduces, medicament for immunity enhancement, hyperplasia and survival signaling inhibitor, the medicine at the interference cell cycle outpost of the tax office, apoptosis inducer and diphosphonate.
When mentioning the compounds of this invention, term administering " and variant (for example, " taking " a kind of compound), refer among the system of the animal of the compounds of this invention or the treatment of its prodrug introducing needs.For example, when the compounds of this invention or one or more active medicines of its prodrug and other (cytotoxic agent), combine while providing, " using " and variant thereof all are interpreted as comprising the compounds of this invention or its prodrug and other medicines simultaneously and order is introduced.
" composition " used herein word comprises the product of the special component that contains specific quantity, and the spawn be combined to form by specific quantity by special component directly or indirectly.
Term used herein " treatment significant quantity " means that the quantity of active compound or medicament produces biology or the medicinal response that researchist, animal doctor, doctor or other clinicist look in tissue, system, animals or humans.
Term " treatment " refers to that treatment suffers from the Mammals of pathological symptom, and refers to by killing and wounding the effect of cancer cells mitigation symptoms, and causes illness to make progress repressed effect, comprise reduce advance rate, resistance stops eating speed, improves symptom and cures illness.Also comprise the treatment as preventive measures (that is, prevention).
Term used herein " pharmaceutically useful " relates to compound, material, composition and/or formulation, within the scope of reliable medical judgment, they are applicable to for example, contacting with the tissue for the treatment of target (people), and there is no too much toxicity, hormesis, irritated response or other problem or complication, there is rational benefit/harm ratio.Various carriers, vehicle etc. with preparation in must be also " acceptable " on the compatible meaning of other composition.
Term " assistant agent " refers to that compound combines use with known treatment means.These means are included in cytotoxic drug scheme and/or the ionizing rays of using in the treatment of dissimilar cancer.Particularly, the known activity compound can strengthen the effect of many cancer chemotherapeutic drugs, these chemotherapeutics are included in topoisomerase enzyme drug toxicity (for example Hycamtin, irinotecan, rubitecan), most of known alkylating reagents (for example DTIC, Temozolomide) and the platinum base medicine (for example carboplatin, cis-platinum) used in the treatment cancer.
Also comprise a kind of method for the treatment of cancer in the scope of the claims in the present invention, comprise the treatment formula I compound of significant quantity and radiotherapy and/or a kind of compound co-administered, this compound is selected from: hdac inhibitor, estrogenic agents, androgen receptor modifier, the retinoid receptor modulators, cytotoxicity/Growth of Cells preparation, anti-proliferative agent, the prenyl protein transferase inhibitor, the HMG-CoA reductase inhibitor, angiogenesis inhibitor, the PPAR-gamma agonist, the PPAR-delta agonists, antiviral drug, the inhibitor of intrinsic multi-medicine resistance, antiemetic, the medicine that is used for the treatment of anaemia, be used for the treatment of the medicine that neutrophil cell increases, medicament for immunity enhancement, the inhibitor of hyperplasia and survival signaling, the medicine at the interference cell cycle outpost of the tax office, apoptosis inducer and diphosphonate.
These aspects of the present invention and other aspect will be apparent according to the instruction comprised herein.
the abbreviation of using in chemical descriptor and following embodiment is:
AcCl (Acetyl Chloride 98Min.); (BzO) 2(benzoyl peroxide); Cbz-Cl (chloroformic acid benzyl ester); DCM (methylene dichloride); DIPEA (diisopropylethylamine); DMF (dimethyl formamide); DMSO (dimethyl sulfoxide (DMSO)); Eq. (equivalent); ES (electron spray(ES)); EtOAc (ethyl acetate); EtOH (ethanol); Mol.sieves (molecular sieve); HATU[phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N N, N ', N '-tetramethyl-urea salt]; MeCN (acetonitrile); MeOH (methyl alcohol); MS (mass spectroscopy); MW (microwave); NBS (N-bromosuccinimide); NMMO (N-methylmorpholine-N-oxide compound); NMR (nucleus magnetic resonance); Pcol (post pressure); IPrOH (Virahol); RT (room temperature); Sat.aq. (saturated aqueous solution); SiO 2(silica gel); THF (tetrahydrofuran (THF)); T-BuOH (trimethyl carbinol); KOAc (potassium acetate); MW (microwave); IST
Figure G2008800019265D00351
sPE column SCX (International Sorbent Technology
Figure G2008800019265D00352
the solid-phase extraction column Zeo-karb); SFC (supercritical fluid chromatography); TBTU (Tetrafluoroboric acid O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea salt); Tcol (column temperature); CDCl 3(deuterate chloroform); TLC (thin-layer chromatography); TFA (trifluoroacetic acid).
Formula I compound can through type IA compound and the ammonia react preparation:
Figure G2008800019265D00353
R wherein 1and R 2as defined above, R xc 1-6alkyl, for example methyl.This reaction generally approximately 70 ℃ use NH 3the aqueous solution in solvent (as THF) in the sealing reactor (carefully) in carry out.Or, can add alkali, for example NaOH or KOH, be hydrolyzed into corresponding carboxylic acid (R by ester xhydrogen), for example, in solvent (as DMF), add NH subsequently under coupling agent (HATU or TBTU) and DIPEA existence 3, reaction is carried out in the room temperature left and right.Or, can use for example Boc 2o, by the activation of this carboxylic acid, forms mixed acid anhydride, then with bicarbonate of ammonia, reacts, and usually at solvent, carries out in as pyridine.Or, can for example, in solvent (methyl alcohol), for example, under approximately 120 ℃ (utilizing microwave), with ammonia, this ester be transformed to accepted way of doing sth IA compound.
Nitrogen-atoms on piperidine ring in formula IA compound can be protected with for example Boc in above synthesizing.
Compound I A can react preparation by through type IB compound with trinitride:
Figure G2008800019265D00354
R wherein 1, R 2and R xas defined above.Can use trinitride, for example NaN 3, in solvent (as DMF), under about 90-140 ℃, reacted.Also can use adducts, for example 2, the 6-lutidine.Reaction can be carried out under nitrogen atmosphere.
Compound I B can through type IC compound and formula ID compound condensation prepare:
Figure G2008800019265D00361
R wherein 1, R 2and R xas defined above, L 1be a leavings group, for example nitro or halogen, as fluorine.Method is included in dewatering agent (as MgSO 4or molecular sieve) have lower condensation, or in alcoholic solvent (as ethanol) reflux.This reaction can be carried out under nitrogen atmosphere.
Can for example, by using oxygenant (NMMO) oxidation-type IE compound, prepare by formula IC compound:
R wherein 1, R xand L 1as defined above, L 2a leavings group, halogen (as bromine) for example, this reaction is carried out usually under about room temperature in solvent (as MeCN).Reaction can be carried out under nitrogen atmosphere.
L wherein 2can for example, by using bromizating agent (as NBS) oxidation-type IF compound under radical initiator (benzoyl peroxide) exists, prepare by the formula IE compound that is bromine:
Figure G2008800019265D00371
R wherein 1, R xand L 1definition the same, this reaction generally at solvent (as CCl 4) under refluxing, carry out.Reaction can be carried out under nitrogen atmosphere.
L wherein 1can prepare by following steps by the formula IF compound that is fluorine: by formula IG compound diazotization:
Figure G2008800019265D00372
R wherein 1and R xas defined above, subsequently this intermediate diazonium salt is decomposed.For example, diazotization can with Tetrafluoroboric acid salt made from earth containing a comparatively high percentage of sodium chloride in solvent (as DCM) in approximately carrying out under 0 ℃.Then can isolate corresponding diazonium tetrafluoroborate, resolve at elevated temperatures subsequently corresponding fluorobenzene derivatives (carefully), for example in solvent (as dichlorobenzene), be heated to 160 ℃.
L wherein 1the formula IF compound that is nitro can pass through formula IH compound is nitrated:
Figure G2008800019265D00373
R wherein 1as defined above, carrying out subsequently esterification prepares.Nitration reaction can for example, be carried out under nitrate (saltpetre) and acid (as sulfuric acid) existence under about room temperature.Esterif iotacation step can be carried out under standard conditions, for example, with formula R xthe alkyl halide of-X (wherein X is halogen, for example iodine) for example, reacts under alkali (cesium carbonate) and solvent (as DMF) existence under about room temperature.Also can under refluxad use formula R xthe alcohol of-OH and a kind of an acidic catalyst, the HCl for example produced from the AcCl/MeOH original position.Then use hydrogen and catalyzer (as carbon carries palladium) that nitro-compound hydrogenation is formed to corresponding aniline, normally at alcoholic solvent, for example in methyl alcohol, obtain desired formula IF compound.
Or formula I compound can pass through the also preparation originally of formula IJ compound:
Figure G2008800019265D00381
R wherein 1and R 2as defined above.This reaction can be reacted according to Fowler, uses chloride of acid (for example CBz-Cl) and reductive agent (as NaBH 4) carry out.Carry hydrogenation on palladium at carbon, complete and react and remove the CBz blocking group.
Formula IJ compound can through type IK compound and the cross coupling of the 3-pyridine boric acid of formula IL prepare:
Figure G2008800019265D00382
R wherein 1, R 2and L 2definition the same.This reaction is carried out usually under Suzuki coupling condition, for example uses catalyzer (as Pd 2(dba) 3with three (tertiary butyl) phosphine) with alkali (as sodium carbonate) and solvent (as DMF and water), approximately carrying out under 90 ℃.
Formula IK compound can through type IM compound and the preparation of formula IN compound condensation:
Figure G2008800019265D00391
R wherein 1, R 2and L 2define the same, L 3be a leavings group (for example halogen, as fluorine), reaction is carried out usually in solvent (as DMF) under about 180 ℃ in microwave oven.Can also add alkali, for example K 2cO 3.
The preparation method of formula IM compound is, formula IO compound:
R wherein 1and R xdefine the samely, for example, with alkali (KOH or NaOH), approximately reacting under room temperature, this ester is hydrolyzed into to corresponding carboxylic acid (R xhydrogen), under existing, coupling agent (as HATU, DIPEA and TBTU) adds NH in solvent (DMF) subsequently 3, this reaction is approximately being carried out under room temperature.
Formula IO compound can be set out by formula IG compound, by solvent (as 1,2-DCE) in approximately 55 ℃ with reagent (as Acetyl Chloride 98Min.) prepared by the aniline group acetylize.Then can for example, by processing with Sodium Nitrite in acid (concentrated hydrochloric acid), be generally to carry out under cosolvent (as toluene and water) is present in approximately 0 ℃, cyclisation forms desired indazole.
Situation in the synthetic method of undeclared intermediate and initiator, these compounds are commercially available on market, perhaps can utilize standard method, or utilize above synthetic method and the expansion of synthetic schemes and embodiment herein, prepare from the commercial goods compound.
Formula I compound can, with currently known methods or in above synthetic scheme and the described method of embodiment part that reaches this paper, change into other formula I compound.
In any composition sequence as herein described, sensitivity or the reaction active groups on be concerned about any molecule may must and/or preferably be protected.This can utilize conventional blocking group, for example, at Protecting Groups in Organic Synthesis, 3rd Edition, Greene, T.W.and Wuts, P.G.M.; Wiley Interscience, 1999 and Kocienski, P.J.Protecting Groups, Thieme, the group described in 1994 is realized.This blocking group can be removed by methods known in the art in suitable subsequent step.For example, when having Boc (tertbutyloxycarbonyl) or benzyloxycarbonyl group blocking group, can be by approximately under room temperature, adding solvent (as TFA, DCM and/or MeCN) to remove.Compound also can be used standard method hydrogenation, for example under nitrogen atmosphere, for example, in solvent (methyl alcohol), with catalyzer (as Pd/C), processes.Can also approximately under room temperature, under HCl and Isosorbide-5-Nitrae-dioxane existence, add EtOAc to remove Boc or benzyloxycarbonyl group blocking group.
According to following scheme, prepared by the compounds of this invention.All variablees in chemical formula all define the same.
When the compounds of this invention has chiral centre, enantiomorph can for example utilize SFC, chirality HPLC or split with chiral acid with the separation method of standard, isolates enantiomorph from racemoid.This separation can be carried out in any stage in the process of the formula of manufacture I compound.For example, separation can be carried out in terminal stage, or can isolate intermediate and isolate subsequently specific enantiomorph with for follow-up reaction, obtains desired product.
scheme 1
A step of the derivative of synthetic the compounds of this invention is shown in scheme 1, and the 2H-indazole wherein replaced is used and the similar route of synthesis preparation described in WO 2005/066136.After 2-nitro-3-methyl benzoic acid derivatives is changed into to corresponding ester, with reagent (as N-bromosuccinimide and benzoyl peroxide), methyl is carried out to the free radical bromination, obtain crucial benzyl bromide derivatives.This bromotoluene compound can be oxidized to corresponding phenyl aldehyde with for example N-methylmorpholine-N-oxide compound and molecular sieve.After this aldehyde and amine condensation, by high temperature process this key intermediate with sodiumazide, realize closing ring, introduce final nitrogen-atoms final extruding nitrogen-atoms to offer the indazole ring.Can also in this reaction, add alkali, for example lutidine.This ester finally changes into primary amide, obtains desired derivative.This can be by heating this ester or carrying out the acid amides coupling and complete by changing into after corresponding carboxylic acid in ammonia solution.
Figure G2008800019265D00411
Scheme 1
scheme 2
A kind of modification of scheme 1 is shown in following scheme 2, and it makes and can on indazole core, introduce substituting group.When needed nitrobenzoic acid during without commercial goods, what they can be by corresponding benzoic acid derivative is nitrated, for example in the vitriol oil, with saltpetre is nitrated, prepares.Above-described synthetic operation is formed corresponding aniline, and it can be by first becoming ring with the Sodium Nitrite cyclisation by the indazole acetylize and in concentrated hydrochloric acid under 0 ℃.Or, can use Tetrafluoroboric acid salt made from earth containing a comparatively high percentage of sodium chloride by this aniline diazotization, and corresponding diazonium tetrafluoroborate is at high temperature utilized to Schiemann reaction decomposes (carefully), form corresponding difluoro bezene derivative.According to the composition sequence described in scheme 1, make the benzyl methyl be oxidized to corresponding aldehyde, and, by with a kind of (mixing) anilide coupling with use the sodiumazide cyclisation, be processed into desired indazole derivatives.
Figure G2008800019265D00421
Scheme 2
scheme 3
Other method relates to functionalized in the latter half of indazole, as shown in scheme 3.This method first changes into corresponding methane amide by the indazole ester, and carries out the nucleophilic aromatic replacement of suitable fluorine (mixing) aryl bromide.This bromizates derivative and is prepared, this derivative under Suzuki coupling condition, for example under alkali (as sodium carbonate) exists with three (tertiary butyl) phosphine and Pd 2(dba) 3as catalyzer, carry out cross coupling.Then (for example CBz-Cl and reductive agent are (as NaBH to use chloride of acid 4), by Fowler, react, realize to the conversion of desired piperidines part.Can produce corresponding piperidine derivative finally by hydrogenation.
Figure G2008800019265D00431
Scheme 3
the PARP-1SPA test
Example compound as herein described is tested in this test, finds its IC 50value is less than 5 μ M, particularly is less than 50nM.
work reagent
Analysis buffer: 100mM Tris pH8,4mM MgCl 2, 4mM spermine, 200mM KCl, 0.04% Nonidet P-40 (Nonidet P40).
Enzyme mixture: analysis buffer (12.5 μ l), 100mM DTT (0.5 μ l), PARP-1 (5nM, Trevigen 4668-500-01), water (to 35 μ l).
Icotinamide-adenine dinucleo (NAD)/DNA mixture: [ 3h-NAD] (250 μ Ci/ml, 0.4 μ l, Perkin-Elmer NET-443H), NAD (1.5mM, 0.05 μ l, SIGMA N-1511), biotinylation NAD (250 μ M, 0.03 μ l, Trevigen 4670-500-01), activation calf thymus (1mg/ml, 0.05 μ l, Amersham Biosciences 27-4575), water (to 10 μ l).Launch mixture: streptavidin SPA pearl (5mg/ml, Amersham Biosciences RPNQ0007) is dissolved in 500mM EDTA.
experimental design
Reaction is carried out in 96 hole microplates, the every hole 50 μ l of final volume.Add 5 μ l 5% DMSO/ compound solutions, add enzyme mixture (35 μ l), by adding NAD/DNA mixture (10 μ l) initial action, under room temperature, incubation is 2 hours.Add and launch mixture (25 μ l) stopped reaction, under room temperature, incubation is 15 minutes.By Packard TOP COUNT apparatus measures.
proliferation test in the reticent HeLa cell of BRCA-1
Abbreviation:
IMDM (the improved Dulbecco substratum of Iscove); RPMI (Roswell Park MemorialInstitute substratum); MOI (infection multiplicity); GFP (green fluorescent protein); PBS (phosphate buffered saline buffer); FCS (foetal calf serum); And DMEM (the improved Eagle substratum of Dulbecco).
The compounds of this invention has also been done the antiproliferative test in pairing cell BRCA1 wt and BRCA1-(shRNA) HeLa cell.This test shows, the PARP inhibitor can demonstrate the selective growth restraining effect to the BRCA deficient cells.The CC of these compounds to the BRCA1 deficient cells 50be less than 5 μ M, and exceed the selectivity of BRCA sound cell more than 10 times.
This test is based on active born of the same parents and redox dye (resazurin) is changed into to the ability of fluorescence end product (resorufin).The quantity of the resorufin produced is directly proportional to cell number.
Clone:
This is with containing for the slow virus of the shRNA of BRCA-1 with to the HeLa cell of the expression cassette transduction of GFP with 100 infection multiplicity for HeLa shBRCA1-GFP.Analyze with Tagman the BRCA-1 recorded reticent over 80%, GFP is expressed on this cytotostatic ground.
This is not express the HeLa cell of the control vector of any shRNA with infection multiplicity 100 use for HeLa THM-GFP.
Scheme
-in 96 holes bottoms transparent black plates in 90 μ l developing mediums *in by 300 cells/well inoculations:
-at 37 ℃, 5% CO 2lower incubation 4 hours
-every hole adds 10X compound (5% DMSO/H of 10 μ l 2o)
-at 37 ℃, 5% CO 2lower incubation 168 hours
-be added in PBS1x and dilute in advance the 10 μ l Celltiter Blue solution (Promega, G8081) of 1: 1
-by this mixture at 37 ℃, 5% CO 2incubation 45 minutes
-room temperature lucifuge incubation 15 minutes
-read plate, ex:550nm, em:590nm on fluorophotometer
*substratum: DMEM (GIBCO, 41966-029), 10% FCS (GIBCO, 10106-169), 0.1mg/ml penicillin-Streptomycin sulphate (GIBCO, 15140-114), 2mM L-glutaminate (GIBCO, 3042190)
proliferation test in natural B RCA deficient cells system
The compounds of this invention also demonstrates the restraining effect to the propagation of natural BRCA-1 (MDA-MB-436) and BRCA-2 (CAPAN-1) deficient cells system, CC 50be less than 5 micromoles.
Proliferation test
Cell is seeded in to 100 μ l suitable culture mediums in 96 orifice plates by 700 cells/well *in/hole.The serial dilutions that adds compound next day, final volume 200 μ l/ holes.Each diluent is tested with triple samples.
After 6 days, use the explanation estimation cell survival of CellTiter-Blue cells survival tester according to manufacturers (Promega).Read plate on Fusion Alpha microplate reader (Packard Bioscience).
For low proliferative cell system (being CAPAN-1), adding compound to carry out proliferation test after 14 days, changed substratum once (170 μ l substratum in extracting every hole out change the fresh culture of 170 μ l containing compound into) at the 7th day.
*substratum:
MDA-MB-436:RPMI (GIBCO), 10% FBS (5% CO 2)
CAPAN-1:IMDM (GIBCO), 20% FBS (5% CO 2)
Test compound demonstrates significant activity level in the oncology model trial in vivo.
Preparation Example
embodiment A
2-phenyl-2H-indoles-7-methane amide (A6)
step 1: 3-methyl-2-nitrobenzene methyl (A1)
Dropwise add AcCl (3.0 equivalent) to the suspension of 3-methyl-2-nitrobenzoic acid (10 equivalent) in methyl alcohol (0.4M) under 0 ℃.Reaction mixture is stirred 20 hours under refluxing.Solvent is removed in decompression, and residue is dissolved in EtOAc, uses NaHCO 3saturated aqueous solution, salt are washed several times, dry (Na 2sO 4).Evaporating solvent, obtain (A1) of white solid, uses it for next step, do not make further purifying.
1h NMR (400MHz, CDCl 3, 300K) δ 7.86 (1H, d, J=7.5Hz), 7.53-7.42 (2H, m), 3.89 (3H, s), 2.36 (3H, s) .MS (ES) C 9h 9nO 4theoretical value: 195, experimental value: 218 (M+Na) +
step 2: 3-(brooethyl)-2-nitrobenzene methyl (A2)
By (A1) (1.0 equivalent), (BzO) 2(0.06 equivalent) and NBS (1.18 equivalent) are at CCl 4in mixture (being 0.2M with regard to A1 speech) at N 2under atmosphere, reflux is 12 hours.Mixture is cooled to room temperature, and with the DCM dilution, concentrating under reduced pressure is added in SiO simultaneously 2upper drying.Residue uses flash column chromatography at SiO 2upper purifying, the EtOAc/ sherwood oil wash-out with 10: 90, obtain desired (A2), is white solid.
1h NMR (400MHz, CDCl 3, 300K) δ 7.93 (1H, d, J=7.7Hz), 7.72 (1H, d, J=7.7Hz), 7.57 (1H, t, J=7.7Hz), 4.43 (2H, s), 3.88 (3H, s) .MS (ES) C 9h 8brNO 4theoretical value: 273:275, experimental value: 242:244 (M-MeO) +, 227:229 (M-NO 2) +.
step 3: 3-formyl radical-2-nitrobenzene methyl (A3)
To (A2) (10 equivalent) and
Figure G2008800019265D00461
the mixture (0.2M) of molecular sieve (15g) in MeCN at room temperature adds NMMO (2.0 equivalent), by reaction mixture at N 2under atmosphere, stir 1.5 hours.Then mixture is diluted with EtOAc, filter, filtrate water, 1N HCl and salt washing, dry (Na 2sO 4).Evaporating solvent, obtain white solid (A3), and it is used to next step, does not make further purifying.
1h NMR (400MHz, CDCl 3, 300K) δ 9.96 (1H, s), 8.26 (1H, d, J=7.9Hz), 8.18 (1H, d, J=7.9Hz), 7.77 (1H, t, J=7.9Hz), 3.93 (3H, s) .MS (ES) C 9h 7nO 5theoretical value: 209, experimental value: 208 (M-H) -.
step 4: 2-nitro-3-[(phenylimino) methyl] methyl benzoate (A4)
By (A3) (1.0 equivalent) and aniline (1.05 equivalent), the mixture (0.2M) in EtOH is in N 2under atmosphere, return stirring is 2 hours, until TCL (hexane/EtOAc=75: 25) Indicator Reaction completes.Evaporating solvent obtains (A4), is white solid, for not making further purifying before next step.
1h NMR (400MHz, CDCl 3, 300K) δ 8.51 (1H, d, J=7.3Hz), (8.41 1H, s), 8.11 (1H, d, J=7.8Hz), 7.67 (1H, t, J=7.8Hz), (7.43 2H, t, J=7.8Hz), 7.31 (1H, t, J=7.3Hz), 7.16 (2H, d, J=7.8Hz), 3.94 (3H, s).
step 5: 2-phenyl-2H-indazole-7-carboxylate methyl ester (A5)
By (A4) (1.0 equivalent) and NaN 3(1.05 equivalent) mixture (0.3M) in dry DMF stirs and spends the night under nitrogen atmosphere and 90 ℃.By the crude product concentrating under reduced pressure, residue is used purified by flash chromatography on silica gel, uses the EtOAc/ sherwood oil gradient elution from 10: 90 to 40: 60, obtains desired (A5), is brown oil.
1h NMR (400MHz, CDCl 3, 300K) δ 8.50 (1H, s), 8.12 (1H, d, J=7.0Hz), 7.96-7.90 (3H, m), 7.49 (2H, t, J=7.6Hz), 7.38 (1H, t, J=7.4Hz), 7.15 (1H, t, J=7.4Hz), 4.03 (3H, s) .MS (ES) C 15h 12n 2o 2theoretical value: 252, experimental value: 253 (M+H) +.
step 6: 2-phenyl-2H-indazole-7-methane amide (A6)
By ester (A5) in the mixture of the ammoniacal liquor of THF and 32% in tube sealing 70 ℃ of heated overnight.Solvent is removed in decompression, and flash chromatography purifying on silica gel for residue is used the EtOAc/ sherwood oil gradient elution from 30: 70 to 50: 50, obtains desired (A6), is white solid.
1h NMR (400MHz, DMSO, 300K) δ 9.33 (1H, s), (8.56 1H, bs), 8.16 (2H, d, J=7.9Hz), 8.08-8.00 (2H, m), 7.88 (1H, bs), 7.63 (2H, t, J=7.7Hz), (7.50 1H, t, 7.4Hz), (7.27 1H, t, J=7.9Hz) .MS (ES) C 14h 11n 3the O theoretical value: 237, experimental value: 238 (M+H) +.
Exemplary embodiment
embodiment 1
chlorination 3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt (B4)
step 1: 3-[4-({ [3-(methoxycarbonyl)-2-nitrophenyl] methylene radical } amino) phenyl] piperidines-1-carboxylic acid tert-butyl ester (B1)
(B1) according to the described general procedure of Preparation Example A step 4, with 3-(4-aminophenyl) piperidines-1-carboxylic acid tert-butyl ester preparation, until TCL (sherwood oil: EtOAc=4: 1) Indicator Reaction completes, and (B1) without being further purified, directly uses next step.
step 2: 2-{4-[1-(tertbutyloxycarbonyl) piperidines-3-yl] phenyl }-2H-indazole-7-carboxylate methyl ester (B2)
(B2) according to the general procedure preparation for Preparation Example A step 5 report, crude product is used purified by flash chromatography on silica gel, uses 20-40% EtOAc/ sherwood oil gradient elution, obtains desired (B2), is yellow solid.
1h NMR (400MHz, CDCl 3, 300K) δ 8.51 (1H, s), 8.13 (1H, d, J=7.1Hz), 7.95 (1H, d, J=8.3Hz), 7.91 (2H, d, J=8.4Hz), 7.39 (2H, d, J=8.4Hz), (7.18 1H, t, J=7.2Hz), 4.30-4.10 (2H, m), (4.00 3H, s), 2.85-2.70 (3H, m), 2.11-2.03 (1H, m), 1.83-1.75 (1H, m), 1.73-1.53 (2H, m and H 2the O signal overlap), 1.48 (9H, s) .MS (ES) C 25h 29n 3o 4theoretical value: 435, experimental value: 436 (M+H) +.
step 3: 3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidines-1-carboxylic acid tert-butyl ester (B3)
By (B2) at 7N NH 3in/MeOH (0.1M), in inherent 60 ℃ of tube sealing, heat 2 days.Concentrating under reduced pressure, crude product Et 2the O wet-milling, obtain desired product (B3), is yellow solid.
1h NMR (400MHz, CDCl 3, 300K) δ 9.04 (1H, br.s), 8.51 (1H, s), 8.31 (1H, d, J=6.8Hz), 7.91 (1H, d, J=8.3Hz), 7.84 (2H, d, J=8.2Hz), 7.42 (2H, d, J=8.2Hz), 7.31-7.22 (1H, m and CDCl 3signal overlap), 5.95 (1H, br.s), 4.40-4.05 (2H, m), 2.90-2.70 (3H, m), 2.15-2.00 (1H, m), 1.85-1.75 (1H, m), 1.75-1.50 (2H, m and H 2the O signal overlap), 1.48 (9H, s) .MS (ES) C 24h 28n 4o 3theoretical value: 420, experimental value: 421 (M+H) +.
step 4: chlorination 3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt (B4)
Under agitation to (B3) (1.0 equivalent), the solution (0.2M) in EtOAc adds 4NHCl/1,4-dioxane solution (10.0 equivalent), and under room temperature, stirred reaction mixture is 3 hours.Remove solvent under reduced pressure, crude product Et 2o wet-milling purifying, obtain desired (B4), is yellow solid.
1h NMR (400MHz, DMSO-d6,300K) δ 9.32 (1H, s), (9.12 1H, br.s), 8.87 (1H, br.s), (8.55 1H, br.s), 8.13 (2H, d, J=8.6Hz), 8.06 (1H, J=7.0Hz), 8.02 (1H, d, J=8.4Hz), 7.89 (1H, br.s), (7.55 2H, d, J=8.6Hz), 7.27 (1H, dd, J=8.4,7.0Hz), 3.43-3.27 (2H, m), (3.17-3.03 2H, m), 3.00-2.85 (1H, m), 2.00-1.70 (4H, m) .MS (ES) C 19h 21clN 4the O theoretical value: 320, experimental value: 321 (M+H) +.
embodiment 2
2-{4-[(3R)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide (C1) and 2-{4-[(3S)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide amine (C2)
Embodiment 1 (B4) is separated to (post: Chiralpak AS-H, 1 * 25mm, flow velocity: 10ml/min, T with chirality SFC col: 35 ℃, P cal: 100 bar, conditioning agent: 55% ( iprOH+4%Et 2nH)), use CO 2as overcritical eluent, obtain two kinds of pure enantiomorphs.
The enantiomorph of first wash-out (C1), retention time (SFC): 4.80min, be white powder.
1h NMR (400MHz, DMSO-d6,300K) δ 9.28 (s, 1H), (8.57 br.s, 1H), 8.06 (d, 2H, J=7.2Hz), 8.04 (d, 2H, J=8.4Hz), 7.88 (br.s, 1H), 7.49 (d, 2H, J=8.4Hz), 7.27 (dd, 1H, J=8.4,7.2Hz), 3.08-2.94 (m, 2H), 2.77-2.67 (m, 1H), (2.64-2.52 m, 1H), 1.98-1.90 (m, 1H), 1.75-1.47 (m, 4H) .MS (ES) C 19h 20n 4the O theoretical value: 320, experimental value: 321 (M+H) +.
This free alkali is changed into to chlorination (3R)-3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt, the specific rotation recorded: [α] 20 d=+133.3 (c 0.15, MeOH).
The enantiomorph of second wash-out (C2), retention time (SFC): 6.51min, be white powder.
1h NMR (400MHz, DMSO-d6,300K) δ 9.28 (s, 1H), (8.57 br.s, 1H), 8.06 (d, 2H, J=7.2Hz), 8.04 (d, 2H, J=8.4Hz), 7.88 (br.s, 1H), 7.49 (d, 2H, J=8.4Hz), 7.27 (dd, 1H, J=8.4,7.2Hz), 3.08-2.94 (m, 2H), 2.77-2.67 (m, 1H), (2.64-2.52 m, 1H), 1.98-1.90 (m, 1H), 1.75-1.47 (m, 4H) .MS (ES) C 19h 20n 4the O theoretical value: 320, experimental value: 321 (M+H) +.
This free alkali is changed into to chlorination (3S)-3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt, the specific rotation recorded: [α] 20 d=-137.9 (c 0.145, MeOH).
embodiment 3
the fluoro-2H-indazole of trifluoroacetic acid 3-{4-[7-(aminocarboxyl)-5--2-yl] phenyl } piperidinium salt (D4)
the fluoro-1H-indazole of step 1:5--7-carboxylate methyl ester (D1)
Solution (0.1M) to embodiment 4 (E3) (10 equivalent) in 1,2-methylene dichloride adds AcCl (5 equivalent) and heats 2 hours at 55 ℃, then removal of solvent under reduced pressure.
By the white solid obtained be dissolved in toluene/water (5: 1,0.1M) in, solution is cooled to 0 ℃, add HCl (10 equivalents, 37%), then add at leisure NaNO in batches 2(10 equivalent), stir mixture 3 hours at 0 ℃.Organic phase washes with water 3 times, dry (MgSO 4), removal of solvent under reduced pressure.
Then the yellow solution in toluene (0.1M) is heated 2 hours at 90 ℃.Evaporation toluene, obtain desired product, is red solid.
1h NMR (400MHz, DMSO, 300K) δ 13.37 (1H, s), 8.23 (1H, s), 7.63 (1H, dd, J=8.6Hz, J=2.5Hz), 7.48 (1H, dd, J=8.6Hz, J=2.5Hz), 3.66 (3H, s) .MS (ES +) C 9h 7fN 2o 2theoretical value: 194, experimental value: 195 (M+H) +.
the fluoro-1H-indazole of step 2:5--7-methane amide (D2)
By (D1) be dissolved in dioxane/water (1: 1,0.1M) in, add KOH (1.5 equivalent).Stir removal of solvent under reduced pressure after 12 hours under room temperature.The white solid obtained is not purified, for follow-up coupled reaction.
This carboxylic acid is dissolved in to (0.1M) in DMF, adds TBU (1.5 equivalent) under 0 ℃.Add DIPEA (20 equivalent) and ammonia (3.0 equivalents, 0.5M dioxane solution) after 15 minutes, mixture is at room temperature stirred 36 hours.Add EtOAc, organic phase NaHCO 3saturated aqueous solution (3x) and salt solution (2x) are washed.By the organic phase drying, reduction vaporization, the crude product purified by flash chromatography, the MeOH/DCM wash-out of use 1-20%, obtain white solid (D2).MS (ES +) C 8h 6fN 3the O theoretical value: 179, experimental value: 180 (M+H) +.
step 3: the fluoro-2H-indazole of 2-(4-bromophenyl)-5--7-methane amide (D3)
Add K to the solution of D2 (1.0 equivalent) in DMF 2cO 3(1.3 equivalent) and 4-bromofluoro benzene (10.0 equivalent) heat reaction mixture 20 minutes in 180 ℃ under microwave condition.Reaction mixture is cooled to constant temperature, dilutes with EtOAc.Organic phase is washed with salt, dry (Na 2sO 4).Obtaining (D3) after evaporating solvent, it is used on silica gel to chromatography purification, with 50-70%EtOAc/ sherwood oil wash-out, obtain title compound, is yellow powder.
1h NMR (400MHz, DMSO-d 6, 300K) δ 9.34 (1H, s), 8.50 (1H, br.s), 8.17 (2H, d, J=9.0Hz), 8.03 (1H, br.s), 7.90-7.80 (4H, m) .MS (ES +) C 14h 9brFN 3the O theoretical value: 334/336, experimental value: 335/337 (M+H) +.
step 4: the fluoro-2-of 5-(4-pyridin-3-yl phenyl)-2H-indazole-7-methane amide (D4)
The mixture (1.0M) in DMF and 2N Na by (D3) (1.0 equivalent) and pyridine-3-boric acid (1.3 equivalent) 2cO 3solution (2.0 equivalent) one is reinstated the Ar air-flow degassed 30 minutes.Add tbu 3pH +bF 4 -(0.05 equivalent) and Pd 2(dba) 3(0.05 equivalent), 90 ℃ of heating 48 hours, be cooled to room temperature by reaction mixture, adds DCM, organic phase NaHCO 3saturated aqueous solution, salt washing, dry (Na 2sO 4).Solution decompression is concentrated, and residue is used chromatography purification on silica gel, with 50-90%EtOAc/ sherwood oil and 10%MeOH/DCM priority wash-out, obtains title compound, is yellow powder.
1h NMR (400MHz, DMSO-d 6, 300K) δ 9.40 (1H, s), 9.01 (1H, d, J=1.6Hz), 8.63 (1H, dd, J=4.8,1.6Hz), (8.57 1H, br.s), 8.32 (2H, d, J=8.8Hz), (8.20 1H, d, J=7.8Hz), 8.10 (1H, br.s), (8.01 2H, d, J=8.8Hz), 7.88-7.82 (2H, m), (7.54 1H, dd, J=7.8,4.8Hz) .MS (ES) C 19h 13fN 4the O theoretical value: 332, experimental value: 333 (M+H +).
step 5: the fluoro-2H-indazole of 3-{4-[7-(aminocarboxyl)-5--2-yl] phenyl } piperidines-1-benzyl carboxylate (D5)
-65 ℃ and stir under to (D4), the solution in anhydrous methanol (0.2M) adds NaBH 4(1.2 equivalent), then dropwise add Cbz-Cl (1.2 equivalent).Make reaction mixture reach ambient temperature overnight, then water quencher reaction.Methyl alcohol is removed in decompression, adds EtOAc.The saturated NaHCO of organic phase 3the aqueous solution is washed, dry (Na 2sO 4).Evaporating solvent, obtain (D5), and it does not do, into lower purifying, to be directly used in next step.MS (ES) C 27h 25fN 4o 3theoretical value: 472, experimental value: 473 (M+H +).
step 6: the fluoro-2H-indazole of trifluoroacetic acid 3-{4-[7-(aminocarboxyl)-5--2-yl] phenyl } piperidinium salt (D6)
Solution (0.2M) to (D5) (1.0 equivalent) in MeOH adds Pd/C 10% (0.05 equivalent) and HCl (1.0 equivalent), by reaction mixture at H 2gas ammonia (1atm) is lower to be stirred 48 hours.Then by this mixture through diatomite filtration, removal of solvent under reduced pressure, obtain (D6), by it with anti-phase RP-HPLC (post: C18) purifying, water (0.1%TFA) and MeCN are as eluent, by desired fraction lyophilize, obtain title compound (D6), be white powder.
1h NMR (400MHz, CD 3cN, 300K) δ 9.28 (1H, s), 8.89 (1H, br.s), (8.60-8.50 2H, m), 8.13 (2H, d, J=8.6Hz), (8.09 1H, br.s), 7.90-7.70 (2H, m), (7.54 2H, d, J=8.6Hz), 3.40-3.30 (2H, m), 3.20-2.80 (3H, m), 2.00-1.90 (2H, m), 1.80-1.70 (2H, m), MS (ES) C 19h 19fN 4the O theoretical value: 338, experimental value: 339 (M+H +).
embodiment 4
the fluoro-2-of trifluoroacetic acid 5-(the fluoro-4-piperidines of 3--3-base phenyl)-2H-indazole-7-methane amide
step 1: the fluoro-3-methyl of 5--2-nitrobenzoic acid (E1)
Slowly add KNO to the solution of the fluoro-5-tolyl acid of 3-(1.0 equivalent) in the vitriol oil under 0 ℃ 3(1: 1 equivalent).Stir this mixture 1 hour under room temperature, then slowly pour in frozen water.After being stirred to ice and melting fully, white precipitate is filtered, use cold wash, drying under reduced pressure.This white solid is not further purified, and is directly used in next step. 1h NMR (400MHz, DMSO, 300K) δ 14.08 (1H, br.s), 7.65 (2H, m), 2.30 (3H, s).
step 2: the fluoro-3-methyl of 5--2-nitrobenzene methyl (E2)
Under room temperature, to (E1) and cesium carbonate (1.5 equivalent), the solution (0.25M) in DMF adds methyl-iodide (1.0 equivalent).Stirring this mixture after 18 hours, add salt solution, mixture extracts with EtOAc.By the dry (Na of organic phase 2sO 4), concentrating under reduced pressure.The yellow solid obtained, for next step, is not further purified.
1h NMR (400MHz, DMSO, 300K) δ 7.63 (2H, m), 3.83 (3H, s), 2.29 (3H, s).
step 3: 2-amino-5-fluorine-3-methyl-toluate (E3)
At room temperature and H 2under atmosphere (1atm), by (E2) (1.0 equivalent) and Pd/C (10%w/w), the mixture (0.25M) in MeOH stirs 3 days.By mixture through diatomite filtration, removal of solvent under reduced pressure then.The white solid obtained, for subsequent step, is not further purified.
1h NMR (400MHz, DMSO, 300K) δ 7.29 (1H, dd, J=9.5Hz, J=3.0Hz), 7.12 (1H, dd, J=9.5Hz, J=3.0Hz), 6.36 (2H, br.s), 3.78 (3H, s), 2.11 (3H, s).
step 4: the fluoro-3-methyl-toluate of 2,5-bis-(E4)
Under 0 ℃, to (E3) (1.0 equivalent), the solution (0.4M) in anhydrous DCM adds the Tetrafluoroboric acid nitrosonium salts in batches.Add anhydrous difluorobenzene (120 equivalent) at 0 ℃ after lower 1 hour, reaction mixture slowly is heated to 160 ℃, steam except DCM simultaneously.After 3 hours, mixture is cooled to room temperature, adds EtOAc, salt washing 2 times for organic phase.Use MgSO 4after drying, solvent is removed in decompression.The crude product purified by flash chromatography, with 1-10%EtOAc/ sherwood oil wash-out, obtain (E4), is yellow oil.
1h NMR (400MHz, CDCl 3, 300K) δ 7.42 (1H, m), 7.06 (1H, m), 3.92 (3H, s), 2.30 (3H, d, J=2.3Hz).
step 5: the fluoro-3-carbamoyl benzoate of 2,5-bis-methyl esters (E5)
(E5) the general procedure preparation according to report in Preparation Example A step 2 and 3 by (E4).The crude product purified by flash chromatography, with 1-20%EtOAc/ sherwood oil wash-out, obtain white solid.
1h NMR (300MHz, DMSO, 300K) δ 10.19 (1H, d, J=2.4Hz), 7.98 (1H, m), 7.86 (1H, m), 3.89 (3H, s) .MS (ES +) C 9h 6f 2o 3theoretical value: 200, experimental value: 201 (M+H) +.
step 6: the fluoro-2-of trifluoroacetic acid 5-(the fluoro-4-piperidines of 3--3-base phenyl)-2H-indazole-7-methane amide (E6)
General procedure by (E5) according to report in Preparation Example A step 4 and 5, change into corresponding indazole with 3-(4-amino-2-fluorophenyl) piperidines-1-carboxylic acid tert-butyl ester.
Formed 2-{4-[1-(tertbutyloxycarbonyl) piperidines-3-yl]-the 3-fluorophenyl }-the fluoro-2H-indazole of 5--7-carboxylate methyl ester is by room temperature using the solution (0.1M) of KOH (1.03 equivalent) in dioxane/water to process 12 hours, changes into corresponding methane amide.Removal of solvent under reduced pressure.This carboxylic acid is dissolved in to DMF (0.1M), adds TBTU (1.5 equivalent).Add DIPEA (2.0 equivalent) and ammonia (3.0 equivalents, 0.5M THF solution) after 15 minutes, by this solution stirring 36 hours.Dilute this mixture with EtOAc, organic phase NaHCO 3saturated aqueous solution is washed.After evaporating solvent, residue, for next step, is not further purified.
In order to go protection, crude product is dissolved in to TFA/DCM (0.1M), under room temperature, stir 3 hours.Steaming desolventizes, and (post: C18) purifying obtains title compound (E6) to the reversed-phase HPLC for residue obtained.
1h NMR (400MHz, DMSO, 300K) δ 9.34 (1H, s), 8.90 (1H, m), 8.61 (1H, m), 8.49 (1H, s), (8.18 1H, dd, J=11.6Hz, 2.0Hz), 8.05 (2H, m), 7.81 (2H, m), 7.63 (1H, m), (3.34 3H, m), 3.13 (1H, m), (2.94 1H, m), 1.95-1.76 (4H, m) .MS (ES +) C 19h 18f 2n 4the O theoretical value: 356, experimental value: 357 (M+H) +.
embodiment 5
4-toluene sulfonic acide (3S)-3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt
step 1: (3S)-3-[4-({ (1E)-[3-(methoxycarbonyl)-2-nitrophenyl] methylene radical } amino) phenyl] piperidines-1-carboxylic acid tert-butyl ester (F1)
(F1) according to described in embodiment 1 (B1), by A3 and (3S)-3-(4-aminophenyl) piperidines-1-carboxylic acid tert-butyl ester (disassemble 3-(4-aminophenyl) piperidines and carry out subsequently the Boc protection in methyl alcohol by the L-dibenzoyl tartaric acid with 2 equivalents and make) preparation.
step 2: 2-{4-[(3S)-1-(tertbutyloxycarbonyl) piperidines-3-yl] phenyl }-2H-indazole-7-carboxylic acid (F2)
The pulp in DCM (0.25M) by (F1) (1 equivalent) and sodiumazide (1 equivalent), blanketing with inert gas, add 2,6-lutidine (1.0 equivalent).Mixture is heated to 110 ℃ of interior temperature, keeps 20 hours.The brown solution of formation is cooled to 20 ℃, adds THF to add the LiCl aqueous solution of 25wt%.Separate two-phase, organic phase is washed 3 times with the 25wt%LiCl aqueous solution.Add 2.0M NaOH (10 equivalent) in above organic solution, this mixture, 35 ℃ of heating 20 hours, then is cooled to 20 ℃, separate two-phase.Organic layer is washed with the mixture of 2.0M hydrochloric acid and salt solution, separates each layer, and organic layer with the salt washing, concentrates and obtains (F2) again, is not further purified.
step 3: (3S)-3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidines-1-carboxylic acid tert-butyl ester (F3)
F2 is dissolved in DCM (0.35M), adds dimethyl dicarbonate butyl ester (1.3 equivalent) and pyridine (1.0 equivalent) under room temperature.Add bicarbonate of ammonia (1.3 equivalent) after 30 minutes, continue to stir 20 hours.Add 1M HCl (5mL/g), separation of phases, organic phase washes with water 2 times, is concentrated into small volume.Rough compound (F3) filters through silicagel pad, then crystallization in methyl tertiary butyl ether.
step 4: 4-toluene sulfonic acide (3S)-3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidinium salt (F4)
F3 is dissolved in to THF (0.15M), adds water (THF 5%).Add tosic acid monohydrate (2.2 equivalent), this mixture is heated to 66 ℃ and also stirs and spend the night.Cooled and filtered is separated desired solid salt, and turns out to be monohydrate (F4).
1h NMR (400MHz, DMSO, 300K) δ 9.34 (1H, s); (9.20 1H, broad s), 8.58 (1H, s), 8.14 (2H, d, J=8.8Hz), 8.05 (2H, ddd, J=1.2,7.2,16.8Hz), 7.93 (1H, s), 7.52 (4H, dd, J=8.8,16.8Hz), 7.27 (1H, dd, J=6.8,8.0Hz), 7.13 (2H, d, J=8Hz), 3.48 (3H, m), 3.10 (2H, m), 2.90 (1H, m); (2.30 3H, s), 1.89 (2H, m), 1.75 (2H, m).
According to the method for previous embodiment, prepared by following examples:
Embodiment Title MW M+H + Embodiment Step
6 Trifluoroacetic acid 3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidines 320 321 1
7 The fluoro-2-of 5-(4-piperidines-3-base phenyl)-2H-indazole-7-methane amide 338 339 3
8 Chlorination (3S)-3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidines 320 321 2
9 Chlorination (3R)-3-{4-[7-(aminocarboxyl)-2H-indazole-2-yl] phenyl } piperidines 320 321 2
10 (R) the fluoro-2-of-5-(4-piperidines-3-base phenyl)-2H-indazole-7-methane amide 338 339 2
11 (S) the fluoro-2-of-5-(4-piperidines-3-base phenyl)-2H-indazole-7-methane amide 338 339 2
12 (R) the fluoro-4-piperidines of the fluoro-2-{3-of-5--3-base phenyl }-2H-indazole-7-methane amide 356 357 2
13 (S) the fluoro-4-piperidines of the fluoro-2-{3-of-5--3-base phenyl }-2H-indazole-7-methane amide 356 357 2

Claims (16)

1. a formula I compound or its pharmaceutically useful salt, steric isomer or tautomer:
It is R 1hydrogen or fluorine, R 2hydrogen or fluorine.
2. the compound of claim 1, wherein said compound is formula II compound, or its pharmaceutically useful salt, steric isomer or tautomer:
R wherein 1and R 2with the definition in claim 1.
3. the compound of claim 1, wherein said compound is the formula III compound, or its pharmaceutically useful salt or tautomer:
Figure FSB00001018423500013
R wherein 1and R 2with the definition in claim 1.
4. the compound of claim 1, wherein said compound is formula IV compound, or its pharmaceutically useful salt or tautomer:
R wherein 1and R 2with the definition in claim 1.
5. the compound of any one, wherein R in claim 1-4 1hydrogen, R 2hydrogen or fluorine.
6. the compound of a claim 1 is selected from:
2-(4-piperidines-3-base phenyl)-2H-indazole-7-methane amide;
2-{4-[(3R)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide;
2-{4-[(3S)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide;
The fluoro-2-of 5-(4-piperidines-3-base phenyl)-2H-indazole-7-methane amide;
The fluoro-2-{4-[(3S of 5-)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide;
The fluoro-2-{4-[(3R of 5-)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide;
The fluoro-2-of 5-(the fluoro-4-piperidines of 3--3-base phenyl)-2H-indazole-7-methane amide;
The fluoro-4-[(3R of the fluoro-2-{3-of 5-)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide;
The fluoro-4-[(3S of the fluoro-2-{3-of 5-)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide;
And their pharmacologically acceptable salt, tautomer or steric isomer.
7. compound: 2-{4-[(3S)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide; Or its pharmacologically acceptable salt or tautomer.
8. compound: 2-{4-[(3R)-piperidines-3-yl] phenyl }-2H-indazole-7-methane amide; Or its pharmacologically acceptable salt or tautomer.
9. a pharmaceutical composition, wherein contain with pharmaceutically useful carrier-bound claim 1-8 in the compound of any one, or its pharmaceutically useful salt, tautomer or steric isomer.
10. the compound that comprises any one in claim 1 to 8, or the molectron of its pharmaceutically useful salt, steric isomer or tautomer and cancer therapy drug.
11. in claim 1 to 8 compound of any one or its pharmaceutically useful salt, steric isomer or tautomer be for the manufacture of the purposes of medicine, this medicine is used for the treatment of or prevents the illness that can improve by suppressing Poly ADP-ribose polymerase (PAPR).
12. in claim 1 to 8, the compound of any one or its pharmaceutically useful salt, steric isomer or tautomer are for the manufacture of the purposes of medicine, this medicine is used for the treatment of or preventing cancer, inflammatory diseases, reperfusion injury, ischemic conditions, apoplexy, renal failure, cardiovascular diseases, cardiovascular diseases outside vascular disease, diabetes, neurodegenerative disease, retroviral infection, retina injury or skin aging, and the skin injury brought out of UV.
13. the compound of any one or its pharmaceutically useful salt in claim 1 to 8, steric isomer or tautomer are for the manufacture of the purposes of medicine, and described medicine is as chemical sensitising agent and/or radiosensitizing agent in cancer therapy.
14. the molectron of the compound of any one or its pharmaceutically useful salt or tautomer and Temozolomide in claim 1 to 8.
15.2-{4-[(3S)-piperidines-3-yl] phenyl }-molectron of 2H-indazole-7-methane amide or its pharmaceutically useful salt and Temozolomide.
16.2-{4-[(3R)-piperidines-3-yl] phenyl }-molectron of 2H-indazole-7-methane amide or its pharmacologically acceptable salt and Temozolomide.
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