CN101578279A - 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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CN101578279A
CN101578279A CNA2008800019265A CN200880001926A CN101578279A CN 101578279 A CN101578279 A CN 101578279A CN A2008800019265 A CNA2008800019265 A CN A2008800019265A CN 200880001926 A CN200880001926 A CN 200880001926A CN 101578279 A CN101578279 A CN 101578279A
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indazole
phenyl
bases
piperidines
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CN101578279B (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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MSD Italia SRL
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Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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 of poly- (ADP ribose) polymerase (PARP) inhibitor
The present invention relates to the indazole compound of acid amides substitution, they are the inhibitor of previously poly- (ADP ribose) polymerase (PARP) of referred to as poly- (ADP ribose) synthase and poly- (ADP ribosyls) transferase.The compound of the present invention can be used for the single therapy in DNA repairs passage with the tumour of specified defect, and be used as the reinforcing agent of some DNA damage agent (such as anticarcinogen and radiotherapy).In addition, the compound of the present invention can be used for reducing meronecrosis (in apoplexy and myocardial infarction), inflammation and tissue damage are lowered, retroviral infection is treated and prevents the toxicity of chemotherapy.
Poly- (ADP ribose) polymerase (PARP) constitutes the superfamily (Bioessays (2004) 26 of 18 kinds of albumen of a catalytic domain containing PARP：1148).These albumen include PARP-1, PARP-2, PARP-3, end anchor enzyme -1, end anchor enzyme -2, dome PARP and TiPARP.Its basic element PARP-1 is made up of three main domains：Amino (N) end DNA binding domain (DBD) containing two zinc fingerses, modifies domain, and carboxyl (C) end catalytic domain automatically.
PARP is by NAD+Cut into niacinamide and ADP ribose, so as to form the ribozyme and kytoplasm enzyme of long and branched ADP ribose polymers on target protein, including topoisomerase, histone and PARP (Biochem.Biophys.Res.Commun. (1998) 245 in itself：1-10).
Poly- (ADP ribosyls), which is changed, participates in several bioprocess, including DNA is repaired, genetic transcription, cell cycle progression, cell death, chromatin function and Genome stability.
It has already been indicated that PARP-1 and PARP-2 catalytic activity can be rapidly excited (see Pharmacological Research (2005) 52 by DNA fracture：25-33).As DNA is impaired, PARP-1 is combined with single-stranded and double-stranded DNA breach.Active very littles of PARP under normal physiological conditions, but in DNA damage, PARP activity is activated until 500 times immediately.PARP-1 and PARP-2 all as breach inductor play a part of detection DNA interrupt there is provided fast signal with stop transcription and damage location raise for the enzyme needed for DNA plerosis.Because the radiotherapy and many embolic chemotherapies in treatment of cancer are worked by radiation-indued DNA damage, PARP inhibitor can as treatment of cancer chemistry and radiosensitizer.PARP inhibitor effective (US 5,032,617, US 5,215,738 and US5,041,653) in terms of radiosensitization hypoxic tumor cell is reported.
PARP most of biological effects are relevant with following factors：The property of target protein and this poly- (the ADP ribosyls) of function is influenceed to change process；The PAR oligomer of special cytosis is assigned when being cut in the albumen changed from poly- (ADP ribosyls)；PARP and nucleoprotein physical association formation functional complex；And its substrate NAD+Cellular level reduction (Nature Review (2005) 4：421-440).
In addition to relevant with DNA reparations, the mediator that PARP is also used as cell death works.Its excessive activation under the pathological conditions such as ischaemic and reperfusion injury, can cause intercellular NAD+Substantial lack, this can cause several NAD+Dependence metabolic pathway impaired simultaneously causes cell death (see Pharmacological Research (2005) 52：44-59).Due to PARP activation, NAD+Level is remarkably decreased.Excessive PARP activation causes NAD in the cell by a large amount of DNA damages+Famine.The short half life of poly- (ADP ribose) causes fast conversion ratio, because poly- (ADP ribose) is just degraded rapidly once being formed by poly- (ADP ribose) glycosyl hydrolase (PARG) of constitutive activity.PARP and PARG form one by a large amount of NAD+The circulation of ADP ribose is changed into, NAD is caused+Less than the 20% of normal level is down to ATP.Such a situation is particularly detrimental during ischemic, and now the missing of oxygen has seriously jeopardized cellular energy output.Then the free radical during Reperfu- sion produces the main cause for being envisioned for tissue damage.Would generally occur ATP declines in many organs during ischemia and reperfusion, one part may change the NAD caused with poly- (ADP ribose)+Lack relevant.Therefore, it is contemplated that PARP suppression can keep cellular energy levels, survived so as to strengthen ischemic tissue after injury.Therefore, illness caused by the cell death that can be used for treatment to be mediated as PARP as the compound of PARP inhibitor, including neuropathic conditions, such as apoplexy, wound and Parkinson's.
PARP inhibitor has been found to the specific killing (Nature (2005) 434 available for BRCA-1 and BRCA-2 defect tumours：913-916 and 917-921；And Cancer Biology＆Therapy (2005) 4：934-936).
PARP inhibitor also shows the effect (PharmacologicalResearch (2005) 52 of enhancing cancer therapy drug：25-33), including platinum compounds, such as cis-platinum and carboplatin (CancerChemother Pharmacol (1993) 33：157-162 and Mol Cancer Ther (2003) 2：371-382).PARP inhibitor also shows increase topoisomerase I inhibitor, such as Irinotecan and Hycamtin, antitumor activity (Mol Cancer Ther (2003) 2：371-382；With Clin Cancer Res (2000) 6：2860-2867), this (JNatl Cancer Inst (2004) 96 that are in vivo confirmed in model：56-67).
PARP inhibitor is shown to recover to the cytotoxicity of Temozolomide (TMZ) and the sensitiveness of anti-proliferative effect (see Curr Med Chem (2002) 9：1285-1301 and Med Chem RevOnline (2004) 1：144-150).This is in 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 in vivo test model (Blood (2002) 99：2241-2244；Clin Cancer Res(2003)9：5370-5379 and JNatl Cancer Inst (2004) 96：It is confirmed in 56-67).PARP inhibitor is also shown to prevent by selective N 3- adenine methylating reagents, such as MeOSO2(CH2)-information translates appearance (the Pharmacological Research (2005) 52 for reading the meronecrosis that molecule (Me-Lex) induces：25-33).
PARP inhibitor, which is shown, plays a part of radiosensitizer.Report that PARP inhibitor is effective in terms of radiosensitization (Hypoxic) tumour cell, and prevented tumour cell possible lethal (Br.J.Cancer (1984) 49 (Suppl.VI) after radiotherapy：34-42；With Int.J. Radiat.Bioi. (1999) 75：91-100) with semilethal (Clin.Oncol. (2004) 16 (1)：29-39) effective in terms of recovery in DNA damage, estimation is due to that they can prevent DNA from being reconnected after being broken and influence several DNA damage signalling channels.
PARP inhibitor, which is also shown, can be used for treating acute and chronic cardiomyopathy (see Pharmacological Research (2005) 52：34-43).For example, it has been demonstrated that single injection PARP inhibitor can reduce infarct size caused by the ischemia and reperfusion of rabbit hearts or skeletal muscle.In these researchs, single injection 3-AB (10mg/kg), either inaccessible previous minute, or Reperfu- sion previous minute, infarct size will be caused to have similar reduction (32-42%), and another PARP inhibitor ISQ (1mg/kg) reduces infarct size with close degree (38-48%).These results allow to reasonably speculate, PARP inhibitor can remedy the reperfusion injury (PNAS (1997) 94 of ischemic heart or skeletal muscle tissue in advance：679-683).For pig (Eur.J.Pharmacol. (1998) 359：143-150 and Ann.Thorac.Surg. (2002) 73：575-581) with dog (Shock. (2004) 21：426-32) also report similar discovery.
PARP inhibitor has been found to can be used for treating some angiosises, septic shock, ischemia injury and neurotoxicity (Biochim.Biophys.Acta (1989) 1014：1-7；J.Clin.Invest.(1997)100：723-735).Oxygen radical DNA damage causes the chain in DNA to be broken, and it is then recognized by PARP, and this damage is the principal element (J.Neurosci.Res. (1994) 39 worked to these morbid states as indicated by being studied PARP inhibitor：38-46 and PNAS (1996) 93：4688-4692).PARP is also proved the (PNAS (2000) 97 that played a role in the pathogenesis of hemorrhagic shock：10203-10208).
PARP inhibitor has been found to can be used for treatment inflammatory disease (see PharmacologicalResearch (2005) 52：72-82 and 83-92).
Also it has proven convenient that the effective retroviral infection of mammalian cell is blocked by suppressing PARP activity.This suppression of recombinant retroviral vector infection has shown that generation (J.Virology, (1996) 70 (6) in various types of cell：3992-A000).Therefore have developed PARP inhibitor is used for antiviral therapy and treatment of cancer (WO 91/18591).
Had confirmed in testing in vitro and in vivo, PARP inhibitor can be used for treating or preventing autoimmunity disease, such as type i diabetes and diabetic complication (Pharmacological Research (2005) 52：60-71).
Once speculated that PARP suppressed to have delayed the beginning (Biochem.Biophys.Res.Comm. (1994) 201 (2) of aging character in human fibroblast：665-672 and Pharmacological Research (2005) 52：93-99).This may (Nature Gen., (1999) 23 (1) relevant with the effect of the whole chain regulator function of PARP controls：76-80).
Up to now most PARP inhibitor all interact with the niacinamide binding domain of enzyme, and seem competitive inhibitor (Expert Opin.Ther.Patents (2004) 14 for NAD+：1531-1551).The analogue of niacinamide, such as benzamide and derivative, belong to first compound studied as PARP inhibitor.However, the inhibitory activity of these molecules is weak, and has and suppress the unrelated other effects of PARP.Accordingly, it is desirable to provide the strong inhibitor of PARP enzymes.
Previously it has been related to the description of PARP inhibitor related in structure.WO 1999/59973 discloses the phenyl ring with the acid amides substitution of 5 yuan of hetero-aromatic ring fusions；WO 2001/85687 discloses the indoles of acid amides substitution；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 benzimidazole of acid amides substitution；WO2000/29384 discloses the benzimidazole and indoles of acid amides substitution；EP 0879820 discloses the benzoxazole of acid amides substitution.
It has now unexpectedly been found that the indazole of the acid amides substitution of the present invention shows the extra high ability for suppressing poly- (ADP ribose) polymerase (PARP) activity.Therefore the compounds of this invention is particularly suitable as PARP-1 and/or PARP-2 inhibitor is used.They also show particularly preferred cytoactive, show the good anti-proliferative effect to BRCA1 and BRCA2 deficient cells system.
The present invention provides compound of formula I or its pharmaceutically useful salt, stereoisomer or dynamic isomer：
Figure A20088000192600091
Wherein：
R1It is hydrogen or fluorine；With
R2It is hydrogen or fluorine.
In an embodiment, R1It is hydrogen.
In another embodiment, R1It is fluorine.
In an embodiment, R2It is hydrogen.
In another embodiment, R2It is fluorine.
In an embodiment, R1It is hydrogen, R2It is hydrogen or fluorine.
In another embodiment, R1It is fluorine, R2It is hydrogen or fluorine.
In another embodiment, R1It is hydrogen, R2It is hydrogen.
In another embodiment, R1It is hydrogen, R2It is fluorine.
In another embodiment, R1It is fluorine, R2It is fluorine.
In another embodiment, R1It is hydrogen or fluorine, R2It is hydrogen.
In another embodiment, R1It is hydrogen or fluorine, R2It is fluorine.
The present invention also provides Formula II compound or its pharmaceutically useful salt, stereoisomer or dynamic isomer：
Figure A20088000192600092
Wherein R1And R2It is as defined above.
The present invention also provides formula III compound or its pharmaceutically useful salt or dynamic isomer：
Figure A20088000192600101
Wherein R1And R2It is as defined above.
The present invention also provides formula IV compound or its pharmaceutically useful salt or dynamic isomer：
Figure A20088000192600102
Wherein R1And R2It is as defined above.
Preferred body in terms of Formula II, III and IV is identical with the definition previously to Formulas I, makees in details suitably modified.
The present invention also includes the N- oxides of above compound of formula I in the range of it.Generally, these N- oxides can be formed on any available nitrogen-atoms.N- oxides can be formed with conventional method, and such as compound of formula I is reacted with oxone in the presence of wet oxidation aluminium.
The present invention includes the prodrug of above compound of formula I in the range of it.Generally, these prodrugs should be the functional derivatives of compound of formula I, and they easily change into required compound of formula I in vivo.The conventional steps for selecting and preparing suitable prodrug derivant are described in for example " in Design ofProdrugs " (ed.H.Bundgaard, Elsevier, 1985).
Prodrug can be the derivative pharmacologically inactivated of bioactive substance (" parent drug " or " parent molecule "), and it needs to convert in vivo to discharge active medicine, and the improved delivery properties with better than parent drug molecule.Conversion can be the oxidation or reduction of the result of some metabolic processes, the chemical hydrolysis or enzymatic hydrolysis of such as carboxylic acid, phosphoric acid or sulfuric ester, or susceptible functionality in vivo.
The scope of the present invention includes the solvate of compound of formula I and its salt, such as hydrate.
The compounds of this invention can have asymmetric center, chiral axis and chiral planes (as described in documents below：E.L.Eliel and S.H.Wilen, Stereochemistry of CarbonCompounds, John Wiley＆Sons, New York, 1994, p.1119-1190), and in the form of racemate, racemic mixture and individual other diastereomer, and all possible isomers and its mixture, include the form presence of optical isomer, all these stereoisomers are all included within the present invention.In addition, compound disclosed herein may have dynamic isomer, two kinds of tautomeric forms are intended to be included within the scope of the present invention, even if only describing a kind of tautomeric structure.
The compounds of this invention can exist with different isomeric forms, and they are all covered by the present invention.
The compounds of this invention may have a variety of different polymorph.
As used herein, C1-6Alkyl is represented containing 1, the radical of saturated aliphatic alkyl of the side chain of 2,3,4,5 or 6 carbon atoms, straight chain and annular.For example, " C1-6Alkyl " specifically includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl etc..It is preferred that alkyl be methyl and ethyl.
Particular compound in the scope of the invention is：
Chlorination 3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt；
2- { 4- [(3R)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides；
2- { 4- [(3S)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides；
Trifluoroacetic acid 3- { 4- [the fluoro- 2H- indazoles -2- bases of 7- (amino carbonyl) -5-] phenyl } piperidinium salt；
The fluoro- 2- of trifluoroacetic acid 5- (the fluoro- 4- piperidines -3- bases phenyl of 3-) -2H- indazole -7- formamides；
Trifluoroacetic acid 3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt；
The fluoro- 2- of 5- (4- piperidines -3- bases phenyl) -2H- indazole -7- formamides；
Chlorination (3S) -3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt；
Chlorination (3R) -3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt；
(R) the fluoro- 2- of -5- (4- piperidines -3- bases phenyl) -2H- indazole -7- formamides；
(S) the fluoro- 2- of -5- (4- piperidines -3- bases phenyl) -2H- indazole -7- formamides；
(R) the fluoro- 2- of -5- { the fluoro- 4- piperidines -3- bases phenyl of 3- } -2H- indazole -7- formamides；
(S) the fluoro- 2- of -5- { the fluoro- 4- piperidines -3- bases phenyl of 3- } -2H- indazole -7- formamides；
And its pharmaceutically useful salt, free alkali or dynamic isomer.Additionally provide the stereoisomer of these compounds.
The present invention a kind of particular compound be：Chlorination 3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt, or its pharmaceutically useful free alkali or dynamic isomer.Additionally provide the stereoisomer of this compound.
The present invention a kind of particular compound be：2- { 4- [(3R)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides, or its pharmaceutically useful salt, free alkali or dynamic isomer.Additionally provide the stereoisomer of this compound.
The present invention a kind of particular compound be：2- { 4- [(3S)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides, or its pharmaceutically useful salt, free alkali or dynamic isomer.Additionally provide the stereoisomer of this compound.
The present invention a kind of particular compound be：Trifluoroacetic acid 3- { 4- [the fluoro- 2H- indazoles -2- bases of 7- (amino carbonyl) -5-] phenyl } piperidinium salt, or its pharmaceutically useful free alkali or dynamic isomer.Additionally provide the stereoisomer of this compound.
The present invention a kind of particular compound be：The fluoro- 2- of trifluoroacetic acid 5- (the fluoro- 4- piperidines -3- bases phenyl of 3-) -2H- indazole -7- formamides, or its pharmaceutically useful free alkali or dynamic isomer.Additionally provide the stereoisomer of this compound.
The present invention a kind of particular compound be：4- toluene sulfonic acides (3S) -3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt, or its pharmaceutically useful free alkali or dynamic isomer.Additionally provide the stereoisomer of this compound.
The present invention includes the free alkali and its pharmaceutically useful salt and stereoisomer of compound of formula I.The compounds of this invention can be protonated at the N atoms of amine and/or the heterocyclic moiety containing N, forming salt." free alkali " one word refers to the amines of salt-independent shape.Included officinal salt not only includes the salt enumerated for particular compound example specifically described herein, but also all typical officinal salts of the compound of formula I including free alkali form.The free form of described specific salt formula compound can be separated with techniques known in the art.For example, the free form can use box-like dilute alkaline aqueous solution, such as NaOH, potassium carbonate, ammonia and sodium acid carbonate dilute aqueous solution handle the salt to regenerate.The free form may be slightly different with respective salt form in terms of some physical properties (such as the solubility in polar solvent), but for the present invention, the acid and basic salt are pharmaceutically equivalent in other side and respective free form.
The officinal salt of the compounds of this invention can be chemically synthesized by the compounds of this invention containing alkalescence or acidic moiety by conventional.Typically, the salt of alkali compounds is prepared by ion-exchange chromatography, or preparation is reacted in suitable solvent or various solvent mixtures by the salt-forming inorganic or organic acid needed for the free alkali and stoichiometric or excessive.Similarly, acid compound with suitable inorganic or organic base reaction by preparing.
Therefore, the officinal salt of the compounds of this invention includes the conventional non-toxic salts for leading to peralkaline the compounds of this invention and the compounds of this invention that is inorganic, organic or polymerizeing acid reaction formation.For example, conventional non-toxic salts are included from inorganic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, sulfamic acid, phosphoric acid, phosphorous acid, salt derived from nitric acid etc., and from organic acid, such as acetic acid, propionic acid, butanedioic acid, hydroxyacetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, Aspirin, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, palmitic acid, gluconic acid, L-aminobutanedioic acid, cinnamic acid, pyruvic acid, ethyl sulfonic acid, valeric acid, trifluoroacetic acid etc., the salt prepared.Suitable polysalt includes the salt as derived from polymeric acid such as tannic acid, carboxymethyl cellulose.Inorganic or organic acid of the pharmaceutically useful salt of the present invention preferably containing 1 equivalent formula (I) compound and 1,2 or 3 equivalents.In an embodiment, formula (I) compound of the pharmaceutically useful salt comprising 2 equivalents of the invention and the inorganic or organic acid of 1 equivalent.More specifically, pharmaceutically useful salt of the invention is trifluoroacetate, chloride or toluene fulfonate.Particularly, pharmaceutically useful salt of the invention is trifluoroacetate or chloride salt.In an embodiment, the salt is trifluoroacetate.In another embodiment, the salt is chloride.In another embodiment, the salt is toluene fulfonate.
Term toluenesulfonic acid can be with 4- toluene sulfonic acide used interchangeablies, and toluene fulfonate (toluene sulfonates) is also referred to as tosilate (tosylate).
When the compounds of this invention is acid compound, suitable " officinal salt " refers to the salt prepared from pharmaceutically useful non-toxic alkali (including inorganic base and organic base).Salt includes aluminium salt, ammonium salt, calcium salt, mantoquita, molysite, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc. as derived from inorganic base.Particularly preferably ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt.Salt includes the salt of following organic base as derived from pharmaceutically useful organic nontoxic alkali：Primary amine, secondary amine and tertiary amine, substituted amine (including naturally occurring substitution amine), cyclammonium and deacidite, such as arginine, lysine, glycine betaine, caffeine, choline, N, N1- dibenzyl-ethylenediamin, ethamine, diethylamine, 2- DEAE diethylaminoethanols, DMAE, monoethanolamine, diethanol amine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, aminoglucose, Glucosamine, histidine, breathe out amine (hydrabamine), isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidines, polyamino resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), tromethamine, dicyclohexyl amine, butylamine, benzylamine, phenylbenzylamine etc..
The preparation of above-described and other typical officinal salts is in Berg etc. (1997) .J.Pharm.Sci., " Pharmaceutical Salts ", 66：It is more fully described below in the texts of 1-19 mono-.
It is also pointed out that, the compounds of this invention is likely to be inner salt or amphion, because the acidic moiety (such as carboxyl) of a deprotonation of compound in physiological conditions can be anionic, the cationic charge of basic moiety (such as quaternary nitrogen atoms) that this electron charge can be internally protonated or alkylation is offset.
The compounds of this invention can be used for the method using therapy for treating human or animal's body.
Can be by suppressing the compound for the illness that poly- (ADP ribose) polymerase (PARP) is improved (see, for example, Nature Review DrugDiscovery (2005) 4 the present invention is provided to treat or prevent：421-440).
Therefore, the present invention provides a kind of compound of formula I for being used to manufacture medicine, and the medicine can be by suppressing the illness that poly- (ADP ribose) polymerase (PARP) is improved for treatment or prevention.
The present invention also provide it is a kind of can be by suppressing the method for the illness that poly- (ADP ribose) polymerase (PARP) is improved for treatment or prevention, this method includes applying patient in need the compound of formula I of effective dose or the composition containing compound of formula I.
The 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 treatingInflammatory disease, including the illness as caused by organ-graft refection, for example：Chronic inflammatory joint disease, including arthritis, rheumatoid arthritis, osteoarthritis and the osteopathy relevant with bone information increase；Inflammatory bowel disease, such as ileitis, ulcerative colitis, Barrett syndrome and regional ileitis；Inflammatory lung disease, such as asthma, ARDS and chronic obstructive airway disease；The inflammatory disease of eye, including corneal dystrophy, trachoma, onchocercosis, uveitis, sympathetic ophthalmia and entophthamia；Chronic inflammatory gingivitis, including oulitis and periodontitis；Tuberculosis；Leprosy；Inflammatory nephrosis, including Uremic complications, glomerulonephritis and nephrosis；Inflammatory dermatosis, including sclerodermatitis, psoriasis and eczema；The inflammatory disease of central nervous system, including chronic demyelinating disease, multiple sclerosis, the neurodegenerative disease relevant with AIDS and the alzheimer disease of nervous system, contagious meningitis, encephalomyelitis, Parkinson's, Huntington disease, ALS and viral or from immune encephalitis；Diabetic complication, includes but is not limited to, immune complex vasculitis, systemic loupus erythematosus (SLE)；The inflammatory disease of heart, such as cardiomyopathy, ischemic heart disease, hypercholesterolemia and atherosclerosis；And can have other various diseases of significant inflammatory component, including pre-eclampsia, chronic liver failure, brain and spinal cord injuries receptor and Multiple Organ's dysfunction syndrome (MODS) (multiple organ failure (MOF)).Inflammatory disease can also be the systemic inflammation of body, such as Gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or the shock induced in response to proinflammatory cytokine due to cancer chemotherapy, such as shock relevant with proinflammatory cytokine.These shocks can be induced because of the chemotherapeutics applied as cancer therapy.
Therefore, the present invention provides a kind of compound of formula I for being used to manufacture medicine, and the medicine is used to treat or prevent inflammatory disease.
The present invention also provides a kind of method for treating or preventing inflammatory disease, and this method includes applying patient in need the compound of formula I of effective dose or the composition containing compound of formula I.
The compounds of this invention can also be used to treat or prevent by abiogenous breaking-out and caused by between surgery average of operation periodsReperfusion injury, such as intestines reperfusion injury；Myocardial reperfusion injury；The reperfusion injury caused by cardiopulmonary bypass surgery, aortic aneurysm prosthesis, carotid endarterectomy or hemorrhagic shock；By the organ transplant Reoxygenation Injury that for example heart, lung, liver, kidney, pancreas, intestines and corneal transplantation are caused.
Therefore, the invention provides a kind of compound of formula I for being used to manufacture the medicine for treating or preventing reperfusion injury.
The present invention also provides a kind of method for treating and preventing reperfusion injury, and this method is included to patient in need using the compound of formula I of effective dose or the composition containing compound of formula I.
The compounds of this invention can also be used to treat or preventIschemic conditionsIncluding the ischemic conditions as caused by organ transplant, such as stable angina cordis, unstable angina pectoris, myocardial ischemia, hepatic ischemia, acute mesenteric artery ischemia, intestine ischemia, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, ischemic nephropathy, ischemic hepatopathy, ischemic retinopathies, septic shock, and the ischemic disease of central nervous system, such as apoplexy or cerebral ischemia.
Therefore, the present invention provides a kind of compound of formula I for being used to manufacture the medicine for treating or preventing ischemic conditions.
The present invention also provides a kind of method for treating or preventing ischemic conditions, and this method is included to patient in need using the compound of formula I of effective dose or the composition comprising compound of formula I.
The present invention provides a kind of compound of formula I for being used to manufacture medicine, and the medicine is used to treat or prevent apoplexy.
The present invention also provides a kind of method for treating or preventing apoplexy, and this method is included to patient in need using the compound of formula I of effective dose or the composition containing compound of formula I.
The compounds of this invention can also be used to treat or preventChronic or acute renal failure。
Therefore, the present invention provides a kind of compound of formula I for being used to manufacture medicine, and the medicine is used to treat or prevent kidney failure.
The present invention also provides a kind of method for treating or preventing kidney failure, and this method is included to patient in need using the compound of formula I of effective dose or the composition comprising compound of formula I.
The compounds of this invention can also be used to treat or preventThe vascular diseases of non-cardiovascular disease, such as peripheral arterial occlusion, embolic occlusion type vasculitis, Raynaud's disease and Raynaud's phenomenon, flesh end cyanosis, erythromelalgia, venous thronbosis, varication, arteriovenous fistula, lymphedema and lipedema.
Therefore, the invention provides a kind of compound of formula I for being used to manufacture medicine, the medicine is used to treat or prevent the vascular diseases outside cardiovascular disease.
The present invention also provides a kind of method for being used to treat or prevent the vascular diseases outside cardiovascular disease, and this method is included to patient in need using the compound of formula I of effective dose or the composition containing compound of formula I.
The compounds of this invention can also be used to treat or preventCardiovascular disease, such as chronic heart failure, atherosclerosis, congestive heart failure, cyclical shock, cardiomyopathy, heart transplant, myocardial infarction, and arrhythmia cordis, such as auricular fibrillation, supraventricular tachycardia, auricular flutter and paroxysmal auricular tachycardia.
Therefore, the present invention provides a kind of compound of formula I for being used to manufacture medicine, and the medicine is used to treat or prevent cardiovascular disease.
The present invention also provides a kind of method for treating or preventing cardiovascular disease, and this method is included to patient in need using the compound of formula I of effective dose or the composition comprising compound of formula I.
The compounds of this invention can also be used to treat and preventDiabetes, including type i diabetes (insulin-dependent diabetes mellitus), type ii diabetes (adult-onset diabetes), gestational diabetes mellitus, certainly immune diabetes, Insulinopathy, the diabetes caused by Pancreas Disease, diabetes (such as Cushing's syndrome, acromegalia, pheochromocytoma, glucagonoma, primary aldosteronism or somatotropin chalone knurl), A type insulin resistance syndrome, Type B insulin resistance syndrome, lipotrophy diabetes and the diabetes that by beta cell toxin are induced relevant with other endocrine diseases.The compounds of this invention can also be used to treat or prevent diabetic complication, such as diabetic cataract, glaucoma, retinopathy, nephrosis (such as microalbuminuria and progressive diabetic nephropathy), DPN, foot gangrene, atherosclerotic coronary artery disease, peripheral arterial disease, non- ketosis hyperglycaemia-hyperosmolar coma, mononeuropathy, autonomic neuropathy, ulcer of foot, joint prob, skin or mucous membrane complication (for example infect, shin spot, monilial infection or necrobiosis lipoidica diabeticorum), hyperlipidemia, hypertension, insulin resistance syndrome, coronary artery disease, retinopathy, diabetic neuropathy, polyneuropathy, mononeuropathy, autonomic neuropathy, ulcer of foot, joint prob, fungal infection, bacterium infection and cardiomyopathy.
Therefore, the present invention provides a kind of compound of formula I for being used to manufacture medicine, and the medicine is used to treat or prevent diabetes.
The present invention also provides a kind of method for treating or preventing diabetes, and this method is included to patient in need using the compound of formula I of effective dose or the composition containing compound of formula I.
The compounds of this invention can also be used to treat or preventCancer, including entity tumor, such as fibrosarcoma, myxosarcoma, embryonal-cell lipoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangioendothelial sarcoma, lymphangioendothelial sarcoma, synovialoma, celiothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney, cancer of pancreas, osteocarcinoma, breast cancer, oophoroma, prostate cancer, the cancer of the esophagus, stomach cancer, carcinoma of mouth, rhinocarcinoma, laryngocarcinoma, squamous cell carcinoma, basal-cell carcinoma, gland cancer, syringocarcinoma, carcinoma of sebaceous glands, papillary carcinoma, emulsus shape gland cancer, cystadenocarcinoma, cephaloma, bronchogenic cancer, clear-cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, spermatogonium cancer, embryonal carcinoma, wilms' tumor, cervical carcinoma, uterine cancer, carcinoma of testis, ED-SCLC, carcinoma of urinary bladder, lung cancer, epithelioma, cutaneum carcinoma, melanoma, neuroblastoma and retinoblastoma；Haematogenous cancer, such as Acute Lymphoblastic Leukemia (" ALL "), acute lymphoblast B- chronic myeloid leukemias, acute lymphoblast T cell leukaemia, acute myeloblastic leukemia (" AML "), acute promyelocitic leukemia (" APL "), acute monoblast leukaemia, Di Guglielmo syndrome, acute megakaryoblastic leukemia, acute myeloid and monocytic leukemia, acute non lymphocytic leukemia, acute undifferentiated cell leukemia, chronic myelocytic leukemia (" CML "), chronic lymphocytic leukemia (" CLL "), hairy cell leukemia and Huppert's disease；Acute and chronic leukaemia, such as lymphoblast leukaemia, myelogene leukemia, lymphocytic leukemia, myelocytic leukemia；Lymthoma, such as Hodgkin's disease, NHL, Huppert's disease, waldenstrom macroglobulinemia disease, heavy chain disease and erythremia；CNS and the cancer of the brain, such as glioma, fibrous astrocytoma, astrocytoma, a modification astrocytoma, glioblastoma multiforme, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neurinoma, mesoglioma, meningioma, vestibular schwannomas, adenoma, metastatic brain tumor, meningioma, vertebra knurl and medulloblastoma.
Therefore, the present invention provides a kind of compound of formula I for being used to manufacture medicine, and the medicine is used to treat or prevent cancer.
The present invention also provides a kind of method for treating or preventing cancer, and this method is included to patient in need using the compound of formula I of effective dose or the composition comprising compound of formula I.
The compounds of this invention can be additionally used in the cancer that treatment lacks homologous recombination (HR) dependent DNA DSB repairing activities (see WO 2006/021801).
HR dependent DNAs DSB repairs passage and is broken (DSB) by homologous mechanism DNA plerosis double center chain, to recover continuous DNA spirals (Nat.Genet. (2001) 27 (3)：247-254).The component that HR dependent DNAs DSB repairs passage includes, but not limited to
ATM(NM-000051),RAD51(NM-002875),RAD51L1(NM-002877),RAD51C(NM-002876),RAD51L3(NM-002878),DMCl(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),NBSl(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,MRE 11,NB51,WRN,BLMKU70,RU80,ATM,ATRCHK1,CHK2,FANCA,FANCB,FANCC,FANCD1,FANCD2,FANCE,FANCF,FANCG,FANCC,FANCD1,FANCD2,FANCE,FANCF,FANCG,RAD1 and RAD9.The other oroteins being related in HR dependent DNAs DSB reparation passages include regulatory factor, such as EMSY (Cell (2003) 115：523-535).
Lacking the cancer of HR dependent DNA DSB repairing activities can contain or including cancer cell as one or more, compared with normal cell, they reduce or disappeared via passage DNA plerosis DSB ability, i.e., in one or more cancer cells, the activity that HR dependent DNAs DSB repairs passage may be reduced or disappeared.
In the individual one or more cancer cells for the cancer for lacking HR dependent DNA DSB repairing activities in patient, the activity that HR dependent DNAs DSB repairs one or more components of passage may disappear.The component that HR dependent DNAs DSB repairs passage (is for example shown in, Science (2001) 291 by abundant confirmation in this area：1284-1289), including component listed above.
The present invention provides a kind of compound of formula I for being used to manufacture medicine, and the medicine is used to treat or prevent the cancer for lacking HR dependent DNA DSB repairing activities.
The present invention also provides a kind of method for the cancer for treating or preventing and lacking HR dependent DNA DSB repairing activities, and this method is included to patient in need using the compound of formula I of effective dose or the composition comprising compound of formula I.
In an embodiment, cancer cell lacks the HR dependent DNA DSB repairing activities of one or more phenotypes, and the phenotype is selected from：ATM(NM-000051),RAD51(NM-002875),RAD51L1(NM-002877),RAD51C(NM-002876),RAD51L3(NM-002878),DMCl(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),NBSl(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 cell has a kind of BRCA1 and/or BRCA2 defects phenotype.Cancer cell containing this phenotype may lack BRCA1 and/or BRCA2, i.e., expression and/or activity of the BRCA1 and/or BRCA2 in the cancer cell may reduce or disappear, for example due to the mutation in code nucleic acid or polymorphism, or due to amplification, mutation or the polymorphicization (Cell (2003) 115 of the gene EMSY genes of BRCA2 regulatory factors (such as encode) that encodes regulatory factor：523-535).
BRCA-1 and BRCA-2 are known tumor inhibitors, and its wild type allele usually loses (Oncogene, (2002) 21 (58) in the tumour of Hybrid Vector：8981-93；Trends Mol.Med., (2002) 8 (12)：571-6).BRCA-1 and/or BRCA-2 mutation also confirm (Exp Clin Cancer Res, (2002) 21 (3Suppl) with contacting for breast cancer by abundant：9-12).It it is known that the amplification of the EMSY genes of coding BRCA-2 binding factors is relevant with mammary gland and oophoroma.The carrier of mutation in BRCA-1 and/or BRCA-2, its oophoroma, the danger of prostate cancer and cancer of pancreas also increase.The detection of variation in BRCA-1 and BRCA-2 is well known in the art, in such as 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)：It is described in 11-16.The measure of BRCA-2 binding factors EMSY amplification is described in Cell115：In 523-535.PARP inhibitor is had proven to available for specific killing BRCA-1 and BRCA-2 defect tumour (Nature (2005) 434：913-916 and 917-920).
Therefore, the present invention provides a kind of compound of formula I for being used to manufacture medicine, and the medicine is used to treat or prevent BRCA-1 or BRCA-2 defect tumours.
The present invention also provides a kind of method for treating or preventing BRCA-1 or BRCA-2 defect tumours, and this method is included to patient in need using the compound of formula I of effective dose or the composition containing compound of formula I.
In an embodiment, PARP inhibitor of the invention can be used for the prophylactic treatment for eliminating BRCA-2 deficient cells (see Cancer Res. (2005) 65：10145).
The compounds of this invention can be used for treating or preventingNeurodegenerative diseaseIncluding, the neurodegeneration relevant with polyglutamine expansion area, Huntington disease, Kennedy disease, spinocebellar ataxia, repeats of dentatorubropallidolatrophy atrophy (DRPLA), the neurodegeneration relevant with protein aggregation, Ma-about disease, alzheimer disease, Parkinson's, ALS, sponge shape encephalopathic, prion relevant disease and multiple sclerosis (MS).
Therefore, the present invention provides a kind of compound of formula I for being used to manufacture medicine, and the medicine is used to treat or prevent neurodegenerative disease.
The present invention also provides a kind of method for treating or preventing neurodegenerative disease, and this method is included to patient in need using the compound of formula I of effective dose or the composition containing compound of formula I.
The compounds of this invention can also be used to treat or prevent retroviral infection (US 5652260), retinal damage (Curr.Eye Res. (2004), 29：403), skin injury (US 5589483 and the Biochem.Pharmacol (2002) 63 that skin senescence and UV induce：921).
The compounds of this invention can be used for generation (the Pharmacological Research (2005) 52 for treating or preventing the presenile aging cell kakergasia relevant with the age with delaying：93-99).
The compounds of this invention can according to standard pharmaceutical operation, individually or with pharmaceutically useful carrier, excipient, diluent, conditioning agent, filler, buffer, stabilizer, preservative, lubricant combination in pharmaceutical composition, mammal, the preferably mankind are administered to.
The compounds of this invention can be administered to treatment target by any convenient method of administration, it can be whole body/periphery or be applied in desired site of action, including but not limited to, orally (for example ingest), local (including it is for example transdermal, it is intranasal, eye, cheek contains and sublingual), lung's (such as using the oral or nasal suction of aerosol or being blown into treatment), rectum, vagina, parenterally (is for example injected, including subcutaneous, it is intracutaneous, it is intramuscular, it is intravenous, intra-arterial, it is intracardiac, it is intrathecal, in vertebra, it is intracapsular, under capsule, in eye socket, intraperitoneal, tracheal strips, under epidermis, it is intra-articular, under arachnoid and in breastbone), and implantation reservoir agent (being for example subcutaneously or intramuscularly implanted into).
Treatment target can be eucaryote, animal, vertebrate, mammal, rodent (such as cavy, hamster, rat, mouse), murine (such as mouse), canid (such as dog), cats (such as cat), equine species (such as horse), primate, anthropoid cape (such as monkey or ape), monkey (such as marmoset, baboon), ape (such as gorilla, chimpanzee, orangutan, gibbon) or people.
The present invention also provides the pharmaceutical composition containing one or more the compounds of this invention and pharmaceutical acceptable carrier.Pharmaceutical composition containing active component can be the form for being adapted to be administered orally, for example, tablet, lozenge, lozenge, water base or oil suspensions, dispersible pulvis or granula, emulsion, hard or soft capsule, or syrup or elixir.It is prepared by any known method that the composition of predetermined oral medication can manufacture pharmaceutical composition according to this area, and one or more reagents selected from sweetener, flavouring agent, colouring agent and preservative can be contained in this based composition, to form pharmaceutically exquisite and tasty preparation.Contain the active component mixed with the nontoxic pharmaceutically acceptable excipient of suitable manufacture tablet in tablet.These excipient can be, for example, inert diluent, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate；Granulating agent and disintegrant, for example, microcrystalline cellulose, sodium carboxymethylcellulose, cornstarch or the alginic acid of crosslinking；Adhesive, such as starch, gelatin, polyvinylpyrrolidone or Arabic gum；And lubricant, such as magnesium stearate, stearic acid or talcum.Tablet can not be coated, or can be coated with known technology, to cover the offending taste of medicine or delay disintegration and absorption in the gastrointestinal tract, so as to provide prolonged continuous action.It is, for example, possible to use water miscible taste masking material, such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or use time delay material, such as ethyl cellulose, cellulose acetate-butyrate.
The form of hard gelatin capsule can also be made in oral formulations, wherein active component and a kind of inert solid diluent, for example mixed with calcium carbonate, calcium phosphate or kaolin, or Perle is made, wherein active component is mixed with water-solubility carrier (such as polyethylene glycol) or oil medium (such as peanut oil, atoleine or olive oil).
Aqueous suspensions contain with being adapted to prepare the active material that the excipient of Aqueous suspensions is mixed.These excipient are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, mosanom, polyvinylpyrrolidone, bassora gum and Arabic gum；Dispersant or wetting agent can be naturally occurring phosphatide, such as lecithin, or the condensation product of oxyalkylene and aliphatic acid, such as Myrj 45, or oxirane and the condensation product of long chain aliphatic, such as hexadecanol polyoxyethylene (17) ether, or oxirane and the condensation product derived from aliphatic acid and the partial ester of hexitol, such as sorbitol polyoxyethylene monoleate, or oxirane and the condensation product derived from aliphatic acid and the partial ester of hexitan, such as anhydrous sorbitol Aceonon 300 MO.Aqueous suspensions can also contain one or more preservatives, such as ethyl-para-hydroxybenzoate or n-propyl, one or more colouring agents, one or more flavouring agents, and one or more sweeteners, such as sucrose, saccharin or aspartame.
Oil suspensions can be by the way that active component be suspended in vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil), or is suspended in mineral oil (such as atoleine) to prepare.Oil suspensions can contain thickener, such as beeswax, hard wax or hexadecanol.Sweetener (as described above those) and flavouring agent can be added to provide tasty oral formulations.These compositions can be by adding antioxidant such as butylated hydroxyanisol or alpha-tocopherol come anti-corrosion.
Fit through to add water and the dispersible pulvis and granula of Aqueous suspensions is made there is provided the active component mixed with dispersant or wetting agent, suspending agent and one or more preservatives.The example of suitable dispersant or wetting agent and suspending agent be it is already mentioned above those.Other excipient, such as sweetener, flavouring agent and colouring agent, can also be present.These compositions can be by adding antioxidant (such as ascorbic acid) come anti-corrosion.
The pharmaceutical composition of the present invention can also be the form of oil/water emulsion.Oil phase can be vegetable oil, such as olive cable oil or peanut oil, or mineral oil, such as atoleine, or these oily mixtures.Suitable emulsifying agent can be naturally occurring phosphatide, such as soybean lecithin, and ester or partial ester, such as sorbitan monooleate as derived from aliphatic acid and hexitan, with above-mentioned partial ester and the condensation product of oxirane, such as anhydrous sorbitol Aceonon 300 MO.Sweetener, flavouring, preservative and antioxidant can also be contained in emulsion.
Syrup and elixir can be prepared with sweetener (such as glycerine, propane diols, sorbierite or sucrose).This kind of preparation can also contain analgestic, preservative, flavouring, colouring agent and antioxidant.
Pharmaceutical composition can be the form of sterile injectable aqueous solutions.Include water, Ringer solution and isotonic sodium chloride solution in the qualified matchmaker's liquid and solvent that can be used.
Sterile ejection preparation can also be the o/w microemulsions of sterile injectable, and wherein active component is dissolved in oil phase.For example, first active component can be dissolved in the mixture of soybean oil and lecithin, then the oil solution is added in the mixture of water and glycerine and processed forms microemulsion.
The solution or microemulsion of injectable can be added in blood stream of patients using local bolus injection.Either, may be favourable to apply solution or microemulsion in the way of the constant circulation composition for keeping the compounds of this invention.In order to keep such a constant concentration, continuous intravenous delivery device can be used.The example of such a device is Deltec CADD-PLUSTM5400 types are injected intravenously pump.
Pharmaceutical composition can be for intramuscular and sterile water for injection base or oil suspensions of subcutaneous administration.This supensoid agent can be prepared according to already known processes using those suitable scattered or wetting agents and suspending agent already mentioned above.Sterile ejection preparation can also be the aseptic injectable solution or suspension in the nontoxic available diluent of parenterally or solvent, such as solution in 1,3-BDO.In addition, being used as solvent or suspension media usually using sterile nonvolatile oil.Any bland expressed oi can be used for this, includes the monoglyceride or diester of synthesis.In addition, aliphatic acid (such as oleic acid) can be used for preparing injection.
Compound of formula I can also be used for the rectally of medicine in the form of suppository.These compositions can be prepared by the way that medicine is mixed with suitable nonirritant excipient, and the excipient is solid at normal temperatures, but be liquid under rectal temperature, therefore can be melted in the rectum, discharge medicine.This kind of material includes the fatty acid ester of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, the mixture of the polyethylene glycol of various molecular weight and polyethylene glycol.
Used for local, using the emulsifiable paste containing compound of formula I, ointment, jelly, solution or supensoid agent etc..(for this purposes, local application should include collutory and gargle).
The compounds of this invention can be applied by the suitable intranasal administration mediator of local application and delivery apparatus in intranasal administration form, or by transdermal route, be administered using the form of transdermal patch well known within the skill of those ordinarily skilled.To be administered in the form of transdermal delivery system, interval should be continuous rather than certainly in the whole period administration of therapeutic regimen.The compounds of this invention can also be delivered using base-materials such as the fatty acid esters of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, the mixture of the polyethylene glycol of various molecular weight and polyethylene glycol with suppository form.
When the compounds of this invention is administered to treatment target, selected dosage level will depend on many factors, including but not limited to, the activity of particular compound, the order of severity of indivedual symptoms, method of administration, administration time, the drainage rate of compound, the duration for the treatment of, other medicines, compound and/or the material being used in combination, and patient age, sex, body weight, situation, general health and previous medical history.The quantity and route of administration of compound are most decided in its sole discretion by doctor at last, but dosage would generally make the local concentration at site of action realize required effect without producing obvious injury or unfavorable side reaction.
Applying in vivo can the continually or intermittently implementation (such as by appropriate intervals divided doses) with dose in whole therapeutic process.The method for determining most effective way and application dosage is well known to those skilled in the art, and will be become with the preparation used in treatment, the purpose for the treatment of, the target cell treated and the object treated.Single or multiple administrations can be carried out, dosage level and pattern are selected by the doctor for being responsible for treatment.
In general, the suitable dose of reactive compound is in every kg treatment targets body weight about 100 μ g to about 250mg daily.It is the situation of salt, ester, prodrug etc. in reactive compound, dosage is calculated on the basis of parent compound, and the actual weight then used is scaling up.
The compounds of this invention can also be used with cancer therapy drug or chemotherapy drugs in combination.
The compounds of this invention can be used for treatment of cancer as chemistry and radiosensitizer.They can be used for the treatment for previously carrying out or carrying out the mammal for the treatment of of cancer.Prior treatment includes previous chemotherapy, radiotherapy, operation or immunotherapy, such as cancer vaccine.
Therefore, the invention provides compound of formula I and the joint of cancer therapy drug, for simultaneously, being separately or sequentially administered.
The present invention also provides the joint of compound of formula I, radiotherapy and other chemotherapeutics, for simultaneously, separately or sequentially applying.
The present invention also provide it is a kind of be used to manufacture the compound of formula I of medicine, the medicine is used in treatment of cancer as assistant agent, or by with ionising radiation and other chemotherapy drugs in combination, for strengthening the effect to tumour cell.The present invention also provides application of the compound of formula I in manufacture medicine, and the medicine uses in treatment of cancer as assistant agent, or by with ionising radiation and other chemotherapy drugs in combination, strengthen the effect to tumour cell.The compounds of this invention can also be used with ionising radiation and other chemotherapy drugs in combination.
The present invention also provides a kind of chemotherapy or the method for radiotherapy, and this method includes the compound of formula I of effective dose to patient in need or the composition containing compound of formula I is applied with ionising radiation or chemotherapy drugs in combination.The compounds of this invention can also be applied with ionising radiation and other chemotherapy drugs in combination.
In conjoint therapy, the compounds of this invention can be (such as 5 points before other cancer therapy drugs be applied to the object for needing to treat, 15 points, 30 points, 45 points, 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 (such as 5 points afterwards, 15 points, 30 points, 45 points, 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) apply.In miscellaneous embodiment, the compounds of this invention and other cancer therapy drugs be separated by 1 point, 10 points, 30 points, less than 1 hour, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours, 8-9 hours, 9-10 hours, 10-11 hours, 11-12 hours, no more than 24 hours, or no more than 48 hours be administered.
The compounds of this invention and other cancer therapy drugs can with adduction or Synergistic work.The synergistic combinations of the compounds of this invention and other cancer therapy drugs cause one of the compounds of this invention and other cancer therapy drugs or the two relatively low dosage and/or less times for spraying can be used, and/or the administration medicine of fewer number can reduce any toxicity relevant with applying medicine to treatment target, without reducing effect of the medicine in treatment of cancer.In addition, synergy can make effect of these medicines in treatment of cancer improve and/or reduce any harmful or undesirable side effect relevant with any medicine is used alone.
It can be found in the following documents for the cancer drug or the example of chemotherapeutics that are used in combination with the compounds of this invention：Cancer Principles and Practice of Oncology by V.T.Devita and S.Hellman (editors), 6thEdition (February 15,2001), LippincottWilliams＆Wilkins Publishers.Those of ordinary skill in the art can judge that the federation of which kind of medicine is useful according to the specific feature of involved 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 inhibitors, HMG-CoA reductase inhibitor, hiv protease inhibitor, the reagent of RTI and other angiogenesis inhibitors, hyperplasia and survival signaling inhibitor, apoptosis inducing agent and interference cell cycle check.The compounds of this invention is especially effective when being co-administered with radiotherapy.
The example of " hdac inhibitor " includes Vorinostat (SAHA), LAQ824, LBH589, PXD101, MS275, FK228, valproic acid, butyric acid and CI-994.
" estrogenic agents " refer to disturb or suppressed the compound that estrogen is combined with acceptor, regardless of its mechanism.The example of estrogenic agents includes, but it is not limited to, TAM, Raloxifene, Idoxifene, LY353381, LY117081, Toremifene, fulvestrant, 4- [7- (2,2- dimethyl -1- oxopropoxy -4- methyl -2- [4- [2- (1- piperidyls) ethyoxyl] phenyl] -2H-1- chromene -3- bases] phenyl -2,2- dimethyl propylene acid esters, 4,4'-Dihydroxybenzophenone -2,4- dinitrophenylhydrazones, and SH646.
" androgen receptor modifier " refers to disturb and suppressed the compound that androgen is combined with acceptor, regardless of its mechanism.The example of androgen receptor modifier includes Finasteride and other 5α-reductase inhibitor, Nilutamide, Flutamide, Bicalutamide, Liarozole and abiraterone acetate.
" Retinoid receptor modulators " refer to interference or suppress the compound that retinoids is combined with acceptor, regardless of its mechanism.The example of this kind of Retinoid receptor modulators includes bexarotene, and Tretinoin, isotretinoin, 9- ties up A acid amides, and N-4- carboxy phenyls dimension A acid amides along Tretinoin, alpha-difluoromethyl ornithine, ILX23-7553, trans- N- (4 '-hydroxy phenyl).
" cytotoxicity/cytostatic agent " refers to the compound that cell death or inhibition of cell proliferation are mainly caused by direct interference cells play function or suppression or interference cell mitosis, including alkylating reagent, TNF, intercalator, the compound of hypoxemia activation, microtubule inhibitors/microtubule stabilizer, mitotic kinesin inhibitors, the kinase inhibitor being related in mitotic progression, antimetabolite, biological response conditioning agent, hormone/anti-hormonal therapeutic agents, hemopoieticgrowth factor, monoclonal antibody target medicine, topoisomerase enzyme inhibitor, proteasome inhibitor and ubiquitinbond enzyme inhibitor.
The example of cytotoxic agent includes,But it is not limited to,Endoxan,Chlorambucil,BCNU (BCNU),Lomustine (CCNU),Busulfan,Treosulfan,sertenef,Cachectin,Ifosfamide,Tasonermin,Lonidamine,Carboplatin,Hemel,Prednimustine,Mitolactol,Ranimustine,Fotemustine,Naphthalene reaches platinum,aroplatin,Oxaliplatin,Temozolomide,Methyl mesylate,Procarbazine,Dacarbazine,Eptaplatin,Estramustine,Toluenesulfonic acid Improsulfan,Trofosfamide,Nimustine,Dibromo spiral shell nitrogen ammonium,Pumitepa,Lobaplatin,Satraplatin,Methylmitomycin,Cis-platinum,Irofulven,Right ifosfamide,Cis- amine dichloro (2- picolines) platinum,Benzyl guanine,Glufosfamide,GPX100,Four chlorinations are (suitable,Instead,Instead) dimethylene (hexane -1,6- diamines) methylene [diamines-platinum (II)] is double [diamines (chlorine) platinum (II)],Two aziridinyl spermine,Arsenic trioxide,1- (11- dodecylamino -10- hydroxyundecyls) -3,7- dimethyl xanthines,Zorubicin,Idarubicin,Daunorubicin,Bisantrene,Mitoxantrone,THP,Pinafide,Valrubicin,Amrubicin,Doxorubicin,Epirubicin,Antineoplaston,3 '-deaminizating -3 '-morpholinyl -13- deoxidation -10- hydroxyl carminomycins,At mycin,Galarubicin,Elinafide,MEN10755 and 4- de-methoxies -3- deaminizes -3- aziridinyl -4- sulfonyloxy methyls daunorubicins (see WO 00/50032).Other examples include Raf kinase (such as Bay43-9006) and mTOR inhibitors (such as Wyeth CCI-779 and Ariad AP23573).Other example is P13K inhibitor (such as LY294002).
In an embodiment, the compounds of this invention can be used in combination with alkylating reagent.
The example of alkylating reagent includes, but not limited to mustargen, endoxan, ifosfamide, Trofosfamide and Chlorambucil；Nitroso ureas：BCNU (BCNU) and lomustine (CCNU)；Alkyl sulfonic ester：Busulfan and Treosulfan；Triazenes：Dacarbazine, procarbazine and Temozolomide；Containing platinum complexes：Cis-platinum, carboplatin, aroplatin and oxaliplatin.
In an embodiment, alkylating reagent is Dacarbazine.Dacarbazine can be with about 150mg/m2(body surface area for the treatment of target) is to about 250mg/m2Dosage be administered to treatment target.In another embodiment, Dacarbazine is with about 150-250mg/m2Dosage once a day to treatment target it is intravenous apply continuous 5 days.
In an embodiment, alkylating reagent is procarbazine.Procarbazine can be with about 50mg/m2(body surface area for the treatment of target) is to about 100mg/m2Dosage be administered to treatment target.In another embodiment, the third carbazine is with about 50-100mg/m2Dosage once a day to treatment target it is intravenous apply continuous 5 days.
In an embodiment, alkylating reagent is Temozolomide.Temozolomide can be with about 150-200mg/m2The dosage of (body surface area for the treatment of target) is administered to treatment target.In another embodiment, Temozolomide is with about 150-200mg/m2Dosage once a day to animal be administered orally continuous 5 days.
The example of anti-mitosis medicine includes：Allocolchicine, halichondrin B, colchicin, colchicine derivative, aplysiatoxin 10, Mei Dengsuo is agile new, N-Desacetylthiocol Chicine alkali and trityl cysteine.
The example of the compound of hypoxemia activation is Tirapazamine.
The example of proteasome inhibitor includes but is not limited to：Lactacystin, bortezomib, epoxomicin and peptide aldehyde (such as MG 132, MG 115 and PSI).
The example of microtubule inhibitors/microtubule stabilizer includes taxol, vindesine sulfate, vincristine, vincaleukoblastinum, vinorelbine, 3, 4 '-two dehydrogenations -4 '-deoxidation -8 '-navelbine, Taxotere, it is agile new, dolastatin, mivobulin isethionate, auristatin, Cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2, 3, 4, 5, the fluoro- N- of 6- five (the fluoro- 4- methoxyphenyls of 3-) benzsulfamide, F 81097, N, N- dimethyl-L-valyl-L- valyl-N- methyl-L- valyls-L- prolyls-L-PROLINE-tert-butylamides, TDX258, Epothilones is (see such as US 6, 284, 781 and 6, 288, and BMS188797 237).
Some examples of topoisomerase enzyme inhibitor are Hycamtins, hycaptamine, Irinotecan, rubitecan, exatecan, gefitinib, Diflomotecan, silyl camptothecin, 9-aminocamptothecin, camptothecine, crisnatol, mitomycin C, 6- ethyoxyls propionyl -3 ', outside 4 '-O--benzal ferment wine rhzomorph, 9- methoxyl groups-N, N dimethyl -5- nitropyrazoles simultaneously [3, 4, 5-kl] acridine -2- (6H) propylamine, 1- amino -9- ethyls -5- fluoro- 2, 3- dihydro -9- hydroxy-4-methyls -1H, 2H- benzos [de] pyrans simultaneously [3 ', 4 '：B, 7] indolizine simultaneously [1, 2b] quinoline -10, 13 (9H, 15H) diketone, Lurtotecan, 7- [2- (N- isopropylaminos) ethyl]-(20S) camptothecine, BNP1350, BNPI1100, BN80915, BN80942, phosphoric acid she hold in the palm pool glycosides, Teniposide, Sobuzoxane, 2 '-dimethylamino -2 '-deoxidation she hold in the palm pool glycosides, GL331, N- [2- (dimethylamino) ethyl] -9- hydroxyls -5, 6- dimethyl -6H- pyridos [4, 3-b] carbazole -1- formamides, asulacrine, (5a, 5aB, 8aa, 9b) -9- [2- [N- [2- (dimethylamino) ethyl]-N- methylaminos] ethyl] -5- [4- hydroxyls -3, 5- Dimethoxyphenyls] -5, 5a, 6, 8, 8a, 9- hexahydro furyls simultaneously (3 ', 4 '：6, 7) naphtho- (2, 3-d) -1, 3- dioxole -6- ketone, 2, 3- (methylene epoxide) -5- methyl -7- hydroxyl -8- methoxyl groups benzos [c]-phenanthridines, 6, 9- bis- [(2- amino-ethyls) amino] benzo [g] isoquinolin -5, 10- diketone, 5- (3- aminopropyl aminos) -7, 10- dihydroxy -2- (2- hydroxyethylaminomethylphosphonics) -6H- pyrazolos [4, 5, 1-de] acridine -6- ketone, N- [1- [2- (diethylamino) ethylamino] -7- methoxyl group -9- oxo -9H- thioxanthene -4- ylmethyls] formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6- [[2- (dimethylamino) ethyl] amino] -3- hydroxyl -7H- indenos [2, 1-c] quinoline -7- ketone and dimesna；The non-inhibitor of camptothecin topoisomerase -1, such as indolocarbazole；And topo repair and II double inhibitors, such as phenonaphthazine, XR20115761MLN 576 and benzo pyridine diindyl.
In an embodiment, topoisomerase enzyme inhibitor is Irinotecan.Irinotecan can be with about 50-150mg/m2The dosage of (experimental subjects body surface area) is administered to treatment target.In another embodiment, Irinotecan is with about 50-150mg/m2Dosage it is intravenous once a day to treatment target successive administration 5 days at the 1-5 days, then with about 50-150mg/m2Dosage at the 28-32 days continuous 5 days of intravenous administration once a day, then again with about 50-150mg/m2Dosage at the 55-59 days continuous 5 days of intravenous administration once a day.
The example of the inhibitor of mitotic kinesins (particularly mankind mitotic kinesins KSP) is described in following patent document：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 includes but is not limited to：KSP inhibitor, MKLP1 inhibitor, CENP-E inhibitor, MCAK inhibitor, Kif14 inhibitor, Mphosph1 inhibitor and Rab6-KIFL inhibitor.
" inhibitor for the kinases being related in mitotic progression " includes, but not limited to aurora kinase inhibitors, Polo samples kinases (PLK) inhibitor (particularly PLK-1 inhibitor), bub-1 inhibitor and bub-R1 inhibitor.
" anti-proliferative drug " includes antisense RNA and DNA oligonucleotides,Such as G3139,ODN698,RVASKRAS,GEM231 and INX3001,And antimetabolite,Such as enocitabine,Carmofur,Tegafur,Pentostatin,Doxifluridine,Trimetrexate,Fludarabine,Capecitabine,Galocitabine,Octadecyl phosphoric acid cytarabine,fosteabine sodiumhydrate,Raltitrexed,paltitrexid,Emitefur,Tiazofurine,Decitabine,Nolatrexed,Pemetrexed,Naphthalene draws shore,2 '-deoxidation -2 '-methylene cytidine,2 '-fluorine -2 '-deoxycytidine of methylene,N-[5-(2,3- dihydro benzo furyls) sulphonyl]-N '-(3,4- dichlorophenyls) urea,N6- [4- deoxidations -4- [N2- [2 (E),4 (E)-ten four diene acyl] Glycinylamino]-L- glycerine-B-L- pyrans mannoheptoses base] adenine,Dehydrodidemnin,Ecteinascidin,Troxacitabine,4- [2- amino -4- oxos -4,6,7,8- tetrahydrochysene -3H- pyrimidos [5,4-b][1,4] thiazine -6- bases-(S)-ethyl] -2,5- thienyls-Pidolidone,Aminopterin,5 FU 5 fluorouracil,Alanosine,11- acetyl -8- (carbamoyloxy group methyl) -4- formyl -6- methoxyl group -14- oxa-s -1,The carbon -2 of 11- diazas Fourth Ring (7.4.1.0.0)-ten four,4,6- triolefin -9- yl acetates,Spherosin,Lometrexol,Dexrazoxane,Methioninase,2 '-cyano group -2 '-'-deoxy-n 4- palmityl -1-B-D- arabino-furanosylcytosines and Trianpine.
The example of monoclonal antibody target medicine is included containing the cytotoxic agent or radioisotopic medicine being attached in monoclonal antibody that cancer cell is special or that target cell is special, and the example includes Bexxar (tositumomab).
" HMG-CoA reductase inhibitor " refers to the inhibitor of 3-hydroxy-3-methylglutaric acid list acyl coenzyme A reductases.The example for the HMG-CoA reductase inhibitor that can be used includes but is not limited to：Lovastatin (
Figure A20088000192600291
See US 4,231,938,4,294,926 and 4,319,039), Simvastatin (
Figure A20088000192600292
See US 4,444,784,4,820,850 and 4,916,239), Pravastatin (
Figure A20088000192600293
See US 4,346,227,4,537,859,4,410,629,5,030,447 and 5,180,589), fluoro statin (
Figure A20088000192600294
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 A20088000192600295
See US 5,273,995,4,681,893,5,489,691 and 5,342,952).The structural formula for these and other HMG-CoA reductase inhibitor that can be used in the present invention is described in M.Yalpani, " Cholesterol Lowering Drugs ", Chemistry ＆Industry, page 87 and US 4 of pp.85-89 (in May, 1996 number), 782, in 082 and 4,885,314.Term " HMG-CoA reductase inhibitor " used herein includes all pharmaceutically useful lactones and open-acid forms with HMG-CoA reductase inhibitor activity (i.e., lactonic ring is opened to form free acid), and the salt and ester-formin of these compounds, therefore these salt, ester, open loop acid and the use of lactone form be included within the scope of the disclosure.
" Prenyl-protein inhibitors " refer to any Prenyl-protein transferase of suppression and its any combination of compound, these enzymes include farnesyl-protein transferase (FPTase), I type Mang ox base Mang ox base protein transferases (GGPTase-I), with II type Mang ox base Mang ox base protein transferases (GGPTase-II, also referred to as Rab GGPTase).
The example of Prenyl-protein inhibitors can be found 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.
It is used as Prenyl-protein inhibitors European J.of Cancer (1999) visible to the example of the effect of angiogenesis, 35 (9)：1394-1401.
" angiogenesis inhibitors " refer to the compound for suppressing neovascularization, regardless of its mechanism.The example of angiogenesis inhibitors includes, but it is not limited to, tyrosine kinase inhibitor (such as tyrosine kinase receptor Flt-1 (VEGFR1) and Flt-1/KDR (VEGFR2) inhibitor), derived from epidermis, fibroblast is derivative or platelet-derived growth factor, MMP (matrix metalloproteinase) inhibitor, integrin blockers agent, interferon-' alpha ', IL-12, PPS, cyclooxygenase-2 inhibitor (including NSAID (NSAIDs), such as aspirin and brufen and selective cyclooxygenase-2 inhibitor, such 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；Cancer Res.(1997)57：1625(1997)；Cell(1998)93：705；Intl.J.Mol.Med.(1998)2：715；J.Biol.Chem.(1999)274：9116)), steroid antiphlogistic (such as corticosteroid, mineralocorticoid, dexamethasone, metacortandracin, prednisolone, methylprednisolone, betamethasone), Carboxyamidotraiazol, windmill suppression alkali A-4, squalamine, 6-O- chloracetyl carbonyl Fumngillins, Thalidomide, angiostatin, troponin -1, angiotensin-ii antagonist is (see J.Lab.Clin.Med. (1985) 105：141-145), and VEGF antibody (see Nature Biotechnology (1999) 17：963-968；Kim etc. (1993) Nature 362：841-844；WO 00/44777 and WO 00/61186).
The regulation that can be used in combination with the compounds of this invention or other medicines of suppression angiogenesis include adjusting or suppress the medicine of blood coagulation and fibrinolytic system (see Clin.Chem.La.Med. (2000) 38：Commentary in 679-692).The exemplary drugs of these regulations or suppression blood coagulation and fibrinolysis pathways include, but not limited to heparin (see Thromb.Haemost. (1998) 80：10-23), (also referred to as the fibrinolysis inhibitor [TAFIa] of active thrombin activatable is (see Thrombosis Res. (2001) 101 for low molecular weight heparin and carboxypeptidase U inhibitor：329-354).TAFIa inhibitor is reported in PCT publication WO 03/013,526 and US60/349,925 (submission on January 18th, 2002).
" reagent of interference cell cycle check " refers to the protein kinase for suppressing transducer cell cycle checkpoint signals, so that the compound that cancer cell is sensitized to DNA damage agent.These reagents include the inhibitor of ATR, ATM, Chk1 and Chk2 kinases, and cdk and cdc kinase inhibitors, and its instantiation is 7- hydroxyls staurosporin, staurosporin, many flavones pyrroles, CYC202 (Cyclacel) and BMS-387032.
" inhibitor of hyperplasia and survival signaling passage " refers to the medicine for suppressing cell surface receptor and the signal transduction cascade system downstream of these surface receptors.This kind of medicine includes EGFR inhibitor (such as Gefitinib and Tarceva), ERB-2 inhibitor (such as Herceptin), IGFR inhibitor (such as disclosed in WO 03/059951 those), the inhibitor of cytokine receptor, MET inhibitor, P13K inhibitor (such as LY294002), serine/threonine kinase (includes but is not limited to Akt inhibitor, for example in 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 inhibitor (such as BAY-43-9006) of Raf kinases, MEK inhibitor (such as CI-1040 and PD-098059) and mTOR inhibitor (such as Wyeth CCI-779 and Ariad AP23573).These medicines include molecule inhibitor compounds and antibody antagonists.
" tune dies inducing agent " includes the activator of TNF receptor families member (including TRAIL acceptors).
In an embodiment, the compounds of this invention can be used to and the one or more selected from Temozolomide, cis-platinum, carboplatin, oxaliplatin, Irinotecan and Hycamtin, particularly a kind of, two or three of medicine, combine for treating cancer.
The compounds of this invention can also combine for treating cancer with one or more following medicines：Abarelix (
Figure A20088000192600311
)；Aldesleukin (
Figure A20088000192600312
)；Aldesleukin (
Figure A20088000192600313
)；Alemtuzumab ()；Alitretinoin (
Figure A20088000192600315
)；Other purine (
Figure A20088000192600316
)；Hemel (
Figure A20088000192600317
)；Amifostine (
Figure A20088000192600318
)；Anastrozole (
Figure A20088000192600319
)；Arsenic trioxide (
Figure A200880001926003110
)；L-Asparaginasum (
Figure A200880001926003111
)；Azacitidine (
Figure A200880001926003112
), Avastin (
Figure A200880001926003113
), bexarotene capsule (
Figure A200880001926003114
)；Bexarotene gel (
Figure A200880001926003115
), bleomycin (
Figure A200880001926003116
)；Bortezomib (
Figure A200880001926003117
), busulfan intravenous injection (
Figure A200880001926003118
)；Busulfan oral agents (
Figure A200880001926003119
)；Calusterone (
Figure A200880001926003120
)；Capecitabine (
Figure A200880001926003121
)；Carboplatin (
Figure A200880001926003122
)；BCNU (
Figure A200880001926003123
Figure A200880001926003124
), BCNU (
Figure A200880001926003125
)；BCNU implant (Gliadel containing Polifeprosan 20
Figure A200880001926003126
)；Sai meter Kao glycosides (
Figure A200880001926003127
)；Cetuximab (
Figure A200880001926003128
)；Chlorambucil (
Figure A200880001926003129
)；Cis-platinum (
Figure A200880001926003130
), Cladribine (
Figure A200880001926003131
)；Clofarabine (), endoxan (
Figure A200880001926003133
Figure A20088000192600321
)；Endoxan (Cytoxan
Figure A20088000192600322
), endoxan (Cytoxan
Figure A20088000192600323
)；Cytarabine (Cytostar-
Figure A20088000192600324
), cytarabine liposome (
Figure A20088000192600325
)；Dacarbazine (DTIC-
Figure A20088000192600326
), D actinomycin D；Actinomycin D (
Figure A20088000192600327
)；Darbepoetin α (
Figure A20088000192600328
)；Daunorubicin liposome (
Figure A20088000192600329
)；Daunorubicin, daunomycin (
Figure A200880001926003210
)；Daunorubicin, daunomycin (
Figure A200880001926003211
)；Denileukin diftitox (
Figure A200880001926003212
)；Dexrazoxane (
Figure A200880001926003213
)；Docetaxel (
Figure A200880001926003214
)；Doxorubicin (Adriamycin
Figure A200880001926003215
)；Doxorubicin ( )；Doxorubicin (Adriamycin PFS
Figure A200880001926003218
)；Mycocet (
Figure A200880001926003219
)；Dromostanolone propionate ()；Dromostanolone propionate (Masterone
Figure A200880001926003221
)；Elliott B solutions (Eliott ' s B
Figure A200880001926003222
)；Epirubicin (
Figure A200880001926003223
)；Epoetin alfa (
Figure A200880001926003224
)；Tarceva (
Figure A200880001926003225
)；Estramustine (
Figure A200880001926003226
)；Etoposide phosphate (
Figure A200880001926003227
)；Etoposide, VP-16 (
Figure A200880001926003228
)；Exemestane (
Figure A200880001926003229
)；Filgrastim (
Figure A200880001926003230
)；Floxuridine (intra-arterial) (
Figure A200880001926003231
)；Fludarabine (
Figure A200880001926003232
)；Fluorouracil, 5-FU (
Figure A200880001926003233
)；Fulvestrant (
Figure A200880001926003234
)；Gefitinib ()；Gemcitabine (
Figure A200880001926003236
)；Lucky trastuzumab ozogamicin (
Figure A200880001926003237
)；Goserelin acetate (
Figure A200880001926003238
)；Goserelin acetate (Zoladex
Figure A200880001926003239
)；Histrelin acetate (Histrelin
Figure A200880001926003240
)；Hydroxycarbamide (
Figure A200880001926003241
)；Ibritumomab tiuxetan (
Figure A200880001926003242
)；Idarubicin (
Figure A200880001926003243
)；Ifosfamide (
Figure A200880001926003244
)；Imatinib mesylate (
Figure A200880001926003245
)；Intederon Alpha-2a (Roferon
Figure A200880001926003246
)；Interferon Alpha-2b (Intron
Figure A200880001926003247
), Irinotecan (
Figure A200880001926003248
)；Lenalidomide (
Figure A200880001926003249
)；Letrozole (
Figure A200880001926003250
)；Folinic acid (
Figure A200880001926003251
)；Leuprolide acetate (
Figure A200880001926003252
)；Levamisol (
Figure A200880001926003253
)；Lomustine, CCNU (
Figure A200880001926003254
)；Meclorethamine, mustargen (
Figure A200880001926003255
)；Megestrol acetate (
Figure A200880001926003256
)；Melphalan, L-PAM (
Figure A200880001926003257
)；Purinethol, 6-MP ()；Mesna ()；Mesna (Mesnex)；Methotrexate (MTX) (
Figure A200880001926003261
)；Methoxsalen ()；Mitomycin C (
Figure A200880001926003263
)；Mitotane (
Figure A200880001926003264
)；Mitoxantrone ()；Nandrolone Phenpropionate (Durabolin-
Figure A200880001926003266
)；Nelarabine (
Figure A200880001926003267
)；Promise not monoclonal antibody (
Figure A200880001926003268
)；Oprelvekin (
Figure A200880001926003269
)；Oxaliplatin ()；Taxol (
Figure A200880001926003271
)；Taxol (
Figure A200880001926003272
)；Taxol protein binding particle (
Figure A200880001926003273
)；Pa Lifuming ()；Pamidronic Acid (
Figure A200880001926003275
)；Pegademase (Adagen
Figure A200880001926003277
)；Pegaspargase ()；Pei Feisi booths ()；Pemetrexed disodium (
Figure A200880001926003280
)；Pentostatin (
Figure A20088000192600331
)；Pipobroman (
Figure A20088000192600332
)；Plicamycin, mithramycin (
Figure A20088000192600333
)；Porfimer Sodium (
Figure A20088000192600334
)；Procarbazine (
Figure A20088000192600335
)；Quina Kelin (
Figure A20088000192600336
)；Rasburicase ()；Rituximab ()；Sargramostim (
Figure A20088000192600339
)；Sargramostim ()；Sorafenib (
Figure A200880001926003311
)；Streptozotocin (
Figure A200880001926003312
)；Sunitinib maleate (
Figure A200880001926003313
)；Talcum (
Figure A200880001926003314
)；TAM ()；Temozolomide (
Figure A200880001926003316
)；Teniposide, VM-26 (
Figure A200880001926003317
)；Testolactone (
Figure A200880001926003318
)；Thioguanine, 6-TG (
Figure A200880001926003319
)；Phosphinothioylidynetrisaziridine (
Figure A200880001926003320
)；Hycamtin (
Figure A200880001926003321
)；Toremifene (
Figure A200880001926003322
)；Tositumomab (
Figure A200880001926003323
)；Tositumomab/[131I] tositumomab (
Figure A200880001926003324
)；Herceptin (
Figure A200880001926003325
)；Tretinoin, ATRA (
Figure A200880001926003326
)；Uracil mastard (Uracil Mustard)；Valrubicin (
Figure A200880001926003328
)；Vincaleukoblastinum (
Figure A200880001926003329
)；Vincristine (
Figure A200880001926003330
)；Vinorelbine (
Figure A200880001926003331
)；SAHA (
Figure A200880001926003332
)；Zoledronate (
Figure A200880001926003333
)；AMN107 (
Figure A200880001926003334
) and Dasatinib (
Figure A200880001926003335
)。
Combine present invention additionally comprises the NSAID with belonging to Selective COX-2 inhibitor.For this manual, the NSAID for belonging to Selective COX-2 inhibitor is according to cell or microsome test, by determining the IC for COX-250With the IC for COX-150The ratio between, it is determined that specifically suppressing at least 100 times more than COX-1 of COX-2 those NSAID.These compounds include, but not limited to the compound disclosed in following patent document：US 5,474,995,5,861,419,6,001,843,6,020,343,5,409,944,5,436,265,5,536,752,5,550,142,5,604,260,5,698,584,5,710,140, WO 94/15932, US 5,344,991,5,134,142,5,380,738,5,393,790,5,466,823,5,633,272 and 5,932,598, they are all incorporated herein in the way of incorporated by reference.
Particularly useful cox 2 inhibitor is the chloro- 3- of 5- (4- methyl sulphonyls) phenyl -2- (2- methyl -5- pyridine radicals) pyridine in subject treatment method, or its pharmaceutically useful salt.
Described as COX-2 specific inhibitors and therefore the compound available for the present invention includes but is not limited to：Parecoxib,WithOr its pharmaceutically useful salt.
Other examples of angiogenesis inhibitors include, but it is not limited to, endostatin, ukrain, ranpirnase, IM862, 5- methoxyl groups -4- [2- methyl -3- (3- methyl-2-butenes base) epoxy ethyl] -1- oxaspiros [2, 5] octyl- 6- bases (chloracetyl) carbamate, Tacedinaline, 5- amino -1- [[3, 5- bis- chloro- 4- (4- chlorobenzoyls) phenyl] methyl] -1H-1, 2, 3- triazole -4- formamides, CM101, squalamine, windmill suppression alkali, RPI4610, NX31838, sulphation sweet dew pentose phosphate ester, 7, 7- (double [imino group-N- the methyl -4 of carbonyl, 2- pyrrolylcarbonyls imino group [N- methyl -4, 2- pyrroles] carbonylimino] double-(1, 3- napadisilates) and 3- [(2, 4- dimethyl pyrrole -5- bases) methylene] -2- indolinones (SU5416).
" integrin blockers agent " word used above, refers to selective antagonism, suppression or resists physiologic ligand and αvβ3The compound that integrin is combined, selective antagonism, suppression or resistance physiologic ligand and αvβ5The compound that integrin is combined, antagonism, suppression or resistance physiologic ligand and αvβ3Integrin and αvβ5The compound that both integrins are combined, and antagonism, the active compound for suppressing or resisting special integrin of the expression on capillary endothelial cell.The noun also refers to αvβ6、αvβ8、α1β1、α2β1、α5β1、α6β1And α6β4The antagonist of integrin.The noun also refers to αvβ3、αvβ5、αvβ6、αvβ8、α1β1、α2β1、β5α1、α6β1And α6β4Any combination of antagonist of integrin.
Some instantiations of tyrosine kinase inhibitor include N- (trifluoromethyl) -5- methyl-isoxazole -4- formamides, 3- [(2, 4- dimethyl pyrrole -5- bases) methylene] indole-2-ketone, 17- (allyl amido) -17- demethoxygeldanamycins, 4- (the chloro- 4- Fluorophenylaminos of 3-) -7- methoxyl groups -6- [3- (4- morpholinyls) propoxyl group] quinazoline, N- (3- ethynyl phenyls) -6, 7- bis- (2- methoxy ethoxies) -4- quinazoline amine, BIBX1382, 2, 3, 9, 10, 11, 12- hexahydros -10- (methylol) -10- hydroxyl -9- methyl -9, the indoles of 12- epoxies -1H- two simultaneously [1, 2, 3-fg：3 ', 2 ', 1 '-kl] pyrrolo- [3,4-i] [1,6] pungent tetraene -1- ketone of benzodiazepine * heterocycle, SH268, tri hydroxy isoflavone, STI571, CEP2563,4- (3- chlorphenylaminos) -5,6- dimethyl -7H- pyrrolo-es [2,3-d] pyrimidine methane sulfonates, 4- (the bromo- 4- hydroxyphenyls of 3-) amino -6,7- dimethoxyquinazolines, 4- (4 '-hydroxyphenyl) amino -6,7 dimethoxyquinazoline, SU6668, STI571A, N-4- chlorphenyl -4- (4- picolyls) -1- phthalazines amine, and EMD 121974.
In an embodiment, the compounds of this invention can be used for treating or preventing by selective N 3- adenines methylating reagent such as MeOSO2(CH2)-lexitropsin (Me-Lex) induce meronecrosis appearance.
With not being to be also included in the inventive method the combining for compound of anticancer compound, for example, the combination medicine of the compounds of this invention and PPAR- γ (that is, PPAR-gamma) activators and PPAR- δ (that is, PPAR-delta) activator can be used for treating some cancers.PPAR- γ and PPAR- δ are core peroxisome proliferators activated receptor γ and δ.Expression of the PPAR- γ on endothelial cell and its participation in vascularization have been reported (see J.Cardiovasc.Phormacol. (1998) 31 in the literature：909-913；J.Biol.Chem.(1999)274：9116-9121；Invest.Ophthalmol Vis.Sci.(2000)41：2309-2317).Recently, have been pointed out suppressing the angiogenesis response to VEGF during PPAR- gamma agonists can be tested in vitro, troglitazone and Rosiglitazone Maleate all suppress the development that retina neovascular is generated in mouse.(Arch.Ophthamol.(2001)119：709-717).The example of PPAR- γ and PPAR- γ/alfa agonists includes, but it is not limited to, thiazolidinedione (such as DRF2725, 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-1s, 2- benzoisoxazole -6- bases) oxygen] -2 Methylpropionic acid (is disclosed in USSN 09/782, 856) (it is disclosed in USSN 60/235 with 2 (R) -7- (3- (the chloro- 4- of 2- (4- fluorophenoxies) phenoxy group) propoxyl group) -2- ethyl coumaran -2- carboxylic acids, 708 and 60/244, 697).
Another embodiment of the present invention is that compound disclosed by the invention is combined for treating cancer with antiviral agent (such as nucleoside analog, including GCV).Referring to WO 98/04290.
Another embodiment of the present invention is that compound disclosed by the invention is combined for treating cancer with gene therapy.Genetic method on treating cancer is referring to (the Am J Hum Genet (1997) 61 such as Hall：785-789 and Kufe etc. (Cancer Medicine, the 5th edition, pp 876-889, BCDecker, Hamilton 2000).Gene therapy can be used to deliver any tumor suppressor gene.The example of this genoid includes, but it is not limited to, (gene transfer that it can be mediated by recombinant virus is delivered p53, for example see US 6,069,134), uPA/uPAR antagonists (" 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 be with intrinsic multi-drug resistance (MDR), and particularly the MDR relevant with the high level expression of transport protein inhibitor is administered in combination.This MDR inhibitor includes the inhibitor of p- glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853, Verapamil and PSC833 (valspodar).
The compound of the present invention can be used in combination with antiemetic, treatment nausea or vomiting caused by being used alone or being used together the compounds of this invention possibility with radiotherapy, including acute, Delayed onset, later stage and anticipatory emesis.To prevent or treating vomiting, the compounds of this invention can be used in combination with other antemetic, especially antagonists of neurokinine-1 receptor, 5HT3 receptor antagonists (such as Ondansetron, Granisetron, Tropisetron and zatisetron), GABABReceptor stimulating agent (such as Baclofen), corticosteroid (such as Decadron (dexamethasone), healthy and free from worry pleasure, Aristocort, nose pine, Preferid, Benecorten or in US 2,789,118,2,990,401st, 3,048,581,3,126,375th, 3,929,768,3,996,359th, 3,928,326 and 3,749, those disclosed in 712), dopamine antagonist medicine, such as phenthazine (such as prochlorperazine, fluphenazinum, thioridazine and mesoridazine), Metoclopramide or Dronabinol.In an embodiment, a kind of antiemetic selected from antagonists of neurokinine-1 receptor, 5HT3 Receptor antagonists and corticosteroid is applied as assistant agent, and the possible caused vomiting of the compounds of this invention is taken for treating or preventing.
The neurokinine-1 receptor antagonist being used in combination with the compounds of this invention is fully described in such as documents below：U.S.5,162,339,5,232,929,5,242,930,5,373,003,5,387,595,5,459,270,5,494,926,5,496,833,5,637,699,5,719,147；EP 0360390, 0394989, 0428434, 0429366, 0430771, 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 publication 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 BP 2266529,2268931,2269170,2269590,2271774,2292144,2293168,2293169, and 2302689.
There is absolutely proving for the preparation to such compound in above-mentioned patent and publication, they are incorporated herein in the way of reference.
In an embodiment, it is selected from the antagonists of neurokinine-1 receptor that the compounds of this invention is used in combination：2- (R)-(1- (R)-(3,5- bis- (trifluoromethyl) phenyl) ethyoxyl) -3- (S)-(4- fluorophenyls) -4- (3- (5- oxos -1H, 4H-1,2,4- triazols) methyl) morpholine, or its pharmaceutically useful salt, the compound is described in US 5, in 719,147.
The compounds of this invention can also with for applying together with treating the medicine of anaemia.This treatment for anemia agent is for example a kind of continuous red blood cell (eythropoiesis) generation receptor activators (such as Epoetin α).
The compounds of this invention can also with for applying together with treating the medicine of neutrocyte reduction.Such a neutropenia treatment medicine is the hemopoieticgrowth factor of such as production of regulation neutrophil cell and function, and such as human granulocyte's colony stimulating factor (G-CSF), G-CSF example includes Filgrastim.
The compounds of this invention can also be taken together with medicament for immunity enhancement, such as levamisol, isoprinosine and Zadaxin (Zadaxin).
The compounds of this invention can also be with diphosphonate (including bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).The example of diphosphate includes but is not limited to：Etidronate (Didronel), Pamidronate Disodium (Aredia), Alendronate sodium (Fosamax), profit plug phosphate (Actonel), zoledronate (Zometa), her spot phosphonate (Boniva), incadronate or BP, clodronate, EB-1053, YM 529, Neridronic Acid salt, NE 97221 and Tiludronate, include their all pharmaceutically useful salt, derivative, hydrate and mixture.
Therefore, the scope of the present invention includes the compounds of this invention and ionising radiation and/and second of compound combined administration, and second of compound is selected from：Hdac inhibitor, estrogenic agents, androgen receptor modifier, Retinoid receptor modulators, cytotoxicity/cytostatic agent, anti-proliferative agent, Prenyl-protein inhibitors, HMG-CoA reductase inhibitor, angiogenesis inhibitors, PPAR- gamma agonists, PPAR- delta agonists, antiviral agent, the inhibitor of intrinsic multiple medicine patience, antiemetic, medicine for treating anaemia, medicine for treating neutrocyte reduction, medicament for immunity enhancement, hyperplasia and survival signaling inhibitor, the medicine of interference cell cycle check, apoptosis inducing agent and diphosphonate.
When mentioning the compounds of this invention, term administering " and its variant (for example, a kind of " taking " compound), refer to introduce the compounds of this invention or its prodrug among the system of the animal of needs treatment.When the compounds of this invention or its prodrug combine offer with other one or more active medicines (such as cytotoxic agent), " administration " and its variant should be understood as including the compounds of this invention or its prodrug with other medicines while and being sequentially introduced.
" composition " one word used herein includes the product containing certain amount of special component, and directly or indirectly by special component the spawn formed is combined by specific quantity.
Term " therapeutically effective amount " used herein means that the quantity of reactive compound or medicament produces biology or medicinal response sought by researcher, animal doctor, doctor or other clinicians in tissue, system, animals or humans.
Term " treatment " refers to mammal of the treatment with pathological symptom, and refers to and mitigate the effect of symptom by killing cancer cell, and causes the repressed effect of disease progression, including reduction tempo, resistance stop eating speed, improve symptom and healing illness.Also include the treatment as precautionary measures (that is, preventing).
Term " pharmaceutically useful " used herein is related to compound, material, composition and/or formulation, within the scope of reliable medical judgment, they are adapted to contact with the tissue for the treatment of target (such as people), without excessive toxicity, stimulation, allergy response or other problems or complication, with rational benefit/harm ratio.Various carriers, excipient etc. also must be " acceptable " in the sense that compatible with other compositions in preparation.
Term " assistant agent " refers to that compound is used in combination with known treatment means.These means are included in the cytotoxic drug scheme used in the treatment of different type cancer and/or ionising radiation.Particularly, known activity compound can strengthen the effect of many cancer chemotherapeutic drugs, these chemotherapeutics are included in the topoisomerase enzyme drug toxicity (such as Hycamtin, Irinotecan, rubitecan) used in treating cancer, most known alkylating reagent (such as DTIC, Temozolomide) and platinum base medicine (such as carboplatin, cis-platinum).
Also include a kind of method for the treatment of cancer within the scope of the claims, including the compound of formula I of therapeutically effective amount and radiotherapy and/or a kind of compound are administered in combination, the compound is selected from：Hdac inhibitor, estrogenic agents, androgen receptor modifier, Retinoid receptor modulators, cytotoxicity/cell growth preparation, anti-proliferative agent, Prenyl-protein inhibitors, HMG-CoA reductase inhibitor, angiogenesis inhibitors, PPAR- gamma agonists, PPAR- delta agonists, antiviral agent, the inhibitor of intrinsic multi-drug resistance, antemetic, medicine for treating anaemia, for treating the medicine that neutrophil cell increases, medicament for immunity enhancement, hyperplasia and the inhibitor of survival signaling, the medicine of interference cell cycle check, apoptosis inducing agent and diphosphonate.
The aspects of the invention and other side would is that obviously according to the teaching included herein.
The abbreviation used in chemical descriptor and following embodiment is：
AcCl (chloroacetic chloride)；(BzO)2(benzoyl peroxide)；Cbz-Cl (benzyl chloroformate)；DCM (dichloromethane)；DIPEA (diisopropylethylamine)；DMF (dimethylformamide)；DMSO (dimethyl sulfoxide (DMSO))；Eq. (equivalent)；ES (electron spray)；EtOAc (ethyl acetate)；EtOH (ethanol)；Mol.sieves (molecular sieve)；HATU [hexafluorophosphoric acid O- (7- azepine benzos triazol-1-yl)-N N, N ', N '-tetramethylurea salt]；MeCN (acetonitrile)；MeOH (methanol)；MS (mass spectrography)；MW (microwave)；NBS (N-bromosuccinimide)；NMMO (N-methylmorpholine-N- oxides)；NMR (nuclear magnetic resonance)；Pcol (post pressure)；IPrOH (isopropanol)；RT (room temperature)；Sat.aq. (saturated aqueous solution)；SiO2(silica gel)；THF (tetrahydrofuran)；T-BuOH (tert-butyl alcohol)；KOAc (potassium acetate)；MW (microwave)；IST
Figure A20088000192600391
SPE column  SCX(International  Sorbent Technology
Figure A20088000192600392
Solid-phase extraction column cationic ion-exchange resin)；SFC (supercritical fluid chromatography)；TBTU (tetrafluoro boric acid O- (1H- BTA -1- bases)-N, N, N ', N '-tetramethylurea salt)；Tcol (column temperature)；CDCl3(Deuterated chloroform)；TLC (thin-layer chromatography)；TFA (trifluoroacetic acid).
Compound of formula I can be reacted by Formulas I A compounds and ammonia to be prepared：
Wherein R1And R2It is as defined above, RxIt is C1-6Alkyl, such as methyl.The reaction typically uses NH at about 70 DEG C3The aqueous solution carried out in solvent (such as THF) in the sealed reactor (careful).Either, alkali, such as NaOH or KOH can be added, by ester hydrolysis into corresponding carboxylic acid (RxIt is hydrogen), NH is then added in solvent (such as DMF) in the presence of coupling agent (such as HATU or TBTU) and DIPEA3, reaction is in room temperature progress.Either, such as Boc can be used2O is carboxylic acid activated by this, forms mixed acid anhydride, is then reacted with ammonium hydrogen carbonate, is carried out generally in solvent such as pyridine.Either, can be in solvent (such as methanol) in the ester is changed into Formulas I A compounds with ammonia under about 120 DEG C (such as utilizing microwave).
The nitrogen-atoms on piperidine ring in Formulas I A compounds can be protected in being synthesized more than with such as Boc.
Compound IA can be reacted by Formulas I B compounds and azide to be prepared：
Wherein R1、R2And RxIt is as defined above.Azide, such as NaN can be used3, it is usually to be reacted in solvent (such as DMF) at about 90-140 DEG C.Adduct, such as 2,6- lutidines can also be used.Reaction can be carried out under nitrogen atmosphere.
Compound IB can be prepared by Formulas I C compounds with Formulas I D compound condensations：
Figure A20088000192600401
Wherein R1、R2And RxIt is as defined above, L1It is a leaving group, such as such as nitro or halogen, fluorine.Method is included in dehydrating agent (such as MgSO4Or molecular sieve) in the presence of be condensed, or be heated at reflux in alcoholic solvent (such as ethanol).The reaction can be carried out under nitrogen atmosphere.
Formulas I C compounds can be prepared by using oxidant (such as NMMO) oxidation-type IE compounds：
Figure A20088000192600402
Wherein R1、RxAnd L1It is as defined above, L2It is a leaving group, such as halogen (such as bromine), the reaction is generally carried out in solvent (such as MeCN) at about room temperatures.Reaction can be carried out under nitrogen atmosphere.
Wherein L2The Formulas I E compounds for being bromine can the oxidation-type IF compounds preparation in the presence of radical initiator (such as benzoyl peroxide) by using bromating agent (such as NBS)：
Wherein R1、RxAnd L1It is defined as above, the reaction is general in solvent (such as CCl4) in carry out in backflow is lower.Reaction can be carried out under nitrogen atmosphere.
Wherein L1It is that the Formulas I F compounds of fluorine can be prepared by following steps：By Formulas I G compound diazotising：
Wherein R1And RxIt is as defined above, then decomposes the middle diazonium salt.For example, diazotising can be carried out with tetrafluoro boric acid salt made from earth containing a comparatively high percentage of sodium chloride in solvent (such as DCM) at about 0 DEG C.Then corresponding diazonium tetrafluoroborate can be isolated, corresponding fluorobenzene derivatives (careful) are then resolved at elevated temperatures, for example, is heated to 160 DEG C in solvent (such as dichloro-benzenes).
Wherein L1The Formulas I F compounds for being nitro can be by the way that Formulas I H compounds be nitrified：
Wherein R1It is as defined above, then is esterified to prepare.Nitration reaction can be in the presence of nitrate (such as potassium nitrate) and sour (such as sulfuric acid) in about carrying out at room temperature.Esterif iotacation step can be carried out at the standard conditions, such as with formula Rx- X alkyl halide (wherein X is halogen, for example iodine) is in the presence of alkali (such as cesium carbonate) and solvent (such as DMF) in about reacting at room temperature.Formula R can also be used under reflux conditionsx- OH alcohol and a kind of acidic catalyst, the HCl for example produced from AcCl/MeOH original positions.Then nitro compound is hydrogenated to form corresponding aniline with hydrogen and catalyst (such as palladium on carbon), is typically in alcoholic solvent such as methanol, to obtain desired Formulas I F compounds.
Either, compound of formula I can be by the way that Formulas I J compounds be also prepared originally：
Figure A20088000192600421
Wherein R1And R2It is as defined above.This reaction can react according to Fowler, with acid chloride (such as CBz-Cl) and reducing agent (such as NaBH4) carry out.Hydrogenated in palladium on carbon, complete to react and remove CBz blocking groups.
Formulas I J compounds can be prepared by Formulas I K compounds with the cross coupling of Formulas I L 3- pyridine boronic acids：
Wherein R1、R2And L2It is defined as above.This reaction is generally carried out under Suzuki coupling conditions, such as using catalyst (such as Pd2(dba)3With three (tert-butyl group) phosphines) carried out with alkali (such as sodium carbonate) and solvent (such as DMF and water) at about 90 DEG C.
Formulas I K compounds can be prepared by Formulas I M compounds and Formulas I N compound condensations：
Figure A20088000192600431
Wherein R1、R2And L2It is defined as above, L3It is a leaving group (such as halogen, such as fluorine), reaction is generally in solvent (such as DMF) in the progress in micro-wave oven at about 180 DEG C.Alkali, such as K can also be added2CO3。
The preparation method of Formulas I M compounds is, Formulas I O compounds：
Figure A20088000192600432
Wherein R1And RxIt is defined as above, is reacted at around room temperature with alkali (such as KOH or NaOH), by the ester hydrolysis into corresponding carboxylic acid (RxIt is hydrogen), NH is then added in solvent (DMF) in the presence of coupling agent (such as HATU, DIPEA and TBTU)3, the reaction carries out at around room temperature.
Formulas I O compounds can be by Formulas I G compounds, by being prepared aniline group acetylation with reagent (such as chloroacetic chloride) in about 55 DEG C in solvent (such as 1,2-DCE).It may then pass through and handled in sour (such as concentrated hydrochloric acid) with natrium nitrosum, be usually to be carried out in the case where cosolvent (such as toluene and water) is present in about 0 DEG C, cyclisation forms desired indazole.
In undeclared intermediate and the situation of the synthetic method of starting material, these compounds are that in the market is commercially available, or can utilize standard method, or utilize the extension of the synthetic method and synthetic schemes herein and embodiment of the above, are prepared from commercial goods compound.
Compound of formula I can use the method described in known method or synthesis more than and scheme herein and embodiment part, change into other compound of formula I.
In any composition sequence as described herein, it may be necessary to and/or preferably sensitivity or reaction active groups of the protection on any molecule of concern.This can be using conventional blocking group, such as in Protecting Groups in Organic Synthesis, 3rd Edition, Greene, T.W.and Wuts, P.G.M.；WileyInterscience, the group described in 1999 and Kocienski, P.J.Protecting Groups, Thieme, 1994 is realized.The blocking group can be removed with methods known in the art in appropriate subsequent step.For example, when there is Boc (tertbutyloxycarbonyl) or benzyloxycarbonyl group blocking group, can be removed by adding solvent (such as TFA, DCM and/or MeCN) at around room temperature.Compound can also be hydrogenated with standard method, such as under a hydrogen atmosphere in solvent (such as methanol) middle catalyst (such as Pd/C) processing.EtOAc can also be added in the presence of HCl and Isosorbide-5-Nitrae-dioxane at around room temperature to remove Boc or benzyloxycarbonyl group blocking group.
The compounds of this invention is prepared according to following scheme.All variables in chemical formula are defined as above.
When the compounds of this invention has chiral centre, enantiomer can use the separation method of standard, for example, split using SFC, chirality HPLC or with chiral acid, enantiomer is isolated from racemate.The separation can be carried out in any stage during manufacturing compound of formula I.For example, separation can be carried out in terminal stage, or intermediate can be isolated and specific enantiomer is subsequently isolated out for follow-up reaction, obtain desired product.
Scheme 1
A step for synthesizing the derivative of the compounds of this invention is shown in scheme 1, wherein the 2H- indazoles replaced are prepared with route of synthesis similar with described in WO 2005/066136.Changed into by 2- nitro -3- methyl benzoic acid derivatives after corresponding ester, methyl is subjected to free radical bromination with reagent (such as N-bromosuccinimide and benzoyl peroxide), obtain the benzyl bromide derivatives of key.This benzylic bromides can be oxidized to corresponding benzaldehyde with such as N-methylmorpholine-N- oxides and molecular sieve.After the aldehyde and amine condensation, handle the key intermediate at high temperature by using sodium azide and realize cyclization, introduce final nitrogen-atoms and finally extrude nitrogen-atoms to be supplied to indazole ring.Alkali, such as lutidines can also be added into this reaction.The ester finally changes into primary amide, obtains desired derivative.This can be by heating the ester or carrying out acid amides coupling by changing into after corresponding carboxylic acid and complete in ammonia solution.
Figure A20088000192600451
Scheme 1
Scheme 2
A kind of modification of scheme 1 is shown in following scheme 2, and it allows to introduce substituent on indazole core.When required nitrobenzoic acid is without commercial goods, they can for example be prepared with potassium nitrate nitrification in concentrated sulfuric acid by the nitrification of corresponding benzoic acid derivative.Above-described synthetic operation enables corresponding aniline to be formed, it can by first by indazole acetylation and in concentrated hydrochloric acid at 0 DEG C with natrium nitrosum cyclisation come cyclic.Either, can be with tetrafluoro boric acid salt made from earth containing a comparatively high percentage of sodium chloride by the aniline diazotising, and corresponding diazonium tetrafluoroborate is decomposed into (careful) using Schiemann reactions at high temperature, form corresponding difluoro bezene derivative.Benzyl methyl is oxidized to corresponding aldehyde according to the composition sequence described in scheme 1, and by being cyclized with a kind of (miscellaneous) anilide coupling and with sodium azide, be processed into desired indazole derivative.
Figure A20088000192600461
Scheme 2
Scheme 3
Another method is related to functionalization of the indazole in the latter half, as shown in scheme 3.Indazole ester is first changed into corresponding formamide by the method, and carries out the nucleophilic aromatic substitution of suitable fluorine (miscellaneous) aryl bromide.This enables brominated derivative to prepare, and the derivative is under Suzuki coupling conditions, such as with three (tert-butyl group) phosphines and Pd in the presence of alkali (such as sodium carbonate)2(dba)3As catalyst, cross coupling is carried out.Then acid chloride (such as CBz-Cl and reducing agent (such as NaBH are used4), reacted by Fowler, realize the conversion to desired piperidine moiety.Last hydrogenated reaction can produce corresponding piperidine derivative.
Figure A20088000192600471
Scheme 3
PARP-1SPA is tested
Example compound as described herein is tested in this test, finds its IC50Value is less than 5 μM, especially less than 50nM.
Working reagent
Analysis buffer：100mM Tris pH8,4mM MgCl2, 4mM spermine, 200mM KCl, 0.04%Nonidet P-40 (Nonidet P40).
Enzymatic 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 mixtures：[3H-NAD] (250 μ Ci/ml, 0.4 μ l, Perkin-Elmer NET-443H), NAD (1.5mM, 0.05 μ l, SIGMA N-1511), (250 μM of biotinylation NAD, 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).Deploy mixture：Streptavidin SPA pearls (5mg/ml, Amersham Biosciences RPNQ0007), are dissolved in 500mM EDTA.
Experimental design
Reaction is carried out in 96 hole microplates, and final volume is per the μ l of hole 50.5 μ l 5%DMSO/ compound solutions are added, enzymatic mixture (35 μ l) is added, by adding NAD/DNA mixtures (10 μ l) initial action, incubated 2 hours at room temperature.Add expansion mixture (25 μ l) and stop reaction, 15 points are incubated at room temperature.With Packard TOP COUNT apparatus measures.
Proliferation test in BRCA-1 silence HeLa cells
Abbreviation：
IMDM (the improved Dulbecco culture mediums of Iscove)；RPMI (Roswell Park MemorialInstitute culture mediums)；MOI (infection multiplicity)；GFP (green fluorescent protein)；PBS (phosphate buffer)；FCS (hyclone)；With DMEM (the improved Eagle culture mediums of Dulbecco).
The compounds of this invention has also made antiproliferative experiment in pairing cell BRCA1wt and BRCA1- (shRNA) HeLa cells.The experiment shows that PARP inhibitor can show selective growth inhibitory action to BRCA deficient cells.CC of these compounds to BRCA1 deficient cells50Less than 5 μM, and beyond the selectivity of more than 10 times of BRCA sound cells.
This experiment is the ability that redox dye (resazurin) is changed into fluorescent end product (resorufin) based on active born of the same parents.The quantity of the resorufin of generation is directly proportional to cell number.
Cell line：
HeLa shBRCA1-GFP this be the HeLa cells that the slow virus containing the shRNA for BRCA-1 is used with 100 infection multiplicity and transduceed to GFP expression cassette.The BRCA-1 silences measured are analyzed more than 80% with Tagman, express GFP the cytotostatic.
HeLa THM-GFP this be HeLa cells with infection multiplicity 100 with the control vector for not expressing any shRNA.
Scheme
- be inoculated with 96 bottom hole portion transparent black plates in 90 μ l culture mediums * by 300 cells/wells：
- in 37 DEG C, 5%CO2It is lower to incubate 4 hours
- every hole adds 10 μ l 10X compounds (5%DMSO/H2O)
- in 37 DEG C, 5%CO2It is lower to incubate 168 hours
10 μ l Celltiter Blue solution (Promega, G8081) of-addition pre-dilution 1: 1 in PBS1x
- by the mixture in 37 DEG C, 5%CO2Incubate 45 points
- in 15 points of room temperature Incubation in dark
- on fluophotometer read plate, ex：550nm, em：590nm
* culture medium：DMEM (GIBCO, 41966-029), 10%FCS (GIBCO, 10106-169), 0.1mg/ml Pen .- Streps (GIBCO, 15140-114), 2mM Glus (GIBCO, 3042190)
Proliferation test in natural B RCA deficient cells system
The compounds of this invention also shows the inhibitory action of the propagation to natural BRCA-1 (MDA-MB-436) and BRCA-2 (CAPAN-1) deficient cells system, CC50Less than 5 micromoles.
Proliferation test
Cell is seeded in 100 μ l suitable culture mediums in 96 orifice plates by 700 cells/wells*In/hole.Next day adds the serial dilutions of compound, the μ l/ holes of final volume 200.Each dilution is tested with triple samples.
After 6 days, cell survival is estimated according to the explanation of manufacturer (Promega) using CellTiter-Blue cells survivals test instrument.The read plate on Fusion Alpha ELIASAs (Packard Bioscience).
For low proliferative cell system (i.e. CAPAN-1), proliferation test is carried out after compound is added 14 days, culture medium once (170 μ l culture mediums, change 170 fresh cultures of the μ l containing compound into extracting out per hole) was changed at the 7th day.
*Culture medium：
MDA-MB-436：RPMI (GIBCO), 10%FBS (5%CO2)
CAPAN-1：IMDM (GIBCO), 20%FBS (5%CO2)
Test compound shows significant activity level in oncology model test in vivo.
Prepare embodiment
Embodiment A
2- phenyl -2H- indoles -7- formamides (A6)
Step 1：3- methyl -2- nitrobenzene methyls (A1)
AcCl (3.0 equivalent) is added dropwise to suspension of the 3- methyl -2- nitrobenzoic acids (10 equivalent) in methanol (0.4M) at 0 DEG C.Reactant mixture is stirred under reflux 20 hours.Solvent is removed in decompression, and residue is dissolved in EtOAc, uses NaHCO3Saturated aqueous solution, salt washing several times, dry (Na2SO4).Evaporation solvent, obtains (A1) of white solid, uses it for next step, does not make further purifying.
                                                         1H NMR (400MHz, CDCl3, 300K) and δ 7.86 (1H, d, J=7.5Hz), 7.53-7.42 (2H, m), 3.89 (3H, s), 2.36 (3H, s) .MS (ES) C9H9NO4Theoretical value：195, experiment value：218(M+Na)+.
Step 2：3- (bromomethyl) -2- nitrobenzene methyls (A2)
By (A1) (1.0 equivalent), (BzO)2(0.06 equivalent) and NBS (1.18 equivalent) are in CCl4In mixture (with regard to A1 speech be 0.2M) in N2It is heated to reflux under atmosphere 12 hours.Mixture is cooled to room temperature, diluted with DCM, is concentrated under reduced pressure, while being added in SiO2Upper drying.Residue flash column chromatography is in SiO2Upper purifying, is eluted with 10: 90 EtOAc/ petroleum ethers, obtains desired (A2), be white solid.
                                          1H NMR (400MHz, CDCl3, 300K) and 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) C9H8BrNO4Theoretical value：273：275, experiment value：242：244(M-MeO)+, 227：229(M-NO2)+.
Step 3：3- formoxyl -2- nitrobenzene methyls (A3)
To (A2) (10 equivalent) and
Figure A20088000192600501
Mixture (0.2M) of the molecular sieve (15g) in MeCN adds NMMO (2.0 equivalent) at room temperature, by reactant mixture in N2Stirred 1.5 hours under atmosphere.Then mixture is diluted with EtOAc, filtered, (Na is dried in filtrate water, 1N HCl and salt washing2SO4).Evaporation solvent, obtains white solid (A3), and it is used for next step, does not make further purifying.
                                             1H NMR (400MHz, CDCl3.300K) 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) C9H7NO5Theoretical value：209, experiment value：208(M-H)-.
Step 4：2- nitros -3- [(phenylimino) methyl] methyl benzoate (A4)
By the mixture (0.2M) of (A3) (1.0 equivalent) and aniline (1.05 equivalent) in EtOH in N2Return stirring 2 hours under atmosphere, until TCL (hexane/EtOAc=75: 25) Indicator Reaction is completed.Evaporation solvent obtains (A4), is white solid, for not making further purifying before next step.
                           1H NMR (400MHz, CDCl3, 300K) and 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 esters (A5)
By (A4) (1.0 equivalent) and NaN3The mixture (0.3M) of (1.05 equivalent) in dry DMF is stirred overnight at blanket of nitrogen and 90 DEG C.Crude product is concentrated under reduced pressure, residue uses purified by flash chromatography on silica gel, using the EtOAc/ petroleum ether gradient elutions from 10: 90 to 40: 60, obtains desired (A5), is brown oil.
                                           1H NMR (400MHz, CDCl3, 300K) and 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) C15H12N2O2Theoretical value：252, experiment value：253(M+H)+.
Step 6：2- phenyl -2H- indazole -7- formamides (A6)
By ester (A5) in mixtures of the THF with 32% ammoniacal liquor in being heated overnight in tube sealing at 70 DEG C.Decompression removes solvent, and residue flash chromatography purifies on silica gel, using the EtOAc/ petroleum ether gradient elutions from 30: 70 to 50: 50, obtains desired (A6), be 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) C14H11N3O theoretical values：237, experiment value：238(M+H)+.
Representative embodiment
Embodiment 1
Chlorination 3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt (B4)
Step 1：3- [4- ({ [3- (methoxycarbonyl group) -2- nitrobenzophenones] methylene } amino) phenyl] piperidines -1- carboxylic acid tert-butyl esters (B1)
(B1) according to the general procedure prepared described in embodiment step A 4, prepared with 3- (4- aminophenyls) piperidines -1- carboxylic acid tert-butyl esters, until TCL (petroleum ethers: EtOAc=4: 1) Indicator Reaction is completed, (B1) without further purification, next step is directly used.
Step 2：2- { 4- [1- (tertbutyloxycarbonyl) piperidines -3- bases] phenyl } -2H- indazole -7- carboxylate methyl esters (B2)
(B2) prepared according to the general procedure reported for preparing embodiment step A 5, crude product uses purified by flash chromatography on silica gel, using 20-40%EtOAc/ petroleum ether gradient elutions, obtains desired (B2), is yellow solid.
                                                                     1H NMR (400MHz, CDCl3, 300K) and 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 H2O signal overlaps), 1.48 (9H, s) .MS (ES) C25H29N3O4Theoretical value：435, experiment value：436(M+H)+.
Step 3：3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidines -1- carboxylic acid tert-butyl esters (B3)
By (B2) in 7N NH3In/MeOH (0.1M) in tube sealing 60 DEG C heat 2 days.It is concentrated under reduced pressure, crude product Et2O wet-millings, obtain desired product (B3), are yellow solid.
                                 1H NMR (400MHz, CDCl3, 300K) and 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 CDCl3Signal 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 H2O signal overlaps), 1.48 (9H, s) .MS (ES) C24H28N4O3Theoretical value：420, experiment value：421(M+H)+.
Step 4：Chlorination 3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt (B4)
4NHCl/1 is added to (B3) (1.0 equivalent) solution (0.2M) in EtOAc, 4- dioxane solutions (10.0 equivalent), at room temperature stirring reaction mixture 3 hours under agitation.Remove solvent, crude product Et under reduced pressure2O wet-millings are purified, and are obtained desired (B4), are yellow solid.
                 1H NMR (400MHz, DMSO-d6.300K the) (1H of δ 9.32, 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) C19H21ClN4O theoretical values：320, experiment can be worth：321(M+H)+.
Embodiment 2
2- { 4- [(3R)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides (C1) and 2- { 4- [(3S)-piperidines - 3- bases] phenyl } -2H- indazole -7- formamides amine (C2)
By embodiment 1 (B4) chirality SFC separation (posts：Chiralpak AS-H, 1 × 25mm, flow velocity：10ml/min, Tcol：35 DEG C, Pcal：100 bars, conditioning agent：55% (1PrOH+4%Et2NH)), using CO2As overcritical eluant, eluent, two kinds of pure enantiomers are obtained.
The enantiomer (C1) of first elution, retention time (SFC)：4.80min, is 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) C19H20N4O theoretical values：320, experiment value：321(M+H)+。
The free alkali is changed into chlorination (3R) -3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt, the optical activity measured：[α]20 D=+133.3 (c0.15, MeOH).
The enantiomer (C2) of second elution, retention time (SFC)：6.51min, is 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) C19H20N4O theoretical values：320, experiment value：321(M+H)+。
The free alkali is changed into chlorination (3S) -3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt, the optical activity measured：[α]20 D=-137.9 (c 0.145, MeOH).
Embodiment 3
Trifluoroacetic acid 3- { 4- [the fluoro- 2H- indazoles -2- bases of 7- (amino carbonyl) -5-] phenyl } piperidinium salt (D4)
Step 1：The fluoro- 1H- indazoles -7- carboxylate methyl esters (D1) of 5-
AcCl (5 equivalent) is added to solution (0.1M) of the embodiment 4 (E3) (10 equivalent) in 1,2- dichloromethane and 2 hours are heated at 55 DEG C, then removal of solvent under reduced pressure.
Obtained white solid is dissolved in toluene/water (5: 1,0.1M), solution is cooled to 0 DEG C, HCl (10 equivalents, 37%) is added, NaNO is then added portionwise at leisure2(10 equivalent), mixture is stirred 3 hours at 0 DEG C.Organic phase is washed with water 3 times, dries (MgSO4), removal of solvent under reduced pressure.
Then the yellow solution (0.1M) in toluene is heated 2 hours at 90 DEG C.Toluene is evaporated, desired product is obtained, is red solid.
                                            1(the 1H of H NMR (400MHz, DMSO, 300K) δ 13.37, 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+)C9H7FN2O2Theoretical value：194, experiment value：195(M+H)+。
Step 2：The fluoro- 1H- indazoles -7- formamides (D2) of 5-
(D1) is dissolved in dioxane/water (1: 1,0.1M), KOH (1.5 equivalent) is added.Removal of solvent under reduced pressure after stirring 12 hours at room temperature.Obtained white solid is not purified, for follow-up coupling reaction.
The carboxylic acid is dissolved in DMF (0.1M), TBU (1.5 equivalent) is added at 0 DEG C.DIPEA (20 equivalent) and ammonia (3.0 equivalents, 0.5M dioxane solutions) are added after 15 minutes, mixture is stirred at room temperature 36 hours.Add EtOAc, organic phase NaHCO3Saturated aqueous solution (3x) and salt solution (2x) are washed.Organic phase is dried, is evaporated under reduced pressure, crude product purified by flash chromatography, is eluted using 1-20% MeOH/DCM, obtains white solid (D2).MS(ES+)C8H6FN3O theoretical values：179, experiment value：180(M+H)+。
Step 3：The fluoro- 2H- indazoles -7- formamides (D3) of 2- (4- bromophenyls) -5-
K is added to solution of the D2 (1.0 equivalent) in DMF2CO3(1.3 equivalent) and 4- bromofluoro benzenes (10.0 equivalent), reactant mixture is heated 20 minutes under microwave condition in 180 DEG C.Reactant mixture is cooled to constant temperature, diluted with EtOAc.Organic phase is washed with salt, dries (Na2SO4).(D3) is obtained after evaporation solvent, it is purified on silica gel with chromatography, is eluted with 50-70%EtOAc/ petroleum ethers, is obtained title compound, be yellow powder.
                          1H NMR (400MHz, DMSO-d6, 300K) and 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+)C14H9BrFN3O theoretical values：334/336, experiment value：335/337(M+H)+.
Step 4：The fluoro- 2- of 5- (4- pyridin-3-yls phenyl) -2H- indazole -7- formamides (D4)
By the mixture (1.0M) of (D3) (1.0 equivalent) and pyridine -3- boric acid (1.3 equivalent) in DMF and 2N Na2CO3Solution (2.0 equivalent) one is reinstated Ar air-flows and deaerated 30 minutes.AddtBu3PH+BF4 -(0.05 equivalent) and Pd2(dba)3(0.05 equivalent), reactant mixture is heated 48 hours at 90 DEG C, is cooled to room temperature, adds DCM, organic phase NaHCO3Saturated aqueous solution, salt washing, dry (Na2SO4).Solution decompression is concentrated, residue is purified on silica gel with chromatography, successively eluted with 50-90%EtOAc/ petroleum ethers and 10%MeOH/DCM, obtain title compound, be yellow powder.
1H NMR (400MHz, DMSO-d6, 300K) and 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) C19H13FN4O theoretical values：332, experiment value：333(M+H+).
Step 5：3- { 4- [the fluoro- 2H- indazoles -2- bases of 7- (amino carbonyl) -5-] phenyl } piperidines -1- benzyl carboxylates (D5)
NaBH is added at -65 DEG C and to the solution (0.2M) of (D4) in absolute methanol under stirring4(1.2 equivalent), is then added dropwise Cbz-Cl (1.2 equivalent).Reactant mixture is reached ambient temperature overnight, be then quenched and reacted with water.Methanol is removed under reduced pressure, EtOAc is added.Organic phase saturation NaHCO3The aqueous solution is washed, and dries (Na2SO4).Evaporation solvent, obtains (D5), and it does not make, into lower purifying, to be directly used in next step.MS(ES)C27H25FN4O3Theoretical value：472, experiment value：473(M+H+)。
Step 6：Trifluoroacetic acid 3- { 4- [the fluoro- 2H- indazoles -2- bases of 7- (amino carbonyl) -5-] phenyl } piperidinium salt (D6)
Pd/C 10% (0.05 equivalent) and HCl (1.0 equivalent) is added to the solution (0.2M) of (D5) (1.0 equivalent) in MeOH, by reactant mixture in H2Stirred 48 hours under gas ammonia (1atm).Then the mixture is filtered through diatomite, removal of solvent under reduced pressure, obtains (D6), by it with anti-phase RP-HPLC (posts：C18) purify, with water (0.1%TFA) and MeCN as eluant, eluent, desired fraction is freeze-dried, title compound (D6) is obtained, is white powder.
                               1H NMR (400MHz, CD3CN, 300K) and 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) C19H19FN4O theoretical values：338, experiment value：339(M+H+).
Embodiment 4
The fluoro- 2- of trifluoroacetic acid 5- (the fluoro- 4- piperidines -3- bases phenyl of 3-) -2H- indazole -7- formamides
Step 1：The fluoro- 3- methyl -2- nitrobenzoic acids (E1) of 5-
At 0 DEG C KNO is slowly added into the solution of the fluoro- 5- methyl benzoic acids of 3- (1.0 equivalent) in concentrated sulfuric acid3(1: 1 equivalent).The mixture is stirred at room temperature 1 hour, then slowly pour into frozen water.After stirring is completely melt to ice, white precipitate is filtered, washed with cold water, is dried under reduced pressure.The 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 -2- nitrobenzene methyls (E2) of 5-
At room temperature methyl iodide (1.0 equivalent) is added to the solution (0.25M) of (E1) and cesium carbonate (1.5 equivalent) in DMF.After the mixture is stirred 18 hours, salt solution is added, mixture is extracted with EtOAc.Organic phase is dried into (Na2SO4), it is concentrated under reduced pressure.Obtained yellow solid is used 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 toluates (E3)
In room temperature and H2Under atmosphere (1atm), the mixture (0.25M) of (E2) (1.0 equivalent) and Pd/C (10%w/w) in MeOH is stirred 3 days.Mixture is filtered through diatomite, then removal of solvent under reduced pressure.Obtained white solid is used 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 4：2,5- bis- fluoro- 3- methyl toluates (E4)
Tetrafluoro boric acid nitrosonium salts are added portionwise to the solution (0.4M) of (E3) (1.0 equivalent) in anhydrous DCM at 0 DEG C.Anhydrous difluorobenzene (120 equivalent) is added after 1 hour at 0 DEG C, reactant mixture is slowly heated to 160 DEG C, while DCM is evaporated off.After 3 hours, mixture is cooled to room temperature, EtOAc is added, organic phase is washed 2 times with salt.Use MgSO4After drying, decompression removes solvent.Crude product purified by flash chromatography, is eluted with 1-10%EtOAc/ petroleum ethers, obtains (E4), be yellow oil.
1H NMR (400MHz, CDCl3, 300K) δ 7.42 (1H, m), 7.06 (1H, m), 3.92 (3H, s), 2.30 (3H, d, J=2.3Hz)
Step 5：2,5- bis- fluoro- 3- carbamoyl benzoates methyl esters (E5)
(E5) prepared by (E4) according to the general procedure reported in embodiment step A 2 and 3 is prepared.Crude product purified by flash chromatography, is eluted with 1-20%EtOAc/ petroleum ethers, obtains 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+)C9H6F2O3Theoretical value：200, experiment value：201(M+H)+.
Step 6：The fluoro- 2- of trifluoroacetic acid 5- (the fluoro- 4- piperidines -3- bases phenyl of 3-) -2H- indazole -7- formamides (E6)
The general procedure that (E5) is reported according to preparing in embodiment step A 4 and 5, corresponding indazole is changed into 3- (4- amino -2- fluorophenyls) piperidines -1- carboxylic acid tert-butyl esters.
2- { 4- [1- (tertbutyloxycarbonyl) piperidines -3- bases] -3- fluorophenyls } the fluoro- 2H- indazoles -7- carboxylate methyl esters of -5- formed change into corresponding formamide by using solution (0.1M) of the KOH (1.03 equivalent) in dioxane/water to handle at room temperature 12 hours.Removal of solvent under reduced pressure.The carboxylic acid is dissolved in DMF (0.1M), TBTU (1.5 equivalent) is added.DIPEA (2.0 equivalent) and ammonia (3.0 equivalents, 0.5M THF solutions) are added after 15 minutes, the solution is stirred 36 hours.The mixture, organic phase NaHCO are diluted with EtOAc3Saturated aqueous solution is washed.After evaporation solvent, residue is used for next step, is not further purified.
In order to deprotect, crude product is dissolved in TFA/DCM (0.1M), stirred 3 hours at room temperature.Solvent is evaporated off, obtained residue reversed-phase HPLC (post：C18) purify, obtain title compound (E6).
                                    1(the 1H of H NMR (400MHz, DMSO, 300K) δ 9.34, 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+)C19H18F2N4O theoretical values：356, experiment value：357(M+H)+.
Embodiment 5
4- toluene sulfonic acides (3S) -3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt
Step 1：(3S) -3- [4- ({ (1E)-[3- (methoxycarbonyl group) -2- nitrobenzophenones] methylene } amino) phenyl] piperidines -1- carboxylic acid tert-butyl esters (F1)
(F1) according to described in embodiment 1 (B1), prepared by A3 and (3S) -3- (4- aminophenyls) piperidines -1- carboxylic acid tert-butyl esters (disassemble 3- (4- aminophenyls) piperidines in methyl alcohol by using the L- dibenzoyl tartaric acids of 2 equivalents and then carry out Boc protections and be made).
Step 2：2- { 4- [(3S) -1- (tertbutyloxycarbonyl) piperidines -3- bases] phenyl } -2H- indazole -7- carboxylic acids (F2)
By (F1) (1 equivalent) and sodium azide (1 equivalent) pulp in DCM (0.25M), blanketing with inert gas adds 2,6- lutidines (1.0 equivalent).Interior 110 DEG C of temperature is heated the mixture to, is kept for 20 hours.The brown solution of formation is cooled to 20 DEG C, the LiCl aqueous solution that THF adds 25wt% is added.Two-phase is separated, organic phase is washed 3 times with the 25wt%LiCl aqueous solution.Add 2.0M NaOH (10 equivalent) in organic solution more than, the mixture is heated 20 hours at 35 DEG C, be subsequently cooled to 20 DEG C, separate two-phase.Organic layer is washed with the mixture of 2.0M hydrochloric acid and salt solution, separates each layer, and organic layer is washed with salt, is concentrated to give (F2), is not further purified again.
Step 3：(3S) -3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidines -1- carboxylic acid tert-butyl esters (F3)
F2 is dissolved in DCM (0.35M), dimethyl dicarbonate butyl ester (1.3 equivalent) and pyridine (1.0 equivalent) are added at room temperature.Ammonium hydrogen carbonate (1.3 equivalent) is added after 30 minutes, continues to stir 20 hours.1M HCl (5mL/g) are added, each phase is separated, organic phase is washed with water 2 times, is concentrated into small size.Rough compound (F3) is filtered through silicagel pad, is then crystallized from methyl tertiary butyl ether(MTBE).
Step 4：4- toluene sulfonic acides (3S) -3- { 4- [7- (amino carbonyl) -2H- indazole -2- bases] phenyl } piperidinium salt (F4)
F3 is dissolved in THF (0.15M), added water (the 5% of THF).P-methyl benzenesulfonic acid monohydrate (2.2 equivalent) is added, the mixture is heated to 66 DEG C and is stirred overnight.Cooled and filtered separates 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)
Following examples are prepared according to the method for previous embodiment：
  Embodiment   Title   MW   M+H +   Embodiment   The step of
  6 Trifluoroacetic acid 3- { 4- [7- (amino carbonyl) -2H- Indazole -2- bases] phenyl } piperidines   320   321   1
  7 The fluoro- 2- of 5- (4- piperidines -3- bases phenyl) -2H- Indazole -7- formamides   338   339   3
    8 Chlorination (3S) -3- { 4- [7- (amino carbonyl) -2H- Indazole -2- bases] phenyl } piperidines     320   321   2
  9 Chlorination (3R) -3- { 4- [7- (amino carbonyl) -2H- Indazole -2- bases] phenyl } piperidines   320   321   2
  10 (R) the fluoro- 2- of -5- (4- piperidines -3- bases phenyl) - 2H- indazole -7- formamides   338   339   2
  11 (S) the fluoro- 2- of -5- (4- piperidines -3- bases phenyl) - 2H- indazole -7- formamides   338   339   2
  12 (R) the fluoro- 2- of -5- { the fluoro- 4- piperidines -3- base benzene of 3- Base } -2H- indazole -7- formamides   356   357   2
  13 (S) the fluoro- 2- of -5- { the fluoro- 4- piperidines -3- base benzene of 3- Base } -2H- indazole -7- formamides   356   357   2

Claims (14)

1. a kind of compound of formula I or its pharmaceutically useful salt, stereoisomer or dynamic isomer：
It is R1It is hydrogen or fluorine, R2It is hydrogen or fluorine.
2. the Formula II compound of claim 1, or its pharmaceutically useful salt, stereoisomer or dynamic isomer：
Figure A2008800019260002C2
Wherein R1And R2With the definition in claim 1.
3. the formula III compound of claim 1, or its pharmaceutically useful salt or dynamic isomer：
Figure A2008800019260002C3
Wherein R1And R2With the definition in claim 1.
4. the formula IV compound of claim 1, or its pharmaceutically useful salt or dynamic isomer：
Figure A2008800019260003C1
Wherein R1And R2With the definition in claim 1.
5. the compound of any preceding claims, wherein R1It is hydrogen, R2It is hydrogen or fluorine.
6. a kind of compound of claim 1, is selected from：
2- (4- piperidines -3- bases phenyl) -2H- indazole -7- formamides；
2- { 4- [(3R)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides；
2- { 4- [(3S)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides；
The fluoro- 2- of 5- (4- piperidines -3- bases phenyl) -2H- indazole -7- formamides；
The fluoro- 2- of 5- { 4- [(3S)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides；
The fluoro- 2- of 5- { 4- [(3R)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides；
The fluoro- 2- of 5- (the fluoro- 4- piperidines -3- bases phenyl of 3-) -2H- indazole -7- formamides；
The fluoro- 2- of 5- { the fluoro- 4- of 3- [(3R)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides；
The fluoro- 2- of 5- { the fluoro- 4- of 3- [(3S)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides；And their officinal salt, dynamic isomer or stereoisomer.
7. the compound of claim 6, is selected from：
2- { 4- [(3R)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides；
2- { 4- [(3S)-piperidines -3- bases] phenyl } -2H- indazole -7- formamides；And its officinal salt or dynamic isomer.
8. a kind of pharmaceutical composition, wherein containing the compound with pharmaceutically useful carrier-bound foregoing any claim, or its pharmaceutically useful salt, dynamic isomer or stereoisomer.
9. the compound of any one of claim 1 to 7, or its pharmaceutically useful salt, stereoisomer, dynamic isomer and a kind of cancer therapy drug simultaneously, separately or sequentially are applied.
10. the compound of any one of claim 1 to 7 or its pharmaceutically useful salt, stereoisomer or dynamic isomer are used to treat.
11. the compound of any one of claim 1 to 7 or its pharmaceutically useful salt, stereoisomer or dynamic isomer are used for the purposes for manufacturing medicine, the medicine is used for treatment or prevention can be by the illness that suppresses poly- (ADP ribose) polymerase (PAPR) and improve.
12. the compound of any one of claim 1 to 7 or its pharmaceutically useful salt, stereoisomer or dynamic isomer are used for the purposes for manufacturing medicine, the medicine is used to treat or prevent angiosis, diabetes, neurodegenerative disease, retroviral infection, retinal damage or the skin senescence outside cancer, inflammatory disease, reperfusion injury, ischemic conditions, apoplexy, kidney failure, cardiovascular disease, cardiovascular disease, and the skin injury that UV induces.
13. the compound of any one of claim 1 to 7 or its pharmaceutically useful salt, stereoisomer or dynamic isomer are used as the chemical sensitising agent and/or the purposes of radiosensitizing agent in treatment of cancer.
14. a kind of method for the skin injury that angiosis, diabetes, neurodegenerative disease, retroviral infection, retinal damage or skin senescence and UV treated or prevented outside cancer, inflammatory disease, reperfusion injury, ischemic conditions, apoplexy, kidney failure, cardiovascular disease, cardiovascular disease induces, this method includes the composition that the compound of the claim 1 of effective dose or the compound containing claim 1 are applied to the patient of needs.
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CN109810047A (en) * 2018-03-02 2019-05-28 上海博邦医药科技有限公司 (R) synthetic method of the chiral intermediate of -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine and Ni Lapani
CN110035744A (en) * 2016-12-16 2019-07-19 苏州苏融生物医药有限公司 A kind of Ni Lapani sustained and controlled release medicament composition and application thereof
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CN107235958A (en) * 2016-09-14 2017-10-10 陕西科技大学 A kind of synthetic method for preparing PARP inhibitor Niraparib
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