CN104788365B - Pyrazinamide derivative, preparation method and application - Google Patents
Pyrazinamide derivative, preparation method and application Download PDFInfo
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- CN104788365B CN104788365B CN201410019845.5A CN201410019845A CN104788365B CN 104788365 B CN104788365 B CN 104788365B CN 201410019845 A CN201410019845 A CN 201410019845A CN 104788365 B CN104788365 B CN 104788365B
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- 0 OC1(C*C1)c1ccccn1 Chemical compound OC1(C*C1)c1ccccn1 0.000 description 2
- IMRWILPUOVGIMU-UHFFFAOYSA-N Brc1ccccn1 Chemical compound Brc1ccccn1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- CKDRCYGACKPBBD-UHFFFAOYSA-N OC1(CNC1)C1NCCCC1 Chemical compound OC1(CNC1)C1NCCCC1 CKDRCYGACKPBBD-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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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
- C07D401/14—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 three or more hetero rings
Abstract
The invention discloses formula (I) Pyrazinamide derivatives and its pharmaceutically acceptable salt, wherein R1、R2、R3It is defined as in the description with A.The invention also discloses the preparation methods of these compounds, the application of pharmaceutical composition containing the compound and the compound in treatment mammal especially human hyperproliferative's disease and in terms of being used to prepare the treatment mammal especially drug of human hyperproliferative's disease.
Description
Technical field
The present invention relates to can be used for treat mammalian hyper-proliferative disease such as tumour Pyrazinamide derivative and its
Preparation method, the pharmaceutical composition containing the compound and the compound are excessive in the treatment mammal especially mankind
Proliferative diseases and it is used to prepare application of the treatment mammal especially in terms of the drug of human hyperproliferative's disease.
Background technology
Cell signaling pathway plays an important role to cell growth, proliferation and differentiation.Mitogen-activated protein kinase
(mitogen-activated protein kinase, MAPK) family's signal transduction is intracellular important signal path, packet
Include the protein kinase (ERK) of extracellular signal regulation and control, the protein kinase (SAPK) for the ends c-JunN kinases (JNK)/stress activate,
4 approach such as P38MAPK and ERK5/BMK1.Wherein ERK (extracellular regulated kinase) is MAPK family
Important member's extracellular signal-regulated kinase of race, signal transduction pathway (Ras-Raf-MEK-ERK) can by a variety of growths because
Son, cell factor and rush disintegrating agent activation, play a significant role in the proliferation of cell, differentiation and apoptosis, are that multi-signal is handed over
Meeting point or co-channel.The GTP combinations Ras of activation causes the cascade activation of serine/threonine kinase, and Raf is activated subsequent
And MEK is activated, MEK belongs to rare dual specificity kinase, makes two regulatory site phosphorylations of Tyr and Thr and activates ERK races
(ERK-1、ERK-2).3 important target molecules that people pay close attention in the access are：Ras, Raf and MEK.
Ras genes are a proto-oncogenes, and family member includes K-Ras, H-Ras and N-Ras.Wherein K-Ras and tumour
Generation and evolving relations it is maximum, the frequency of mutation also highest in tumour.Research is found：Cancer of pancreas (90%), colon cancer
(50%), lung cancer (30%), oophoroma (15%), thyroid cancer (50%), carcinoma of urinary bladder (6%), erythematosus lupus (SLE), breast
Gland cancer, liver cancer, cutaneum carcinoma, rheumatoid arthritis (RA), kidney and certain leukaemia (Leukemia) have higher
KRas mutation are horizontal.
Raf is one of most important proto-oncogene of the mankind, and Raf albumen is a serine threonine kinase, and there are three hypotype A-
Raf, B-Raf and C-Raf.In terms of being catalyzed substrate, A-Raf can only be using MEK1 as substrate；B-raf then using MEK1/2 as substrate,
It is also the most important upstream activating kinases of MEK；And C-Raf divided by MEK1/2 is outside substrate, also with Retinoblastoma Protein
(Rb), BCL2/BCL-XL associated deaths promotive factor (BAD) etc. is substrate, therefore the effect of B-Raf is more likely in Ras-
Ras and MEK is connected in Raf-MEK-ERK signal paths.B-Raf mutation occur for about 8% human tumor.B-Raf's is exhausted
Most of mutant form is mutated for B-RafV600E, which leads to downstream MEK-ERK signal path sustained activations, to tumour
Growing multiplication and invasion transfer are most important.B-Raf mutation take place mostly in melanoma, colon cancer and thyroid cancer.
B-Raf mutation rates highest in melanoma, there are about 40%~68% pernicious (metastatic) melanomas, and B-Raf mutation occur.It should
Mutation is first high-frequency mutator being found in melanoma, has become the therapeutic target of melanoma at present
Mark.B-Raf mutation also occur for other 5%~8% colon cancer.In addition B-Raf mutation rates in thyroid cancer are about 30%, wherein
Mutation rate highest in thyroid papillary carcinoma hypotype, mutation rate are 30%~70%.B-Raf mutation also have been reported that in lung cancer,
But mutation rate is relatively low, is 2% or so.
MEK belongs to dual specificity kinase, and family member includes MEK1/MEK2, is typically expressed as MEK1/2.Their work
There was only ERK1 and ERK2 with substrate.It can be tumor phenotypes by transforming mammalian cells by the MEK1 of sustained activation, and pass through suppression
The activation energy of MEK processed and then prevention ERK prevent the growth of the cell of Ras mutation in vitro.Mek inhibitor and general kinase inhibition
Agent is different, not with the ATP-binding site of ATP competitive target kinases, does not also compete MEK1/2 binding sites with ERK1/2, but
It is combined with the hydrophobic region that MEK closes on.Since mek inhibitor is non ATP competitive inhibitor, so B-Raf inhibitor is compared, choosing
Selecting property is more preferable, while the binding site of mek inhibitor does not have homologous sequence on other kinases, is special in all kinase inhibitors
It is anisotropic strongest.In addition, the effect of many such mek inhibitors is reversible, kinases can be reactivated after deactivating.Also it reduces
Due to the generation of irreversible side effect caused by mek inhibitor.
Since K-RAS mutation, B-Raf are mutated the high rate in each comfortable tumour, and the two often mutual exclusion, cause to swell
Activation probability extremely high Ras-Raf-MEK in tumor.Therefore by inhibiting MEK, Ras-Raf-MEK-ERK signal paths is interrupted and are lived
The proliferation signal that tumour is given in change presents a good foreground in theory to reach oncotherapy effect.
MEK is inhibited to show potential treatment benefit in multinomial research.International patent application WO2002/006213
The oxygen conjunction ester for disclosing the 4- iodoanilino benzohydroxamic acids of following (1) formula can be used for treating various increments as mek inhibitor
Property morbid state, such as it is related to the illness of MEK hyperfunctions and the disease by MEK Cascade controls.Wherein representative compound
For PD0325901, but it is clinic II phase halted states at present.
International patent application WO2003/077914 discloses the N3 alkylated benzimidazole derivatives as mek inhibitor,
For treating excess proliferative disease in mammal, such as cancer and inflammation, general structure such as following formula (2) is shown, wherein representing
Property compound be AZD6244, the treatment of itself and chemotherapeutics docetaxel (Docetaxel) combination at present KRas is mutated non-small cell
Lung cancer has been enter into the clinical III phases.
International patent application WO2006/045514, which is disclosed, can be used for treating excess proliferative disease such as cancer and inflammation
A series of substituted 3- arylamino pyridine derivatives, shown in general structure such as following formula (3).
International patent application WO2007/044515 discloses the azete for the mek inhibitor that can be used for treating proliferative disease
Pyridine, shown in general structure such as following formula (4), representative compound GDC0973 be good mek inhibitor (Exelixis Inc.,
210East Grand Avenue, South San Francisco, California94080, United States, ACS
Med.Chem.Lett.2012,3,416-421), at present with one line metastatic disease of Wei Luofeini (Vemurafenib) combination therapy
The research of disease has been enter into the clinical III phases.
GSK1120212 (Trametinib) is to ratify (in May, 2013) MEK by FDA first in similar drugs to inhibit
Agent is listed as single medicine, for treating the metastasis melanin tumor with B-RafV600E/V600K mutators and cannot go
The melanoma patient of operative treatment.GSK1120212 structures are as follows.
The country is in the elementary step to the exploitation of mek inhibitor at present, and still no compound enters clinic.New suppression is provided
Preparation inhibits Ras-Raf-MEK-ERK signal transductions, to effectively inhibit cell Proliferation, and then develop safely and effectively to resist to swell
Tumor medicine is still that clinical application is required, this undoubtedly will be helpful to the therapeutic advance for promoting cancer.
Invention content
The present invention provides a kind of new inhibitor, can effectively inhibit Ras-Raf-MEK-ERK signal transductions, can not only
Inhibit phosphorylation of the upstream kinases to MEK, additionally it is possible to inhibit phosphorylations of the MEK to ERK, there is both inhibitory effects, Neng Gougeng
Add effective inhibition cell Proliferation, treats mammalian hyper-proliferative disease such as tumour.
With regard to this, the present invention provides a kind of such as following formula (I) compound or its pharmaceutically acceptable salt：
In formula, R1And R2It is each independently selected from hydrogen, C1-C4Alkyl ,-O (CH2)2OH、Or R1And R2With it
The nitrogen-atoms that is connected formed together
R3Selected from halogen ,-S- (C1-C4Alkyl) or C1-C4Alkoxy；
The substituent group that A is the aryl for the substituent group for being selected from B group groups with 1~3, is selected from B group groups with 1~3
Heteroaryl, with 1~3 selected from B group groups substituent group C3-C8Naphthenic base is selected from taking for B group groups with 1~3
The Heterocyclylalkyl of Dai Ji,
Wherein, B groups group is selected from following one group：Hydrogen, halogen, alkyl, alkoxy, halogenated alkyl ,-OH ,-SH ,-NO2、-
CN、-COH、-COOH、-CONH2、-CONH-C1-C4Alkyl ,-CONH-C3-C6Naphthenic base ,-C1-C4Alkyl-OH ,-S-C1-C4Alkane
Base ,-NR4R5、-SO2R6、-COR6、-COOR6,-aryl ,-O- aryl ,-NH- aryl ,-S- aryl ,-SO2Aryl ,-CO- virtues
Base ,-CO2Aryl ,-CONH- aryl ,-naphthenic base ,-heteroaryl ,-Heterocyclylalkyl；
R4And R5It is each independently hydrogen ,-COR6、-SO2R6、-COOR6；
R6Selected from-C1-C4Alkyl ,-C1-C4Halogenated alkyl ,-C3-C6Naphthenic base.
The present invention also provides the preparation methods of the formula (I) compound.
The present invention also provides a kind of pharmaceutical composition, containing the formula (I) compound or its pharmaceutically acceptable salt,
And pharmaceutically acceptable carrier, excipient or diluent.
Change the present invention also provides the formula (I) compound or its pharmaceutically acceptable salt and containing the formula (I)
It closes object or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, the pharmaceutical composition of excipient or diluent is used as and controls
Treat the drug of excess proliferative disease.
Change the present invention also provides the formula (I) compound or its pharmaceutically acceptable salt and containing the formula (I)
It closes object or is prepared by its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, the pharmaceutical composition of excipient or diluent
Treat the application in terms of the drug of excess proliferative disease.
Change the present invention also provides the formula (I) compound or its pharmaceutically acceptable salt and containing the formula (I)
It closes object or is prepared by its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, the pharmaceutical composition of excipient or diluent
Treat the application in terms of the drug of tumour.
Mitogen-activated protein kinase kinases (MEK) activity and obstruction mitogen can be inhibited to live the present invention also provides a kind of
Change method of the protein kinase kinase kinase (Raf) to the phosphorylation of MEK, includes formula (I) change for applying therapeutically effective amount to patient
Close object or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, excipient or diluent.
The present invention also provides the methods for the treatment of excess proliferative disease, including give object in need a effective amount of institute
It states formula (I) compound or its pharmaceutically acceptable salt or contains the formula (I) compound or its pharmaceutically acceptable salt
The step of with the pharmaceutical composition of pharmaceutically acceptable carrier, excipient or diluent.
The present invention also provides the methods for the treatment of tumour, including give a effective amount of formula (I) of object in need and change
It closes object or its pharmaceutically acceptable salt or contains the formula (I) compound or its pharmaceutically acceptable salt and pharmaceutically may be used
The step of pharmaceutical composition of the carrier of receiving, excipient or diluent.
In a preferred embodiment of the invention, formula (I) compound or its pharmaceutically acceptable salt, in formula
R1And R2Be each independently hydrogen,Or R1And R2Nitrogen-atoms connected to them is formed togetherPreferred R1And R2For hydrogen.
In a preferred embodiment of the invention, formula (I) compound or its pharmaceutically acceptable salt, in formula
R3Selected from halogen or-S- (C1-C4Alkyl), preferred R3For I or-SMe.
In a preferred embodiment of the invention, formula (I) compound or its pharmaceutically acceptable salt, in formula
A be with 1~3 selected from B group groups substituent group aryl, with 1~3 be selected from B group groups substituent group heteroaryl,
The C of the substituent group selected from B group groups with 1~33-C8Naphthenic base, the heterocycle with 1~3 substituent group selected from B group groups
Alkyl,
Wherein, B groups group is selected from following one group：Hydrogen, halogen, alkyl, alkoxy, halogenated alkyl ,-OH ,-SH ,-NO2、-
CN、-COH、-COOH、-CONH2、-CONH-C1-C4Alkyl ,-CONH-C3-C6Naphthenic base ,-C1-C4Alkyl-OH ,-S-C1-C4Alkane
Base ,-NR4R5、-SO2R6、-COR6、-COOR6；R4And R5It is each independently hydrogen ,-COR6、-SO2R6、-COOR6；R6Selected from-C1-
C4Alkyl ,-C1-C4Halogenated alkyl ,-C3-C6Naphthenic base；
It is furthermore preferred that B group groups are hydrogen or-NR4R5, R4For hydrogen ,-COR6、-SO2R6Or-COOR6, R5For hydrogen, R6For-C1-
C4Alkyl ,-C1-C4Halogenated alkyl or-C3-C6Naphthenic base.
In a preferred embodiment of the invention, formula (I) compound or its pharmaceutically acceptable salt, in formula
A is the aryl with 1~3 substituent group selected from B group groups, wherein B group groups are selected from following one group：Hydrogen, halogen, alkyl,
Alkoxy, halogenated alkyl ,-OH ,-SH ,-NO2、-CN、-COH、-COOH、-CONH2、-CONH-C1-C4Alkyl ,-CONH-C3-C6
Naphthenic base ,-C1-C4Alkyl-OH ,-S-C1-C4Alkyl ,-NR4R5、-SO2R6、-COR6、-COOR6,-aryl ,-O- aryl ,-NH-
Aryl ,-S- aryl ,-SO2Aryl ,-CO- aryl ,-CO2Aryl ,-CONH- aryl ,-naphthenic base ,-heteroaryl ,-heterocycle alkane
Base；R4And R5It is each independently hydrogen ,-COR6、-SO2R6、-COOR6；R6Selected from-C1-C4Alkyl ,-C1-C4Halogenated alkyl ,-C3-
C6Naphthenic base.
In another preferred embodiment of the present invention, formula (I) compound or its pharmaceutically acceptable salt, formula
Middle A is the aryl with 1~3 substituent group selected from B group groups, and wherein B groups group is selected from following one group：Hydrogen, halogen, alkane
Base, alkoxy, halogenated alkyl ,-OH ,-SH ,-NO2、-CN、-COH、-COOH、-CONH2、-CONH-C1-C4Alkyl ,-CONH-C3-
C6Naphthenic base ,-C1-C4Alkyl-OH ,-S-C1-C4Alkyl ,-NR4R5、-SO2R6、-COR6、-COOR6；R4And R5It is each independently
Hydrogen ,-COR6、-SO2R6、-COOR6；R6Selected from-C1-C4Alkyl ,-C1-C4Halogenated alkyl ,-C3-C6Naphthenic base；
It is furthermore preferred that B group groups are hydrogen or-NR4R5, R4For hydrogen ,-COR6、-SO2R6Or-COOR6, R5For hydrogen, R6For-C1-
C4Alkyl ,-C1-C4Halogenated alkyl or-C3-C6Naphthenic base.
In a preferred embodiment of the invention, formula (I) compound or its pharmaceutically acceptable salt, in formula
A is the phenyl with 1~3 substituent group selected from B group groups, wherein B group groups are selected from following one group：Hydrogen, halogen, alkyl,
Alkoxy, halogenated alkyl ,-OH ,-SH ,-NO2、-CN、-COH、-COOH、-CONH2、-CONH-C1-C4Alkyl ,-CONH-C3-C6
Naphthenic base ,-C1-C4Alkyl-OH ,-S-C1-C4Alkyl ,-NR4R5、-SO2R6、-COR6、-COOR6,-aryl ,-O- aryl ,-NH-
Aryl ,-S- aryl ,-SO2Aryl ,-CO- aryl ,-CO2Aryl ,-CONH- aryl ,-naphthenic base ,-heteroaryl ,-heterocycle alkane
Base；R4And R5It is each independently hydrogen ,-COR6、-SO2R6、-COOR6；R6Selected from-C1-C4Alkyl ,-C1-C4Halogenated alkyl ,-C3-
C6Naphthenic base.
In another preferred embodiment of the present invention, formula (I) compound or its pharmaceutically acceptable salt, formula
Middle A is the phenyl with 1~3 substituent group selected from B group groups, and wherein B groups group is selected from following one group：Hydrogen, halogen, alkane
Base, alkoxy, halogenated alkyl ,-OH ,-SH ,-NO2、-CN、-COH、-COOH、-CONH2、-CONH-C1-C4Alkyl ,-CONH-C3-
C6Naphthenic base ,-C1-C4Alkyl-OH ,-S-C1-C4Alkyl ,-NR4R5、-SO2R6、-COR6、-COOR6；R4And R5It is each independently
Hydrogen ,-COR6、-SO2R6、-COOR6；R6Selected from-C1-C4Alkyl ,-C1-C4Halogenated alkyl ,-C3-C6Naphthenic base；
It is furthermore preferred that B group groups are hydrogen or-NR4R5, R4For hydrogen ,-COR6、-SO2R6Or-COOR6, R5For hydrogen, R6For-C1-
C4Alkyl ,-C1-C4Halogenated alkyl or-C3-C6Naphthenic base.
In a preferred embodiment of the invention, formula (I) compound or its pharmaceutically acceptable salt, in formula
A is the phenyl replaced selected from B group group substitutions, and wherein B groups group is selected from following one group：Hydrogen, halogen, alkyl, alkoxy,
Halogenated alkyl ,-OH ,-SH ,-NO2、-CN、-COH、-COOH、-CONH2、-CONH-C1-C4Alkyl ,-CONH-C3-C6Naphthenic base ,-
C1-C4Alkyl-OH ,-S-C1-C4Alkyl ,-NR4R5、-SO2R6、-COR6、-COOR6,-aryl ,-O- aryl ,-NH- aryl ,-S-
Aryl ,-SO2Aryl ,-CO- aryl ,-CO2Aryl ,-CONH- aryl ,-naphthenic base ,-heteroaryl ,-Heterocyclylalkyl.
In another preferred embodiment of the present invention, formula (I) compound or its pharmaceutically acceptable salt, formula
Middle A is the phenyl replaced selected from B group group substitutions, and wherein B groups group is selected from following one group：Hydrogen, halogen, alkyl, alcoxyl
Base, halogenated alkyl ,-OH ,-SH ,-NO2、-CN、-COH、-COOH、-CONH2、-CONH-C1-C4Alkyl ,-CONH-C3-C6Cycloalkanes
Base ,-C1-C4Alkyl-OH ,-S-C1-C4Alkyl ,-NR4R5、-SO2R6、-COR6、-COOR6；R4And R5Be each independently hydrogen ,-
COR6、-SO2R6、-COOR6；R6Selected from-C1-C4Alkyl ,-C1-C4Halogenated alkyl ,-C3-C6Naphthenic base；
It is furthermore preferred that B group groups are hydrogen or-NR4R5, R4For hydrogen ,-COR6、-SO2R6Or-COOR6, R5For hydrogen, R6For-C1-
C4Alkyl ,-C1-C4Halogenated alkyl or-C3-C6Naphthenic base.
In a preferred embodiment of the invention, formula (I) compound or its pharmaceutically acceptable salt, in formula
A is by-NR4R5Substituted phenyl, the compound have such as following formula (Ia) structure：
Wherein, R4Selected from hydrogen ,-COR6、-SO2R6、-COOR6, R5For hydrogen；
R6Selected from-C1-C4Alkyl ,-C1-C4Halogenated alkyl ,-C3-C6Naphthenic base；
R1And R2It is each independently selected from hydrogen, C1-C4Alkyl ,-O (CH2)2OH、Or R1And R2With they institute
The nitrogen-atoms of connection is formed together
R3Selected from halogen ,-S- (C1-C4Alkyl) or C1-C4Alkoxy.
In a preferred embodiment of formula (Ia) compound, R4For-COR6, wherein R6For-C1-C4Alkyl
Or-C1-C4Halogenated alkyl, preferred R6For-C1-C4Alkyl.
In a preferred embodiment of formula (Ia) compound, R4For-SO2R6, wherein R6For-C1-C4Alkyl
Or-C3-C6Naphthenic base.
In a preferred embodiment of formula (Ia) compound, R4For-COOR6, wherein R6For-C1-C4Alkyl.
In a preferred embodiment of formula (Ia) compound, R4For hydrogen.
In another preferred embodiment of formula (Ia) compound, R1And R2Be each independently selected from hydrogen,Or R1And R2Nitrogen-atoms connected to them is formed togetherR3For halogen.
In another preferred embodiment of formula (Ia) compound, R1And R2Be each independently selected from hydrogen orR3For halogen or-S- (C1-C4Alkyl).
In another preferred embodiment of formula (Ia) compound, R1And R2For hydrogen；R3For halogen.
In the present invention, it as the compound or its pharmaceutically acceptable salt represented by formula (I), can specifically refer to：
3- [(3- t-butoxycarbonyl aminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide；
3- (3- aminobenzene-thios) -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide；
3- [(3- acetylaminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide；
3- [(3- methanesulfonamidos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide；
3- [(the third sulfonamido of 3- rings) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide；
3- [(3- trifluoroacetamidos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide；
3- [(3- methanesulfonamidos) thiophenyl] -5- [(the fluoro- 4- methyl mercaptos phenyl of 2-) amino] Pyrazinamide；
(S) -3- [(3- acetylaminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino]-N- [(2,3- dihydroxy) third
Base] Pyrazinamide；
(S) -3- [(3- methanesulfonamidos) thiophenyl] -5- [(the fluoro- 4- methyl mercaptos phenyl of 2-) amino]-N- [(2,3- dihydroxies
Base) propyl] Pyrazinamide；
1- ({ 3- [(3- acetylaminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] pyridin-4-yl } carbonyl) -3-
(piperidin-2-yl) azetidine -3- alcohol.
The present invention also provides the methods of formula (Ia) compound, it includes the following steps：
Wherein, R4Selected from hydrogen ,-COR6、-SO2R6、-COOR6, R5For hydrogen；R6Selected from-C1-C4Alkyl ,-C1-C4Alkyl halide
Base ,-C3-C6Naphthenic base；R1And R2It is each independently selected from hydrogen, C1-C4Alkyl ,-O (CH2)2OH、Or R1And R2With
The nitrogen-atoms that they are connected is formed togetherR3Selected from halogen ,-S- (C1-C4Alkyl) or C1-C4Alkoxy.
With 3,5- difluoro isonicotinic acid for starting material, 3,5- difluoro isonicotinic acid are sent out with compound (b) under suitable conditions
Raw substitution reaction, obtains compound (c)；Compound (c) is condensed to yield general formula compound (d) in the presence of CDI with ammonium hydroxide；Chemical combination
With 3- sulfydryl phenylaminos t-butyl formate in the presence of a base organic solvent substitution reaction occurs for object (d), obtains compound (Ie)；Change
It closes object (Ie) and takes off Boc in organic solvent in presence of an acid and protect to obtain compound (If)；Compound (If) is in the presence of an organic base
Acylation reaction occurs with acyl chlorides or acid anhydrides in organic solvent, obtains compound (Ig)；Compound (Ig) hydrolysis obtains compound
(Ih)；Compound (Ih) is condensed to yield compound (Ia) in organic solvent in the presence of condensing agent, organic amine through acid amide.
The preparation method of formula (Ia) compound of the present invention, wherein compound (d) occur substitution reaction and obtain compound
(Ie), the alkali is to commonly use inorganic base, including but not limited to potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide etc.,
The organic solvent is common organic solvent, including but not limited to DMF, THF, DMSO, acetone etc.；Compound (Ie) takes off Boc and protects
Shield obtains compound (If), and the acid is described to commonly use organic acid or inorganic acid, including but not limited to hydrochloric acid, trifluoroacetic acid etc.
Organic solvent is common organic solvent, including but not limited to ethyl acetate, dichloromethane, DMF etc.；Compound (If) is through acylated
To compound (Ig), the organic base includes but not limited to pyridine, triethylamine etc., and the organic solvent is common organic solvent,
Including but not limited to dichloromethane, THF, DMF etc.；Compound (Ig) hydrolysis obtains compound (m), the hydrolysising condition include but
It is not limited to be hydrolyzed in acetic acid in the presence of sodium nitrite/concentrated sulfuric acid, hydrolyze in ethyl alcohol in the presence of sodium hydroxide etc.；
Compound (Ih) is condensed to yield compound (Ia) through acid amide, and the organic amine includes but not limited to DIPEA, TEA, the condensing agent
Including but not limited to HOBT/EDCI, HOBT/HATU, PyBOP, the organic solvent include but not limited to DMF, CH2Cl2、THF。
In another preparation method embodiment of the invention, the preparation method of compound V is as follows：
Using the bromo- pyridines of 2- as raw material, react with 1- tertbutyloxycarbonyl -3- aza cyclo-butanones in the presence of n-BuLi
Obtain compound (i)；Compound (i) obtains compound (j) through reduction；It is deprotected to obtain compound (a) with trifluoroacetic acid again.
Abbreviation noun in above-mentioned each preparation process indicates respectively：
THF tetrahydrofurans
CH2Cl2Dichloromethane
DMSO dimethyl sulfoxide (DMSO)s
DMF n,N-Dimethylformamide
DIPEA n,N-diisopropylethylamine
TFA trifluoroacetic acids
TEA triethylamines
CDI carbonyl dimidazoles
HOBT I-hydroxybenzotriazoles
EDCI 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
HATU 2- (7- azos benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid esters
PyBOP hexafluorophosphoric acid benzotriazole -1- bases-oxygroup tripyrrole alkyl
In the present invention, halogen refers to fluorine, chlorine, bromine, iodine etc., preferably fluorine, chlorine, bromine.
C1-C4Alkyl refer to methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl or tertiary butyl；It is preferred that first
Base, ethyl, propyl, isopropyl or butyl, more preferable methyl.
C1-C4Alkoxy refers to methoxyl group, ethyoxyl, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary
Butoxy or tert-butoxy；It is preferred that methoxyl group, ethyoxyl, n-propoxy, isopropoxy or n-butoxy；More preferable methoxy
Base.
-S-(C1-C4Alkyl) refer to methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio, Zhong Ding sulphur
Base or tertiary butylthio；It is preferred that methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl or butylthio, more preferable methyl mercapto.
C3-C6Naphthenic base is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；It is preferred that cyclopropyl.
C3-C8Naphthenic base is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl；It is preferred that cyclohexyl.
-C1-C4Halogenated alkyl refers to by one or more halogens, and preferably one to five halogen atom replaces as defined herein
C1-C4Alkyl, including but not limited to trifluoromethyl, trifluoroethyl, difluoromethyl, chloro- 2 fluoro ethyls of 1- etc..
Halogenated alkyl refers to by one or more halogens, the alkane as defined herein of preferably one to five halogen atom substitution
Base, including but not limited to trifluoromethyl, trifluoroethyl, difluoromethyl, chloro- 2 fluoro ethyls of 1- etc..
Alkyl refers to the straight chain saturation monovalent hydrocarbon of one to eight carbon atom or the branch saturation one of three to eight carbon atoms
Valency alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, butyl (including all isomeric forms), amyl are (including all
Isomeric form) etc..
Alkoxy refers to-OR groups, and wherein R is alkyl defined herein, including but not limited to methoxyl group, ethyoxyl, n-
Propoxyl group, isopropoxy, n-butoxy etc..
Naphthenic base refers to monocycle or fused bicyclic, saturation or part undersaturated (but non-aromatic), three to ten carbon
The monovalent hydrocarbon radical of annular atom.One or two ring carbon atom can be substituted by-C (O)-,-C (S)-or-C (=NH)-group.
The naphthenic base includes but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, hexamethylene -3- alkenyls etc..
Heterocyclylalkyl refers to the monovalent monocyclic base of saturation or part undersaturated (but non-aromatic) three to eight annular atoms
Group, or saturation or part undersaturated (but non-aromatic) five to 12 annular atoms monovalence fused bicyclic group, wherein one
For a or multiple ring hetero atoms independently selected from O, S, N, remaining annular atom is carbon.One or two ring carbon atom can be by-C
(O)-,-C (S)-or-C (=NH)-group substitute.The Heterocyclylalkyl includes but not limited to azete piperidinyl, pyrrolidinyl, piperazine
Piperidinyl, morpholinyl, piperazinyl, 2- oxopiperazinyls, THP trtrahydropyranyl, 2- oxo-piperidine bases, pyrazolidinyl, imidazolinyl, miaow
Oxazolidinyl, dihydropyridine base, tetrahydro pyridyl, oxazolinyl, oxazolidine radical, isoxazole alkyls, thiazolinyl, thiazolidinyl,
Octahydro indyl, octahydro isoindolyl, tetrahydrofuran base, tetrahydrochysene pyrrole feed base etc..
Aryl refers to aromatic ring alkyl, and preferably carbon atom number is 6 to 14, more preferably 6 to 10 aryl, such as benzene
Base and naphthalene, more preferable phenyl.
Heteroaryl refers to heteroatomic 5 to the 6 unit monocycle heteroaryl for being selected from N, S or O containing 1 to 4 or it is thick with phenyl ring
Made of dicyclic heteroaryl.The heteroaryl include but not limited to furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl,
Thiazolyl, isothiazolyl, oxazolyl, isoxazolyls, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, benzofuranyl, benzo thiophene
Pheno base, benzothiazolyl, benzimidazolyl, indyl, isoindolyl, quinolyl, isoquinolyl and quinazolyl, preferably imidazoles
Base, thiazolyl, pyrazinyl, benzimidazolyl and quinolyl.
The present invention also includes formula (I) compound pharmaceutically acceptable salt.Term " pharmaceutically acceptable salt " refers to
The acid-addition salts or base addition salts of the compounds of this invention of relative nontoxic.The acid-addition salts be formula (I) compound of the present invention and
The salt that suitable inorganic acid or organic acid are formed, these salt can be prepared in the last separation of compound and purification process, or
Person used can make formula (I) compound of purifying, and free alkali form is reacted with suitable organic acid or inorganic acid to make together
It is standby.Representative acid-addition salts include hydrobromate, hydrochloride, sulfate, sulphite, acetate, oxalates, valerate, oil
Hydrochlorate, palmitate, stearate, moon silicate, borate, benzoate, lactate, phosphate, toluate, lemon
Hydrochlorate, maleate, fumarate, succinate, tartrate, benzoate, mesylate, tosilate, grape
Sugar lime, Lactobionate and lauryl sulfonate etc..The base addition salts are formula (I) compound and suitable inorganic base or have
Machine alkali formed salt, including for example with alkali metal, alkaline-earth metal, quaternary ammonium cation formed salt, such as sodium salt, lithium salts, sylvite,
Calcium salt, magnesium salts, tetramethyl based quaternary ammonium salt, tetrem based quaternary ammonium salt etc.；Amine salt, including with ammonia (NH3), primary amine, secondary amine or tertiary amine formed
Salt, such as methylamine salt, dimethylamine salt, front three amine salt, triethylamine salt, ethylamine salt.
It includes people that the compound of the present invention, which can deliver medicine to mammal, can be taken orally, rectum, parenteral (intravenous, muscle
It is interior or subcutaneous), administration in local administration (pulvis, ointment or drops) or tumor.The compound can be administered alone, or
With other pharmaceutically acceptable compound administering drug combinations.It may be noted that the compound of the present invention can mix administration.
The present invention also provides pharmaceutical compositions, it contains formula (I) compound of the present invention or its pharmaceutically acceptable salt is made
For active constituent and pharmaceutically acceptable carrier, excipient or diluent.When preparing pharmaceutical composition, typically it incite somebody to action this
Invention formula (I) compound or its pharmaceutically acceptable salt are mixed with pharmaceutically acceptable carrier, excipient or diluent.
Routinely preparation method the present composition can be formulated as traditional drug formulations.Such as tablet, pill,
Capsule, powder, granule, emulsion agent, mixed floating agent, dispersion liquid, solution, syrup, elixir, ointment, drops, suppository,
Inhalant, propellant etc..
The present composition includes such as capsule, tablet, pill, powder and particle for the solid dosage forms of oral medication
Agent etc..In these solid dosage forms, formula (I) compound of the present invention is as active constituent and at least one conventional inert excipients
(or carrier) mixes, for example, with sodium citrate or Dicalcium Phosphate, or mix with following compositions：(1) filler or bulking agent, for example,
Starch, lactose, sucrose, glucose, mannitol and silicic acid etc.；(2) adhesive, for example, hydroxymethyl cellulose, alginates, gelatin,
Polyvinylpyrrolidone, sucrose and Arabic gum etc.；(3) moisturizer, for example, glycerine etc.；(4) disintegrant, such as agar, carbon
Sour calcium, potato starch or tapioca, alginic acid, certain composition silicates and sodium carbonate etc.；(5) retarding solvent, such as paraffin etc.；
(6) absorbsion accelerator, for example, quaternary ammonium compound etc.；(7) wetting agent, such as cetanol and glycerin monostearate etc.；(8) it inhales
Attached dose, for example, kaolin etc.；(9) lubricant, for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, 12
Or mixtures thereof sodium alkyl sulfate etc.,.It also may include buffer in capsule, tablet and pill.
Coating and shell material such as enteric can be used in the solid dosage forms such as tablet, sugar-pill, capsule, pill and granule
Clothing and other materials well known in the art are coated or microencapsulation.They may include opacifying agent, also, in this composition
The release of active constituent can discharge in certain part in the digestive tract in a delayed fashion.The example of adoptable embedding component
It is polymeric material and wax material.When necessary, active constituent also can be with one or more formation microcapsules in above-mentioned excipient
Form.
Present composition liquid formulation for oral administration include to learn acceptable lotion, solution, suspension,
Syrup and tincture etc..Other than as the formula of active constituent (I) compound, what liquid dosage form may include routinely using in this field
Inert diluent, such as water and other solvents, solubilizer and emulsifier, for example, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate,
Propylene glycol, 1,3-BDO, dimethylformamide and oils, especially cottonseed oil, peanut oil, maize germ, olive oil, castor
The mixture etc. of sesame oil and sesame oil etc. or these substances.
Other than these inert diluents, fluid present invention dosage form also may include conven-tional adjuvants, as wetting agent, emulsifier and
Suspending agent, sweetener, corrigent and fragrance etc..
The suspending agent includes, for example, ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and anhydro sorbitol only,
The mixture of microcrystalline cellulose, aluminium methoxide and agar etc. or these substances.
Dosage form of the present composition for parenteral injection may include physiologically acceptable sterile, aqueous or without water-soluble
Liquid, dispersion liquid, suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.
Suitable carrier, diluent, solvent or excipient includes water, ethyl alcohol, polyalcohol and its suitable mixture.
The preparation formulation of inventive mixture for local administration includes ointment, powder, suppository, drops, propellant
With inhalant etc..Formula (I) compound of the present invention as active constituent aseptically with physiologically acceptable carrier and
Optional preservative, buffer, or the propellant that may be needed when necessary are mixed together.
Therefore, the present invention also provides a kind of pharmaceutical preparations, it contains 1-1000mg formula (I) compounds of the present invention or its pharmacy
Upper acceptable salt and pharmaceutically acceptable carrier, excipient or diluent.
The present invention also provides a kind of methods for treating tumour.The tumour can be by inhibiting MEK activity to be able to mitigate or control
Treat, include to patient in need for the treatment of using 0.1-50mg/kg body weight/days formula (I) compound of the present invention or its pharmaceutically may be used
The step of salt of receiving.
Pass through cell experiment and zoopery, it was demonstrated that formula (I) compound of the present invention has cancer cell multiplication inhibiting effect, can
For treating cancer and the drug for treating cancer is prepared, the cancer includes but not limited to melanoma, breast cancer, colon
Cancer, the carcinoma of the rectum, non-small cell lung cancer or Small Cell Lung Cancer, liver cancer, kidney etc..
The compounds of this invention inhibits the drug effect of cancer cell multiplication that can be measured with conventional method, and a kind of preferred evaluation method is
Sulforhodamine B (SulforhodamIne B, SRB) protein staining method, produced by measuring drug effect after cancer cell
The variation of absorbance value calculate inhibiting rate of the drug to cancer cell multiplication.
Inhibiting rate (%)=[(blank control OD- dosing OD)/blank control OD] × 100%
Blank control OD：Refer to the OD values in the hole of the cell of no drug effect normal growth.
Dosing OD：Refer to the OD values in the hole for the cell that compound effects to be screened are added.
Half inhibitor concentration (IC50) value use 5.0 version of GraphPad companies PrIsm softwares, four parameter fitness methods
It calculates.Each experiment is repeated 3 times, and finds out the average IC of 3 experiments50Value is the final index of rejection ability.
It is tested by protein immunoblotting, also confirms that the compounds of this invention has MEK inhibitory activity, can effectively inhibit
The kinase activity of MEK.
Description of the drawings
Attached drawing 1 be -3 pairs of Raf-MEK-ERK signal path MEK phosphorylations of the compounds of this invention If-2 and Compound Ig per and
ERK inhibition of phosphorylation acts on lab diagram.
Attached drawing 2 is the human colon carcinoma under the compounds of this invention Ig-3 and positive control AZD6244 and GSK1120212 administration
HT-29 mice with tumor tumour growth curves.
Attached drawing 3 is the human colon carcinoma HCT116 lotus knurls under the compounds of this invention Ig-3 and positive control GSK1120212 administrations
Mouse tumour growth curve.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are only used for illustrating this
It invents rather than limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal
Rule condition, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise parts and percentages be respectively parts by weight and
Weight percent.
Specific implementation mode
I. the compounds of this invention prepares embodiment
Intermediary (a)：3- hydroxyls -3- (piperidin-2-yl) azetidine trifluoroacetate (a)
N-Boc-3- hydroxyls -3- (pyridine -2- bases) azetidine (i)
2- bromopyridines (1.57g, 10mmol) are dissolved in anhydrous THF, nitrogen protection is cooled to -78 DEG C, is slowly added dropwise
4.8mL2.5M n-butyllithium solution.It is stirred 1 hour at -78 DEG C, by 1-Boc- aza cyclo-butanones (1.71g, 10mmol)
10mLTHF solution is slowly added dropwise into reaction solution, and 1 hour is stirred at -78 DEG C, and i.e. the reaction was complete.It is quenched with saturated aqueous ammonium chloride
Go out, ethyl acetate extraction, anhydrous sodium sulfate drying, filtering is concentrated to give crude product, cross column purification (dichloromethane: methanol=100:
1) 1.8g products, yield 72% are obtained.
1HNMR (400MHz, CDCl3) δ 8.55-8.50 (m, 1H), 7.84 (td, J=7.8,1.7Hz, 1H), 7.70 (d, J=
8.0Hz, 1H), 7.31 (ddd, J=7.4,5.0,0.9Hz, 1H), 5.97 (br s, 1H), 4.32 (d, J=9.5Hz, 2H), 4.13
(d, J=9.5Hz, 2H), 1.50 (s, 9H).
N-Boc-3- hydroxyls -3- (piperidin-2-yl) azetidine (j)
2g N-Boc-3- hydroxyls -3- (pyridine -2- bases) azetidine (i) is dissolved in 100mL ethyl alcohol, 20mg is added
Platinum dioxide, in 60atm, 60 DEG C are reacted 40 hours, are crossed column and (dichloromethane: methanol=100: 1- methanol: triethylamine=100: 1) are obtained
To 1g products.
1H NMR (400MHz, CDCl3) δ 3.91 (dd, J=9.2,4.1Hz, 2H), 3.82 (t, J=9.5Hz, 2H), 3.19-
3.10 (m, 1H), 2.79-2.77 (m, 1H), 2.72-2.66 (m, 1H), 1.98-1.89 (m, 1H), 1.71-1.64 (m, 2H),
1.44 (s, 9H), 1.40-1.34 (m, 3H).
3- hydroxyls -3- (piperidin-2-yl) azetidine trifluoroacetate (a)
4ml dichloromethane is added in 500mg N-Boc-3- hydroxyls -3- (piperidin-2-yl) azetidine (j), under ice bath
It is cooling, 2ml trifluoroacetic acids are slowly added dropwise, warm naturally to room temperature reaction overnight, concentration, crude product is dissolved in toluene, is condensed into again
For the solid of viscosity, it is directly used in subsequent reactions.
Embodiment 1：3- [(3- t-butoxycarbonyl aminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide
(Ie-1)
It synthesizes to obtain compound (d-1) with reference to the preparation method of PCT Patent WO2012/055953 intermediates 2.A.Compound
(d-1) (0.35mmol), (3- sulfydryls benzene) ammonia t-butyl formate (0.455mmol), cesium carbonate (1.05mmol) is at DMF (7mL)
In 60 DEG C react 4 hours, be added 20ml water, extracted repeatedly with ethyl acetate 3 times, merge organic phase, saturated common salt water washing 2 times
Anhydrous sodium sulfate is dried afterwards.Preparative separation purifies to obtain solid 3- [(3- t-butoxycarbonyl aminos) thiophenyl] -5- [(fluoro- 4- of 2-
Iodophenyl) amino] Pyrazinamide (Ie-1) 0.25mmol, yield 71.4%.
ESI(+)m/z：581
Embodiment 2：3- (3- aminobenzene-thios) -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide (If-2)
Compound (Ie-1) (0.5mmol) is dissolved in 20ml ethyl acetate, and 5ml trifluoracetic acids are added at O DEG C, are stirred at room temperature
Overnight, 40ml saturated sodium bicarbonate solutions are added to neutralize, detach organic phase, organic phase anhydrous sodium sulfate is dried, and preparative separation is pure
Change obtains solid 3- (3- aminobenzene-thios) -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide (If-2) 0.41mmol, yield
It is 82%.
ESI(+)m/z：481
H1- NMR (deuterated DMSO)：δ 8.13 (s, 1H), δ 8.04 (s, 1H), δ 7.88 (d, 2H), δ 7.61 (d, 1H), δ
7.47 (s, 1H), δ 7.41 (d, 1H), δ 7.04 (t, 1H), δ 6.93 (t, 1H), δ 6.63 (s, 1H), δ 6.54 (dd, 2H), δ 5.30
(s, 2H).
Embodiment 3：3- [(3- acetylaminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide (Ig-3)
Compound (If-2) (0.26mmol) is dissolved in the in the mixed solvent of 3ml pyridines and 3ml dichloromethane, is added under ice bath
Chloroacetic chloride (0.52mmol).It is stirred at room temperature 5 hours, 1Oml water and 10ml dichloromethane is added, detach organic phase, organic phase is anhydrous
Sodium sulphate is dried.Preparative separation purifies to obtain solid 3- [(3- acetylaminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino]
Pyrazinamide (Ig-3) 0.21mmol, yield 81%.
ESI(+)m/z：523
H1- NMR (deuterated DMSO)：δ 10.05 (s, 1H), δ 8.18 (s, 1H), δ 8.07 (s, 1H), δ 7.90-7.93 (d,
2H), δ 7.68 (s, 1H), δ 7.59 (d, 1H), δ 7.51 (m, 2H), δ 7.42 (d, 1H), δ 7.32 (t, 1H), δ 7.05 (d, 1H), δ
6.96 (t, 1H), δ 7.05 (s, 3H).
Embodiment 4：3- [(3- methanesulfonamidos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide (Ig-
4)
Compound (If-2) (0.26mmol) is dissolved in the in the mixed solvent of 3ml pyridines and 3ml dichloromethane, is added under ice bath
Mesyl chloride (0.52mmol).Be stirred at room temperature 5 hours, 10ml water and 10ml dichloromethane be added, detach organic phase, organic phase without
Aqueous sodium persulfate is dried.Preparative separation purifies to obtain solid 3- [(3- methanesulfonamidos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-)
Amino] Pyrazinamide (Ig-4) 0.16mmol, yield 61.5%.
ESI(+)m/z：559
Embodiment 5：3- [(the third sulfonamido of 3- rings) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide
(Ig-5)
Compound (If-2) (0.26mmol) is dissolved in the in the mixed solvent of 3ml pyridines and 3ml dichloromethane, is added under ice bath
The third sulfonic acid chloride of ring (0.52mmol).It is stirred at room temperature 5 hours, 10ml water and 10ml dichloromethane is added, detach organic phase, organic phase
Anhydrous sodium sulfate is dried.Preparative separation purifies to obtain solid 3- [(the third sulfonamido of 3- rings) thiophenyl] -5- [(fluoro- 4- iodobenzenes of 2-
Base) amino] Pyrazinamide (Ig-5) 0.23mmol, yield 88%.
ESI(+)m/z：585
Embodiment 6：3- [(3- trifluoroacetamidos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide
(Ig-6)
Compound (If-2) (0.26mmol) is dissolved in the in the mixed solvent of 3ml pyridines and 3ml dichloromethane, is added under ice bath
Trifluoro-acetic anhydride (0.52mmol).It is stirred at room temperature 5 hours, 10ml water and 10ml dichloromethane is added, detach organic phase, organic phase
Anhydrous sodium sulfate is dried.Preparative separation purifies to obtain solid 3- [(3- trifluoroacetamidos) thiophenyl] -5- [(fluoro- 4- iodobenzenes of 2-
Base) amino] Pyrazinamide (Ig-6) 0.14mmol, yield 53.8%.
ESI(+)m/z：577
Embodiment 7：3- [(3- methanesulfonamidos) thiophenyl] -5- [(the fluoro- 4- methyl mercaptos phenyl of 2-) amino] Pyrazinamide
(Ig-7)
The synthetic method of 2 compound of reference implementation example (If-2), synthesis obtain compound (If-7).Compound (If-7)
(0.26mmol) is dissolved in the in the mixed solvent of 3ml pyridines and 3ml dichloromethane, and mesyl chloride (0.52mmol) is added under ice bath.
It is stirred at room temperature 5 hours, 10ml water and 10ml dichloromethane is added, detach organic phase, the drying of organic phase anhydrous sodium sulfate.It prepares and divides
Solid 3- [(3- methanesulfonamidos) thiophenyl] -5- [(the fluoro- 4- methyl mercaptos phenyl of 2-) amino] Pyrazinamide is obtained from purifying
(Ig-7) 0.19mmol, yield 73%.
ESI(+)m/z：479
Embodiment 8：(S) -3- [(3- acetylaminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino]-N- [(2,3- bis-
Hydroxyl) propyl] Pyrazinamide (Ia-8)
Compound (Ig-3) (0.38mmol) is suspended in 5ml acetic acid, is slowly added into the dense sulphur of sodium nitrite (0.5mmol)
Acid solution (0.25ml) is stirred at room temperature reaction and obtains compound (Ih-8) overnight.Compound (Ih-8) (0.09mmol), (S) -3-
Amino -1,2-PD (0.18mmol), PyBop (0.105mmol), DIPEA (0.6mmol) room temperature reaction in DMF (3mL)
Overnight.10ml water is added, is extracted repeatedly with ethyl acetate 3 times, merges organic phase, anhydrous sodium sulfate after saturated common salt is washed 2 times
It is dry.Preparative separation purifies to obtain solid (S) -3- [(3- acetylaminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] -
N- [(2,3- dihydroxy) propyl] Pyrazinamide (Ia-8) 0.045mmol, yield 50%.
ESI(+)m/z：597
Embodiment 9：(S) -3- [(3- methanesulfonamidos) thiophenyl] -5- [(the fluoro- 4- methyl mercaptos phenyl of 2-) amino]-N-
[(2,3- dihydroxy) propyl] Pyrazinamide (Ia-9)
The synthetic method of 4 compound of reference implementation example (Ig-4), synthesis obtain compound (Ig-9).Compound (Ig-9)
(0.31mmol) is dissolved in 10ml ethyl alcohol, and sodium hydroxide (0.45mmol) is added, and reflux obtains compound (Ih-9) in 3 hours.Change
Close object (Ih-9) (0.20mmol), (S) -3- amino -1,2-PD (0.40mmol), PyBop (0.26mmol), DIPEA
(1.0mmol) room temperature reaction in DMF (5mL) overnight, is added 10ml water, is extracted repeatedly with ethyl acetate 3 times, merges organic
Phase, anhydrous sodium sulfate is dried after saturated common salt is washed 2 times.Preparative separation purifies to obtain solid (S) -3- [(3- methanesulfonamidos)
Thiophenyl] -5- [(the fluoro- 4- methyl mercaptos phenyl of 2-) amino]-N- [(2,3- dihydroxy) propyl] Pyrazinamide (Ia-9)
0.12mmol, yield 60%.
ESI(+)m/z：553
Embodiment 10：1- ({ 3- [(3- acetylaminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] pyridin-4-yl }
Carbonyl) -3- (piperidin-2-yl) azetidine -3- alcohol (Ia-10)
Compound (Ih-8) (0.09mmol), intermediary (a) (0.18mmol), PyBop (0.11mmol), DIPEA
(0.92mmol) room temperature reaction in DMF (3mL) is stayed overnight.10ml water is added, is extracted repeatedly with ethyl acetate 3 times, merges organic
Phase, anhydrous sodium sulfate is dried after saturated common salt is washed 2 times.Preparative separation purifies to obtain solid 1- ({ 3- [(3- acetylaminos) benzene
Sulfenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] pyridin-4-yl } carbonyl) -3- (piperidin-2-yl) azetidine -3- alcohol (Ia-10)
0.035mmol, yield 38.8%.
ESI(+)m/z：662
(II) the compounds of this invention active testing embodiment
Testing example 1：The compounds of this invention is to application on human skin cancer cell (A375), human colon cancer cell (HT-29), human milk
Adenocarcinoma cell (MDA-MB-231) inhibited proliferation
Taking the cell inoculation in exponential phase, (cell concentration is 5000/hole in 96 orifice plates；180 μ of cell suspension
The holes l/), 37 DEG C, 5%CO2Culture keeps cell adherent in 24 hours.Each compound is dissolved in DMSO and is configured to 10mM's in advance
Storing liquid is diluted to 10 times of purpose concentration when detection with complete medium in another 96 orifice plate again, then thin in inoculation
20 holes μ l/ of compound are added in 96 orifice plates of born of the same parents, that is, reach purpose concentration.Each concentration sets 3 multiple holes, and sets blank control.
Continue in 37 DEG C, 5%CO2In continue culture 72 hours.Culture is terminated, 50% 3 chloroethene of 50 μ l precoolings (4 DEG C) is added per hole
Acid is TCA (final concentration 10%), is placed on 4 DEG C and fixes 1 hour, with purifying water washing at least 5 times, is spontaneously dried in air or 60
DEG C oven drying.100 μ l, room are added per hole by Sulforhodamine B, that is, SRB that 4mg/ml is prepared with the purified water containing 1% glacial acetic acid
Temperature dyeing 1 hour, abandons supernatant, and at least 5 times removing non-specific bindings, dried for standby are washed with 1% glacial acetic acid.150 μ are added per hole
The Tris-HCl solution of the 10mM of l dissolves, and OD values are surveyed at 510nm wavelength, and carries out data preparation and calculate inhibiting rate.As a result see
Table 1：
Table 1
Note：AZD6244 preparation methods are with reference to WO2003/077914 embodiments 10；GDC0973 preparation method references
WO2007/044515 embodiments 22
Test result shows：The compounds of this invention is to application on human skin cancer cell (A375), human colon cancer cell (HT-29), people
Breast cancer cell (MDA-MB-231) has good inhibited proliferation.Wherein -3 pairs of application on human skin cancer cells of Compound Ig per
(A375), human colon cancer cell (HT-29), human breast cancer cell (MDA-MB-231) inhibited proliferation are substantially better than AZD-
6244 and GDC-0973.
In the same way, B-RafV600 mutation colon cancer cell Colon205, K-Ras mutation human lung cancer cell A549,
Ig-3 compound on tumor is tested in colon cancer cell HCT116, pancreatic cancer cell MIA-Paca2 and non-small cell lung cancer H2122
Cell growth inhibition IC50 values, the results are shown in Table 2.
Table 2
Note：*：K-Ras mutation；#：B-Raf V600E mutation
Test result shows：The compounds of this invention Ig-3 is to B-RafV600 mutation colon cancer cells Colon205, K-Ras
It is mutated human lung cancer cell A549, colon cancer cell HCT116, pancreatic cancer cell MIA-Paca2 and non-small cell lung cancer H2122 tools
There is good inhibited proliferation, and is better than AZD6244.
Testing example 2：- 3 pairs of Raf-MEK-ERK signal transduction inhibiting effect of compound If-2 and Compound Ig per
Taking the human colon cancer cell (HT-29) in exponential phase to be seeded in 6 orifice plates, (cell concentration is 1 × 106
A/hole；Cell suspension 2ml complete mediums/hole), 37 DEG C, 5%CO2Culture keeps cell adherent in 24 hours.Positive compound
AZD6244, GSK1120212, test compound If-2 and Ig-3 are dissolved in the storage that 10mM is configured in DMSO in advance respectively
Liquid is diluted to 1000 times of purpose concentration when detection, then in inoculating cell with complete medium in another 6 orifice plates again
Compound is separately added into 6 orifice plates, achieve the goal concentration：
AZD624410nM, 50nM, 250nM；
GSK1120212 10nM, 50nM；
If-2 2nM, 10nM, 50nM；
Ig-3 2nM, 10nM, 50nM
Administration timing of drug is set to 2 hours.After cell administration stimulates 2 hours, the 1*SDS of 100 μ l is added per hole for Aspirate medium
Cell pyrolysis liquid, cell scraper are collected, are transferred in centrifuge tube with pipettor, 95 DEG C, 5min, and centrifuge 10000g centrifuges 5 points
Clock carries out electrophoretic analysis, and constant pressure 100V turns 2-3 hours, and albumen is gone to PVDF (polyvinylidinedifluoride) film
On.Pvdf membrane is taken out, 1-2min is rinsed in purified water, room temperature in confining liquid is put into and closes 1H.(confining liquid is to be prepared with TBST
5% skimmed milk power.) by 5%BSA (TBST preparations), as primary antibody in the advance hybridization bag of primary antibody dilution, is added, (p-ERK is anti-
Body, ERK antibody, P-MEK, MEK antibody) dilution ratio is 1: 1000 (Actin 1: 10000), then by the pvdf membrane after closing
It is cut, is put into corresponding hybridization bag by purpose band, sealed, 4 DEG C of overnight incubations.Primary antibody is recycled, hybond membrane is put into TBST
In, wash 6 × 5min of film.It regard 5% skimmed milk power (TBST preparations) as secondary antibody diluent, it is 1: 200- that primary antibody dilution ratio, which is added,
1: 500, then hybond membrane is put into corresponding secondary antibody (mountains coupling HRP- sheep anti mouse/rabbit monoclonal antibodies), it is incubated at room temperature 1H.Recycling
Primary antibody, hybond membrane are put into TBST, wash 6 × 5min of film.Developed with ECL luminescence reagent boxes, and tabletting.Test result is shown in attached drawing 1.
Test result shows：The compounds of this invention has good inhibiting effect to Raf-MEK-ERK signal transductions, right
The phosphorylation of MEK and ERK has different degrees of inhibiting effect.Wherein Ig-3 compounds are to ERK albumen phosphorus under 2nM concentration
Acidification has inhibition, and inhibition is suitable under 250nM concentration with AZD6244, while also having certain inhibition to MEK phosphorylations, and
AZD6244 is without this inhibiting effect.Compound Ig per -3 and GSK1120212 has the phosphorylation of MEK and ERK the suppression of equal extent
It makes and uses.
Testing example 3：To the growth inhibition effect of human colon carcinoma HT-29 nude mouse subcutaneous transplantation tumors
The antitumor action of evaluation test drug Ig-3 treatment human colon carcinoma HT-29 cell strain animal xenografts models and
Safety research.
Method：HT-29 cells are cultivated in the Mcloy's5A culture mediums added with 10%, are placed on 37 DEG C containing 5%CO2's
It is cultivated in constant incubator.The cell of exponential phase of growth and counting are collected, is resuspended with physiological saline, it is small to be inoculated in Balb/c-nu
The right dorsal scapular position of mouse, establishes human colon carcinoma heterograft model in situ.Back inoculation 6 × 10 on the right side of every mouse6Number
HT-29 cells.Wait for tumor average volume 128mm3When, it is grouped at random according to tumor size.Experiment is divided into test medicine Ig-3's
25mg/kgBID (twice a day) group, positive controls AZD624450mg/kg BID and GSK11202123mg/kg QD groups, often
14day is administered in group 6, oral administration gavage.Safety evaluatio is carried out according to the weight of animals variation and death condition, according to Relative tumor
Appreciation rate (T/C%) and tumour delay time carry out therapeutic evaluation.After tumor inoculation, routine monitoring includes tumour growth and controls
Influence to animal normal behaviour is treated, particular content has the activity of experimental animal, ingests and situation of drinking water, weight gain or drop
Low (weight measures weekly 2 times) situation, eyes, hair and other abnormal conditions.
Gross tumor volume calculation formula is：Major diameter × minor axis2/2。
Relative tumor proliferation rate T/C (%)：In sometime point, the percentage for the treatment of group and control group relative tumour volume
Value.T and C is respectively the relative tumour volume (RTV) for the treatment of group and control group in a certain particular point in time.Calculation formula is：T/
C%=TRTV/CRTV× 100%.(TRTV：Treatment group RTV；CRTV：Negative control group RTV).Evaluation criterion is：T/C (%)>40%
It is invalid；T/C (%)≤40%, and it is statistically analyzed P<0.05 is effective.
As a result：Testing drug Ig-3 (25mg/kg BID) treatment groups show tumor suppression work in administration last day
With T/C (%) is 13.2% respectively, compares negative control group statistically significant difference P<0.001；Positive control drug
AZD624450mg/kg BID groups and GSK1120212mg/kg QD administrations last day T/C (%) are 29.5% He respectively
8.9%, P value<0.001, positive control is effectively reliable.Four experimental group tumor growth curves are shown in attached drawing 2,
Test result shows：The compounds of this invention has the growth of human colon carcinoma HT-29 nude mouse subcutaneous transplantation tumors good
Good inhibiting effect, and show preferable safety.Testing drug Ig-3 shows good drug effect at 25mg/kg BID and makees
With, and toxicity is also in tolerance interval.
Testing example 4：To the growth inhibition effect of human colon carcinoma HCT116 nude mouse subcutaneous transplantation tumors
Evaluation test drug Ig-3 treatment KRas mutant human colon cancer HCT116 cell strain animal xenografts models
Antitumor action and safety research.
Method：HCT116 cells are cultivated in the Mcloy's5A culture mediums added with 10%, are placed on 37 DEG C containing 5%CO2's
It is cultivated in constant incubator.The cell of exponential phase of growth and counting are collected, is resuspended with physiological saline, it is small to be inoculated in Balb/c-nu
The right dorsal scapular position of mouse, establishes human colon carcinoma heterograft model in situ.Back inoculation 2.5 × 10 on the right side of every mouse6Number
HCT-116 cells.Wait for tumor average volume 200mm3When, it is grouped at random according to tumor size.Experiment is divided into test medicine Ig-3
25mg/kg BID (twice a day) and positive control drug GSK11202123mg/kg QD (once a day) groups and Vehicle controls
Group, every group 6,14day is administered in oral administration gavage.Safety evaluatio is carried out according to the weight of animals variation and death condition, according to phase
Therapeutic evaluation is carried out to tumour appreciation rate (T/C%) and tumour delay time.After tumor inoculation, routine monitoring includes tumour life
Influence long and that treatment is to animal normal behaviour, particular content have the activity of experimental animal, ingest and situation of drinking water, weight increase
Add or reduce (weight measures weekly 2 times) situation, eyes, hair and other abnormal conditions.
Gross tumor volume calculation formula is：Major diameter × minor axis2/2。
Relative tumor proliferation rate T/C (%)：In sometime point, the percentage for the treatment of group and control group relative tumour volume
Value.T and C is respectively the relative tumour volume (RTV) for the treatment of group and control group in a certain particular point in time.Calculation formula is：T/
C%=TRTV/CRTV× 100%.(TRTV：Treatment group RTV；CRTV：Negative control group RTV).Evaluation criterion is：T/C (%)>40%
It is invalid；T/C (%)≤40%, and it is statistically analyzed P<0.05 is effective.
As a result：Testing drug Ig-3 (25mg/kg BID) treatment groups show apparent tumor suppression in administration last day
Effect, T/C (%) is 12.6%, compares negative control group statistically significant difference P<0.001；Positive control drug
GSK11202123mg/kg QD groups administration last day T/C (%) is 7.8%, P values<0.001, positive control is effectively reliable.Three
A experimental group tumor growth curve is shown in attached drawing 3.
Test result shows：The compounds of this invention has the growth of human colon carcinoma HCT116 nude mouse subcutaneous transplantation tumors good
Good inhibiting effect, and show preferable safety.Testing drug Ig-3 shows good drug effect at 25mg/kg BID and makees
With, and toxicity is also in tolerance interval.
Referenced herein all documents are incorporated by reference in the application.Additionally it is noted that, readding
After having read the above disclosure of the application, those skilled in the art may not need away from the spirit and scope of the present invention, right
The present invention makes various modifications, change or modification, but these versions equally should all fall within the application the appended claims
Recorded range.
Claims (6)
1. a kind of lower formula (I) compound or its pharmaceutically acceptable salt：
In formula, R1And R2It is each independently selected from hydrogen；
R3Selected from halogen；
A is the phenyl with 1 substituent group selected from B group groups, wherein B group groups are-NR4R5；
R4For-COR6；
R5For hydrogen；
R6Selected from-C1-C4Alkyl.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that the compound is 3-
[(3- acetylaminos) thiophenyl] -5- [(the fluoro- 4- iodophenyls of 2-) amino] Pyrazinamide.
3. a kind of pharmaceutical composition, including (I) compound of formula described in claims 1 or 2 or its pharmaceutically acceptable salt and
Drug acceptable carrier, excipient or diluent.
4. compound as claimed in claim 1 or 2 answering in terms of the drug for preparing treatment mammalian hyper-proliferative disease
With.
5. application as claimed in claim 4, the mammal is the mankind.
6. application of the compound as claimed in claim 1 or 2 in terms of the drug for preparing treatment tumour.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1652776A (en) * | 2002-03-13 | 2005-08-10 | 阵列生物制药公司 | N3 alkylated benzimidazole derivatives as MEK inhibitors |
| CN1219753C (en) * | 2000-07-19 | 2005-09-21 | 沃尼尔·朗伯公司 | Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids |
| CN101065358A (en) * | 2004-10-20 | 2007-10-31 | 应用研究***Ars股份公司 | 3-arylamino pyridine derivatives |
| US20090012091A1 (en) * | 2007-07-02 | 2009-01-08 | Kinagen, Inc. | Oximide derivatives and their therapeutical application |
| CN101365676A (en) * | 2005-10-07 | 2009-02-11 | 埃克塞利希斯股份有限公司 | Azetidines as mek inhibitors for the treatment of proliferative diseases |
| WO2012000598A1 (en) * | 2010-07-01 | 2012-01-05 | Merck Patent Gmbh | Method for the preparation of cis-1,2-diols in the kilogram scale |
| CN103282351A (en) * | 2010-10-29 | 2013-09-04 | 拜耳知识产权有限责任公司 | Substituted phenoxypyridines |
-
2014
- 2014-01-16 CN CN201410019845.5A patent/CN104788365B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1219753C (en) * | 2000-07-19 | 2005-09-21 | 沃尼尔·朗伯公司 | Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids |
| CN1652776A (en) * | 2002-03-13 | 2005-08-10 | 阵列生物制药公司 | N3 alkylated benzimidazole derivatives as MEK inhibitors |
| CN101065358A (en) * | 2004-10-20 | 2007-10-31 | 应用研究***Ars股份公司 | 3-arylamino pyridine derivatives |
| CN101365676A (en) * | 2005-10-07 | 2009-02-11 | 埃克塞利希斯股份有限公司 | Azetidines as mek inhibitors for the treatment of proliferative diseases |
| US20090012091A1 (en) * | 2007-07-02 | 2009-01-08 | Kinagen, Inc. | Oximide derivatives and their therapeutical application |
| WO2012000598A1 (en) * | 2010-07-01 | 2012-01-05 | Merck Patent Gmbh | Method for the preparation of cis-1,2-diols in the kilogram scale |
| CN103282351A (en) * | 2010-10-29 | 2013-09-04 | 拜耳知识产权有限责任公司 | Substituted phenoxypyridines |
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Address after: 201203 floor 5, No. 1227, zhangheng Road, Shanghai pilot free trade zone and No. 1118, Halley Road Patentee after: Shanghai ALLIST medicine Polytron Technologies Inc. Address before: 201203, Zhangjiang hi tech park, Shanghai, Harley Road, No. 5, building 1118 Patentee before: SHANGHAI ALLIST PHARMACEUTICALS, Inc. |
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