CN103570594A - Diarylamine compound and application of diarylamine compound in preparation of anti-malignant tumour medicine - Google Patents

Diarylamine compound and application of diarylamine compound in preparation of anti-malignant tumour medicine Download PDF

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CN103570594A
CN103570594A CN201210269549.1A CN201210269549A CN103570594A CN 103570594 A CN103570594 A CN 103570594A CN 201210269549 A CN201210269549 A CN 201210269549A CN 103570594 A CN103570594 A CN 103570594A
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compound
formula
prodrug
acceptable salt
pharmacologically acceptable
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殷建明
朱惠霖
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METABOMICS Inc
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METABOMICS Inc
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Abstract

The invention relates to a diarylamine compound which can be used as a mitogen activated protein kinase/ERK (extracellular signal-regulated kinase) kinase 1/2(MEK1/2) inhibitor and application of the diarylamine compound in preparation of an anti-malignant tumour medicine. The diarylamine compound is a high-selectivity MEK1/2 kinase inhibitor and can be used for preventing or treating malignant tumour, especially for treating melanoma, colorectal cancer, breast cancer, pancreatic cancer, pancreatic cancer, epidermoid tumour, brain tumour and liver cancer.

Description

Diarylamine compounds and the purposes in preparing anti-malignant tumor medicine thereof
Technical field
The present invention relates to a kind of diarylamine compounds, it is mitogen activated protein kinase/ERK kinases 1/2 (MEK1/2) inhibitor of efficient selective; The invention still further relates to the purposes of described diarylamine compounds in preparing anti-malignant tumor medicine.
Background technology
Mitogen activated protein kinase (mitogen-activated protein kinases, MAPKs) is an intracellular class serine/threonine protein kitase.MAPKs signal transduction pathway is present in most cells, by extracellular stimulus signal transduction to cell and core thereof, and cause in the process of cytobiology reaction (as cell proliferation, differentiation, conversion and apoptosis etc.) to there is vital effect.MAPKs adopts three grades of kinase cascade transmission of signals of high conservative, by activation sequence, is that silk splits protein kinase-kinases-kinases (MAPKK)-MAPKK-MAPK that element activates, and they have formed a continuous activated pathway.MAPK signal cascade path can be transmitted to nucleus inside by the extracellular signal being mediated by surface receptor.In MAPK cascade path, after accepting extracellular signal stimulation, extracellular signal-regulated kinase (extracellular signal regulated kinase, ERK) is the unique material that can assemble in core, mainly regulates growth and the differentiation of cell.The acceptor of receptor tyrosine kinase, G albumen coupling and part cytokine receptor all can activate ERK signal transduction pathway.MAPKs can promote vascular endothelial cell proliferation and neovascularity to generate.Neovascularity can be tumour after generating more nutrition is provided, and accelerates the growth of tumour, promotes the diffusion of cancer cells.
Hepatocellular carcinoma (Hepatocellular carcinoma, HCC) is one of modal malignant tumour in the world.To studies show that of the signal transduction pathway of HCC, abnormal generation and the development that has participated in HCC of multi-signal Signal Transduction Pathways; MAPKs as signal from cell surface to one of nucleus inside important pipeline, in the signal transduction chain of liver cancer cell, relate to multi-signal transduction pathway, having of playing a major role promotes the Ras-MAPK approach that cell proliferation regulatory gene are transcribed and the JAK-STAT approach that regulates effector to transcribe, wherein MAPKs cascade reaction is the final common pathway of this two barss transduction pathway, it is in key position, and this is the major cause of onset of liver cancer.
Mitogen activated protein kinase/ERK kinases 1/2 (mitogen-activated ERK kinase1/2, MEK1/2) be a kind of Threonine/tyrosine dual specificity kinases, and be responsible for to regulate very crucial integral part in the RAS/RAF/MEK/ERK signal transduction pathway of Growth of Cells, in numerous tumours, this signal transduction pathway is in constitutively activate (constitutive activation) state, accelerate the growth of tumour, promote the diffusion of cancer cells.The MEK1/2 inhibitor that diarylamine compounds of the present invention is efficient selective, it can suppress mitogen activated protein kinase kinases 1 (mitogen-activated protein kinase kinase 1 (MAP2K1 or MAPK/ERK kinases 1), thereby the cell signaling that inhibition somatomedin regulates and the propagation of tumour cell specifically.
Summary of the invention
Technical problem to be solved by this invention is to provide the diarylamine compounds that can be used as selectivity mitogen activated protein kinase/ERK kinases (MEK) 1/2 inhibitor, and it can be for the preparation of the medicine preventing and/or treating of malignant tumour.
For solving above technical problem, the present invention takes following technical scheme:
The compound with general formula (I), its pharmacologically acceptable salt or prodrug,
In formula (I):
R 1represent hydrogen, C 1～C 12saturated alkyl or C 2～C 12unsaturated thiazolinyl or alkynyl or Ene alkynyl base, OC nh 2n+1, OC nh 2n-1, OC nh 2n+1o, OC nh 2n-1o, OC nh 2nn, OC nh 2n-2n, OC nh 2n-2nO, OC nh 2nnO 2, OC nh 2n-2nO 2, NH 2, N (C nh 2n+1) (C mh 2m+1), NH (C 6h 5), NH (C 6h 4w), NH (C 5h 4n), NH (C 5h 3nW), wherein, n and m are the integer between 1～12, and W is CF 3, CHF 2, CN, F, Cl, Br and I;
R 2, R 3, R 4, R 5, R 6, R 7and R 8be hydrogen independently, C 1～C 12saturated alkyl or C 2～C 12unsaturated thiazolinyl or alkynyl or Ene alkynyl base, CF 3, CHF 2, CN, F, Cl, Br or I;
R 9representative-C fh 2f+1o ,-C fh 2f+1o 2,-C fh 2f+1n 2,-C fh 2f+1n 2o ,-C fh 2f+1n 2o 2,-OC fh 2f+1o ,-OC fh 2f+1o 2,-OC fh 2f+1n 2,-OC fh 2f+1n 2o ,-OC fh 2f+1n 2o 2,-NC fh 2f+1n ,-NC fh 2f+1nO ,-NC fh 2f+1nO 2,-NC fh 2f+2o ,-NC fh 2f+2o 2,-NC fh 2f+2n 2,-NC fh 2f+2n 2o or-NC fh 2f+2n 2o 2, wherein, f is the integer between 2～12;
Or, R 9representative-C kh 2k-1o ,-C kh 2k-1o2 ,-C kh 2k-1n 2,-C kh 2k-1n 2o ,-C kh 2k-1n 2o 2,-OC kh 2k-1o ,-OC kh 2k-1o 2,-OC kh 2k-1n 2,-OC kh 2k-1n 2o ,-OC kh 2k-1n 2o 2,-NC kh 2k-1n ,-NC kh 2k-1nO ,-NC kh 2k-1nO 2,-C kh 2kn ,-C kh 2knO ,-C kh 2knO 2,-OC kh 2kn ,-OC kh 2knO ,-OC kh 2knO 2,-NC kh 2ko ,-NC kh 2ko 2,-NC kh 2kn 2,-NC kh 2kn 2o ,-NC kh 2kn 2o 2,-C kh 2k-2n ,-C kh 2k-2nO ,-C kh 2k-2nO 2,-OC kh 2k-2n ,-OC kh 2k-2nO or-OC kh 2k-2nO 2, wherein, k is the integer between 2～12.
X represents N, C-H, C-C nh 2n+1, C-C nh 2n-1, C-F, C-Cl, C-Br, C-I, C-CN, C-CF 3, C-CHF 2, C-CCH, C-OC nh 2n+1, C-OCF 3, C-OCHF 2, C-OCF 2cHF 2and C-OCF 2cF 3;
Y representative-CONH-,-NHCO-,-NHSO-,-SONH-,-NHSO 2-or-SO 2nH-;
Described diarylamine analog derivative, with and pharmacologically acceptable salt, hydrate, in the meta-bolites that prodrug or in any form metabolism form, the hydrogen of commutativity can be replaced by deuterium.
According to the present invention, representational compound has the compound that for example formula (III), formula (IV), formula (V) and formula (VI) represent.
Figure BDA00001959313700031
According to the present invention, described compound, it not only comprises certain single compound form, also comprise that various structures meets the form of mixtures of the compound of general formula (I) requirement, and such as racemic modification, enantiomer, diastereomer etc. of different isomerization bodily form formula of same compound.Described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, maleate, mesylate, benzene sulfonate, benzoic acid salt, toluenesulfonate, succinate, fumarate, fumarate, tartrate, gallate, Citrate trianion etc.It is described that " prodrug with the compound of general formula (I) " refers to a kind of material, after adopting appropriate means to use, can in subject, carry out metabolism or chemical reaction and be transformed at least one compound or its salt of structural formula (I).
According to the present invention, described " alkyl ", except as otherwise noted, refers to straight chain, side chain or cyclic hydrocarbon radical, and for example alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl etc.Described " thiazolinyl ", except as otherwise noted, refers to the straight chain, side chain or the cyclic hydrocarbon radical that contain one or more carbon-carbon double bonds, and for example thiazolinyl includes but not limited to vinyl, 2-propenyl, crotyl etc.Described " alkynyl ", except as otherwise noted, refers to the straight chain, side chain or the cyclic hydrocarbon radical that contain one or more carbon carbon triple bonds; Described " Ene alkynyl base " except as otherwise noted, refers to the straight chain, side chain or the cyclic hydrocarbon radical that contain at least one carbon-carbon double bond and at least one carbon carbon triple bond simultaneously.
Compound provided by the invention is a kind of MEK1/2 inhibitor of efficient selective, it can suppress mitogen activated protein kinase kinases 1 (mitogen-activated protein kinase kinase 1 (MAP2K1 or MAPK/ERK kinases 1), thereby the cell signaling that inhibition somatomedin regulates and the propagation of tumour cell specifically.MEK is a kind of Threonine/tyrosine dual specificity kinases, and be responsible for to regulate very crucial integral part in the RAS/RAF/MEK/ERK signal transduction pathway of Growth of Cells, in numerous tumours, this signal transduction pathway is in constitutively activate (constitutive activation) state, accelerate the growth of tumour, promote the diffusion of cancer cells.Thereby compound of the present invention can be used for treating treatment and the prevention of malignant tumour, particularly melanoma, colorectal cancer, mammary cancer, carcinoma of the pancreas, epidermoid, brain tumor and liver cancer.
The invention still further relates to above-mentioned compound, the meta-bolites that its pharmacologically acceptable salt or prodrug form in any form, they also can be for preventing and/or treating the indication relevant with mitogen activated protein kinase/ERK kinase function.
Due to the enforcement of above technical scheme, the present invention compared with prior art tool has the following advantages:
Compound first pass effect of the present invention is less, and effectively bioavailability is high, has using dosage few, the advantage that side effect is little when treating the indication relevant with MEK1/2 function.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the present invention is not limited to following examples.
Embodiment 1
The compound that the present embodiment provides a kind of formula (III) to represent:
Embodiment 2
The compound that the present embodiment provides a kind of formula (IV) to represent:
Figure BDA00001959313700052
Embodiment 3
The compound that the present embodiment provides a kind of formula (V) to represent:
Figure BDA00001959313700053
Embodiment 4
The compound that the present embodiment provides a kind of formula (VI) to represent:
Figure BDA00001959313700061
Above-described embodiment is only explanation technical conceive of the present invention and feature, and its object is to allow person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.

Claims (8)

1. the compound with general formula (I), its pharmacologically acceptable salt, hydrate, the meta-bolites that prodrug or in any form metabolism form,
It is characterized in that: in described formula (I):
R 1represent hydrogen, C 1～C 12saturated alkyl or C 2～C 12unsaturated thiazolinyl or alkynyl or Ene alkynyl base, OC nh 2n+1, OC nh 2n-1, OC nh 2n+1o, OC nh 2n-1o, OC nh 2nn, OC nh 2n-2n, OC nh 2n-2nO, OC nh 2nnO 2, OC nh 2n-2nO 2, NH 2, N (C nh 2n+1) (C mh 2m+1), NH (C 6h 5), NH (C 6h 4w), NH (C 5h 4n) or NH (C 5h 3nW), wherein, n and m are the integer between 1～12 independently, and W is CF 3, CHF 2, CN, F, Cl, Br and I;
R 2, R 3, R 4, R 5, R 6, R 7and R 8be hydrogen independently, C 1～C 12saturated alkyl or C 2～C 12unsaturated thiazolinyl or alkynyl or Ene alkynyl base, CF 3, CHF 2, CN, F, Cl, Br or I;
R 9representative-C fh 2f+1o ,-C fh 2f+1o 2,-C fh 2f+1n 2,-C fh 2f+1n 2o ,-C fh 2f+1n 2o 2,-OC fh 2f+1o ,-OC fh 2f+1o 2,-OC fh 2f+1n 2,-OC fh 2f+1n 2o ,-OC fh 2f+1n 2o 2,-NC fh 2f+1n ,-NC fh 2f+1nO ,-NC fh 2f+1nO 2,-NC fh 2f+2o ,-NC fh 2f+2o 2,-NC fh 2f+2n 2,-NC fh 2f+2n 2o or-NC fh 2f+2n 2o 2, wherein, f is the integer between 2～12;
Or, R 9representative-C kh 2k-1o ,-C kh 2k-1o 2,-C kh 2k-1n 2,-C kh 2k-1n 2o ,-C kh 2k-1n 2o 2,-OC kh 2k-1o ,-OC kh 2k-1o 2,-OC kh 2k-1n 2,-OC kh 2k-1n 2o ,-OC kh 2k-1n 2o 2,-NC kh 2k-1n ,-NC kh 2k-1nO ,-NC kh 2k-1nO 2,-C kh 2kn ,-C kh 2knO ,-C kh 2knO 2,-OC kh 2kn ,-OC kh 2knO ,-OC kh 2knO 2,-NC kh 2ko ,-NC kh 2ko 2,-NC kh 2kn 2,-NC kh 2kn 2o ,-NC kh 2kn 2o 2,-C kh 2k-2n ,-C kh 2k-2nO ,-C kh 2k-2nO 2,-OC kh 2k-2n ,-OC kh 2k-2nO or-OC kh 2k-2nO 2, wherein, k is the integer between 2～12;
X represents N, C-H, C-C nh 2n+1, C-C nh 2n-1, C-F, C-Cl, C-Br, C-I, C-CN, C-CF 3, C-CHF 2, C-CCH, C-OC nh 2n+1, C-OCF 3, C-OCHF 2, C-OCF 2cHF 2or C-OCF 2cF 3;
Y representative-CONH-,-NHCO-,-NHSO-,-SONH-,-NHSO 2-or-SO 2nH-;
Described diarylamine analog derivative, with and pharmacologically acceptable salt, hydrate, in the meta-bolites that prodrug or in any form metabolism form, the hydrogen of commutativity can be replaced by deuterium.
2. the compound with general formula (I) according to claim 1, its pharmacologically acceptable salt, hydrate, the meta-bolites that prodrug or in any form metabolism form, is characterized in that: in formula (I), R 6for I, R 8for F, X, Y, R 1, R 2, R 3, R 4, R 5, R 7and R 9definition with claim 1.
3. the compound with general formula (I) according to claim 1, its pharmacologically acceptable salt, hydrate, the meta-bolites that prodrug or in any form metabolism form, is characterized in that: in formula (I), X is C-OCF 3, Y is-SO 2nH-, R 4, R 5and R 7for hydrogen, R 1, R 2, R 3, R 6, R 8and R 9definition with claim 1.
4. the compound with general formula (I) according to claim 3, its pharmacologically acceptable salt, hydrate, the meta-bolites that prodrug or in any form metabolism form, is characterized in that: described compound is the compound that formula (II) represents:
Figure FDA00001959313600021
In formula (II), R 1, R 2, R 3and R 9definition with claim 1.
5. the compound with general formula (I) according to claim 1, its pharmacologically acceptable salt, hydrate, the meta-bolites that prodrug or in any form metabolism form, is characterized in that: described compound is a kind of in the compound that represents of formula (III), formula (IV), formula (V) and formula (VI).
Figure FDA00001959313600022
。
6. the compound described in any one claim in claim 1 to 5, its pharmacologically acceptable salt or prodrug prevent and/or treat the purposes in the medicine of the indication relevant with mitogen activated protein kinase/ERK kinases 1/2 function in preparation.
7. purposes according to claim 6, is characterized in that: the described indication relevant with mitogen activated protein kinase/ERK kinases 1/2 function comprises melanoma, colorectal cancer, mammary cancer, carcinoma of the pancreas, epidermoid, brain tumor and liver cancer.
8. purposes according to claim 6, is characterized in that: comprise with the combination of other relevant medicines and be jointly applied to clinical pharmaceutical composition, and with the combination clinical application of pharmaceutically available carrier.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109475729A (en) * 2016-07-21 2019-03-15 昂热大学 Implantable medical device for locally injecting
US11780862B2 (en) 2022-03-04 2023-10-10 Kinnate Biopharma Inc. Inhibitors of MEK kinase

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1867543A (en) * 2003-10-21 2006-11-22 沃纳-兰伯特公司 Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
TW201028381A (en) * 2008-07-14 2010-08-01 Shionogi & Co Pyridine derivative having ttk inhibition activity
CN102131771A (en) * 2008-04-14 2011-07-20 阿迪生物科学公司 Compositions and methods for preparing and using same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1867543A (en) * 2003-10-21 2006-11-22 沃纳-兰伯特公司 Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
CN102131771A (en) * 2008-04-14 2011-07-20 阿迪生物科学公司 Compositions and methods for preparing and using same
TW201028381A (en) * 2008-07-14 2010-08-01 Shionogi & Co Pyridine derivative having ttk inhibition activity

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109475729A (en) * 2016-07-21 2019-03-15 昂热大学 Implantable medical device for locally injecting
US11780862B2 (en) 2022-03-04 2023-10-10 Kinnate Biopharma Inc. Inhibitors of MEK kinase

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