CN102649773A - Amino aromatic hydrocarbon compound and application thereof to preparation of medicine for resisting malignant tumor - Google Patents

Amino aromatic hydrocarbon compound and application thereof to preparation of medicine for resisting malignant tumor Download PDF

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Publication number
CN102649773A
CN102649773A CN2011100427959A CN201110042795A CN102649773A CN 102649773 A CN102649773 A CN 102649773A CN 2011100427959 A CN2011100427959 A CN 2011100427959A CN 201110042795 A CN201110042795 A CN 201110042795A CN 102649773 A CN102649773 A CN 102649773A
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compound
prodrug
acceptable salt
pharmacologically acceptable
formula
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殷建明
朱惠霖
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SUZHOU BORUI PARMACEUTICALS Inc
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SUZHOU BORUI PARMACEUTICALS Inc
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Abstract

The invention relates to an amino aromatic hydrocarbon compound capable of serving as an active-mitogen-activated protein kinase/extracellular signal regulated kinase (ERK) 1/2 inhibitor and application of the amino aromatic hydrocarbon compound to preparation of a medicine for resisting malignant tumor. The amino aromatic hydrocarbon compound is a selective active-mitogen-activated protein kinase/ERK 1/2 inhibitor and can be used for preventing or treating malignant tumor, in particular for treating melanoma, colorectal cancer, breast cancer, pancreatic cancer, epidermoid tumor, brain tumor and liver cancer.

Description

Amino compound fragrant hydrocarbon and the purposes in the preparation anti-malignant tumor medicine thereof
Technical field
The present invention relates to a kind of amino compound fragrant hydrocarbon, it is mitogen activated protein kinase/ERK kinases 1/2 (MEK1/2) suppressor factor optionally; The invention still further relates to the purposes of said amino compound fragrant hydrocarbon in the preparation anti-malignant tumor medicine.
Background technology
(mitogen-activated protein kinases MAPKs) is intracellular one type of serine/threonine protein kitase to MAPK.The MAPKs signal transduction pathway is present in the most cells, in extracellular stimulus signal transduction to cell and nuclear thereof, and causes in the process of cytobiology reaction (like cell proliferation, differentiation, conversion and apoptosis etc.) to have crucial effects.MAPKs adopts three grades of kinase cascades of high conservative to transmit signal, splits plain activated protein kinase-kinases-kinases (MAPKK)-MAPKK-MAPK by activation sequence for silk, and they have constituted a successive activated pathway.MAPK signal cascade path can be transmitted to nucleus inside by the extracellular signal of surface receptor mediation.In MAPK cascade path, after accepting the extracellular token stimulus, extracellular signal-regulated kinase (extracellular signal regulated kinase, ERK) be unique can be in nuclear the accumulative material, mainly regulate the growth and the differentiation of cell.The acceptor of receptor tyrosine kinase, G albumen coupling and part cytokine receptor all can activate the ERK signal transduction pathway.MAPKs can promote vascular endothelial cell proliferation and neovascularity to generate.Can be tumour after neovascularity generates more nutrition is provided, quicken growth of tumor, promote the diffusion of cancer cells.
(Hepatocellular carcinoma HCC) is one of modal malignant tumour in the world to hepatocellular carcinoma.Research to the signal transduction pathway of HCC shows the unusual generation and the development of having participated in HCC of multiple signal transduction pathway; MAPKs is as an important pipeline of signal inside from the cell surface to the nucleus; In the signal transduction chain of liver cancer cell, relate to multiple signal transduction pathway; Having of playing a major role promotes the Ras-MAPK approach that cell proliferation and regulatory gene are transcribed and regulates the JAK-STAT approach that effector is transcribed; Wherein the MAPKs cascade reaction is the final common pathway of this two barss transduction pathway, and it is in key position, and this is the major cause of onset of liver cancer.
Summary of the invention
Technical problem to be solved by this invention provides the amino compound fragrant hydrocarbon that can be used as selectivity mitogen activated protein kinase/ERK kinases 1/2 suppressor factor, and it can be used for preventing and/or treating of malignant tumour.
For solving above technical problem, the present invention takes following technical scheme:
Compound with logical formula I, its pharmacologically acceptable salt or prodrug,
Figure BSA00000437913200021
In the formula I:
R 1Represent H ,-C nH m,-OC nH m,-OR 11,-F ,-Cl ,-Br or-I, wherein, R 11Representative-C nH mO ,-C nH mO 2,-C nH mN ,-C nH mNO or-C nH mNO 2, n is the integer between 1～12, m=2n-2, and 2n-1,2n or 2n+1, and m is more than or equal to 2;
R 2, R 3, R 4, R 5, R 6, R 7And R 8Be independently-C iH 2i+1,-C jH 2j-1,-F ,-Cl ,-Br or-I, wherein, i is the integer between 1～12, j is the integer between 2～12;
X represents N, C-C nH 2n+1, C-C nH 2n-1, C-F, C-Cl, C-Br or C-I;
Y representative-CONH-,-NHCO-,-NHSO 2-or-SO 2NH-;
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 1～12;
Perhaps, 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.
According to a preferred aspect of the present invention, the hydrogen of part at least in the said compound is replaced by deuterium.
According to the present invention, representational compound has the for example compound of formula II, formula III, formula IV and formula (V) expression.
According to the present invention, described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, PHENRAMINE MALEATE, benzene sulfonate, toluenesulfonate, fumarate, tartrate etc.
The compound that the present invention is above-mentioned; Its pharmacologically acceptable salt or prodrug are ideal mitogen activated protein kinase/ERK kinases 1/2 suppressor factor; It can suppress MAPK kinases 1 (mitogen-activated protein kinase kinase 1 (MAP2K1 or MAPK/ERK kinases 1), thereby the cell signaling that the inhibition growth factor is regulated 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 cell growth; This signal transduction pathway is in constitutively activate (constitutive activation) state in numerous tumours; Quicken growth of tumor, promote the diffusion of cancer cells.Thereby compound of the present invention can be used for treating the 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 used to prevent and/or treat and mitogen activated protein kinase/relevant indication of ERK kinase function.
The invention still further relates to and comprised one or more above-mentioned compounds, the pharmaceutical composition of its pharmacologically acceptable salt or prodrug, they can be used to prevent and/or treat and mitogen activated protein kinase/relevant indication of ERK kinase function.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
Compound first pass effect of the present invention is less, and effectively bioavailability is high, and it is few when the treatment indication relevant with mitogen activated protein kinase/ERK kinases (MEK1/2) function, to have a using dosage, the advantage that spinoff is little.
Embodiment
Below in conjunction with specific embodiment the present invention is done further detailed explanation, but the present invention is not limited to following examples.
Embodiment 1
The compound that present embodiment provides a kind of formula II to represent, it is an ideal MEK1/2 suppressor factor.
Figure BSA00000437913200041
Embodiment 2
The compound that present embodiment provides a kind of formula III to represent, ideal MEK1/2 suppressor factor.
Embodiment 3
The compound that present embodiment provides a kind of formula IV to represent, ideal MEK1/2 suppressor factor.
Figure BSA00000437913200051
Embodiment 4
Present embodiment provides the compound of a kind of formula (V) expression, ideal MEK1/2 suppressor factor.
Figure BSA00000437913200052
The foregoing description only is explanation technical conceive of the present invention and characteristics, and its purpose is to let the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences of doing based on spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.

Claims (9)

1. the compound that has logical formula I, its pharmacologically acceptable salt or prodrug,
Figure FSA00000437913100011
It is characterized in that: in the said formula I:
R 1Represent H ,-C nH m,-OC nH m,-OR 11,-F ,-Cl ,-Br or-I, wherein, R 11Representative-C nH mO ,-C nH mO 2,-C nH mN ,-C nH mNO or-C nH mNO 2, n is the integer between 1～12, m=2n-2, and 2n-1,2n or 2n+1, and m is more than or equal to 2;
R 2, R 3, R 4, R 5, R 6, R 7And R 8Be independently-C iH 2i+1,-C jH 2j-1,-F ,-Cl ,-Br or-I, wherein, i is the integer between 1～12, j is the integer between 2～12;
X represents N, C-C nH 2n+1, C-C nH 2n-1, C-F, C-Cl, C-Br or C-I;
Y representative-CONH-,-NHCO-,-NHSO 2-or-SO 2NH-;
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 1～12;
Perhaps, 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.
2. compound according to claim 1, its pharmacologically acceptable salt or prodrug is characterized in that: the hydrogen of part at least in the said compound is replaced by deuterium.
3. compound according to claim 2, its pharmacologically acceptable salt or prodrug is characterized in that: said compound be formula II, formula III, formula IV and formula (V) expression compound in a kind of.
Figure FSA00000437913100021
4. the described compound of each claim in the claim 1 to 3, its pharmacologically acceptable salt or prodrug are optionally being regulated mitogen activated protein kinase/ERK kinases 1/2 purposes aspect active.
5. the described compound of each claim in the claim 1 to 3, 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.
6. purposes according to claim 5 saidly comprises melanoma, colorectal cancer, mammary cancer, carcinoma of the pancreas, epidermoid, brain tumor and liver cancer with mitogen activated protein kinase/relevant indication of ERK kinases 1/2 function.
7. the described compound of each claim in the claim 1 to 3, the meta-bolites that its pharmacologically acceptable salt or prodrug form in any form.
8. the described meta-bolites of claim 7 prevents and/or treats the purposes in the indication medicine relevant with mitogen activated protein kinase/ERK kinases 1/2 function in preparation.
9. comprise the described compound of each claim in one or more claims 1 to 3, the pharmaceutical composition of its pharmacologically acceptable salt or prodrug.
CN2011100427959A 2011-02-23 2011-02-23 Amino aromatic hydrocarbon compound and application thereof to preparation of medicine for resisting malignant tumor Pending CN102649773A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11780862B2 (en) 2022-03-04 2023-10-10 Kinnate Biopharma Inc. Inhibitors of MEK kinase

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1446197A (en) * 2000-07-19 2003-10-01 沃尼尔·朗伯公司 Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids
WO2005040098A1 (en) * 2003-10-21 2005-05-06 Warner-Lambert Company Llc Polymorphic form of n-[(r)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
US20080058340A1 (en) * 2005-07-21 2008-03-06 Ardea Biosciences, Inc. Derivatives of n-(arylamino) sulfonamides as inhibitors of mek
WO2009036020A1 (en) * 2007-09-10 2009-03-19 Curis, Inc. Mek inhibitors containing a zinc binding moiety
CN101808516A (en) * 2007-07-30 2010-08-18 阿迪生物科学公司 The N-that comprises polymorph (virtue is amino) sulfamide derivative and composition, its using method and preparation method as mek inhibitor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1446197A (en) * 2000-07-19 2003-10-01 沃尼尔·朗伯公司 Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids
WO2005040098A1 (en) * 2003-10-21 2005-05-06 Warner-Lambert Company Llc Polymorphic form of n-[(r)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
US20080058340A1 (en) * 2005-07-21 2008-03-06 Ardea Biosciences, Inc. Derivatives of n-(arylamino) sulfonamides as inhibitors of mek
CN101808516A (en) * 2007-07-30 2010-08-18 阿迪生物科学公司 The N-that comprises polymorph (virtue is amino) sulfamide derivative and composition, its using method and preparation method as mek inhibitor
WO2009036020A1 (en) * 2007-09-10 2009-03-19 Curis, Inc. Mek inhibitors containing a zinc binding moiety

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11780862B2 (en) 2022-03-04 2023-10-10 Kinnate Biopharma Inc. Inhibitors of MEK kinase

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Application publication date: 20120829