CN102649778A - Quinazoline derivative and purposes thereof in preparing antineoplastic drugs - Google Patents

Quinazoline derivative and purposes thereof in preparing antineoplastic drugs Download PDF

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CN102649778A
CN102649778A CN2011100428078A CN201110042807A CN102649778A CN 102649778 A CN102649778 A CN 102649778A CN 2011100428078 A CN2011100428078 A CN 2011100428078A CN 201110042807 A CN201110042807 A CN 201110042807A CN 102649778 A CN102649778 A CN 102649778A
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compound
formula
hydrogen
prodrug
hydrate
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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 a novel quinazoline derivative and purposes thereof in preparing medicines capable of preventing/treating malignant tumours. The phenyl quinazoline compound is an ideal EGFR and HER2 kinase suppressing agent and can be used for treating breast cancers, ovarian cancers, colorectal cancers, lung cancers, head and neck squamous carcinomas, prostate cancers, nasopharynx cancers and various malignant tumours.

Description

Quinazoline derivant and the purposes in the preparation anti-malignant tumor medicine thereof
Technical field
The present invention relates to quinazoline derivant and prevent and/or treat the purposes in the medicine of malignant tumour in preparation.
Background technology
(HER1/erbB1) one of molecule the most representative in the receptor type tyrosine kinase of film is striden to EGF-R ELISA by family, has biological function widely for epidermal growth factor receptor, EGFR.Multiple part such as Urogastron and transforminggrowthfactor-can combine with EGFR extracellular part, the mitotic division signal is transmitted in cell, thereby cell cycle regulation is regulated the cell normal differentiation, promotes injury repairing.But EGFR also the vascular epidermis growth factor receptors in its downstream of activation (vascular epidermal growth factor receptor VEGFR), promotes the solid tumor Capillary network to form.Therefore EGFR plays an important role in generation, development, differentiation, reparation and the transfer of tumour cell.Research shows, in the tumour in multiple epithelial cell such as mammary cancer, large bowel cancer, lung cancer, Head and Neck squama cancer and carcinoma of the pancreas source, all exists abnormal activation, amplification and the over-expresses of EGFR gene.A lot of with EGFR as the research of treatment target spot, wherein with its monoclonal antibody and tyrosine kinase inhibitor (tyrosine kinase inhibitor, TKI) successful.TKI acts on the EGFR cell interior, combines with ATP is competitive, suppresses kinase whose activity and phosphorylation, thereby and sealing EGFR SRCA TP binding site reach the purpose of specificity inhibition EGFR.
Human epidermal growth factor acceptor-2 (human epidermal growth factor receptor; HER2/neu; ErbB-2) be a transmembrane receptor; Over-expresses in many epidermis tumours such as mammary cancer, ovarian cancer, prostate cancer, nonsmall-cell lung cancer, nasopharyngeal carcinoma etc., there is the over-expresses of HER2/neu gene in the primary breast cancer of about 25%-30%.
Summary of the invention
Technical problem to be solved by this invention provides a kind of quinazoline derivant; It is ideal EGFR and HER2 SU11752, can be used for treating multiple malignancy diseases such as mammary cancer, ovarian cancer, large bowel cancer, lung cancer, Head and Neck squama cancer, carcinoma of the pancreas, prostate cancer and nasopharyngeal carcinoma.
For solving above technical problem, the present invention takes following technical scheme:
Compound or pharmaceutically acceptable salt thereof, hydrate or prodrug with logical formula I,
Figure BSA00000437916000021
In the above-mentioned formula I:
Y represents N or C-CN;
R 1Be C 1～C 12Saturated alkyl or C 2～C 12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base, perhaps, R 1Representative-OR 11Or cyanic acid, wherein, R 11Be C 3～C 12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base ,-C nH 2n-1O ,-C nH 2nN ,-C nH 2nNO, C nH 2n+2N 2,-C nH 2n+2NO ,-C nH 2n+1N 2Or-C nH 2n+1N 2O, R 1In hydrogen not by or the part by or all be selected from deuterium, fluorine, chlorine, one or more elements in bromine and the iodine replace, n is the integer between 3～12;
R 2, R 3, R 4, R 7, R 8, R 9Be hydrogen or deuterium independently;
R 5Be fluorine, chlorine, bromine, iodine, cyanic acid, C 1～C 12Saturated alkyl or C 2～C 12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base;
R 6Be hydrogen, fluorine, chlorine, bromine, iodine ,-OC iH 2iC 6H 4X ,-OC iH 2iC 5H 4N ,-OC iH 2iC 4H 3N 2Or-OC iH 2iC 3H 2N 3, wherein X is for being selected from fluorine, chlorine, bromine, iodine ,-N (C mH 2m+1) 2,-N (C mH 2m+1) (CO C mH 2m+1) ,-OC mH 2m+1And-SC mH 2m+1In a kind of, i, m are the integer between 1～12;
R 10Representative-NR 12R 13, wherein, R 12, R 13Be hydrogen, C independently 1～C 12Saturated alkyl, C 2～C 12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base ,-C jH 2jN ,-C jH 2jNO ,-C jH 2j+1N 2,-C jH 2j+1N 2O and-C jH 2j-1N 2A kind of among the O, and R 12, R 13Be not hydrogen simultaneously; R 10In hydrogen not by or the part by or all replaced by deuterium, j is the integer between 3～12.
The another preferred aspect according to the present invention, R 12, R 13Be that part hydrogen is by the substituted C of deuterium independently 1～C 12Saturated alkyl, more specifically, R 12, R 13Be independently-CD 3,-CH 2CD 3,-CH 2CH 2CD 3And-CH 2CH (CD 3) 2In a kind of.
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 and contains one or more carbon carbon triple-linked straight chains, side chain or cyclic hydrocarbon radical; Described " Ene alkynyl base " except as otherwise noted, refers to and contains at least one carbon-carbon double bond and at least one carbon carbon triple-linked straight chain, side chain or cyclic hydrocarbon radical simultaneously.
According to the present invention, above-mentioned chemical group and representative example thereof can be referring to tables 1.
Table 1
Figure BSA00000437916000031
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.
Among the present invention, described " prodrug with compound of logical 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 a compound or its salt of structure formula I.
Be representative compound more of the present invention below:
Figure BSA00000437916000041
Quinazoline derivant provided by the invention is a kind of tyrosine kinase inhibitor; Combine with ATP is competitive through acting on the EGFR intracellular portion; Suppress kinase whose activity and phosphorylation, thereby and sealing EGFR SRCA TP binding site reach the purpose that specificity suppresses EGFR.Therefore The compounds of this invention can be used for preparing treatment or prevents the various indications relevant with the HER2 kinase function with EGFR, includes but not limited to multiple malignant tumours such as mammary cancer, ovarian cancer, large bowel cancer, lung cancer, Head and Neck squama cancer, carcinoma of the pancreas, prostate cancer and nasopharyngeal carcinoma.
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 the HER2 kinase function with EGFR, 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:
Figure BSA00000437916000051
Embodiment 2
The compound that present embodiment provides a kind of formula III to represent:
Embodiment 3
The compound that present embodiment provides a kind of formula IV to represent:
Figure BSA00000437916000053
Embodiment 4
Present embodiment provides the compound of a kind of formula (V) expression:
Figure BSA00000437916000061
Embodiment 5
The compound that present embodiment provides a kind of formula VI to represent:
Figure BSA00000437916000062
Embodiment 6
Present embodiment provides the compound of a kind of formula (VII) expression:
Figure BSA00000437916000063
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 or pharmaceutically acceptable salt thereof, hydrate or the prodrug that have logical formula I,
Figure FSA00000437915900011
It is characterized in that: in the said formula I:
Y represents N or C-CN;
R 1Be C 1～C 12Saturated alkyl or C 2～C 12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base, perhaps, R 1Representative-OR 11Or cyanic acid, wherein, R 11Be C 3～C 12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base ,-C nH 2n-1O ,-C nH 2nN ,-C nH 2nNO, C nH 2n+2N 2,-C nH 2n+2NO ,-C nH 2n+1N 2Or-C nH 2n+1N 2O, R 1In hydrogen not by or the part by or all be selected from deuterium, fluorine, chlorine, one or more elements in bromine and the iodine replace, n is the integer between 3～12;
R 2, R 3, R 4, R 7, R 8, R 9Be hydrogen or deuterium independently;
R 5Be fluorine, chlorine, bromine, iodine, cyanic acid, C 1～C 12Saturated alkyl or C 2～C 12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base;
R 6Be hydrogen, fluorine, chlorine, bromine, iodine ,-OC iH 2iC 6H 4X ,-OC iH 2iC 5H 4N ,-OC iH 2iC 4H 3N 2Or-OC iH 2iC 3H 2N 3, wherein X is for being selected from fluorine, chlorine, bromine, iodine ,-N (C mH 2m+1) 2,-N (C mH 2m+1) (COC mH 2m+1) ,-OC mH 2m+1And-SC mH 2m+1In a kind of, i, m are the integer between 1～12;
R 10Representative-NR 12R 13, wherein, R 12, R 13Be hydrogen, C independently 1～C 12Saturated alkyl, C 2～C 12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base ,-C jH 2jN ,-C jH 2jNO ,-C jH 2j+1N 2,-C jH 2j+1N 2O and-C jH 2j-1N 2A kind of among the O, and R 12, R 13Be not hydrogen simultaneously; R 10In hydrogen not by or the part by or all replaced by deuterium, j is the integer between 3～12.
2. compound or pharmaceutically acceptable salt thereof according to claim 1, hydrate or prodrug is characterized in that: R 12, R 13Be that part hydrogen is by the substituted C of deuterium independently 1～C 12Saturated alkyl.
3. compound or pharmaceutically acceptable salt thereof according to claim 2, hydrate or prodrug is characterized in that: R 12, R 13Be independently-CD 3,-CH 2CD 3,-CH 2CH 2CD 3And-CH 2CH (CD 3) 2In a kind of.
4. compound or pharmaceutically acceptable salt thereof according to claim 3, hydrate or prodrug is characterized in that: said compound is a kind of in the compound of formula II, formula III, formula IV, formula (V), formula VI and formula (VII) expression.
Figure FSA00000437915900021
In the claim 1 to 4 the described compound or pharmaceutically acceptable salt thereof of each claim, hydrate or prodrug in the purposes of optionally regulating aspect EGFR and the HER2 kinase activity.
6. the described compound or pharmaceutically acceptable salt thereof of each claim, hydrate or prodrug prevent and/or treat the purposes in the medicine of the indication relevant with EGFR and HER2 kinase function in preparation in the claim 1 to 4.
7. purposes according to claim 6 is characterized in that: saidly comprise mammary cancer, ovarian cancer, large bowel cancer, lung cancer, Head and Neck squama cancer, carcinoma of the pancreas, prostate cancer and nasopharyngeal carcinoma with EGFR and the relevant indication of HER2 kinases.
8. the meta-bolites that the described compound or pharmaceutically acceptable salt thereof of each claim, hydrate or prodrug form in any form in the claim 1 to 4.
9. the described meta-bolites of claim 8 prevents and/or treats the purposes in the medicine of the indication relevant with EGFR and HER2 kinase function in preparation.
CN2011100428078A 2011-02-23 2011-02-23 Quinazoline derivative and purposes thereof in preparing antineoplastic drugs Pending CN102649778A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104774184A (en) * 2015-04-17 2015-07-15 中国药科大学 Alpha-cyano-alpha, beta-unsaturated amide compound and medical application thereof
US9556191B2 (en) 2013-04-28 2017-01-31 Sunshine Lake Pharma Co., Ltd. Aminoquinazoline derivatives and their salts and methods of use thereof

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CN101180273A (en) * 2005-05-25 2008-05-14 惠氏公司 Methods of synthesizing 6-alkylaminoquinoline derivatives
CN101180269A (en) * 2005-05-25 2008-05-14 惠氏公司 Method of preparing 3-cyano-quinolines and intermediates made thereby
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CN101180269A (en) * 2005-05-25 2008-05-14 惠氏公司 Method of preparing 3-cyano-quinolines and intermediates made thereby
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WO2010130757A1 (en) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh New combination therapy in treatment of oncological and fibrotic diseases
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9556191B2 (en) 2013-04-28 2017-01-31 Sunshine Lake Pharma Co., Ltd. Aminoquinazoline derivatives and their salts and methods of use thereof
CN104774184A (en) * 2015-04-17 2015-07-15 中国药科大学 Alpha-cyano-alpha, beta-unsaturated amide compound and medical application thereof

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Application publication date: 20120829