CN103159742B - 5-chloropyrimide compounds and the application as EGFR tyrosine kinase inhibitor thereof - Google Patents
5-chloropyrimide compounds and the application as EGFR tyrosine kinase inhibitor thereof Download PDFInfo
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- CN103159742B CN103159742B CN201110425602.8A CN201110425602A CN103159742B CN 103159742 B CN103159742 B CN 103159742B CN 201110425602 A CN201110425602 A CN 201110425602A CN 103159742 B CN103159742 B CN 103159742B
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- JQRGHEJKLKKCRF-UHFFFAOYSA-N CN(CC1)CCC1NC(c(cc1)ccc1Nc(nc1)nc(Oc2cc(NC(C3)CN3C(C=C)=O)ccc2)c1Cl)=O Chemical compound CN(CC1)CCC1NC(c(cc1)ccc1Nc(nc1)nc(Oc2cc(NC(C3)CN3C(C=C)=O)ccc2)c1Cl)=O JQRGHEJKLKKCRF-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses EGF-R ELISA EGFR tyrosine kinase inhibitor, its structural formula is such as formula shown in (I).The present invention also discloses the purposes of any one compound and pharmacologically acceptable salts thereof shown in formula (I), and the present invention also provides treatment a kind of pharmaceutical composition, compound and EGFR conditioning agent shown in contained (I).
Description
Technical field
The present invention relates to field of medicaments, particularly EGFR tyrosine kinase inhibitor and application thereof.
Background technology
Cancer, also known as malignant tumour, has become serious harm human life and healthy second largest disease.According to statistics, in 6,600,000,000 populations of the whole world, annual new tumour patient about 1,000 ten thousand, about more than 500 ten thousand people dies from cancer, and such numeral is also presenting ever-increasing trend.The Ministry of Health of China " Cancer in China Prevention and controls planning outline (2004-2010) " specifies, 8 kinds of cancers totals such as lung cancer, liver cancer, cancer of the stomach, the esophageal carcinoma, colorectal cancer, mammary cancer, cervical cancer and nasopharyngeal carcinoma account for more than 80% of the cancer cause of the death, are that China is from now on by the major cancers of keypoint control.
Research finds, all has the overactive phenomenon of protein tyrosine kinase (PTK) signal path in the generation of most of tumour, development.The medicinal design undertaken by suppressing tyrosine kinase activity to reach inhibition tumor cell hyper-proliferative, the appearance of tyrosine kinase inhibitor (TKI), becomes the landmark progress of anti-cancer field.Especially the research of targeting epidermal growth factor receptor (EGFR) Tyrosylprotein kinase, achieves considerable progress in the past few decades.
EGFR signal transduction pathway plays an important role in the propagation of tumour cell, injury repairing, invasion and attack and new vessel formation etc.EGFR is a kind of transmembrane receptor, and EGF is incorporated into ectodomain, and receptors dimerize also activates tyrosine kinase domain in born of the same parents, causes the phosphorylation of kinases autophosphorylation and downstream molecules, activates the various kinds of cell function comprising propagation and survival.According to the different positions of drug effect at EGFR, mainly define two kinds of strategies, one acts on extracellular region, mainly monoclonal antibodies medicine; Another kind acts on catalysis region in born of the same parents, and interference ATP combines thus stops functional protein to carry out the micromolecular inhibitor of phosphorylation.
Lung cancer is the class malignant tumour that lethality rate is very high, lung cancer is divided into by histology small cell lung cancer (SCLC) and nonsmall-cell lung cancer (NSCLC), the latter comprises gland cancer, squamous cell carcinoma and large cell carcinoma etc., account for the 80-85% of lung cancer sum, about 65% such patient has belonged to late period (IIIB/IV) when making a definite diagnosis this disease, now, cancer cells has been invaded important organ or has been shifted, operative treatment cannot be taked, chemotherapy can only be considered, radiotherapy or Chinese medicine expectant treatment, current First-line chemotherapy is based on the two medicine chemotherapy regimens containing platinum medicine, but remission rate is less than 30%, rhuMAb-VEGF (vascular epidermal growth factor antibody) is used even if add, total survival median is still less than 12 months.Although docetaxel and pemetrexed have been used as the second line treatment of advanced NSCLC, often prognosis mala.
In recent years, molecular targeted therapy has become the new tool of oncotherapy, and it has efficiently, specific killing tumour cell, and normal tissue and the little feature of cell injury.In the understanding in depth of the molecule parting to lung cancer, continuous three the extensive Randomized controlled clinical study of NSCLC to EGFR sudden change: IPASS, WJTOG3405 and NEJ002, confirm a line in the NSCLC patient of EGFR sudden change and use the curative effect of EGF-R ELISA-tyrosine kinase inhibitor (EGFR-TKI) Gefitinib to be better than traditional platiniferous two medicine chemotherapy regimen.EGFR-TKI Gefitinib and Tarceva have gone through to be used as the NSCLC patient of a line platinum-based chemotherapy failure, play an important role in the treatment of EGFR saltant type NSCLC late.People observe from the clinical trial of Gefitinib and Tarceva, and they only treat sensitivity (Paez et al Scinece 2004 to the crowd of EGFR saltant type NSCLC; Lynch et al.NEJM 2004; Pao et al.PNAS 2004), this sudden change is the L858R sudden change that exons 19 lacks (E19del) and exon 21 more than 90%, such case is common in Asia, non-smoking, female patient, the EGFR mutation rate high (Shigematsu et al.JNCI 2005) of gland cancer especially bronchovesicular cancer and the high NSCLC of differentiation degree.
Research shows, the EGFR saltant type patient of about 75% is responsive to EGFR-TKI, and all the other insensitive sudden changes, as the insertion mutation of extron 20, are observed in the NSCLC case of 5%.In addition, using the NSCLC of Gefitinib or Tarceva treatment EGFR-TKI responsive type, all there is secondary resistance after the month in 6-12, and wherein about 50% comprises T790M sudden change (the Kosakaet al.CCR 2006 encoded by extron 20; Balak et al.CCR2006 and Engelman et al.Science), other sudden change (as D761Y, L747S, T845A) only accounts for less than 5%; In addition, also having an appointment 20% comprises MET oncogene and to increase the resistance caused, and wherein half also and deposit T790M sudden change.More than research shows, T790M sudden change is the major cause (Kobayashi et al.N.Engl.J.Med) to EGFR-TKIs resistance.In addition, research finds, containing KRAS (accounting for 15-25%) in NSCLC, BRAF sudden change (accounting for 2-3%) or ALK sudden change (accounting for 5%) is also insensitive to EGFR-TKI.
The EGFR of the two sudden change of L858R-T790M contrasts the EGFR of L858R single mutation, to ATP, there is higher avidity, namely T790M sudden change reduces the usefulness (Yun CH et al.PNAS) of the ATP such as Gefitinib and Tarceva competitive inhibitor, and so the appearance of resistance have also been obtained explanation.In order to overcome because T90M sudden change causes EGFR to the sudden change caused by the binding ability recovery of ATP, developing the emulative irreversible inhibitor of non ATP, be called s-generation EGFR-TKI, the compound that this class is being ground has HKI-272, BIBW2992, PF-00299804 etc., they can form covalent linkage with the Cys797 at the ATP binding pocket place of EGFR, all demonstrate the anti-T790M mutation effect being better than Gefitinib and Tarceva in vivo with in experiment in vitro.But clinical trial shows, the amplification produced immediately or high expression level T790M suddenly change the resistance that will cause these irreversible inhibitors; On the other hand, owing to being limited to pharmacokinetic profile, they are difficult to reach the concentration that can suppress needed for T790M sudden change clinically.WZ4002 is a kind of anilino-pyrimidine that adopts of report in 2009 is the new E GFR irreversible inhibitor (Wenjun Zhou et al.Nature) of parent nucleus, also referred to as third generation EGFR-TKI.In vivo with in experiment in vitro, it is better than the sudden change of independent medicaments insensitive (E19del or L858R) and Wild type EGFR the suppression of the two sudden change of EGFR E19del-T790M and L858R-T790M, therefore produces the toxic side effect such as fash and diarrhoea because suppressing Wild type EGFR in nonneoplastic tissue and can greatly reduce.The another kind of strategy for resistance is the inhibitor share other signal path of target, as conbined usage Mammals rapamycin target protein (mTOR) inhibitor everolimus, in addition, multiple dosage regimen of share has started preparation and has carried out clinical trial.
Summary of the invention
Present invention finds the irreversible inhibitor of a class EGFR Catastrophic selection, experiment in vitro shows its propagation that can suppress the two mutant clone H1975 of L858R-T790M under nanomolar concentration; Meanwhile, also there is very high inhibition strength to EGFR sensitive mutation cell strain HCC827 (Del E746_A750), then relatively weak to the suppression of Wild type EGFR cell strain A431.Therefore, this class formation not only can be used for the treatment of EGFR sensitive mutant cancer, is also applicable to the case producing secondary resistance during current EGFR-TKI treats; Meanwhile, its Catastrophic selection substantially reduces the toxic side effect produced because suppressing Wild type EGFR, is the ideal substitute of first-generation EGFR-TKI.
An object of the present invention is to provide the irreversible inhibitor of a class EGFR Catastrophic selection, is compound or its pharmacy acceptable salt of formula (I), solvate or prodrug:
Wherein, X is selected from O, NR
8or disappearance;
M is selected from 1 or 2;
N is selected from 1,2 or 3;
A ring and B ring are independently selected from C
5-8aryl or heteroaryl, C
3-8cycloalkyl, C
3-8heterocyclylalkyl, 8-14 unit condensed ring, and can not to be substituted or by one or more nitro, halogen, cyano group, C
1-6alkyl, the C of halogen substiuted
1-6alkyl, C
1-6alkoxyl group, the C of halogen substiuted
1-6alkoxyl group replaced;
R
1be selected from hydrogen, N (R
4) (R
5), N (R
4) CO (R
5), N (R
4) SO
2(R
5), N (R
4) SO (R
5), C (O) OR
4, C (O) N (R
4) (R
5), SO
2r
4, SOR
4, SR
4, SO
2nR
4r
5, OR
4, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
3-8heterocyclylalkyl, C
5-8aryl, C
5-8heteroaryl, C
3-8heterocyclylalkyl-C
1-6alkyl, C
3-8heterocyclylalkyl-C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl-SO
2-C
1-6alkyl, C
3-8heterocyclylalkyl-C
1-6alkyl-C
5-8aryl, heteroaryl or C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl-C
5-8aryl or heteroaryl, C
3-8heterocyclylalkyl-CO-C
1-6alkyl, C
3-8heterocyclylalkyl-C (O) N-C
1-6alkyl or C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl-CO
2-C
1-6alkyl, C
3-8heterocyclylalkyl-CO-C
3-8cycloalkyl or Heterocyclylalkyl, above each group can not be substituted or by one or more halogen, cyano group, amino, C
1-6the amido that alkyl replaces, C
1-6alkyl, the C of halogen substiuted
1-6alkyl, C
1-6alkoxyl group, the C of halogen substiuted
1-6alkoxyl group replaced;
R
2be selected from
R
3be selected from hydrogen, C
1-6alkyl, CO-C
1-6alkyl, CO-C
2-6thiazolinyl, CO-C
2-6alkynyl, the C of halogen substiuted
1-6alkyl, C
3-8cycloalkyl, C
3-8heterocyclylalkyl
R
4and R
5independently selected from hydrogen, C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
3-8heterocyclylalkyl, C
5-8aryl or heteroaryl, C
1-6alkyl-C
3-8heterocyclylalkyl, C
1-6alkyl-C
5-8aryl or heteroaryl, C
3-8heterocyclylalkyl-C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl-C
5-8aryl or heteroaryl.Wherein, R
4and R
5also can be connected to form 5-8 unit Heterocyclylalkyl, ring can not to be substituted or by one or more halogen, cyano group, amido, C
1-6the amido that alkyl replaces, C
1-6alkyl, the C of halogen substiuted
1-6alkyl, C
1-6alkoxyl group, the C of halogen substiuted
1-6alkoxyl group replaced;
R
6and R
7independently selected from hydrogen, halogen, C
1-6alkyl, C
3-8cycloalkyl, C
3-8heterocyclylalkyl, C
5-8aryl or heteroaryl, also can be connected to form C
3-8heterocyclylalkyl or cycloalkyl;
R
8be selected from hydrogen, C
1-6alkyl, the C of halogen substiuted
1-6alkyl, C
3-8cycloalkyl, C
3-8heterocyclylalkyl.
As preferably, compound provided by the invention or its pharmacy acceptable salt, solvate or prodrug, wherein compound is selected from formula (II):
Wherein A ring and B ring are independently selected from hexa-atomic virtue (mixing) ring, and can not be substituted or by one or more nitro, halogen, cyano group, C
1-6alkyl, C
1-6alkoxyl group replaced;
R
1be selected from hydrogen, N (R
4) (R
5), C (O) N (R
4) (R
5), C
3-8heterocyclylalkyl-C
1-6alkyl, C
3-8heterocyclylalkyl-C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl-SO
2-C
1-6alkyl, C
3-8heterocyclylalkyl-C
1-6alkyl-C
5-8aryl, heteroaryl or C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl-C
5-8aryl or heteroaryl, C
3-8heterocyclylalkyl-CO-C
1-6alkyl, C
3-8heterocyclylalkyl-C (O) N-C
1-6alkyl or C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl-CO
2-C
1-6alkyl, C
3-8heterocyclylalkyl-CO-C
3-8cycloalkyl or Heterocyclylalkyl, above each group can not be substituted or by one or more halogen, cyano group, amino, C
1-6the amido that alkyl replaces, C
1-6alkyl, the C of halogen substiuted
1-6alkyl, C
1-6alkoxyl group, the C of halogen substiuted
1-6alkoxyl group replaced;
R
2be selected from
R
3be selected from hydrogen, methyl;
R
4and R
5independently selected from hydrogen, C
1-6alkyl-C
3-8heterocyclylalkyl, R
4and R
5also can be connected to form 5-8 unit Heterocyclylalkyl, ring can not to be substituted or by one or more halogen, cyano group, amido, C
1-6the amido that alkyl replaces, C
1-6alkyl, the C of halogen substiuted
1-6alkyl, C
1-6alkoxyl group, the C of halogen substiuted
1-6alkoxyl group replaced.
Preferred, described compound or its pharmacy acceptable salt, solvate or prodrug, wherein compound is selected from formula (III)
X is selected from O, NH or disappearance;
M is selected from 1 or 2;
N is selected from 1 or 2; When and if only if m is 1, n is selected from 1,2 or 3;
K is selected from 1,2 or 3;
J is selected from 0,1 or 2;
R
9be selected from C
1-6alkyl, C
3-8cycloalkyl, C
3-8heterocyclylalkyl, C
5-8aryl or heteroaryl, CO-C
1-6alkyl, CO-C
3-8cycloalkyl, SO
2-C
1-6alkyl, C
1-6alkyl-C
5-8aryl or heteroaryl, CONH-C
1-6alkyl, CONH-C
3-8cycloalkyl, COO-C
1-6alkyl, COO-C
3-8cycloalkyl.
In a particular embodiment of the present invention, the compound provided or its pharmacy acceptable salt or solvate, described structural formula of compound is selected from:
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-N-(1-base base piperazine-4-base) benzamide
1-(3-(3-(the chloro-2-of 5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) the third-2-alkene-1-ketone
1-(4-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-ethyl piperazidine-1-base)-2-anisole amido) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-base) the third-2-alkene-1-ketone
7-(4-(3-(1-acryl azetidine-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one
1-(3-(3-(the chloro-2-of 5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(3,4-lupetazin-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-ethyl piperazidine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-morpholine anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-parathiazan anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(the fluoro-4-of 3-(4-methyl piperidine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-(methylsulfonyl) piperazine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-(2-(dimethylamine) ethyl) piperazine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(2-(4-(4-acetylpiperazine-1-base) anilino)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(2-(4-(4-benzyl diethylenediamine-1-base) anilino)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-phenylpiperazine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(2,6-dimethylated morpholinyl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(piperidin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-(cyclopropane carbonyl) piperazine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(3,5-lupetazin-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl amido) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(2-(4-methylpiperazine-1-yl) ethylamino-) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(piperazine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
4-(4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido) phenyl)-NEP-1-carboxamide
6-(4-(3-(acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-3,4-dihydronaphthalene-1 (2H)-one
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl amido) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino)-N, N-dimethyl azetidin-1-carboxamide
(E)-1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) but-2-ene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base)-3-methyl but-2-ene-1-ketone
Tertiary butyl 4-(4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido) phenylpiperazine-1-manthanoate
1-(3-(3-(2-(3-bromobenzene amido)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
Cell growth inhibition test shows, and in the present invention, section Example compound shows stronger inhibit activities to EGFR mutant cell, and shows more weak inhibit activities to EGFR wild-type cell, therefore has good selectivity to EGFR Mutant Cells; There is extremely weak restraining effect to Hs-27 human skin fibroblast in cytotoxicity experiment, therefore show lower cytotoxicity; EGFR kinase inhibition assay shows, contrast Wild type EGFR, and section Example has higher suppression selectivity to mutant egf R kinases; Stability study display in hepatomicrosome, compounds exhibit of the present invention goes out good Microsomal Stability.The compound of such as embodiment 2 and the embodiment 19 residue per-cent after hatching 60 minutes is more than 50%; Section Example compound in the present invention all only has faint suppression or unrestraint to various CYP enzyme, its half-inhibition concentration all higher than or close to 20 μMs.Compounds exhibit of the present invention goes out good bioavailability simultaneously.
The present invention also provides medicinal compositions, comprises compound described in above-mentioned any one or pharmacologically acceptable salts, solvate or prodrug and pharmaceutically acceptable carrier.
Another object of the present invention is the purposes of compound openly described in above-mentioned any one or its pharmacy acceptable salt, solvate or the prodrug purposes in the medicine of preparation regulation and control EGFR tyrosine kinase activity or the medicine at preparation treatment EGFR relative disease, as preferably, described EGFR relative disease is cancer, diabetes, disease of immune system, nerve degenerative diseases or cardiovascular disorder.
As preferably, described cancer is nonsmall-cell lung cancer, head and neck cancer, mammary cancer, kidney, carcinoma of the pancreas, cervical cancer, esophagus cancer, carcinoma of the pancreas, prostate cancer, bladder cancer, colorectal carcinoma, ovarian cancer, cancer of the stomach, brain cancer comprises glioblastoma etc., or their any combination.
The present invention also provides above-mentioned arbitrary compound or pharmaceutically acceptable salt thereof, solvate or the prodrug disease preparing treatment EGFR unconventionality expression or the purposes had during using EGFR modulators for treatment in the disease of acquired resistance.
Described acquired resistance is that the T790 encoded by EGFR extron 20 suddenlys change the resistance caused, as T790M.
In the present invention, EGFR conditioning agent refers to the small molecule tyrosine kinase inhibitors of targeting EGFR, as Gefitinib, and Tarceva, Conmana, lapatinibditosylate.
The present invention also provides a kind of medicinal compositions, comprise the compound described in above-mentioned any one or its pharmacy acceptable salt, solvate or prodrug and be selected from: Gefitinib, Tarceva, Conmana, lapatinibditosylate, XL647, NVP-AEE-788, ARRY-334543, EKB-569, BIBW2992, HKI272, BMS-690514, CI-1033, ZD6474, PF00299804, WZ4002, Cetuximab, Herceptin, Pa Ni dashes forward monoclonal antibody, horse trastuzumab, Buddhist nun's trastuzumab, prick Shandong wood monoclonal antibody, handkerchief trastuzumab, MDX-214, CDX-110, IMC-11F8, Zemab, Her2 vaccine PX 1041 and HSP90 inhibitor, CNF2024, KOS-953, Ah's Spiramycin Base, IPI-504, one or more the combination of SNX-5422 and NVP-AUY922, be used for the treatment of the disease of EGFR unconventionality expression, as cancer, diabetes, disease of immune system, nerve degenerative diseases or cardiovascular disorder.
Formula one compound as therepic use usually can with the form administration of pharmaceutical composition.
On the one hand, the invention provides formula (I) compound as medicine or its pharmacologically acceptable salts.On the other hand, the present invention also provides pharmaceutical composition, and it comprises formula (I) compound, pharmacologically acceptable salts and pharmaceutically acceptable carrier.
Usually, the compounds of this invention or its pharmacologically acceptable salts can form applicable formulation with one or more pharmaceutical carriers and use.These formulations are applicable to administration and other parenteral routes in oral, rectal administration, topical, mouth and use (such as, subcutaneous, muscle, vein etc.).Such as, the formulation being applicable to oral administration comprises capsule, tablet, granule and syrup etc.The compound of the present invention comprised in these preparations can be pressed powder or particle; Solution in water-based or non-aqueous liquid or suspension; Water-in-oil or oil-in-water emulsion etc.Above-mentioned formulation can be made up via general practice of pharmacy of active compound and one or more carriers or auxiliary material.Above-mentioned carrier needs and active compound or other auxiliary materials compatibility.For solid preparation, conventional non-toxic carrier includes but not limited to N.F,USP MANNITOL, lactose, starch, Magnesium Stearate, Mierocrystalline cellulose, glucose, sucrose etc.Carrier for liquid preparation comprises water, physiological saline, D/W, ethylene glycol and polyoxyethylene glycol etc.Active compound can form solution or suspension with above-mentioned carrier.
Concrete administering mode and formulation depend on compound itself physico-chemical property and apply the severity etc. of disease.
Compound of the present invention in some disease can with other drug combined utilization, to reach the result for the treatment of of expection.The example of a combined utilization is used to treat advanced NSCLC.Such as, compound shown in formula (I) can with mTOR inhibitors coupling (such as rapamycin); With Met inhibitor (comprising Met antibody MetMAb and Met micromolecular inhibitor PF02341066) coupling; With IGF1R inhibitor coupling (such as OSI-906); With heat shock protein inhibitors coupling etc.
On the one hand, compound of the present invention or formulation are applicable to warm blooded animal; On the other hand, compound of the present invention and formulation are applicable to Mammals, such as the mankind.
Composition of the present invention is prepared in the mode meeting medical practice specification, quantitative and administration.The factors such as " significant quantity " individuality by the concrete illness that will treat, treatment of compound, the cause of illness, the target spot of medicine and administering mode that give determine.Usually, generally through the dosage of parenteral administration be 1-100mg/kg.The formulation of oral administration can contain 1-500mg/kg compound of the present invention.
Term definition:
" alkyl ", as group or a part for other groups, the alkyl that the alkyl of such as halogen substiuted, hydroxyl replace can be straight chain or side chain.Such as, C1-6 alkyl represents the alkyl of 1 to 6 carbon, includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl.
" alkoxyl group " refer to alkyl and Sauerstoffatom link after generation group, include but not limited to methoxyl group, oxyethyl group, isopropoxy, ring propoxy-etc.
" halogen " refers to fluorine, chlorine, bromine and iodine.Particularly preferably be fluorine and chlorine.
" aryl " refers to the monocycle comprising six to ten carbon atoms or the aromatic ring condensed (such as phenyl and naphthyl).
" heteroaryl " refers to any condensing or the aromatic ring system of non-condensed, and wherein at least one ring is selected from heteroatomic five of nitrogen, oxygen and sulphur to octatomic ring containing 1-4, and preferably at least one heteroatoms is selected from nitrogen.Heteroaryl includes but not limited to thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzimidazolyl-, benzopyrazoles base, indyl etc.
" cycloalkyl " refers to the undersaturated monocycle of saturated or part, condensed ring or the bridged ring that comprise the carbon atom specified number.Such as, C3-8 cycloalkyl refers to the cycloalkyl of three to eight carbon, comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
" Heterocyclylalkyl " refers to the cycloalkyl defined in the present invention, and the carbon atom on wherein one or more rings is replaced by groups such as oxygen, nitrogen ,-NR-, sulphur, carbonyl ,-S (O)-or-S (O) 2; Heterocyclylalkyl includes but not limited to morpholinyl, piperazinyl, piperidyl, thio-morpholinyl etc.
" pharmacy acceptable salt " comprises the acceptable acid salt of pharmacy and the acceptable base addition salt of pharmacy." pharmaceutically acceptable acid salt " refers to the biological effectiveness that can retain free alkali and without other side effects, the salt formed with mineral acid or organic acid.Inorganic acid salt includes but not limited to hydrochloride, hydrobromate, vitriol, phosphoric acid salt etc.; Organic acid salt includes but not limited to formate, acetate, propionic salt, glycollate, gluconate, lactic acid salt, oxalate, maleate, succinate, fumarate, tartrate, Citrate trianion, glutaminate, aspartate, benzoate, mesylate, tosilate and salicylate etc.These salt are prepared by the method that this specialty is known.
The acceptable base addition salt of pharmacy, includes but not limited to that the salt of mineral alkali is as sodium salt, sylvite, calcium salt and magnesium salts etc.Include but not limited to the salt of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginic acid salt etc.These salt are prepared by the method that this specialty is known.
Inhibitor: refer to can with receptors bind (such as EGFR), and suppress this receptor to play the compound of physiological action.
Pharmaceutical compositions: refer to a kind of combination, comprise the acceptable auxiliary material of pharmacy or the carrier of at least one compound of the present invention and at least one.Pharmaceutical compositions can be prepared by the method that this specialty is known.
Treatment effective dose: refer to and can produce the active compound of physiology or pharmacological action or the amount of pharmaceutical compositions in animals or humans body.The effect that effective dose produces generally includes prophylactic generation, suppresses the progress of disease or alleviates the symptom of disease.Effective dose is usually by investigator, and doctor or other healthcare givers decide.
Some formula (I) compound can exist more than a kind of crystal formation, the present invention includes various crystal formation and composition thereof.
" solvate " mentioned in the present invention refers to the title complex that compound of the present invention and solvent are formed.They or in a solvent reaction or from solvent Precipitation or crystallize out.Such as, a title complex formed with water is called " hydrate ".The solvate of formula (I) compound belongs within the scope of the invention.
Compound shown in formula (I) can contain one or more chiral centre, and exists with different optical active forms.When compound contains a chiral centre, compound comprises enantiomer.The present invention includes the mixture of these two kinds of isomer and isomer, as racemic mixture.Enantiomer can be split by the method that this specialty is known, the such as method such as crystallization and chiral chromatography.When formula one compound contains more than one chiral centre, diastereomer can be there is.The present invention includes the mixture of optically pure specific isomer and the diastereomer split.Diastereomer can be split by this professional currently known methods, such as crystallization and preparative chromatography.
The present invention includes the prodrug of above-claimed cpd.Prodrug comprises known amino protecting group and carboxyl-protecting group, is hydrolyzed in physiological conditions or obtains parent compound via enzyme reaction release.Concrete front medicament preparation can refer to (Saulnier, M.G.; Frennesson, D.B.; Deshpande, M.S.; Hansel, S.B and Vysa, D.M.Bioorg.Med.Chem Lett.1994,4,1985-1990.Greenwald, R.B.; Choe, Y.H.; Conover, C.D.; Shum, K.; Wu, D.; Royzen, M.J.Med.Chem.2000,43,475.).
Embodiment
The invention discloses the preparation method of a compounds and compound, medicine composition and treatment plan, those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Product of the present invention, method and application are described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope methods and applications as herein described are changed or suitably change with combination, realize and apply the technology of the present invention.
Disclosure sets forth a compounds, they, to the cancer of EGFR dependent process LAN, have therapeutic efficiency.In addition, these compounds preparation method, medicine composition and treatment plan be also described.
In order to make those skilled in the art understand technical scheme of the present invention better, below in conjunction with specific embodiment, the present invention is described in further detail.
Syntheti c route
Compound in the present invention easily can be prepared by multiple synthetic operation, and these operations are that one of ordinary skill in the art grasp when skilled.The specific preparation method of these compounds includes, but is not limited to flow process hereinafter described.
Flow process 1
The chlorine that pyrimidine is 2 replaces with amine, needs at a certain temperature, uses suitable catalyzer and suitable solvent just can carry out.Use acid catalysis, catalyzer can be but be not limited to TFA or tosic acid.Use Buchwald-Hartwig amination method, palladium catalyst used can be but be not limited to Pd
2(dba)
3, part used can be but be not limited to BINAP, and alkali used can be but be not limited to potassium tert.-butoxide.
Flow process 2
The derivative that pyrimidine 4 replaces with arylamine and azacycloalkyl ketone carry out ammonification reduction reaction, and used original reagent of going back can be but be not limited to acetic acid sodium borohydride, need use ice bath temperature control during use.Further alkylation, optional corresponding halohydrocarbon, acyl chlorides etc. are as raw material, and prerequisite ensures R
2upper without sensitive group participation reaction.
Flow process 3
This nitro-compound is converted into corresponding amino-complex and can in acid condition, reduces with metal (can be but be not limited to iron powder, zinc powder).
Flow process 4
With 2,4,5-trichloropyrimidine for starting raw material, multiple functional group can be introduced at its 4 with different conditions.Phenol and arylamine can, under acid binding agent (can be but be not limited to DIEA) exists, realize transforming in alcohol.Phenols at room temperature can complete reaction smoothly, and the introducing of arylamine generally needs to carry out at a certain temperature.Pyrimidine 4 directly replaces with aromatic ring, and can adopt Suzuki linked reaction condition, carry out coupling with corresponding phenylo boric acid, catalyzer can be but be not limited to tetrakis triphenylphosphine palladium.
Flow process 5
The nitro of this compounds is reduced, realizes by catalytic hydrogenation.
Flow process 6
To nitro halobenzene and ring secondary amine, under proper temperature (heating or microwave), solvent condition, carry out substitution reaction.Alternative method also has Buchwald-Hartwig amination method.
Flow process 7
The azacycloalkyl ketone of Boc protection removes Boc in acid condition, and form hydrochloride, in the basic conditions, can be condensed into acid amides with corresponding acyl chlorides, this conversion needs to complete in a suitable solvent.
The preparation of embodiment 1, compound
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1:3-(2,5-dichloro pyrimidine-4-base oxygen base) aniline
By 2,4,5-trichloropyrimidine (3.67g, 20mmol), a hydroxyl oil of mirbane (2.78g, 20mmol) and diisopropyl ethyl amine (7mL, 40mmol) join in 30mL dehydrated alcohol respectively.Stirred at ambient temperature, system becomes muddy gradually, visible a large amount of rice white Precipitation, and after 2 hours, thin-layer chromatography monitoring display raw material transforms substantially completely.Decompress filter, filter cake n-hexane twice, obtains 5.32g (93%) beige solid after drying.
This white solid is all dissolved in 30mL tetrahydrofuran (THF), add zinc powder (6g, 93mmol), water (8mL) and ammonium chloride (5g, 93mmol) reflux 5 hours, thin-layer chromatography monitoring display is without raw material point, let cool, cross solid residues such as filtering excessive zinc powder, filtrate reduced in volume adds 50mL acetic acid ethyl dissolution except after organic solvent, wash twice with saturated aqueous common salt, separate organic layer, after anhydrous sodium sulfate drying, concentrated, the white solid product 4.0g (84.2%) of decompression purification by column chromatography (n-hexane/ethyl acetate=6/1).MS(m/z)256.1(M+1)。
2:1-acryl azetidin-3-ketone
By 1-tertbutyloxycarbonyl azetidin-3-ketone (3.66g, 21.4mmol) be dissolved in 20mL dioxane, slowly pass into hydrogen chloride gas 2 hours, filter to obtain white solid, use a small amount of n-hexane, after drying, obtain white solid 2.07g (90.2%).
This white solid (1g, 9.3mmol) is dissolved in the mixing solutions of tetrahydrofuran (THF) (15mL) and water (10ml), slowly adds sodium bicarbonate (1.72g, 20.5mmol).Under ice bath, in 30 minutes, drip the tetrahydrofuran solution (20mL) of acrylate chloride (756 μ L, 9.3mmol).Ice bath.After reaction 5h, decompression steams organic solvent, adds diluted ethyl acetate, after a small amount of brine It, after organic over anhydrous dried over sodium sulfate, concentrates to obtain yellow oil product 1.1g (94.5%), and this purity can be directly used in next step reaction.
3:1-(3-(3-(2,5-dichloro pyrimidine-4-base oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
By 3-(2; 5-dichloro pyrimidine-4-base oxygen base) aniline (2.25g; 8.8mmol); 1-acryl azetidin-3-ketone and anhydrous sodium sulphate (6.24g; 44.0mmol) be dissolved in 15mL acetic acid, under ice-water bath temperature control, slowly add acetic acid sodium borohydride (2.05g, 9.7mmol); keep temperature less than 10 DEG C, reaction is spent the night.After decompression steams most of acetic acid, system add water 15mL dilution, pH is neutralized to for about 7 with saturated sodium bicarbonate aqueous solution, be extracted with ethyl acetate (3 × 15mL), merge organic phase, with anhydrous sodium sulfate drying, after concentrated, normal pressure pillar layer separation (methylene chloride/methanol=50/1) obtains white solid 2.68g (83.8%).MS(m/z)365.2(M+1)，387.1(M+23)。
4:4-(4-methylpiperazine-1-yl) aniline
By parachloronitrobenzene (20g, 127mmol) with methylpiperazine (25.4g, 254mmol) mix, after stirring makes solid all dissolve, react after 4 hours at 90 DEG C, reaction solution impouring is about in 200mL frozen water, separate out a large amount of yellow solid, suction filtration, filter cake washes with water, obtains yellow solid 27.9g (99.3%) after drying.
This yellow solid (100mg, 0.45mmol) be dissolved in methyl alcohol (15mL), add 10% palladium carbon (10mg), react 2 hours in a hydrogen atmosphere, substrate transforms substantially completely, cross and filter palladium carbon, filtrate evaporate to dryness concentrates to obtain yellow liquid 89mg (100%).MS(m/z)192.0(M+1)。
5:1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
By 1-(3-(3-(2,5-dichloro pyrimidine-4-base oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone (170mg, 0.465mmol), 4-(4-methylpiperazine-1-yl) aniline (89mg, 0.465mmol), join in 2-butanols (15mL), add trifluoroacetic acid (104 μ L, 1.395mmol) and reflux 20 hours afterwards.After system saturated sodium bicarbonate is neutralized to neutrality, thin up, with extraction into ethyl acetate (2 × 15mL), after merging organic phase, with saturated common salt water washing, after anhydrous sodium sulfate drying, concentrated, with high-efficient liquid phase chromatogram purification after frequent compression leg chromatogram preliminary purification (methylene chloride/methanol=15/1), obtain white solid 42.77mg (17.7%).
1HNMR 300MHz(CDCl
3)δ8.15(s，1H)，7.28-7.32(m，1H)，7.16(d，J＝8.7Hz，2H)，6.70(d，J＝8.7Hz，2H)，6.57(dd，J＝1.5Hz，J＝14.1Hz，1H)，6.62(d，J＝8.1Hz，1H)，6.31(d，J＝17.1Hz，1H)，6.15(s，1H)，6.10(dd，J＝14.1Hz，J＝10.2Hz，1H)，5.68(dd，J＝1.5Hz，J＝10.2Hz，1H)，4.45(t，J＝8.1Hz，J＝15.9Hz，1H)，4.31-4.36(m，1H)，4.17-4.20(m，1H)，3.73-3.83(m，2H)，3.59-3.61(m，2H)，3.40-3.41(m，4H)，3.07-3.09(m，2H)，2.88(s，3H).MS(m/z)：520.3(M+1)。
The preparation of embodiment 2, compound
4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-N-(1-base base piperazine-4-base) benzamide
1:4-amido-N-(1-methyl piperidine-4-base) benzamide
By 1-methyl piperidine-4-amine (228mg, 2mmol), p-nitrobenzoic acid (335mg, 2mmol) and diisopropyl ethyl amine (1.04mL, 6mmol) are dissolved in N, in N-N,N-DIMETHYLACETAMIDE (10mL), after separately HATU (1.14g, 3.0mml) being dissolved in N,N-dimethylacetamide (10mL), join in above-mentioned reaction solution, react 3 hours under room temperature.Decompression steams N, N-N,N-DIMETHYLACETAMIDE, add saturated sodium bicarbonate aqueous solution (100mL), cross and filter insolubles, aqueous phase with in 2N hydrochloric acid and after with dichloromethane extraction, organic phase is used and saturated common salt water washing, and after anhydrous sodium sulfate drying, normal pressure purification by column chromatography obtains light yellow solid 500mg (95.0%).
Light yellow solid obtained above (500mg) is dissolved in methyl alcohol (25mL), add 10% palladium carbon (50mg), react 2 hours in a hydrogen atmosphere, substrate transforms substantially completely, cross and filter palladium carbon, filtrate evaporate to dryness concentrates to obtain yellow liquid 440mg (99.3%).MS(m/z)234.0(M+1)。
2:4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-N-(1-base base piperazine-4-base) benzamide
By 1-(3-(3-(2,5-dichloro pyrimidine-4-base oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone (186mg, 0.51mmol), 4-amido-N-(1-methyl piperidine-4-base) benzamide (120mg, 0.51mmol), join in 2-butanols (15mL), add trifluoroacetic acid (76 μ L, 1.02mmol) and reflux 20 hours afterwards.After system saturated sodium bicarbonate is neutralized to neutrality, thin up, with extraction into ethyl acetate (2 × 15mL), after merging organic phase, with saturated common salt water washing, after anhydrous sodium sulfate drying, concentrated, with high-efficient liquid phase chromatogram purification after frequent compression leg chromatogram preliminary purification (methylene chloride/methanol=15/1), obtain white solid 10.4mg (3.6%).
1HNMR 300MHz(CDCl
3)δ8.43(s，1H)，8.25(s，1H)，7.53(d，J＝8.4Hz，2H)，7.32(m，2H)，6.71(d，J＝6.6Hz，1H)，6.67(d，J＝7.8Hz，1H)，6.59(dd，J＝1.8Hz，J＝17.1Hz，1H)，6.28(s，1H)，6.25(m，1H)，6.09(dd，J＝10.2Hz，J＝17.1Hz，1H)，5.67(dd，J＝1.8Hz，J＝10.2Hz，1H)，4.46-4.52(m，1H)，4.35-4.38(m，1H)，4.23-4.25(m，2H)，3.83-3.90(m，2H)，3.62(d，J＝11.2Hz，2H)，2.84-2.85(m，2H)，2.83(s，3H)，2.29-2.33(m，2H)，2.16-2.21(m，2H).MS(m/z)：562.5(M+1).
Embodiment 3, cell growth inhibition test
1. materials and methods
Cell growth medium: RPMI1640 (Gibco, 22400089) adds 10%FBS (Gibco, 10099141)
Detection kit: CCK-8 detection reagent (DojinDo, CK04-20)
Clone: A431 (EGFR WT, Chinese Academy of Sciences's Shanghai cell bank), NCI-H1975 (EGFRL858R/T790M, Chinese Academy of Sciences's Shanghai cell bank), HCC827 (EGFR Del E746_A750,
S. Korea and the USA of Korea S medicine), Hs-27 (human skin fibroblast, S. Korea and the USA of Korea S medicine)
TECANIF200 microplate reader
Invitrogen Countess cell counter (C10227)
2. cell inoculation
With the cell of 0.25% trysinization logarithmic phase.Single cell suspension is made into the RPMI1640 substratum containing 10%FBS.Invitrogen Countess carries out cell counting.A431, NCI-H1975, HCC827 and Hs-27 are all inoculated in 96 orifice plates (brassboard and control board) with 5000 cells/well/100uL.Blank group adds 100uL substratum.Culture plate is put in incubator, 37 DEG C, 5%CO
2overnight incubation.
3. control board Growth of Cells measures
In incubator, take out control board, discard substratum in hole, add the fresh culture containing 10%CCK-8,100uL/ hole.After adding, 96 orifice plates are put back in incubator, continue to cultivate 1-4h, until present significantly orange red.450nm measures absorbance value, is OD value before drug treating.
4. drug treating
Each testing sample is from 10uM, and 10 times of dilutions, arrange 6 drug levels, and each concentration does the test of multiple hole.For A431, NCI-1975, HCC827 clone, with the substratum gradient dilution testing sample containing 0.1% foetal calf serum, and be 2 times of final concentration.For Hs-27 cell, be 2 times of final concentration with the substratum dilution containing 10% foetal calf serum.Taking-up brassboard adds the substratum containing 2 times of medicine final concentrations to be measured, and brassboard is taken out in 100uL/ hole, discards substratum in hole, adds the fresh substratum 100uL/ hole containing 0.1% foetal calf serum; Add the substratum containing 2 times of medicine final concentrations to be measured again, 100uL/ hole.96 orifice plates are put back to incubator, 37 DEG C, 5%CO
2act on 72 hours.Control group adds the substratum of not drug containing.
5. colour developing and GI
50calculating
After effect in 72 hours, in incubator, take out 96 orifice plates, discard substratum in hole, add the fresh culture containing 10%CCK-8,100uL/ hole.After adding, 96 orifice plates are put back in incubator, continue to cultivate 1-4h (consistent with control board developing time).450nm measures photoabsorption.Cell growth rate %=[(administration group OD value-brassboard blank OD value)-(OD value before drug treating-control board blank OD value)]/[(control group OD value-brassboard blank group OD value)-(OD value before drug treating-control board blank OD value)] × 100.Carry out logistic matching with origin8, calculate the GI of counter sample
50value, GI
50the growth-inhibiting of lower explanation medicine to cell is more obvious.
GI in # table
50interval residing for value is represented by the number of asterisk: 1nM≤GI
50≤ 10nM:**** (activity is very strong); 10nM < GI
50≤ 100nM:*** (activity is stronger); 100nM < GI
50≤ 1000nM:** (active medium); 1000nM < GI
50≤ 10000nM:* (activity is more weak).
Carry out cytotoxicity experiment according to above-mentioned experimental technique, investigate the compound of the embodiment of the present invention to the growth-inhibiting effect of normal people skin flbroblast Hs-27.Wherein, section Example compounds exhibit goes out lower cytotoxicity, such as the compound of embodiment 1, embodiment 2 and embodiment 19, and they are to the GI of Hs-27 cell
50be respectively 1032,1584 and 1992nM.
Embodiment 4, kinase inhibition are tested
Kinase inhibition test adopts concentration shown in following table:
#km value equals enzymatic reaction speed and reaches concentration of substrate corresponding to maximum reaction velocity one half, and the same enzyme is also different from different substrate reactions Km value.The avidity size of the reaction enzyme-to-substrate that Km value can be similar to: Km value is large, shows that avidity is little; Km value is little, shows that avidity is large.
1. 4 times that with distilled water, compound are carried out that serial dilution is final concentration.
2. preparation test required solution (1X RB:40mM Tris, 7.5; 20mM MgCl
2; 0.1mg/mlBSA; 2mM MnCl
2, 50 μMs of DTT).
3. composition added by control group:
CK-：10uL ddH
2O+5uL 4X R.B.(EGFR)+ATP&S(EGFR)
CK+：5uL ddH
2O+10uL 2X EGFR(WT)in 2X R.B.+ATP&S(EGFR)
4. adding with distilled water dilution is the compound 5uL/ hole of final concentration 4 times.
5.2X EGFR (WT/T790M/T790M & L858R/L858R) in 2X R.B., 10uL/ hole, at room temperature hatches 10 minutes after mixing.
6.4X ATP+S.in 1X ddH
2o, 5uL/, hatch 60 minutes (WT, T790M) and 120min (T790M/L858R, L858R) respectively under room temperature
7. add ADP-Glo reagent, 20uL/ hole, after mixing, incubated at room temperature 40 minutes.
8. add kinase assay reagent, 40uL/ hole, incubated at room temperature 40 minutes after mixing.
9. survey fluorescence enzyme values.
According to above experimental technique, in the present invention, part of compounds demonstrates good EGFR Catastrophic selection inhibition.
IC in table
50be worth less, represent that relative rejection ability is stronger.
Embodiment 5, the compound stability study in hepatomicrosome
1. testing compound is dissolved in acetonitrile, makes the storing solution that concentration is 0.5mM.
2.2 μ L storing solutions add in 1.5mL centrifuge tube, then add 148 μ L phosphoric acid buffer (100mM, pH7.4) and 10 μ L hepatomicrosomes (protein concentration is 20mg/mL) suspension; Control group adds 158 μ L phosphoric acid buffers (100mM, pH 7.4).
3. the mixed system prepared in step 2, incubates 3 minutes in advance in 37 DEG C of water-baths, then adds 40 μ LNADPH and system occurs (containing NADP
+: 6.5mM, Glucose-6-phosphate:16.5mM, MgCl
2: 16.5mM, Glucose-6-phosphate dehydrogenase:2U/mL) start reaction, and 1 hour is hatched in 37 DEG C of water-baths.
4. after reaction carries out 1 hour, taken out from water-bath by centrifuge tube, and add 400 μ L acetonitrile termination reactions, then vortex shakes 3 minutes, finally centrifugal (13000rpm, 4 DEG C) 5 minutes, gets supernatant liquor HPLC and detects residual drug concentration C r.
5. 0 minute response sample preparation method of parallel preparation: the mixed system prepared in step 2, incubates in advance after 3 minutes and takes out, add 400 μ L acetonitriles in 37 DEG C of water-baths, then adds 40 μ L NADPH and system occurs.Mediation concussion is after 3 minutes, and centrifugal (13000rpm, 4 DEG C) 5 minutes, get supernatant liquor HPLC detection of drugs concentration C 0.
6., after hatching through 60 minutes, the residue per-cent of medicine in incubation system calculates according to the following formula:
Medicine residue (%)=Cr ÷ C0 × 100%
According to above-mentioned experimental technique, the section Example compounds exhibit in the present invention goes out good Microsomal Stability.The residue per-cent of compound after hatching 60 minutes (%, successively in the hepatomicrosome enzyme of people/rat/dog/mouse) of such as embodiment 2 and embodiment 19 is respectively: 76.24/84.67/48.33/67.67 and 79.2/87.55/62.54/61.82.
Embodiment 6, assessing compound are to CYP enzyme inhibition
Method: this experiment uses the CYP Inhibitor Screening Kit test kit of BD Gentest company to complete.All experimental implementation are carried out according to the product instruction in test kit.Experimental procedure is as follows:
1. be preheated to 37 DEG C in deionized water and buffering brine bath.
2. prepare NADPH generation systems.
3. the first row of black 96 orifice plate, adds the NADPH generation systems 144 μ L that step 2 is prepared.
4. according to the instruction of test kit, preparation cofactor-ACN solution.
The secondary series of 5.96 orifice plates, to the 12 row, adds the cofactor-ACN of preparation in 100 μ L steps 4.
6.6uL positive inhibitor, testing compound are added to the first hole of respective test set.After using volley of rifle fire piping and druming mixing, 50 μ L serial dilutions are to the 8th row.8th row, after piping and druming mixing, take out 50 μ L solution and abandon.
7. 96 orifice plate shrouding films are sealed, hatch 10min for 37 DEG C.
8. according to the instruction preparation enzyme-substrate mixture of test kit.
9. hatch 96 orifice plates of 10min in step 7, first row to the tenth every hole of row adds 100 μ L enzyme-substrate mixtures (adding speed slightly fast, to ensure abundant mixing solutions).
10. again build shrouding film, hatch certain hour (different CYP hypotype incubation times is different) according to the instruction 37 DEG C of test kit.
11. hatch after 96 orifice plates, every hole adds 75 μ L reaction terminating liquids.
11 row of 12.96 orifice plates and the 12 row, add 100 μ L enzyme-substrate mixtures.
13., according to the instruction of test kit, detect the fluorescence intensity in every hole, and calculate IC by microplate reader
50.
According to above-mentioned experimental technique, the section Example compound in the present invention all only has faint suppression or unrestraint to various CYP enzyme.The compound of such as embodiment 2 and embodiment 19 to the half-inhibition concentration of various CYP hypotype (1A2,2D6,2C9,2C19,3A4) all higher than or close to 20 μMs.
The pharmacokinetics research in rat body of embodiment 7, compound
1., after male SD rat is bought in, raise 7 days in this laboratory adaptability.
2.6 SD rats are divided into 2 groups at random, often organize 3, and one group is used for gastric infusion, and another group is used for tail vein injection administration.The rat of gastric infusion group, needs overnight fast before administration.
3., after rat administration, adopt the method for orbital venous plexus blood sampling at following time point blood sample collection: 0min (before administration), 5min, 15min, 30min, 1h, 2h, 3h, 5h, 7h, 24h.Each blood sampling time point blood sampling volume is about 300 μ L.
4. the blood sample gathered with the centrifugal 5min of the rotating speed of 12000rpm at 4 DEG C, then gathers upper plasma sample, and preserves to be measured in-20 DEG C of refrigerators.
5. experimental implementation is summed up and is seen the following form:
6. use the compound concentration in the LC-MS/MS detection blood plasma in this laboratory.
7. use the pharmacokinetics professional software WinNonlin in this laboratory to calculate pharmacokinetic parameter.
According to above-mentioned experimental technique, compounds exhibit of the present invention goes out good bioavailability, and the compounds exhibit as embodiment 1 goes out the bioavailability of 5.7%.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (16)
1. the compound of formula I or its pharmacy acceptable salt:
Wherein, X is selected from O, NR
8or disappearance;
M is selected from 1 or 2;
N is selected from 1,2 or 3;
A ring is selected from hexa-atomic aromatic ring or 8-14 unit condensed ring, and hexa-atomic aromatic ring can not be substituted or by one or more halogen, C
1-6alkoxyl group replaced, and B ring is selected from hexa-atomic aromatic ring;
R
1be selected from hydrogen, N (R
4) (R
5), C (O) N (R
4) (R
5);
R
2be selected from
R
3be selected from hydrogen;
R
4and R
5independently selected from hydrogen, C
1-6alkyl-C
3-8heterocyclylalkyl, wherein, R
4and R
5also can be connected to form 5-8 unit Heterocyclylalkyl, ring can not to be substituted or by one or more halogen, cyano group, amido, C
1-6the amido that alkyl replaces, C
1-6alkyl, the C of halogen substiuted
1-6alkyl, C
1-6alkoxyl group, the C of halogen substiuted
1-6alkoxyl group replaced;
R
6and R
7independently selected from hydrogen, C
1-6alkyl;
R
8be selected from hydrogen.
2. compound described in claim 1 or its pharmacy acceptable salt, wherein compound is selected from formula II:
Wherein A ring and B ring are independently selected from hexa-atomic aromatic ring;
R
1be selected from hydrogen, N (R
4) (R
5), C (O) N (R
4) (R
5);
R
2be selected from
R
3be selected from hydrogen;
R
4and R
5independently selected from hydrogen, C
1-6alkyl-C
3-8heterocyclylalkyl, R
4and R
5also can be connected to form 5-8 unit Heterocyclylalkyl, ring can not to be substituted or by one or more halogen, cyano group, amido, C
1-6the amido that alkyl replaces, C
1-6alkyl, the C of halogen substiuted
1-6alkyl, C
1-6alkoxyl group, the C of halogen substiuted
1-6alkoxyl group replaced.
3. compound or its pharmacy acceptable salt, is characterized in that, described structural formula of compound is selected from:
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-N-(1-base base piperazine-4-base) benzamide
1-(3-(3-(the chloro-2-of 5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) the third-2-alkene-1-ketone
1-(4-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-ethyl piperazidine-1-base)-2-anisole amido) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-base) the third-2-alkene-1-ketone
7-(4-(3-(1-acryl azetidine-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-one
1-(3-(3-(the chloro-2-of 5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(3,4-lupetazin-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-ethyl piperazidine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-morpholine anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-parathiazan anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(the fluoro-4-of 3-(4-methyl piperidine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-(methylsulfonyl) piperazine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(2-(4-(4-acetylpiperazine-1-base) anilino)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(2-(4-(4-benzyl diethylenediamine-1-base) anilino)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-phenylpiperazine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(2,6-dimethylated morpholinyl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(piperidin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-(cyclopropane carbonyl) piperazine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(3,5-lupetazin-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl amido) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(2-(4-methylpiperazine-1-yl) ethylamino-) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(piperazine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
4-(4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido) phenyl)-NEP-1-carboxamide
6-(4-(3-(acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-3,4-dihydronaphthalene-1 (2H)-one
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl amido) anilino) azetidin-1-base) the third-2-alkene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone
3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino)-N, N-dimethyl azetidin-1-carboxamide
(E)-1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) but-2-ene-1-ketone
1-(3-(3-(the chloro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base)-3-methyl but-2-ene-1-ketone
Tertiary butyl 4-(4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido) phenylpiperazine-1-manthanoate
1-(3-(3-(2-(3-bromobenzene amido)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone.
4.1-(3-(3-(the chloro-2-of 5-(4-(4-(2-(dimethylamine) ethyl) piperazine-1-base) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-base) the third-2-alkene-1-ketone.
5. medicinal compositions, comprises compound described in any one of claim 1-4 or pharmacologically acceptable salts and pharmaceutically acceptable carrier.
6. the compound according to any one of claim 1-4 or its pharmacy acceptable salt purposes in the medicine of preparation regulation and control EGFR tyrosine kinase activity.
7. the compound according to any one of claim 1-4 or its pharmacy acceptable salt treat the purposes of the medicine of EGFR relative disease in preparation.
8. purposes according to claim 7, is characterized in that, described EGFR relative disease is the disease of EGFR unconventionality expression.
9. purposes according to claim 8, is characterized in that, the disease of described EGFR unconventionality expression is cancer, diabetes, disease of immune system, nerve degenerative diseases or cardiovascular disorder.
10. purposes according to claim 9, is characterized in that, described cancer is nonsmall-cell lung cancer, head and neck cancer, mammary cancer, kidney, carcinoma of the pancreas, cervical cancer, esophagus cancer, carcinoma of the pancreas, prostate cancer, bladder cancer, colorectal carcinoma, ovarian cancer, cancer of the stomach, glioblastoma, or their any combination.
11. purposes according to claim 7, is characterized in that, described EGFR relative disease has the disease of acquired resistance during also comprising use EGFR modulators for treatment.
12. purposes according to claim 11, is characterized in that, described acquired resistance be by or comprise EGFR extron 20 encode T790 suddenly change caused by.
13. purposes according to claim 12, is characterized in that, the T790 of described EGFR extron 20 coding sports T790M.
14. purposes according to claim 11, is characterized in that, described EGFR conditioning agent is the small molecule tyrosine kinase inhibitors of targeting EGFR.
15. purposes according to claim 14, is characterized in that, the small molecule tyrosine kinase inhibitors of described targeting EGFR is from Gefitinib, Tarceva, Conmana, lapatinibditosylate.
16. 1 kinds of medicinal compositionss, comprise compound or its pharmacy acceptable salt according to any one of claim 1-4 and be selected from: Gefitinib, Tarceva, Conmana, lapatinibditosylate, XL647, NVP-AEE-788, ARRY-334543, EKB-569, BIBW2992, HKI272, BMS-690514, CI-1033, ZD6474, PF00299804, WZ4002, Cetuximab, Herceptin, Pa Ni dashes forward monoclonal antibody, horse trastuzumab, Buddhist nun's trastuzumab, prick Shandong wood monoclonal antibody, handkerchief trastuzumab, MDX-214, CDX-110, IMC-11F8, Zemab, Her2 vaccine PX 1041 and HSP90 inhibitor, CNF2024, KOS-953, Ah's Spiramycin Base, IPI-504, one or more the combination of SNX-5422 and NVP-AUY922.
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