CN104151321B - N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-methanamide compound and its production and use - Google Patents

N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-methanamide compound and its production and use Download PDF

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CN104151321B
CN104151321B CN201310179739.9A CN201310179739A CN104151321B CN 104151321 B CN104151321 B CN 104151321B CN 201310179739 A CN201310179739 A CN 201310179739A CN 104151321 B CN104151321 B CN 104151321B
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chloro
thiazole
amino
aminomethyl phenyl
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CN104151321A (en
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董肖椿
赵伟利
赵逸超
林赵虎
陆秀宏
王雯
董潜
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Fudan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Abstract

The invention belongs to pharmaceutical synthesis field, relate to formula (I)N(2 chlorine 6 aminomethyl phenyl) 2 [(2 methylpyrimidine 4 base) amino] thiazole 5 benzamide compound, particularly relates to a kind of 6 quaternary heterocycles of pyrimidine or volution is substitutedN(2 chlorine 6 aminomethyl phenyl) 2 [(2 methylpyrimidine 4 base) amino] thiazole 5 benzamide compound, and preparation method thereof and application medically.The compound of the present invention is tested by external ABL kinase inhibiting activity and antitumor activity, and result shows, described compound has good ABL kinase inhibiting activity and antitumor activity, can prepare new antineoplastic further.

Description

N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound and its production and use
Technical field
The invention belongs to pharmaceutical synthesis field, relate to new N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) Amino] thiazole-5-methanamide compound, preparation method and application.It is specifically related to a kind of 6 quaternary heterocycles of pyrimidine or volution replaces N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-methanamide compound, and preparation side Method and application medically.
Background technology
Prior art discloses chronic myelocytic leukemia (chronic myelogenous leukemia, CML) is to send out It is born in the hematological system malignant clone proliferative disease of candidate stem cell, is also one of 4 kinds of modal leukaemia, accounts for white blood The 15%-20% of sick case, the incidence of disease is 1.6/10 ten thousand, all can fall ill at each age group, is common with person in middle and old age's case.According to Report, in the U.S., CML patient's newly-increased about 5000 examples every year, M-F is 1.4:1, existence more than 20 years less than 10%.
Research display, the breakpoint gathering district that the oncogene c-ABL on No. 9 chromosomes of human body is linked on No. 22 chromosome (breakpoint cluster region, BCR), forms p210 BCR-ABL fusion and p185 BCR-ABL merges base Cause, BCR-ABL track fusion BCR-ABL protein kinase, this kinases plays important work in cell signalling and conversion With, it is by phosphorylation and activates a series of stream substrates, causes cell proliferation, sticks and the change of character of surviving, and causes producing Raw chronic myelocytic leukemia and the generation of acute myeloblastic leukemia.Due to BCR-ABL kinases not table in normal cell Reaching, therefore, this area researcher thinks that it is the treatment preferable drug targets of CML.
Early 1990s, Novartis Co., Ltd (Novartis) is by obtaining miazines to the high flux screening of compound library Lead compound, synthesized a series of micromolecular compound based on 2-phenylamino pyrimidine on this basis, in 1992 years It is found to the reactive compound STI571 of specific suppression BCR-ABL EGFR-TK, develops through the times of about ten years, The treatment that Imatinib (Imatinib, trade name Gleevec) is approved by the fda in the United States for CML May 10 calendar year 2001, this It is the BCR-ABL tyrosine kinase of first treatment CML, there is epoch-making meaning, listed in by the U.S.'s " science " magazine The big science and technology news of calendar year 2001 degree ten.
Although the listing of Imatinib obtains huge success, but the generation of mutant strain causes imatinib-resistant Generation, Imatinib list after several years in, have some patients disease relapse, death even occur.
Dasatinib was examined by U.S. FDA on June 28th, 2006, for treating CML and Philadelphia Chromosome Positive Acute lymphatic leukemia (ph+ALL).Dasatinib comes from the lymphocyte EGFR-TK of a kind of Src-family (lymphocyte cell kinase, LCK) inhibitor, it not only can suppress BCR-ABL kinases under nanomolar concentration, and Almost can suppress all of ABL mutant (except T315I mutant).
Although above two BCR-ABL inhibitors of kinases shows preferable curative effect, but due to the ever-increasing resistance to the action of a drug, And the difference between treatment crowd's individuality, force the least molecule that the continuous research and development of researcher's need is new in the industry Compound is in order to suppress ABL kinases.
Summary of the invention
It is an object of the invention to provide new N-(2-chloro-6-aminomethyl phenyl)-2 [(the 2-first with good antitumor activity Yl pyrimidines-4-base) amino] thiazole-5-methanamide compound, it is specifically related to a kind of 6 quaternary heterocycles of pyrimidine or volution is substituted N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-methanamide compound.
It is a further object of the present invention to provide above-mentioned new N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) Amino] preparation method of thiazole-5-methanamide compound, particularly relate to prepare 6 quaternary heterocycles of pyrimidine or the substituted N-of volution The method of (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-methanamide compound.
N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-formamide chemical combination of the present invention Thing has a structure of following formula (I):
Wherein
R =Or
N=1 or 2
X=O or S or SO or SO2Or NCH2CH2OH
R1=OH or OCH3Or F or NHBoc,
R2=H or F,
In the present invention, preferred compound has a structure of following compound 1,2,3,4,5,6,7,8,9,10:
1 2
3 4
5 6
7 8
9 10
6 quaternary heterocycles of the pyrimidine of the present invention or the substituted N-of volution (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine- 4-yl) amino] thiazole-5-methanamide compound preparation method in, with N-(2-chloro-6-aminomethyl phenyl)-2-[(6-chloro-2-first Yl pyrimidines-4-base) amino] thiazole-5-formamide is raw material, with DIPEA as alkali, in Isosorbide-5-Nitrae-dioxane Carry out nucleophilic substitution from different amine and obtain described compound.
In the present invention, as a example by compound 1, its preparation process is as follows:
The compound that the present invention prepares has carried out the test of ABL kinase inhibiting activity and anti tumor activity in vitro is tested, result Display, described compound has good ABL kinase inhibiting activity and antitumor activity, can develop further as novel Antineoplastic.
The present invention carries out inhibitory activity test to ABL kinases, and result shows, described compound demonstrates preferable ABL Kinase inhibiting activity, all compounds are to ABL kinase inhibiting activity IC50Being respectively less than 0.6nM, wherein compound 1 and 8 is for ABL Kinase inhibiting activity IC50Value is less than 0.2nM, similar with antineoplastic Dasatinib.
The compound of the present invention can prepare abl kinase inhibitor further.
The present invention is studied by Pharmacodynamic, PC3 prostate gland cancer cell thin to K562 leukemia tumor and MDA-MB- 231 breast cancer cells carry out anti tumor activity in vitro test, and result shows, the compound of the present invention is to K562 leukemia tumor Carefully, PC3 prostate gland cancer cell and MDA-MB-231 breast cancer cell have relatively powerful antitumor activity, IC50Value is nM level, its In, the extracorporeal anti-tumor IC of 1,7,8 and 10 pairs of K562 leukemia tumor cells of compound50Value is respectively less than 1nM, compound 2 and 10 Extracorporeal anti-tumor IC to PC3 prostate gland cancer cell50Value is respectively less than 100nM, and compound 1 is to MDA-MB-231 breast cancer cell Extracorporeal anti-tumor IC50Value is less than 300nM, close with antineoplastic Dasatinib.
The compound of the present invention can prepare new antineoplastic further.
In the present invention, the pharmacodynamics test method used, is art technology and the method known to personnel.
In the present invention, the ABL kinases used and K562 leukemia tumor are carefully, PC3 prostate cancer is thin, MDA-MB-231 is newborn Adenocarcinoma cell is that those skilled in the art can be obtained by commercial approach.
In view of BCR ABL oncogene is the product of Philadelphia chromosome, Philadelphia chromosome is chronic myelocytic leukemia Clinical diagnosis mark, there are about the chronic myelocytic leukemia people of 95 and the ALL (Acute of 25% Lymphoblastic Leukemia, ALL) adult and 5% ALL children's body in there is Philadelphia chromosome, Bcr/abl is carcinogenic The albumen (P210) of gene code tool tyrosine kinase activity, this albumen and cellular signal transduction protein-interacting, upset Cellular informatics transmittance process, makes CML cell proliferation and differentiation out of control.Therefore, the N-(2-chloro-6-aminomethyl phenyl)-2 of the present invention [(2-methylpyrimidine-4-base) amino] thiazole-5-methanamide compound especially can prepare treatment EGFR-TK functional disturbance institute Causing the medicine of relevant disease, relevant disease caused by this described BCR-ABL EGFR-TK functional disturbance includes, chronic Myelogenous is white Blood sick (CML), cancer of the stomach, gastrointestinal stromal knurl, ALL, the Ph chromatin-positive of intractable or recurrence Acute lymphatic leukemia, gastrointestinal stromal cytoma and the systemic mastocytosis just controlled and concurrent Disease.
Detailed description of the invention:
Embodiment 1: synthesis compound 1, N-(2-chloro-6-aminomethyl phenyl)-2-[[2-methyl-6-(2-oxa--6-azaspiro [3.3] heptane-6-base) pyrimidine-4-yl] amino] thiazole-5-formamide
Under stirring at room temperature, 2-oxygen-6 nitrogen spiral shell [3,3] heptane oxalate (0.92 g, 0.8 mmol) is added 2-((6- Chloro-2-methyl pyrimidine-4-yl) amino)-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-formamide (0.3 g, 0.76 mmol) and In Isosorbide-5-Nitrae-dioxane (10 mL) solution of DIPEA (0.56 mL, 1.6 mmol), it is warming up to backflow, reaction Overnight, TLC monitoring raw material disappears.Stopping reaction and be down to room temperature, remove solvent, gained solid is respectively with methyl alcohol, ether washing two Secondary, column chromatogram chromatography, obtain white solid (20 mg, productivity 6%).1 H NMR (400 MHz, DMSO-d6) δ 11.47 (br s, 1H), 9.88 (s, 1H), 8.22 (s, 1H), 7.40 (dd, J = 7.5, 1.6 Hz, 1H), 7.35 – 7.20 (m, 2H), 5.69 (s, 1H), 4.72 (s, 4H), 4.15 (s, 4H), 2.39 (s, 3H), 2.23 (s,3H)。
Embodiment 2: synthesis compound 2, N-(2-chloro-6-aminomethyl phenyl)-2-[[2-methyl-6-(2-thia-6-azaspiro [3.3] heptane-6-base) pyrimidine-4-yl] amino] thiazole-5-formamide
Under stirring at room temperature, ((6-is chloro-2-sulphur-6 nitrogen spiral shell [3,3] heptane oxalate (128mg, 0.4mmol) to be added 2- 2-methylpyrimidine-4-base) amino)-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-formamide (158mg, 0.4mmol) and N, N-bis- In Isosorbide-5-Nitrae-dioxane (5mL) solution of wopropyl ethyl amine (0.56mL, 1.6mmol), being warming up to backflow, overnight, TLC supervises in reaction Survey raw material disappears.Stopping reaction and be down to room temperature, remove solvent, gained solid washes twice with methyl alcohol, ether respectively, column chromatography layer Analysis, obtains white solid (10mg, productivity 5%).1 H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.89 (s, 1H), 8.22 (s, 1H), 7.40 (dd, J = 7.2, 1.2 Hz, 1H), 7.34 – 7.19 (m, 2H), 5.69 (s, 1H), 4.04 (s, 4H), 3.40 (s, 4H), 2.40 (s, 3H), 2.24 (s, 3H)。
Embodiment 3: synthesis compound 3, N-(2-chloro-6-aminomethyl phenyl)-2-[[2-methyl-6-(2-oxygen-2-thia-6- Azepine spiroheptane-6-base) pyrimidine-4-yl] amino] thiazole-5-formamide
Under stirring at room temperature, by 2-oxa--6-thia spiral shell [3.3] heptane-6-oxide oxalates (55,359 mg, 1.02 Mmol) add 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-formamide (52, 200 mg, 0.51 mmol) and the Isosorbide-5-Nitrae-dioxane (5 mL) of DIPEA (0.356 mL, 2.04 mmol) molten In liquid, being warming up to backflow, overnight, TLC monitoring raw material disappears in reaction.Stopping reaction and be down to room temperature, remove solvent, gained solid divides Not washing twice with methyl alcohol, ether, high performance liquid chromatography separates preparation, obtains faint yellow solid (10 mg, productivity 4%).1 H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.89 (s, 1H), 8.23 (s, 1H), 7.40 (dd, J = 7.6, 1.6 Hz, 1H), 7.34 – 7.19 (m, 2H), 5.68 (s, 1H), 4.05 (s, 4H), 3.99 (dd, J = 9.2, 3.1 Hz, 2H), 3.61 – 3.42 (m, 2H), 2.39 (s, 3H), 2.24 (s, 3H)。
Embodiment 4: synthesis compound 4, N-(2-chloro-6-aminomethyl phenyl)-2-[[6 (2,2-dioxo-2-thia-6- Azepine spiroheptane-6-base)-2-methylpyrimidine-4-base] amino] thiazole-5-formamide
Under stirring at room temperature, by 2-oxa--6-thia spiral shell [3.3] heptane 6,6-dioxide oxalates (56,300 mg, 1.27 mmol) add 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-formamide (52,300 mg, 0.76 mmol) and the Isosorbide-5-Nitrae-dioxane (5 mL) of DIPEA (0.58 mL, 3.3 mmol) In solution, being warming up to backflow, overnight, TLC monitoring raw material disappears in reaction.Stop reaction and be down to room temperature, remove solvent, gained solid Washing twice with methyl alcohol, ether respectively, high performance liquid chromatography separates preparation, obtains faint yellow solid (10 mg, productivity 2.6%).1 H NMR (400 MHz, DMSO-d6) δ 11.67 (br s, 1H), 9.97 (s, 1H), 8.28 (s, 1H), 7.40 (dd, J = 7.5, 1.6 Hz, 1H), 7.33 – 7.20 (m, 2H), 5.75 (s, 1H), 4.51 (s, 4H), 4.23 (s, 4H), 2.41 (s, 3H), 2.24 (s, 3H)。
Embodiment 5: synthesis compound 5, N-(2-chloro-6-aminomethyl phenyl)-2-[[6-(3-methoxyl group azetidine-1- Base)-2-methylpyrimidine-4-base] amino] thiazole-5-formamide
Under stirring at room temperature, 3-methoxyl group azetidine (57,70 mg, 0.8 mmol) is added 2-((6-chloro-2-first Yl pyrimidines-4-base) amino)-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-formamide (52,158 mg, 0.4 mmol) and N, N- In Isosorbide-5-Nitrae-dioxane (5 mL) solution of diisopropylethylamine (0.14 mL, 0.8 mmol), it is warming up to backflow, reacts overnight, TLC monitoring raw material disappears.Stopping reaction and be down to room temperature, remove solvent, gained solid washes twice with methyl alcohol, ether respectively, high Effect liquid phase chromatogram separates preparation, obtains faint yellow solid (10 mg, productivity 5.6%).1 H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.88 (s, 1H), 8.23 (s, 1H), 7.40 (dd, J = 7.2, 1.6 Hz, 1H), 7.34 – 7.20 (m, 2H), 5.71 (s, 1H), 4.38 – 4.23 (m, 1H), 4.28 – 4.09 (m, 2H), 3.92 – 3.69 (dd, J = 9.6, 4.0 Hz, 1H), 2.40 (s, 3H), 2.24 (s, 3H), 1.34 – 1.26 (m, 3H)。
Embodiment 6: synthesis compound 6, N-(2-chloro-6-aminomethyl phenyl)-2-[[6-(3,3-difluoro azetidines- 1-)-2-methylpyrimidine-4-base] amino] thiazole-5-formamide
Under stirring at room temperature, by 3,3-difluoro azetidine hydrochloride (58,104 mg, 0.8 mmol) adds 2-((6- Chloro-2-methyl pyrimidine-4-yl) amino)-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-formamide (52,158 mg, 0.4 mmol) With in Isosorbide-5-Nitrae-dioxane (5 mL) solution of DIPEA (0.14 mL, 0.8 mmol), it is warming up to backflow, instead Should overnight, TLC monitoring raw material disappears.Stopping reaction and be down to room temperature, remove solvent, gained solid is respectively with methyl alcohol, ether washing Twice, high performance liquid chromatography separates preparation, obtains faint yellow solid (10 mg, productivity 5.5%).1 H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.91 (s, 1H), 8.24 (s, 1H), 7.42 (dd, J = 7.2, 1.6 Hz, 1H), 7.34 – 7.20 (m, 2H), 5.86 (s, 1H), 4.45 (t, J = 12.4 Hz, 4H), 2.45 (s, 3H), 2.25 (s, 3H)。
Embodiment 7: synthesis compound 7, the tert-butyl group (1-(6-((5-((2-chloro-6-aminomethyl phenyl) carbamoyl) thiophene Azoles-2-) amino)-2-methylpyrimidine-4-) azetidine-3-) t-butyl carbamate
Under stirring at room temperature, azetidine-3-carbamate (59,138 mg, 0.8 mmol) is added 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-formamide (52,158 mg, 0.4 Mmol) and in Isosorbide-5-Nitrae-dioxane (5 mL) solution of DIPEA (0.14 mL, 0.8 mmol), it is warming up to back Stream, overnight, TLC monitoring raw material disappears in reaction.Stopping reaction and be down to room temperature, remove solvent, gained solid is respectively with methyl alcohol, ether Washing twice, high performance liquid chromatography separates preparation, obtains faint yellow solid (10 mg, productivity 4.7%).1 H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.88 (s, 1H), 8.22 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.42 (dd, J = 7.6, 1.6 Hz, 1H), 7.32 – 7.16 (m, 2H), 5.68 (s, 1H), 4.40 (br s, 1H), 4.20 (t, J = 8.0 Hz, 1H), 3.88 – 3.67 (m, 2H), 2.40 (d, J = 5.6 Hz, 3H), 2.24 (s, 3H), 1.40 (s, 9H)。
Embodiment 8: synthesis compound 8, N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[6-(2-ethoxy)-2,6-phenodiazine Miscellaneous spiral shell [3.3] heptane-2-]-2-methylpyrimidine-4-base] amino] thiazole-5-formamide
Under stirring at room temperature, 2-(2,6-diaza spiroheptane-2-) ethanol (60,86 mg, 0.6 mmol) is added Enter 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-formamide (52,158 mg, 0.4 mmol) and Isosorbide-5-Nitrae-dioxane (5 mL) solution of DIPEA (0.14 mL, 0.8 mmol) in, heat up To backflow, overnight, TLC monitoring raw material disappears in reaction.Stop reaction and be down to room temperature, remove solvent, gained solid respectively with methyl alcohol, Ether washes twice, and high performance liquid chromatography separates preparation, obtains faint yellow solid (10 mg, productivity 5%).1 H NMR (400 MHz, DMSO-d6) δ 11.48 (br s, 1H), 9.91 (s, 1H), 8.24 (s, 1H), 7.40 (dd, J = 7.6, 1.6 Hz, 1H), 7.33 – 7.18 (m, 2H), 5.69 (s, 1H), 4.07 (s, 4H), 3.64 (s, 6H), 3.17 (s, 1H), 2.69 (t, J = 5.6 Hz, 2H), 2.39 (s, 3H), 2.24 (s, 3H)。
Embodiment 9: synthesis compound 9, N-(2-chloro-6-aminomethyl phenyl)-2-[[6-(3-hydroxy azetidine-1-)- 2-methylpyrimidine-4-base] amino] thiazole-5-formamide
Under stirring at room temperature, 3-hydroxy azetidine (61,58 mg, 0.8 mmol) is added 2-((6-chloro-2-methyl Pyrimidine-4-yl) amino)-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-formamide (52,158 mg, 0.4 mmol) and N, N-bis- In Isosorbide-5-Nitrae-dioxane (5 mL) solution of wopropyl ethyl amine (0.14 mL, 0.8 mmol), it is warming up to backflow, reacts overnight, TLC monitoring raw material disappears.Stopping reaction and be down to room temperature, remove solvent, gained solid washes twice with methyl alcohol, ether respectively, high Effect liquid phase chromatogram separates preparation, obtains faint yellow solid (10 mg, productivity 5.8%).1 H NMR (400 MHz, DMSO-d6) δ 11.45 (br s, 1H), 9.87 (s, 1H), 8.22 (s, 1H), 7.52 – 7.35 (m, 1H), 7.35 – 7.14 (m, 2H), 5.75 (d, J = 6.4 Hz, 1H), 5.68 (s, 1H), 4.59 (m, 1H), 4.19 (t, J = 7.6 Hz, 2H), 3.70 (q, J = 4.4 Hz, 2H), 2.39 (s, 3H), 2.24 (s, 3H)。
Embodiment 10: synthesis compound 10, N-(2-chloro-6-aminomethyl phenyl)-2-[[2-methyl-6-(2-oxa--6-azepine Spiral shell [3.4] octane-6-) pyrimidine-4-yl] amino] thiazole-5-formamide
Under stirring at room temperature, 2-oxa--6-azaspiro [3.4] octane (62,50 mg, 0.44 mmol) is added 2-((6- Chloro-2-methyl pyrimidine-4-yl) amino)-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-formamide (52,158 mg, 0.4 mmol) With in Isosorbide-5-Nitrae-dioxane (5 mL) solution of DIPEA (0.14 mL, 0.8 mmol), it is warming up to backflow, instead Should overnight, TLC monitoring raw material disappears.Stopping reaction and be down to room temperature, remove solvent, gained solid is respectively with methyl alcohol, ether washing Twice, high performance liquid chromatography separates preparation, obtains faint yellow solid (10 mg, productivity 5.3%).1 H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 9.87 (s, 1H), 8.22 (s, 1H), 7.40 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 – 7.17 (m, 2H), 5.80 (s, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.50 (d, J = 6.0 Hz, 2H), 3.60 (br s, 2H), 3.42 (br s, 2H), 2.41(s, 3H), 2.25 (s, 5H)。
Embodiment 11: vitro kinase inhibitory activity is tested
The test of compound external inhibitory activity kinase whose to ABL utilizes the mobility detection technique of microfluidic chip technology (Mobility-Shift Assay) completes；ABL kinases is purchased from Carna Biosciences company.
The mobility detection technique (Mobility-Shift Assay) of microfluidic chip technology is by the base of Capillary Electrophoresis This theory is applied in microfluidic environment, and the substrate for experiment is with fluorescently-labeled polypeptide, enzyme in reaction system Under effect, substrate is changed into product, and its electric charge carried also there occurs corresponding change, and Mobility-Shift Assay is just Utilize substrate and the charged difference of product, the two is separated, and detects respectively.
The source of strength separated sample in micro-fluid chip is in two different aspects, electrodynamics and liquid Pressure.During work, the reaction system in 384 orifice plates is inhaled into chip by the suction needle of chip bottom under the effect of negative pressure In internal pipeline；Owing to being applied in voltage on separate lines in chip, produce with fluorescently-labeled peptide substrate and reaction Thing is separated due to the difference of electric charge, then carries out exciting and detecting of signal at detection window；When detecting each sample, The signal of substrate and product can be simultaneously viewed；The amount of product is by calculating Conversion value, the i.e. aspect ratio at product peak Upper substrate peak and product peak heights sum (Product peak height/(Substrate+Product peak Height)), it is estimated.
In the present embodiment, determine positive drug Dasatinib and obtained compound respectively at 10000nM, Under ten variable concentrations of 3333nM, 1111nM, 370nM, 123nM, 41nM, 14nM, 4.6nM, 1.5nM and 0.51nM, ABL is swashed The inhibitory activity of enzyme；ABL is used ATP Km value is 12 μMs；It is calculated compound to ABL kinase inhibiting activity IC50Value, tool Body result is as shown in table 1；Test result indicate that, the compound of the present invention demonstrates preferable ABL kinase inhibiting activity, allization Compound is to ABL kinase inhibiting activity IC50Being respectively less than 0.6nM, wherein compound 1 and 8 is for ABL kinase inhibiting activity IC50It is worth little In 0.2nM, similar with positive control antineoplastic Dasatinib；Described compound can prepare abl kinase inhibitor, as New antineoplastic.
Embodiment 12: extracorporeal anti-tumor cytoactive is tested
Take and be in the tumour cell kind of Exponential growth stage in 96 orifice plates, cultivate 24 h and make cell attachment, remove supernatant, add 200 μ L/pore area medicine fresh culture: obtained compound is first dissolved in DMSO or physiological saline, is finished during test Full culture medium is diluted to desired concn, and each concentration sets 6 multiple holes, and sets blank control wells (only adding culture medium) and feminine gender is right According to, set 6 multiple holes equally；Continuing to cultivate to the experimental design time, terminate cultivating, remove supernatant, every hole adds 10% trichloroacetic acid 200 μ L, 4 DEG C of conditions are fixed l h, are rinsed 5 times with redistilled water, naturally dry rear every hole and add 4 mg/mL SRB solution, Under room temperature dye 15min, abandon supernatant, with 1% acetic acid rinse 5 times with removal non-specific binding dyestuff, every hole adds 100 μ L 10mM Tris solution, surveys OD value under A490 wavelength, and calculates the measured object inhibiting rate to growth of cancer cells by following equation.
And make regression equation with the logarithm of compound concentration and inhibiting rate, calculate IC50；Result shows, the chemical combination of the present invention Thing all demonstrates preferable antineoplastic activity (as shown in table 1), PC3 prostate gland cancer cell thin to K562 leukemia tumor and The anti tumor activity in vitro IC of MDA-MB-231 breast cancer cell50Value is nM level, and wherein 1,7,8 and 10 couples of K562 of compound are white The extracorporeal anti-tumor IC of blood disease tumour cell50Value is respectively less than 1nM, and the In Vitro Anti of compound 2 and 10 pairs of PC3 prostate gland cancer cells swells Knurl IC50Value is respectively less than 100nM, the compound 1 extracorporeal anti-tumor IC to MDA-MB-231 breast cancer cell50Value is less than 300nM, Close with positive control antineoplastic Dasatinib.The compound of the present invention can prepare new type antineoplastic medicine further.
Table 1 is that the compound of the present invention is to ABL kinase inhibiting activity and extracorporeal anti-tumor cytoactive result.
Table 1

Claims (14)

1.N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-methanamide compound, its feature It is that described compound is that [(2-methyl is phonetic for 6 quaternary heterocycles of pyrimidine or the substituted N-of volution (2-chloro-6-aminomethyl phenyl)-2 Pyridine-4-base) amino] thiazole-5-methanamide compound, there is the structure of logical formula (I),
Wherein
N=1 or 2
X=O or S or SO or SO2Or NCH2CH2OH
R1=OH or OCH3Or F or NHBoc,
R2=H or F.
N-the most according to claim 1 (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound, is characterized in that, described compound is the compound 1 with following structure,
N-the most according to claim 1 (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound, is characterized in that, described compound is the compound 2 with following structure,
N-the most according to claim 1 (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound, is characterized in that, described compound is the compound 3 with following structure,
N-the most according to claim 1 (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound, is characterized in that, described compound is the compound 4 with following structure,
N-the most according to claim 1 (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound, is characterized in that, described compound is the compound 5 with following structure,
N-the most according to claim 1 (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound, is characterized in that, described compound is the compound 6 with following structure,
N-the most according to claim 1 (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound, is characterized in that, described compound is the compound 7 with following structure,
N-the most according to claim 1 (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound, is characterized in that, described compound is the compound 8 with following structure,
N-the most according to claim 1 (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound, is characterized in that, described compound is the compound 9 with following structure,
11. N-according to claim 1 (2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5- Benzamide compound, is characterized in that, described compound is the compound 10 with following structure,
N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-formamide of 12. claims 1 Compound purposes in preparing abl kinase inhibitor.
N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-formamide of 13. claims 1 Compound purposes in preparation treatment malignant tumor medicine.
14. purposes according to claim 13, it is characterised in that described malignant tumour is caused by EGFR-TK functional disturbance Related neoplasms, for the cancer of the brain, lung cancer, kidney, osteocarcinoma, liver cancer, carcinoma of urinary bladder, cancer of the stomach, cancer of pancreas, breast cancer, incidence cancer, esophagus Cancer, prostate cancer, colon cancer, oophoroma, cervix cancer or thyroid cancer.
CN201310179739.9A 2013-05-15 2013-05-15 N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-methanamide compound and its production and use Expired - Fee Related CN104151321B (en)

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