CN104151321A - N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound as well as preparation method and application thereof - Google Patents
N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN104151321A CN104151321A CN201310179739.9A CN201310179739A CN104151321A CN 104151321 A CN104151321 A CN 104151321A CN 201310179739 A CN201310179739 A CN 201310179739A CN 104151321 A CN104151321 A CN 104151321A
- Authority
- CN
- China
- Prior art keywords
- compound
- chloro
- thiazole
- amino
- methylpyrimidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 Cc(cccc1Cl)c1NC(c1cnc(Nc2cc(NCC3(C*)COC3)nc(C)n2)[s]1)=O Chemical compound Cc(cccc1Cl)c1NC(c1cnc(Nc2cc(NCC3(C*)COC3)nc(C)n2)[s]1)=O 0.000 description 1
Classifications
-
- 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 the field of medicament synthesis, relates to an N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound shown in a general formula (b), and in particular relates to a pyrimidine 6-bit four-membered heterocyclic ring or spiro ring substituted N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound, a preparation method of the pyrimidine 6-bit four-membered heterocyclic ring or spiro ring substituted N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound, and an application of the pyrimidine 6-bit four-membered heterocyclic ring or spiro ring substituted N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound in medical science. The compound disclosed by the invention is subjected to in-vitro ABL kinase inhibitory activity and anti-tumor activity tests, and results show that the compound has good ABL kinase inhibitory activity and anti-tumor activity and can be further used for preparing a new anti-tumor medicament.
Description
Technical field
The invention belongs to the synthetic field of medicine, relate to new
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, preparation method and application.Be specifically related to 6 quaternary heterocycles of a kind of pyrimidine or spiral shell cyclosubstituted
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, and preparation method thereof and in application medically.
Background technology
Prior art discloses chronic myelocytic leukemia (chronic myelogenous leukemia, CML) be the blood system malignant clone proliferative disease that betides hemopoietic stem cell, also be one of 4 kinds of modal leukemia, account for the 15%-20% of leukemia case, sickness rate is 1.6/10 ten thousand, at each age group, all can fall ill, take person in middle and old age's case as common.It is reported, in the U.S., CML patient is newly-increased approximately 5000 examples every year, and M-F is 1.4:1, existence surpass 20 years less than 10%.
Studies show that, oncogene c-ABL on No. 9 karyomit(e)s of human body is linked to breakpoint Cu Ji district (the breakpoint cluster region on karyomit(e) No. 22, BCR), form p210 BCR-ABL fusion gene and p185 BCR-ABL fusion gene, BCR-ABL fusion gene is expressed BCR-ABL protein kinase, this kinases plays a significant role at cell signalling with in transforming, it is by phosphorylation and a series of downstreams of activation substrate, cause cell proliferation, stick and the change of the character of surviving, cause producing the generation of chronic myelocytic leukemia and acute myeloblastic leukemia.Because BCR-ABL kinases is not expressed in normal cell, therefore, this area researchist thinks that it is the desirable drug targets for the treatment of CML.
Early 1990s, Novartis Co.,Ltd (Novartis) is by obtaining miazines lead compound to the high flux screening of compound library, synthesized on this basis the micromolecular compound that a series of 2-of take phenylamino pyrimidines are main body, in 1992, find can specific inhibition BCR-ABL Tyrosylprotein kinase active compound STI571, time exploitation through approximately ten years, imatinib (Imatinib, trade(brand)name Gleevec) treatment for CML by U.S. FDA approval May 10 calendar year 2001, this is the BCR-ABL tyrosine kinase inhibitor of first treatment CML, there is epoch-making meaning, by U.S. < < science > > magazine, listed in calendar year 2001 degree ten large science and technology news.
Although the listing of imatinib has obtained huge success, the generation of mutant strain causes the generation of imatinib resistance, in several years after imatinib listing, has some patients were disease relapse, even occurs dead.
Dasatinib was examined by U.S. FDA on June 28th, 2006, was used for the treatment of the acute lymphoblastic leukemia (ph+ALL) of CML and the Philadelphia chromosome positive.Dasatinib comes from lymphocyte Tyrosylprotein kinase (the lymphocyte cell kinase of a kind of Src-family, LCK) inhibitor, it not only can suppress BCR-ABL kinases under nanomolar concentration, and almost can suppress all ABL mutant (except T315I mutant).
Although above-mentioned two kinds of BCR-ABL kinase inhibitor show good curative effect, but due to ever-increasing resistance, and the difference between treatment crowd individuality, force investigator in the industry to need the new micromolecular compound safely and effectively of continuous research and development in order to suppress ABL kinases.
Summary of the invention
The object of this invention is to provide and there is the new of good anti-tumor activity
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, be specifically related to 6 quaternary heterocycles of a kind of pyrimidine or spiral shell cyclosubstituted
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound.
Another object of the present invention is to provide above-mentioned new
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] preparation method of thiazole-5-methanamide compound, relate in particular to prepare 6 quaternary heterocycles of pyrimidine or spiral shell cyclosubstituted
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] method of thiazole-5-methanamide compound.
Of the present invention
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound have following general formula (
i) structure:
Wherein
R=
or
N=1 or 2
X=O or S or SO or SO
2or NCH
2cH
2oH
R
1=OH or OCH
3or F or NHBoc,
R
2=H or F,
In the present invention, preferred compound has following compound
1,
2,
3,
4,
5,
6,
7,8,9,10structure:
1 2
3 4
5 6
7 8
9 10
6 quaternary heterocycles of pyrimidine of the present invention or spiral shell are cyclosubstituted
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] in the preparation method of thiazole-5-methanamide compound, with
n-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl pyrimidine-4-yl) amino] thiazole-5-methane amide is raw material, with N, N-diisopropylethylamine is alkali, carries out nucleophilic substitution reaction obtain described compound in Isosorbide-5-Nitrae-dioxane from different amine.
In the present invention, take compound 1 as example, its preparation process is as follows:
The compound that the present invention makes has carried out the test of ABL kinase inhibiting activity and anti tumor activity in vitro test, result demonstration, and described compound has good ABL kinase inhibiting activity and anti-tumor activity, can further develop as novel antitumor drug.
The present invention suppresses active testing to ABL kinases, result demonstration, and described compound demonstrates good ABL kinase inhibiting activity, and all compounds are to ABL kinase inhibiting activity IC
50all be less than 0.6nM, wherein compound
1with
8for ABL kinase inhibiting activity IC
50value is less than 0.2nM, similar with antitumor drug Dasatinib.
Compound of the present invention can further be prepared abl kinase inhibitor.
The present invention studies by Pharmacodynamic,, PC3 prostate cancer cell thin to K562 leukemia tumour and MDA-MB-231 breast cancer cell carry out anti tumor activity in vitro test, result shows, compound of the present invention is thin to K562 leukemia tumour, PC3 prostate cancer cell and MDA-MB-231 breast cancer cell have compared with powerful antitumor activity, IC
50value is nM level, wherein, and compound
1,
7,
8with
10extracorporeal anti-tumor IC to K562 leukemia tumour cell
50value is all less than 1nM, compound
2with
10extracorporeal anti-tumor IC to PC3 prostate cancer cell
50value is all less than 100nM, compound
1extracorporeal anti-tumor IC to MDA-MB-231 breast cancer cell
50value is less than 300nM, approaches with antitumor drug Dasatinib.
Compound of the present invention can further be prepared new antitumor drug.
In the present invention, the pharmacodynamics test method adopting, is the known method of art technology and personnel.
In the present invention, the ABL kinases adopting and K562 leukemia tumour are thin, PC3 prostate cancer is thin, MDA-MB-231 breast cancer cell is that those skilled in the art can obtain by commercial approach.
In view of BCR – ABL oncogene is the product of Philadelphia chromosome, Philadelphia chromosome is the clinical diagnosis mark of chronic myelocytic leukemia, approximately there are the chronic myelocytic leukemia people of 95 ℅ and 25% acute lymphoblastic leukemia (Acute Lymphoblastic Leukemia, ALL) in grownup and 5% ALL children body, there is Philadelphia chromosome, the albumen (P210) of Bcr/abl oncogene coding tool tyrosine kinase activity, this albumen and cell signaling protein-interacting, upset cell information exchanging process, make CML cell proliferation and differentiation out of control.Therefore, of the present invention
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound especially can prepare the medicine of relative disease due to treatment Tyrosylprotein kinase functional disorder, due to this described BCR-ABL Tyrosylprotein kinase functional disorder, relative disease comprises, acute lymphoblastic leukemia, gastrointestinal stromal glucagonoma and the systemic mastocytosis of just controlling and the complication thereof of the Ph chromatin-positive of chronic myelogenous leukemia (CML), cancer of the stomach, gastrointestinal stromal knurl, acute lymphoblastic leukemia, intractable or recurrence.
embodiment:
Embodiment 1: synthetic compound
1, N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[2-methyl-6-(2-oxa--6-azepine spiroheptane-6-yl) pyrimidine-4-yl] and amino] thiazole-5-methane amide
Under stirring at room, by 2-oxygen-6 nitrogen spiral shell [3,3] heptane oxalate (0.92 g, 0.8 mmol) adds 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (0.3 g, 0.76 mmol) and N, N-diisopropylethylamine (0.56 mL, 1.6 mmol), in Isosorbide-5-Nitrae-dioxane (10 mL) solution, be warming up to backflow, reaction is spent the night, and TLC monitoring raw material disappears.Stopped reaction is down to room temperature, and except desolventizing, gained solid is used respectively methyl alcohol, ether washed twice, and column chromatogram chromatography obtains white solid (20 mg, productive rate 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: synthetic compound
2, N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[2-methyl-6-(2-thia-6-azepine spiroheptane-6-yl) pyrimidine-4-yl] and amino] thiazole-5-methane amide
Under stirring at room, by 2-sulphur-6 nitrogen spiral shell [3,3] heptane oxalate (128mg, 0.4mmol) adds 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (158mg, 0.4mmol) and N, N-diisopropylethylamine (0.56mL, in Isosorbide-5-Nitrae-dioxane 1.6mmol) (5mL) solution, be warming up to backflow, reaction is spent the night, and TLC monitoring raw material disappears.Stopped reaction is down to room temperature, and except desolventizing, gained solid is used respectively methyl alcohol, ether washed twice, and column chromatogram chromatography obtains white solid (10mg, productive rate 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: synthetic compound 3, N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[2-methyl-6-(2-oxygen-2-thia-6-azepine spiroheptane-6-yl) pyrimidine-4-yl] amino] thiazole-5-methane amide
Under stirring at room, 2-oxa--6-thia spiroheptane-6-oxide compound oxalate (55,359 mg, 1.02 mmol) is added to 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (52,200 mg, 0.51 mmol) and DIPEA (0.356 mL, 2.04 mmol) 1, in 4-dioxane (5 mL) solution, be warming up to backflow, reaction is spent the night, and TLC monitoring raw material disappears.Stopped reaction is down to room temperature, and except desolventizing, gained solid is used respectively methyl alcohol, ether washed twice, and the separated preparation of high performance liquid chromatography, obtains faint yellow solid (10 mg, productive rate 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: synthetic compound
4, N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[6 – (2,2-dioxo-2-thia-6-azepine spiroheptane-6-yl)-2-methylpyrimidine-4-yl] and amino] thiazole-5-methane amide
Under stirring at room, by 2-oxa--6-thia spiroheptane 6,6-dioxide oxalate (56,300 mg, 1.27 mmol) add 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (52,300 mg, 0.76 mmol) and N, N-diisopropylethylamine (0.58 mL, 3.3 mmol), in Isosorbide-5-Nitrae-dioxane (5 mL) solution, be warming up to backflow, reaction is spent the night, and TLC monitoring raw material disappears.Stopped reaction is down to room temperature, and except desolventizing, gained solid is used respectively methyl alcohol, ether washed twice, and the separated preparation of high performance liquid chromatography, obtains faint yellow solid (10 mg, productive rate 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: synthetic compound
5, N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[6-(3-methoxyl group azetidine-1-yl)-2-methylpyrimidine-4-yl] and amino] thiazole-5-methane amide
Under stirring at room, 3-methoxyl group azetidine (57,70 mg, 0.8 mmol) is added to 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (52,158 mg, 0.4 mmol) and DIPEA (0.14 mL, 0.8 mmol) 1, in 4-dioxane (5 mL) solution, be warming up to backflow, reaction is spent the night, and TLC monitoring raw material disappears.Stopped reaction is down to room temperature, and except desolventizing, gained solid is used respectively methyl alcohol, ether washed twice, and the separated preparation of high performance liquid chromatography, obtains faint yellow solid (10 mg, productive rate 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: synthetic compound
6, N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[6-(3,3-difluoro azetidine-1-)-2-methylpyrimidine-4-yl] and amino] thiazole-5-methane amide
Under stirring at room, by 3,3-difluoro azetidine hydrochloride (58,104 mg, 0.8 mmol) add 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (52,158 mg, 0.4 mmol) and N, N-diisopropylethylamine (0.14 mL, 0.8 mmol), in Isosorbide-5-Nitrae-dioxane (5 mL) solution, be warming up to backflow, reaction is spent the night, and TLC monitoring raw material disappears.Stopped reaction is down to room temperature, and except desolventizing, gained solid is used respectively methyl alcohol, ether washed twice, and the separated preparation of high performance liquid chromatography, obtains faint yellow solid (10 mg, productive rate 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: synthetic compound
7, the tertiary butyl (1-(6-((5-((the chloro-6-aminomethyl phenyl of 2-) formamyl) thiazole-2-) amino)-2-methylpyrimidine-4-) azetidine-3-) t-butyl carbamate
Under stirring at room, azetidine-3-aminocarbamic acid tert-butyl ester (59,138 mg, 0.8 mmol) is added to 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (52,158 mg, 0.4 mmol) and DIPEA (0.14 mL, 0.8 mmol) 1, in 4-dioxane (5 mL) solution, be warming up to backflow, reaction is spent the night, and TLC monitoring raw material disappears.Stopped reaction is down to room temperature, and except desolventizing, gained solid is used respectively methyl alcohol, ether washed twice, and the separated preparation of high performance liquid chromatography, obtains faint yellow solid (10 mg, productive rate 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: synthetic compound
8, N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[6-[6-(2-hydroxyethyl)-2,6-diaza spiroheptane-2-] and-2-methylpyrimidine-4-yl] amino] thiazole-5-methane amide
Under stirring at room, by 2-(2,6-diaza spiroheptane-2-) ethanol (60,86 mg, 0.6 mmol) add 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (52,158 mg, 0.4 mmol) and N, N-diisopropylethylamine (0.14 mL, 0.8 mmol), in Isosorbide-5-Nitrae-dioxane (5 mL) solution, be warming up to backflow, reaction is spent the night, and TLC monitoring raw material disappears.Stopped reaction is down to room temperature, and except desolventizing, gained solid is used respectively methyl alcohol, ether washed twice, and the separated preparation of high performance liquid chromatography, obtains faint yellow solid (10 mg, productive rate 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: synthetic compound
9, N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[6-(3-hydroxy azetidine-1-)-2-methylpyrimidine-4-yl] and amino] thiazole-5-methane amide
Under stirring at room, 3-hydroxy azetidine (61,58 mg, 0.8 mmol) is added to 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (52,158 mg, 0.4 mmol) and DIPEA (0.14 mL, 0.8 mmol) 1, in 4-dioxane (5 mL) solution, be warming up to backflow, reaction is spent the night, and TLC monitoring raw material disappears.Stopped reaction is down to room temperature, and except desolventizing, gained solid is used respectively methyl alcohol, ether washed twice, and the separated preparation of high performance liquid chromatography, obtains faint yellow solid (10 mg, productive rate 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: synthetic compound
10, N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[2-methyl-6-(2-oxa--6-azaspiro [3.4] octane-6-) pyrimidine-4-yl] and amino] thiazole-5-methane amide
Under stirring at room, 2-oxa--6-azaspiro [3.4] octane (62,50 mg, 0.44 mmol) is added to 2-((6-chloro-2-methyl pyrimidine-4-yl) amino)-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (52,158 mg, 0.4 mmol) and DIPEA (0.14 mL, 0.8 mmol) 1, in 4-dioxane (5 mL) solution, be warming up to backflow, reaction is spent the night, and TLC monitoring raw material disappears.Stopped reaction is down to room temperature, and except desolventizing, gained solid is used respectively methyl alcohol, ether washed twice, and the separated preparation of high performance liquid chromatography, obtains faint yellow solid (10 mg, productive rate 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 suppresses active testing
Compound utilizes the mobility detection technique (Mobility-Shift Assay) of microfluidic chip technology to complete to the kinase whose vitro inhibition active testing of ABL; ABL kinases is purchased from Carna Biosciences company.
The mobility detection technique of microfluidic chip technology (Mobility-Shift Assay) is applied to the basic concept of capillary electrophoresis in microfluidic environment, the substrate that is used for testing is with fluorescently-labeled polypeptide, in reaction system under the effect of enzyme, substrate changes product into, its with electric charge also there is corresponding variation, Mobility-Shift Assay utilizes substrate and the charged difference of product just, and the two is carried out to separation, and detects respectively.
In micro-fluid chip to sample carry out separated source of strength in two different aspect, electrodynamics and liquid pressure.During work, the suction needle by chip bottom under the effect of negative pressure of the reaction system in 384 orifice plates is inhaled in the pipeline of chip internal; Owing to being applied in voltage on separated pipeline in chip, difference separated with fluorescently-labeled peptide substrate and reaction product due to electric charge, then carries out exciting and detecting of signal at detection window; When detecting each sample, can see the signal of substrate and product simultaneously; The amount of product is by calculating Conversion value, i.e. substrate peak and product peak heights sum (Product peak height/(Substrate+Product peak height) in the aspect ratio at product peak), assess.
In the present embodiment, measured respectively positive drug Dasatinib and prepared compound at 10000nM, 3333nM, 1111nM, 370nM, 123nM, 41nM, 14nM, 4.6nM, active to the kinase whose inhibition of ABL under ten different concns of 1.5nM and 0.51nM; It is 12 μ M that ABL is adopted to ATP Km value; Calculate compound to ABL kinase inhibiting activity IC
50value, concrete outcome is as shown in table 1; Experimental result shows, compound of the present invention demonstrates good ABL kinase inhibiting activity, and all compounds are to ABL kinase inhibiting activity IC
50all be less than 0.6nM, wherein compound
1with
8for ABL kinase inhibiting activity IC
50value is less than 0.2nM, similar with positive control antitumor drug Dasatinib; Described compound can be prepared abl kinase inhibitor, as new antitumor drug.
Embodiment 12: the test of extracorporeal anti-tumor cytoactive
Get tumour cell kind in Exponential growth stage in 96 orifice plates, cultivate 24 h and make cell attachment, remove supernatant, add 200 μ L/pore area medicine fresh cultures: prepared compound is first dissolved in DMSO or physiological saline, during test, with perfect medium, be diluted to desired concn, each concentration is established 6 multiple holes, and establishes blank hole (only adding substratum) and negative control, establishes equally 6 multiple holes; Continue to be cultured to the test design time, stop cultivating, remove supernatant, every hole adds 10% trichoroacetic acid(TCA) 200 μ L, 4 ℃ of conditions are l h fixedly, with redistilled water, rinses 5 times, naturally dries rear every hole and adds 4 mg/mL SRB solution, 15min dyes under room temperature, abandon supernatant, with 1% acetic acid, rinse 5 times to remove the dyestuff of non-specific binding, every hole adds 100 μ L 10mM Tris solution, under A490 wavelength, survey OD value, and calculate the inhibiting rate of analyte to growth of cancer cells by following formula.
Control group OD value-treatment group OD value
Inhibiting rate=
* 100%
Control group OD value
And make regression equation with logarithm and the inhibiting rate of compound concentration, calculate IC
50; Result shows, compound of the present invention all demonstrates good antineoplastic activity (as shown in table 1), the anti tumor activity in vitro IC of, PC3 prostate cancer cell thin to K562 leukemia tumour and MDA-MB-231 breast cancer cell
50value is nM level, wherein compound
1,
7,
8with
10extracorporeal anti-tumor IC to K562 leukemia tumour cell
50value is all less than 1nM, compound
2with
10extracorporeal anti-tumor IC to PC3 prostate cancer cell
50value is all less than 100nM, compound
1extracorporeal anti-tumor IC to MDA-MB-231 breast cancer cell
50value is less than 300nM, approaches with positive control antitumor drug Dasatinib.Compound of the present invention can further be prepared new type antineoplastic medicine.
Table 1 is that compound of the present invention is to ABL kinase inhibiting activity and extracorporeal anti-tumor cytoactive result.
Table 1
Claims (14)
1.N-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is that 6 quaternary heterocycles of pyrimidine or spiral shell are cyclosubstituted
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, have general formula (
i) structure,
Wherein
R=
or
N=1 or 2
X=O or S or SO or SO
2or NCH
2cH
2oH
R
1=OH or OCH
3or F or NHBoc,
R
2=H or F.
2. according to claim
1described
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is the compound with following structure
1,
1 。
3. according to claim
1described
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is the compound with following structure
2,
2 。
4. according to claim
1described
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is the compound with following structure
3,
3 。
5. according to claim
1described
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is the compound with following structure
4,
4 。
6. according to claim
1described
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is the compound with following structure
5,
5 。
7. according to claim
1described
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is the compound with following structure
6,
6 。
8. according to claim
1described
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is the compound with following structure
7,
7 。
9. according to claim
1described
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is the compound with following structure
8,
8 。
10. according to claim
1described
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is the compound with following structure
9,
9 。
11. according to claim
1described
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] thiazole-5-methanamide compound, it is characterized in that, described compound is the compound with following structure
10,
10 。
12. claims
1's
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] purposes of thiazole-5-methanamide compound in preparing abl kinase inhibitor.
13. claims
1's
n-(the chloro-6-aminomethyl phenyl of 2-)-2[(2-methylpyrimidine-4-yl) amino] purposes of thiazole-5-methanamide compound in preparation treatment malignant tumor medicine.
14. by the purposes of claim 13, it is characterized in that, described malignant tumour is the related neoplasms due to Tyrosylprotein kinase functional disorder, comprises the cancer of the brain, lung cancer, kidney, osteocarcinoma, liver cancer, bladder cancer, cancer of the stomach, carcinoma of the pancreas, mammary cancer, incidence cancer, esophagus cancer, prostate cancer, colorectal carcinoma, ovarian cancer, cervical cancer or thyroid carcinoma.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310179739.9A CN104151321B (en) | 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 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310179739.9A CN104151321B (en) | 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 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104151321A true CN104151321A (en) | 2014-11-19 |
CN104151321B CN104151321B (en) | 2016-09-07 |
Family
ID=51876974
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310179739.9A Expired - Fee Related CN104151321B (en) | 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 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104151321B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180099959A1 (en) * | 2016-12-13 | 2018-04-12 | Princeton Drug Discovery Inc | Protein kinase inhibitors |
CN114366740A (en) * | 2021-09-18 | 2022-04-19 | 江苏海洋大学 | Application of compound A-6 in preparation of broad-spectrum anticancer drugs |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1348370A (en) * | 1999-04-15 | 2002-05-08 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
WO2005094376A2 (en) * | 2004-03-31 | 2005-10-13 | Bristol-Myers Squibb Company | Synergistic methods and compositions for treating cancer |
CN1764454A (en) * | 2003-03-24 | 2006-04-26 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
WO2006099474A1 (en) * | 2005-03-15 | 2006-09-21 | Bristol-Myers Squibb Company | 'n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamides metabolites |
CN101591357A (en) * | 2008-11-20 | 2009-12-02 | 杜晓敏 | One group is suppressed the kinase whose phosphate/phosphate ester compounds of BCR-ABL |
-
2013
- 2013-05-15 CN CN201310179739.9A patent/CN104151321B/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1348370A (en) * | 1999-04-15 | 2002-05-08 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
CN1764454A (en) * | 2003-03-24 | 2006-04-26 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
WO2005094376A2 (en) * | 2004-03-31 | 2005-10-13 | Bristol-Myers Squibb Company | Synergistic methods and compositions for treating cancer |
WO2006099474A1 (en) * | 2005-03-15 | 2006-09-21 | Bristol-Myers Squibb Company | 'n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamides metabolites |
CN101591357A (en) * | 2008-11-20 | 2009-12-02 | 杜晓敏 | One group is suppressed the kinase whose phosphate/phosphate ester compounds of BCR-ABL |
Non-Patent Citations (2)
Title |
---|
ALBAN J. ALLENTOFF, ET AL.,: "Synthesis of 14C-labeled and 13C-,15N-labeled dasatinib and its piperazine N-dealkyl metabolite", 《J. LABEL COMPD. RADIOPHARM》, vol. 51, no. 1, 8 January 2008 (2008-01-08), pages 41 - 47, XP002601139, DOI: doi:10.1002/jlcr.1469 * |
JIAZHONG LI, ET AL.,: "Validated quantitative structure–activity relationship analysis of a series of 2-aminothiazole based p56Lck inhibitors", 《ANALYTICA CHIMICA ACTA》, vol. 631, no. 1, 21 October 2008 (2008-10-21), pages 29 - 39, XP025713785, DOI: doi:10.1016/j.aca.2008.10.026 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180099959A1 (en) * | 2016-12-13 | 2018-04-12 | Princeton Drug Discovery Inc | Protein kinase inhibitors |
KR20190091312A (en) * | 2016-12-13 | 2019-08-05 | 프린스턴 드러그 디스커버리 인크 | Protein kinase inhibitors |
US10479786B2 (en) * | 2016-12-13 | 2019-11-19 | Princeton Drug Discovery, Inc | Protein kinase inhibitors |
JP2020503376A (en) * | 2016-12-13 | 2020-01-30 | プリンストン ドラッグ ディスカバリー インコーポレイテッド | Protein kinase inhibitor |
US10556897B2 (en) | 2016-12-13 | 2020-02-11 | Princeton Drug Discovery, Inc | Protein kinase inhibitors |
US11236080B2 (en) | 2016-12-13 | 2022-02-01 | Princeton Drug Discovery, Inc | Protein kinase inhibitors |
JP7077335B2 (en) | 2016-12-13 | 2022-05-30 | プリンストン ドラッグ ディスカバリー インコーポレイテッド | Protein kinase inhibitor |
KR102582752B1 (en) | 2016-12-13 | 2023-09-22 | 프린스턴 드러그 디스커버리 인크 | Protein Kinase Inhibitors |
CN114366740A (en) * | 2021-09-18 | 2022-04-19 | 江苏海洋大学 | Application of compound A-6 in preparation of broad-spectrum anticancer drugs |
CN114366740B (en) * | 2021-09-18 | 2023-08-22 | 江苏海洋大学 | Application of compound A-6 in preparation of broad-spectrum anticancer drugs |
Also Published As
Publication number | Publication date |
---|---|
CN104151321B (en) | 2016-09-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107108648B (en) | Thieno [2,3-c] pyrroles's -4- ketone derivatives as ERK inhibitor | |
AU2022206702B2 (en) | Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl compounds | |
CN114057771B (en) | Macrocyclic compounds, their preparation and use | |
US20150246047A1 (en) | Novel egfr modulators and uses thereof | |
HUE031955T2 (en) | Novel pyrrolopyrimidine compounds as inhibitors of protein kinases | |
CN104080773A (en) | Azaheterocyclic compounds | |
US9586965B2 (en) | Pyrrolo[2,3-d]pyrimidine compounds as inhibitors of protein kinases | |
JP6426745B2 (en) | Conformationally immobilized PI3K and mTOR inhibitors | |
WO2021074251A1 (en) | Pyrrolo[2,3-d]pyrimidine derivatives and their use in the treatment of cancer | |
El-Moghazy et al. | Novel pyrazolo [3, 4-d] pyrimidines as dual Src-Abl inhibitors active against mutant form of Abl and the leukemia K-562 cell line | |
CN104151321A (en) | N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound as well as preparation method and application thereof | |
JP2024023246A (en) | Agents to differentiate stem cells and treat cancer | |
CN103360407B (en) | A kind of Thienopyrimidine analog derivative, its preparation method and in application pharmaceutically | |
JP6826526B6 (en) | Quinoxaline compounds, how to prepare them and their use | |
KR20230026445A (en) | Aryl Oxide Compounds and Uses Thereof | |
CN103772411B (en) | Sulfur-bearing 6-furyl quinazoline-4-amines and its production and use | |
CA3188077A1 (en) | Egfr inhibitor, preparation method therefor and application thereof | |
CA3148436A1 (en) | Application of fluoro-substituted 2-aminothiazole-5-aromatic carboxamide | |
CN104119351A (en) | 4-(3-chloro-4-fluorophenylamino)-7-methoxy-quinazoline compounds, and preparation method and application thereof | |
WO2021032129A1 (en) | Kinase inhibitor, preparation therefor, pharmaceutical composition thereof and use thereof | |
CN103772371A (en) | 6-furyl quinazoline-4-amine compound as well as preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160907 Termination date: 20200515 |
|
CF01 | Termination of patent right due to non-payment of annual fee |