CN104262262B - A kind of N, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor and its preparation method and application - Google Patents
A kind of N, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor and its preparation method and application Download PDFInfo
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- CN104262262B CN104262262B CN201410437921.4A CN201410437921A CN104262262B CN 104262262 B CN104262262 B CN 104262262B CN 201410437921 A CN201410437921 A CN 201410437921A CN 104262262 B CN104262262 B CN 104262262B
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- -1 phenylbenzene pyrimidine-4-amine class Chemical class 0.000 title claims abstract description 51
- 229940118364 Bcr-Abl inhibitor Drugs 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 89
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 97
- 239000000243 solution Substances 0.000 claims description 66
- KWNPRVWFJOSGMZ-UHFFFAOYSA-N 2-boronobenzoic acid Chemical compound OB(O)C1=CC=CC=C1C(O)=O KWNPRVWFJOSGMZ-UHFFFAOYSA-N 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- 239000000706 filtrate Substances 0.000 claims description 19
- 239000012074 organic phase Substances 0.000 claims description 19
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 18
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 claims description 12
- LBBMOAOCCQOIAQ-UHFFFAOYSA-N methoxy(phenyl)borinic acid Chemical compound COB(O)C1=CC=CC=C1 LBBMOAOCCQOIAQ-UHFFFAOYSA-N 0.000 claims description 11
- NHWKHNPRDPAXLM-UHFFFAOYSA-N n-(2-aminoethyl)benzamide Chemical compound NCCNC(=O)C1=CC=CC=C1 NHWKHNPRDPAXLM-UHFFFAOYSA-N 0.000 claims description 11
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 10
- 238000013019 agitation Methods 0.000 claims description 10
- HCFPRFJJTHMING-UHFFFAOYSA-N ethane-1,2-diamine;hydron;chloride Chemical compound [Cl-].NCC[NH3+] HCFPRFJJTHMING-UHFFFAOYSA-N 0.000 claims description 10
- ZBTMRBYMKUEVEU-UHFFFAOYSA-N 1-bromo-4-methylbenzene Chemical compound CC1=CC=C(Br)C=C1 ZBTMRBYMKUEVEU-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
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- 239000011780 sodium chloride Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 7
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 5
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- 238000010992 reflux Methods 0.000 claims description 4
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- NFGNNSSFOGRWAJ-UHFFFAOYSA-N 2-pyrimidin-4-ylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=NC=N1 NFGNNSSFOGRWAJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000003747 Grignard reaction Methods 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
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- 239000011737 fluorine Substances 0.000 claims description 2
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- 239000012048 reactive intermediate Substances 0.000 claims description 2
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 18
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 abstract description 12
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 abstract description 12
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- 101000823316 Homo sapiens Tyrosine-protein kinase ABL1 Proteins 0.000 abstract description 5
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- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
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- 125000001302 tertiary amino group Chemical group 0.000 abstract 1
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- 239000000047 product Substances 0.000 description 19
- 230000000694 effects Effects 0.000 description 17
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 16
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 14
- FQXQBFUUVCDIRK-UHFFFAOYSA-N 3-trifluoromethylbenzoic acid Chemical compound OC(=O)C1=CC=CC(C(F)(F)F)=C1 FQXQBFUUVCDIRK-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 108091000080 Phosphotransferase Proteins 0.000 description 8
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- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
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- 229940125773 compound 10 Drugs 0.000 description 6
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 6
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 150000008064 anhydrides Chemical class 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
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- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 5
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- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- RUVWGQHNZCDFBC-UHFFFAOYSA-N n-(2-aminoethyl)-2-chlorobenzamide Chemical compound NCCNC(=O)C1=CC=CC=C1Cl RUVWGQHNZCDFBC-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- NEGFNJRAUMCZMY-UHFFFAOYSA-N 3-(dimethylamino)benzoic acid Chemical compound CN(C)C1=CC=CC(C(O)=O)=C1 NEGFNJRAUMCZMY-UHFFFAOYSA-N 0.000 description 2
- KDVYCTOWXSLNNI-UHFFFAOYSA-N 4-t-Butylbenzoic acid Chemical compound CC(C)(C)C1=CC=C(C(O)=O)C=C1 KDVYCTOWXSLNNI-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
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- 239000012286 potassium permanganate Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 150000003512 tertiary amines Chemical group 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- JUVDEAXMLQQRFP-UHFFFAOYSA-N 1h-imidazol-2-yl(phenyl)methanone Chemical compound C=1C=CC=CC=1C(=O)C1=NC=CN1 JUVDEAXMLQQRFP-UHFFFAOYSA-N 0.000 description 1
- XNTIGDVFBDJLTQ-UHFFFAOYSA-N 2-chloro-6-fluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC=C1Cl XNTIGDVFBDJLTQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- XNBIQVTWZIVWTO-UHFFFAOYSA-N COc(cc1)ccc1Nc1ncnc(-c(cc2)ccc2C(NCCNC(c(c(Cl)ccc2)c2F)=O)=O)c1 Chemical compound COc(cc1)ccc1Nc1ncnc(-c(cc2)ccc2C(NCCNC(c(c(Cl)ccc2)c2F)=O)=O)c1 XNBIQVTWZIVWTO-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 108010056708 bcr-abl Fusion Proteins Proteins 0.000 description 1
- 102000004441 bcr-abl Fusion Proteins Human genes 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000003995 blood forming stem cell Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
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- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a kind of N, and 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor and its preparation method and application, the structural formula of this inhibitor is
Description
Technical field
The invention belongs to biomedicine technical field, it relates to a kind of antineoplastic compound, in particular to a kind of N, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor and its preparation method and application.
Background technology
Chronic granulocytic leukemia (CML) a kind of the blood system sex clone proliferative disease in hemopoietic stem cell occurs, and is also the most common a kind of leukemia. In western countries, CML accounts for into the 15-20% of human leukemia, all can fall ill at each age group, taking person in middle and old age's case as common. CML is by t (9; 22) (q34; Q11) the Bcr-Abl albumen of breaking point Cu Ji district-Ai Beierxun leukosis virus (BCR-ABL) the fusion gene overexpression that chromosome translocation is formed causes. At present, occur that multiple is the micromolecular inhibitor of target for BCR-ABL, but all there is drug resistance problems, therefore Bcr-Abl mutant drug-resistant is a big difficult problem, the thereupon research and development of novel B cr-Abl inhibitor just one of focus becoming pharmaceutical field of this research field.
Summary of the invention
The problem that the present invention solves is to provide a kind of N, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor and its preparation method and application, it is possible to be applied to the preparation of antitumor drug.
For achieving the above object, the present invention is achieved through the following technical solutions:
A kind of N, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, have following structural formula:
Wherein, R base is monosubstituted base or disubstituted, and substituting group is alkyl, halogen or tertiary amine groups.
When described R base is monosubstituted base, ortho position, a position or the contraposition that substituting group is positioned on phenyl ring carboxyl;
When described R base is disubstituted, two substituting groups are identical or different, and the position of substitution is adjacent or alternate.
A kind of N, the preparation method of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, comprises the following steps:
1) 4,6-dichloro pyrimidine and P-nethoxyaniline generation electrophilic substitution reaction obtain the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine;
2) the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine and Carboxybenzeneboronic acid is obtained 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl by SUZUKI linked reaction phenylformic acid;
3) preparation of N-(2-amino-ethyl) benzamide: containing phenylformic acid and the N of different substituents, N-carbonyl dimidazoles is obtained by reacting reactive intermediate, then is obtained by reacting the N-containing different substituents (2-amino-ethyl) benzamide with ethylenediamine monohydrochloride salt;
4) 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid obtains N by mixed acid anhydride method, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor with containing N-(2-amino-ethyl) benzamide of different substituents.
Described N, the preparation of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor comprises the following steps:
Described step 1) be specifically operating as: by 4,6-dichloro pyrimidine and P-nethoxyaniline are dissolved in anhydrous isopropyl alcohol, add the vitriol oil of catalytic amount under agitation, heating reflux reaction, reaction solution is put into cold the putting of refrigerator and is spent the night after terminating by reaction, takes out filter after precipitating out solid, filter cake dehydrated alcohol recrystallization, obtains the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine;
Described step 2) be specifically operating as: by chloro-for 6-N-(4-p-methoxy-phenyl) pyrimidine 4-amine, Carboxybenzeneboronic acid, tetra-triphenylphosphine palladium and cesium carbonate are dissolved in the mixing solutions of acetonitrile and water, it is warming up to 90 DEG C of reactions 12 hours, reaction takes out filter after terminating, filtrate be cooled to room temperature after with salt acid for adjusting pH value to precipitating out solid, then filter, obtain 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl phenylformic acid.
Described step 3) be specifically operating as: will containing the phenylformic acid of different substituents and N, N-carbonyl dimidazoles joins in beaker, and mechanical stirring forms dope to reaction system; Then, under agitation, disposable add quadrol and the mixed sodium chloride solution of ethylenediamine-hydrochloride, reaction 4h, reaction takes out filter after terminating, and filtrate is adjusted to pH=10 with sodium hydroxide solution, then with dichloromethane extraction, merge organic phase, then use anhydrous sodium sulfate drying organic phase, must containing N-(2-amino-ethyl) benzamide of different substituents.
Described step 4) be specifically operating as: by 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid and 4-methylmorpholine join in anhydrous methylene chloride successively, under condition of ice bath, drip the dichloromethane solution adding isobutyl chlorocarbonate, at 0 DEG C, react 30��40min; After having reacted, under condition of ice bath, drip the dichloromethane solution of N-(2-amino-ethyl) benzamide and the 4-methylmorpholine added containing different substituents, after dripping, remove ice bath, rise to room temperature reaction and spend the night, after reaction terminates, add methylene dichloride dilution, washing, organic phase is dry with anhydrous slufuric acid ammonium, then through column chromatography separating purification, obtain N, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor.
The described preparation process to Carboxybenzeneboronic acid is: para-bromo toluene prepares grignard reagent by grignard reaction, grignard reagent and trimethyl borate are obtained by reacting methylphenylboronic acid ester, methylphenylboronic acid Ester hydrolysis is obtained methylphenylboronic acid, methylphenylboronic acid oxidation is obtained Carboxybenzeneboronic acid.
The preparation process of Carboxybenzeneboronic acid is specially: Mg bar and iodine are added in reaction flask, with nitrogen protection, add the anhydrous THF solution to first bromobenzene in a heated condition, back flow reaction, room temperature it is cooled to after having reacted, reaction unit is transferred in low-temp reaction instrument, add the anhydrous THF solution of trimethyl borate, room temperature reaction, add HCl solution afterwards to be hydrolyzed, after reacting completely, revolve except THF, aqueous phase is extracted with ethyl acetate, merge organic phase, with anhydrous sodium sulfate drying, take out filter, filtrate is revolved except solvent, dehydrated alcohol recrystallization must to methylphenylboronic acid,To methylphenylboronic acid be dissolved in the NaOH solution of 1mol/L under condition of ice bath, it is added dropwise to KMnO afterwards4, Tetrabutyl amonium bromide the aqueous solution in, after dripping, remove ice bath, rise to room temperature reaction and spend the night, add a small amount of ethanol cancellation after having reacted, then take out filter, filtrate, obtains Carboxybenzeneboronic acid to precipitating out solid by concentrated hydrochloric acid adjust ph.
Described N, the application of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor in preparation Bcr-Abl inhibitor medicaments.
Described N, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor are in the application prepared in antitumor drug.
Described antitumor drug is the medicine for the treatment of leukemia.
Compared with prior art, the present invention has following useful effect:
N provided by the invention, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, are the novel compounds with anti-Bcr-Abl kinase activity, in vitro Bcr-Abl kinases are had good inhibit activities. Bcr-Abl kinases plays a significant role in cell signalling and conversion, and it impels the ripe unlimited hyperplasia of granulocyte of CML by phosphorylation and a series of stream substrates of activation. Bcr-Abl does not express in normal cell, is the desirable target for the treatment of CML. By suppressing, Bcr-Abl kinase activity can reach the object for the treatment of CML to Bcr-Abl inhibitor. Experimental result shows the N prepared by the present invention, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor can suppress the active of Bcr-Abl and the growth of inhibition tumor cell and propagation effectively, N prepared by explanation, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor can be used for preparation Bcr-Abl inhibitor medicaments and antitumor drug.
N provided by the invention, the preparation method of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, has raw material and is easy to get, and reaction conditions is gentle, and reaction process is simple to operate, the advantage that agents useful for same is cheap.
Accompanying drawing explanation
Fig. 1 is N, the synthetic route chart of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor;
Wherein compound 1 is para-bromo toluene, and compound 2 is the grignard reagent of para-bromo toluene, and compound 3 is to methylphenylboronic acid, compound is 4 is to Carboxybenzeneboronic acid, compound 5 is 4, 6-dichloro pyrimidine, compound 6 is P-nethoxyaniline, compound 7 is the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine, compound 8 is 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid, compound 9 is the phenylformic acid of different substituents, compound 10 is the benzoyl imidazole intermediates of different substituents, compound 11 is N-(2-amino-ethyl) benzamide of different substituents, compound E1-E10 is target compound and N, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor.
What mark in figure is specially:
(a).Mg,I2, THF, backflow, N2; (b) B (OMe)3, THF ,-20 DEG C; (c) .NaOH (1M), KMnO4,TBAB,H2O; (d) conc.H2SO4, i-PrOH, backflow; (e) Pd (Pph3)4,Cs2CO3,CH3CN/H2O (V:V=3:2), 90 DEG C; (f) CDI, r.t., 30min; (g) DEA/ethylenediaminehydrochloride (1:1), NaCl (20%), r.t.; (h) ClCOO-iBu, NMM, DCM, 0 DEG C; Monoacylateddiethylamine, NMM, DCM, 0 DEG C �� r.t.
Embodiment
The present invention provides the N of a kind of tool anti-tumor activity, and 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, such inhibitor embodies Bcr-Abl kinase inhibiting activity in vitro, it is possible to be applied to the preparation of antitumor drug.
The present invention being described in detail below in conjunction with drawings and Examples, the explanation of the invention is not limited.
The N with anti-tumor activity provided by the invention, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, its chemical structural formula is:
Wherein, R base is monosubstituted base or disubstituted, and substituting group is alkyl, halogen or tertiary amine groups.
Further, when described R base is monosubstituted base, ortho position, a position or the contraposition that substituting group is positioned on phenyl ring carboxyl;
When described R base is disubstituted, two substituting groups are identical or different, and the position of substitution is adjacent or alternate.
Below in conjunction with the synthetic route shown in Fig. 1 and concrete synthesis example, N is described in detail, the preparation method of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor and screening active ingredients.
Embodiment 1
In the structural formula of this inhibitor, R base is m-trifluoromethyl, is prepared by following step:
1) to the preparation of Carboxybenzeneboronic acid (compound 4)
Adding Mg bar (2.15g, 90mmol) processed in the two-neck bottle of 250ml, 2 iodine, nitrogen protection, vacuumizes 3 times. compound is slowly added to first bromobenzene (compound 1 in a heated condition with syringe, anhydrous THF solution 60mmol), reaction is in reflux state after causing, continue to add surplus solution, add rear back flow reaction 5 hours, obtain the grignard reagent (compound 2) of para-bromo toluene, after being cooled to room temperature, reaction unit is transferred in low-temp reaction instrument, temperature is adjusted to-20 DEG C, trimethyl borate (9.36g is added with syringe after 5 minutes, anhydrous THF solution 90mmol), add rear room temperature reaction 3 hours, the HCl solution adding 100ml2mol/L afterwards is hydrolyzed reaction, TLC detection reaction. after reacting completely, decompression is revolved except THF, aqueous phase is extracted with ethyl acetate 3 times, merging the organic phase of extraction, organic phase washed with water, saturated common salt are washed to neutrality, then with anhydrous sodium sulfate drying, take out filter, filtrate decompression is revolved except solvent, and dehydrated alcohol recrystallization must to methylphenylboronic acid (compound 3) 4.66g, product rate 57%.
Methylphenylboronic acid (compound 3,4.66g, 34.26mmol) will be dissolved in the NaOH solution (103mL) of 1mol/L under condition of ice bath. After to be dissolved, under condition of ice bath, above-mentioned solution is added drop-wise to KMnO4In water (340mL) solution of (16.24g, 102.79mmol), Tetrabutyl amonium bromide (0.34g). After dripping, remove ice bath, rise to room temperature reaction and spend the night. Reaction adds a small amount of ethanol cancellation, takes out filter after terminating, and filtrate is adjusted to pH=2 with concentrated hydrochloric acid, precipitates out solid, obtains Carboxybenzeneboronic acid (compound 4) 5.69g.
2) preparation of the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7)
4,6-dichloro pyrimidine (compound 5,3.88g, 26mmol) it is dissolved in 30ml Virahol with P-nethoxyaniline (4-anisidine) (compound 6,2.46g, 20mmol), add vitriol oil 1.4ml under agitation, afterwards heating reflux reaction 5h. Reaction solution is put into refrigerator after terminating by reaction, and cold putting is spent the night, and precipitates out solid, takes out filter, and filter cake dehydrated alcohol recrystallization, obtains product 4.29g, product rate 91%.
3) the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7) and Carboxybenzeneboronic acid (compound 4) is obtained 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl by SUZUKI linked reaction phenylformic acid (compound 8)
In 250ml reaction flask, add Carboxybenzeneboronic acid (compound 4,2.49g, 15mmol), the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7,3.53g, 15mmol), tetra-triphenylphosphine palladium (0.9g, 0.75mmol), anhydrous cesium carbonate (19.5g, 60mmol), adds acetonitrile/water (V:V=3:2) 160ml afterwards.N2Protection, oil bath is warming up to 90 DEG C of reaction 12h. Reaction takes out filter after terminating while hot, and filtrate is adjusted to pH=4 with 6mol/L hydrochloric acid, precipitates out solid, takes out filter, and filter cake is 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (compound 8) 3.86g, product rate 80%.
4) m-trifluoromethylbenzoic acid (compound 9) and quadrol obtain N-(2-amino-ethyl)-3-trifluoromethyl benzamide (compound 11) by CDI condensation
By m-trifluoromethylbenzoic acid (compound 9,10mmol), N, N-carbonyl dimidazoles (1.94g, 12mmol) joining in 100ml beaker, mechanical stirring forms dope and active intermediate (compound 10) to reaction system.
Under agitation, disposable 20% sodium chloride solution (4gNaCl/20ml water) adding quadrol (3.34ml, 50mmol) and ethylenediamine-hydrochloride (6.65g, 50mmol), reaction 4h, TLC detection (chlorine: first=10:1). Reaction takes out filter after terminating, and filtrate is adjusted to pH=10 with sodium hydroxide solution, with dichloromethane extraction (20ml �� 3), merges organic phase, anhydrous sodium sulfate drying. Taking out filter, filtrate is revolved except solvent, obtains product N-(2-amino-ethyl)-3-trifluoromethyl benzamide benzamide (compound 11) 1.94g, product rate 70%.
5) 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (compound 8) and N-(2-amino-ethyl)-3-trifluoromethyl benzamide (compound 11) obtain target compound E1 by mixed anhydride method
In 100ml reaction flask, by 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (compound 8,1.28g, 4.0mmol), 4-methylmorpholine (1.3ml, 12mmol) joins in 15ml anhydrous methylene chloride successively. Under condition of ice bath, methylene dichloride (8ml) solution of isobutyl chlorocarbonate (0.8ml, 6mmol) is slowly added drop-wise in above-mentioned solution, reacts 30 minutes at 0 DEG C. After having reacted, under condition of ice bath, the dichloromethane solution (10ml) of N-(2-amino-ethyl)-3-trifluoromethyl benzamide (compound 11,6mmol) and 4-methylmorpholine (1.3ml, 12mmol) is joined in above-mentioned reaction system. After dripping, remove ice bath, rise to room temperature reaction and spend the night. After reaction terminates, adding methylene dichloride (20ml) dilution, washing (10mL �� 2), saturated sodium carbonate solution is washed (10mL �� 3), and saturated nacl aqueous solution is washed (10mL). Organic phase is dry with anhydrous slufuric acid ammonium, then through column chromatography separating purification (sherwood oil: ethyl acetate=1:5), obtains target compound E10.53g, product rate 25%.
The structure of gained compound is as follows:
Its physico-chemical property is: Mp240-242 DEG C, EI-MS (m/z): 535.2 [M]+��
Hydrogen spectrum nuclear magnetic resonance data:1HNMR(400MHz,DMSO-d6): ��=8.67 (s, 1H), 8.20 (s, 1H), 8.16 (d, J=7.8Hz, 1H), 8.09 (d, J=8.2Hz, 2H), 7.99 (d, J=8.2Hz, 2H), 7.92 (d, J=7.8Hz, 1H), 7.73 (t, J=7.8Hz, 1H), 7.58 (d, J=8.7Hz, 2H), 7.19 (s, 1H), 6.95 (d, J=8.8Hz, 2H), 3.75 (s, 3H), 3.49 (s, 4H).
Embodiment 2
In the structural formula of this inhibitor, wherein R base is adjacent chlorine, is prepared by following step
Step 1)��3) with embodiment 1 in step 1)��3) identical, namely prepare Carboxybenzeneboronic acid (compound 4) by para-bromo toluene (compound 1), 4, 6-dichloro pyrimidine and P-nethoxyaniline obtain the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7) by electrophilic substitution reaction, the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7) and Carboxybenzeneboronic acid (compound 4) is obtained 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl by SUZUKI linked reaction phenylformic acid (compound 8).
4) 0-chloro-benzoic acid (compound 9) and quadrol obtain N-(2-amino-ethyl)-2-chlorobenzamide (compound 11) by CDI condensation
By 0-chloro-benzoic acid (compound 9,10mmol), N, N '-carbonyl dimidazoles (1.94g, 12mmol) joins in 100ml beaker, and mechanical stirring forms dope and active intermediate (compound 10) to reaction system.
Under agitation, disposable 20% sodium chloride solution (4gNaCl/20ml water) adding quadrol (3.34ml, 50mmol) and ethylenediamine-hydrochloride (6.65g, 50mmol), reaction 4h, TLC detection (chlorine: first=10:1). Reaction takes out filter after terminating, and filtrate is adjusted to pH=10 with sodium hydroxide solution, with dichloromethane extraction (20ml �� 3), merges organic phase, then through anhydrous sodium sulfate drying. Taking out filter, filtrate is revolved except solvent, obtains product N-(2-amino-ethyl)-2-chlorobenzamide benzamide (compound 11) 1.68g, product rate 85%.
5) 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (compound 8) and N-(2-amino-ethyl)-2-chlorobenzamide (compound 11) obtain target compound E5 by mixed anhydride method
In 100ml reaction flask, by 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (compound 8,1.28g, 4.0mmol), 4-methylmorpholine (1.3ml, 12mmol) joins in 15ml anhydrous methylene chloride successively. Under condition of ice bath, methylene dichloride (8ml) solution of isobutyl chlorocarbonate (0.8ml, 6mmol) is slowly added drop-wise in above-mentioned solution, reacts 40 minutes at 0 DEG C. After having reacted, under condition of ice bath, the dichloromethane solution (10ml) of N-(2-amino-ethyl)-2-chlorobenzamide (compound 11,6mmol) and 4-methylmorpholine (1.3ml, 12mmol) is joined in above-mentioned reaction system. After dripping, remove ice bath, rise to room temperature reaction and spend the night. After reaction terminates, adding methylene dichloride (20ml) dilution, washing (10mL �� 2), saturated sodium carbonate solution is washed (10mL �� 3), and saturated nacl aqueous solution is washed (10mL). Organic phase is dry with anhydrous slufuric acid ammonium, then through column chromatography separating purification (sherwood oil: ethyl acetate=1:1), obtains target compound E50.6g, product rate 30%.
Gained compound structure is as follows:
Its physico-chemical property is: Mp226-228 DEG C, EI-MS (m/z): 501.0 [M]+��
Hydrogen spectrum nuclear magnetic resonance data:1HNMR (400MHz, DMSO-d6): ��=8.67 (s, 1H), 8.09 (d, J=8.5Hz, 2H), 7.99 (d, J=8.5Hz, 2H), 7.58 (d, J=8.9Hz, 2H), 7.49 (d, J=2.0Hz, 1H), 7.48 7.44 (m, 1H), 7.40 (dd, J=7.2,1.5Hz, 2H), 7.19 (s, 1H), 6.95 (d, J=9.0Hz, 2H), 3.76 (s, 3H), 3.53 3.40 (m, 4H).
Embodiment 3
In the structural formula of this inhibitor, R base is to the tertiary butyl, is prepared by following step
Step 1)��3) with embodiment 1 in step 1)��3) identical, namely prepare Carboxybenzeneboronic acid (compound 4) by para-bromo toluene (compound 1), 4, 6-dichloro pyrimidine and P-nethoxyaniline obtain the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7) by electrophilic substitution reaction, the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7) and Carboxybenzeneboronic acid (compound 4) is obtained 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl by SUZUKI linked reaction phenylformic acid (compound 8).
4) p-tert-butyl benzoic acid (compound 9) and quadrol obtain N-(2-amino-ethyl)-4-tert.-butylbenzene acid amides (compound 11) by CDI condensation
By p-tert-butyl benzoic acid (compound 9,10mmol), N, N '-carbonyl dimidazoles (1.94g, 12mmol) joining in 100ml beaker, mechanical stirring forms dope and active intermediate (compound 10) to reaction system.
Under agitation, disposable 20% sodium chloride solution (4gNaCl/20ml water) adding quadrol (3.34ml, 50mmol) and ethylenediamine-hydrochloride (6.65g, 50mmol), reaction 4h, TLC detection (chlorine: first=10:1). Reaction takes out filter after terminating, and filtrate is adjusted to pH=10 with sodium hydroxide solution, with dichloromethane extraction (20ml �� 3), merges organic phase, then through anhydrous sodium sulfate drying. Taking out filter, filtrate is revolved except solvent, obtains product N-(2-amino-ethyl)-4-tert.-butylbenzene acid amides (compound 11) 1.32g, product rate 60%.
5) 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (compound 8) and N-(2-amino-ethyl)-4-tert.-butylbenzene acid amides (compound 11) obtain target compound E6 by mixed anhydride method
In 100ml reaction flask, by 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (compound 8,1.28g, 4.0mmol), 4-methylmorpholine (1.3ml, 12mmol) joins in 15ml anhydrous methylene chloride successively. Under condition of ice bath, methylene dichloride (8ml) solution of isobutyl chlorocarbonate (0.8ml, 6mmol) is slowly added drop-wise in above-mentioned solution, reacts 35 minutes at 0 DEG C. After having reacted, under condition of ice bath, the dichloromethane solution (10ml) of N-(2-amino-ethyl)-4-tert.-butylbenzene acid amides (compound 11,6mmol) and 4-methylmorpholine (1.3ml, 12mmol) is joined in above-mentioned reaction system. After dripping, remove ice bath, rise to room temperature reaction and spend the night. After reaction terminates, adding methylene dichloride (20ml) dilution, washing (10mL �� 2), saturated sodium carbonate solution is washed (10mL �� 3), and saturated nacl aqueous solution is washed (10mL). Organic phase anhydrous slufuric acid ammonium is dry, and column chromatography separating purification (sherwood oil: ethyl acetate=1:3), obtains target compound E60.58g, product rate 28%.
Gained compound structure is as follows:
Its physico-chemical property is: Mp260-261 DEG C, EI-MS (m/z): 523.1 [M]+��
Hydrogen spectrum nuclear magnetic resonance data:1HNMR (400MHz, DMSO-d6): ��=8.67 (s, 1H), 8.09 (d, J=8.1Hz, 2H), 7.99 (d, J=8.1Hz, 2H), 7.80 (d, J=8.2Hz, 2H), 7.58 (d, J=8.5Hz, 2H), 7.48 (d, J=8.1Hz, 2H), 7.19 (s, 1H), 6.95 (d, J=8.8Hz, 2H), 3.76 (s, 3H), 3.46 (s, 4H), 1.30 (s, 9H).
Embodiment 4
In the structural formula of this inhibitor, R base is m-dimethyl amino, is prepared by following step
Step 1)��3) with embodiment 1 in step 1)��3) identical, namely prepare Carboxybenzeneboronic acid (compound 4) by para-bromo toluene (compound 1), 4, 6-dichloro pyrimidine and P-nethoxyaniline obtain the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7) by electrophilic substitution reaction, the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7) and Carboxybenzeneboronic acid (compound 4) is obtained 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl by SUZUKI linked reaction phenylformic acid (compound 8).
4) m-dimethyl amino benzoic acid (compound 9) and quadrol obtain N-(2-amino-ethyl)-3-dimethylamino benzamide (compound 11) by CDI condensation
By m-dimethyl amino benzoic acid (compound 9,10mmol), N, N '-carbonyl dimidazoles (1.94g, 12mmol) joining in 100ml beaker, mechanical stirring forms dope and active intermediate (compound 10) to reaction system.
Under agitation, disposable 20% sodium chloride solution (4gNaCl/20ml water) adding quadrol (3.34ml, 50mmol) and ethylenediamine-hydrochloride (6.65g, 50mmol), reaction 4h, TLC detection (chlorine: first=10:1).Reaction takes out filter after terminating, and filtrate is adjusted to pH=10 with sodium hydroxide solution, with dichloromethane extraction (20ml �� 3), merges organic phase, then through anhydrous sodium sulfate drying. Taking out filter, filtrate is revolved except solvent, obtains product N-(2-amino-ethyl)-3-dimethylamino benzamide (compound 11) 1.35g, product rate 65%.
5) 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (8) and N-(2-amino-ethyl)-3-dimethylamino benzamide (compound 11) obtain target compound E7 by mixed anhydride method
In 100ml reaction flask, by 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (compound 8,1.28g, 4.0mmol), 4-methylmorpholine (1.3ml, 12mmol) joins in 15ml anhydrous methylene chloride successively. Under condition of ice bath, methylene dichloride (8ml) solution of isobutyl chlorocarbonate (0.8ml, 6mmol) is slowly added drop-wise in above-mentioned solution, reacts 30 minutes at 0 DEG C. After having reacted, under condition of ice bath, the dichloromethane solution (10ml) of N-(2-amino-ethyl)-3-dimethylamino benzamide (compound 11,6mmol) and 4-methylmorpholine (1.3ml, 12mmol) is joined in above-mentioned reaction system. After dripping, remove ice bath, rise to room temperature reaction and spend the night. After reaction terminates, adding methylene dichloride (20ml) dilution, washing (10mL �� 2), saturated sodium carbonate solution is washed (10mL �� 3), and saturated nacl aqueous solution is washed (10mL). Organic phase is dry with anhydrous slufuric acid ammonium, then through column chromatography separating purification (sherwood oil: ethyl acetate=1:5), obtains target compound E70.41g, product rate 20%.
Gained compound structure is as follows:
Its physico-chemical property is: Mp190-193 DEG C, EI-MS (m/z): 510.2 [M]+��
Hydrogen spectrum nuclear magnetic resonance data:1HNMR (400MHz, DMSO-d6): ��=8.67 (s, 1H), 8.09 (d, J=8.0Hz, 2H), 7.99 (d, J=8.2Hz, 2H), 7.58 (d, J=8.5Hz, 2H), 7.29 7.21 (m, 1H), 7.18 (d, J=10.3Hz, 2H), 7.13 (d, J=7.6Hz, 2H), 6.95 (d, J=8.6Hz, 2H), 6.87 (d, 1H), 3.76 (s, 3H), 3.46 (s, 4H), 2.93 (s, 6H).
Embodiment 5
In the structural formula of this inhibitor, R base is the chloro-6-fluorine of 2-, is prepared by following step
Step 1)��3) with embodiment 1 in step 1)��3) identical, namely prepare Carboxybenzeneboronic acid (compound 4) by para-bromo toluene (compound 1), 4, 6-dichloro pyrimidine and P-nethoxyaniline obtain the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7) by electrophilic substitution reaction, the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine (compound 7) and Carboxybenzeneboronic acid (compound 4) is obtained 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl by SUZUKI linked reaction phenylformic acid (compound 8).
4) 2-chloro-6-fluorobenzoic acid (compound 9) and quadrol obtain the chloro-6-fluorobenzene acid amides (compound 11) of N-(2-amino-ethyl)-2-by CDI condensation
By chloro-for 2-6-fluorobenzoic acid (compound 9,10mmol), N, N '-carbonyl dimidazoles (1.94g, 12mmol) joining in 100ml beaker, mechanical stirring forms dope and active intermediate (compound 10) to reaction system.
Under agitation, disposable 20% sodium chloride solution (4gNaCl/20ml water) adding quadrol (3.34ml, 50mmol) and ethylenediamine-hydrochloride (6.65g, 50mmol), reaction 4h, TLC detection (chlorine: first=10:1). Reaction takes out filter after terminating, and filtrate is adjusted to pH=10 with sodium hydroxide solution, with dichloromethane extraction (20ml �� 3), merges organic phase, then through anhydrous sodium sulfate drying.Taking out filter, filtrate is revolved except solvent, obtains product N-(2-amino-ethyl)-2-chloro-6-fluorobenzene acid amides (compound 11) 1.21g, product rate 56%.
5) 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (compound 8) and the chloro-6-fluorobenzene acid amides (compound 11) of N-(2-amino-ethyl)-2-obtain target compound E10 by mixed anhydride method
In 100ml reaction flask, by 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid (compound 8,1.28g, 4.0mmol), 4-methylmorpholine (1.3ml, 12mmol) joins in 15ml anhydrous methylene chloride successively. Under condition of ice bath, methylene dichloride (8ml) solution of isobutyl chlorocarbonate (0.8ml, 6mmol) is slowly added drop-wise in above-mentioned solution, reacts 30 minutes at 0 DEG C. After having reacted, under condition of ice bath, the dichloromethane solution (10ml) of N-(2-amino-ethyl)-2-chloro-6-fluorobenzene acid amides (compound 11,6mmol) and 4-methylmorpholine (1.3ml, 12mmol) is joined in above-mentioned reaction system. After dripping, remove ice bath, rise to room temperature reaction and spend the night. After reaction terminates, adding methylene dichloride (20ml) dilution, washing (10mL �� 2), saturated sodium carbonate solution is washed (10mL �� 3), and saturated nacl aqueous solution is washed (10mL). Organic phase is dry with anhydrous slufuric acid ammonium, then through column chromatography separating purification (sherwood oil: ethyl acetate=1:5), obtains target compound E100.37g, product rate 18%.
Gained compound structure is as follows:
Its physico-chemical property is: Mp242-245 DEG C, EI-MS (m/z): 519.0 [M]+��
Hydrogen spectrum nuclear magnetic resonance data:1HNMR(400MHz,DMSO-d6): ��=8.67 (s, 1H), 8.09 (d, J=8.5Hz, 2H), 7.99 (d, J=8.5Hz, 2H), 7.58 (d, J=8.9Hz, 2H), 7.48 (d, J=6.2Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.29-7.33 (t, J=8.0Hz, 1H), 7.19 (s, 1H), 6.95 (d, J=9.0Hz, 2H), 3.76 (s, 3H), 3.47 (s, 4H).
Measure inhibitor provided by the invention below to the inhibit activities of Bcr-Abl Tyrosylprotein kinase.
Measuring method is specific as follows:
Kinases ABL1 and substrate A bltide, purchased from Signal-Chem company, selects the ADP-Glob of Promega companyTMThe Inhibiting enzyme activity of KinaseAssays detection kit detection target compound, working method illustrates according to test kit and carries out.
By ATP (1mM) buffer (2 ��) (Tris80mM, MgCl220mM, BSA0.2mg/mL, DTT2mM) dilute buffer (2 ��) solution that 80 times are mixed with ATP (125 ��Ms); The mixing solutions that the ATP solution of 125 ��Ms and Abltide liquor capacity 1:1 are hybridly prepared into ATP (62.5 ��Ms)-Abltide (0.5 �� g/ �� l) is for subsequent use; ABL1 kinase solution buffer (1 ��) (Tris40mM, MgCl210mM, BSA0.1mg/mL, DTT1mM) dilute buffer (1 ��) solution for standby that 100 times are mixed with ABL1 (10ng/ �� l);
Target compound (E1��E10) and positive control drug (Imatinib) buffer (1 ��) are mixed with 1.5 �� 10 respectively-5Mol/L, 1.5 �� 10-6Mol/L, 1.5 �� 10-7Mol/L, 1.5 �� 10-8, 1.5 �� 10-9, 1.5 �� 10-10The sample solution of mol/L concentration gradient, on 384 orifice plates, every hole adds the mixing solutions of 2 �� LATP-Abltide successively, 1 �� L sample solution, 2 �� L enzyme solution; The mixing solutions of blank well adds 3 �� L damping fluid and 2 �� LATP-Abltide; The mixing solutions of control wells adds 2 �� LATP-Abltide, 1 �� L damping fluid, 2 �� L enzyme solution, finish, hatch 60min at 30 DEG C;Add ADP-Glo reagent 5 �� L, at 25 DEG C, hatch 40min; Add Kinasedetection reagent, then hatch 30min at 25 DEG C. Adopt the chemoluminescence module of the multi-functional microplate reader of PerkinElmer to measure the luminous value in every hole, calculate inhibitor to the inhibiting rate of ABL1 and IC50��
The inhibitor of the present invention is to Bcr-Abl tyrosine-kinase enzyme inhibition activity result, and as shown in table 1, the structural formula of this inhibitor is as follows:
Table 1 inhibitor is to the inhibit activities result (IC of Bcr-Abl Tyrosylprotein kinase50)
Result display N, Bcr-Abl kinases is had stronger inhibit activities by 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, Bcr-Abl kinases plays a significant role in cell signalling and conversion, it is by phosphorylation and a series of stream substrates of activation, impel the ripe unlimited hyperplasia of granulocyte of CML, Bcr-Abl does not express in normal cell, is the desirable target for the treatment of CML. By suppressing, Bcr-Abl kinase activity can reach the object for the treatment of CML to Bcr-Abl inhibitor.
Measure inhibitor provided by the invention below to the growth inhibitory activity of tumour cell.
Adopting mtt assay inspection N, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor are to the growth inhibitory activity effect of tumour cell:
N provided by the invention, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor have antitumor action, tumour cell is had vitro inhibition proliferation activity effect, human leukemia cell's (K562 cell) has the proliferation activity effect of inhibition tumor cell, it is possible to for the treatment to leukemia.
The human leukemia cell's (K562 cell) taken the logarithm vegetative period, is diluted to 10 with RPMI1640 substratum4The cell solution of individual/mL, parallel is inoculated in 96 well culture plates (2000/hole), and every hole inoculation volume is 200 �� L, 37 DEG C, 5%CO2Incubator is cultivated 12h;
Every hole adds the testing compound 20 �� L of different concns, makes the final concentration of compound in hole be: 1.5 �� 10-7Mol/L, 1.5 �� 10-6Mol/L, 1.5 �� 10-5Mol/L, 1.5 �� 10-4Mol/L, each concentration establishes 3 multiple holes, and negative control adds cell and do not add compound, if 6 multiple holes, nilotinib is positive control, continues to cultivate 48h;
Every hole adds MTT (5mg/mL) 10 �� L, make the final concentration 0.5mg/mL of MTT in hole, 37 DEG C of incubators hatch 4h, careful suction abandons supernatant, every hole adds DMSO150 �� L, vibration 15min, and enzyme-linked immunosorbent assay instrument measures the ultraviolet absorption value (OD value) at 490nm place, each hole, then calculate cell inhibitory rate, and obtain IC50 value according to inhibiting rate;
The calculation formula of cell inhibitory rate is:
Inhibiting rate %=(control wells mean OD value-medication group mean OD value)/control wells mean OD value �� 100%
Detected result shows: compared with negative control group, N, above-mentioned tumour cell is had vitro inhibition effect in various degree by 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, as shown in table 2.
Table 2 inhibitor is to the inhibit activities result IC of K56250(��M)
Inhibitor prepared by result display can the growth of inhibition tumor cell, N provided by the invention is described, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor are good to the proliferation inhibiting effect of tumour cell, can be applicable to the preparation of antitumor drug.
Claims (5)
1. a N, the preparation method of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, it is characterised in that, comprise the following steps:
1) 4,6-dichloro pyrimidine and P-nethoxyaniline generation nucleophilic substitution reaction obtain the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine;
2) the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine and Carboxybenzeneboronic acid is obtained 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl by SUZUKI linked reaction phenylformic acid;
3) preparation of N-(2-amino-ethyl) benzamide: containing phenylformic acid and the N of different substituents, N-carbonyl dimidazoles is obtained by reacting reactive intermediate, then is obtained by reacting the N-containing different substituents (2-amino-ethyl) benzamide with ethylenediamine monohydrochloride salt;
4) 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid obtains N with containing N-(2-amino-ethyl) benzamide of different substituents by mixed acid anhydride method, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, obtained N, the structural formula of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor is:
Wherein, R base is 3-CF3��3-OCH3��3-F��2-CH3, 2-Cl, 4-F, 2-Cl-6-F, 4-tertiary butyl, 3-dimethylamino or 3,4-bis-fluorine.
2. N according to claim 1, the preparation method of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, it is characterized in that: described step 1) be specifically operating as: by 4,6-dichloro pyrimidine and P-nethoxyaniline are dissolved in anhydrous isopropyl alcohol, add the vitriol oil of catalytic amount under agitation, heating reflux reaction, after reaction terminates, reaction solution is put into cold the putting of refrigerator spend the night, filter is taken out after precipitating out solid, filter cake dehydrated alcohol recrystallization, obtains the chloro-N-of 6-(4-p-methoxy-phenyl) pyrimidine 4-amine;
Described step 2) be specifically operating as: by chloro-for 6-N-(4-p-methoxy-phenyl) pyrimidine 4-amine, Carboxybenzeneboronic acid, tetra-triphenylphosphine palladium and cesium carbonate are dissolved in the mixing solutions of acetonitrile and water, it is warming up to 90 DEG C of reactions 12 hours, reaction takes out filter after terminating, filtrate be cooled to room temperature after with salt acid for adjusting pH value to precipitating out solid, then filter, obtain 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl phenylformic acid.
3. N according to claim 1, the preparation method of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, it is characterized in that: described step 3) be specifically operating as: will containing the phenylformic acid of different substituents and N, N-carbonyl dimidazoles joins in beaker, and mechanical stirring forms dope to reaction system; Then, under agitation, the disposable sodium chloride solution adding quadrol and ethylenediamine-hydrochloride, reaction 4h, reaction takes out filter after terminating, and filtrate is adjusted to pH=10 with sodium hydroxide solution, then with dichloromethane extraction, merge organic phase, then use anhydrous sodium sulfate drying organic phase, must containing N-(2-amino-ethyl) benzamide of different substituents.
4. N according to claim 1, the preparation method of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, it is characterized in that: described step 4) be specifically operating as: by 4-{6-[(4-p-methoxy-phenyl) amino] pyrimidine 4-yl } phenylformic acid and 4-methylmorpholine join in anhydrous methylene chloride successively, under condition of ice bath, drip the dichloromethane solution adding isobutyl chlorocarbonate, at 0 DEG C, react 30��40min; After having reacted, under condition of ice bath, drip the dichloromethane solution of N-(2-amino-ethyl) benzamide and the 4-methylmorpholine added containing different substituents, after dripping, remove ice bath, rise to room temperature reaction and spend the night, after reaction terminates, add methylene dichloride dilution, washing, organic phase is dry with anhydrous slufuric acid ammonium, then through column chromatography separating purification, obtain N, 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor.
5. N according to claim 1, the preparation method of 6 phenylbenzene pyrimidine-4-amine class Bcr-Abl inhibitor, it is characterized in that: the described preparation process to Carboxybenzeneboronic acid is: para-bromo toluene prepares grignard reagent by grignard reaction, grignard reagent and trimethyl borate are obtained by reacting methylphenylboronic acid ester, methylphenylboronic acid Ester hydrolysis is obtained methylphenylboronic acid, methylphenylboronic acid oxidation is obtained Carboxybenzeneboronic acid.
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