CN116120322A - Salt of aza-condensed ring amide compound, crystal form and use thereof - Google Patents
Salt of aza-condensed ring amide compound, crystal form and use thereof Download PDFInfo
- Publication number
- CN116120322A CN116120322A CN202211426259.3A CN202211426259A CN116120322A CN 116120322 A CN116120322 A CN 116120322A CN 202211426259 A CN202211426259 A CN 202211426259A CN 116120322 A CN116120322 A CN 116120322A
- Authority
- CN
- China
- Prior art keywords
- formula
- salt
- ray powder
- alternatively
- compound
- 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.)
- Pending
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 73
- 239000013078 crystal Chemical group 0.000 title claims abstract description 29
- -1 amide compound Chemical group 0.000 title abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 175
- 239000003814 drug Substances 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 74
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 50
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
- 238000002360 preparation method Methods 0.000 claims description 28
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 24
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 24
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 14
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 13
- 230000005855 radiation Effects 0.000 claims description 12
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 7
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 230000002062 proliferating effect Effects 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
- 208000027753 pain disease Diseases 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 208000035473 Communicable disease Diseases 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 abstract description 81
- 230000005764 inhibitory process Effects 0.000 abstract description 27
- 230000000694 effects Effects 0.000 abstract description 19
- 238000001727 in vivo Methods 0.000 abstract description 7
- 102000001253 Protein Kinase Human genes 0.000 abstract description 2
- 108060006633 protein kinase Proteins 0.000 abstract description 2
- 230000000857 drug effect Effects 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 38
- 230000004580 weight loss Effects 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- 230000035772 mutation Effects 0.000 description 25
- 239000003921 oil Substances 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 23
- 229940079593 drug Drugs 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 17
- 108090000623 proteins and genes Proteins 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 108091000080 Phosphotransferase Proteins 0.000 description 15
- 102000020233 phosphotransferase Human genes 0.000 description 15
- 238000001757 thermogravimetry curve Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 230000004927 fusion Effects 0.000 description 13
- 230000008707 rearrangement Effects 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 208000035475 disorder Diseases 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- OEBIHOVSAMBXIB-SJKOYZFVSA-N selitrectinib Chemical compound C[C@@H]1CCC2=NC=C(F)C=C2[C@H]2CCCN2C2=NC3=C(C=NN3C=C2)C(=O)N1 OEBIHOVSAMBXIB-SJKOYZFVSA-N 0.000 description 11
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 9
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 229950003970 larotrectinib Drugs 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 101150035397 Ros1 gene Proteins 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- HAYYBYPASCDWEQ-UHFFFAOYSA-N n-[5-[(3,5-difluorophenyl)methyl]-1h-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC(C1=C2)=NNC1=CC=C2CC1=CC(F)=CC(F)=C1 HAYYBYPASCDWEQ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 5
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 229960001456 adenosine triphosphate Drugs 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000006285 cell suspension Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000002411 thermogravimetry Methods 0.000 description 5
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 description 4
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 4
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 4
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 description 4
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 230000001174 ascending effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 101100091501 Mus musculus Ros1 gene Proteins 0.000 description 3
- 102100029166 NT-3 growth factor receptor Human genes 0.000 description 3
- 101150117329 NTRK3 gene Proteins 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 230000003698 anagen phase Effects 0.000 description 3
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000007405 data analysis Methods 0.000 description 3
- 230000003831 deregulation Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- HJWRQXVNUJEQOJ-IINYFYTJSA-N 5-[(2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(C[C@H](C1)F)C1=NC=2N(C=C1)N=CC=2C(=O)O HJWRQXVNUJEQOJ-IINYFYTJSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 102000005937 Tropomyosin Human genes 0.000 description 2
- 108010030743 Tropomyosin Proteins 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000001099 axilla Anatomy 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000011067 equilibration Methods 0.000 description 2
- XHUWDDXMORFULQ-UHFFFAOYSA-N ethyl 2h-pyrimidine-1-carboxylate Chemical compound CCOC(=O)N1CN=CC=C1 XHUWDDXMORFULQ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 201000010175 gallbladder cancer Diseases 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000009520 phase I clinical trial Methods 0.000 description 2
- NENLIGJPMYKXNE-UHFFFAOYSA-N phenyl piperazine-1-carboxylate Chemical compound C1CNCCN1C(=O)OC1=CC=CC=C1 NENLIGJPMYKXNE-UHFFFAOYSA-N 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000010512 thermal transition Effects 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- SMQYQMQTCFRHEJ-OIBJUYFYSA-N (2r,4s)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine Chemical compound C1[C@H](F)CN[C@H]1C1=CC(F)=CC=C1F SMQYQMQTCFRHEJ-OIBJUYFYSA-N 0.000 description 1
- QUGUFLJIAFISSW-UHFFFAOYSA-N 1,4-difluorobenzene Chemical compound FC1=CC=C(F)C=C1 QUGUFLJIAFISSW-UHFFFAOYSA-N 0.000 description 1
- 102100026205 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 Human genes 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940126069 ALK kinase inhibitor Drugs 0.000 description 1
- 101710197633 Actin-1 Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 206010066476 Haematological malignancy Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 101000691599 Homo sapiens 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 Proteins 0.000 description 1
- 101000687448 Homo sapiens REST corepressor 1 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 1
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000012515 Protein kinase domains Human genes 0.000 description 1
- 108050002122 Protein kinase domains Proteins 0.000 description 1
- 102100024864 REST corepressor 1 Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000027520 Somatoform disease Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000006180 TBST buffer Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940076840 Tropomyosin receptor kinase inhibitor Drugs 0.000 description 1
- 241000711955 Turkey rhinotracheitis virus Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 101150010487 are gene Proteins 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- XDXFALYQLCMAQN-BTJKTKAUSA-N butanedioic acid;(z)-but-2-enedioic acid Chemical compound OC(=O)CCC(O)=O.OC(=O)\C=C/C(O)=O XDXFALYQLCMAQN-BTJKTKAUSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 238000013500 data storage Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 210000001787 dendrite Anatomy 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000010696 ester oil Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FJORAQVWRUARQI-BLLLJJGKSA-N ethyl 5-[(2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound CCOC(=O)C1=C2N=C(C=CN2N=C1)N1C[C@@H](F)C[C@@H]1C1=C(F)C=CC(F)=C1 FJORAQVWRUARQI-BLLLJJGKSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- RXFHRKPNLPBDGE-UHFFFAOYSA-N tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(N)C=C1 RXFHRKPNLPBDGE-UHFFFAOYSA-N 0.000 description 1
- 230000008791 toxic response Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 108010064892 trkC Receptor Proteins 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a salt of an aza-condensed ring amide compound, a crystal form and application thereof, and provides a salt of a compound shown as a formula (A-1), a salt of a compound shown as a formula (A-1) in a crystal form, a specific salt form and a crystal form thereof, a pharmaceutical composition containing the same and application thereof, wherein the salt form has good crystallinity and stability, and a bodyThe internal and external drug effects show that the salt of the compound shown in the formula (A-1) has good inhibition effect on wild type and mutant kinase, cells and in-vivo tumors, and has good patent medicine potential.
Description
The present invention claims the priority of the prior application entitled "salt of aza-condensed ring amide-like compound and its use", filed by applicant in 2021, 11 and 15 to the national intellectual property agency of China, with patent application number 202111345223.8. The entirety of the prior application is incorporated by reference into this application.
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a salt of an aza-condensed ring amide compound, a crystal form and application thereof.
Background
Tropomyosin-related kinase or Tropomyosin Receptor Kinase (TRK) is a class of nerve growth factor receptors whose family consists of three subtypes, TRKA, TRKB and TRKC, of high homology, encoded by the neurotrophic receptor tyrosine kinase 1 (NTRK 1), NTRK2 and NTRK3 genes, respectively. When the TRK receptor protein binds to the corresponding ligand, different physiological functions can be achieved by activating downstream signaling pathways, such as the RAS/MAPK pathway, plcγ pathway, and PI3K pathway. TRK family proteins are normally expressed primarily in neural tissues, involved in neural cell differentiation and survival, and in axon and dendrite formation, and play an important role in embryonic development and maintenance of normal function of the nervous system.
TRK kinase is activated in malignant tumors by a variety of mechanisms, mainly structural rearrangements and changes in expression. For example, the rearrangement of the gene NTRK encoding the TRK kinase with other genes results in fusion oncogenes, which result in structural and expression changes in the TRK kinase that are no longer regulated and controlled by nerve growth factor ligands, constitutive activation occurs, and neoplastic development is promoted. In addition, the results of gene sequencing also show that TRK kinase has a close relationship with the occurrence, metastasis and exacerbation of various tumors, and is expressed in various tumors, such as non-small cell lung cancer, colorectal cancer, melanoma, gall bladder cancer, thyroid cancer, glioblastoma and the like.
Currently, the first generation TRK inhibitors Larotrectinib (LOXO-101) and Entrectrinib (RXDX-101) were approved for sale by the U.S. Food and Drug Administration (FDA) in 2018 and 2019, respectively. Larotrectinib is a potent, oral, selective tropomyosin receptor kinase inhibitor whose efficacy data was published as early as the ASCO conference at 2017, month 6, and in phase I and phase II clinical trials 55 subjects were enrolled, of which 46 had an estimated Overall Response Rate (ORR) of 78%. Entrectrinib is a potent inhibitor of TRK, ROS1 and ALK proteins, and can pass the blood brain barrier, with 79% of the ORRs in 24 evaluable patients in phase I clinical trials.
Like other targeted drugs, TRK inhibitors also face drug resistance issues. Mutations in the NTRK kinase domain cause conformational changes in the TRK family of protein kinase domains or changes in binding affinity to ATP, thereby affecting binding of the TRK inhibitor to the target, types of mutations are G595R, G639R, G667C, etc. In order to solve the problem of drug resistance of the first generation TRK inhibitors, although the second generation TRK inhibitors such as LOXO-195, TPX-005, etc. have been studied, new drugs have been developed.
Disclosure of Invention
In order to solve the above problems, the present invention provides a salt of a compound represented by the formula (A-1):
Wherein HA is an acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid; more preferably hydrochloric acid, sulfuric acid or methanesulfonic acid; further preferred is hydrochloric acid or sulfuric acid;
n is an integer or a half integer of 1/2 to 4; preferably an integer or half-integer of 1/2 to 3; further preferably 0.5, 1, 1.5 or 2.
According to an embodiment of the present invention, the salt of the compound represented by the formula (A-1) is a salt of the compound represented by the formula (A-1) in a crystalline form.
According to an embodiment of the present invention, the salt of the compound represented by the formula (a-1) is a hydrochloride represented by the formula (1):
wherein n is 0.5, 1, 1.5 or 2; preferably 1 or 2.
According to an embodiment of the present invention, the hydrochloride represented by formula (1) is a hydrochloride represented by formula (1-1):
according to an embodiment of the present invention, the hydrochloride represented by formula (1-1) is a hydrochloride represented by formula (1-1) in a crystalline form.
According to an embodiment of the present invention, the hydrochloride salt of formula (1-1) in the crystalline form is its crystalline form I, and the X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2θ angles (±0.2°) using cu—kα radiation: 5.7 °,6.3 °,11.6 °,17.1 °,19.1 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the hydrochloride salt of formula (1-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,6.3 °,11.6 °,11.8 °,17.1 °,19.1 °,19.3 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the hydrochloride salt of formula (1-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,6.3 °,7.5 °,11.6 °,11.8 °,12.7 °,17.1 °,19.1 °,19.3 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the hydrochloride salt represented by formula 1-1 has characteristic diffraction peaks at the following 2θ angles (±0.2°). 5.7 °,6.3 °,7.5 °,11.6 °,11.8 °,12.7 °,15.1 °,17.1 °,19.1 °,19.3 °,25.8 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the hydrochloride salt of formula (1-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,6.3 °,7.5 °,11.6 °,11.8 °,12.7 °,15.1 °,16.3 °,17.1 °,19.1 °,19.3 °,24.7 °,25.8 °.
According to an embodiment of the present invention, form I of the hydrochloride salt of formula (1-1) uses Cu-ka radiation having an X-ray powder diffraction pattern substantially as shown in figure 1.
According to an embodiment of the present invention, the differential scanning calorimetry curve of the crystal form I of the hydrochloride represented by the formula (1-1) has an endothermic peak at 174.7.+ -. 5 ℃.
According to an embodiment of the present invention, the differential scanning calorimetry curve of the form I of the hydrochloride represented by the formula (1-1) has endothermic peaks at 62.61.+ -. 5 ℃, 119.14.+ -. 5 ℃ and 174.70.+ -. 5 ℃.
According to an embodiment of the present invention, the hydrochloride salt of formula (1-1) of form I has a DSC profile substantially as shown in figure 2.
According to an embodiment of the present invention, the thermogravimetric analysis curve of form I of the hydrochloride salt of formula (1-1) has a weight loss of 3.2847% + -0.2% between (120-170) + -5deg.C.
According to some embodiments of the invention, the thermogravimetric analysis of form I of the hydrochloride salt of formula (1-1) has a weight loss of 3.2847% + -0.2% between 115-175 ℃, or 120-175 ℃, or 125-175 ℃, or 115-170 ℃, or 120-170 ℃, or 125-170 ℃, or 115-165 ℃, or 120-165 ℃, or 125-165 ℃.
According to some embodiments of the invention, the thermogravimetric analysis curve of form I of the hydrochloride salt of formula (1-1) has a weight loss of 3.2847% ± 0.2% between 120 and 170.
According to an embodiment of the present invention, the thermogravimetric analysis curve of form I of the hydrochloride salt of formula (1-1) has a weight loss of 1.5910% + -0.2% between (room temperature-50 ℃) and + -5 ℃, a weight loss of 1.9155% + -0.2% between (50-120) + -5 ℃ and a weight loss of 3.2847% + -0.2% between (120-170) + -5 ℃.
According to some embodiments of the invention, the thermogravimetric analysis curve of form I of the hydrochloride salt of formula (1-1) has a weight loss of 1.5910% + -0.2% between room temperature and 45℃or between room temperature and 50℃or between room temperature and 55℃and a weight loss of 1.9155% + -0.2% between 45-115℃or between 45-120℃or between 45-125℃or between 50-115℃or between 50-120℃or between 55-115℃or between 55-120℃or between 55-125℃or between 55-125℃and a weight loss of 3.2847% + -0.2% between 115-175℃or between 120-175℃or between 125-175℃or between 115-170℃or between 120-170℃or between 125-170℃or between 115-165℃or between 120-165℃or between 125-165 ℃.
According to some embodiments of the invention, the thermogravimetric analysis of form I of the hydrochloride salt of formula (1-1) has a weight loss of 1.5910% ± 0.2% between room temperature and 50 ℃, a weight loss of 1.9155% ± 0.2% between 50 and 120 ℃ and a weight loss of 3.2847% ± 0.2% between 120 and 170 ℃.
According to an embodiment of the present invention, the crystalline form I of the hydrochloride salt of formula (1-1) has a TGA profile substantially as shown in figure 2.
According to an embodiment of the present invention, the salt of the compound represented by the formula (a-1) is a sulfate represented by the formula (2):
wherein n is 0.5 or 1; preferably 0.5.
According to an embodiment of the present invention, the sulfate represented by formula (2) is a sulfate represented by formula (2-1):
according to an embodiment of the present invention, the sulfate represented by formula (2-1) is a sulfate represented by formula (2-1) in a crystalline form.
According to an embodiment of the present invention, the sulfate represented by formula (2-1) in the crystalline form is its crystalline form I, and the X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2θ angles (±0.2°) using cu—kα radiation: 7.8 °,17.5 °,18.9 °,19.7 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the sulfate salt of formula (2-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,7.8 °,17.5 °,18.9 °,19.7 °,24.6 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the sulfate salt of formula (2-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,7.8 °,12.5 °,17.5 °,18.9 °,19.7 °,23.6 °,24.6 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the sulfate salt of formula (2-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,7.8 °,12.5 °,17.5 °,18.9 °,19.4 °,19.7 °,23.6 °,24.6 °,25.3 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the sulfate salt of formula (2-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,7.8 °,12.5 °,17.5 °,18.9 °,19.4 °,19.7 °,20.5 °,23.6 °,24.6 °,25.3 °,26.1 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the sulfate salt of formula (2-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,7.8 °,12.5 °,17.5 °,18.9 °,19.4 °,19.7 °,20.5 °,23.6 °,24.6 °,25.3 °,26.1 °,31.7 °,33.9 °.
According to an embodiment of the present invention, form I of the sulfate salt of formula (2-1) uses Cu-ka radiation having an X-ray powder diffraction pattern substantially as shown in fig. 3.
According to an embodiment of the present invention, the differential scanning calorimetry curve of the sulfate form I represented by the formula (2-1) has an endothermic peak at 241.+ -. 5 ℃.
According to an embodiment of the present invention, the differential scanning calorimetry curve of the sulfate form I represented by the formula (2-1) has endothermic peaks at 235 ℃ + -5 ℃ and 241+ -5 ℃.
According to an embodiment of the present invention, the crystalline form I of the sulfate salt of formula (2-1) has a DSC profile substantially as shown in figure 4.
According to an embodiment of the present invention, the crystalline form I of the sulfate salt of formula (2-1) has a TGA profile substantially as shown in figure 4.
According to an embodiment of the present invention, the sulfate represented by formula (2-1) in the crystalline form is form II, and the X-ray powder diffraction pattern thereof has characteristic diffraction peaks (±0.2°) at the following 2θ angles using cu—kα radiation: 5.5,7.6, 16.5, 18.9.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of the sulfate salt form II represented by the formula (2-1) has characteristic diffraction peaks (±0.2°): 3.9,5.5,7.6, 16.5, 18.9.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of the sulfate salt form II represented by the formula (2-1) has characteristic diffraction peaks (±0.2°): 3.9,5.5,7.6, 10.9, 16.5, 18.9.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of the sulfate salt form II represented by the formula (2-1) has characteristic diffraction peaks (±0.2°): 3.9,5.5,7.6, 10.9, 16.0, 16.5, 18.9.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of the sulfate salt form II represented by the formula (2-1) has characteristic diffraction peaks (±0.2°): 3.9,5.5,7.6, 10.9, 12.6, 16.0, 16.5, 18.9.
According to an embodiment of the present invention, form II of the sulfate salt of formula (2-1) uses Cu-ka radiation having an X-ray powder diffraction pattern substantially as shown in fig. 5.
According to an embodiment of the present invention, the differential scanning calorimetry curve of the crystal form II of the sulfate represented by the formula (2-1) has an endothermic peak at 227.22 ±5 ℃.
According to an embodiment of the present invention, the crystalline form II of the sulfate salt of formula (2-1) has a DSC profile substantially as shown in figure 6.
According to an embodiment of the present invention, form II of the sulfate salt of formula (2-1) has a TGA profile substantially as shown in figure 6.
According to an embodiment of the present invention, the salt of the compound represented by the formula (a-1) is a methanesulfonate salt represented by the formula (3):
wherein n is 0.5, 1, 1.5 or 2; preferably 1.
According to an embodiment of the present invention, the methanesulfonic acid salt represented by formula (3) is a methanesulfonic acid salt represented by formula (3-1):
according to an embodiment of the present invention, the methanesulfonic acid salt represented by the formula (3-1) is a methanesulfonic acid salt represented by the formula (3-1) in a crystalline form.
According to an embodiment of the present invention, the mesylate salt represented by formula (3-1) in the crystalline form is crystalline form I thereof, and has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles (±0.2°) using cu—kα radiation: 6.8 °,8.1 °,10.6 °,11.9 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the mesylate salt of formula (3-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°). 6.8 °,8.1 °,10.6 °,11.9 °,15.5 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the mesylate salt of formula (3-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°). 6.8 °,8.1 °,10.6 °,11.9 °,15.5 °,18.9 °,21.1 °.
According to an embodiment of the present invention, the X-ray powder diffraction pattern of form I of the mesylate salt of formula (3-1) has characteristic diffraction peaks at the following 2θ angles (±0.2°). 6.8 °,8.1 °,10.6 °,11.9 °,15.5 °,18.0 °,18.9 °,21.1 °,26.3 °.
According to an embodiment of the present invention, form I of the mesylate salt of formula (3-1) uses Cu-ka radiation, which has an X-ray powder diffraction pattern substantially as shown in fig. 7.
According to an embodiment of the present invention, the differential scanning calorimetry trace of form I of the mesylate salt of formula (3-1) has an endothermic peak at 180.62 ±5℃.
According to an embodiment of the present invention, the differential scanning calorimetry curve of form I of the mesylate salt of formula (3-1) has endothermic peaks at 71.95.+ -. 5 ℃ and 180.62.+ -. 5 ℃.
According to an embodiment of the present invention, the form I of the mesylate salt of formula (3-1) has a DSC pattern substantially as shown in FIG. 8.
According to an embodiment of the present invention, the thermogravimetric analysis curve of form I of the mesylate salt of formula (3-1) has a weight loss of 1.1072% + -0.2% between (100-200 ℃) 5 ℃.
According to some embodiments of the invention, the thermogravimetric analysis curve of form I of the mesylate salt of formula (3-1) has a weight loss of 1.1072% ± 0.2% between 95-205 ℃ or 100-205 ℃ or 105-205 ℃ or 95-200 ℃ or 100-200 ℃ or 105-200 ℃ or 95-195 ℃ or 100-195 ℃ or 105-195 ℃.
According to some embodiments of the invention, the thermogravimetric analysis of form I of the mesylate salt of formula (3-1) has a weight loss of 1.1072% ± 0.2% between 100 and 200 ℃.
According to an embodiment of the present invention, the thermogravimetric analysis curve of form I of the mesylate salt of formula (3-1) has a weight loss of 1.9565% + -0.2% between (room temperature-100 ℃) + -5deg.C and 1.1072% + -0.2% between (100-200 ℃) + -5deg.C.
According to some embodiments of the invention, the thermogravimetric analysis curve of form I of the mesylate salt of formula (3-1) has a weight loss of 1.9565% + -0.2% between room temperature and 95℃or between room temperature and 100℃or between room temperature and 105℃and a weight loss of 1.1072% + -0.2% between 95-205℃or between 100-205℃or between 105-205℃or between 95-200℃or between 105-195℃or between 100-195℃or between 95-195 ℃.
According to some embodiments of the invention, the thermogravimetric analysis of form I of the mesylate salt of formula (3-1) has a weight loss of 1.9565% ± 0.2% between room temperature and 100 ℃ and a weight loss of 1.1072% ± 0.2% between 100 and 200 ℃.
According to an embodiment of the present invention, form I of the mesylate salt of formula (3-1) has a TGA profile substantially as shown in figure 8.
According to an embodiment of the present invention, there is also provided a pharmaceutical composition comprising a salt of the compound of the aforementioned formula (a-1) or a salt of the aforementioned compound of the aforementioned crystalline form of formula (a-1), optionally further comprising one or more pharmaceutically acceptable carriers.
According to an embodiment of the present invention, the above-mentioned pharmaceutical composition comprises the hydrochloride of the compound represented by the above-mentioned formula (1), the hydrochloride of the compound represented by the above-mentioned formula (1-1) or a crystalline form of the hydrochloride of the compound represented by the above-mentioned formula (1-1), optionally, further comprising one or more pharmaceutically acceptable carriers.
According to an embodiment of the present invention, the above-mentioned pharmaceutical composition comprises a sulfate salt of the compound represented by the above-mentioned formula (2), a sulfate salt of the compound represented by the above-mentioned formula (2-1), a crystalline form of the sulfate salt of the compound represented by the above-mentioned formula (2-1), a crystalline form I of the sulfate salt of the compound represented by the above-mentioned formula (2-1) or a crystalline form II of the sulfate salt of the compound represented by the above-mentioned formula (2-1), optionally, further comprising one or more pharmaceutically acceptable carriers.
According to an embodiment of the present invention, the above-mentioned pharmaceutical composition comprises the methanesulfonate salt of the compound represented by the above-mentioned formula (3), the methanesulfonate salt of the compound represented by the above-mentioned formula (3-1) or the crystalline form of the methanesulfonate salt of the compound represented by the above-mentioned formula (3-1), optionally, further comprises one or more pharmaceutically acceptable carriers.
According to an embodiment of the present invention, there is also provided a salt of the compound represented by the aforementioned formula (A-1), a salt of the aforementioned compound represented by the aforementioned formula (A-1) in crystalline form, a hydrochloride of the aforementioned compound represented by the aforementioned formula (1-1) in crystalline form I, a sulfate of the aforementioned compound represented by the aforementioned formula (2) in crystalline form, a sulfate of the aforementioned compound represented by the aforementioned formula (2-1) in crystalline form I, a sulfate of the aforementioned compound represented by the aforementioned formula (2-1) in crystalline form II, a mesylate of the aforementioned compound represented by the aforementioned formula (3) in crystalline form, a mesylate of the aforementioned compound represented by the aforementioned formula (3-1) in crystalline form I, a sulfate of the aforementioned compound represented by the aforementioned formula (1-1) in crystalline form I, a sulfate of the aforementioned compound represented by the aforementioned formula (2-1) in crystalline form I, a sulfate of the aforementioned compound represented by the aforementioned formula (2-1) in crystalline form I, or a pharmaceutical composition.
According to an embodiment of the invention, the medicament is for the treatment of pain disorders, cell proliferative disorders, inflammatory disorders, neurodegenerative disorders or infectious disorders.
According to an embodiment of the invention, the medicament is for the prevention and/or treatment of a disease mediated by one or more of TRK, ROS1 or ALK.
According to an embodiment of the invention, the medicament is for the prevention and/or treatment of NTRK gene rearrangement/fusion and/or drug resistant mutation positive tumors, or ROS1 gene rearrangement/fusion and/or drug resistant mutation positive tumors; preferably, the tumor is a solid tumor or a hematological tumor; further preferably, the tumor is a solid tumor.
According to an embodiment of the invention, the NTRK resistant mutation is NTRK1-G595R, NTRK1-G667C, NTRK-G623R or NTRK3-G696A; preferably, the NTRK resistance mutation is NTRK1-G595R, NTRK1-G667C or NTRK3-G623R; further preferably, the NTRK resistant mutation is NTRK1-G595R or NTRK1-G667C.
According to an embodiment of the present invention, there is also provided a salt of the compound represented by the aforementioned formula (A-1), a salt of the aforementioned compound represented by the aforementioned formula (A-1) in crystalline form, a hydrochloride of the aforementioned compound represented by the aforementioned formula (1-1) in crystalline form I of the aforementioned compound represented by the aforementioned formula (1-1), a sulfate of the aforementioned compound represented by the aforementioned formula (2-1) in crystalline form I of the aforementioned compound represented by the aforementioned crystalline form (2-1), a sulfate of the aforementioned compound represented by the aforementioned formula (2-1) in crystalline form II, a mesylate of the aforementioned compound represented by the aforementioned formula (3), a mesylate of the aforementioned compound represented by the aforementioned formula (3-1) in crystalline form I of the aforementioned compound, a sulfate of the aforementioned compound represented by the aforementioned formula (3-1) in crystalline form I of the aforementioned compound represented by the aforementioned formula (3-1) or at least one of the aforementioned compound represented by the aforementioned formula (1) in crystalline form I, for the prevention and/or treatment of diseases mediated by one or more of TRK, ROS1 or ALK.
According to an embodiment of the present invention, there is also provided a method of preventing and/or treating a disease selected from the group consisting of a pain disease, a cell proliferative disease, an inflammatory disease, a neurodegenerative disease, or an infectious disease, the method comprising: administering to the patient a therapeutically effective amount of a salt of the compound of formula (a-1), a salt of the compound of formula (a) -1 in crystalline form, a hydrochloride of the compound of formula (1), a hydrochloride of the compound of formula (1-1) in crystalline form, a crystalline form I of the hydrochloride of the compound of formula (1-1), a sulfate of the compound of formula (2-1) in crystalline form, a crystalline form I of the sulfate of the compound of formula (2-1) in crystalline form, a crystalline form II of the sulfate of the compound of formula (2-1), a methanesulfonate of the compound of formula (3-1) in crystalline form, a methanesulfonate of the compound of formula (3-1), or a pharmaceutical composition of formula (1).
According to an embodiment of the present invention, there is also provided a method of preventing and/or treating a disease mediated by one or more of TRK, ROS1 or ALK, comprising: administering to the patient a therapeutically effective amount of a salt of the compound of formula (a-1), a salt of the compound of formula (a) -1 in crystalline form, a hydrochloride of the compound of formula (1), a hydrochloride of the compound of formula (1-1) in crystalline form, a crystal form I of the hydrochloride of the compound of formula (1-1), a sulfate of the compound of formula (2-1) in crystalline form, a crystal form I of the sulfate of the compound of formula (2-1) in crystalline form, a crystal form II of the sulfate of the compound of formula (2-1), a methanesulfonate of the compound of formula (3-1) in crystalline form, a methanesulfonate of the compound of formula (3-1), or a pharmaceutical composition of formula (1).
According to an embodiment of the invention, the above-mentioned disease is selected from pain diseases, cell proliferative diseases, inflammatory diseases, neurodegenerative diseases or infectious diseases.
According to an embodiment of the invention, the above-mentioned diseases are NTRK gene rearrangement/fusion and/or drug resistance mutation positive tumors, or ROS1 gene rearrangement/fusion and/or drug resistance mutation positive tumors; preferably, the tumor is a solid tumor or a hematological tumor; further preferably, the tumor is a solid tumor.
According to an embodiment of the invention, the NTRK resistant mutation is NTRK1-G595R, NTRK1-G667C, NTRK-G623R or NTRK3-G696A; preferably, the NTRK resistance mutation is NTRK1-G595R, NTRK1-G667C or NTRK3-G623R; further preferably, the NTRK resistant mutation is NTRK1-G595R or NTRK1-G667C.
In one embodiment, the TRK mediated disease described above is selected from a disease mediated through one, two, or three of TRKA, TRKB, or TRKC.
In one embodiment, the above-described diseases involve deregulation of the NTRK gene, the TRK protein, or their expression, activity or level; preferably, it involves NTRK gene fusion, amplification, rearrangement, mutation or high expression; further preferred are directed to NTRK gene fusions or mutations.
According to an embodiment of the invention, the NTRK is mutated to NTRK1-G595R, NTRK1-G667C, NTRK3-G623R or NTRK3-G696A; preferably, the NTRK resistance mutation is NTRK1-G595R, NTRK1-G667C or NTRK3-G623R; further preferably, the NTRK resistant mutation is NTRK1-G595R or NTRK1-G667C.
In one embodiment, the above-described diseases involve deregulation of the ROS1 gene, ROS1 protein, or their expression, activity, or level; preferably, ROS1 gene fusion, amplification, rearrangement, mutation or high expression is involved; further preferred are ROS1 gene rearrangements/fusions or mutations.
In one embodiment, the disease described above involves a deregulation of the expression, activity or level of one or more genes, proteins, or thereof in TRK, ALK, ROS 1; preferably involving fusion, amplification, rearrangement, mutation or high expression of one or more of NTRK, ALK, ROS genes; further preferred are gene rearrangements/fusions or mutations involving one or more of NTRK, ALK, ROS 1.
In one embodiment, the cell proliferative disorder described above is a tumor or cancer.
In one embodiment, the tumor or cancer is a solid tumor or a hematological tumor; preferably a solid tumor; further preferred are solid tumors positive for NTRK gene rearrangement/fusion and/or resistance mutation, or solid tumors positive for ROS1 gene rearrangement/fusion and/or resistance mutation.
According to an embodiment of the invention, the NTRK resistant mutation is NTRK1-G595R, NTRK1-G667C, NTRK-G623R or NTRK3-G696A; preferably, the NTRK resistance mutation is NTRK1-G595R, NTRK1-G667C or NTRK3-G623R; further preferably, the NTRK resistant mutation is NTRK1-G595R or NTRK1-G667C.
In one embodiment, the tumor or cancer is a hematological malignancy, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma, colorectal cancer, melanoma, cancer of the head and neck, gall bladder cancer, thyroid cancer, glioblastoma, gastric cancer, neuroblastoma, or salivary gland cancer; preferably, the lung cancer is non-small cell lung cancer.
According to an embodiment of the present invention, there is provided a method for producing a salt of a compound represented by formula (a-1), comprising reacting a compound represented by formula (a) with an acid in a reaction solvent, and separating to obtain a salt of a compound represented by formula (a-1):
wherein, the liquid crystal display device comprises a liquid crystal display device,
HA is selected from the acids defined above. The acid is preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid; further preferred are hydrochloric acid, sulfuric acid or methanesulfonic acid; still more preferably hydrochloric acid or sulfuric acid;
n is an integer or a half integer of 1/2 to 4; preferably an integer or half-integer of 1/2 to 3; further preferably 0.5, 1, 1.5 or 2.
According to the preparation method of the invention, the molar ratio of the compound shown in the formula (A) to the acid is 1-2:0.5-2, preferably 1:0.6-1.1.
According to the preparation method of the present invention, the reaction temperature is 0 to 70 ℃, preferably 5 to 60 ℃, more preferably room temperature to 50 ℃.
According to the preparation method of the invention, the reaction solutionThe agent is selected from one or two of alcohols, esters, nitriles, ketones, water or a heterocyclic hydrocarbon solvent; preferably ROH, RCOOR 1 、RCN、RCOR 1 One or a combination of two of water or a heterocyclic hydrocarbon solvent, wherein R and R 1 Each independently selected from C 1-6 Linear or branched alkyl; preferably, R and R 1 Each independently selected from C 1-4 Linear or branched alkyl; preferably, the reaction solvent is selected from one or two of methanol, ethanol, ethyl acetate, acetone, butanone, acetonitrile, water or tetrahydrofuran; when the solvent is a mixed solvent composed of two solvents, the volume ratio of the two solvents is 1-10:10-1, preferably 1-5:5-1, and more preferably 1-3:3-1.
According to the preparation method, after the reaction is finished, the temperature is reduced to 0-30 ℃, standing crystallization is carried out for 0.5-24 hours, solids are separated, and the salt of the compound shown in the formula (A-1) is obtained after drying. Preferably, the crystallization temperature is room temperature and the crystallization time is 1-20 h.
According to the production method of the present invention, the separation step comprises separating the salt of the compound represented by the formula (A-1) obtained from the crystal liquid by a suitable method such as suction filtration, centrifugation, etc.
According to the preparation method of the present invention, the drying method may be any suitable known method, preferably room temperature drying or drying at 50 ℃. Specific drying conditions are, for example, drying time of preferably 1 to 50 hours, more preferably 3 to 24 hours. Regardless of the drying means, the residual solvent content in the obtained product is suitable for meeting the quality standard.
Definition and description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular phrase or terminology, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense.
The term "half-integer" refers to a number having the form (2m+1)/2, where m is selected from natural numbers that meet the numerical ranges set forth herein and below. For example, when n is a half integer of 1/2 to 4, m in the above formula may be selected from 0, 1, 2 or 3.
The "salt of the compound represented by the formula (A-1) in a crystalline form", "hydrochloride of the compound represented by the formula (1-1) in a crystalline form", "sulfate of the compound represented by the formula (2-1) in a crystalline form" or "methanesulfonate of the compound represented by the formula (3-1) in a crystalline form" referred to in the present application mean, respectively, a salt of the compound represented by the formula (A-1), a hydrochloride of the compound represented by the formula (1-1), a sulfate of the compound represented by the formula (2-1) or a methanesulfonate of the compound represented by the formula (3-1), including a salt of the compound represented by the formula (A-1), a hydrochloride of the compound represented by the formula (1-1), a sulfate of the compound represented by the formula (2-1) or a methanesulfonate of the compound represented by the formula (3-1) in an anhydrous and solvent-free form, a hydrate form or a solvate form.
The term "solvate" or "solvate" refers to an association of a stoichiometric or non-stoichiometric ratio of a solvent molecule with a salt of a compound of formula (A-1) of the present application, a hydrochloride salt of a compound of formula (1-1), a sulfate salt of a compound of formula (2-1) or a mesylate salt of a compound of formula (3-1), and includes an association containing both a water molecule and one or more other solvent molecules, and an association containing only one or more other solvent molecules.
The term "hydrate" refers to an association of a stoichiometric or non-stoichiometric ratio of water molecules with a salt of the compound represented by formula (A-1) of the present application, a hydrochloride of the compound represented by formula (1-1), a sulfate of the compound represented by formula (2-1), or a methanesulfonate of the compound represented by formula (3-1).
The "anhydrous and solvent-free form" means that no water molecule or solvent molecule is contained, or water molecule or solvent molecule is combined with a salt of the compound represented by formula (A-1), a hydrochloride of the compound represented by formula (1-1), a sulfate of the compound represented by formula (2-1) or a mesylate of the compound represented by formula (3-1) in a non-intermolecular force, for example, in an adsorption manner.
The "room temperature" is room temperature in the conventional sense in the art, typically 10 to 30 ℃, preferably 25 ℃ ± 5 ℃, such as 20 ℃, 25 ℃, 30 ℃.
In an X-ray powder diffraction pattern, the term "substantially" or "substantially as shown" refers to a substantially pure crystalline form in which at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in the powder X-ray diffraction pattern appear in the given pattern. Further, as the content of a certain crystal form in a product gradually decreases, some diffraction peaks ascribed to the crystal form in the X-ray powder diffraction pattern thereof may be reduced due to factors of the detection sensitivity of the instrument. Furthermore, there may be slight errors in the position of the peaks for any given crystal form, which is also well known in the crystallography arts. For example, the position of the peak may be shifted due to a change in temperature at the time of analyzing the sample, a shift in the sample, calibration of the instrument, or the like, and a measurement error of the 2θ value is sometimes about ±0.3°, typically about ±0.2°. Thus, this error should be taken into account when determining each crystal structure, and the term "substantially" or "substantially as shown in the drawings" is also intended to cover such differences in diffraction peak positions, meaning ± 0.3 °, preferably ± 0.2 °.
In a DSC profile or TGA profile, the term "substantially" or "substantially as shown" means that for an isomorphous form of an isomorphous compound, the errors in thermal transition onset temperature, endothermic peak temperature, exothermic peak temperature, melting point, weight loss onset temperature, or weight loss end point temperature, etc., are typically within about 5 ℃, usually within about 3 ℃, in a continuous analysis. When describing a compound as having a given thermal transition onset temperature, endothermic peak temperature, exothermic peak temperature, melting point, weight loss onset temperature, or weight loss end temperature, etc., this temperature is referred to as + -5 deg.c.
The term "cell proliferative disorder" as used herein refers to a condition in which the growth rate of a population of cells is lower or higher than the expected rate for a given physiological state and condition.
The term "tumor" encompasses benign tumors, malignant tumors, and borderline tumors, wherein malignant tumors are also collectively referred to as cancers.
The term "preventing" as used herein refers to a compound or drug that, when used in a disease or disorder (e.g., cancer), reduces the frequency of symptoms of or delays the onset of a medical disorder in a subject as compared to a subject to whom the compound or drug (e.g., a combination product as claimed herein) was not administered.
The term "treating" as used herein refers to alleviating, alleviating or ameliorating a symptom of a disease or disorder, ameliorating a symptom of underlying metabolism, inhibiting a disease or symptom, e.g., preventing the development of a disease or disorder, alleviating a disease or disorder, causing regression of a disease or disorder, alleviating a condition caused by a disease or disorder, or preventing a symptom of a disease or disorder.
The term "pharmaceutically acceptable carrier", also known as "pharmaceutically acceptable adjuvant" refers to those carriers or adjuvants which do not have a significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound.
Intermediate compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.
The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is suitable for the chemical changes of the present application and the reagents and materials needed. In order to obtain the compounds of the present application, modifications or choices of synthesis steps or reaction schemes based on the existing embodiments are sometimes required by those skilled in the art.
The present application will be specifically described by examples, which are not meant to be limiting in any way.
All solvents used in this application are commercially available and can be used without further purification.
Technical effects
The salt of the compound shown in the formula (A-1), the salt of the compound shown in the formula (A-1) in a crystal form, and a specific salt form and a crystal form thereof provided by the invention have one or more of the following beneficial effects:
(1) The salt of the compound shown in the formula (A-1) is easy to prepare, purify and isolate, and has high purity of more than 98 percent;
(2) The salt of the compound represented by the formula (A-1) in a crystalline form has good crystallinity, for example, the crystalline form I of the hydrochloride represented by the formula (1-1), the crystalline form I of the sulfate represented by the formula (2-1), the crystalline form II of the sulfate represented by the formula (2-1) and the methanesulfonic acid salt represented by the formula (3-1);
(3) Preferably, the salt and the crystal form thereof have good physical stability and chemical stability, and have good medicinal prospect;
(4) In vitro kinase activity inhibition assays showed: the compound shown in the formula (A) shows excellent inhibitory activity on various kinases (such as TRK, ALK, ROS 1) and mutants thereof, particularly TRK and mutant forms thereof, and has good application prospect in developing the salt formula (A-1) of the compound shown in the formula (A) on the basis;
(5) In vitro cytostatic activity assays showed: the compound shown in the formula (A) has strong inhibition effect on various TRK mutant cells and IC on inhibition activity of 6 cells 50 Below 10nM, preferably below 5nM, more preferably below 1 nM;
(6) The in vivo tumor inhibition test results show that: compared with a control compound, the compound shown in the formula (A) has better in-vivo anti-tumor effect, better tolerance and higher possibility of drug forming;
(7) The in vivo action mechanism research experiment shows that: the compound shown in the formula (A) can inhibit TRK phosphorylation in tumor tissues, and further effectively inhibit the phosphorylation of PLC gamma 1 and AKT, and inhibit the growth of the tumor tissues.
Drawings
Fig. 1: x-ray powder diffraction pattern of form I of the hydrochloride salt of example 1.
Fig. 2: DSC-TGA spectrum of form I of the hydrochloride of example 1.
Fig. 3: x-ray powder diffraction pattern of crystalline form I of the sulfate salt of example 2.
Fig. 4: DSC-TGA spectrum of crystalline form I of sulfate salt of example 2.
Fig. 5: x-ray powder diffraction pattern of crystalline form II of the sulfate salt of example 3.
Fig. 6: DSC-TGA spectrum of form II of sulfate of example 3.
Fig. 7: x-ray powder diffraction pattern of form I of the mesylate salt of example 4.
Fig. 8: DSC-TGA spectrum of form I of the mesylate salt of example 4.
Fig. 9: test example 4 results.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
X-ray powder diffraction (X-ray powder diffractometer, XRPD)
Instrument model: bruker D8 advanced X-ray powder diffractometer
The testing method comprises the following steps: about 5-20 mg sample for XRPD detection
The detailed XRPD parameters are as follows:
light pipe voltage: 40kV, light pipe current: 40mA
Scanning range: 3-40 ° (2 theta)
Scanning step length: 0.02 degree
Sample tray: zero background sample tray.
2. Differential scanning calorimetric analysis (Differential Scanning Calorimeter, DSC)
Instrument model: TA Q200 differential scanning calorimeter
The testing method comprises the following steps: the sample was placed in a perforated aluminum crucible and heated to the final temperature at a ramp rate of 10 ℃/min after equilibration at 25 ℃.
Sample amount: 1-3 mg
Type of air flow: nitrogen gas
Flow rate: 50mL/min
Heating initiation temperature: 25 DEG C
Termination temperature: 300 ℃.
3. Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA)
Instrument model: TA Q500 thermogravimetric analyzer (TA, US)
The testing method comprises the following steps: the sample was placed in an aluminum crucible peeled in advance, and after the sample mass was automatically weighed in a TGA furnace, the sample was heated to the final temperature at a rate of 10 ℃/min.
Sample amount: 1-5 mg
Type of air flow: nitrogen gas
Sample cell airflow rate: 25mL/min
Heating initiation temperature: room temperature
Termination temperature: 300 ℃.
4. Dynamic moisture desorption analysis (DVS)
Instrument model: DVS Intrinsic dynamic steam adsorber (SMS)
The testing method comprises the following steps: a sufficient amount of sample (10-20 mg) was placed in the sample chamber previously peeled and automatically weighed. The sample was dried at 40℃until dm/dt was less than 0.002% (only for anhydrate, starting at 25℃for hydrate). Cool to 25 ℃, and start the test using the operating parameters in the table below.
|
60 minutes |
Drying/ |
40℃/25℃ |
Circulation | Whole cycle |
Each |
1 hour |
Data storage rate | 5 seconds |
Total air flow | 200sccm |
Total air flow rate after the experiment | 200sccm |
5. High Performance Liquid Chromatography (HPLC)
Instrument model: agilent 1260 services (Waters, US)
test conditions: wavelength 248nm; column temperature 40 DEG C
Flow rate: 1.0mL/min
Sample injection volume: 5. Mu.L.
6. Nuclear magnetic resonance spectrum (Nuclear Magnetic Resonance Spectroscopy NMRS)
Instrument model: bruker AVANCE III 400 (Bruker, GER)
Content and test solvent: 1 H-NMR, test solvent was DMSO-d6.
Abbreviations: DCM: dichloromethane; DIPEA: diisopropylethylamine; DMF: n, N-dimethylformamide; EA: ethyl acetate; PE: petroleum ether; DMSO: dimethyl sulfoxide; TBTU: O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroboric acid; BOP: benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate; ATP: adenosine 5' -triphosphate; DTT:1, 4-dithiothreitol; MTT:3- (4, 5-dimethyl-2-thiazole) -2, 5-diphenyl tetrazolium bromide thiazole blue.
Preparation example 1: preparation of Compounds of formula (A)
Step a: (2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidine (5.8236 g,28.958 mmol), 5-chloropyrazolo [1,5-a ]]A mixed solution of pyrimidine-3-carboxylic acid ethyl ester (6.534 g,28.958 mmol), n-butanol (50 mL) and diisopropylamine (8.780 g,86.874 mmol) was reacted at 100deg.C for 4h and concentrated under reduced pressure to give 5- ((2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ]Pyrimidine-3-carboxylic acid ethyl ester crude (B1). No purification was carried out and used directly in the next reaction, (ES, m/z): 391.05[ M+H ]] + 。
Step b: 5- ((2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a]The crude pyrimidine-3-carboxylic acid ethyl ester was dissolved in absolute ethanol (50 mL), stirred at 75deg.C until the system was clear and transparent, then LiOH (4.86 g,115.832 mmol) aqueous solution (50 mL) was added and stirred at 75deg.C for 5h. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove absolute ethanol. Slowly dripping 1N HCl aqueous solution to adjust the pH value to 3-4, precipitating a large amount of white solid, stirring at room temperature for 30min, filtering, and washing a filter cake with a small amount of purified water. The filter cake is collected, dried and weighed to obtain white powdery solid 5- ((2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1, 5-a)]Pyrimidine-3-carboxylic acid (9.9 g). The filtrate was extracted with EA (2X 50 mL), the organic phases were combined, washed with water (2X 50 mL) and saturated aqueous NaCl solution (50 mL), and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Column chromatography purification (PE: ea=4:1-2:1, v/v), collection of the product points, concentration under reduced pressure, yield 5- ((2 r,4 s) -2- (2, 5-difluorobenzene) as a white powdered solidPhenyl) -4-fluoropyrrolidin-1-yl pyrazolo [1,5-a ]]Pyrimidine-3-carboxylic acid (386 mg). Co-yield 5- ((2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ]Pyrimidine-3-carboxylic acid purification (B2, 10.284 g, 98%), (ES, m/z): 363.04[ M+H ]] + 。
Step c: 1-Boc-4- (4-aminophenyl) piperazine (918 mg,3.312 mmol) was added to a solution containing 5- ((2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid (intermediate B2, 1000mg,2.76 mmol) was reacted with TBTU (1063 mg,3.312 mmol) in anhydrous DMF (10 mL) followed by dropwise addition of DIPEA (1284 mg,9.936 mmol) at 0deg.C overnight at room temperature. The reaction solution was stirred with water (50 mL) to precipitate a solid, which was filtered under reduced pressure to give a cake, which was dried in a vacuum oven to give tert-butyl 4- (4- (5- ((2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1, 5-a)]Pyrimidine-3-carboxamido) phenylpiperazine-1-carboxylate (B3, 1320mg, 77%). (ES, m/z): 622.09[ M+H ]] + 。
Step d: to tert-butyl 4- (4- (5- ((2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1, 5-a)]Pyrimidine-3-carboxamide) phenylpiperazine-1-carboxylate (1.320 g,2.125 mmol) was added with DCM and CF 3 COOH (12 mL,3/1, v/v), stirring at room temperature for 4 hours, concentrating the reaction solution under reduced pressure, adding water (80 mL) and EA (10 mL) to the residue, adjusting the base (pH=9) with ammonia water, stirring to precipitate a solid, obtaining a filter cake by vacuum filtration, rinsing the filter cake with a small amount of water, air-drying, and weighing to obtain 5- ((2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -N- (4- (piperazin-1-yl) phenyl) pyrazolo [1, 5-a) ]Pyrimidine-3-carboxamide (B4,227 mg, 82%), (ES, m/z): 522.09[ M+H ]] + 。
Step e: glycolic acid (306 mg,4.026 mmol) was added to a solution containing 5- ((2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -N- (4- (piperazin-4-yl) phenyl) pyrazolo [1, 5-a)]Pyrimidine-3-carboxamide (intermediate B4, 700mg, 1.348 mmol) was reacted with BOP (710 mg,1.610 mmol) in anhydrous DMF (10 mL) followed by dropwise addition of DIPEA (520 mg,4.026 mmol) at 0deg.C with stirring at room temperature for 4h. The reaction mixture was mixed with water (80 mL), the mixture was extracted with EA (55 mL. Times.2), and the mixture was extracted with H 2 O (80 mL), brine (80 mL) wash the combined organic phases, anhydrous sodium sulfateDrying, filtration, concentration of the filtrate under reduced pressure, elution with a column chromatography silica gel column, followed by elution with 1% (v/v) MeOH-DCM and then with 2% (v/v) MeOH-DCM, collection of the product points and concentration gives 5- ((2R, 4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) -N- (4- (4- (2-hydroxyacetyl) piperazin-1-yl) phenyl) pyrazolo [1, 5-a)]Pyrimidine-3-carboxamide (A, 666mg, 86%), (ES, m/z): 580.14[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ9.810(s,1H),8.906-8.723(m,1H),8.283-8.229(m,1H),7.623(s,1H),7.343(s,1H),7.210(s,2H),7.061-6.842(m,4H),5.711-5.495(m,2H),4.631(t,J=5.4Hz,1H),4.556-4.548(m,1H),4.318-4.225(m,1H),4.150(d,J=5.4Hz,2H),3.637(s,2H),3.513(s,2H),3.124-3.106(m,4H),2.957-2.912(m,1H)。
Control preparation examples 1-5:
another: compounds D1 to D5 were prepared by the procedures described in the patent documents WO2019029629A1 and WO2012034095A 1.
Example 1: preparation of form I of hydrochloride represented by formula (1-1)
A sample (301.9 mg) of the compound of formula (A) of preparation example 1 was weighed at room temperature into a reaction flask, a mixed solution (6.04 mL, v/v=1/2) of ethyl acetate and methanol was added, hydrochloric acid (1.1 eq) was added dropwise to the system, stirred at room temperature for 18 hours, and a solid was obtained by filtration. The obtained solid was dried at 50℃for 4 hours to obtain 202.3mg of a solid in a yield of 63%, and the detection was conducted to confirm that the salt had been formed and that the alkali/acid ratio was 1:1, to obtain a hydrochloride represented by the formula (1-1).
The sample was taken for X-ray powder diffraction and shown to be a crystalline solid (form I) with good crystallinity, the spectrum is shown in figure 1 and the XRPD diffraction peak data is shown in table 1. Samples were taken for DSC-TGA testing, DSC plots showing endothermic peaks at 62.61 ℃, 119.14 ℃ and 174.70 ℃, TGA plots showing samples with 1.5910% weight loss between room temperature and 50 ℃, 1.9155% weight loss between 50 and 120 ℃, and 3.2847% weight loss between 120 and 170 ℃, see FIG. 2.
TABLE 1 XRPD diffraction peak data for form I of hydrochloride salt of formula (1-1)
Peak position (2θ) ° | Relative strength% | Peak position (2θ) ° | Relative strength% | Peak position (2θ) ° | Relative strength% |
5.811 | 30.8 | 15.229 | 24.4 | 24.045 | 12.2 |
6.399 | 19.7 | 16.107 | 7.9 | 24.775 | 11.0 |
7.579 | 19.8 | 17.240 | 100.0 | 25.485 | 7.6 |
11.693 | 30.5 | 19.230 | 38.5 | 25.890 | 10.2 |
12.824 | 15.1 | 22.912 | 11.7 |
Note that: peaks with a relative peak intensity >7.0% were selected and listed in the table.
Example 2: preparation of Crystal form I of sulfate represented by formula (2-1)
A sample (about 30 mg) of the compound of formula (A) of preparation example 1 was weighed into a reaction flask at room temperature, a mixed solution (0.8 mL, v/v=1/1) of acetonitrile and methanol was added, a methanol solution (1 mol/L,0.6 eq) of sulfuric acid was added dropwise to the system, stirred at room temperature for 14 hours, and a solid was obtained by filtration. After the obtained solid was dried at room temperature under nitrogen atmosphere for 4 days, it was checked to confirm that salt formation was completed and the alkali/acid ratio was 1:0.5, to obtain a sulfate represented by the formula (2-1).
The sample was taken for X-ray powder diffraction and showed a crystalline solid (form I) with good crystallinity, the spectrum is shown in figure 3 and the XRPD diffraction peak data is shown in table 2. Samples were taken for DSC-TGA testing, and DSC plots showed endothermic peaks at 235℃and 241℃as shown in FIG. 4.
TABLE 2 XRPD diffraction peak data for form I of sulfate salt of formula (2-1)
Peak position (2θ) ° | Relative strength% | Peak position (2θ) ° | Relative strength% | Peak position (2θ) ° | Relative strength% |
5.671 | 21.0 | 18.893 | 66.1 | 26.128 | 11.8 |
7.751 | 56.3 | 19.375 | 24.5 | 26.883 | 7.2 |
9.129 | 7.0 | 19.746 | 100.0 | 28.826 | 5.4 |
11.486 | 4.5 | 20.543 | 13.1 | 29.155 | 7.1 |
12.211 | 8.5 | 21.109 | 6.0 | 29.856 | 4.1 |
12.532 | 20.3 | 21.798 | 8.6 | 31.689 | 11.0 |
12.935 | 9.3 | 23.069 | 11.3 | 32.084 | 7.8 |
14.628 | 4.1 | 23.604 | 23.4 | 33.853 | 10.1 |
15.947 | 6.2 | 24.592 | 31.6 | ||
17.451 | 70.9 | 25.323 | 15.2 |
Note that: peaks with a relative peak intensity >4.0% were selected and listed in the table.
Example 3: preparation of form II of sulfate represented by formula (2-1)
A sample (502.1 mg) of the compound of formula (A) of preparation example 1 was weighed into a reaction flask at room temperature, a mixed solution (10 v, v/v=1/1, 5 mL) of acetone and ethyl acetate was added, a methanol solution (1 mol/L,1.1 eq) of sulfuric acid was added dropwise to the system, and after stirring at 50℃for 3 hours, the temperature was lowered to room temperature and stirring was continued for 14 hours, and a solid was obtained by filtration. The resulting solid was dried at 50℃for 16 hours to give 409.2mg of solid in 69.7% yield. Through detection, the salt formation is confirmed, and the alkali/acid ratio is 1:0.5, so that the sulfate shown in the formula (2-1) is obtained.
The sample was taken for X-ray powder diffraction and showed a crystalline solid (form II) with good crystallinity, the spectrum is shown in fig. 5 and the XRPD diffraction peak data is shown in table 3. Samples were taken for DSC-TGA testing and DSC plots showed an endothermic peak at 227.22C, see FIG. 6.
TABLE 3 XRPD diffraction peak data for form II of sulfate salt of formula (2-1)
Peak position (2θ) ° | Relative strength% | Peak position (2θ) ° | Relative strength% | Peak position (2θ) ° | Relative strength% |
3.866 | 18.1 | 12.565 | 14.6 | 21.757 | 7.8 |
5.456 | 100.0 | 16.001 | 26.0 | 22.347 | 7.0 |
7.609 | 28.1 | 16.512 | 41.9 | 22.748 | 10.2 |
8.650 | 9.6 | 17.274 | 9.7 | 23.440 | 6.5 |
8.932 | 6.6 | 18.524 | 28.0 | 24.859 | 7.4 |
10.911 | 15.9 | 18.921 | 80.4 | 25.362 | 9.7 |
12.263 | 6.8 | 19.355 | 17.7 | 25.853 | 7.1 |
Note that: peaks with a relative peak intensity >6.0% were selected and listed in the table.
Example 4: preparation of form I of the mesylate salt of formula (3-1)
A sample (about 30 mg) of the compound of formula (A) of preparation example 1 was weighed into a reaction flask at room temperature, methanol (0.5 mL) was added, methanesulfonic acid (1.1 eq) was added dropwise to the system, stirred at 50℃for 1 hour, then stirred at room temperature for 3 hours, and then filtered to obtain a solid. The obtained solid was dried at 50℃for 15 hours, and then examined to confirm that the salt had been formed and that the alkali/acid ratio was 1:1, to obtain the methanesulfonic acid salt represented by the formula (3-1).
The sample was taken for X-ray powder diffraction and showed a crystalline solid (form I) with good crystallinity, the spectrum is shown in fig. 7 and the XRPD diffraction peak data is shown in table 4. Samples were taken for DSC-TGA testing, DSC plots showing endothermic peaks at 71.95 ℃and 180.62 ℃and TGA plots showing 1.9565% weight loss of samples between room temperature and 100℃and 1.1072% weight loss between 100 and 200℃as shown in FIG. 8.
TABLE 4 XRPD diffraction peak data for form I of mesylate salt of formula (3-1)
Peak position (2θ) ° | Relative strength% | Peak position (2θ) ° | Relative strength% | Peak position (2θ) ° | Relative strength% |
5.388 | 9.7 | 15.480 | 14.7 | 20.187 | 7.4 |
5.879 | 6.2 | 15.917 | 6.6 | 21.118 | 11.9 |
6.356 | 7.2 | 16.092 | 10.5 | 21.925 | 9.2 |
6.816 | 100.0 | 17.748 | 5.3 | 25.951 | 13.8 |
8.145 | 15.2 | 18.023 | 13.5 | 26.268 | 19.7 |
10.558 | 29.1 | 18.898 | 15.5 | ||
11.917 | 15.2 | 19.385 | 12.3 |
Note that: peaks with a relative peak intensity >5.0% were selected and listed in the table.
Example 5: preparation of p-toluenesulfonate salt
A sample (about 30 mg) of the compound of formula (A) of preparation example 1 was weighed into a reaction flask at room temperature, acetonitrile (0.5 mL) was added, p-toluenesulfonic acid (1.1 eq) was added dropwise to the system, stirred at room temperature for 3 hours, and filtered to obtain a solid. After drying the solid at 50℃for 15 hours, it was checked to confirm that the salt had formed.
Samples were taken and subjected to X-ray powder diffraction and showed almost amorphous.
Example 6: preparation of benzenesulfonate salts
Using a method similar to example 5, benzenesulfonate was prepared and samples were subjected to X-ray powder diffraction and showed almost amorphous.
Comparative example 1: preparation of maleates, succinates, malates, citrates, fumarates and tartrates
Dissolving proper amount of maleic acid, succinic acid, malic acid, citric acid, fumaric acid or tartaric acid in methanol respectively to prepare an acid solution with the concentration of 0.1M; a sample (about 300 mg) of the compound of formula (A) obtained in preparation example 1 was dissolved in a mixed solution (10 mL, v/v=1/1) of methylene chloride and methanol to bring the concentration of the compound of formula (A) in the solution to 30mg/mL.
The above solution of the compound of formula (A) was added to the well plate (100. Mu.L per well), followed by adding the above-mentioned prepared acid solution (1.1 eq), and after the solvent in the well plate had completely volatilized at room temperature, 200. Mu.L of the selected solvent listed in the following table was added to each well, the well plate was sealed with a sealing film, and then the well was punched, followed by slow evaporation of the solvent. The results are shown in Table 5.
TABLE 5 salt formation reaction results
Maleic acid | Succinic acid | Malic acid | Citric acid | Fumaric acid | Tartaric acid | |
Methanol | Oil | Oil | Oil | G | G | G |
Isopropyl alcohol | Oil | Oil | Oil | G | G | G |
Tetrahydrofuran (THF) | Oil | G | G | Oil | Oil | Oil |
Acetonitrile | Oil | G | G | Oil | Oil | Oil |
Methyl tert-butyl ether | Oil | G | G | G | G | Oil |
Acetone (acetone) | Oil | G | G | G | G | Oil |
Water and its preparation method | Oil | Oil | Oil | G | G | G |
Acetic acid ethyl ester | Oil | Oil | Oil | G | G | G |
Note that: oil represents an Oil; g represents a glassy state.
The results show that: no solid precipitation was observed in the reaction system. Further, after the solvent is volatilized, all samples obtained after the reaction of the six acids with the compound of formula (a) are oily or glassy.
Test example 1: solid stability test of different Crystal forms of Compound of formula (A-1)
The samples of example 1 (form I of the hydrochloride salt) and example 3 (form II of the sulfate salt) were weighed into vials and placed under high temperature (60 ℃, sealed) and accelerated (40 ℃/75% rh, open) conditions for 7 days, respectively, and the samples were subjected to purity detection and X-ray powder diffraction, respectively, and the stability of example 1 (form I of the hydrochloride salt) and example 3 (form II of the sulfate salt) under different conditions was examined, and the results are shown in table 6.
TABLE 6 results of solid stability experiments
Note that: and/indicates undetected.
The data indicate that: both example 1 (form I of the hydrochloride salt) and example 3 (form II of the sulfate salt) remained chemically stable and form stable in the solid stability test.
Test example 2: example 3 (Crystal form II of sulfate) DVS test
A sample of example 3 (form II of the sulfate salt) was taken and placed in a DVS sample chamber for testing. The sample after DVS was subjected to X-ray powder diffraction, and the results are shown in table 7.
TABLE 7 DVS test results for example 3 (Crystal form II of sulfate)
Examples and initial crystalline forms | DVS post-crystal form |
Example 3 (Crystal form II of sulfate) | The crystal form is unchanged |
The data indicate that: example 3 (form II of sulfate) the sample remained unchanged after DVS testing.
Test example 1 TRK kinase inhibition test
1. The operation steps are as follows:
1.1 kinase reaction:
adding a compound to be tested, enzyme solution (negative control well added with kinase buffer (1 Xkinase buffer (Cisbio, cat#62EZBFDD), pH 7.5, 5mM MgCl) with a certain concentration gradient into the compound plate 2 1mM DTT)), and centrifuged at 1000rpm for 30 seconds. Plates were sealed and incubated in a constant temperature incubator at 25℃for 30 minutes. A substrate solution of TK-Sub-biotin (Cisbio, cat#61 TKOBL) and ATP (Sigma, cat#R0441) was prepared, and the substrate mixed solution was added to a 384-well plate and centrifuged at 1000rpm for 30 seconds. Plates were sealed and incubated in a constant temperature incubator at 25℃for 60 minutes.
1.2 kinase assay:
TK antibody and XL665 were diluted, mixed and added to assay plates and centrifuged at 1000rpm for 30 seconds. Plates were sealed and incubated in a constant temperature incubator at 25℃for 60 minutes. The assay plate was placed on an Envision machine to read. (HTRF 665/615 ratio: 665nm signal value/615 nm signal value)
Inhibition ratio = (ratio) Negative control well -ratio of Compound pore ) Ratio (ratio) Negative control well -ratio of Enzyme-free control wells )×100%
1.3 data analysis and Curve fitting
Fitting data in XLFit excel plug-in version 5.4.0.8 to obtain IC 50 Values.
1.4QC parameters
The reference compound is contained in each plate and its IC 50 Each time within 3 times.
2. Test results: as shown in Table 8
TABLE 8 kinase inhibitory Activity of different test compounds against TRK
Remarks: the RXDX-101, LOXO-195 and LOXO-101 are all disclosed compounds and can be commercially obtained into marketed products (pharmaceutical or chemical grade products); a compound of formula (a): preparation example 1 sample.
The results show that: the compound shown in the formula (A) has higher kinase inhibition activity in various kinases, and the activity in TRKA, TRKB, TRKC and TRKC-G696A is superior to that of RXDX-101, LOXO-101 and LOXO-195 or equivalent; whereas in the case of multiple mutant drug-resistant kinases (G595R, G667C, G623R) the inhibitory activity was significantly better than that of RXDX-101, LOXO-195 and LOXO-101.
Test example 2, ALK and ROS1 kinase inhibition assay
1. The operation steps are as follows:
1.1 kinase reaction:
the compound was diluted to a concentration in DMSO and diluted 4-fold gradient. Respectively adding a compound with a certain concentration into a 384-well plate, and incubating for 10min at room temperature with an enzyme solution and DMSO; adding fluorescein labeled peptide, and incubating at 28deg.C for a certain time with ATP (sigma, cat. No.: A7699-1G, lot. No.: 987-65-5); adding a stop solution. And (5) reading.
Inhibition ratio formula corresponding to single concentration: inhibition ratio= (OD Negative control well -OD Compound pore )/(OD Negative control well -OD Enzyme-free control wells )×100%
1.2 data analysis and Curve fitting
Fitting data in XLFit excel plug-in version 4.3.1 to obtain IC 50 Values, results are shown in Table 9.
TABLE 9 ALK and ROS1 kinase inhibitory Activity of different Compounds
Note that: a compound of formula (a): preparation example 1 sample.
The results show that: the compound shown in the formula (A) has stronger inhibition activity in ROS1 kinase, and is obviously superior to RXDX-101 and LOXO-101 and is superior to LOXO-195; the ALK kinase inhibitor also has good inhibition activity, and is obviously superior to LOXO-101 and LOXO-195.
Test example 3 in vitro cytostatic test
1. Cell lines
6 sources of cell lines for the test: kang Yuanbo Biotechnology (Beijing) Co., ltd
Cell type: murine B cells
Culture medium: RPMI-1640+10% FBS
2. Test method
Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Uniformly inoculating a cell suspension with a certain density into a 96-well plate by blowing, vibrating and uniformly dispersing the cell suspension into each hole by 100 mu L of each hole; adding 100 mu L of a drug solution with a certain concentration gradient into each hole, and setting three compound holes for each drug concentration; CO at 37 DEG C 2 Culturing in an incubator for 72 hours; adding MTT workerWorking fluid (5 mg/mL), 20. Mu.L per well; acting at 37 ℃ for 4 hours; the plate centrifuge is centrifuged at 1000rpm/min for 5min, 180 mu L of culture medium is sucked and removed, 150 mu L of DMSO is added, a micropore oscillator is used for shaking and mixing uniformly, the bottom of the plate is wiped clean, and an Optical Density (OD) value is detected at 550nm of an enzyme-labeling instrument.
3. Data analysis
Inhibition ratio = (control well OD-test well OD)/(control well OD-blank well OD) ×100% and half inhibition concentration IC was calculated from each concentration inhibition ratio using SPSS software 50 Values.
4. Test results: the results are shown in tables 10 and 11:
TABLE 10 inhibitory Activity of different Compounds against different cell lines
Note that: a compound of formula (a): preparation example 1 sample.
TABLE 11 inhibitory Activity of control Compounds against different cell lines
The results show that: the compound shown in the formula (A) shows better in-vitro cell activity in various wild type and mutant drug-resistant cell strains, and is obviously superior to RXDX-101, LOXO-195, LOXO-101 and the compounds D1-D5 in the prior art.
Test example 4: research on in vivo mechanism of Compounds of formula (A)
1. Test method
1.1 model preparation:
taking mutant drug-resistant cells Ba/F3 LMNA-NTRK1-G595R in logarithmic growth phase, collecting, and re-suspending in serum-free culture medium to make cell concentration 6×10 7 -10×10 7 individual/mL, and to cellsAdding equal volume of Matrigel to the suspension to give a final concentration of cells of 3×10 7 -5×10 7 And each mL. Nunununu mice (4-6 weeks, females) were inoculated subcutaneously with 0.1mL of tumor cell suspension in the anterior axilla with an inoculum size of 3×10 6 -5×10 6 Animal models were prepared.
1.2 test groups:
the maximum tumor diameter and the minimum tumor diameter of the nude mice transplanted tumor are measured by a vernier caliper, and the tumor volume is calculated: the calculation formula of Tumor Volume (TV) is: v=1/2×a×b 2 Wherein a and b represent the maximum and minimum diameters, respectively, of the tumor mass. Nude mice with proper tumor volume are selected, and animals are equally divided into 7 groups (200-300 mm) according to tumor volume by adopting a random digital method 3 ) Each group of 3.
1.3 administration of drugs
The compound represented by the formula (A) was administered by gavage according to the body weight of the animal in a volume of 10mL/kg, and the compound represented by the formula (A) was formulated to have a desired administration concentration using "3% DMSO+96% HP-. Beta. -CD (0.5 g/mL) +1% HCL".
Three control groups are adopted, and tumor tissues are frozen and stored 4 hours after the solvent is added. The other groups were given 100mg/kg of the compound represented by the formula (A), and tumor tissues were frozen at 0.25h, 1h, 4h, 8h, 12h and 24h, respectively.
1.4 protein extraction and quantification
Tumor tissue of a certain mass was taken and added to a corresponding volume of protein lysate (RIPA lysate (Thermo Fisher, cat. No. 89900) of protease inhibitor (clomplete, mini, EDTA-free, EASYpack; roche, cat. No. 04693159001) of phosphatase inhibitor (photosstop, EASYpack; roche, cat. No. 04906837001) =8:1:1), homogenized and lysed in ice bath for 30min. The supernatant was subjected to low-temperature high-speed centrifugation, and BCA protein was quantified (according to BCA protein quantification kit (Tiangen, cat# PA 115-01). Finally, the protein concentration is regulated to uniform concentration by using the lysate, loading buffer is added, and the mixture is boiled for 10min at 100 ℃.
1.5Western-blot
4-20% of 10-hole preformed adhesive is adopted; the loading amount is 100 mug; 140V electrophoresis for 1-1.5h; wet converting 300mA for 1.5-2 h; blocking with 5% BSA for 2-3h; incubation at 4deg.C overnight (Trk 1:5000, p-Trk, PLCγ1, p-PLCγ1, AKT, p-AKT, actin 1:1000); 4X 5min 0.1% TBST wash; the secondary antibody was incubated for 2h (1:5000) at room temperature, ECL luminescence, exposure.
2. Test results: as shown in fig. 9.
From the test results, it can be seen that: as time goes on, TRK, p-TRK, p-PLC gamma 1 and p-AKT in FIG. 9 are obviously reduced, and the compound shown in the formula (A) can obviously reduce the protein level of TRK, p-TRK, and further effectively inhibit phosphorylation of p-PLC gamma 1/PLC gamma 1 and p-AKT/AKT so as to regulate and control cell growth and proliferation.
Test example 5: in vivo efficacy experiment of compound on NTRK mutant drug-resistant tumor model
Test method
1.1 model preparation
Collecting cells in logarithmic growth phase, collecting, and re-suspending in serum-free medium to give cell concentration of 6X10 7 -10×10 7 Each mL, and an equal volume of Matrigel was added to the cell suspension to give a final cell concentration of 3X 10 7 -5×10 7 And each mL. Nunununu mice (4-6 weeks, females) were inoculated subcutaneously with 0.1mL of tumor cell suspension in the anterior axilla with an inoculum size of 3×10 6 -5×10 6 Animal models were prepared.
1.2 test group
The maximum tumor diameter and the minimum tumor diameter of the nude mice transplanted tumor are measured by a vernier caliper, and the tumor volume is calculated: the calculation formula of Tumor Volume (TV) is: v=1/2×a×b 2 Wherein a and b represent the maximum and minimum diameters, respectively, of the tumor mass. Nude mice with proper tumor volume are selected, and animals are equally divided into 7 groups (100-200 mm) according to tumor volume by adopting a random digital method 3 ) Each group had 6.
1.3 observations index
The animals were dosed by stomach irrigation at the same day as the day of the group, the dosing volume was 10mL/kg, LOXO-195 was formulated as the desired dosing solution using 0.5% CMC-Na, and the compound of formula (A) was formulated as the desired dosing solution using "3% DMSO+96% HP-beta-CD (0.5 g/mL) +1% HCL". Tumor diameters were measured twice weekly and tumor volumes were calculated. The specific indexes are as follows:
animal body weight: animals were weighed daily prior to the morning dosing, and a weight loss of greater than 20% was defined as a toxic response to the drug (the next day of last dosing was observed);
tumor volume (Tumor volume, TV) =v=1/2×a×b 2 Wherein a and b represent the maximum and minimum diameters, respectively, of the tumor mass (the next day of last administration was observed);
relative tumor proliferation rate T/C (%): T/C (%) =trtv/crtv×100% (TRTV: dosing group RTV, CRTV: control group RTV);
tumor Growth Inhibition (TGI) = [1- (Ti-T0)/(Vi-V0) ]x100%. (wherein Ti represents the average tumor volume of the administration group on a certain day; T0 represents the average tumor volume of the administration group at the beginning of administration; vi represents the average tumor volume of the vehicle control group on a certain day (same day as Ti; V0 represents the average tumor volume of the vehicle control group at the beginning of administration);
Tumor inhibition rate: at the end of the experiment, animals were sacrificed by cervical removal, tumor masses were removed and weighed, photographed, and tumor inhibition was calculated as tumor inhibition = (average tumor weight of control group-average tumor weight of dosing group)/average tumor weight of control group x 100%.
Test results
2.1Ba/F3 LMNA-NTRK1-G667C model
2.1.1 Effect of drug on body weight of tumor-bearing mice
The body weight of each dose group of each compound had an ascending trend, and the ascending trend was more pronounced than that of the control group. The weight of each dose group of each compound is obviously increased, which is possibly related to the compound, and the condition of mice is better and the weight is obviously increased due to the inhibition of tumor growth. The results are shown in Table 12.
2.1.2 effects of drugs on tumor weight and tumor inhibition Rate in tumor-bearing mice
The data results show that: at the same administration dose (100 mg/kg), the compound shown in the formula (A) has more remarkable inhibition on tumor growth compared with LOXO-195; further, the compound represented by the formula (A) (100 mg/kg) also exhibited a better tumor suppressing effect than the LOXO-195 group (200 mg/kg) at a higher administration dose. The results are shown in Table 12.
TABLE 12 in vivo results of Ba/F3 LMNA-NTRK1-G667C model
2.2Ba/F3 LMNA-NTRK1-G595R model
2.2.1 Effect of drug on body weight of tumor-bearing mice
The body weight of each dose group of each compound had an ascending trend, and the ascending trend was more pronounced than that of the control group. The weight of each dose group of each compound is obviously increased, which is possibly related to the compound, and the condition of mice is better and the weight is obviously increased due to the inhibition of tumor growth. The results are shown in Table 13.
2.2.2 effects of drugs on tumor weight and tumor inhibition Rate in tumor-bearing mice
The data results show that: compared with LOXO-195 (100 mg/kg), the compound shown in the formula (A) can realize remarkable inhibition of tumor tissue weight at a lower administration dosage (50 mg/kg), and the tumor weight inhibition rate is more than 90%. The results are shown in Table 13.
TABLE 13 in vivo results for Ba/F3 LMNA-NTRK1-G595R model
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Salts of the compounds represented by the formula (A-1),
wherein HA is an acid selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid; preferably hydrochloric acid, sulfuric acid or methanesulfonic acid; further preferred is hydrochloric acid or sulfuric acid;
n is an integer or a half integer of 1/2 to 4; preferably an integer or half-integer of 1/2 to 3; further preferably 0.5, 1, 1.5 or 2.
2. The salt of the compound of formula (a-1) according to claim 1, wherein the salt is a salt of the compound of formula (a-1) in a crystalline form.
4. a salt of a compound of formula (a-1) according to claim 3, wherein the salt is a hydrochloride salt of formula (1-1) in crystalline form;
preferably, the salt is form I of the hydrochloride salt of formula (1-1), using Cu-ka radiation, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,6.3 °,11.6 °,17.1 °,19.1 °;
alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,6.3 °,11.6 °,11.8 °,17.1 °,19.1 °,19.3 °;
alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,6.3 °,7.5 °,11.6 °,11.8 °,12.7 °,17.1 °,19.1 °,19.3 °;
alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ (±0.2°) angles: 5.7 °,6.3 °,7.5 °,11.6 °,11.8 °,12.7 °,15.1 °,17.1 °,19.1 °,19.3 °,25.8 °;
alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7,6.3,7.5, 11.6, 11.8, 12.7, 15.1, 16.3, 17.1, 19.1, 19.3, 24.7, 25.8;
Alternatively, the crystalline form I has an X-ray powder diffraction pattern substantially as shown in figure 1;
preferably, the differential scanning calorimetry curve of the crystal form I has an endothermic peak at 174.7 +/-5 ℃;
alternatively, the crystalline form I has a DSC profile substantially as shown in figure 2.
6. the salt of the compound represented by the formula (A-1) according to claim 5, wherein the salt is a sulfate represented by the formula (2-1) in a crystalline form.
7. The salt of the compound of formula (a-1) according to claim 5 or 6, wherein the salt is the crystalline form I of the sulfate salt of formula (2-1), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles (±0.2°) using Cu-ka radiation: 7.8 °,17.5 °,18.9 °,19.7 °;
alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,7.8 °,17.5 °,18.9 °,19.7 °,24.6 °;
alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,7.8 °,12.5 °,17.5 °,18.9 °,19.7 °,23.6 °,24.6 °;
Alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,7.8 °,12.5 °,17.5 °,18.9 °,19.4 °,19.7 °,23.6 °,24.6 °,25.3 °;
alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles (±0.2°): 5.7 °,7.8 °,12.5 °,17.5 °,18.9 °,19.4 °,19.7 °,23.6 °,24.6 °,25.3 °,26.1 °;
alternatively, the crystalline form I has an X-ray powder diffraction pattern substantially as shown in figure 3;
alternatively, the salt is form II of the sulfate salt of formula (2-1), having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°) using cu—kα radiation: 5.5 °,7.6 °,16.5 °,18.9 °;
alternatively, the X-ray powder diffraction pattern of form II has characteristic diffraction peaks at the following 2θ angles (±0.2°): 3.9 °,5.5 °,7.6 °,16.5 °,18.9 °;
alternatively, the X-ray powder diffraction pattern of form II has characteristic diffraction peaks at the following 2θ angles (±0.2°): 3.9 °,5.5 °,7.6 °,10.9 °,16.5 °,18.9 °;
alternatively, the X-ray powder diffraction pattern of form II has characteristic diffraction peaks at the following 2θ angles (±0.2°): 3.9 °,5.5 °,7.6 °,10.9 °,16.0 °,16.5 °,18.9 °;
Alternatively, the X-ray powder diffraction pattern of form II has characteristic diffraction peaks at the following 2θ angles (±0.2°): 3.9 °,5.5 °,7.6 °,10.9 °,12.6 °,16.0 °,16.5 °,18.9 °; alternatively, the form II has an X-ray powder diffraction pattern substantially as shown in figure 5;
preferably, the differential scanning calorimetry curve of the crystal form II has an endothermic peak at 227.22 +/-5 ℃;
alternatively, the form II has a DSC profile substantially as shown in figure 6.
8. A salt of the compound of formula (A-1) according to claim 1 or 2, which is a methanesulfonate salt represented by formula (3),
wherein n is 0.5, 1, 1.5 or 2; preferably 1;
preferably, the salt is a methanesulfonate salt represented by the formula (3-1),
preferably, the salt is a mesylate salt represented by formula (3-1) in a crystalline form;
preferably, the salt is form I of the mesylate salt of formula (3-1), having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles (±0.2°) using cu—kα radiation: 6.8 °,8.1 °,10.6 °,11.9 °;
alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.8 °,8.1 °,10.6 °,11.9 °,15.5 °;
Alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.8 °,8.1 °,10.6 °,11.9 °,15.5 °,18.9 °,21.1 °;
alternatively, the X-ray powder diffraction pattern of form I has characteristic diffraction peaks at the following 2θ angles (±0.2°): 6.8 °,8.1 °,10.6 °,11.9 °,15.5 °,18.0 °,18.9 °,21.1 °,26.3 °;
alternatively, the crystalline form I has an X-ray powder diffraction pattern substantially as shown in figure 7;
preferably, the differential scanning calorimetry curve of the crystal form I has an endothermic peak at 180.62 +/-5 ℃;
alternatively, the crystalline form I has a DSC profile substantially as shown in figure 8.
9. A pharmaceutical composition comprising a salt of a compound of formula (a-1) as defined in any one of claims 1 to 8, optionally further comprising one or more pharmaceutically acceptable carriers.
10. Use of a salt of a compound of formula (a-1) according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 as a medicament or in the preparation of a medicament; preferably, the medicament is for the prevention and/or treatment of one or more of TRK, ROS or ALK mediated diseases; further preferably, the disease is selected from pain diseases, cell proliferative diseases, inflammatory diseases, neurodegenerative diseases or infectious diseases.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111345223 | 2021-11-15 | ||
CN2021113452238 | 2021-11-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116120322A true CN116120322A (en) | 2023-05-16 |
Family
ID=86310689
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211426259.3A Pending CN116120322A (en) | 2021-11-15 | 2022-11-14 | Salt of aza-condensed ring amide compound, crystal form and use thereof |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN116120322A (en) |
WO (1) | WO2023083357A1 (en) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102264736A (en) * | 2008-10-22 | 2011-11-30 | 阵列生物制药公司 | Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors |
WO2012034095A1 (en) * | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
CN111039946A (en) * | 2018-10-15 | 2020-04-21 | 上海轶诺药业有限公司 | Preparation and application of imidazo aromatic ring compounds |
CN111542522A (en) * | 2017-08-11 | 2020-08-14 | 苏州韬略生物科技有限公司 | Substituted pyrazolopyrimidines useful as kinase inhibitors |
WO2021228248A1 (en) * | 2020-05-15 | 2021-11-18 | 石药集团中奇制药技术(石家庄)有限公司 | Fused aza-heterocyclic amide compound and use thereof |
CN115448874A (en) * | 2021-06-09 | 2022-12-09 | 石药集团中奇制药技术(石家庄)有限公司 | Solid form of cyclin-dependent kinase 9 inhibitor and use thereof |
CN116120323A (en) * | 2021-11-15 | 2023-05-16 | 石药集团中奇制药技术(石家庄)有限公司 | Solid form aza-condensed ring amide compound and use thereof |
-
2022
- 2022-11-14 CN CN202211426259.3A patent/CN116120322A/en active Pending
- 2022-11-14 WO PCT/CN2022/131768 patent/WO2023083357A1/en unknown
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102264736A (en) * | 2008-10-22 | 2011-11-30 | 阵列生物制药公司 | Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors |
WO2012034095A1 (en) * | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
CN111542522A (en) * | 2017-08-11 | 2020-08-14 | 苏州韬略生物科技有限公司 | Substituted pyrazolopyrimidines useful as kinase inhibitors |
CN111039946A (en) * | 2018-10-15 | 2020-04-21 | 上海轶诺药业有限公司 | Preparation and application of imidazo aromatic ring compounds |
WO2021228248A1 (en) * | 2020-05-15 | 2021-11-18 | 石药集团中奇制药技术(石家庄)有限公司 | Fused aza-heterocyclic amide compound and use thereof |
CN115551859A (en) * | 2020-05-15 | 2022-12-30 | 石药集团中奇制药技术(石家庄)有限公司 | Aza condensed ring amide compound and application thereof |
CN115448874A (en) * | 2021-06-09 | 2022-12-09 | 石药集团中奇制药技术(石家庄)有限公司 | Solid form of cyclin-dependent kinase 9 inhibitor and use thereof |
CN116120323A (en) * | 2021-11-15 | 2023-05-16 | 石药集团中奇制药技术(石家庄)有限公司 | Solid form aza-condensed ring amide compound and use thereof |
Also Published As
Publication number | Publication date |
---|---|
WO2023083357A1 (en) | 2023-05-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3740206B1 (en) | Inhibitors of cyclin-dependent kinase 7 (cdk7) | |
JP2023535746A (en) | Compounds used as CDK7 kinase inhibitors and their applications | |
JP7100625B2 (en) | Crystal form, salt type and method for producing the substituted 2-H-pyrazole derivative | |
CN107151249A (en) | It is used as the pteridine ketone derivatives of FLT3 inhibitor and application | |
WO2021228248A1 (en) | Fused aza-heterocyclic amide compound and use thereof | |
CN114437077A (en) | Compounds useful as kinase inhibitors and uses thereof | |
CN113024544A (en) | Cyano-containing heterocyclic compound and application thereof | |
CN116120323A (en) | Solid form aza-condensed ring amide compound and use thereof | |
CN115466266B (en) | mTOR protein degradation targeting chimeric body, preparation method and application thereof | |
WO2020007219A1 (en) | Crystalline form of egfr inhibitor and preparation method therefor | |
WO2022063229A1 (en) | Salt of arylaminoquinazoline-containing compound, and preparation method therefor and use thereof | |
WO2023036252A1 (en) | Pyrrolopyrimidine or pyrrolopyridine derivative and medical use thereof | |
CN116120322A (en) | Salt of aza-condensed ring amide compound, crystal form and use thereof | |
CN115322158A (en) | As KRAS G12C Substituted quinazoline compounds of protein inhibitor | |
CN114292270A (en) | BTK inhibitor and preparation method and application thereof | |
CN109422739B (en) | Deuterated indoleamine 2, 3-dioxygenase inhibitor and application thereof | |
JP2022517396A (en) | EGFR inhibitor salt, crystalline form and method for producing it | |
WO2019149128A1 (en) | 5-chloro-2,4-pyrimidine derivative used as anti-tumor drug | |
WO2023104107A1 (en) | Salt of 3,4-dihydroisoquinoline compound and use thereof | |
AU2018278283A1 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
CN104119321B (en) | The 2-maleate and its polymorph of indolinone derivative | |
CN112020357B (en) | Salt of indazolyl-containing tricyclic derivative and crystal form thereof | |
RU2811975C9 (en) | Condensed aza-heterocyclic amide compound and its use | |
RU2811975C1 (en) | Condensed aza-heterocyclic amide compound and its use | |
AU2021270672B2 (en) | Fused aza-heterocyclic amide compound and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |