CN108047231A - [1,2,4] the triazine simultaneously hydrochloride of [6,1-a] iso-indoles compound and its application - Google Patents
[1,2,4] the triazine simultaneously hydrochloride of [6,1-a] iso-indoles compound and its application Download PDFInfo
- Publication number
- CN108047231A CN108047231A CN201810002521.9A CN201810002521A CN108047231A CN 108047231 A CN108047231 A CN 108047231A CN 201810002521 A CN201810002521 A CN 201810002521A CN 108047231 A CN108047231 A CN 108047231A
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- Prior art keywords
- compound
- iso
- triazine
- application
- reaction
- Prior art date
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Links
- -1 iso-indoles compound Chemical class 0.000 title claims abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title abstract description 3
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 239000000651 prodrug Substances 0.000 claims description 14
- 229940002612 prodrug Drugs 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000008187 granular material Substances 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- 150000002518 isoindoles Chemical class 0.000 abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 5
- 230000009977 dual effect Effects 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 4
- 230000000452 restraining effect Effects 0.000 abstract description 4
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 abstract description 3
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 3
- 102000020233 phosphotransferase Human genes 0.000 abstract description 3
- 239000002552 dosage form Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 150000002240 furans Chemical class 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 150000003851 azoles Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- IYWQCCHIVFXZML-UHFFFAOYSA-N 1-iodopyrazole Chemical class IN1C=CC=N1 IYWQCCHIVFXZML-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 2
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
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- 229940125532 enzyme inhibitor Drugs 0.000 description 2
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- FVNAFVGZFQMIQX-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazin-6-ylmethanol Chemical compound N=1N2C(C=NC1)=CC(=C2)CO FVNAFVGZFQMIQX-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 238000003809 water extraction Methods 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
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- ZPWFQEVSUIVLDY-UHFFFAOYSA-N C1(=CC=CC=C1)ON(P(=O)(O)O)C1=CC=CC=C1 Chemical class C1(=CC=CC=C1)ON(P(=O)(O)O)C1=CC=CC=C1 ZPWFQEVSUIVLDY-UHFFFAOYSA-N 0.000 description 1
- 102100027100 Echinoderm microtubule-associated protein-like 4 Human genes 0.000 description 1
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- 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
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 1
- 229940124647 MEK inhibitor Drugs 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 102100022678 Nucleophosmin Human genes 0.000 description 1
- 108010025568 Nucleophosmin Proteins 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940124674 VEGF-R inhibitor Drugs 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 description 1
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- 230000033228 biological regulation Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
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- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- NGPSPIMZXYNMSK-UHFFFAOYSA-N cyclopentene methyl formate Chemical class COC=O.C1=CCCC1 NGPSPIMZXYNMSK-UHFFFAOYSA-N 0.000 description 1
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- XPFVYQJUAUNWIW-UHFFFAOYSA-N furfuryl alcohol Chemical class OCC1=CC=CO1 XPFVYQJUAUNWIW-UHFFFAOYSA-N 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
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- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
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- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- CRXFROMHHBMNAB-UHFFFAOYSA-N methyl 2-isocyanoacetate Chemical class COC(=O)C[N+]#[C-] CRXFROMHHBMNAB-UHFFFAOYSA-N 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- IRWXYFWBGITFAG-UHFFFAOYSA-N piperidin-4-yl methanesulfonate Chemical class CS(=O)(=O)OC1CCNCC1 IRWXYFWBGITFAG-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
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- 230000002265 prevention Effects 0.000 description 1
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- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- KGRPHHFLPMPUBB-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazine Chemical compound C1=NC=NN2C=CC=C21 KGRPHHFLPMPUBB-UHFFFAOYSA-N 0.000 description 1
- SFUIIJZOWVIBHA-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid Chemical compound C1=NC=NN2C=C(C(=O)O)C=C21 SFUIIJZOWVIBHA-UHFFFAOYSA-N 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- KHDBMTLGTSGEEG-UHFFFAOYSA-M sodium;2-methylbenzenesulfinate Chemical compound [Na+].CC1=CC=CC=C1S([O-])=O KHDBMTLGTSGEEG-UHFFFAOYSA-M 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to chemical medicines, it is related to a kind of [1,2,4] triazine with ALK/C MET kinases dual restraining activities simultaneously [6,1 a] iso-indoles compound, and the pharmaceutical composition containing the compound and application of the compound or composition in medicine preparation, and in particular to [1,2,4] triazine simultaneously [6,1 a] iso-indoles compound hydrochloride and its application, the compound have good dissolubility and stability, provide better choice for dosage form research.
Description
Technical field
The invention belongs to chemical medicines, and in particular to it is a kind of with ALK/C-MET kinases dual restraining activities [1,
2,4] triazine simultaneously [6,1-a] iso-indoles compound and pharmaceutical composition containing the compound and the compound or composition
Application in medicine preparation.
Background technology
Receptor type tyrosine kinase anaplastic lymphoma kinase (Anaplastic lymphoma kinase, ALK) is earliest
It is found in primary cutaneous type (Anaplastic large cell lymphoma, ALCL), by No. 2 and No. 5 dyes
The fused protein that colour solid transposition is formed contains 3 ' the end intracellular domain and nuclear phosphoprotein of ALK
The structural domain at the 5 ' ends of (Nucleophosmin, NPM).The study found that in non-small cell lung cancer, ALK positive rates are about
Specific chromosome translocation can occur for 3%-5%, patient, form EML4 and ALK fusion proteins, cause tumour cell because of gene table
It is proliferated and survives up to misregistration signal.
C-MET is a kind of protein product encoded by C-MET proto-oncogenes, is hepatocyte growth factor (HGF) receptor, has
There is tyrosine kinase activity, it is related with a variety of oncoproteins and regulatory protein, participate in cellular informatics conduction, cytoskeleton rearrangement
Regulation and control, be cell Proliferation, differentiation and movement an important factor for.Research shows that the generation of C-MET and a variety of cancers and transfer are close
Correlation, massive tumor patient have C-MET transition expression and gene magnification in the mode and transfer process of its tumour.
Gram azoles of U.S. FDA approval listing in 2011, can dose-dependent inhibition tumour cell for Buddhist nun (Crizotinib)
C-MET and ALK, the tumour cell for ALK gene occurring transposition or inversion also have potent inhibitory action.Clinical research shows gram
Azoles replaces Survival be significantly improved effect of the Buddhist nun to ALK positive Patients with Non-small-cell Lung, and tolerance is good, security compared with
Height can effectively treat the Locally Advanced of the ALK positives or the non-small cell lung cancer of transfer.
Therefore, drug of the exploitation with C-MET and ALK dual restraining activities, will clinically there is good application
Prospect.
The content of the invention
It is an object of the present invention to provide the compound furans -2- methyl with ALK/C-MET dual restraining activities
4- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
Hydrochloride or its solvate, crystallization or prodrug, the compound have good dissolubility and stability, are carried for dosage form research
Better choice is supplied.
It is another object of the present invention to provide contain furans -2- methyl 4- (1- (piperidin-4-yl) 1H- pyrazoles -3
Base) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazine simultaneously [6,1-a] iso-indoles -7- methyl ether hydrochlorides or its solvate, crystallization or
The pharmaceutical composition of prodrug and pharmaceutically acceptable carrier and include furans -2- methyl 4- (1- (piperidin-4-yl) 1H- pyrroles
- 3 base of azoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazine simultaneously [6,1-a] iso-indoles -7- methyl ether hydrochlorides or its solvate, knot
The brilliant or composition of prodrug and one or more protein tyrosine kinase inhibitors.
It is yet a further object of the present invention to provide furans -2- methyl 4- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,
6,7,8- tetrahydrochysenes-[1,2,4] triazine simultaneously [6,1-a] iso-indoles -7- methyl ether hydrochlorides or solvate, crystallization or prodrug or its
The method of medicine composite for curing and/or pre- preventing tumor and they prepare to treat and/or the drug of pre- preventing tumor in
Purposes.
For above-mentioned purpose, the present invention provides following technical scheme：
In a first aspect, a kind of compound or its solvate of offer formula of the present invention, crystallization or prodrug,
Second aspect, the present invention provide pharmaceutical composition, it includes the compound of the present invention or its solvate, crystallization or
Prodrug and pharmaceutically acceptable carrier.
In some embodiments, the present invention provide pharmaceutical composition, it includes the compound of the present invention, solvate,
Crystallization or prodrug also include the one or more selected from following composition：Tyrosine protein enzyme inhibitor, EGFR inhibitor, VEGFR
Inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, histone deacetylase
Enzyme inhibitor, VEGF antibody, EGF antibody, HIV kinases inhibitors, HMG-CoA reductase inhibitor etc..
Can by the compound of the present invention, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, diluent or
Excipient is prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication include, but are not limited to it is intracutaneous,
It is intramuscular, peritonaeum is interior, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, such as be passed through
It is transfused or injects, the approach absorbed by transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) is applied.Administration can be with
It is whole body or local.The example of oral administration preparation include solid or liquid dosage form, specifically, including tablet, pill,
Granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can be prepared by methods known in the art, and comprising
The conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
The third aspect, the present invention provide the compound of the present invention, solvate, crystallization or the medicine group of prodrug or the present invention
The method for closing object treatment and/or pre- preventing tumor and the application in prevention and/or tumor is prepared, including easy to tumour
Hair crowd or tumor patient apply the compound of the present invention, solvate, crystallization or prodrug or comprising the compound of the present invention,
The pharmaceutical composition of solvate, crystallization or prodrug, effectively to reduce Tumor incidence, extend tumor patient life.
Specific embodiment
Representative embodiment is the protection model and is not intended to limit the present invention in order to which the present invention is better described below
It encloses.
Embodiment 1
The synthesis of chloro- penta rings of 6,7- dihydros -5H- of 4- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- methanol
The synthesis of the iodo- 2- p-toluenesulfonyls -4- methyl formates-pentamethylene of step 1 1-
At -5 DEG C -5 DEG C, 5g 3- cyclopentene -1- methyl formates and 12.6g sodium toluene sulfinate are weighed in reaction bulb,
Add in 300mL methylene chloride/waters mixed solvent (volume ratio 1:1) after, reacting 1.5h, 10g I are added in2, it is small to be warmed to room temperature reaction 2
When, reaction finishes, and separates organic phase, and water mutually extracts, and merges, molten with aqueous solution of sodium bisulfite, saturated sodium bicarbonate water successively
Liquid and saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, filtering are spin-dried for, obtain title compound, without purifying, directly
For reacting in next step.
ESI-MS m/z:409[M+H]+,447[M+K]+。
The synthesis of step 2 1- p-toluenesulfonyls -4- methyl formates-cyclopentene
10.6g step 1 gained compounds are weighed in reaction bulb, are slowly added to 3.5g triethylamines, 200mL acetonitriles, 70 DEG C
When lower reaction 2.5 is small, reaction finishes, and is spin-dried for, and adds in the dissolving of 100mL ethyl acetate, successively with saturated sodium bicarbonate aqueous solution and
Saturated common salt aqueous solution washs, and anhydrous sodium sulfate drying, filtering is spin-dried for, obtains title compound, without further purification, be directly used in down
Single step reaction.
ESI-MS m/z:281[M+H]+。
The synthesis of-penta ring of step 3 2,4- dicarboxylic acid methyl esters simultaneously [3,4] pyrroles
1g NaH are weighed in reaction bulb, add in the anhydrous THF of 70mL, 100mL is added portionwise at 0-5 DEG C walks dissolved with 2.8g
The anhydrous THF solution of rapid 2 gained compound and 1.88g Methyl isocyanoacetates, the reaction was continued at 0-5 DEG C 1.5 it is small when, reacted
Finish, add in 1mL absolute methanols, stirring is spin-dried for, and ethyl acetate dissolving, diatomite filtering, filter cake acetic acid second are added in residue
Ester washs, and merges organic phase, saturated common salt water washing, and anhydrous sodium sulfate drying filters, is spin-dried for, obtains dark oil object, column chromatography
Purifying, obtains title compound.
ESI-MS m/z:224[M+H]+,262[M+K]+。
The synthesis of-penta ring of step 4N- amino -2,4- dicarboxylic acid methyl esters simultaneously [3,4] pyrroles
24mg NaH are weighed in reaction bulb, add in 5mL anhydrous DMFs, instilling 2mL at 0-5 DEG C is dissolved with 90mg steps 3 institute
Compound anhydrous DMF solution, 120mg diphenyl phosphono azanols are added portionwise, at room temperature in the reaction was continued at 0-5 DEG C 0.5h
The reaction was continued 0.5h, reaction finish, and add in ethyl acetate and ice water extraction, take organic layer, and aqueous layer with ethyl acetate extraction merges
Organic layer, saturated salt solution washed once, and anhydrous sodium sulfate drying, filtering is spin-dried for, column chromatography purifies to obtain title compound.
ESI-MS m/z:239[M+H]+。
Penta rings of step 5 4- hydroxyl -6,7- dihydros -5H- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- formic acid first
The synthesis of ester
0.7g step 4 gained compounds are weighed in reaction bulb, 5mL formyl amine solvents is added in, reacts 2 at 180-200 DEG C
Hour, reaction finishes, reaction solution is poured into 10mL ice water, ethyl acetate extraction, combined ethyl acetate, saturated common salt washing
It washs, anhydrous sodium sulfate drying, filtering is spin-dried for, and column chromatography purifying obtains title compound.
1H NMR(300M Hz,DMSO-d6):δ12.45(s,1H),7.68(s,1H),7.26(s,1H),3.72-3.66
(m,1H),3.63(s,3H),3.20-3.02(m,4H)。
ESI-MS m/z:234[M+H]+。
Chloro- penta rings of 6,7- dihydros -5H- of step 6 4- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- methyl formates
Synthesis
100mg step 5 gained compounds are weighed in reaction bulb, the dissolving of 20mL toluene is added in, sequentially adds 5 equivalent trichlorines
Oxygen phosphorus, 5 equivalent n,N-diisopropylethylamine, when reaction 6 is small at 110 DEG C, reaction finishes, and is spin-dried for, and adds in ethyl acetate dissolving, ice
Bath is lower to add in saturated sodium bicarbonate aqueous solution adjusting pH to 6-7, separates organic layer, saturated common salt water washing, anhydrous sodium sulfate is done
Dry, filtering is spin-dried for obtaining title compound.
ESI-MS m/z:252[M+H]+。
The conjunction of chloro- penta rings of 6,7- dihydros -5H- of step 7 4- simultaneously [3,4] pyrrolo- [2,1-f] [1,2,4] triazine -6- methanol
Into
20mL tetrahydrofurans and 54mg Lithium Aluminium Hydrides are added in reaction bulb, stirs the lower 20mL that is added dropwise dissolved with 400mg steps
The anhydrous tetrahydrofuran solution of rapid 6 gained compound stirs 0.5h, and reaction is finished, is quenched, ethyl acetate extraction, anhydrous slufuric acid
Sodium dries organic phase, and filtering is spin-dried for, and title compound is made.
1H NMR(300M Hz,DMSO-d6):δ10.05(s,1H),6.11(s,1H),3.65-3.62(m,2H),3.40-
3.36(m,1H),2.55-2.52(m,3H),2.28-2.25(m,2H)。
ESI-MS m/z:224[M+H]+。
Embodiment 2
The synthesis of the iodo- 1H- pyrazoles of 1- (N-Boc- piperidin-4-yls) -3-
The synthesis of step 1 piperidin-4-yl methanesulfonates
10g4- hydroxy piperidines are weighed in reaction bulb, anhydrous tetrahydro furan 200mL is added in and dissolves, at 0 DEG C, be slowly added dropwise
100mL is dissolved with 25g (Boc)2The anhydrous tetrahydrofuran solution of O, drop finish, and react at room temperature 12h, are spin-dried for, and it is molten to add in dichloromethane
Liquid, saturated common salt water washing, anhydrous sodium sulfate drying, filtering are spin-dried for obtaining title compound, without purifying, are directly used in next
Step.
ESI-MS m/z:180[M+H]+。
The synthesis of step 2N-BOC piperidin-4-yl methanesulfonates
5.4g step 1 gains are weighed in reaction bulb, 100mL dichloromethane is added in and dissolves, at 0 DEG C, be slowly added dropwise
4.2mL triethylamines, drop finish, and mesyl chloride 2.32mL and DMAP 40mg is slowly added dropwise, and drop finishes, and reacts at room temperature 8h, and reaction terminates,
Add water, dichloromethane extraction merges organic phase, and saturated common salt water washing, anhydrous sodium sulfate drying, filtering is spin-dried for titled
Object is closed, without purifying, is directly used in next step.
ESI-MS m/z:218[M+H]+。
The synthesis of the iodo- 1H- pyrazoles of step 3 1- (N-Boc- piperidin-4-yls) -3-
9.7g 4- iodine pyrazoles is weighed in reaction bulb, adds in 100mL DMF dissolving, is added portionwise 2.4g sodium hydrogen at 0 DEG C, 0
After reacting 1h at DEG C, 15.3g step 2 gains are added in, react 12h at 100 DEG C, reaction terminates, and water is added to quench, ethyl acetate extraction
It takes, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying is filtered, is spin-dried for, column chromatography purifies to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):7.53(s,1H),7.47(s,1H),4.23(m,3H),2.85-2.88
(m,2H),2.07-2.09(m,2H),1.88(m,2H),1.44(s,9H)。
ESI-MS m/z:378[M+H]+。
Embodiment 3
Furans -2- methyl 4- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazine simultaneously [6,
1-a] iso-indoles -7- methyl ethers synthesis
The chloro- 5,6,7,8- tetrahydrochysenes of step 1 furans -2- methyl 4--[1,2,4] triazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
1 gains of 10g embodiments are weighed in reaction bulb, the dissolving of 200mL tetrahydrofurans is added in, sequentially adds 8.6g 2-
Hydroxymethylfurans and 18.6g triphenylphosphines after reacting at room temperature 5h, are cooled to 0 DEG C, add in 15mL DIAD, react 12h at 0 DEG C,
Reaction finishes, and is spin-dried for, and column chromatography purifies to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):10.08(s,1H),7.67-7.68(m,1H),6.47-6.49(m,1H),
6.39-6.41(m,1H),6.08(s,1H),4.48(s,2H),3.46-3.49(m,1H),3.19-3.22(m,1H),2.52-
2.58(m,3H),2.27-2.29(m,2H)。
ESI-MS m/z:304[M+H]+。
Step 2 furans -2- methyl 4- (- 3 base of 1- (N-Boc- piperidin-4-yls) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,
4] triazine simultaneously [6,1-a] iso-indoles -7- methyl ethers
Weigh 4.09g PdCl2(dppf) in reaction bulb, 2 gains of 9.4g embodiments, 9.5g connection boric acid frequency are added in where
Alcohol ester, 9.7g potassium acetates and 150mL dimethyl sulfoxides react 3h at 80 DEG C, are cooled to room temperature, and add in 30mL and are dissolved with 7.6g steps
Dimethyl sulfoxide solution, the 20mL of 1 gains are dissolved with the aqueous solution of 6.6g sodium carbonate, 80 DEG C of reaction 4h, and reaction is finished, is cooled to
Room temperature, filtering, ethyl acetate washing filter cake take filtrate, add water, and ethyl acetate extraction merges organic layer, saturated common salt washing
It washs, anhydrous sodium sulfate drying is filtered, and concentration, column chromatography purifies to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):10.05(s,1H),7.94-7.97(m,2H),7.67-7.68(m,1H),
6.47-6.49(m,1H),6.37-6.39(m,1H),6.08(s,1H),4.48(s,2H),3.69-3.71(m,1H),3.21-
3.46(m,6H),2.55-2.58(m,2H),2.48-2.51(m,2H),2.27-2.33(m,1H),2.06-2.09(m,2H),
1.81-1.83(m,2H),1.38(s,9H)。
ESI-MS m/z:519[M+H]+。
Step 3 furans -2- methyl 4- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazine
And [6,1-a] iso-indoles -7- methyl ethers
1.0g step 2 gains are weighed in reaction bulb, add in dichloromethane 2mL, add in trifluoracetic acid 5mL, room temperature is stirred
8h is mixed, solvent and trifluoracetic acid is evaporated off, adds in dichloromethane dissolving, pH to 12-13 is adjusted with 20% sodium hydrate aqueous solution, point
From organic layer, water layer continues to be extracted with dichloromethane, merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, mistake
Filter, concentration, column chromatography purify to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):10.05(s,1H),7.94-7.97(m,2H),7.67-7.68(m,1H),
6.47-6.48(m,1H),6.39-6.41(m,1H),6.08(s,1H),4.48(s,2H),3.70-3.72(m,1H),3.45-
3.47(m,1H),3.21-3.23(m,1H),2.69-2.79(m,4H),2.52-2.58(m,3H),2.27-2.30(m,2H),
2.00-2.06(m,3H),1.81-1.83(m,2H)。
ESI-MS m/z:419[M+H]+。
Embodiment 4
Furans -2- methyl 4- (- 3 base of 1- (piperidin-4-yl) 1H- pyrazoles) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazine simultaneously [6,
1-a] iso-indoles -7- methyl ether hydrochlorides synthesis
3 gains of 15g embodiments are weighed in reaction bulb, ethyl acetate 50ml dissolvings is added in, chlorination hydroacetic acid second is added dropwise
Ester solution pours out supernatant, adds in acetone 50ml to pH to 6,0 DEG C of stirring 10min, and 0.5h, precipitation solid, mistake is stirred at room temperature
Filter, 40 DEG C of vacuum drying 2h, obtains title compound.
Stability experiment
4 parts of 4 compound of 0.5g embodiments is weighed, respectively under the conditions of illumination 4500Lx, under the conditions of RH70%75 DEG C,
It is placed under room temperature 6 months with RH70% under the conditions of RH70%60 DEG C, experimental result is shown in Table 1.
Table 1
The experimental results showed that 4 compound of the embodiment of the present invention has very high stability.
Solubility experiment
Solubility is measured using HPLC methods, experimental result is shown in Table 2.
Table 2
| Water | |
| 3 compound of embodiment | 15.2mg/ml |
| 4 compound of embodiment | 207.6mg/ml |
Vitro enzyme activity rating
ALK kinases behaviours source recombinant protein used, the enzyme are containing 50mM HEPES (pH7.5), 10mM MgCl2,2M
In the buffer solution of DTT (1000x) and the reaction system of 30 μM of ATP with peptide substrate and the test-compound of various concentration
It is reacted jointly (25 DEG C, 45min), substrate is marked in subsequent FAM labelled antibodies, finally in a manner of time-resolved fluorescence
ALK kinase activity is quantitative determined, the IC measured50Value is (required during for by certain density inhibition of enzyme activity to 50%
Compound concentration) it is shown in Table 3.
Table 3
| Compound | ALK kinase inhibitions IC50It is worth (nM) |
| Gram azoles replaces Buddhist nun | 0.52 |
| 3 compound of embodiment | 0.35 |
| 4 compound of embodiment | 0.31 |
Can be seen that the compound of the present invention from more than experimental result has preferable inhibitory activity to ALK kinases.
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair
The present invention can be carry out various modifications and changed on the premise of bright spirit and scope.The interest field of the present invention is not limited to
The detailed description made above, and claims should be belonged to.
Claims (6)
1. a kind of compound or its solvate, crystallization or prodrug,
2. a kind of pharmaceutical preparation, it includes compound described in claim 1 or its solvate, crystallization or prodrug, Yi Jiyi
Kind or a variety of pharmaceutically acceptable carriers.
3. pharmaceutical preparation according to claim 2, it is characterised in that：It is configured to be suitable for it is oral or it is parenteral to
Medicine.
4. pharmaceutical preparation according to claim 3, it is characterised in that：It is tablet, pill, granule, pulvis, capsule
Agent, syrup, emulsion, suspension.
5. any one of a kind of compound as described in claim 1 or its solvate, crystallization or prodrug or claim 2~4
Application of the pharmaceutical preparation in preparing for the drug for the treatment of and/or pre- preventing tumor.
6. application according to claim 5, it is characterised in that：The tumour is lung cancer.
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| WO2007066187A2 (en) * | 2005-12-05 | 2007-06-14 | Pfizer Products Inc. | Method of treating abnormal cell growth |
| CN104725381A (en) * | 2013-12-19 | 2015-06-24 | 南京圣和药业股份有限公司 | Growth factor receptor inhibitor and application thereof |
| CN104876941A (en) * | 2014-02-28 | 2015-09-02 | 南京圣和药业股份有限公司 | Fused tricyclic compound and applications thereof |
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| WO2007066187A2 (en) * | 2005-12-05 | 2007-06-14 | Pfizer Products Inc. | Method of treating abnormal cell growth |
| CN104725381A (en) * | 2013-12-19 | 2015-06-24 | 南京圣和药业股份有限公司 | Growth factor receptor inhibitor and application thereof |
| CN104876941A (en) * | 2014-02-28 | 2015-09-02 | 南京圣和药业股份有限公司 | Fused tricyclic compound and applications thereof |
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