UA76760C2 - Піролопіримідини як інгібітори протеїнкінази - Google Patents

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Publication number

UA76760C2

UA76760C2 UA2004010502A UA200410502A UA76760C2 UA 76760 C2 UA76760 C2 UA 76760C2 UA 2004010502 A UA2004010502 A UA 2004010502A UA 200410502 A UA200410502 A UA 200410502A UA 76760 C2 UA76760 C2 UA 76760C2

Authority

UA

Ukraine

Prior art keywords

alkyl

compound according

compound

aryl

substituted

Prior art date

2001-06-23

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• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 3
• 239000003909 protein kinase inhibitor Substances 0.000 title description 3
• DDWJFSYHYPDQEL-UHFFFAOYSA-N pyrimidine;1h-pyrrole Chemical class C=1C=CNC=1.C1=CN=CN=C1 DDWJFSYHYPDQEL-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 243
• 238000000034 method Methods 0.000 claims abstract description 64
• 150000003839 salts Chemical class 0.000 claims abstract description 50
• 239000000203 mixture Substances 0.000 claims abstract description 33
• 239000002253 acid Substances 0.000 claims abstract description 31
• 239000000651 prodrug Substances 0.000 claims abstract description 16
• 229940002612 prodrug Drugs 0.000 claims abstract description 16
• 239000012453 solvate Substances 0.000 claims abstract description 14
• 125000000217 alkyl group Chemical group 0.000 claims description 71
• -1 cyclic acetal Chemical class 0.000 claims description 70
• 125000003118 aryl group Chemical group 0.000 claims description 38
• 125000001072 heteroaryl group Chemical group 0.000 claims description 32
• 229910052739 hydrogen Inorganic materials 0.000 claims description 26
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
• 239000001257 hydrogen Substances 0.000 claims description 25
• 125000001041 indolyl group Chemical group 0.000 claims description 22
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
• 125000003342 alkenyl group Chemical group 0.000 claims description 17
• 229910052736 halogen Inorganic materials 0.000 claims description 17
• 150000002367 halogens Chemical class 0.000 claims description 17
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
• 150000002431 hydrogen Chemical class 0.000 claims description 14
• 206010028980 Neoplasm Diseases 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 11
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 11
• 230000003197 catalytic effect Effects 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 239000003112 inhibitor Substances 0.000 claims description 7
• 125000000304 alkynyl group Chemical group 0.000 claims description 6
• 206010003246 arthritis Diseases 0.000 claims description 6
• 201000011510 cancer Diseases 0.000 claims description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
• 201000010099 disease Diseases 0.000 claims description 5
• 125000005843 halogen group Chemical group 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 206010006187 Breast cancer Diseases 0.000 claims description 4
• 208000026310 Breast neoplasm Diseases 0.000 claims description 4
• 125000002252 acyl group Chemical group 0.000 claims description 4
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 4
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 4
• 230000001668 ameliorated effect Effects 0.000 claims description 4
• 208000006673 asthma Diseases 0.000 claims description 4
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 4
• 208000027866 inflammatory disease Diseases 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 206010009944 Colon cancer Diseases 0.000 claims description 3
• 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
• 201000004624 Dermatitis Diseases 0.000 claims description 3
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
• 201000004681 Psoriasis Diseases 0.000 claims description 3
• 208000015634 Rectal Neoplasms Diseases 0.000 claims description 3
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
• 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
• 201000010105 allergic rhinitis Diseases 0.000 claims description 3
• 208000010668 atopic eczema Diseases 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 208000020816 lung neoplasm Diseases 0.000 claims description 3
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
• 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 2
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
• 206010060862 Prostate cancer Diseases 0.000 claims description 2
• 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
• 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
• 229910052770 Uranium Inorganic materials 0.000 claims description 2
• 208000002205 allergic conjunctivitis Diseases 0.000 claims description 2
• 208000024998 atopic conjunctivitis Diseases 0.000 claims description 2
• 230000002757 inflammatory effect Effects 0.000 claims description 2
• 208000018937 joint inflammation Diseases 0.000 claims description 2
• 201000005202 lung cancer Diseases 0.000 claims description 2
• 201000008482 osteoarthritis Diseases 0.000 claims description 2
• 206010038038 rectal cancer Diseases 0.000 claims description 2
• 201000001275 rectum cancer Diseases 0.000 claims description 2
• 201000005404 rubella Diseases 0.000 claims description 2
• 208000017520 skin disease Diseases 0.000 claims description 2
• 125000003107 substituted aryl group Chemical group 0.000 claims description 2
• 201000002510 thyroid cancer Diseases 0.000 claims description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 3
• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 2
• 206010010741 Conjunctivitis Diseases 0.000 claims 1
• 206010011686 Cutaneous vasculitis Diseases 0.000 claims 1
• 206010012468 Dermatitis herpetiformis Diseases 0.000 claims 1
• 206010048768 Dermatosis Diseases 0.000 claims 1
• 208000000453 Skin Neoplasms Diseases 0.000 claims 1
• 206010047124 Vasculitis necrotising Diseases 0.000 claims 1
• 230000000172 allergic effect Effects 0.000 claims 1
• 201000000849 skin cancer Diseases 0.000 claims 1
• 238000012876 topography Methods 0.000 claims 1
• 238000011282 treatment Methods 0.000 abstract description 29
• 150000001204 N-oxides Chemical class 0.000 abstract 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 76
• 239000000243 solution Substances 0.000 description 49
• 230000003993 interaction Effects 0.000 description 47
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 42
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 36
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
• 230000000052 comparative effect Effects 0.000 description 32
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
• 230000002829 reductive effect Effects 0.000 description 25
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• 238000010992 reflux Methods 0.000 description 24
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
• 108091000080 Phosphotransferase Proteins 0.000 description 18
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
• 102000020233 phosphotransferase Human genes 0.000 description 18
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
• 235000019341 magnesium sulphate Nutrition 0.000 description 17
• 125000004432 carbon atom Chemical group C* 0.000 description 16
• 239000012074 organic phase Substances 0.000 description 16
• 239000007787 solid Substances 0.000 description 16
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 15
• 230000008569 process Effects 0.000 description 15
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
• 239000002585 base Substances 0.000 description 14
• 239000000377 silicon dioxide Substances 0.000 description 14
• 238000003818 flash chromatography Methods 0.000 description 13
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• 210000004027 cell Anatomy 0.000 description 12
• 239000011541 reaction mixture Substances 0.000 description 12
• 239000012312 sodium hydride Substances 0.000 description 12
• 229910000104 sodium hydride Inorganic materials 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
• 229910052740 iodine Inorganic materials 0.000 description 11
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
• 102000001253 Protein Kinase Human genes 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 239000002904 solvent Substances 0.000 description 10
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 9
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• 239000007864 aqueous solution Substances 0.000 description 9
• IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 9
• 108060006633 protein kinase Proteins 0.000 description 9
• 235000017557 sodium bicarbonate Nutrition 0.000 description 9
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 8
• 238000006243 chemical reaction Methods 0.000 description 8
• 150000002148 esters Chemical class 0.000 description 8
• 239000011630 iodine Substances 0.000 description 8
• 229910052763 palladium Inorganic materials 0.000 description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 7
• 230000029936 alkylation Effects 0.000 description 7
• 238000005804 alkylation reaction Methods 0.000 description 7
• 239000000460 chlorine Substances 0.000 description 7
• 229910052801 chlorine Inorganic materials 0.000 description 7
• 239000012458 free base Substances 0.000 description 7
• 239000012442 inert solvent Substances 0.000 description 7
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
• 241000282414 Homo sapiens Species 0.000 description 6
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 6
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 6
• 150000001450 anions Chemical class 0.000 description 6
• 239000000427 antigen Substances 0.000 description 6
• 108091007433 antigens Proteins 0.000 description 6
• 102000036639 antigens Human genes 0.000 description 6
• 239000012298 atmosphere Substances 0.000 description 6
• 210000003630 histaminocyte Anatomy 0.000 description 6
• 150000004677 hydrates Chemical class 0.000 description 6
• 230000007062 hydrolysis Effects 0.000 description 6
• 238000006460 hydrolysis reaction Methods 0.000 description 6
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
• 229910052757 nitrogen Inorganic materials 0.000 description 6
• 239000003960 organic solvent Substances 0.000 description 6
• 238000002360 preparation method Methods 0.000 description 6
• 125000004076 pyridyl group Chemical group 0.000 description 6
• 230000004044 response Effects 0.000 description 6
• GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
• 239000000126 substance Substances 0.000 description 6
• ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 6
• 238000002560 therapeutic procedure Methods 0.000 description 6
• 230000004913 activation Effects 0.000 description 5
• 125000001931 aliphatic group Chemical group 0.000 description 5
• 210000003719 b-lymphocyte Anatomy 0.000 description 5
• 239000012267 brine Substances 0.000 description 5
• 239000000872 buffer Substances 0.000 description 5
• 239000003795 chemical substances by application Substances 0.000 description 5
• 238000005859 coupling reaction Methods 0.000 description 5
• 230000002401 inhibitory effect Effects 0.000 description 5
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
• 230000008018 melting Effects 0.000 description 5
• 238000002844 melting Methods 0.000 description 5
• 125000002950 monocyclic group Chemical group 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• 125000006239 protecting group Chemical group 0.000 description 5
• 102000005962 receptors Human genes 0.000 description 5
• 108020003175 receptors Proteins 0.000 description 5
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
• 239000003826 tablet Substances 0.000 description 5
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
• 150000007513 acids Chemical class 0.000 description 4
• 230000006978 adaptation Effects 0.000 description 4
• 125000004644 alkyl sulfinyl group Chemical group 0.000 description 4
• 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
• 125000004414 alkyl thio group Chemical group 0.000 description 4
• 150000001412 amines Chemical class 0.000 description 4
• CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 4
• 125000003435 aroyl group Chemical group 0.000 description 4
• 229910052799 carbon Inorganic materials 0.000 description 4
• 230000008878 coupling Effects 0.000 description 4
• 238000010168 coupling process Methods 0.000 description 4
• 125000004122 cyclic group Chemical group 0.000 description 4
• 238000001704 evaporation Methods 0.000 description 4
• 230000008020 evaporation Effects 0.000 description 4
• 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 4
• 230000005764 inhibitory process Effects 0.000 description 4
• 102000006495 integrins Human genes 0.000 description 4
• 108010044426 integrins Proteins 0.000 description 4
• 230000003647 oxidation Effects 0.000 description 4
• 238000007254 oxidation reaction Methods 0.000 description 4
• 125000003367 polycyclic group Chemical group 0.000 description 4
• 230000019491 signal transduction Effects 0.000 description 4
• 230000011664 signaling Effects 0.000 description 4
• 235000012239 silicon dioxide Nutrition 0.000 description 4
• 239000000725 suspension Substances 0.000 description 4
• 238000012360 testing method Methods 0.000 description 4
• 230000001225 therapeutic effect Effects 0.000 description 4
• 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 4
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
• YMQRPXBBBOXHNZ-UHFFFAOYSA-N 2-chloro-1-morpholin-4-ylethanone Chemical compound ClCC(=O)N1CCOCC1 YMQRPXBBBOXHNZ-UHFFFAOYSA-N 0.000 description 3
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
• MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
• 239000000654 additive Substances 0.000 description 3
• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
• 239000004037 angiogenesis inhibitor Substances 0.000 description 3
• 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 3
• 125000004659 aryl alkyl thio group Chemical group 0.000 description 3
• 125000002102 aryl alkyloxo group Chemical group 0.000 description 3
• 230000037396 body weight Effects 0.000 description 3
• 238000009835 boiling Methods 0.000 description 3
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
• 229910052794 bromium Inorganic materials 0.000 description 3
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
• 239000003054 catalyst Substances 0.000 description 3
• 125000000392 cycloalkenyl group Chemical group 0.000 description 3
• 238000010828 elution Methods 0.000 description 3
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
• 125000005842 heteroatom Chemical group 0.000 description 3
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
• 238000002347 injection Methods 0.000 description 3
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• 229910052751 metal Inorganic materials 0.000 description 3
• 239000002184 metal Substances 0.000 description 3
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
• 230000004048 modification Effects 0.000 description 3
• 238000012986 modification Methods 0.000 description 3
• 231100000252 nontoxic Toxicity 0.000 description 3
• 230000003000 nontoxic effect Effects 0.000 description 3
• 239000003791 organic solvent mixture Substances 0.000 description 3
• 230000002018 overexpression Effects 0.000 description 3
• 239000012071 phase Substances 0.000 description 3
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
• 239000000047 product Substances 0.000 description 3
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
• 235000010265 sodium sulphite Nutrition 0.000 description 3
• 239000007858 starting material Substances 0.000 description 3
• 125000000547 substituted alkyl group Chemical group 0.000 description 3
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
• AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical class O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 2
• LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
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