CN110964018B - Indole derivative and application thereof - Google Patents
Indole derivative and application thereof Download PDFInfo
- Publication number
- CN110964018B CN110964018B CN201911217790.8A CN201911217790A CN110964018B CN 110964018 B CN110964018 B CN 110964018B CN 201911217790 A CN201911217790 A CN 201911217790A CN 110964018 B CN110964018 B CN 110964018B
- Authority
- CN
- China
- Prior art keywords
- indole
- triazino
- hydrazino
- ylidene
- dihydro
- 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.)
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- 150000002475 indoles Chemical class 0.000 title claims abstract description 51
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 201000011510 cancer Diseases 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 abstract description 20
- 229940079593 drug Drugs 0.000 abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 6
- 125000001041 indolyl group Chemical group 0.000 abstract description 5
- 230000002062 proliferating effect Effects 0.000 abstract description 5
- 230000005918 in vitro anti-tumor Effects 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 41
- 238000001228 spectrum Methods 0.000 description 25
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 23
- 239000002994 raw material Substances 0.000 description 15
- 239000007858 starting material Substances 0.000 description 15
- ZULJQRMXUOTWBU-UHFFFAOYSA-N 5,6-dihydrocyclopenta[b]pyridin-7-one Chemical compound C1=CN=C2C(=O)CCC2=C1 ZULJQRMXUOTWBU-UHFFFAOYSA-N 0.000 description 12
- JIAKIQWNYAZUJD-UHFFFAOYSA-N 6,7-dihydro-5h-quinolin-8-one Chemical compound C1=CN=C2C(=O)CCCC2=C1 JIAKIQWNYAZUJD-UHFFFAOYSA-N 0.000 description 12
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 8
- UQOSBPRTQFFUOA-SRZZPIQSSA-N 6-methyl-n-[(e)-1-pyridin-2-ylethylideneamino]-5h-[1,2,4]triazino[5,6-b]indol-3-amine Chemical compound N=1N=C(C2=CC=CC(C)=C2N2)C2=NC=1N\N=C(/C)C1=CC=CC=N1 UQOSBPRTQFFUOA-SRZZPIQSSA-N 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
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- DXVCYURKUXXEFS-UHFFFAOYSA-N (6-fluoro-5H-[1,2,4]triazino[5,6-b]indol-3-yl)hydrazine Chemical compound C1=CC2=C(C(=C1)F)NC3=C2N=NC(=N3)NN DXVCYURKUXXEFS-UHFFFAOYSA-N 0.000 description 5
- MFGJQOJJIQYMOS-UHFFFAOYSA-N (6-methoxy-5H-[1,2,4]triazino[5,6-b]indol-3-yl)hydrazine Chemical compound COC1=CC=CC2=C1NC3=C2N=NC(=N3)NN MFGJQOJJIQYMOS-UHFFFAOYSA-N 0.000 description 5
- IENCLQAXYAPTJO-UHFFFAOYSA-N (6-methyl-5h-[1,2,4]triazino[5,6-b]indol-3-yl)hydrazine Chemical compound N1C2=NC(NN)=NN=C2C2=C1C(C)=CC=C2 IENCLQAXYAPTJO-UHFFFAOYSA-N 0.000 description 5
- UFRCSMTZLCANHO-UHFFFAOYSA-N (8-fluoro-5h-[1,2,4]triazino[5,6-b]indol-3-yl)hydrazine Chemical compound C1=C(F)C=C2C3=NN=C(NN)N=C3NC2=C1 UFRCSMTZLCANHO-UHFFFAOYSA-N 0.000 description 5
- JVBPCXUAXZHKMG-UHFFFAOYSA-N (8-methoxy-5H-[1,2,4]triazino[5,6-b]indol-3-yl)hydrazine Chemical compound COc1ccc2[nH]c3nc(NN)nnc3c2c1 JVBPCXUAXZHKMG-UHFFFAOYSA-N 0.000 description 5
- YLPMAXDBFIGJGF-UHFFFAOYSA-N 5h-[1,2,4]triazino[5,6-b]indol-3-ylhydrazine Chemical compound C1=CC=C2C3=NN=C(NN)N=C3NC2=C1 YLPMAXDBFIGJGF-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- FSEXUSFSPLZUJY-UHFFFAOYSA-N (6-bromo-5H-[1,2,4]triazino[5,6-b]indol-3-yl)hydrazine Chemical compound C1=CC2=C(C(=C1)Br)NC3=C2N=NC(=N3)NN FSEXUSFSPLZUJY-UHFFFAOYSA-N 0.000 description 4
- OMGGGTACHGBYIJ-UHFFFAOYSA-N (8-bromo-5h-[1,2,4]triazino[5,6-b]indol-3-yl)hydrazine Chemical compound C1=C(Br)C=C2C3=NN=C(NN)N=C3NC2=C1 OMGGGTACHGBYIJ-UHFFFAOYSA-N 0.000 description 4
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 4
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- -1 nitro, amino Chemical group 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
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- QNIGVTNBJSLTIS-UHFFFAOYSA-N (8-methyl-5h-[1,2,4]triazino[5,6-b]indol-3-yl)hydrazine Chemical compound NNC1=NN=C2C3=CC(C)=CC=C3NC2=N1 QNIGVTNBJSLTIS-UHFFFAOYSA-N 0.000 description 3
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 3
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- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 3
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- HSDMBJODORFRNX-UHFFFAOYSA-N (6,8-dimethyl-5h-[1,2,4]triazino[5,6-b]indol-3-yl)hydrazine Chemical compound NNC1=NN=C2C3=CC(C)=CC(C)=C3NC2=N1 HSDMBJODORFRNX-UHFFFAOYSA-N 0.000 description 2
- RPEJKVRRTJDBSN-UHFFFAOYSA-N 2,5-dihydro-[1,2,4]triazino[5,6-b]indole-3-thione Chemical compound C12=CC=CC=C2NC2=C1N=NC(=S)N2 RPEJKVRRTJDBSN-UHFFFAOYSA-N 0.000 description 2
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- YMUAYOVHQINORF-UHFFFAOYSA-N 6-chloro-2,5-dihydro-[1,2,4]triazino[5,6-b]indole-3-thione Chemical compound Clc1cccc2c3n[nH]c(=S)nc3[nH]c12 YMUAYOVHQINORF-UHFFFAOYSA-N 0.000 description 2
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
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- 230000033115 angiogenesis Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- 125000005597 hydrazone group Chemical group 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
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- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000007788 liquid Substances 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
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- 239000002207 metabolite Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical Kinetics & Catalysis (AREA)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses an indole derivative which is a derivative containing an indole structure with a novel structure, and the in vitro antitumor activity of the derivative is tested to discover that the compound has a remarkable antitumor effect and can be applied to the preparation of medicines for treating or preventing cancer diseases and other proliferative diseases, so that the treatment or prevention of the cancer diseases and other proliferative diseases is realized, and therefore, the indole derivative has an excellent application prospect in the aspect of developing antitumor drugs.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to indole derivatives, including geometric isomers or pharmaceutically acceptable salts thereof, and application thereof in preparing medicines for treating and/or preventing various cancer diseases.
Background
Tumor is a disease seriously threatening human life and health, and in recent years, the incidence and death rate of tumor have a trend to rise year by year. Cytotoxic drugs can kill tumor cells, but do not kill cancer cells in the dormant stage, which results in extremely high recurrence rate of tumors, so that finding a tumor drug capable of eliminating dormant cells responsible for tumor recurrence is a crucial issue for tumor treatment.
The tumor blood vessel can provide nutrition for tumor tissues, transport metabolites away, contribute to invasion, metastasis and malignant process of tumors, because the over-expression of the angiogenesis promoting factor causes the tumor blood vessel to be abnormal, the tumor blood vessel abnormality can promote the generation of a tissue microenvironment which lacks oxygen and nutrient substances, the microenvironment can effectively protect cells with slow growth and metabolic stress, while cells growing in tissue microenvironments lacking nutrients grow at a much slower rate than cells growing in normal vascularization, even in a quiescent state (dormant tumor cells), and exhibit altered phenotypic characteristics, the phenotypic change of these cells enables them to survive chemotherapy more aggressively and to divide new tumor cells, resulting in tumor recurrence.
Patent WO 2014/046589 discloses a series of indole derivatives, which not only can selectively act on tumor resting cells, but also can induce autophagy of tumor cells. Meanwhile, the growth of malignant proliferated tumor cells can be inhibited, and the metastasis and the diffusion of abnormal cells can be prevented. Among them, VLX-600 is most active.
Studies have shown (DOI:10.1038/ncomms 4295): VLX-600 can induce mitochondrial inactivation in a metabolism-damaged tumor microenvironment to play an anti-tumor role, and can effectively prevent the growth of dormant cells in solid tumors and induce autophagy of the dormant cells. Meanwhile, when the compound is combined with irinotecan, the compound has good anti-solid tumor effect and is in the phase I clinical research stage at present.
The inventor designs and synthesizes a series of brand new indole compounds on the basis of reference to a VLX-600 structure and literature reports thereof. In vitro activity screening shows that the compounds have obvious antitumor activity.
Disclosure of Invention
The invention aims to provide indole derivatives which have obvious anti-tumor effect and can be applied to the preparation of medicaments for treating or preventing cancer diseases and other proliferative diseases.
The invention also aims to provide application of the indole derivatives in preparing medicines for treating and/or preventing various cancer diseases.
In order to achieve the above purpose, the solution of the invention is:
an indole derivative, the structural general formula of which is shown as I,
wherein X is N or CH, Y is N or CH, N is 0-4 and is an integer, R is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, ester group, sulfonyl, sulfinyl, amido, carbamoyl, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio and C1-C6 alkyl acyl; .
R1Is a substituent selected from hydrogen, C1-C6 alkyl, unsubstituted or differently substituted benzyl;
R2is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, ester group, sulfonyl, sulfenyl, amido, carbamoyl, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio and C1-C6 alkylacyl.
Preferably, X and Y are both N, N is 1-2, R is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkylamino; r1Is hydrogen, R2Is hydrogen.
Preferably, the indole derivatives are selected from the following compounds:
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-methyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-methyl-5H- [1,2,4] triazido [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-methyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-methyl-5H- [1,2,4] triazido [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole.
The indole derivatives include geometric isomers thereof or pharmaceutically acceptable salts thereof, which may be any salt suitable for stabilizing the stable free base of formula i, i.e. acidic salts, such as hydrochloride, nitrate, methanesulfonate, maleate, sulfate and the like, and which may be mono (mono) or di (di) salts, preferably, which may be mono or di, most preferably, which is dihydrochloride.
The indole derivatives can be used for preparing medicines for treating and/or preventing various cancer diseases.
After the technical scheme is adopted, the indole derivatives are widely researched, the methyl group on the VLX-600 original hydrazone structure and the 3-position of a pyridine ring are subjected to ring closing by adopting a ring closing principle, different substituents are introduced on the indole ring at the same time, a series of novel indole structure-containing derivatives are designed and synthesized, and the compounds are found to have remarkable anti-tumor effect by testing the in vitro anti-tumor activity of the derivatives, can be applied to the preparation of medicines for treating or preventing cancer diseases and other proliferative diseases, so that the treatment or prevention of the cancer diseases and other proliferative diseases is realized, and therefore, the indole derivatives have excellent application prospects in the aspect of developing anti-tumor medicines.
Detailed Description
In order to further explain the technical solution of the present invention, the present invention is explained in detail by the following specific examples.
An indole derivative, the structural general formula of which is shown as I,
wherein X is N or CH, Y is N or CH, N is 0-4 and is an integer, R is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, ester group, sulfonyl, sulfinyl, amido, carbamoyl, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio and C1-C6 alkyl acyl; .
R1Is a substituent selected from hydrogen, C1-C6 alkyl, unsubstituted or differently substituted benzyl;
R2is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, ester group, sulfonyl, sulfenyl, amido, carbamoyl, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio and C1-C6 alkylacyl.
Preferably, X and Y are both N, N is 1-2, R is hydrogen or 1-3 substituents selected from hydroxyl, halogen, carboxyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkylamino; r1Is hydrogen, R2Is hydrogen.
Preferably, the indole derivatives are selected from the following compounds:
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-methyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-methyl-5H- [1,2,4] triazido [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-methyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-methyl-5H- [1,2,4] triazido [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-chloro-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-chloro-5H- [1,2,4] triazino [5,6-b ] indole
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-bromo-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole
(E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole;
(E) -3- (2- (6, 7-dihydroquinolin-8- (5H) -ylidene) hydrazino) -6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole.
Furthermore, the invention also relates to application of the indole derivative in preparing medicaments for treating and/or preventing various cancer diseases.
The present invention will be further described with reference to the following examples.
Synthetic route of indole derivatives
When X and Y are both N, R1And R2All are hydrogen, and the synthetic route is as follows:
wherein n is 1 or 2, R is H on the indole ring or one of methyl, fluorine, chlorine, bromine, methoxy and dimethyl substituted on different positions on the indole ring.
Synthesis of di-and indole derivatives
The starting reagents used in the examples were commercially available analytical or chemical grade chemicals, and the NMR spectra of the synthesized compounds were determined using Bruker ARX-400 and the mass spectra were determined using Agilent 1100 LC/MSD.
The structural formulas of the indole derivatives synthesized in examples 1 to 24 are shown in table 1.
TABLE 1 chemical name and structural formula of indole derivatives synthesized in each example
Example 1
Step A, preparation of 6-methyl-5H- [1,2,4] triazino [5,6-b ] indole-3-thiol (1 a):
32.2g of 7-methyl-2, 3-indoledione (0.20mol), 20.0g of thiosemicarbazide (0.22mol) and 41.4g of K are added at room temperature2CO3(0.3mol) and 300mL of water are stirred at room temperature for 2h, then the temperature is raised to 100 ℃, the reflux reaction is carried out for 5h, after the reaction is finished, the reaction liquid is cooled to room temperature, the suction filtration is carried out, the pH of the filtrate is adjusted to acidity by acetic acid, a large amount of solid is separated out, the suction filtration, the water washing and the drying are carried out, 43.5g of orange yellow solid is obtained, and the crude product is recrystallized by ethanol, thus obtaining 31.0g of off-white solid product. MS (ESI) M/z (%): 215.1[ M-H]-。
Step B, preparation of 3-hydrazino-6-methyl-5H- [1,2,4] triazino [5,6-B ] indole (2 a):
adding 30.0g of the 6-methyl-5H- [1,2,4] prepared in the step A at room temperature]Triazino [5,6-b]Indole-3-thiol (1a) (0.14mol), adding 150mL 80% hydrazine hydrate, stirring, carrying out oil bath reaction at 120 ℃ for 3h, cooling the reaction solution to room temperature after the reaction is finished, pouring into 500 mL of water, stirring for 10min, precipitating a large amount of solid, carrying out suction filtration, washing a filter cake with water, carrying out rinsing with ethanol, drying to obtain 28.0g of a crude product which is a grey brown solid, and recrystallizing the crude product with ethanol to obtain 27.5g of a yellow white powder product. MS (ESI) M/z (%): 215.0[ M + H]+。
Step C preparation of (E) -3- (2- (5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-ylidene) hydrazino) -6-methyl-5H- [1,2,4] triazino [5,6-b ] indole:
and (3) at room temperature, adding 0.1g of 3-hydrazino-6-methyl-5H- [1,2,4] triazeno [5,6-B ] indole (2a) (0.4mmol) prepared in the step B and 0.07g of 5, 6-dihydro-7H-cyclopenta [ B ] pyridin-7-one (0.44mmol) into absolute ethyl alcohol, adding a drop of glacial acetic acid, carrying out reflux reaction, completing TLC detection reaction, cooling, carrying out suction filtration, washing a filter cake with diethyl ether to obtain a yellow solid, thus obtaining the indole derivatives shown in the structural formula in the table 1, wherein the mass spectrum and the hydrogen spectrum data are shown in the table 2.
Example 2
Referring to the preparation method of example 1, except that 3-hydrazinyl-6-methyl-5H- [1,2,4] triazino [5,6-b ] indole (2a) and 6, 7-dihydro-5H-quinolin-8-one are used as raw materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared, and the mass spectrum and hydrogen spectrum data are shown in Table 2.
Example 3
Referring to step A of example 1, starting from 7-fluoro-2, 3-indoledione, 6-fluoro-5H- [1,2,4] was prepared]Triazino [5,6-b]Indole-3-thiol (1b), MS (ESI) M/z (%). 219.1[ M-H]-。
With reference to step B of example 1, with 6-fluoro-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1b) is used as a raw material to prepare 3-hydrazino-6-fluoro-5H- [1,2,4]Triazino [5,6-b]Indole (2b), MS (ESI) M/z (%): 219.2[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole (2b) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared, and the mass and hydrogen spectra data are shown in Table 2.
Example 4
Referring to the preparation of example 3, except that 3-hydrazino-6-fluoro-5H- [1,2,4] triazino [5,6-b ] indole (2b) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 5
Referring to step A of example 1, starting from 7-chloro-2, 3-indoledione, 6-chloro-5H- [1,2,4] was prepared]Triazino [5,6-b]Indole-3-thiol (1c), MS (ESI) M/z (%): 235.0 [ M-H]-。
With reference to step B of example 1, with 6-chloro-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1c) is used as a raw material to prepare 3-hydrazino-6-chloro-5H- [1,2,4]Triazino [5,6-b]Indole (2c), MS (ESI) m/z (％):235.6[M+H]+。
Referring to step C of example 1, starting from 3-hydrazino-6-chloro-5H- [1,2,4] triazino [5,6-b ] indole (2C) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 6
Referring to the preparation of example 5, except that 3-hydrazino-6-chloro-5H- [1,2,4] triazino [5,6-b ] indole (2C) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 7
Referring to step A of example 1, starting from 7-bromo-2, 3-indoledione, 6-bromo-5H- [1,2,4] was prepared]Triazino [5,6-b]Indole-3-thiol (1d), MS (ESI) M/z (%): 279.0[ M-H]-。
With reference to step B of example 1, with 6-bromo-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1d) is used as a raw material to prepare 3-hydrazino-6-bromine-5H- [1,2,4]Triazino [5,6-b]Indole (2d), MS (ESI) M/z (%): 280.0[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-6-bromo-5H- [1,2,4] triazino [5,6-b ] indole (2d) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared, and the mass and hydrogen spectra data are shown in Table 2.
Example 8
Referring to the preparation of example 7, except that 3-hydrazino-6-bromo-5H- [1,2,4] triazino [5,6-b ] indole (2d) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 9
Referring to step A of example 1, 7-methoxy-2, 3-indoledione was used as a starting material to prepare 6-methoxy-5H- [1,2, 4%]Triazino [5,6-b]Indole-3-thiol (1e), MS (ESI) M/z (%): 231.1[ M-H]-。
With reference to step B of example 1, with 6-methoxy-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1e) is used as a raw material to prepare 3-hydrazino-6-methoxyl-5H- [1,2,4]Triazino [5,6-b]Indole (2e), MS (ESI) M/z (%): 231.1[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole (2e) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 10
Referring to the preparation of example 9, except that 3-hydrazino-6-methoxy-5H- [1,2,4] triazino [5,6-b ] indole (2e) and 6, 7-dihydro-5H-quinolin-8-one were used as raw materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared, and the mass and hydrogen spectra data are shown in Table 2.
Example 11
With reference to step A of example 1,2, 3-indoledione was used as a starting material to prepare 5H- [1,2,4]]Triazino [5,6-b]Indole-3-thiol (1f), MS (ESI) M/z (%): 201.1[ M-H]-。
With reference to step B of example 1, with 5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1f) is used as raw material to prepare 3-hydrazino-5H- [1,2,4]Triazino [5,6-b]Indole (2f), MS (ESI) M/z (%): 201.2[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-5H- [1,2,4] triazino [5,6-b ] indole (2f) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared, the mass and hydrogen spectra data of which are shown in Table 2.
Example 12
Referring to the preparation method of example 11, except that 3-hydrazino-5H- [1,2,4] triazino [5,6-b ] indole (2f) and 6, 7-dihydro-5H-quinolin-8-one are used as raw materials in step C, indole derivatives having the structural formula shown in Table 1 are prepared, and the mass spectrum and hydrogen spectrum data are shown in Table 2.
Example 13
Reference is made to step A in example 1, at 5Preparing 8-methyl-5H- [1,2,4] by using (E) -methyl-2, 3-indole dione as raw material]Triazino [5,6-b]Indole-3-thiol (1g), MS (ESI) M/z (%): 215.1[ M-H]-。
With reference to step B of example 1, with 8-methyl-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1g) is used as raw material to prepare 3-hydrazino-8-methyl-5H- [1,2,4]Triazino [5,6-b]Indole (2g), MS (ESI) M/z (%): 219.2[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-8-methyl-5H- [1,2,4] triazino [5,6-b ] indole (2g) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 14
Referring to the preparation of example 13, except that 3-hydrazino-8-methyl-5H- [1,2,4] triazino [5,6-b ] indole (2g) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 15
Referring to step A of example 1, 5-fluoro-2, 3-indoledione was used as a starting material to prepare 8-fluoro-5H- [1,2, 4%]Triazino [5,6-b]Indole-3-thiol (1H), MS (ESI) M/z (%): 219.1[ M-H]-。
With reference to step B of example 1, with 8-fluoro-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1H) is used as a raw material to prepare 3-hydrazino-8-fluoro-5H- [1,2,4]Triazino [5,6-b]Indole (2H), MS (ESI) M/z (%): 219.1[ M + H]+。
Referring to step C of example 1, starting with 3-hydrazino-8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole (2H) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared with mass and hydrogen spectra data as shown in Table 2.
Example 16
Referring to the preparation of example 15, except that 3-hydrazino-8-fluoro-5H- [1,2,4] triazino [5,6-b ] indole (2H) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 17
Referring to step A of example 1, 5-chloro-2, 3-indoledione was used as a starting material to prepare 8-chloro-5H- [1,2, 4%]Triazino [5,6-b]Indole-3-thiol (1i), MS (ESI) M/z (%): 235.0 [ M-H]-。
With reference to step B of example 1, with 8-chloro-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1i) is used as a raw material to prepare 3-hydrazino-8-chloro-5H- [1,2,4]Triazino [5,6-b]Indole (2i), MS (ESI) M/z (%): 235.6[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-8-chloro-5H- [1,2,4] triazino [5,6-b ] indole (2i) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 18
Referring to the preparation of example 17, except that 3-hydrazino-8-chloro-5H- [1,2,4] triazino [5,6-b ] indole (2i) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 19
Referring to step A of example 1, starting from 5-bromo-2, 3-indoledione, 8-bromo-5H- [1,2,4] was prepared]Triazino [5,6-b]Indole-3-thiol (1j), MS (ESI) M/z (%): 279.5[ M-H]-。
With reference to step B of example 1, with 8-bromo-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1j) is used as a raw material to prepare 3-hydrazino-8-bromine-5H- [1,2,4]Triazino [5,6-b]Indole (2j), MS (ESI) M/z (%): 280.1[ M + H)]+。
Referring to step C of example 1, starting from 3-hydrazino-8-bromo-5H- [1,2,4] triazino [5,6-b ] indole (2j) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the formula shown in Table 1 were prepared and the mass spectral data are shown in Table 2.
Example 20
Referring to the preparation of example 19, except that 3-hydrazino-8-bromo-5H- [1,2,4] triazino [5,6-b ] indole (2j) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 21
Referring to step A of example 1, 5-methoxy-2, 3-indoledione was used as a starting material to prepare 8-methoxy-5H- [1,2, 4%]Triazino [5,6-b]Indole-3-thiol (1k), MS (ESI) M/z (%): 231.1[ M-H]-。
With reference to step B of example 1, with 8-methoxy-5H- [1,2,4]Triazino [5,6-b]Indole-3-thiol (1k) is used as a raw material to prepare 3-hydrazino-8-methoxyl-5H- [1,2,4]Triazino [5,6-b]Indole (2k), MS (ESI) M/z (%): 231.1[ M + H]+。
Referring to step C of example 1, starting from 3-hydrazino-8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole (2k) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 22
Referring to the preparation of example 21, except that 3-hydrazino-8-methoxy-5H- [1,2,4] triazino [5,6-b ] indole (2k) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 23
Referring to step A of example 1, 5, 7-dimethyl-2, 3-indoledione was used as a starting material to prepare 6, 8-dimethyl-5H- [1,2,4]]Triazino [5,6-b]Indole-3-thiol (1l), MS (ESI) M/z (%): 229.2[ M-H]-。
With reference to step B of example 1, the reaction mixture was washed with 6, 8-dimethyl-5H- [1,2,4]]Triazino [5,6-b]Indole-3-thiol (1l) is used as raw material to prepare 3-hydrazino-6, 8-dimethyl-5H- [1,2,4]]Triazino [5,6-b]Indole (2l), MS (ESI) M/z (%): 229.2[ M + H)]+。
Referring to step C of example 1, starting from 3-hydrazino-6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole (2l) and 5, 6-dihydro-7H-cyclopenta [ b ] pyridin-7-one, indole derivatives of the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 24
Referring to the preparation of example 23, except that 3-hydrazino-6, 8-dimethyl-5H- [1,2,4] triazino [5,6-b ] indole (2l) and 6, 7-dihydro-5H-quinolin-8-one were used as starting materials in step C, indole derivatives having the structural formula shown in Table 1 were prepared and the mass and hydrogen spectra data are shown in Table 2.
Example 25
Preparation of indole derivative hydrochloride ethanol cocrystal:
at room temperature, 100mg of the indole derivative (0.29 mmol) prepared in example 23 was added to 3mL of absolute ethanol, 1.45mmol of ethanol hydrochloride solution was added dropwise, after the addition, stirring was continued at room temperature for 5 hours, and suction filtration was carried out to give 112mg of a pale yellow solid. The hydrogen spectrum data are shown in table 2, confirming that the product is the hydrochloride ethanol co-crystal form.
TABLE 2 Mass and Hydrogen spectra of indole derivatives synthesized in the examples
In-vitro anti-tumor activity of indole derivatives
The indole derivatives prepared in examples 1-24 were subjected to in vitro activity tests for inhibiting human non-small cell lung cancer A549, human breast cancer cell MCF-7, human cervical cancer cell Hela and human hepatoma cell HepG-2, and the marketed drugs Sorafenib and VLX-600 were positive control drugs.
The experimental steps are as follows:
(1) plate paving: a549 cells, MCF-7 cells, Hela cells and HepG-2 cells in logarithmic growth phase and good state are taken and inoculated into a 96-well plate by 1.0 x 104 cells/well, wherein the culture medium of the A549 cells, the culture medium of the Hela cells and the culture medium of the HepG-2 cells are RPMI1640, the culture medium of the MCF-7 cells is DMEM, and subsequent experiments are carried out after 24h of culture;
(2) preparing the medicine: taking out each DMSO dissolved compound (including the compound in example 1-24, sorafenib and VLX-600), performing ultrasonic treatment for 20min before use to ensure that the compound is completely dissolved, and respectively diluting the compound with culture medium to 7 concentrations of 0.25. mu.M, 0.5. mu.M, 0.75. mu.M, 1. mu.M, 2. mu.M, 5. mu.M and 10. mu.M;
(3) adding medicine: discarding the culture medium in a 96-well cell plate, adding the culture medium containing the compound, setting a blank control (the concentration of the compound is 0 mu M), setting 3 multiple wells in each group, culturing for 48h in a constant-temperature incubator, wherein each well is 100 microliters;
(4) adding CCK-8 reagent: adding 8 mul of CCK-8 reagent into each hole under the condition of keeping out of the sun, placing the hole in a constant temperature incubator for culture, and observing the color of the liquid in real time;
(5) and (3) testing: after the reaction is sufficient, placing the 96-well plate in an enzyme-labeling instrument to detect the absorbance (A) value of each well under the wavelength of 450nm, and setting the reference wavelength to be 650 nm;
(6) data processing, calculating the median inhibitory concentration, i.e. IC50The value is obtained.
The results are shown in table 3, and it is clear from the results shown in table 3 that the compound of formula i prepared by the present invention generally has significant anti-tumor activity. The compounds of example 1, example 3, example 5, example 7, example 13, example 15, example 17, example 19 and example 23 show outstanding antitumor activity, IC against one or more tumor cells50A value of less than 10. mu. mol, comparable or superior to the antitumor activity of the control drugs sorafenib and VLX-600, wherein the activity of the compounds of examples 5 and 23 is optimal forIC of multiple tumor cell lines50The value is less than 1. mu. mol. Therefore, the compound claimed by the invention has good application prospect in preparing medicines for treating and/or preventing various cancer diseases.
TABLE 3 antitumor Activity of the Compounds in vitro
Note: "-" indicates that the activity of the compound was not tested.
The above embodiments are not intended to limit the form and style of the present invention, and any suitable changes or modifications made by those skilled in the art should be considered as not departing from the scope of the present invention.
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