CN114573517B - Quinoxaline compound and preparation method and application thereof - Google Patents
Quinoxaline compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN114573517B CN114573517B CN202210233387.XA CN202210233387A CN114573517B CN 114573517 B CN114573517 B CN 114573517B CN 202210233387 A CN202210233387 A CN 202210233387A CN 114573517 B CN114573517 B CN 114573517B
- Authority
- CN
- China
- Prior art keywords
- compound
- quinoxaline
- preparation
- substituted
- halogen
- 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.)
- Active
Links
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title claims abstract description 21
- -1 Quinoxaline compound Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 100
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000003252 quinoxalines Chemical class 0.000 abstract description 18
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 12
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 abstract description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 10
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 10
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 10
- 150000002475 indoles Chemical class 0.000 abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 10
- 125000000217 alkyl group Chemical group 0.000 abstract description 9
- 229910052736 halogen Inorganic materials 0.000 abstract description 9
- 150000002367 halogens Chemical group 0.000 abstract description 8
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 229940125782 compound 2 Drugs 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 abstract description 3
- 150000002825 nitriles Chemical class 0.000 abstract description 3
- 125000004076 pyridyl group Chemical group 0.000 abstract description 3
- 125000001544 thienyl group Chemical group 0.000 abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 3
- 125000005843 halogen group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KLLLJCACIRKBDT-UHFFFAOYSA-N 2-phenyl-1H-indole Chemical compound N1C2=CC=CC=C2C=C1C1=CC=CC=C1 KLLLJCACIRKBDT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 230000026045 iodination Effects 0.000 description 2
- 238000006192 iodination reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 1
- MHQULXYNBKWNDF-UHFFFAOYSA-N 3,4-dimethylbenzene-1,2-diamine Chemical compound CC1=CC=C(N)C(N)=C1C MHQULXYNBKWNDF-UHFFFAOYSA-N 0.000 description 1
- JKZOMQGCLXJWFO-UHFFFAOYSA-N 5,5-diiodoimidazolidine-2,4-dione Chemical compound IC1(I)NC(=O)NC1=O JKZOMQGCLXJWFO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a quinoxaline compound, a preparation method and application thereof, comprising the following steps of S1: the substituted indole 1 and the 1, 3-dicarbonyl compound 2 substituted by alpha-2, 6-tetramethyl piperidine oxide are subjected to serial reaction in an acid solvent to prepare quinoxaline compounds 3 and S2, wherein R1 is alkyl, alkoxy, halogen, polyfluoroalkyl and nitro; r2 is phenyl, alkyl substituted phenyl, halogen substituted phenyl, thienyl, pyridyl, cyclopropyl; nitro or nitrile, R3 is alkyl, alkoxy, halogen, trifluoromethyl. According to the invention, a series of quinoxaline derivatives are synthesized by the o-phenylenediamine, the substituted indole and the iodinated reagent through multi-step conversion reaction, the synthesis process is simple and easy to control, the structure types of target products are various, and various substituents can be introduced into the 2-position, the 3-position, the 5-position, the 6-position and the 7-position of the quinoxaline structure parent nucleus, so that a foundation is laid for synthesizing the quinoxaline structure-containing drug molecules.
Description
Technical Field
The invention relates to the technical field of synthesis and anti-tumor application of quinoxaline derivatives, in particular to a quinoxaline compound, and a preparation method and application thereof.
Background
The existing synthetic method of 2, 3-diaryl is mainly condensation cyclization of o-phenylenediamine and 1, 2-dicarbonyl compound, R2 and R3 structure types in synthetic molecular structure are less, substituents on a left benzene ring are generally symmetrical, and the substitution type of the synthesized compound is relatively monotonous, therefore, we propose a quinoxaline compound and a preparation method and application thereof.
Disclosure of Invention
Therefore, the invention aims to provide a quinoxaline compound, a preparation method and application thereof, wherein a series of quinoxaline derivatives are synthesized by carrying out multi-step conversion reaction on o-phenylenediamine, substituted indole and iodinated reagent, the synthesis process is simple and easy to control, the structure types of target products are various, and various substituents can be introduced into the 2-position, 3-position, 5-position, 6-position and 7-position of a quinoxaline structure parent nucleus, so that a foundation is laid for synthesizing a medicine molecule containing a quinoxaline structure.
In order to solve the technical problems, according to one aspect of the present invention, the following technical solutions are provided:
A quinoxaline compound, a preparation method and application thereof, comprising:
S1: the substituted indole 1 and the 1, 3-dicarbonyl compound 2 substituted by alpha-2, 6-tetramethyl piperidine oxide are subjected to series reaction in an acid solvent to prepare a quinoxaline compound 3;
s2: the reaction equation of the reaction process is:
wherein R1 is alkyl, alkoxy, halogen, polyfluoroalkyl or nitro; r2 is phenyl, alkyl substituted phenyl, halogen substituted phenyl, thienyl, pyridyl, cyclopropyl; nitro or nitrile, R3 is alkyl, alkoxy, halogen, trifluoromethyl.
As a preferred scheme of the quinoxaline compound, the preparation method and the application thereof, the molar ratio of the substituted indole 1 to the iodination reagent to the o-phenylenediamine compound is 1:1-1.1:1.
As a preferable scheme of the quinoxaline compound, the preparation method and the application thereof, the iodination reagent is iodine simple substance, diiodohydantoin or N-iodosuccinimide.
As a preferable scheme of the quinoxaline compound, the preparation method and the application thereof, the reaction temperature in the step S1 is 20-100 ℃.
As a preferable scheme of the quinoxaline compound, the preparation method and the application thereof, 43 quinoxaline compounds are prepared in the step S1.
As a preferable scheme of the quinoxaline compound, the preparation method and the application thereof, the preparation method of the compound 3-1 in 43 quinoxaline compounds is as follows: 0.2mmol of 2-phenylindole and 0.2mmol of NIS are dissolved in 20mL of dimethyl sulfoxide, stirred at room temperature for 2 hours, then 0.2mmol of o-phenylenediamine is added to the reaction mixture, stirred at room temperature for 6 hours, 20mL of water is added to the reaction mixture after the reaction is completed, the reaction mixture is extracted with ethyl acetate for 3 times, the organic phases are combined, the ethyl acetate is removed by rotary evaporation, column chromatography and eluent: petroleum ether: ethyl acetate=10:1, and quinoxaline derivative 3-1, 83% was isolated.
Compared with the prior art, the invention has the following beneficial effects: a series of quinoxaline derivatives are synthesized by multi-step conversion reaction of o-phenylenediamine, substituted indole and iodinated reagent, the synthesis process is simple and easy to control, the structure types of target products are various, various substituents can be introduced into the 2-position, 3-position, 5-position, 6-position and 7-position of a quinoxaline structure parent nucleus, a foundation is laid for synthesizing quinoxaline structure-containing drug molecules, when the preparation method is specifically used, the substituted indole 1 and alpha-position 2, 6-tetramethyl piperidine oxide substituted 1, 3-dicarbonyl compound 2 are subjected to serial reaction in an acid solvent to prepare quinoxaline compounds 3, 43 quinoxaline compounds are prepared in total, and the prepared quinoxaline compounds are sequentially, compound 3-1, compound 3-2, compound 3-3, compound 3-4, compound 3-6, compound 3-7, compound 3-8, compound 3-9, compound 3-10, compound 3-11, compound 3-12, compound 3-13, compound 3-14, compound 3-15, compound 3-16, compound 3-17, compound 3-18, compound 3-19, compound 3-20, compound 3-21, compound 3-22, compound 3-23, compound 3-24, compound 3-25, compound 3-26, compound 3-27, compound 3-28, compound 3-29, compound 3-30, compound 3-31, compound 3-32, compound 3-33, compound 3-34, compound 3-35, compound, compound 3-36, compound 3-37, compound 3-38, compound 3-39, compound 3-40, compound 3-41, compound 3-42, compound 3-43, wherein the preparation method of compound 3-1 comprises the following steps: 0.2mmol of 2-phenylindole and 0.2mmol of NIS are dissolved in 20mL of dimethyl sulfoxide, stirred at room temperature for 2 hours, then 0.2mmol of o-phenylenediamine is added to the reaction mixture, stirred at room temperature for 6 hours, 20mL of water is added to the reaction mixture after the reaction is completed, the reaction mixture is extracted with ethyl acetate for 3 times, the organic phases are combined, the ethyl acetate is removed by rotary evaporation, column chromatography and eluent: petroleum ether: ethyl acetate=10:1, quinoxaline derivative 3-1, 83% is obtained by separation, other kinds of compounds are the same as the preparation method of the compound 3-1, the prepared quinoxaline compound is subjected to application test detection, log phase cells are collected, inoculated onto a 96-hole cell culture plate, and medicine solutions with different concentrations to be detected are added. After 72 hours of incubation, 10% trichloroacetic acid was added, incubated at 4℃for 1 hour, washed 5 times with tap water and air-dried, surviving cells were stained with 0.4% (w/v) sulfonylrhodamine B at room temperature for 20min, washed 5 times with 1% acetic acid, dissolved in 10mM Tris solution, absorbance of each well was measured at 540nm of ELISA, and half-inhibitory concentrations of compounds 3-6, 3-7, 3-17, 3-21, 3-22, 3-34, 3-38 on human lung cancer cells were calculated as 1.2 and 2.4. Mu.M, respectively, based on inhibition (%) = (average of non-drug cell control well A value-average of drug well A value)/average of non-drug cell control well A value X100%.
Detailed Description
The following detailed description of the present invention will provide further details in order to make the above-mentioned objects, features and advantages of the present invention more comprehensible.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
To make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention are described in further detail below.
The invention provides a quinoxaline compound, a preparation method and application thereof, wherein a series of quinoxaline derivatives are synthesized by carrying out multi-step conversion reaction on o-phenylenediamine, substituted indole and iodinated reagent, the synthesis process is simple and easy to control, the structure types of target products are various, and various substituents can be introduced into the 2-position, 3-position, 5-position, 6-position and 7-position of a quinoxaline structure parent nucleus, so that a foundation is laid for synthesizing a quinoxaline structure-containing drug molecule.
A quinoxaline compound, a preparation method and application thereof, comprising:
S1: the quinoxaline compound 3 is prepared by the tandem reaction of substituted indole 1 and alpha-2, 6-tetramethyl piperidine oxide substituted 1, 3-dicarbonyl compound 2 in an acid solvent, and the prepared quinoxaline compounds have 43 kinds in total and have the following specific molecular formulas:
s2: the reaction equation of the reaction process is:
wherein R1 is alkyl, alkoxy, halogen, polyfluoroalkyl or nitro; r2 is phenyl, alkyl substituted phenyl, halogen substituted phenyl, thienyl, pyridyl, cyclopropyl; nitro or nitrile, R3 is alkyl, alkoxy, halogen, trifluoromethyl.
Preparation of Compound 3-1
0.2Mmol of 2-phenylindole and 0.2mmol of NIS are dissolved in 20mL of dimethyl sulfoxide, the mixture is stirred at room temperature for 2 hours, then 0.2mmol of o-phenylenediamine is added into the reaction mixture, the mixture is stirred at room temperature for 6 hours, 20mL of water is added after the reaction is completed, the reaction solution is extracted for 3 times by ethyl acetate, the organic phases are combined, the ethyl acetate is removed by rotary evaporation, and column chromatography (eluent: petroleum ether: ethyl acetate=10:1) is separated to obtain quinoxaline derivative 3-1 (83%).
1H NMR(400MHz,CDCl3)δ8.24–8.15(m,1H),8.15–8.06(m, 1H),7.84–7.72(m,2H),7.65–7.52(m,2H),7.42–7.29(m,3H), 7.20–7.08(m,1H),6.91–6.78(m,2H),6.55(t,J＝7.5Hz,1H), 4.62(s,2H);
Preparation of Compound 3-2
Compound 3-2 was produced in the same manner as compound 3-1, except that 3, 4-dimethyl-o-phenylenediamine was substituted for o-phenylenediamine.
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.85(s,1H),7.58–7.51(m,2H),7.34–7.27(m,3H),7.10(td,J＝8.1,1.5Hz,1H),6.84(dd,J＝7.7,1.4Hz,1H),6.79(d,J＝7.6Hz,1H),6.54(td,J＝7.6, 1.0Hz,1H),4.57(s,2H),2.52(s,3H),2.51(s,3H).
The preparation method of the compound 3-3, the compound 3-4, the compound 3-6, the compound 3-7, the compound 3-8, the compound 3-9, the compound 3-10, the compound 3-11, the compound 3-12, the compound 3-13, the compound 3-14, the compound 3-15, the compound 3-16, the compound 3-17, the compound 3-18, the compound 3-19, the compound 3-20, the compound 3-21, the compound 3-22, the compound 3-23, the compound 3-24, the compound 3-25, the compound 3-26, the compound 3-27, the compound 3-28, the compound 3-29, the compound 3-30, the compound 3-31, the compound 3-32, the compound 3-33, the compound 3-34, the compound 3-35, the compound 3-36, the compound 3-37, the compound 3-38, the compound 3-39, the compound 3-40, the compound 3-41, the compound 3-42 and the compound 3-43 is the same as the preparation method of the compound 1.
Experimental test examples:
the test principle is as follows: the sulfonyl rhodamine colorimetry is mainly used for detecting the proliferation condition of cells. SRB is a pink anionic dye, readily soluble in water, and specifically binds to basic amino acids of intracellular constituent proteins under acidic conditions; the absorbance peak is generated at the wavelength of 540nm, and the absorbance value is linearly and positively correlated with the cell quantity, so that the method can be used for quantitative detection of the cell quantity.
The test method comprises the following steps:
Sample preparation: dissolving compound in DMSO, ultrasonically dissolving, and storing the obtained medicinal solution at-20deg.C at concentration of 100 mM/L;
The log phase cells were collected, inoculated onto 96 well cell culture plates, and the drug solutions to be tested were added at different concentrations. After 72 hours of incubation, 10% trichloroacetic acid was added, incubated at 4℃for 1 hour, washed 5 times with tap water and air-dried, and surviving cells were stained with 0.4% (w/v) sulforhodamine B for 20min at room temperature, washed 5 times with 1% acetic acid, dissolved in 10mM Tris solution, and absorbance of each well was measured at 540nm in an ELISA.
The test data calculation method comprises the following steps:
Inhibition (%) = (average value of no drug cell control well a value-average value of drug administration well a value)/average value of no drug cell control well a value x 100%.
Based on the experimental results, data on all IC50 values, which are quite close to the normal method, were calculated according to the dot-skew method principle.
The basic formula:
1.IC50:IC50＝Log-1[Xm-i×(∑p–0.5)+i/4×(1-Pm-Pn)]
2. LD50 with 0% and 100% mortality:
IC50＝Log-1[Xm-i×(∑p–0.5)]
wherein Xm is the dose logarithmic value of the group with highest mortality rate Pm, i is the group distance, pm is the highest mortality rate, pn is the lowest mortality rate, and n is the number of animals in each group.
The activity results are shown in the following table:
From the above anti-tumor activity results, it can be seen that the compounds 3-6, 3-7, 3-17, 3-21, 3-22, 3-34, 3-38 of the present invention have significant cancer cell inhibitory activity, and the half-inhibitory concentrations of the compounds 3-7, 3-17 on human lung cancer cells are 1.2 and 2.4. Mu.M, respectively.
In specific use, 1, 3-dicarbonyl compound 2 substituted by substituted indole 1 and alpha-position 2, 6-tetramethylpiperidine oxide is subjected to serial reaction in an acid solvent to prepare 3 quinoxaline compounds, 43 quinoxaline compounds are prepared, and the three are sequentially 3-1, 3-2, 3-3, 3-4, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-21, 3-22, 3-23, 3-24, 3-25, 3-26, 3-27, 3-34, 3-30, 3-35, 3-34, 3-30, 3-34, 3-30, 3-35, 3-34 and 43 are prepared, wherein the three are prepared by the steps of: 0.2mmol of 2-phenylindole and 0.2mmol of NIS are dissolved in 20mL of dimethyl sulfoxide, stirred at room temperature for 2 hours, then 0.2mmol of o-phenylenediamine is added to the reaction mixture, stirred at room temperature for 6 hours, 20mL of water is added to the reaction mixture after the reaction is completed, the reaction mixture is extracted with ethyl acetate for 3 times, the organic phases are combined, the ethyl acetate is removed by rotary evaporation, column chromatography and eluent: petroleum ether: ethyl acetate=10:1, quinoxaline derivative 3-1, 83% is obtained by separation, other kinds of compounds are the same as the preparation method of the compound 3-1, the prepared quinoxaline compound is subjected to application test detection, log phase cells are collected, inoculated onto a 96-hole cell culture plate, and medicine solutions with different concentrations to be detected are added. After 72 hours of incubation, 10% trichloroacetic acid was added, incubated at 4℃for 1 hour, washed 5 times with tap water and air-dried, surviving cells were stained with 0.4% (w/v) sulfonylrhodamine B at room temperature for 20min, washed 5 times with 1% acetic acid, dissolved in 10mM Tris solution, absorbance of each well was measured at 540nm of ELISA, and half-inhibitory concentrations of compounds 3-6, 3-7, 3-17, 3-21, 3-22, 3-34, 3-38 on human lung cancer cells were calculated as 1.2 and 2.4. Mu.M, respectively, based on inhibition (%) = (average of non-drug cell control well A value-average of drug well A value)/average of non-drug cell control well A value X100%.
Although the invention has been described hereinabove with reference to embodiments, various modifications thereof may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In particular, the features of the disclosed embodiments may be combined with each other in any manner as long as there is no structural conflict, and the exhaustive description of these combinations is not given in this specification merely for the sake of omitting the descriptions and saving resources. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.
Claims (1)
1. Use of a quinoxaline compound in the manufacture of a medicament for inhibiting human lung cancer, wherein the compound is as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210233387.XA CN114573517B (en) | 2022-03-10 | 2022-03-10 | Quinoxaline compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210233387.XA CN114573517B (en) | 2022-03-10 | 2022-03-10 | Quinoxaline compound and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114573517A CN114573517A (en) | 2022-06-03 |
| CN114573517B true CN114573517B (en) | 2024-04-26 |
Family
ID=81773292
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210233387.XA Active CN114573517B (en) | 2022-03-10 | 2022-03-10 | Quinoxaline compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114573517B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1196784A (en) * | 1967-11-16 | 1970-07-01 | Sumitomo Chemical Co | Quinoxaline Derivatives |
| CN104995182A (en) * | 2013-02-07 | 2015-10-21 | 默克专利股份公司 | Substituted quinoxaline derivatives and their use as positive allosteric modulators of mglur4 |
| WO2015161142A1 (en) * | 2014-04-18 | 2015-10-22 | Millennium Pharmaceuticals, Inc. | Quinoxaline compounds and uses thereof |
| CN105017167A (en) * | 2015-07-20 | 2015-11-04 | 新乡医学院 | Preparation method of quinoxaline compounds |
| CN110627732A (en) * | 2019-10-12 | 2019-12-31 | 同济大学 | Method for synthesizing nitroquinoxaline or derivative thereof and aminoquinoxaline or derivative thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003226271B2 (en) * | 2002-04-08 | 2007-10-18 | Merck Sharp & Dohme Corp. | Fused quinoxaline derivatives as inhibitors of Akt activity |
| ZA200801822B (en) * | 2005-08-26 | 2009-09-30 | Serono Lab | Pyrazine derivatives and use as p13k inhibitors |
-
2022
- 2022-03-10 CN CN202210233387.XA patent/CN114573517B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1196784A (en) * | 1967-11-16 | 1970-07-01 | Sumitomo Chemical Co | Quinoxaline Derivatives |
| CN104995182A (en) * | 2013-02-07 | 2015-10-21 | 默克专利股份公司 | Substituted quinoxaline derivatives and their use as positive allosteric modulators of mglur4 |
| WO2015161142A1 (en) * | 2014-04-18 | 2015-10-22 | Millennium Pharmaceuticals, Inc. | Quinoxaline compounds and uses thereof |
| CN105017167A (en) * | 2015-07-20 | 2015-11-04 | 新乡医学院 | Preparation method of quinoxaline compounds |
| CN110627732A (en) * | 2019-10-12 | 2019-12-31 | 同济大学 | Method for synthesizing nitroquinoxaline or derivative thereof and aminoquinoxaline or derivative thereof |
Non-Patent Citations (1)
| Title |
|---|
| Jianwei Yan，et al..Indoles Oxidative Ring-Opening/Cyclization Cascade with the 1,2- Diaminoarenes: Direct Synthesis of 2‑Aryl-3-(2- aminoaryl)quinoxalines.《J. Org. Chem.》.2022,第87卷6347-6351. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114573517A (en) | 2022-06-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Jeyakkumar et al. | Design, synthesis and biological evaluation of berberine-benzimidazole hybrids as new type of potentially DNA-targeting antimicrobial agents | |
| Kalaria et al. | Synthesis, characterization and biological screening of novel 5-imidazopyrazole incorporated fused pyran motifs under microwave irradiation | |
| JP6629218B2 (en) | N-benzyltryptansulin derivatives, and their preparation and use | |
| Bärfacker et al. | Discovery of BAY 94‐8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases | |
| Beck et al. | Synthesis and biological evaluation of new carbohydrate-substituted indenoisoquinoline topoisomerase I inhibitors and improved syntheses of the experimental anticancer agents indotecan (LMP400) and indimitecan (LMP776) | |
| JP2016535788A5 (en) | ||
| Meragelman et al. | Unusual sulfamate indoles and a novel indolo [3, 2-a] carbazole from Ancorina sp. | |
| JP2010512358A (en) | Sulfonamides and their use as drugs | |
| Zhao et al. | Discovery and optimization of thienopyridine derivatives as novel urea transporter inhibitors | |
| Baruah et al. | Synthesis and cytotoxic activity of novel quinazolino-β-carboline-5-one derivatives | |
| Büttner et al. | Two novel series of allocolchicinoids with modified seven membered B-rings: design, synthesis, inhibition of tubulin assembly and cytotoxicity | |
| CN108069929A (en) | 3- substituted cumarins analog derivative and the agonist of application and GPR35 receptors | |
| WO2016086824A1 (en) | Bouchardatine and bouchardatine derivatives, and preparation method and application therefor | |
| CN109535176B (en) | Quinolone imidazole compound and preparation method and application thereof | |
| CN110437233B (en) | Tryptanthrin derivative containing olefine acid and preparation method and application thereof | |
| Abouelenein et al. | Synthesis, DFT calculations, In silico studies, and biological evaluation of pyrano [2, 3-c] pyrazole and pyrazolo [4′, 3′: 5, 6] pyrano [2, 3‐d] pyrimidine derivatives | |
| CN114573517B (en) | Quinoxaline compound and preparation method and application thereof | |
| Adhikari et al. | Microwave assisted synthesis of novel thiazolidinone analogues as possible bioactive agents | |
| CN112480140A (en) | C5-substituted tetrandrine derivative and preparation method and application thereof | |
| Othman et al. | Synthesis of Pyrano [3, 2‐c] quinoline‐3‐carboxaldehyde and 3‐(Ethoxymethylene)‐pyrano [3, 2‐c] quinolinone and Their Chemical Behavior toward Some Nitrogen and Carbon Nucleophiles | |
| CN108947916B (en) | Perimidine quinone derivative and preparation method and application thereof | |
| Sahu et al. | ‘Cephalandole A’analogues as a new class of antioxidant agents: Design, microwave-assisted synthesis, bioevaluation, SAR and in silico studies | |
| CN107973788B (en) | BBI608 derivative and preparation and application thereof | |
| CN115124531A (en) | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof | |
| CN110041335B (en) | Method for improving water solubility of tryptanthrin, tryptanthrin derivative, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |