CN105418608A - 7-benzo[b]-[1,10]o-phenanthroline pyridine carboxamide thiourea as well as preparation method and application thereof - Google Patents
7-benzo[b]-[1,10]o-phenanthroline pyridine carboxamide thiourea as well as preparation method and application thereof Download PDFInfo
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- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- -1 pyridine carboxamide thiourea Chemical compound 0.000 title abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 7
- 125000000641 acridinyl group Chemical class C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims abstract 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 47
- 238000006243 chemical reaction Methods 0.000 claims description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 25
- 125000003368 amide group Chemical group 0.000 claims description 23
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- ALXBXKJAVGIBDQ-UHFFFAOYSA-N 2-(quinolin-2-ylamino)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=C(C=CC=C2)C2=N1 ALXBXKJAVGIBDQ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 229940027998 antiseptic and disinfectant acridine derivative Drugs 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 claims description 3
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical compound C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 3
- 239000010813 municipal solid waste Substances 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 238000010025 steaming Methods 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N o-aminobenzenecarboxylic acid Natural products NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 125000005605 benzo group Chemical group 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 7
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 6
- 150000001251 acridines Chemical class 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical compound N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses 7-benzo[b]-[1,10]o-phenanthroline pyridine carboxamide thiourea as well as a preparation method and application thereof. The structural form is shown in the specification; the 7-site of the benzo[b]-[1,10]o-phenanthroline ring is connected with an active group acylaminothiourea structure to synthesize a novel acridine derivative which has extremely strong antitumor activity and can be applied to the preparation of antitumor drugs.
Description
Technical field
The present invention relates to medical art, particularly antitumor drug technical field, specifically a kind of preparation method and purposes with 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide of anti-tumor activity
Background technology
Acridine is the nitrogenous organic heterocyclic molecule that a class is subject to extensive concern, because its structure is large ring conjugated system, tool rigid planar structure, can be used as the macromolecular embedded bodies such as DNA, very strong physiologically active is all shown in antitumor, antiviral, anti-malarial, antibacterial, biological fluorescent labeling and treatment acquired immune deficiency syndrome (AIDS) etc., people have extracted or have adopted the method for chemosynthesis to obtain a large amount of acridine compounds from natural product, have studied their pharmacologically active and the mechanism of action.In order to improve it to the affine performance of DNA, the rejection of multiple enzyme and cytotoxicity etc., continuous exploration and improvement have been carried out to its structure of modification, innovation of the present invention is by benzo [b]-[1, the 7-position of 10] o-phenanthroline ring connects active group amide group thiocarbamide structure, synthesizing new acridine derivatives, this derivative not yet has report at present.
Summary of the invention
The object of the invention is to overcome the problems referred to above, a kind of compound with anti-tumor activity is provided, at benzo [b]-[1, the 7-position of 10] o-phenanthroline ring connects active group amide group thiocarbamide structure, synthesizing new acridine derivatives, there is extremely strong anti-tumor activity, can be applied in the preparation of antitumor drug.
Another object of the present invention prepares the method with anti-tumor activity medicine to provide a kind of, improves anti-tumor activity medicine to the affine performance of DNA, the consistent performance of multiple enzyme and cytotoxicity to its structure of modification.
Another object of the present invention is to provide a kind of 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide preparing the application of antitumor drug.
In order to realize object of the present invention and other advantages, provide a kind of 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, its structural formula is:
Described 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide molecular formula is C
23h
16n
6oS, relative molecular weight is 424.48, and physico-chemical property is: yellow powder, m.p.175-181 DEG C,
1hNMR (DMSO-d
6, 400MHz), δ: 12.89 (br, s, 1H,-NH), 12.41 (br, s, 1H,-NH), 11.07 (br, s, 1H,-NH), 10.99 (s, 1H, ArH), 10.22 (d, 1H, J=9.0, ArH), 9.09 (d, 1H, J=8.5, ArH), 8.82 (s, 1H, ArH), 8.64 (d, 2H, J=7.2, ArH), 8.47 (d, 1H, J=7.2, ArH), 8.24-8.36 (m, 2H, ArH), 7.86-7.96 (m, 2H, ArH), 7.83 (d, 1H, J=7.2, ArH), 7.77 (d, 1H, J=7.2, ArH), 7.66-7.74 (m, 2H, ArH),
13cNMR (DMSO-d
6, 100MHz), δ 189.70,170.21,150.34,149.89,145.21,134.38,133.78,133.42,132.18,131.29,130.55,130.21,129.67,129.27,128.54,127.64,126.79,124.35,123.78.
The preparation method of 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, is obtained by following synthetic route:
Preferably, the preparation method of described 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, concrete steps are:
Step one, 20-30 part o-bromobenzoic acid and 30-40 part 8-quinolylamine is added in a reservoir as raw material according to weight part, 6-8 part salt of wormwood and 0.2-0.4 part copper powder are catalyzer, add 20-50mL Pentyl alcohol or primary isoamyl alcohol as solvent, be heated to 130-150 DEG C of backflow 1.5-3 hour, after reaction terminates, remove solvent under reduced pressure, then in solid residue, add water continue reaction 15-30 minute, temperature of reaction controls at 70-90 DEG C, filters, filtrate is regulated pH, suction filtration, obtains compound N-quinolyl anthranilic acid;
Step 2, mixes the compound N obtained-quinolyl anthranilic acid with the pure phosphorus oxychloride of 7-7.5mL, and oil bath is heated, reaction 1-3 hour, obtained compound 7-chlorobenzene also [b]-[1,10] o-phenanthroline;
Step 3, add 0.2-0.4 part described compound 7-chlorobenzene also [b]-[1 in a reservoir, 10] o-phenanthroline and 25-35mL acetone, backflow adds 0.275 part of sodium sulfocynanate and 0.0075 part of Tetrabutyl amonium bromide after dissolving, continue back flow reaction 2-4 hour, to there being yellow solid powder to separate out, suction filtration, washing obtains compound 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates;
Step 4, add 0.2-0.3 part in a reservoir by compound 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates and 20-40mL acetonitrile solution, then vazadrine is added, back flow reaction 1-3 hour, there is a large amount of yellow powder solid to separate out in reaction process, after filtering and washing, namely obtain target product 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide.
Preferably, the preparation method of described 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, regulates pH by filtrate in described step one, adds concentrated hydrochloric acid and regulate pH to 1.5-2.5 in filtrate.
Preferably, the preparation method of described 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, when in described step 2, compound N-quinolyl anthranilic acid and phosphorus oxychloride close ring, in 10-15min, oil bath is heated to 85-90 DEG C; When there is vigorous reaction, remove heating bath immediately; If reaction is too fierce, available cold water cooling flask, treat that boiling eases up, oil bath temperature is increased to 135 ~ 140 DEG C, reaction 1-3 hour.
Preferably, the preparation method of described 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, after in described step 2, reaction terminates, residuum is poured into weight ratio be 1: 1-2: 1-2 strong aqua, trash ice and chloroform mixture in, solids dissolves, isolate chloroform layer, water layer continues to use chloroform extraction 2-3 time, combined chloroform extracting solution, dry 10-24 hour, filter, steaming desolventizes, and namely obtains compound 7-chlorobenzene also [b]-[1,10] o-phenanthroline.
7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide is preparing the application in antitumor drug.
The invention has the beneficial effects as follows, the present invention passes through at benzo [b]-[1, the 7-position of 10] o-phenanthroline ring connects active group amide group thiocarbamide structure, synthesizing new acridine derivatives, improve acridine derivatives to the affinity of DNA, the rejection of multiple enzyme and cytotoxicity, for acridine type chemosensitive test provides new thinking.
Embodiment
Embodiment 1
The preparation of 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide
Step one, in 250mL three-necked bottle, add 26g o-bromobenzoic acid, 34g (34mmoL) 8-quinolylamine, 7.5g (36.2mmoL) salt of wormwood and 0.3g (4.7mmoL) copper powder, add 30mL primary isoamyl alcohol again as solvent, be heated to 140 DEG C of return stirring 2h.After reaction terminates, remove solvent under reduced pressure, gained residue adds 600mL water, control temperature is at 80 DEG C of reaction 20min, filtered while hot, washing leaching cake, combining water layer, water layer concentrated hydrochloric acid is acidified to pH2, separate out a large amount of black powder, suction filtration, gained solid acetone recrystallization, obtain compound N-quinolyl anthranilic acid, productive rate 36%;
Step 2, in 100mL round-bottomed flask, adds the compound N-quinolyl anthranilic acid (9moL) and the pure phosphorus oxychloride of 7.2mL that obtain, in 15min, reactant is heated to 85 DEG C by oil bath; When there is vigorous reaction, remove heating bath immediately; If reaction is too fierce, available cold water cooling flask, treat that boiling eases up, oil bath temperature is increased to 135 DEG C, reaction 2h.After reaction terminates, residuum after the cooling period slowly impouring well-beaten according to weight ratio to be weight ratio be 1: 1: 2 strong aqua, trash ice and chloroform mixture in, with chloroform and ammonia water mixture washing flask, undissolved solids is no longer included after 30min, isolate chloroform layer, water layer continues to use chloroform extraction 3 times, combined chloroform extracting solution, dry 10 hours of Calcium Chloride Powder Anhydrous, filter, steaming desolventizes, and obtains compound 7-chlorobenzene also [b]-[1,10] o-phenanthroline, productive rate 18%;
Step 3, in 100mL round-bottomed flask, add 0.3g (1.1mmoL) 7-chlorobenzene also [b]-[1,10] o-phenanthroline and 30mL acetone, backflow adds 0.275gNaSCN (3.3mmoL) and 0.075g (0.23mmoL) Tetrabutyl amonium bromide after dissolving, after back flow reaction 3h, there is yellow solid powder to separate out, suction filtration, after water washing, obtain compound 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates, 94%;
Step 4, in 100mL round-bottomed flask, add 0.24g (0.8mmoL) compound 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates and 35mL acetonitrile, after add 1mmoL benzoyl hydrazine, back flow reaction 2h, have a large amount of solid to separate out in reaction process, cooling suction filtration obtains bright yellow solid and is 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, productive rate 57.2%, m.p.175-181 DEG C,
1hNMR (DMSO-d
6, 400MHz), δ: 12.89 (br, s, 1H,-NH), 12.41 (br, s, 1H,-NH), 11.07 (br, s, 1H,-NH), 10.99 (s, 1H, ArH), 10.22 (d, 1H, J=9.0, ArH), 9.09 (d, 1H, J=8.5, ArH), 8.82 (s, 1H, ArH), 8.64 (d, 2H, J=7.2, ArH), 8.47 (d, 1H, J=7.2, ArH), 8.24-8.36 (m, 2H, ArH), 7.86-7.96 (m, 2H, ArH), 7.83 (d, 1H, J=7.2, ArH), 7.77 (d, 1H, J=7.2, ArH), 7.66-7.74 (m, 2H, ArH),
13cNMR (DMSO-d
6, 100MHz), δ 189.70,170.21,150.34,149.89,145.21,134.38,133.78,133.42,132.18,131.29,130.55,130.21,129.67,129.27,128.54,127.64,126.79,124.35,123.78, this medicine can make common dosage forms pharmaceutically, comprises and makes injection, tablet, pill, capsule, suspension agent or emulsion.
Embodiment 2
Anti tumor activity in vitro is tested
One, cell cultivation and go down to posterity
Selected cell strain is all placed in 37 DEG C, incubator under the abundant humidifying condition of 5%CO2, is inoculated in the PPMI1640 nutrient solution containing 10% deactivation new-born calf serum and cultivates.With inverted microscope observation of cell growing state, change weekly 2 ~ 3 subcultures, within 6 ~ 7 days, go down to posterity once, go down to posterity with 0.25% tryptic digestion during inoculation, usually get and go down to posterity 3 ~ 4 times, be in logarithmic phase cell for experiment.
Two, the preparation of liquid
Accurately take sample, be added in the 1.5mL centrifuge tube of sterilizing, add DMSO and be made into 2mM compound stock solution ,-20 DEG C of freezen protective.Respective concentration application is diluted to appropriate D-hanks after melting before use.The compound concentration that measuring is selected is respectively 20uM.
Three, MTT experiment method
Get the cell being in logarithmic phase, every hole 180uL (an about 4500-5000 cell) celliferous culture medium inoculated in 96 well culture plates, in 37 DEG C, 5%CO
224h is cultivated under abundant humidifying condition.After cell attachment, add sample by the amount of every hole 20uL, 6 multiple holes established by each sample, set corresponding blank simultaneously.After continuing to cultivate 48h, every hole adds 10uLMTT reagent (concentration is 2mg/mL), and after continuing to hatch 4h, inhale and abandon supernatant liquor, every hole adds 150uLDMSO again, and slight concussion reaction 5-8min, makes crystalline particle fully dissolve.Blank group returns to zero, with microplate reader with 490nm wavelength measure the absorbance after removing bias light absorption value (
value), the IC of corresponding cell strain is by 5 concentration gradients
50value, all experiments are averaged after all repeating 3 times.
Table 17-benzo [c] acridine benzoylamino thiocarbamide is to the medium effective concentration (IC of tumor cell line
50)
Table 1
As can be seen from the result of embodiment 2,7-benzo [b] of the present invention-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide shows through anticancer experiment in vitro, and this compound has strong anti-tumor activity.The present invention is that the new acridine type antitumor drug of research and development provides new thinking.
Although embodiment of the present invention are open as above, but it is not restricted to listed in specification sheets and embodiment utilization, it can be applied to various applicable the field of the invention completely, for those skilled in the art, can easily realize other amendment, therefore be not limited to specific details not deviating from the present invention under the universal that claim and equivalency range limit.
Claims (7)
1. 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, it is characterized in that, the structural formula of described acridine derivatives is:
2. the preparation method of 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide as claimed in claim 1, is characterized in that, obtained by following synthetic route:
3. the preparation method of 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide as claimed in claim 2, concrete steps are:
Step one, 20-30 part o-bromobenzoic acid and 30-40 part 8-quinolylamine is added in a reservoir as raw material according to weight part, 6-8 part salt of wormwood and 0.2-0.4 part copper powder are catalyzer, then 20-50mL Pentyl alcohol or primary isoamyl alcohol is added as solvent, be heated to 130-150 DEG C of backflow 1.5-3 hour, after reaction terminates, remove solvent under reduced pressure, then in solid residue, add water continue reaction 15-30 minute, temperature of reaction controls at 70-90 DEG C, filters, filtrate is regulated pH, suction filtration, obtains compound N-quinolyl anthranilic acid;
Step 2, mixes the compound N obtained-quinolyl anthranilic acid with the pure phosphorus oxychloride of 7-7.5mL, and oil bath is heated, reaction 1-3 hour, obtained compound 7-chlorobenzene also [b]-[1,10] o-phenanthroline;
Step 3, add 0.2-0.4 part described compound 7-chlorobenzene also [b]-[1 in a reservoir, 10] o-phenanthroline and 25-35mL acetone, backflow adds 0.275 part of sodium sulfocynanate and 0.0075 part of Tetrabutyl amonium bromide after dissolving, continue back flow reaction 2-4 hour, to there being yellow solid powder to separate out, suction filtration, washing obtains compound 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates;
Step 4, add 0.2-0.3 part in a reservoir by compound 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates and 20-40mL acetonitrile, then vazadrine is added, back flow reaction 1-3 hour, there is a large amount of yellow powder solid to separate out in reaction process, after filtering and washing, namely obtain target product 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide.
4. the preparation method of 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide as claimed in claim 3, is characterized in that, in described step one, filtrate is regulated pH, adds concentrated hydrochloric acid and regulate pH to 1.5-2.5 in filtrate.
5. 7-benzo [b]-[1 as claimed in claim 3,10] preparation method of o-phenanthroline pyridinecarboxylic amido thiocarbamide, it is characterized in that, when in described step 2, compound N-quinolyl anthranilic acid and phosphorus oxychloride close ring, in 10-15min, oil bath is heated to 85-90 DEG C; When there is vigorous reaction, remove heating bath immediately; If reaction is too fierce, available cold water cooling flask, treat that boiling eases up, oil bath temperature is increased to 135 ~ 140 DEG C, reaction 1-3 hour.
6. 7-benzo [b]-[1 as claimed in claim 5,10] preparation method of o-phenanthroline pyridinecarboxylic amido thiocarbamide, it is characterized in that, after in described step 2, reaction terminates, residuum is poured into weight ratio be 1: 1-2: 1-2 strong aqua, trash ice and chloroform mixture in, solids dissolves, isolate chloroform layer, water layer continues to use chloroform extraction 2-3 time, combined chloroform extracting solution, dry 10-24 hour, filter, steaming desolventizes, and namely obtains compound 7-chlorobenzene also [b]-[1,10] o-phenanthroline.
7. 7-benzo [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide is preparing the application in antitumor drug.
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| CN104327050A (en) * | 2014-09-30 | 2015-02-04 | 广西中医药大学 | Acridine amide thiourea derivative, preparation method and uses thereof |
| WO2015142684A1 (en) * | 2014-03-15 | 2015-09-24 | Wake Forest University | Design, synthesis, and biological activity of platinum-benz[c]acridine hybrid agents and methods associated therewith |
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| WO2015142684A1 (en) * | 2014-03-15 | 2015-09-24 | Wake Forest University | Design, synthesis, and biological activity of platinum-benz[c]acridine hybrid agents and methods associated therewith |
| CN104326979A (en) * | 2014-09-30 | 2015-02-04 | 广西中医药大学 | 2-methyl-9-acridine(p-methoxy benzamido)thiourea, preparation method and uses thereof |
| CN104327050A (en) * | 2014-09-30 | 2015-02-04 | 广西中医药大学 | Acridine amide thiourea derivative, preparation method and uses thereof |
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