CN105418608B - 7 benzos [b] [1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide and its production and use - Google Patents
7 benzos [b] [1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide and its production and use Download PDFInfo
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- CN105418608B CN105418608B CN201510870314.1A CN201510870314A CN105418608B CN 105418608 B CN105418608 B CN 105418608B CN 201510870314 A CN201510870314 A CN 201510870314A CN 105418608 B CN105418608 B CN 105418608B
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- phenanthroline
- benzos
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- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 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 35
- 229940049706 benzodiazepine Drugs 0.000 title claims abstract description 32
- 125000003368 amide group Chemical group 0.000 title claims abstract description 23
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 125000005605 benzo group Chemical group 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 7
- 229940027998 antiseptic and disinfectant acridine derivative Drugs 0.000 claims abstract description 6
- 125000000641 acridinyl group Chemical class C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims abstract 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 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 7
- 238000001914 filtration Methods 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- -1 compound N- quinolyl ortho-aminobenzoic acids Chemical class 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 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
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000001556 precipitation 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
- 150000005012 8-aminoquinolines Chemical class 0.000 claims description 2
- 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
- 229910019213 POCl3 Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229960003350 isoniazid Drugs 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
- 239000010813 municipal solid waste Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 150000001251 acridines Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 230000008901 benefit Effects 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
- 238000002474 experimental method Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 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
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XYSPFGJDNFRHLS-UHFFFAOYSA-N N=C=S.N1=CC=CC2=CC=CC=C21 Chemical class N=C=S.N1=CC=CC2=CC=CC=C21 XYSPFGJDNFRHLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical compound C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 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
- 206010011224 Cough Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 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
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical class NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000002779 inactivation 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
- 239000007788 liquid Substances 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 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
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000012588 trypsin Substances 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
Abstract
The invention discloses a kind of 7 benzos [b] [1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide and its production and use, its structural formula is
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to antineoplastic technical field, is specifically a kind of swollen with resisting
The preparation method and purposes of the 7- benzos [b] of tumor activity-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide
Background technology
Acridine is a kind of nitrogenous organic heterocyclic molecule received significant attention, because its structure is big ring conjugated system, tool
Rigid planar structure, it can be visited as the insert of the macromoleculars such as DNA in antitumor, antiviral, anti-malarial, antibacterial, bioluminescence
Pin and treatment AIDS etc. show very strong physiologically active, and people are extracted from natural products or closed using chemistry
Into method obtain substantial amounts of acridine compound, have studied their pharmacological activity and the mechanism of action.It is right in order to improve it
DNA affine performance, the rejection of a variety of enzymes and cytotoxicity etc., continuous exploration is carried out to its structure of modification with changing
Enter, innovation of the invention is by connecting active group acid amides on the 7- positions of benzo [b]-[1,10] o-phenanthroline ring
Base thiocarbamide structure, synthesizing new acridine derivatives, the derivative not yet have been reported that at present.
The content of the invention
The invention aims to overcome above mentioned problem, there is provided a kind of compound with antitumor activity, in benzo
Active group amide groups thiocarbamide structure, synthesizing new acridine derivatives, tool are connected on the 7- positions of [b]-[1,10] o-phenanthroline ring
There is extremely strong antitumor activity, can be applied in the preparation of antineoplastic.
Another object of the present invention be to provide for it is a kind of prepare the method with anti-tumor activity medicine, to its structure
Anti-tumor activity medicine is improved to DNA affine performance, the consistent performance and cytotoxicity of a variety of enzymes.
Another object of the present invention is to provide for a kind of 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido
Thiocarbamide is preparing the application of antineoplastic.
In order to realize the purpose of the present invention and other advantages, there is provided a kind of 7- benzos [b]-[1,10] o-phenanthroline pyridine first
Amide groups thiocarbamide, its structural formula are：
The 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide molecular formula is C23H16N6OS, average molecular
Measure as 424.48, physicochemical property is：Yellow powder, m.p.175-181 DEG C；1H NMR(DMSO-d6, 400M Hz), 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)；13C NMR(DMSO-d6, 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- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, by following synthetic route system
：
Preferably, the preparation method of the 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, specifically
Step is：
Step 1, add 20-30 parts o-bromobenzoic acid and 30-40 part 8- aminoquinoline conducts in a reservoir according to parts by weight
Raw material, 6-8 parts potassium carbonate and 0.2-0.4 parts copper powder are catalyst, add 20-50mL n-amyl alcohols or isoamyl alcohol as solvent, add
Heat to 130-150 DEG C backflow 1.5-3 hours, reaction terminate after, remove solvent under reduced pressure, then into solid residue add water after
Continuous to continue to react 15-30 minutes, reaction temperature is controlled at 70-90 DEG C, filtering, filtrate is adjusted into pH, is filtered, obtain compound N-
Quinolyl ortho-aminobenzoic acid；
Step 2, obtained compound N-quinolyl ortho-aminobenzoic acid is mixed with the pure POCl3s of 7-7.5mL, oil bath
Heating, 1-3 hours are reacted, compound 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline is made；
Step 3,0.2-0.4 parts compound 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline and 25- are added in a reservoir
35mL acetone, 0.275 part of sodium sulfocynanate and 0.0075 part of TBAB are added after backflow dissolving, continues back flow reaction 2-4
Hour, to there is the precipitation of yellow solid powder, filter, washing obtains compound 7- benzos [b]-[1,10] o-phenanthroline isothiocyanic acid
Ester；
Step 4,0.2-0.3 parts are added in a reservoir by compound 7- benzos [b]-[1,10] o-phenanthroline isothiocyanic acid
Ester and 20-40mL acetonitrile solutions, then add isoniazid, back flow reaction 1-3 hours, have a large amount of yellow powders to consolidate in course of reaction
Body is separated out, and target product 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide is produced after filtering and washing.
Preferably, the preparation method of the 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, it is described
Filtrate is adjusted into pH in step 1, concentrated hydrochloric acid regulation pH to 1.5-2.5 is added into filtrate.
Preferably, the preparation method of the 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, it is described
In step 2 when compound N-quinolyl ortho-aminobenzoic acid and POCl3 cyclization, oil bath heating is to 85-90 in 10-15min
℃；When vigorous reaction occurs, heating bath is removed immediately；If reaction is excessively fierce, flask can be cooled down with cold water, treat that boiling eases up,
Oil bath temperature is increased to 135~140 DEG C, reacts 1-3 hours.
Preferably, the preparation method of the 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, it is described
After reaction terminates in step 2, residue is poured into mixture of the weight ratio for 1: 1-2: 1-2 concentrated ammonia liquor, trash ice and chloroform
In, solids dissolving, chloroform layer is isolated, water layer continues to be extracted 2-3 times with chloroform, merges chloroform extracted solution, it is small to dry 10-24
When, filtering, solvent is evaporated off, that is, obtains compound 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline.
7- benzos [b]-application of [1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide in antineoplastic is prepared.
The invention has the advantages that the present invention is lived by being connected on the 7- positions of benzo [b]-[1,10] o-phenanthroline ring
Property group amide groups thiocarbamide structure, synthesizing new acridine derivatives, improve compatibility of the acridine derivatives to DNA, a variety of enzymes
Rejection and cytotoxicity, provide new thinking for acridine type chemosensitive test.
Embodiment
Embodiment 1
The preparation of 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide
Step 1, in 250mL three-necked bottles, add 26g o-bromobenzoic acids, 34g (34mmoL) 8- aminoquinolines, 7.5g
(36.2mmoL) potassium carbonate and 0.3g (4.7mmoL) copper powder, 30mL isoamyl alcohol is added as solvent, is heated to 140 DEG C of backflows
Stir 2h.After reaction terminates, solvent is removed under reduced pressure, gained residue adds 600mL water, and control temperature is reacted 20min at 80 DEG C, taken advantage of
Heat filtering, filter cake, combining water layer are washed, water layer is acidified to pH2 with concentrated hydrochloric acid, separates out a large amount of black powders, filters, gained solid
With acetone recrystallization, compound N-quinolyl ortho-aminobenzoic acid, yield 36% are obtained；
Step 2, in 100mL round-bottomed flasks, add obtained compound N-quinolyl ortho-aminobenzoic acid (9moL) and
The pure POCl3s of 7.2mL, in reactant is heated into 85 DEG C in oil bath in 15min；When vigorous reaction occurs, heat is removed immediately
Bath；If reaction is excessively fierce, flask can be cooled down with cold water, treat that boiling eases up, oil bath temperature is increased to 135 DEG C, reacts 2h.Reaction
After end, it is concentrated ammonia liquor, broken that weight ratio is 1: 1: 2 according to weight ratio that residue is slowly poured into be sufficiently stirred after the cooling period
In the mixture of ice and chloroform, flask is washed with chloroform and ammonia water mixture, there is no undissolved solids after 30min, point
Chloroform layer is separated out, water layer continues to be extracted 3 times with chloroform, merges chloroform extracted solution, and anhydrous calcium chloride is dried 10 hours, is filtered, and is steamed
Except solvent, compound 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline, yield 18% are obtained；
Step 3, in 100mL round-bottomed flasks, add 0.3g (1.1mmoL) 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline
And 30mL acetone, 0.275g NaSCN (3.3mmoL) and 0.075g (0.23mmoL) TBAB is added after backflow dissolving,
After back flow reaction 3h, there is the precipitation of yellow solid powder, filter, obtaining compound 7- benzos [b]-[1,10] adjacent phenanthrene after water washing coughs up
Quinoline isothiocyanates, 94%；
Step 4, in 100mL round-bottomed flasks, it is adjacent luxuriant and rich with fragrance to add 0.24g (0.8mmoL) compound 7- benzos [b]-[1,10]
Quinoline isothiocyanates and 35mL acetonitriles are coughed up, rear to add 1mmoL benzoyl hydrazines, back flow reaction 2h, there are a large amount of solids in course of reaction
Separate out, cooling filter bright yellow solid is 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, yield
57.2%, m.p.175-181 DEG C；1HNMR(DMSO-d6, 400M Hz), 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)；13C NMR(DMSO-d6, 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；Common dosage forms pharmaceutically can be made in the medicine, including injection, piece is made
Agent, pill, capsule, suspending agent or emulsion.
Embodiment 2
Anti tumor activity in vitro is tested
First, the culture and passage of cell
Selected cell line is placed in 37 DEG C, in the incubator under the conditions of the abundant humidifyings of 5%CO2, is inoculated in containing 10% inactivation
Cultivated in the PPMI1640 nutrient solutions of NBCS.Cell growth status is observed with inverted microscope, is changed 2~3 times weekly
Culture medium, passage in 6~7 days once, are passed on during inoculation with 0.25% Trypsin Induced, generally take passage 3~4 times, in pair
Number growth period cell is used to test.
2nd, the preparation of decoction
Sample accurately is weighed, is added in the 1.5mL centrifuge tubes of sterilizing, DMSO is added and is made into 2mM compound deposits
Liquid, -20 DEG C of freezen protectives.After melting before use respective concentration application is diluted to appropriate D-hanks.The change that measuring is selected
Compound concentration is respectively 20uM.
3rd, MTT experiment method
The cell in exponential phase is taken, per hole 180uL (about 4500-5000 cell) celliferous culture medium inoculated
In 96 well culture plates, in 37 DEG C, 5%CO224h is cultivated under the conditions of abundant humidifying.After cell attachment, add by every hole 20uL amount
Enter sample, each sample sets 6 multiple holes, concurrently sets corresponding blank control.Continue after cultivating 48h, 10uL is added per hole
MTT reagents (concentration 2mg/mL), continue after being incubated 4h, supernatant is abandoned in suction, and 150uL DMSO are added per hole, and slight concussion is anti-
5-8min is answered, crystalline particle is fully dissolved.Blank control group returns to zero, and is determined with ELIASA with 490nm wavelength and removes bias light
After absorption value absorbance (Value), the IC of corresponding cell line is of 5 concentration gradients50Value, after all experiments are repeated 3 times
Average.
Medium effective concentration (IC of 7- benzos [c] the acridine benzamido thiocarbamide of table 1 to tumor cell line50)
Table 1
7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido of the present invention is can be seen that from the result of embodiment 2
Thiocarbamide shows that the compound has strong antitumor activity through anticancer experiment in vitro.The present invention is the new acridine of research and development
Type antineoplastic provides new thinking.
Although embodiment of the present invention is disclosed as above, it is not restricted in specification and embodiment listed
With it can be applied to various suitable the field of the invention completely, can be easily for those skilled in the art
Other modification is realized, therefore the present invention is not limited under the universal limited without departing substantially from claim and equivalency range
Specific details.
Claims (6)
- A kind of 1. 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, it is characterised in that the acridine derivatives Structural formula be：The 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide Preparation method, concretely comprise the following steps：Step 1,20-30 parts o-bromobenzoic acid and 30-40 part 8- aminoquinolines are added in a reservoir according to parts by weight as former Material, 6-8 parts potassium carbonate and 0.2-0.4 parts copper powder be catalyst, and then addition 20-50mL n-amyl alcohols or isoamyl alcohol be as solvent, 130-150 DEG C of backflow 1.5-3 hour is heated to, after reaction terminates, solvent is removed under reduced pressure, water is then added into solid residue Continue to react 15-30 minutes, reaction temperature is controlled at 70-90 DEG C, filtering, filtrate is adjusted into pH, is filtered, is obtained compound N- quinolyl ortho-aminobenzoic acids；Step 2, obtained compound N-quinolyl ortho-aminobenzoic acid is mixed with the pure POCl3s of 7-7.5mL, oil bath adds Heat, 1-3 hours are reacted, compound 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline is made；Step 3,0.2-0.4 parts compound 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline and 25-35mL are added in a reservoir Acetone, 0.275 part of sodium sulfocynanate and 0.0075 part of TBAB are added after backflow dissolving, continues back flow reaction 2-4 hours, To there is the precipitation of yellow solid powder, filter, washing obtains compound 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates；Step 4, add in a reservoir 0.2-0.3 parts by compound 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates and 20-40mL acetonitriles, then add isoniazid, back flow reaction 1-3 hours, have a large amount of yellow powder solids to separate out in course of reaction, Target product 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide is produced after filtering and washing.
- 2. a kind of preparation method of 7- benzos [b]-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide as claimed in claim 1, Characterized in that, it is made by following synthetic route：
- 3. the preparation method of 7- benzos [b] as claimed in claim 1-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, it is special Sign is, filtrate is adjusted into pH in the step 1, and concentrated hydrochloric acid regulation pH to 1.5-2.5 is added into filtrate.
- 4. the preparation method of 7- benzos [b] as claimed in claim 1-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, it is special Sign is, when compound N-quinolyl ortho-aminobenzoic acid is with POCl3 cyclization in the step 2, oil bath in 10-15min It is heated to 85-90 DEG C；When vigorous reaction occurs, heating bath is removed immediately；If reaction is excessively fierce, flask can be cooled down with cold water, Treat that boiling eases up, oil bath temperature is increased to 135~140 DEG C, reacts 1-3 hours.
- 5. the preparation method of 7- benzos [b] as claimed in claim 4-[1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide, it is special Sign is, after reaction terminates in the step 2, residue is poured into weight ratio for 1:1-2:1-2 concentrated ammonia liquor, trash ice and chlorine In imitative mixture, solids dissolving, chloroform layer is isolated, water layer continues to be extracted 2-3 times with chloroform, merges chloroform extracted solution, 10-24 hours are dried, filtering, solvent is evaporated off, that is, obtains compound 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline.
- A kind of 6. 7- benzos [b]-application of [1,10] o-phenanthroline pyridinecarboxylic amido thiocarbamide in antineoplastic is prepared.
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| 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 |
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| 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 |
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