CN104725366A - Preparation method and application of trifluoromethyl pyrazole oxime derivative containing 5-alkoxy thiadiazole structure - Google Patents
Preparation method and application of trifluoromethyl pyrazole oxime derivative containing 5-alkoxy thiadiazole structure Download PDFInfo
- Publication number
- CN104725366A CN104725366A CN201510092407.6A CN201510092407A CN104725366A CN 104725366 A CN104725366 A CN 104725366A CN 201510092407 A CN201510092407 A CN 201510092407A CN 104725366 A CN104725366 A CN 104725366A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- general formula
- iii
- phenyl ring
- 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.)
- Granted
Links
- -1 trifluoromethyl pyrazole oxime Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 230000000694 effects Effects 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 52
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 230000000259 anti-tumor effect Effects 0.000 claims description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 19
- 238000001816 cooling Methods 0.000 description 11
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 201000007270 liver cancer Diseases 0.000 description 7
- 208000014018 liver neoplasm Diseases 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 4
- 0 *Oc1nnc(CCl)[s]1 Chemical compound *Oc1nnc(CCl)[s]1 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 201000005296 lung carcinoma Diseases 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 201000010897 colon adenocarcinoma Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 201000001281 rectum adenocarcinoma Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method and an application of a trifluoromethyl pyrazole oxime derivative (I) containing a 5-alkoxy thiadiazole structure. The method is characterized in that the trifluoromethyl pyrazole oxime derivative is obtained by condensation of 5-alkoxythiadiazole alkane chloride (II) and trifluoromethyl pyrazole oxime (III). The trifluoromethyl pyrazole oxime derivative (I) containing the 5-alkoxy thiadiazole structure shows good prevention and treatment effects on tumor cells such as SMMC-7721, Hep G2 and NCL-1975, and the trifluoromethyl pyrazole oxime derivative can be used for preparing anti-tumor drugs in the field of medical use, etc.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of preparation method and medicinal use of the trifluoromethyl pyrazol oxime derivatives containing 5-alkoxyl group thiadiazoles structure
Background technology
The control of tumour is the core realm of medical science research all the time, and widely using of anti-tumor agents makes most tumors cell obtain effective treatment.But along with the continuous expansion of medical anti-tumor agents application scale, the resistance problems of conventional medicament kind highlights day by day, adds the continuous appearance of new tumor disease, the continuation of newtype drug is researched and developed becomes inevitable choice.
Pyrazoles oxime compounds is the nitogen-contained heterocycle derivant that a class has broad-spectrum biological activity, very important effect is played at anti-tumor aspect, the compd A found as Park etc. and B show cytotoxicity to tumor line, and wherein, compd A is to the IC of people's Colon and rectum adenocarcinoma cell HCT15
50value is 0.10 μ g/mL; To the IC of human A549 cell lines
50value is 0.13 μ g/mL; Compd B is to the IC of Proliferation of Human Ovarian Cell Skov-3
50value is 9.06 μ g/mL; To the IC of people's central nerve neuroma XF498
50value is 3.87 μ g/mL (Bioorg.Med.Chem.Lett., 2005,15,3307-3312).
In recent years, thiadiazole compound also enjoys researcher to pay close attention to because it has excellent biological activity.Compound C ~ the F prepared as Ling etc. presents obvious inhibit activities to tumour cell MDA-MB-231, Bel7402 and H520, and wherein Compound C ~ F is to the IC of Breast cancer lines MDA-MB-231
50value is respectively 23.0,19.4,15.8 and 18.7 μm of ol/L; Compound C ~ F is to the IC of human liver cancer cell Bel7402
50value is respectively 25.1,21.1,20.5 and 18.7 μm of ol/L; Compound C ~ F is to the IC of human lung carcinoma cell H520
50value is respectively 21.9,20.5,13.2 and 20.4 μm of ol/L (Chin.Chem.Lett., 2012,23,1141-1144).
Therefore, in order to continue to find the lead drug with good anti-tumor activity from pyrazoles oxime compounds, we intend using active group splicing principle, are incorporated into by thiadiazoles activity unit in pyrazoles oxime molecular structure.The invention discloses the trifluoromethyl pyrazol oxime derivatives containing 5-alkoxyl group thiadiazoles structure that a class has pharmaceutical use.
Summary of the invention
The object of this invention is to provide the trifluoromethyl pyrazol oxime derivatives of a class containing 5-alkoxyl group thiadiazoles structure, to meet new type antineoplastic medicine Treatment need.
Another object of the present invention is to provide the preparation method of above-claimed cpd.
A further object of the invention is to provide the purposes that above-claimed cpd possesses anti-tumor activity aspect.
The object of the invention reaches by following measures:
Trifluoromethyl pyrazol oxime derivatives containing 5-alkoxyl group thiadiazoles structure of the present invention, it is characterized in that possessing as
Structure shown in formula I:
Wherein, R
1for CH
3, CH
2cH
3, CH
2cH
2cH
3or CH
2cH
2cH
2cH
3.
On phenyl ring, the position of substitution represents with 2 ~ 5; R
2for H, Cl, Br, F, CH
3, OCH
3, OCF
3, t-C
4h
9or NO
2;
R
2the position of substitution on phenyl ring can two or three-digit or 4 or 5.
Such, containing the trifluoromethyl pyrazol oxime derivatives preparation method of 5-alkoxyl group thiadiazoles structure, is characterized in that the compound shown in formula I is obtained by reacting under alkali effect by the compound shown in general formula II and general formula III.
Wherein, R
1for CH
3, CH
2cH
3, CH
2cH
2cH
3or CH
2cH
2cH
2cH
3.
On phenyl ring, the position of substitution represents with 2 ~ 5; R
2for H, Cl, Br, F, CH
3, OCH
3, OCF
3, t-C
4h
9or NO
2; R
2the position of substitution on phenyl ring can two or three-digit or 4 or 5.
Wherein alkali is: the one in sodium carbonate, sodium bicarbonate, salt of wormwood, cesium carbonate, triethylamine, 4-N, N-lutidine, pyridine.The consumption of alkali is generally 1.3 ~ 12 times of the molar weight of compound shown in general formula III.
Wherein solvent for use is: Isosorbide-5-Nitrae-dioxane, acetonitrile, DMF, methyl-sulphoxide, the one in N,N-dimethylacetamide.
The molar weight of its formula of II compound is 0.8 ~ 2.2 times of general formula III compound molar weight.
General formula II compound reference literature (Chem.J.Chin.Univ., 2010,31,708-713) method is prepared from;
The method of general formula III compound reference literature (J.Heterocycl.Chem., 1990,27,243-245) is prepared from.
Compound of Formula I presents excellent inhibition to tumour cell, and thus compound of the present invention can be used as preparing anti-tumor agents.Described tumour cell has SMMC-7721, Hep G2, NCL-1975 etc.
When the compound of the present invention represented by general formula I is used as antitumor drug, can be used alone, or use in the mode of anti-tumor compositions, namely with formula I for activeconstituents, add that the carrier combinations that this area is commonly used makes preparation for administration, also can be made into oral dosage form as tablet, granule, capsule etc.
The various formulations of pharmaceutical composition of the present invention can be prepared according to the method known in pharmaceutical field.Containing the activeconstituents with such as 0.05% to 90% weight of carrier combinations, also this dosage range can be exceeded according to the different using dosages of disease severity or formulation in these medicinal preparationss.
Trifluoromethyl pyrazol oxime derivatives containing 5-alkoxyl group thiadiazoles structure disclosed by the invention presents good result for the treatment of to tumour cell, therefore can be used to the antitumor drug for the preparation of medicine and other fields.
Embodiment
For the ease of to further understanding of the present invention, the embodiment provided below has done more detailed description to it.These embodiments only are not used for limiting scope of the present invention or implementation principle for describing.
Embodiment 1:
The synthesis of Compound I a (R in general formula II
1for-CH
3, R in III
2for 3-Cl)
In one 100 ml flasks, add 30 milliliters of acetonitriles, 4mmol compound III, 5.2mmol compound ii, 13mmol cesium carbonate, reflux 12 hours.TLC monitors reaction, cooling, suction filtration, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains target compound Ia, yield 52%;
1h NMR (300MHz, CDCl
3): δ 7.98 (s, 1H, CH=N), 7.23 – 7.29 (m, 1H, Ar-H), 7.10 – 7.13 (m, 1H, Ar-H), 6.76 – 6.87 (m, 2H, Ar-H), 5.04 (s, 2H, CH
2), 4.17 (s, 3H, OCH
3), 3.78 (s, 3H, N-CH
3).
Embodiment 2:
Synthesis (synthesis of reference Ia, the R in general formula II of compounds ib
1for-CH
3, R in III
2for 4-CH
3)
In one 100 ml flasks, add 35 milliliters of Isosorbide-5-Nitrae-dioxane, 6mmol compound III, 8mmol compound ii, 15mmol sodium bicarbonate, 85 DEG C are reacted 16 hours.TLC monitors reaction, cooling reaction solution, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains product I b, yield 58%;
1h NMR (300MHz, CDCl
3): δ 7.94 (s, 1H, CH=N), 7.11 (d, J=8.4Hz, 2H, ArH), 6.75 (d, J=8.4Hz, 2H, ArH), 5.06 (s, 2H, CH
2), 4.16 (s, 3H, OCH
3), 3.76 (s, 3H, N-CH
3), 2.32 (s, 3H, Ar-CH
3).
Embodiment 3:
Synthesis (synthesis of reference Ia, the R in general formula II of Compound I c
1for-CH
3, R in III
2for 2-Br)
In one 100 ml flasks, add 40 milliliters of DMFs, 3mmol compound III, 4.5mmol compound ii, 8mmol salt of wormwood, 75 DEG C are reacted 13 hours.TLC monitors reaction, cooling reaction solution, suction filtration, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains product Ic, yield 50%;
1h NMR (400MHz, CDCl
3): δ 7.98 (s, 1H, CH=N), 6.71 – 7.63 (m, 4H, Ar-H), 5.05 (s, 2H, CH
2), 4.14 (s, 3H, OCH
3), 3.84 (s, 3H, N-CH
3).
Embodiment 4:
Synthesis (synthesis of reference Ia, the R in general formula II of Compound I d
1for-CH
3, R in III
2for 2-F)
In one 100 ml flasks, add 35 milliliters of N,N-dimethylacetamide, 5mmol compound III, 4mmol compound ii, 13mmol triethylamine, 70 DEG C are reacted 18 hours.TLC monitors reaction, cooling, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains product I d, yield 55%;
1h NMR (300MHz, CDCl
3): δ 7.95 (s, 1H, CH=N), 7.02 – 7.21 (m, 3H, Ar-H), 6.75 – 6.81 (m, 1H, Ar-H), 5.01 (s, 2H, CH
2), 4.17 (s, 3H, OCH
3), 3.84 (s, 3H, N-CH
3).
Embodiment 5:
Synthesis (synthesis of reference Ia, the R in general formula II of Compound I e
1for-CH
3, R in III
2for 3-F)
In one 100 milliliters of single port bottles, add 20 milliliters of Isosorbide-5-Nitrae-dioxane, 4mmol compound ii, 5mmol compound III, 10mmol 4-N, N-lutidine, 85 DEG C are reacted 15 hours.TLC monitors reaction, cooling reaction solution, suction filtration, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains target compound Ie, yield 58%;
1h NMR (400MHz, CDCl
3): δ 7.98 (s, 1H, CH=N), 7.26 – 7.32 (m, 1H, Ar-H), 6.83 – 6.87 (m, 1H, Ar-H), 6.61 – 6.69 (m, 2H, Ar-H), 5.05 (s, 2H, CH
2), 4.18 (s, 3H, OCH
3), 3.79 (s, 3H, N-CH
3).
Embodiment 6:
Synthesis (synthesis of reference Ia, the R in general formula II of Compound I f
1for-CH
3, R in III
2for-H)
In one 100 milliliters of single port bottles, add 25 milliliters of DMFs, 6mmol compound ii, 7.8mmol compound III, 11mmol sodium carbonate, 80 DEG C are reacted 19 hours.TLC monitors reaction, cooling reaction solution, suction filtration, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains target compound If, yield 60%;
1h NMR (300MHz, CDCl
3): δ 7.95 (s, 1H, CH=N), 7.30-7.35 (m, 2H, ArH), 7.10-7.15 (m, 1H, ArH), 6.87 (d, J=8.1Hz, 2H, ArH), 5.02 (s, 2H, CH
2), 4.16 (s, 3H, OCH
3), 3.77 (s, 3H, N-CH
3).
Embodiment 7:
Synthesis (synthesis of reference Ia, the R in general formula II of Compound Ig per
1for-CH
3, R in III
2be 3,4-(CH
3)
2)
In one 100 milliliters of single port bottles, add 20 milliliters of Isosorbide-5-Nitrae-dioxane, 5mmol compound ii, 5.5mmol compound III, 20mmol pyridine, 80 DEG C are reacted 15 hours.TLC monitors reaction, cooling reaction solution, suction filtration, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains target compound Ig, yield 48%;
1h NMR (400MHz, CDCl
3): δ 7.95 (s, 1H, CH=N), 7.05 (d, J=8.4Hz, 1H, ArH), 6.68 (s, 1H, ArH), 6.59 (d, J=8.0Hz, 1H, ArH), 5.08 (s, 2H, CH
2), 4.14 (s, 3H, OCH
3), 3.75 (s, 3H, N-CH
3), 2.12 (s, 6H, 2 × Ar-CH
3).
Embodiment 8:
Synthesis (synthesis of reference Ia, the R in general formula II of Compound I h
1for-CH
2cH
3, R in III
2for 2-F)
In one 100 milliliters of single port bottles, add 20 milliliters of acetonitriles, 3mmol compound ii, 4.8mmol compound III, 8.5mmol 4-N, N-lutidine, heating reflux reaction 11 hours.TLC monitors reaction, cooling reaction solution, suction filtration, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains target compound Ih, yield 52%;
1h NMR (300MHz, CDCl
3): δ 7.95 (s, 1H, CH=N), 7.04-7.20 (m, 3H, ArH), 6.79-6.84 (m, 1H, ArH), 5.01 (s, 2H, CH
2), 4.56 (q, J=7.2Hz, 2H, CH
2), 3.84 (s, 3H, N-CH
3), 1.46 (t, J=7.2Hz, 3H, CH
3).
Embodiment 9:
Synthesis (synthesis of reference Ia, the R in general formula II of Compound I i
1for-CH
2cH
3, R in III
2for 4-CH
3)
In one 100 milliliters of single port bottles, add 40 milliliters of N,N-dimethylacetamide, 5mmol compound ii, 7mmol compound III, 18mmol triethylamine, 60 DEG C are reacted 11 hours.TLC monitors reaction, cooling reaction solution, suction filtration, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains target compound Ii, yield 61%;
1h NMR (300MHz, CDCl
3): δ 7.94 (s, 1H, CH=N), 7.11 (d, J=8.4Hz, 2H, ArH), 6.75 (d, J=8.4Hz, 2H, ArH), 5.06 (s, 2H, CH
2), 4.54 (q, J=7.2Hz, 2H, CH
2), 3.76 (s, 3H, N-CH
3), 2.32 (s, 3H, Ar-CH
3), 1.46 (t, J=7.2Hz, 3H, CH
3).
Embodiment 10:
Synthesis (synthesis of reference Ia, the R in general formula II of Compound I j
1for-CH
2cH
3, R in III
2for-H)
In one 100 milliliters of single port bottles, add 40 milliliters of DMFs, 4mmol compound ii, 6.8mmol compound III, 10mmol 4-N, N-lutidine, 70 DEG C are reacted 10 hours.TLC monitors reaction, cooling reaction solution, suction filtration, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains target compound Ij, yield 56%;
1h NMR (400MHz, CDCl
3): δ 7.97 (s, 1H, CH=N), 7.32-7.36 (m, 2H, ArH), 7.12-7.16 (m, 1H, ArH), 6.89 (d, J=7.2Hz, 2H, ArH), 5.03 (s, 2H, CH
2), 4.57 (q, J=7.2Hz, 2H, CH
2), 3.79 (s, 3H, N-CH
3), 1.48 (t, J=7.2Hz, 3H, CH
3).
Embodiment 11:
Synthesis (synthesis of reference Ia, the R in general formula II of Compound I k
1for-CH
2cH
3, R in III
2be 2,4-F
2)
In one 100 milliliters of single port bottles, add 40 milliliters of Isosorbide-5-Nitrae-dioxane, 4mmol compound ii, 4.8mmol compound III, 16mmol salt of wormwood, 80 DEG C are reacted 16 hours.TLC monitors reaction, cooling reaction solution, suction filtration, and after revolving desolventizing, gained residue over silica gel column chromatography for separation obtains target compound Ik, yield 46%;
1h NMR (400MHz, CDCl
3): δ 7.93 (s, 1H, CH=N), 6.89-6.93 (m, 1H, ArH), 6.75-6.79 (m, 2H, ArH), 5.03 (s, 2H, CH
2), 4.53 (q, J=7.2Hz, 2H, CH
2), 3.82 (s, 3H, N-CH
3), 1.43 (t, J=7.2Hz, 3H, CH
3).
Embodiment 12:
Sample is to the screening active ingredients of tumour cell
Adopt blue colorimetry (MTT) antitumor activity in vitro of tetramethyl-nitrogen azoles.Examination object is supplied to be human liver cancer cells Hep G2, human liver cancer cell Hep G2 and human lung carcinoma cell NCL-1975.Select 5 FU 5 fluorouracil (5-FU) as positive control drug.Get and be in one bottle, cell in good condition exponential phase of growth, add 0.25% tryptic digestion, attached cell is come off, make every milliliter containing 2 × 10
4~ 4 × 10
4the suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 180 μ L, puts constant temperature CO
2cultivate 24 hours in incubator.Change liquid, add test-compound Ia-Ik (with PBS dilution after compound dmso solution, Test compound concentrations is required test concentrations), every hole 20 μ L, cultivates 48 hours.MTT is added in 96 orifice plates, every hole 20 μ L, react 4 hours in incubator.Suck supernatant liquor, add dimethyl sulfoxide (DMSO), every hole 150 μ L, jolting 5 minutes on plate shaker.Be the optical density in the every hole of mensuration, 570nm place at wavelength with enzyme-linked immunosorbent assay instrument, calculate cell inhibitory rate.Cell inhibitory rate=(negative control group OD value-tested material group OD value)/negative control group OD value × 100%.Then its IC is calculated by software GraphPadPrism (Version 4.03)
50value.Experimental result as shown in Table 1 and Table 2.
Table 1.Ia-Ik is to the inhibiting rate (%) of tumor cell proliferation
Table 2.Ia-Ik is to the IC of Partial tumors cell proliferation
50value
Test-results finds, when test concentrations is 10 μm of ol/L, most compounds has good inhibit activities to human liver cancer cells Hep G2 and human liver cancer cell Hep G2, and part of compounds demonstrates cytotoxicity in various degree to human lung carcinoma cell NCL-1975; The further test of pesticide effectiveness shows, great majority will apparently higher than positive control drug 5-FU to the cytotoxicity of human liver cancer cells Hep G2 and human liver cancer cell Hep G2.Listed data presentation, in trifluoromethyl pyrazol oxime activity unit, introduce the thiadiazoles structure that 5-alkoxyl group replaces, some target compound of formation shows obvious prevention effect to tumour cell SMMC-7721, Hep G2 and NCL-1975.Part of compounds can be used as drug leads and does deep research.
Claims (6)
1., containing a trifluoromethyl pyrazol oxime derivatives for 5-alkoxyl group thiadiazoles structure, it is characterized in that the structure possessed as shown in formula I:
Wherein, R
1for CH
3, CH
2cH
3, CH
2cH
2cH
3or CH
2cH
2cH
2cH
3.
On phenyl ring, the position of substitution represents with 2 ~ 5; R
2for H, Cl, Br, F, CH
3, OCH
3, OCF
3, t-C
4h
9or NO
2; R
2the position of substitution on phenyl ring can two or three-digit or 4 or 5.
2. the preparation method of a kind of trifluoromethyl pyrazol oxime derivatives containing 5-alkoxyl group thiadiazoles structure as claimed in claim 1, is characterized in that the compound shown in formula I is obtained by reacting under alkali effect by the compound shown in general formula II and general formula III;
Wherein, R
1for CH
3, CH
2cH
3, CH
2cH
2cH
3or CH
2cH
2cH
2cH
3;
On phenyl ring, the position of substitution represents with 2 ~ 5; R
2for H, Cl, Br, F, CH
3, OCH
3, OCF
3, t-C
4h
9or NO
2; R
2the position of substitution on phenyl ring can two or three-digit or 4 or 5.
3. preparation method as claimed in claim 2, wherein alkali is: sodium carbonate, sodium bicarbonate, salt of wormwood, cesium carbonate, triethylamine, 4-N, one in N-lutidine, pyridine, the consumption of alkali is generally 1.3 ~ 12 times of the molar weight of compound shown in general formula III.
4. preparation method as claimed in claim 2, wherein solvent for use is: Isosorbide-5-Nitrae-dioxane, acetonitrile, DMF, methyl-sulphoxide, the one in N,N-dimethylacetamide.
5. preparation method as claimed in claim 2, the molar weight of its formula of II compound is 0.8 ~ 2.2 times of general formula III compound molar weight.
6. the purposes of the compound as shown in claim 1 in treating malignant tumor, is characterized in that: this compound is used alone; Or use with the mode of other antitumor combination clinical.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510092407.6A CN104725366B (en) | 2015-02-28 | 2015-02-28 | The preparation method and purposes of the trifluoromethyl pyrazol oxime derivatives of the thiadiazoles structure of alkoxy containing 5- |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510092407.6A CN104725366B (en) | 2015-02-28 | 2015-02-28 | The preparation method and purposes of the trifluoromethyl pyrazol oxime derivatives of the thiadiazoles structure of alkoxy containing 5- |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104725366A true CN104725366A (en) | 2015-06-24 |
| CN104725366B CN104725366B (en) | 2018-06-19 |
Family
ID=53449844
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510092407.6A Expired - Fee Related CN104725366B (en) | 2015-02-28 | 2015-02-28 | The preparation method and purposes of the trifluoromethyl pyrazol oxime derivatives of the thiadiazoles structure of alkoxy containing 5- |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104725366B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105712932A (en) * | 2016-03-08 | 2016-06-29 | 南通大学 | Preparation and application of pyrazole oxime ether compound with 1-methyl-3-aryl-4-chloropyrazole structure |
| CN110003184A (en) * | 2019-02-01 | 2019-07-12 | 南通大学 | The preparation and application of pyrazoles oxime derivatives of the one kind containing 1,2,4- triazole structures |
| CN111393413A (en) * | 2020-05-12 | 2020-07-10 | 南通大学 | Pyrazole compound containing chloropyridine biphenyl unit, and preparation method and application thereof |
| CN111423415A (en) * | 2020-05-05 | 2020-07-17 | 南通大学 | Pyrazole oxime derivative containing chloropyridine ring dipyrazole unit, and preparation method and application thereof |
| CN111423413A (en) * | 2020-05-12 | 2020-07-17 | 南通大学 | Preparation and application of pyrazole derivative containing (3-methoxy-4-substituted pyridylmethoxy) phenyl unit |
| CN111440153A (en) * | 2020-05-21 | 2020-07-24 | 南通大学 | Preparation and application of pyrazole compound containing (3-methoxy-4-pyrimidinyloxy) phenyl unit |
| CN111440163A (en) * | 2020-05-12 | 2020-07-24 | 南通大学 | Pyrazole compound containing methoxy-substituted 1,3, 4-thiadiazole unit, and preparation and application thereof |
| CN111518084A (en) * | 2020-05-21 | 2020-08-11 | 南通大学 | Pyrazole derivative containing pyrimidine heterocyclic unit and preparation method and application thereof |
| WO2024143338A1 (en) * | 2022-12-28 | 2024-07-04 | 日本曹達株式会社 | Five-membered heteroaryl compound and agricultural and horticultural bactericide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007084868A2 (en) * | 2006-01-17 | 2007-07-26 | Kalypsys, Inc. | Treatment of disorders by activation of the unfolded protein response |
| CN102675205A (en) * | 2012-05-25 | 2012-09-19 | 安徽农业大学 | Pyrazol oxime ether compound and preparation method and application thereof in anticancer therapy |
-
2015
- 2015-02-28 CN CN201510092407.6A patent/CN104725366B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007084868A2 (en) * | 2006-01-17 | 2007-07-26 | Kalypsys, Inc. | Treatment of disorders by activation of the unfolded protein response |
| CN102675205A (en) * | 2012-05-25 | 2012-09-19 | 安徽农业大学 | Pyrazol oxime ether compound and preparation method and application thereof in anticancer therapy |
Non-Patent Citations (1)
| Title |
|---|
| HYUN-JA PARK ET AL.: "Identification of antitumor activity of pyrazole oxime ethers", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105712932B (en) * | 2016-03-08 | 2019-01-22 | 南通大学 | A kind of preparation and application of the pyrazoles oxime ether compound of -3- of methyl containing 1- aryl -4- chlorine pyrrazole structure |
| CN105712932A (en) * | 2016-03-08 | 2016-06-29 | 南通大学 | Preparation and application of pyrazole oxime ether compound with 1-methyl-3-aryl-4-chloropyrazole structure |
| CN110003184A (en) * | 2019-02-01 | 2019-07-12 | 南通大学 | The preparation and application of pyrazoles oxime derivatives of the one kind containing 1,2,4- triazole structures |
| CN111423415A (en) * | 2020-05-05 | 2020-07-17 | 南通大学 | Pyrazole oxime derivative containing chloropyridine ring dipyrazole unit, and preparation method and application thereof |
| CN111393413B (en) * | 2020-05-12 | 2022-05-27 | 南通大学 | Pyrazole compound containing chloropyridine biphenyl unit, and preparation method and application thereof |
| CN111423413A (en) * | 2020-05-12 | 2020-07-17 | 南通大学 | Preparation and application of pyrazole derivative containing (3-methoxy-4-substituted pyridylmethoxy) phenyl unit |
| CN111440163A (en) * | 2020-05-12 | 2020-07-24 | 南通大学 | Pyrazole compound containing methoxy-substituted 1,3, 4-thiadiazole unit, and preparation and application thereof |
| CN111393413A (en) * | 2020-05-12 | 2020-07-10 | 南通大学 | Pyrazole compound containing chloropyridine biphenyl unit, and preparation method and application thereof |
| CN111423413B (en) * | 2020-05-12 | 2022-06-03 | 南通大学 | Preparation and application of pyrazole derivative containing (3-methoxy-4-substituted pyridylmethoxy) phenyl unit |
| CN111440163B (en) * | 2020-05-12 | 2022-09-02 | 南通大学 | Pyrazole compound containing methoxy-substituted 1,3, 4-thiadiazole unit, and preparation and application thereof |
| CN111440153A (en) * | 2020-05-21 | 2020-07-24 | 南通大学 | Preparation and application of pyrazole compound containing (3-methoxy-4-pyrimidinyloxy) phenyl unit |
| CN111518084A (en) * | 2020-05-21 | 2020-08-11 | 南通大学 | Pyrazole derivative containing pyrimidine heterocyclic unit and preparation method and application thereof |
| CN111440153B (en) * | 2020-05-21 | 2022-06-03 | 南通大学 | Preparation and application of pyrazole compound containing (3-methoxy-4-pyrimidinyloxy) phenyl unit |
| CN111518084B (en) * | 2020-05-21 | 2022-08-09 | 南通大学 | Pyrazole derivative containing pyrimidine heterocyclic unit and preparation method and application thereof |
| WO2024143338A1 (en) * | 2022-12-28 | 2024-07-04 | 日本曹達株式会社 | Five-membered heteroaryl compound and agricultural and horticultural bactericide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104725366B (en) | 2018-06-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104725366B (en) | The preparation method and purposes of the trifluoromethyl pyrazol oxime derivatives of the thiadiazoles structure of alkoxy containing 5- | |
| CN101184734B (en) | Compound and methods of treating cell proliferation disorders | |
| CA2748289C (en) | Preparation method of dihydroindene amide compounds,their pharmaceutical compositions containing compounds thereof and use as protein kinase inhibitor | |
| US20200247750A1 (en) | Indirubin derivatives, and uses thereof | |
| CN103450152B (en) | Based on the substituted bisarylurea structure antineoplastic drug of indazole, indoles or azaindazole, azaindole | |
| AU2021105895A4 (en) | Lycoline B-aryl acrylate derivatives, preparation method and application thereof | |
| CN105712932A (en) | Preparation and application of pyrazole oxime ether compound with 1-methyl-3-aryl-4-chloropyrazole structure | |
| CN107235902A (en) | The licochalcone A pyrazoline analog derivative and its synthetic method of one class tool antitumor activity | |
| Venkat Swamy et al. | Amide derivatives of 4-azaindole: Design, synthesis, and EGFR targeting anticancer agents | |
| CN107311937A (en) | The licochalcone A dihydro amino-metadiazine compound and its synthetic method of one class tool antitumor activity | |
| CN106496123B (en) | A kind of pyrazoline analog derivative and its preparation method and application | |
| CN105017245B (en) | Imidazopyridine compound and preparation method and application thereof | |
| CN102942529A (en) | 4-(4-substituted piperazine)-5,6,7-trialkoxy quinazoline type compound as well as preparation method and application of 4-(4-substituted piperazine)-5,6,7-trialkoxy quinazoline type compound | |
| CN106966986B (en) | N- benzyl heterocyclic nitro ketene semiamine analog derivative and synthetic method and antitumor application thereof | |
| CN106866642B (en) | Quinazoline compound containing aryl acylhydrazone structure and application thereof | |
| CN108623511A (en) | A kind of indole amides class compound can be used for treating cancer | |
| CS et al. | Synthesis and antiproliferative activity of substituted diazaspiro hydantoins: a structure–activity relationship study | |
| CN104557711B (en) | The preparation and application of the pyrazoles oxime compound of the structure containing FTS | |
| CN106977508A (en) | Pyrazole derivatives with isatin structure are used for the medicine and its preparation method of anti-curing oncoma | |
| CN103012394B (en) | Rhodanine derivative and preparation method thereof | |
| CN104829534A (en) | Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs | |
| CN108047154A (en) | A kind of preparation method and purposes with anti-cancer active compound | |
| CN104402785A (en) | Novel bisamides derivative and preparation method and application thereof | |
| CN101423513B (en) | Amine pyrimidine derivates, and production method thereof, and medicament composition and use | |
| CN102600164A (en) | Application of pyrimidine ether compounds in preparing anti-tumor medicines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190708 Address after: No. 9, Nantong City, Jiangsu, Jiangsu Patentee after: Center for technology transfer, Nantong University Address before: 226019 No. 9 Tanyuan Road, Nantong City, Jiangsu Province Patentee before: Nantong University |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191119 Address after: No.1, floor 3, No.319, zhanggongshan Road, Yuhui District, Bengbu City, Anhui Province Patentee after: Bengbu guijiu Intellectual Property Service Co., Ltd Address before: 226019 Jiangsu city of Nantong province sik Road No. 9 Patentee before: Center for technology transfer, Nantong University |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191224 Address after: Room 322, science and technology innovation base, No. 3, Hengda Road, Nanjing Economic and Technological Development Zone, Jiangsu Province Patentee after: Nanjing Haiwei Pharmaceutical Technology Co., Ltd Address before: No.1, floor 3, No.319, zhanggongshan Road, Yuhui District, Bengbu City, Anhui Province Patentee before: Bengbu guijiu Intellectual Property Service Co., Ltd |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180619 Termination date: 20210228 |