CN104672213A - Amide compound with antitumor activity, and application thereof - Google Patents
Amide compound with antitumor activity, and application thereof Download PDFInfo
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- CN104672213A CN104672213A CN201510117494.6A CN201510117494A CN104672213A CN 104672213 A CN104672213 A CN 104672213A CN 201510117494 A CN201510117494 A CN 201510117494A CN 104672213 A CN104672213 A CN 104672213A
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- VCTBEBAPSWPLBS-UHFFFAOYSA-N O=C(c1ccccc1)N(CCC1NCc2cccc(C(F)(F)F)c2)c(cc2)c1cc2F Chemical compound O=C(c1ccccc1)N(CCC1NCc2cccc(C(F)(F)F)c2)c(cc2)c1cc2F VCTBEBAPSWPLBS-UHFFFAOYSA-N 0.000 description 1
- QYOFGPLRMJKRLX-UHFFFAOYSA-N O=C(c1ccccc1)N(CCC1Nc(cc2)ccc2-c2ccccc2)c(cc2)c1cc2Br Chemical compound O=C(c1ccccc1)N(CCC1Nc(cc2)ccc2-c2ccccc2)c(cc2)c1cc2Br QYOFGPLRMJKRLX-UHFFFAOYSA-N 0.000 description 1
- IIVCWWWNIZEAKK-UHFFFAOYSA-N O=C(c1ccccn1)N(CCC1NCc2cc(C(F)(F)F)ccc2)c(cc2)c1cc2Cl Chemical compound O=C(c1ccccn1)N(CCC1NCc2cc(C(F)(F)F)ccc2)c(cc2)c1cc2Cl IIVCWWWNIZEAKK-UHFFFAOYSA-N 0.000 description 1
- IIHODBJBYQMCRD-UHFFFAOYSA-N O=C(c1ccccn1)N(CCC1Nc2cc(C(F)(F)F)ccc2)c(cc2)c1cc2Cl Chemical compound O=C(c1ccccn1)N(CCC1Nc2cc(C(F)(F)F)ccc2)c(cc2)c1cc2Cl IIHODBJBYQMCRD-UHFFFAOYSA-N 0.000 description 1
- WQWLCTRCUJNTLD-UHFFFAOYSA-N O=C(c1ccccn1)N(CCC1Nc2cccc(C(F)(F)F)c2)c(cc2)c1cc2F Chemical compound O=C(c1ccccn1)N(CCC1Nc2cccc(C(F)(F)F)c2)c(cc2)c1cc2F WQWLCTRCUJNTLD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine, and particularly relates to an amide compound with antitumor activity and application of the amide compound. The amide compound is shown as a general formula (I). In the formula, R is independently selected from a group consisting of hydrogen, halogen, cyano group, hydroxyl, halogen alkyl, aralkyl, alkoxyl, alkoxyl alkyl, alkyl amine or alkyl amine alkyl; X is halogen; Z is a carbon or nitrogen atom. A pharmacological activity result of the amide compound provided by the invention shows that the amide compound has a good inhibiting effect on tumor cell strains.
Description
Technical field
The invention belongs to medical art, is a kind of amides and application thereof with anti-tumor activity specifically.
Background technology
Tumour has become the second killer threatening human life, dies from malignant tumour person every year on average and reach 6,900,000 people in the whole world more than 50 hundred million population, and new cases are 8,700,000 examples, and this numeral is also increasing year by year.Therefore, national governments, research institution and drugmaker are paid much attention to tumor research and antitumor drug for a long time always, in the research of antitumor drug, achieve major progress at present.In recent years, the development of molecular weight tumor, molecular pharmacology makes tumour essence progressively illustrate; The invention of the modern techniquies such as extensive rapid screening, combinatorial chemistry, genetically engineered and application acceleration drug development process; The research and development of antitumor drug have entered brand-new epoch.Antitumor drug just develops from traditional cytotoxic drug to the new type antineoplastic medicine of the too many levels effect for mechanism.Antitumor drug new development in recent years, comprise cytotoxic anti-tumor drug, take cellular signal transduction molecule as the fast development of the life science such as antitumor drug, angiogensis inhibitor, tumor drug resistance reversal agent, endocrine therapy medicine of target spot, the understanding deep to tumour and successfully control produce new opportunity.The various characteristics such as new drug demonstrates wider antitumor spectra in recent years, efficiently, easily tolerates, easy to use.In the future, searching has no side effect and new antitumoral medicine may become a main development direction efficiently, antimetabolite, topoisomerase enzyme inhibitor and Antitubulin will further develop, molecular targeted agents is if angiogenesis inhibitor, protein tyrosine kinase inhibitor etc. are by fast development, gene therapy medicament will complications develop, but new type antineoplastic medicine research and development will reach real tumour of curing also needs a very long process.The invention provides one and there is the novel amides medicines structure of anti-tumor activity, there is important development prospect.
Summary of the invention
The object of the present invention is to provide a kind of amides and the application thereof with anti-tumor activity.
The technical solution used in the present invention is for achieving the above object:
Have an amides for anti-tumor activity, amides is as shown in general formula (I):
In formula: R is selected from hydrogen, halogen, cyano group, hydroxyl, haloalkyl, aralkyl, alkoxyl group, alkoxyalkyl, alkylamino radical or alkylamino radical alkyl; X is halogen; Z is carbon or nitrogen-atoms;
Wherein, haloalkyl is selected from 3 ~ 6 saturated carbon atoms or the cyclic saturated hydrocarbon that formed with nitrogen-atoms or the straight or branched saturated hydrocarbyl having 1 ~ 6 saturated carbon atom or formed with nitrogen;
In the definition of the compound of Formula I provided above, collect term used and be generally defined as follows:
Halogen: refer to fluorine, chlorine, bromine or iodine.Haloalkyl: straight or branched alkyl, the hydrogen atom on these alkyl can partly or entirely replace by halogen atom, such as, chloromethyl, dichloromethyl, trichloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl etc.Alkoxyl group: straight or branched alkyl, is connected in structure through Sauerstoffatom key.Alkoxyalkyl: alkyl-O-alkyl-, such as CH
3oCH
2-.Alkylamino radical: straight or branched alkyl, is connected in structure through nitrogen-atoms key.Alkylamino radical alkyl: alkyl-N-alkyl-, such as CH
3nCH
2-.
Described amides is compound (1), compound (2), compound (3), compound (4), compound (5) or compound (6), and concrete structure formula is:
Having an application for the amides of anti-tumor activity, is active fraction preparation treatment, prevention or the medicine of tumor remission with general formula (I) compound or its isomer.
Active constituents of medicine is the amides shown in one or more general formula Is.
The weight percentage of described active ingredient is 0.5-99.5%.
The weight percentage of described active ingredient is 60-99.5%.
Described being applied to is prepared treatment, prevention or alleviates in mammary cancer, cervical cancer, liver-cancer medicine.
The advantage that the present invention has: amides provided by the invention, this compounds pharmacologically active result shows it and has good restraining effect to tumor cell line.
Accompanying drawing specification sheets
The collection of illustrative plates of the compound (1) that Fig. 1 provides for the embodiment of the present invention.
The collection of illustrative plates of the compound (2) that Fig. 2 provides for the embodiment of the present invention.
The collection of illustrative plates of the compound (3) that Fig. 3 provides for the embodiment of the present invention.
Embodiment
Following synthetic example, Pharmacological Examples, comparative example result can be used to further illustrate the present invention, but do not mean that restriction the present invention, in the present invention except as otherwise indicate outside, raw materials used all have commercially available.
The amides with anti-tumor activity obtains according to the preparation of following synthetic route, specifically with 4-halo aniline for starting raw material, at 100 DEG C, acylation reaction is carried out with vinylformic acid, then carry out into acid amides to react protect amino with Tosyl chloride, the F-K reaction of self is carried out again under aluminum chloride Lewis acid condition, slough protection p-toluenesulfonyl protecting group more in acid condition, then the acyl chlorides replaced with aryl carries out into acid amides and reacts, finally under titanium tetrachloride/boryl sodium cyanide condition, carry out dehydration condensation obtains target compound.
The present invention includes the preparation that compound that above-mentioned general formula I comprises is the formulation ingredients that is mixed with of activeconstituents and its preparation composition.Formulation preparation method for: obtain formulation soln in compound dissolution the present invention contained to the tensio-active agent of water miscible organic solvent, nonionic, water miscible lipoid, various cyclodextrin, lipid acid, fatty acid ester, phosphatide or its combination solvent; Add the carbohydrate that physiological saline obtains 1-20%.Described organic solvent comprises polyoxyethylene glycol (PEG), ethanol, the combination solvent of propylene glycol or these solvents.
The compound contained in general formula I of the present invention and prodrug are for the preparation for the treatment of, prevention or alleviate antitumor drug or pharmaceutical preparation, and active constituents of medicine is the compound shown in one or more general formula Is.Be particularly useful for the cancer that treatment or alleviation tissue or organ tumor cell cause.The preferred colorectal carcinoma of indication cancer, liver cancer, lymphoma, lung cancer, the esophageal carcinoma, mammary cancer, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, kidney, leukemia, prostate cancer, carcinoma of the pancreas, bladder cancer, the rectum cancer or cancer of the stomach etc.
The compound of the present invention's synthesis can be used for the activeconstituents of antitumor drug, can be used alone, also can, antiviral drug combination antitumor with other.In the drug combination therapeutic process of indication of the present invention, comprise using together with at least one the compounds of this invention and one or more anti-tumor virus drugs of its reactive derivative and other and use to increase general curative effect.Dose during drug combination and administration time should be determined according to most rational therapy effect acquired when different.
The medicament compatibility contained comprises the effective dose of the compound in general formula I." effective dose " herein refers to the consumption that can produce this compound required for result for the treatment of for institute's treatment target.This effective dose or dosage can by there being experience person different according to the suggestion of different situations.Such as, the tumor class for the treatment of is different, and the usage of medicine is different; Whether share with other methods for the treatment of such as other antitumor drugs or antiviral, dosage all can change.Any spendable preparation formulation can be made.If some has alkalescence or acidic cpd also can form avirulent acid or salt, the form of the salt of this compound can be used.In pharmacy, spendable organic acid salt comprises spendable anion salt on physiology, as toluenesulfonate, metilsulfate, acetate, benzoate, Citrate trianion, malate, tartrate, maleate, succinate, ascorbate salt or glycerophosphate etc.; Spendable inorganic salt comprise muriate, bromide, fluorochemical, iodide, vitriol, nitrate, supercarbonate, carbonate or phosphoric acid salt etc.; The form of described salt can be made if any the compound of the alkalescence as amine and suitable acid; The compound of carboxylic-acid can form spendable salt with basic metal or alkaline-earth metal.
The compound contained in formula of I of the present invention is generally readily soluble in the mixed solvent of organic solvent, water-soluble solvent and organic solvent and water-soluble solvent and water.Water-soluble solvent preferred alcohols, poly ethylene glycol, N-methyl-2-pyrrolinone, N,N-dimethylacetamide, DMF, methyl-sulphoxide, acetonitrile and its share.Described alcohol particular methanol, ethanol, Virahol, glycerol or ethylene glycol.The compounds of this invention can mix with conventional preparations carrier and make preparation.Drug solution is obtained in compound dissolution to water miscible organic solvent, non-protonic solvent, water-soluble lipid, cyclodextrin, lipid acid, phosphatide or in the mixed solvent of these solvents; Add the carbohydrate that physiological saline obtains 1-20% again, as the aqueous solution of glucose.Preparation stabilization obtained therefrom for animal and clinical.
With the product medicine that compound in above-mentioned general formula I becomes for active fraction preparation, oral or parenteral administration can be passed through, also by transplant medicine pump in body and additive method administration, herein the parenteral administration of indication refer in subcutaneous intracutaneous, intramuscular, intravenously, intra-arterial, atrium, in synovial membrane, in breastbone, in sheath, in wound site, intracranial injection or drip infusion technique etc.Use conventional method proportioning by technician, mixing finally becomes required pharmaceutical dosage form.Can be tablet, pill, capsule, electuary, syrup, injection liquid, freeze-dried powder formulation, emulsion, pulvis, lyophilized powder, dripping pill, emulsion suspension liquid, water hang solution, the aqueous solution, colloid, colloidal solution, sustained release preparation, nanometer formulation or with other forms of formulation for animal or clinical.
Compound in general formula I of the present invention is used for the treatment of or alleviates the preparation of cancer drug of a certain tissue or organ.Indication cancer comprises but is not only limited to colorectal carcinoma, liver cancer, lymphoma, lung cancer, the esophageal carcinoma, mammary cancer, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, kidney, leukemia, prostate cancer, carcinoma of the pancreas, bladder cancer, the rectum cancer or cancer of the stomach etc.
Synthetic example
Embodiment 1: the synthesis of compound (1)
By 4-chlorophenethylamine 50g; 391.95mmol, 1.00N (N represents mol ratio), 50mL purified water and vinylformic acid 17g; 235.9mmol; 0.60N is placed in the round-bottomed flask of 500mL, under nitrogen protection, is heated to 100 DEG C and keeps 3h; naturally cool to room temperature; drip 125mL aqueous sodium hydroxide solution, 2.0N, this reaction of quencher.By reaction system extracted with diethyl ether 100mL × 2, aqueous phase 1mol/L dilute hydrochloric acid is adjusted pH=3.0, then is extracted with ethyl acetate 100mL × 2, merge organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure, finally adopts silica gel column chromatography separating-purifying, eluent is petrol ether/ethyl acetate=4:1 (v/v, volume ratio), obtain light tan solid 3-(4-chloroanilino) propionic acid 32.5g, yield 76.1%, (ES, m/z): 200.2 [M+H]
+ 1, 202.2 [M+H+2]
+ 1.
By above-mentioned light tan solid 30.0g, 125.25mmol, in the benzene that 1.00N is dissolved in 250mL and 50mL pyridine, add Tosyl chloride 24.5g again, 128.5mmol, 1.04N, stir at 100 DEG C and spend the night, naturally cool to room temperature, removed by filtration pyridine hydrochloride, and use benzene washing leaching cake, mother liquor and washings are merged, and wash 200mL × 2 with the dilute hydrochloric acid of 10%, 200mL × 3 are washed again by purified water, organic phase is washed once with the potassium hydroxide aqueous solution 150mL of 2% again, aqueous phase 1mol/L dilute hydrochloric acid is adjusted pH=3.0, use ethyl acetate 200mL × 2 aqueous phase extracted again, merge organic phase, last more respectively with saturated aqueous common salt and purified water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain light yellow solid 3-(N-(4-chlorobenzene)-4-Methyl benzenesulfonyl base) propionic acid crude product 30.0g, yield 94.0%, directly cast single step reaction.
Under nitrogen protection; by above-mentioned light yellow solid 25g; 70.65mmol; 1.00N is dissolved in the dichlorobenzene of 100mL, then adds phosphorus pentachloride 14.7g, 14.12mmol; 1.00N; stirring at room temperature 1h, concentrating under reduced pressure steams dichlorobenzene, then is dissolved in (solution A) in the methylene dichloride of 150mL.Under nitrogen protection, by aluminum chloride 14.1g, 105.75mmol, 1.50N are placed in the methylene dichloride of 150mL, drip inward and slowly drip solution A at 0 ~ 5 DEG C, and drip and terminate rear continuation stirring 2h, reaction is finished.By reaction system with 10% dilute hydrochloric acid washing 150mL once; use saturated common salt water washing 200mL × 3 again; finally adopt silica gel column chromatography separating-purifying; eluent is petrol ether/ethyl acetate=10:1; obtain light yellow solid 6-chloro-1-p-toluenesulfonyl-2,3-dihydroquinoline-4 (1H)-one 13.0g, yield 55.0%; (ES, m/z): 336.2 [M+H]
+ 1, 338.2 [M+H+2]
+ 1.
By above-mentioned light yellow solid 24.0g, 71.4mmol, 1.00N are placed in acetic acid/HCl/H
2in the mixed solution of O (50mL/50mL/10mL), then add Tosyl chloride 24.5g, 128.5mmol, 1.04N, stir 4h, naturally cool to room temperature at 100 DEG C, reaction is finished, and adds 100mL diluted ethyl acetate reaction system.200mL × 2 and saturated common salt water washing 200mL × 3 are washed again with the aqueous sodium carbonate of 10%, anhydrous sodium sulfate drying, concentrating under reduced pressure, finally use normal hexane crystallization, obtain chloro-2,3-dihydroquinoline-4 (1H) the-one 12.0g of light yellow solid 6-, yield 92%, (ES, m/z): 182.2 [M+H]
+ 1, 184.2 [M+H+2]
+ 1.
By above-mentioned light yellow solid 750mg, 3.86mmol, 1.00N are dissolved in the methylene dichloride of 20mL, add N-ethyl-N-iospropyl propyl group-2-amine 1.994g again, 15.44mmol, 4.00N, then 10mL N is used in its instillation inward, the pyridinecarboxylic chloride 1.09g of dinethylformamide dilution, 7.7mmol, 2.00N diluent, time for adding is about 20min, stirred overnight at room temperature, reaction is finished.Add 100mL diluted ethyl acetate reaction solution; use saturated common salt water washing 150mL × 2 and purified water washing 200mL × 2 more respectively; anhydrous sodium sulfate drying, concentrating under reduced pressure, finally adopts silica gel column chromatography separating-purifying; eluent is petrol ether/ethyl acetate=3:1; obtain off-white color solid 6-chloro-1-picolinoyl-2,3-dihydroquinoline-4 (1H)-one 740mg, yield 67%; (ES, m/z): 287.2 [M+H]
+ 1, 289.2 [M+H+2]
+ 1.
By above-mentioned off-white color solid 200mg, 0.70mmol, 1.00N is dissolved in methylene dichloride 20mL, it drips titanium tetrachloride 146mg successively inward again, 0.76mmol, 2.20N, with 3-(trifluoromethyl) aniline 224mg, 1.40mmol, 2.00N, at room temperature stir 3h, again toward the instillation boryl sodium cyanide 44mg of 10mL dissolve with methanol in it, 0.70mmol, 2.20N, stirring at room temperature 2h, with the aqueous sodium hydroxide solution of 5mol/L10%, the aqueous phase of system is adjusted pH=10.0, add the diluted ethyl acetate reaction solution of 100mL again, saturated common salt water washing, be dissolved in the mixed solution of 20mL methylene dichloride, time for adding is 30min, after stirring 1h again, add methylene dichloride 50mL to dilute, use water and saturated common salt water washing 100mL × 2 respectively, anhydrous sodium sulfate drying, concentrating under reduced pressure, finally adopt silica gel column chromatography separating-purifying, eluent is petrol ether/ethyl acetate=1:1 (v/v), obtain white powdery solids compound (1) 80mg, yield 27%, (ES, m/z): 432.2 [M+H]
+ 1, 434.2 [M+H+2]
+ 1.H NMR(300MHz,CD
3OD)δ:8.50(d,J=3.9Hz,1H),7.92(m,1H),7.63(d,J=7.8Hz,1H),7.47(m,1H),7.33(m,2H),7.01(m,4H),6.87(d,J=7.5Hz,1H),6.65(m,1H),4.78(s,1H),3.96(d,J=6.9Hz,1H),3.69(m,2H),2.24(m,1H),1.85(m,1H)。See Fig. 1.
Embodiment 2: the synthesis of compound (2)
Difference from Example 1 is, final step is that keto compounds carries out dehydrating condensation with (3-(trifluoromethyl) phenyl) methylamine, according to synthetic method and the synthetic route I of embodiment 1, can obtain compound (2), concrete structure formula is as follows:
(ES,m/z):446.2[M+H]
+1,448.2[M+H+2]
+1。H NMR(300MHz,CDCl
3)δ:9.51(s,1H),9.03(s,1H),8.49(d,J=4.2Hz,1H),7.96(m,2H),7.76(m,5H),7.52(m,1H),7.21(m,1H),4.77(s,1H),4.47(s,1H),4.31(s,1H),4.05(m,1H),3.77(m,1H),2.41(m,1H)。See Fig. 2.
Embodiment 3: the synthesis of compound (3)
Difference from Example 1 is, final step keto compounds and phenylbenzene-4-amine carry out dehydrating condensation, and according to the synthetic method of embodiment 1, can obtain compound (3), concrete structure formula is as follows:
(ES,m/z):440.2[M+H]
+1,442.2[M+H+2]
+1;H NMR(300MHz,CDCl
3)δ:8.54(d,J=4.2Hz,1H),7.93(m,1H),7.64(d,J=7.8Hz,1H),7.58(d,J=7.2Hz,1H),7.49(d,J=8.7Hz,.3H),7.39(m,2H),7.25(s,1H),7.23(m,1H),7.08(m,1H),6.81(d,J=8.7Hz,2H),4.72(m,2H),3.90(s,2H),3.72(m,1H),2.27(d,J=6.9Hz,1H),1.89(m,1H)。See Fig. 3.
Embodiment 4: the synthesis of compound (4)
Difference from Example 1 is, what starting raw material adopted is 4-fluorophenethylamine, and according to the synthetic method of embodiment 1, can obtain compound (4), concrete structure formula is as follows:
(ES,m/z):416.2[M+H]
+1,418.2[M+H+2]
+1;H NMR(300MHz,CDCl
3)δ:8.51(d,J=3.9Hz,1H),7.93(m,1H),7.64(d,J=7.8Hz,1H),7.46(m,1H),7.31(m,2H),7.06(m,4H),6.87(d,J=7.5Hz,1H),6.66(m,1H),4.77(s,1H),3.95(d,J=6.9Hz,1H),3.69(m,2H),2.21(m,1H),1.83(m,1H)。
Embodiment 5: the synthesis of compound (5)
Difference from Example 2 is, what penultimate stride adopted is Benzoyl chloride is reagent, and according to the synthetic method of embodiment 2, can obtain compound (5), concrete structure formula is as follows:
(ES,m/z):429.2[M+H]
+1,431.2[M+H+2]
+1;H NMR(300MHz,CDCl
3)δ:9.52(s,1H),9.04(s,1H),8.49(d,J=4.2Hz,1H),7.98(m,2H),7.75(m,5H),7.51(m,1H),7.23(m,1H),4.70(s,1H),4.51(s,1H),4.29(s,1H),4.06(m,1H),3.78(m,1H),2.51(m,1H)。
Embodiment 6: the synthesis of compound (6)
Difference from Example 3 is, what starting raw material adopted is 4-Bretylium Tosylate, and what penultimate stride adopted is Benzoyl chloride is reagent, and according to the synthetic method of embodiment 3, can obtain compound (6), concrete structure formula is as follows:
(ES,m/z):483.2[M+H]
+1,485.2[M+H+2]
+1;H NMR(300MHz,CDCl
3)δ:8.53(d,J=4.2Hz,1H),7.91(m,1H),7.65(d,J=7.8Hz,1H),7.56(d,J=7.2Hz,1H),7.49(d,J=8.7Hz,.3H),7.41(m,3H),7.24(s,1H),7.25(m,1H),7.11(m,1H),6.82(d,J=8.7Hz,2H),4.74(m,2H),3.95(s,2H),3.76(m,1H),2.29(d,J=6.9Hz,1H),1.91(m,1H)。
Embodiment 7: compound pharmacological evaluation
Testing compound is to MCF-7 (human breast cancer cell), and HeLa (human cervical carcinoma cell) tumour cell and BEL-7402 (human liver cancer cell), as research object, adopt tetrazolium-based colorimetric assay, i.e. mtt assay.Active half-inhibition concentration (IC
50) represent, unit is μM.
For MCF-7 cell:
Get the MCF-7 cell of 0.25% tryptic digestion monolayer culture, be made into single cell suspension with the RPMI1640 nutrient solution containing 10% foetal calf serum, be inoculated in 96 orifice plates, every hole 200 μ L is (containing 3 × 10
4-5 × 10
4individual cell).Culture plate is put into CO2 incubator, at 37 DEG C, 5%CO
2under condition, add the testing compound of different concns after culturing cell is adherent, each compound tests 4 concentration (1 × 10
-5, 1 × 10
-6, 1 × 10
-7, 1 × 10
-8mol/L), control group adds solvent isopyknic with administration group.Continue at CO
2in 37 DEG C, 5%CO in incubator
272h is cultivated under condition.Every hole adds 20 μ L MTT solution (5mg/mL), continue to hatch 4h in 37 DEG C, stop to cultivate, discard culture supernatant in hole, every hole adds 150 μ L DMSO, gentle agitation 10min, select 570nm wavelength, microplate reader measures each hole absorbance value (OD value), with the inhibiting rate of formulae discovery compound on tumor cell the following, and calculates IC
50.Repeated test 3 times, averages as net result.
Table 1
Compound (1) is best to MCF-7 inhibit activities as can be seen from the table, active lower nearly three times than contrast medicine 5-Fu; Compound (1) is best to HeLa inhibit activities, active lower nearly four times than contrast medicine 5-Fu; In table, listed compound is overall to BEL-7402 difference, only has the IC of compound (6)
50μM just reach 7.54.
Should be understood that, for those of ordinary skills, can be improved according to the above description or convert, and all these improve and convert the protection domain that all should belong to claims of the present invention.
Claims (7)
1. there is an amides for anti-tumor activity, it is characterized in that: amides is as shown in general formula (I):
General formula (I)
In formula: R is selected from hydrogen, halogen, cyano group, hydroxyl, haloalkyl, aralkyl, alkoxyl group, alkoxyalkyl, alkylamino radical or alkylamino radical alkyl; X is halogen; Z is carbon or nitrogen-atoms;
X is halogen; Z is carbon or nitrogen-atoms.
2. by the amides with anti-tumor activity according to claim 1, it is characterized in that: described amides is compound (1), compound (2), compound (3), compound (4), compound (5) or compound (6), and concrete structure formula is:
3. there is an application for the amides of anti-tumor activity, it is characterized in that: be active fraction preparation treatment, prevention or the medicine of tumor remission with general formula (I) compound or its isomer.
4. by the application with the amides of anti-tumor activity according to claim 3, it is characterized in that: described activeconstituents is the amides shown in one or more general formula Is.
5. by the application with the amides of anti-tumor activity according to claim 3, it is characterized in that: the weight percentage of described active ingredient is 0.5-99.5%.
6. by the application with the amides of anti-tumor activity according to claim 5, it is characterized in that: the weight percentage of described active ingredient is 60-99.5%.
7. by the application with the amides of anti-tumor activity according to claim 3, it is characterized in that: described tumour is mammary cancer, cervical cancer or liver cancer.
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CN112341392A (en) * | 2019-08-08 | 2021-02-09 | 北京颖泰嘉和生物科技股份有限公司 | Process for preparing 1- (4-chlorophenyl) -pyrazolidin-3-one |
CN114149370A (en) * | 2020-09-07 | 2022-03-08 | 北京颖泰嘉和生物科技股份有限公司 | Preparation method of 1- (4-halophenyl) -pyrazolidin-3-one |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN112341392A (en) * | 2019-08-08 | 2021-02-09 | 北京颖泰嘉和生物科技股份有限公司 | Process for preparing 1- (4-chlorophenyl) -pyrazolidin-3-one |
CN112341392B (en) * | 2019-08-08 | 2022-04-12 | 北京颖泰嘉和生物科技股份有限公司 | Process for preparing 1- (4-chlorophenyl) -pyrazolidin-3-one |
CN114149370A (en) * | 2020-09-07 | 2022-03-08 | 北京颖泰嘉和生物科技股份有限公司 | Preparation method of 1- (4-halophenyl) -pyrazolidin-3-one |
CN114149370B (en) * | 2020-09-07 | 2024-02-27 | 北京颖泰嘉和生物科技股份有限公司 | Process for the preparation of 1- (4-halophenyl) -pyrazolidin-3-one |
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