CN103755695A - Amide compounds with antitumor activity and application of amide compounds - Google Patents
Amide compounds with antitumor activity and application of amide compounds Download PDFInfo
- Publication number
- CN103755695A CN103755695A CN201310713940.0A CN201310713940A CN103755695A CN 103755695 A CN103755695 A CN 103755695A CN 201310713940 A CN201310713940 A CN 201310713940A CN 103755695 A CN103755695 A CN 103755695A
- Authority
- CN
- China
- Prior art keywords
- amides
- compound
- tumor activity
- amide compounds
- application
- 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
- 0 *c(nc1)cnc1Br Chemical compound *c(nc1)cnc1Br 0.000 description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N C1CCNCC1 Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N OC(c1ccccn1)=O Chemical compound OC(c1ccccn1)=O SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
- QUHHKRGBBWLJMI-UHFFFAOYSA-N [O-][N+](c(c(C(Nc1ncc(-c2cccc(C(F)(F)F)c2)nc1)=O)c1)ccc1N1CCCCC1)=O Chemical compound [O-][N+](c(c(C(Nc1ncc(-c2cccc(C(F)(F)F)c2)nc1)=O)c1)ccc1N1CCCCC1)=O QUHHKRGBBWLJMI-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/14—Nitrogen atoms
-
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines and particularly relates to amide compounds with antitumor activity and an application of the amide compounds. The amide compounds are as shown in the general formula (I), wherein R1 and R2 can be same or different and are respectively and independently selected from hydrogen, halogen, a cyan, hydroxyl, halogenated alkyl, alkoxy, alkoxylalkyl, alkylamino or alkylaminoalkyl; R3 is triazole, 1, 3, 4-oxa-diazole, carbonyl and respective corresponding electro-withdrawing or electron donating substituent groups; and X is carbon or nitrogen atoms. A pharmacological activity result of the amide compounds provided by the invention shows that the amide compounds have favorable inhibiting effect for tumor cell strains.
Description
Technical field
The invention belongs to medical technical field, is a kind of amides and application thereof with anti-tumor activity specifically.
Background technology
Tumour has become the second killer who threatens human life, dies from every year on average malignant tumour person and reach 6,900,000 people in the whole world more than 50 hundred million populations, and new cases are 8,700,000 examples, and 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, have obtained at present major progress.The development of molecular weight tumor in recent years,, molecular pharmacology is progressively illustrated tumour essence; 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 is just from traditional cytotoxic drug, to the new type antineoplastic medicine development of the too many levels effect for machine-processed.Antitumor drug new development in recent years, the fast development of the life sciences such as the antitumor drug that comprise cytotoxicity antitumor drug, the cellular signal transduction molecule of take is target spot, angiogensis inhibitor, tumor drug resistance reversal agent, endocrine therapy medicine, produces new opportunity to the deep understanding of tumour and successful control.New drug demonstrates wider antitumor spectra in recent years, efficient, easily tolerance, the various characteristics that waits easy to use.In the future, searching has no side effect and efficient new antitumoral medicine may become a main development direction, 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 healing tumour, also needs a very long process.The invention provides a kind of novel amides medicines structure of anti-tumor activity that has, there is important development prospect.
Summary of the invention
The object of the present invention is to provide a kind of amides and application thereof with anti-tumor activity.
The technical solution used in the present invention is for achieving the above object:
An amides with anti-tumor activity, amides is as shown in general formula (I):
In formula: R
1, R
2can be identical or different, be selected from independently of one another respectively hydrogen, halogen, cyano group, hydroxyl, haloalkyl, alkoxyl group, alkoxyalkyl, alkylamino radical or alkylamino radical alkyl;
R
3triazole, 1,3,4-4-oxadiazole, carbonyl and each self-corresponding electrophilic or electron donating group; X is carbon or nitrogen-atoms.
Further, in general formula (I): R
1, R
2can be identical or different, be selected from respectively hydrogen, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, haloalkyl, alkoxyl group, alkoxyalkyl, alkylamino radical or alkylamino radical alkyl;
R
3triazole, 1,3,4-4-oxadiazole, carbonyl, nitro, bromine or cyano group.
Wherein, haloalkyl is to be selected from 3～6 saturated carbon atoms or the cyclic saturated hydrocarbon that forms with nitrogen-atoms or the straight or branched saturated hydrocarbyl that has 1～6 saturated carbon atom or form with nitrogen;
Described amides is compound (1), compound (2), compound (3), compound (4) or compound (5), and concrete structure formula is:
There is an application for the amides of anti-tumor activity, take the medicine that general formula (I) compound or its isomer be active fraction preparation treatment, prevention or tumor remission.
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 in preparation treatment, prevention or alleviation mammary cancer, cervical cancer, liver-cancer medicine.
The present invention has advantages of: amides provided by the invention, this compounds pharmacologically active result shows that it has good restraining effect to tumor cell line.
Accompanying drawing explanation
The compound that Fig. 1 provides for the embodiment of the present invention (1) H NMR collection of illustrative plates;
The compound that Fig. 2 provides for the embodiment of the present invention (2) H NMR collection of illustrative plates;
The compound that Fig. 3 provides for the embodiment of the present invention (3) H NMR collection of illustrative plates;
The compound that Fig. 4 provides for the embodiment of the present invention (4) H NMR collection of illustrative plates;
The compound that Fig. 5 provides for the embodiment of the present invention (5) H NMR collection of illustrative plates.
Embodiment
Following synthetic example, pharmacology embodiment, 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 outside indicating, raw materials used all have commercially available.
Medicines structure general formula of the present invention is as follows:
Wherein, R
1and R
2can be identical or different, be selected from independently of one another respectively hydrogen, halogen, cyano group, hydroxyl, haloalkyl, alkoxyl group, alkoxyalkyl, alkylamino radical or alkylamino radical alkyl;
R
3triazole, 1,3,4-4-oxadiazole, carbonyl and each self-corresponding electrophilic or electron donating group;
X is carbon or nitrogen-atoms;
Wherein haloalkyl is to be selected from 3～6 saturated carbon atoms or the cyclic saturated hydrocarbon that forms with nitrogen-atoms or the straight or branched saturated hydrocarbyl that has 1～6 saturated carbon atom or form with nitrogen.Halogen is fluorine, chlorine, bromine or iodine;
In the present invention, further preferred compound is the amides with following structure:
In the definition of the compound of Formula I providing, collect term General Definition used as follows above:
Halogen: refer to fluorine, chlorine, bromine or iodine.Haloalkyl: straight or branched alkyl, the hydrogen atom on these alkyl can partly or entirely be replaced by halogen atom, for example, 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-, CH for example
3oCH
2-.Alkylamino radical: straight or branched alkyl, is connected in structure through nitrogen-atoms key.Alkylamino radical alkyl: alkyl-N-alkyl-, CH for example
3nCH
2-.
The present invention includes compound that above-mentioned general formula I comprises and be preparation composition that activeconstituents is mixed with and the preparation that forms of preparation.Formulation preparation method is: the compound dissolution that the present invention is contained makes formulation soln in 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 physiological saline to obtain the carbohydrate of 1-20%.Described organic solvent comprises polyoxyethylene glycol (PEG), ethanol, the combination solvent of propylene glycol or these solvents.
The compound of containing 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 synthetic compound of the present invention can be used for the activeconstituents of antitumor drug, can use separately, also can, antiviral drug combination antitumor with other.In the drug combination therapeutic process of indication of the present invention, comprise use at least one the compounds of this invention with and one or more anti-tumor virus drugs of reactive derivative and other together with use to increase general curative effect.Dose during drug combination and administration time should be determined according to rational therapy effect obtained in different situations.
The medicament compatibility of containing comprises the effective dose of the compound in general formula I." effective dose " herein refers to the consumption that can produce required this compound of result for the treatment of for institute's treatment target.This effective dose or dosage can be by having experience person according to the suggestion of different situations difference.Such as, the tumour kind for the treatment of is different, and the usage of medicine is different; Whether share etc. as other antitumor drugs or antiviral with other methods for the treatment of, dosage all can change.Can make any spendable preparation formulation.If some has alkalescence or acidic cpd and can form avirulent acid or salt, can use the form of the salt of this compound.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.; If any the alkaline compound as amine and suitable acid, can make the form of described salt; The compound of carboxylic-acid can form spendable salt with basic metal or alkaline-earth metal.
The compound of containing in formula of I of the present invention is general 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 with and 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.Compound dissolution is in water miscible organic solvent, non-protonic solvent, water-soluble lipid, cyclodextrin, lipid acid, phosphatide or in the mixed solvent of these solvents and make drug solution; Add again physiological saline to obtain the carbohydrate of 1-20%, as the aqueous solution of glucose.The preparation stabilization making therefrom for animal and clinical.
The compound in above-mentioned general formula I of take is the product medicine that active fraction preparation becomes, can be by oral or parenteral route administration, also can be by transplant medicine pump in body and additive method administration, the parenteral route administration of indication herein refers to subcutaneous intracutaneous, intramuscular, intravenously, intra-arterial, atrium in, in synovial membrane, in breastbone, in sheath, interior, the intracranial injection of wound site or drip infusion technique etc.By technician, use conventional method proportioning, mix and finally become needed pharmaceutical dosage form.Can be the outstanding solution of tablet, pill, capsule, electuary, syrup, injection liquid, freeze-dried powder formulation, emulsion, pulvis, lyophilized powder, dripping pill, emulsion suspension liquid, water, 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 the 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: compound (1) synthetic
By 4-amino-benzene oxygen carbonyl chloride 1.6g, 7.98mmol, 1.05N(N represents mol ratio) be dissolved in the methylene dichloride of 8mL, after dissolving under 0 ℃ and nitrogen protection condition, drip 3, 4-xylidine 970mg, 8.00mmol, 1.05N is dissolved in the mixed solution of 12mL methylene dichloride, dropping finishes rear continuation and stirs 2h, add respectively again N-ethyl-N sec.-propyl propyl group-2-amine 1.47g, 11.38mmol, 1.50N and 2-nitro-5-(piperidyl-1) phenylhydrazine 2.0g, 7.26mmol, 1.00N, 96%, stir again 3h, add methylene dichloride 150mL dilution, by 200mL saturated sodium-chloride water dissolution and wash 3 times, anhydrous sodium sulfate drying, concentrating under reduced pressure, finally adopt silica gel column chromatography separating-purifying, eluent is petrol ether/ethyl acetate=4:1(v/v, volume ratio), obtain light yellow solid 4-(3, 4-3,5-dimethylphenyl)-1-(2-nitro-5-(piperidyl-1) benzoyl) half diaminourea 2.0g, yield 67%, (ES, m/z): 412.2[M+H]
+ 1.
By above-mentioned light yellow solid 1.4g, 3.40mmol, 1.00N is dissolved in 1 of 140mL, in 2-ethylene dichloride, add respectively again triphenylphosphine 1.34g, 5.11mmol, 1.50N and triethylamine 2.06g, 20.36mmol, 6.00N, under nitrogen protection condition, adding volume ratio is tetrahydrofuran (THF) and the chloroform mixed solution 33mL of 2:1, then whole system is warming up to 85 ℃ and stir and to spend the night, concentrating under reduced pressure, finally adopt silica gel column chromatography separating-purifying, eluent is petrol ether/ethyl acetate=5:1(v/v), obtain light yellow solid 5-(2-amino-5-(piperidines-1) phenyl)-N-(3, 4-3,5-dimethylphenyl)-1, 3, 4-oxygen diazole-2-amine 1.02g, yield 75%, (ES, m/z): 394.2[M+H]
+ 1.
By above-mentioned light yellow solid 230mg, 0.58mmol, 1.00N and palladium/carbon 0.03g of 10% are placed in anhydrous methanol 30mL, under room temperature, under reaction liquid level, pour hydrogen into, stir after 5h, remove by filter insoluble solid, concentrating under reduced pressure, obtain yellow solid 5-(2-amino-5-(piperidines-1) phenyl)-N-(3,4-3,5-dimethylphenyl l)-1,3,4-oxygen diazole-2-amine 0.20g, yield 94%, (ES, m/z): 364.2[M+H]
+ 1.
By above-mentioned yellow solid 150mg, 0.41mmol, 1.00N is dissolved in methylene dichloride 20mL, add again N-ethyl-N-sec.-propyl propyl group-2-amine 159mg, 1.23mmol, 3.00N, under 0 ℃ of condition, splash into again pyridine formyl chloride 70mg, 0.49mmol, 1.20N is dissolved in the mixed solution of 20mL methylene dichloride, time for adding is 30min, stir again after 1h, add methylene dichloride 50mL dilution, water and saturated common salt water washing respectively, anhydrous sodium sulfate drying, concentrating under reduced pressure, finally adopt silica gel column chromatography separating-purifying, eluent is petrol ether/ethyl acetate=2:1(v/v), obtain light yellow compound (1) 110mg, yield 46%, (ES, m/z): 469.2[M+H]
+ 1.H NMR (300MHz, CD
3oD) δ: 12.87 (s, 1H), 9.17～9.14 (d, J=9.3Hz, 1H), 8.85～8.84 (d, J=4.2Hz, 1H), 8.34 (s, 1H), 8.28～8.26 (d, J=8.1Hz, 1H), 7.93～7.90 (m, 1H), 7.88 (s, 1H), 7.53～7.48 (t, J=1.8Hz, 2H), 7.36～7.34 (d, J=6.6Hz, 2H), 7.17～7.14 (d, J=8.1Hz, 1H), 3.49 (m, 4H), 2.30～2.25 (m, 6H), 2.14 (m, 4H), 1.76 (m, 2H) (referring to Fig. 1).
Embodiment 2: compound (2) synthetic
By benzoyl lsothiocyanates 1.5g; 9.09mmol; 1.00N is dissolved in acetone 15mL, then adds 3-(trifluoromethyl) aniline 1.5g, 9.32mmol; 1.02N; whole system is spent the night 0 ℃ of stirring, and concentrating under reduced pressure obtains off-white color solid 1-benzoyl-3-(3-(trifluoromethyl) phenyl) thiocarbamide 2.7g, yield 92%; (ES, m/z): 325.2[M+H]
+ 1, 327.2[M+H+2]
+ 1.
By above-mentioned off-white color solid 3.2g, 9.88mmol, 1.00N is dissolved in 50mL methyl alcohol, add again sodium hydroxide 565mg, 14.12mmol, 1.43N, pure water 40mL, whole system stirs 2h concentrating under reduced pressure at 80 ℃, with the extraction of methylene dichloride 30mL * 3, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains light yellow solid 1-(3-(trifluoromethyl) phenyl) thiocarbamide 2g, yield 92%, (ES, m/z): 221.2[M+H]
+ 1, 223.2[M+H+2]
+ 1.
By above-mentioned light yellow solid 1g, 4.55mmol, 1.00N is dissolved in acetonitrile 30mL, add methyl iodide 3.2g, 22.70mmol, 4.99N, whole system is heated to 40 ℃ and stir 1h, concentrating under reduced pressure, finally adopts silica gel column chromatography separating-purifying, and eluent is methylene chloride/methanol=2:1, obtain light yellow oily 2-methyl isophthalic acid-(3-(trifluoromethyl) phenyl) thiocarbamide 800mg, yield 75%, (ES, m/z): 235.2[M+H]
+ 1, 237.2[M+H+2]
+ 1.
By 2-nitro-5-(piperidyl-1) benzoyl hydrazine 900mg, 3.41mmol, 1.00N is dissolved in anhydrous piperidines 27mL, add again above-mentioned light yellow oil 800mg, 3.42mmol, 1.00N, whole system is heated to 80 ℃ and stirs 2h, is regenerated to 120 ℃ and stirs 3h, and reaction is finished.Concentrating under reduced pressure, finally adopt silica gel column chromatography separating-purifying, eluent is methylene chloride/methanol=3:1, obtain yellow solid 5-(2-nitro-5-(piperidyl-1) phenyl)-N-(3-(trifluoromethyl) phenyl)-4H-1,2,4-triazole-3-amine 800mg, yield 54%, (ES, m/z): 433.2[M+H]
+ 1, 435.2[M+H+2]
+ 1.
By above-mentioned yellow solid 500mg, 1.16mmol, 1.00N is dissolved in 30mL anhydrous methanol, add 10% palladium/carbon 500mg, under reaction liquid level, pour hydrogen into, stirring at room 3h simultaneously, remove by filter insoluble solid, concentrating under reduced pressure, obtains brown solid 5-(2-amino-5-(piperidines-1) phenyl)-N-(3-(trifluoromethyl) phenyl)-4H-1,2,4-triazole-3-amine 450mg, yield 97%, (ES, m/z): 403.2[M+H]
+ 1, 405.2[M+H+2]
+ 1.
By 2-pyridine carboxylic acid 91mg, 0.74mmol, 1.98N be dissolved in N, in dinethylformamide 10mL, add respectively again 2-(7-azepine-1H-benzotriazole-1-yl)-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester (HATU) 212mg, 0.56mmol, 1.50N and N, N-diisopropyl ethyl amine (DIPEA) 192mg, 1.49mmol, 3.99N, after whole system stirring at room 20min, toward it, add above-mentioned brown solid 150mg again, 0.37mmol, 1.00N, stirred overnight at room temperature, add ethyl acetate 20mL, with saturated aqueous common salt 20mL * 3, wash, anhydrous sodium sulfate drying, concentrating under reduced pressure, finally adopt silica gel column chromatography to carry out separating-purifying, eluent is methylene chloride/methanol=3:1, obtain yellow solid compound (2) 104.3mg, yield 55%, (ES, m/z): 508.2[M+H]
+ 1, 510.2[M+H+2]
+ 1.H?NMR(300MHz,CDCl
3)δ:11.78(s,1H),9.82(s,1H),8.72(s,1H),8.31(s,1H),8.16-8.14(d,J=6.9Hz,2H),8.05-8.00(t,1H),7.89-7.86(d,J=7.5Hz,1H),7.59-7.17(m,5H),3.32(s,4H),1.73-1.61(m,6H)。See Fig. 2.
Embodiment 3: compound (3) synthetic
Difference from Example 1 is, adopting 2-nitro-5-(piperidines-1)-sulfo--benzene first methyl hydrazine is raw material, according to the synthetic method of embodiment 1, can make compound (3), and concrete structure formula is as follows:
(ES,m/z):635.2[M+H]
+1，637.2[M+H+2]
+1;HNMR(300MHz,CDCl
3)δ:9.05-9.02(d,J=9.3Hz,1H),8.45(s,1H),8.24-8.13(m,2H),8.10-7.87(m,2H),7.84-7.70(m,1H),7.51-7.45(m,3H),7.29-7.26(d,J=7.8Hz,1H),3.98-3.95(s,2H),3.72-3.64(m,4H),3.45-3.41(m,2H),3.26-3.19(m,5H),3.12-3.08(m,2H),2.52(s,3H),2.08-2.06(m,4H),1.86-1.85(m,2H),1.37-1.29(m,6H)。See Fig. 3.
Embodiment 4: compound (4) synthetic
By 5-bromine piperazine-2-amine 4g, 22.99mmol, 1.00N is dissolved in the mixing solutions of Isosorbide-5-Nitrae-dioxane 68mL and anhydrous methanol 46mL, add respectively again 3-(trifluoromethyl) phenyl-boron dihydroxide 4.46g, 23.48mmol, 1.02N, sodium carbonate 4.88g, 46.04mmol, 2.00N and Pd (PPh
3)
4532mg, 0.46mmol, 0.02N, whole system is heated to 135 ℃, stirring is spent the night, concentrating under reduced pressure, finally adopts silica gel column chromatography separating-purifying, and eluent is petrol ether/ethyl acetate=5:1, obtain yellow solid 5-(3-(trifluoromethyl) phenyl) piperazine-2-amine 4.4g, yield 80%, (ES, m/z): 240.2[M+H]
+ 1, 242.2[M+H+2]
+ 1.
By above-mentioned yellow solid 1.3g, 5.43mmol, 1.00N is dissolved in the mixed solvent of methylene dichloride 15mL and pyridine 2mL, splash into the chloro-2-nitrobenzoyl chloride of 5-1.2g, 5.45mmol, the mixed solution of 1.00N and 5mL methylene dichloride, stirring at room 2h, adds methylene dichloride 100mL, with the washing of dilute hydrochloric acid 30mL * 3, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains the chloro-2-nitro-N-of yellow solid 5-(5-(3-(trifluoromethyl) phenyl) piperazine-2) benzamide 2.0g, yield 87%, (ES, m/z): 423.2[M+H]
+ 1, 425.2[M+H+2]
+ 1.
By above-mentioned yellow solid 2.0g, 4.73mmol, 1.00N is dissolved in DMF 30mL, then adds respectively piperidinyl-1 .0g, 11.74mmol, 2.50N and salt of wormwood 2g, 14.47mmol, 3.00N, is warming up to 100 ℃ of stirrings and spends the night, and reaction is finished.Add ethyl acetate 150mL dilution, use again the washing of pure water 50mL * 3, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain yellow solid 2-nitro-5-(piperidines-1)-N-(5-(3-(trifluoromethyl) phenyl) piperazine-2) benzamide 1.7g, yield 76%, (ES, m/z): 472.2[M+H]
+ 1, 474.2[M+H+2]
+ 1.
By above-mentioned yellow solid 140mg, 0.30mmol, 1.00N is dissolved in the mixed solution of methyl alcohol 5mL and tetrahydrofuran (THF) 2mL, add again palladium/carbon 140mg of 10%, under reaction liquid level, pour hydrogen into simultaneously, whole system at room temperature stirs 1h, remove by filter insoluble solid, add ethyl acetate 50mL dilution, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain yellow solid 2-amino-5-(piperidines-1)-N-(5-(3-(trifluoromethyl) phenyl) piperazine-2) benzamide 100mg, yield 76%, (ES, m/z): 442.2[M+H]
+ 1, 444.2[M+H+2]
+ 1.
By above-mentioned yellow solid 140mg, 0.30mmol, 1.00N is dissolved in the mixed solution of methyl alcohol 5mL and tetrahydrofuran (THF) 2mL, add again palladium/carbon 140mg of 10%, under reaction liquid level, pour hydrogen into simultaneously, whole system at room temperature stirs 1h, remove by filter insoluble solid, add ethyl acetate 50mL dilution, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain yellow solid 2-amino-5-(piperidines-1)-N-(5-(3-(trifluoromethyl) phenyl) piperazine-2) benzamide 100mg, yield 76%, by 2-pyridine carboxylic acid 37mg, 0.30mmol, 1.10N be dissolved in N, in dinethylformamide 5mL, add respectively again 2-(7-azepine-1H-benzotriazole-1-yl)-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester (HATU) 413mg, 1.09mmol, 4.00N and N-ethyl-N-sec.-propyl propyl group-2-amine 140mg, 1.08mmol, 4.00N, again toward splashing into 2-amino-5-(piperidines-1)-N-(5-(3-(trifluoromethyl) phenyl) piperazine-2) benzamide (120mg in it, 0.27mmol, 1.00N is dissolved in the N of 5mL, dinethylformamide mixed solution, whole system at room temperature stirs and spends the night, reaction is finished, add ethyl acetate 50mL dilution, again respectively with saturated ammonium chloride and salt solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain yellow product (4) 76mg, yield 52%, (ES, m/z): 547.2[M+H]
+ 1, 549.2[M+H+2]
+ 1, H NMR (300MHz, CDCl
3) δ: 12.16 (s, 1H), 11.61 (s, 1H), 9.49 (s, 1H), 9.27 (s, 1H), 8.74 (d, J=3.9,1H), 8.56 (d, J=8.7,1H), 8.49 (s, 2H), 8.15 (m, 1H), 8.06 (m, 1H), 7.06 (m, 4H), 7.47 (s, 1H), 3.37 (d, 4H), 1.75 (s, 4H), 1.60 (s, 2H).See Fig. 4.
Embodiment 5: compound (5) synthetic
Adopt identical starting raw material with embodiment 4, but adopt 3-(((2-(diethylamide) ethyl) (methyl) amino) methyl) phenylformic acid in last one-tenth acid amides reaction, again according to the synthetic method of embodiment 4, can make compound (5), concrete structure formula is as follows:
(ES,m/z):688.2[M+H]
+1，690.2[M+H+2]
+1;H?NMR(300MHz,CDCl
3)δ:11.51(s,1H),11.02(s,1H),9.44(d,J=1.2,1H),9.24(d,J=1.2,1H),8.46(s,1H),8.03(m,3H),7.84(m,2H),7.63(d,J=8.4,2H),7.49(s,1H),7.26(d,J=7.2,1H),3.15(m,12H),1.68(m,6H),1.17(m,6H)。See Fig. 5.
Embodiment 6: 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 tetramethyl-azo azoles salt colorimetry, i.e. mtt assay.Active in half-inhibition concentration (IC
50) represent, unit is μ M.
Take MCF-7 cell as example:
Get the MCF-7 cell of 0.25% tryptic digestion monolayer culture, with the RPMI1640 nutrient solution containing 10% foetal calf serum, be made into single cell suspension, be inoculated in 96 orifice plates, every hole 200 μ L(are containing 3 * 10
4-5 * 10
4individual cell).Culture plate is put into CO2 incubator, at 37 ℃, 5%CO
2under condition, after culturing cell is adherent, add the testing compound of different concns, 4 concentration (1 * 10 of each compound test
-5, 1 * 10
-6, 1 * 10
-7, 1 * 10
-8mol/L), control group adds and the isopyknic solvent of administration group.Continuation is at CO
2in incubator in 37 ℃, 5%CO
2under condition, cultivate 72h.Every hole adds 20 μ L MTT solution (5mg/mL), in 37 ℃, continue to hatch 4h, end to cultivate, discard culture supernatant in hole, every hole adds 150 μ L DMSO, gentle agitation 10min, select 570nm wavelength, in microplate reader, measure each hole absorbance value (OD value), use the inhibiting rate of formula computerized compound to tumour cell below, and calculate IC
50.Repeated test 3 times, averages as net result.
Table 1
Known by the data in table 1, five compounds have shown that to BEL-7402 tumour cell poor inhibition is active, and MCF-7 and HeLa tumour cell have been shown to obvious inhibition is active, and wherein compound 1 is active best, has the value of further research.
Should be understood that, for those of ordinary skills, can be improved according to the above description or convert, and all these improvement and conversion all should belong to the protection domain of claims of the present invention.
Claims (8)
1. an amides with anti-tumor activity, is characterized in that: amides is as shown in general formula (I):
In formula: R
1, R
2can be identical or different, be selected from independently of one another respectively hydrogen, halogen, cyano group, hydroxyl, haloalkyl, alkoxyl group, alkoxyalkyl, alkylamino radical or alkylamino radical alkyl;
R
3triazole, 1,3,4-4-oxadiazole, carbonyl and each self-corresponding electrophilic or electron donating group; X is carbon or nitrogen-atoms.
2. by the amides with anti-tumor activity claimed in claim 1, it is characterized in that: in general formula (I):
R
1, R
2can be identical or different, be selected from respectively hydrogen, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, haloalkyl, alkoxyl group, alkoxyalkyl, alkylamino radical or alkylamino radical alkyl;
R
3triazole, 1,3,4-4-oxadiazole, carbonyl, nitro, bromine or cyano group.
3. by the amides with anti-tumor activity claimed in claim 1, it is characterized in that: described amides is compound (1), compound (2), compound (3), compound (4) or compound (5), and concrete structure formula is:
4. there is an application for the amides of anti-tumor activity, it is characterized in that: take the medicine that general formula (I) compound or its isomer be active fraction preparation treatment, prevention or tumor remission.
5. by the application with the amides of anti-tumor activity claimed in claim 4, it is characterized in that: active constituents of medicine is the amides shown in one or more general formula Is.
6. by the application with the amides of anti-tumor activity claimed in claim 4, it is characterized in that: the weight percentage of described active ingredient is 0.5-99.5%.
7. by the application with the amides of anti-tumor activity claimed in claim 6, it is characterized in that: the weight percentage of described active ingredient is 60-99.5%.
8. by the application with the amides of anti-tumor activity claimed in claim 4, it is characterized in that: described in be applied to preparation treatment, prevention or alleviate in mammary cancer, cervical cancer, liver-cancer medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310713940.0A CN103755695B (en) | 2013-12-20 | 2013-12-20 | A kind of amides and application thereof with anti-tumor activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310713940.0A CN103755695B (en) | 2013-12-20 | 2013-12-20 | A kind of amides and application thereof with anti-tumor activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103755695A true CN103755695A (en) | 2014-04-30 |
| CN103755695B CN103755695B (en) | 2016-04-06 |
Family
ID=50523054
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310713940.0A Expired - Fee Related CN103755695B (en) | 2013-12-20 | 2013-12-20 | A kind of amides and application thereof with anti-tumor activity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103755695B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772374A (en) * | 2014-02-24 | 2014-05-07 | 陕西理工学院 | Novel heterocyclic compound and application thereof |
| CN104693182A (en) * | 2015-03-17 | 2015-06-10 | 陕西理工学院 | Amide compounds having antineoplastic activity and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005004818A2 (en) * | 2003-07-09 | 2005-01-20 | Imclone Systems Incorporated | Heterocyclic compounds and their use as anticancer agents |
| WO2012006475A1 (en) * | 2010-07-07 | 2012-01-12 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
| WO2012006473A1 (en) * | 2010-07-07 | 2012-01-12 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
-
2013
- 2013-12-20 CN CN201310713940.0A patent/CN103755695B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005004818A2 (en) * | 2003-07-09 | 2005-01-20 | Imclone Systems Incorporated | Heterocyclic compounds and their use as anticancer agents |
| WO2012006475A1 (en) * | 2010-07-07 | 2012-01-12 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
| WO2012006473A1 (en) * | 2010-07-07 | 2012-01-12 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772374A (en) * | 2014-02-24 | 2014-05-07 | 陕西理工学院 | Novel heterocyclic compound and application thereof |
| CN103772374B (en) * | 2014-02-24 | 2016-04-06 | 陕西理工学院 | A kind of heterocyclic compound and application thereof |
| CN104693182A (en) * | 2015-03-17 | 2015-06-10 | 陕西理工学院 | Amide compounds having antineoplastic activity and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103755695B (en) | 2016-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW200906834A (en) | Axl kinase inhibitors | |
| WO2023072188A1 (en) | Kras g12d inhibitors and use thereof in medicine | |
| CN101323591A (en) | 5- or 6-substited naphthoyl imines compounds and antineoplastic application | |
| CN104080455A (en) | Certain chemical entities, compositions, and methods | |
| ES2945573T3 (en) | Dioxazoline compound, preparation method and uses thereof | |
| KR20160048807A (en) | Combination of a mek inhibitor and an erk inhibitor for use in treatment of hyperproliferative diseases | |
| CN104341425A (en) | Deuterated acetylenic derivative, pharmaceutical composition and application thereof | |
| CN105143228A (en) | [1,2,4]triazol[4,3-a]pyridine derivate, preparation method therefor or medical application thereof | |
| CN105985323A (en) | Novel epidermal growth factor receptor inhibitor and application thereof | |
| WO2013032797A2 (en) | Oxetane 3,3-dicarboxamide compounds and methods of making and using same | |
| CN103755695B (en) | A kind of amides and application thereof with anti-tumor activity | |
| WO2024041589A1 (en) | Nitrogen-containing heterocyclic compound, preparation method therefor, intermediate thereof, and use thereof | |
| CN107531685A (en) | Compound with antitumor activity | |
| WO2013007172A1 (en) | Platinum compounds for treating cell proliferative disease, preparation methods and uses thereof | |
| CN111171018B (en) | Chalcone compound and application thereof | |
| CN107001617B (en) | PEG derivative | |
| CN104672213A (en) | Amide compound with antitumor activity, and application thereof | |
| US20190233415A1 (en) | N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2h-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-cyclopropanecarboxamide dimethyl sulfoxide solvate as an mek1/2 inhibitor | |
| CN112778217B (en) | Quinazoline compound and application thereof | |
| PT2699240E (en) | Acadesine derivatives, products and compositions including same, therapeutic uses thereof, and methods for synthesizing same | |
| CN103772374B (en) | A kind of heterocyclic compound and application thereof | |
| CN103429586A (en) | Piperazinedione compounds | |
| CN102002044A (en) | Purine-8-ketone and thiazolopyrimidine derivatives, and preparation method and medicinal application thereof | |
| CN103509024B (en) | Kui Linpyrimido quinoline benzazepine compounds and the application as antitumor drug thereof | |
| CN105541792A (en) | Polycyclic PI3K inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Jiang Min Inventor after: Lu Jiufu Inventor before: Lu Jiufu |
|
| COR | Change of bibliographic data | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160406 Termination date: 20161220 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |