CN104402785A - Novel bisamides derivative and preparation method and application thereof - Google Patents
Novel bisamides derivative and preparation method and application thereof Download PDFInfo
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- CN104402785A CN104402785A CN201410519816.5A CN201410519816A CN104402785A CN 104402785 A CN104402785 A CN 104402785A CN 201410519816 A CN201410519816 A CN 201410519816A CN 104402785 A CN104402785 A CN 104402785A
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Abstract
The invention relates to a novel bisamides derivative and a preparation method and an application thereof. A general formula of the novel bisamides derivative is shown as follows, and each group is shown in patent claims. The novel bisamides derivative has good antineoplastic activity, such as lung cancer, liver cancer and intestinal cancer. partial compound has higher in-vitro inhibition rate on three cancer cell bacterial strains than a control sample 5-fluorouracil, partial compound has in-vitro inhibition rate on lung adenocarcinoma (A549), liver cancer(Bel7402) and intestinal cancer (HCT-8) three cancer cell bacterial strains as high as more than 85%, and most compound has in-vitro inhibition rate on liver cancer (Bel7402) cell bacterial strain as high as more than 80%. The novel bisamides derivative can possibly be an antitumor drug.
Description
Technical field
The present invention relates to the preparation method and application of new compound, specifically novel bisamide analog derivative preparation method with as the application preparing antitumor drug.
Background technology
Tumour is a global problem of facing mankind, and the mortality ratio that this kind of fatal disease causes comes the first place causing human death's cause of disease.Current chemotherapy occupies very important status in solution malignant tumour problem.Such as directly act on the medicine of DNA: n-formyl sarcolysine (formylmerphalan), endoxan (cyclophophamide), carmustine (carmusrtin), camptothecin analogues etc.; Antimetabolic anti-tumor drug: 5 FU 5 fluorouracil (5-fluorouracil), Spongocytidine-hydrochloride (cytarabine hydrochloride) etc.; Antimitotic medicine and the medicine etc. based on tumor signal transduction mechanism.Scientific workers are devoted to the antitumor drug finding new high-efficiency always.In the prior art, there is not been reported in the application of the preparation of the bisamide analog derivative of novel structure and anti-tumor activity thereof as representative of the present invention.
Summary of the invention
The object of the present invention is to provide the synthetic method of the novel bisamide analog derivative shown in a kind of formula I and prepare inhibition tumor cell active in the application of medicine.
Bisamide derivatives provided by the invention has following general formula:
In formula: X is C or N.
R
1h, halogen, cyano group, nitro, amino, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group, C
1-C
6acyl group, halo C
1-C
6acyl group, C
1-C
6alkyl amido, halo C
1-C
6alkyl amido, C
1-C
6alkylamino, halo C
1-C
6alkylamino, C
1-C
6alkylthio, halo C
1-C
6alkylthio, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
6cycloalkyl, phenyl, chlorophenyl, phenoxy group, halogenated phenoxy, benzenesulfonyl, halobenzenelsulfonyl.
R
2c
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkylthio, halo C
1-C
6alkylthio, C
2-C
6alkene oxygen base, halo C
2-C
6alkene oxygen base, C
2-C
6alkynyloxy group, halo C
2-C
6alkynyloxy group, C
2-C
6alkanoyloxy or halo C
2-C
6alkanoyloxy, C
1-C
6alkyl-carbonyl, C
1-C
6alkoxy C
1-C
6alkyl, halo C
1-C
6alkoxy C
1-C
6alkyl, C
1-C
6alkylthio C
1-C
6alkyl or
M is 0,1 or 2; N is 0 or 1.
R
3h, cyano group, nitro, thiocyanogen, hydroxyl, guanidine radicals, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group, C
1-C
6alkyl acyl, halo C
1-C
6alkyl acyl, aminoalkyl group acyl group, aminothiocarbonyl, haloacetamido thiocarbonyl.
R
4h, cyano group, nitro, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group;
R
5h, cyano group, nitro, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group;
R
6h, cyano group, nitro, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group; R
7h, C
1-C
6alkyl.
R
7h, cyano group, nitro, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group; R
7h, C
1-C
6alkyl.
R
8h, C
1-C
6alkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, C
2-C
6cycloalkyl.
R
9h, C
1-C
6alkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, C
2-C
6cycloalkyl.
R
10haloacetyl, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group, C
2-C
6thiazolinyl, phenyl, phenoxy group, benzyl, benzamide, phenylamino, 5 or 6 yuan of heterocycle aromatic ring yls, naphthyl or aromatics 8,9 or 10 yuan of assorted bicyclic systems condensed, or each ring ring system optional by 1-5 separately independently substituting group replace, these substituting groups separately independence from halogen, cyano group, nitro, C
1-C
6alkyl acyl, halo C
1-C
6alkyl acyl, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group, C
2-C
6thiazolinyl, halo C
2-C
6thiazolinyl, alkyl sulfenyl, haloalkylthio, alkyl sulfuryl, haloalkyl sulfuryl, C
1-C
6alkoxy carbonyl, halo C
1-C
6alkoxy carbonyl, C
1-C
6alkyl amino-carbonyl, halo C
1-C
6alkyl amino-carbonyl, C
1-C
6alkyl sulphonyl, halo C
1-C
6alkyl sulphonyl.
In the definition of above-claimed cpd, no matter term used is used alone or is used in compound word, represent following substituting group:
Halogen is fluorine, chlorine, bromine or iodine; Alkyl is straight or branched alkyl; Haloalkyl is straight or branched alkyl, and the hydrogen atom on these alkyl can partly or entirely be replaced by halogen atom; Thiazolinyl is have the straight or branched of 2-6 carbon atom and can have double bond on any position; Alkynyl is have the straight or branched of 2-6 carbon atom and can have triple bond on any position; In five yuan or hexa-member heterocycle, heteroatoms is N, O and S.
Alternatively, X is C or N.
R
1h, halogen, cyano group, nitro, amino, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, cyclohexyl, chloromethyl, one chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, seven fluorine sec.-propyls, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy, propoxy-, ethanoyl, one chloracetyl, dichloro-acetyl, tribromo-acetyl base, acetyl bromide, formamido-, kharophen, chloro acetylamino, acetyl fluoride is amino, methylthio group, chloromethane sulfenyl, fluorine methylthio group, methylsulfonyl, halo methylsulfonyl.
R
2c
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkylthio, halo C
1-C
6alkylthio, C
2-C
6alkene oxygen base, halo C
2-C
6alkene oxygen base, C
2-C
6alkynyloxy group, halo C
2-C
6alkynyloxy group, C
2-C
6alkanoyloxy or halo C
2-C
6alkanoyloxy, C
1-C
6alkyl-carbonyl, C
1-C
6alkoxy C
1-C
6alkyl, halo C
1-C
6alkoxy C
1-C
6alkyl, C
1-C
6alkylthio C
1-C
6alkyl or
M is 0,1 or 2; N is 0 or 1.
R
3h, cyano group, nitro, thiocyanogen, hydroxyl, guanidine radicals, trifluoroacetyl group, trifluoroacetamido ethanoyl, aminothiocarbonyl.
R
4, R
5, R
6, R
7h, cyano group, nitro, methyl, ethyl, n-propyl, sec.-propyl, chloromethyl, a chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy.
R
8, R
9h, methyl.
R
10it is haloacetyl, methyl, ethyl, n-propyl, sec.-propyl, chloromethyl, one chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy, chlorovinyl, phenyl, phenoxy group, benzyl, benzamide, phenylamino, 5 or 6 yuan of heterocycle aromatic ring yls, 8,9 or 10 yuan of assorted bicyclic systems condensed of naphthyl or aromatics, or each ring ring system optional by 1-5 separately independently substituting group replace, these substituting groups separately independence from halogen, cyano group, nitro, methyl, ethyl, n-propyl, sec.-propyl, chloromethyl, one chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group, seven fluorine sec.-propyls, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy, chlorovinyl, methylthio group, chloromethane sulfenyl, methylsulfonyl, chloromethane sulfuryl, ethanoyl, one chloracetyl, dichloro-acetyl, tribromo-acetyl base, acetyl bromide, amino-carbonyl, chloromethane aminocarboxyl, methoxycarbonyl, chloromethVloxvcarbonyl, formamido-, chloroformyl amido, methanoyl, chloromethane acyloxy, methylsulfonyl, chloromethanesulfonyl.
More preferably, X is C and N.
R
1h, halogen, CN, NO
2, NH
2, kharophen, a chloro acetylamino, dichloro acetamino.
R
2c
1-C
6alkyl, halo C
1-C
6alkyl or
r
3cyano group, trifluoroacetyl group, glycyl, trifluoroacetamido ethanoyl, kharophen ethanoyl.
R
8, R
9h, methyl.
R
10it is substituted-phenyl; ring by 1-5 separately independently substituting group replace, these substituting groups separately independence from halogen, cyano group, nitro, methyl, ethyl, n-propyl, sec.-propyl, a chloroethyl, methoxyl group, chlorine methoxyl group, oxyethyl group, fluorine oxyethyl group, a chloracetyl, dichloro-acetyl, tribromo-acetyl base, acetyl bromide, amino-carbonyl, chloromethane aminocarboxyl, methoxycarbonyl, chloromethVloxvcarbonyl.
The step that bisamide derivatives preparation method provided by the invention comprises:
Bisamide derivatives (I) synthetic method one:
Compounds of formula II and compound of formula III, mol ratio 1: 1, be dissolved in organic solvent, then organic bases is added, at room temperature react 0.5-48 hour, then add appropriate amount of acid acidifying and obtain compound IV, directly next step adds organic solvent, then organic bases and Methanesulfonyl chloride is added, the mol ratio of Methanesulfonyl chloride and compound IV is 1: 1, at temperature less than 10 DEG C reaction 0.5-3 hour, obtained compound V, the compound VI of monovalent is joined in a upper reaction system, then appropriate organic bases is added, 0.5-48 hour obtained target compound VII is reacted under temperature is for-10 DEG C to boiling point, compound VI I is dissolved in the organic solvent containing organic bases under condition of ice bath, then adds compound VI II, reacts 3-24h and obtain target compound I under 0 DEG C to room temperature condition, in reaction formula, each group is as shown in claim 1.
Described organic solvent is selected from methylene dichloride, chloroform, tetracol phenixin, benzene,toluene,xylene, normal hexane, hexanaphthene, ethyl acetate, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF or dimethyl sulfoxide (DMSO).
Described acid is selected from: methylsulphonic acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid, acetic acid, phosphoric acid ester, or hydrochloric acid, sulfuric acid or phosphoric acid;
Described alkali is selected from organic bases: triethylamine, pyridine, 1,8-diaza-dicyclo (5,4,0) 11 carbon-7-alkene or DMA;
Bisamide derivatives (I) synthetic method two:
Compounds of formula II and compound of formula VI, mol ratio is 1: 1, is dissolved in acetic acid, reacts 0.5-12 hour obtained target compound IX at the boiling point; Formula IX compound and compound of formula III, mol ratio is 1: 1, is dissolved in organic solvent, then adds appropriate acid or alkali, under temperature is for-10 DEG C to boiling point, react 0.5-48 hour obtained compounds X.Compounds X is dissolved in the organic solvent containing organic bases under condition of ice bath, then adds compounds X I, reacts 3-24h and obtain target compound I under 0 DEG C to room temperature condition; In reaction formula, each group is as shown in claim 1; R
2except, R
2for C
1-C
5direct-connected alkyl or haloalkyl.
Described organic solvent is selected from methylene dichloride, chloroform, tetracol phenixin, benzene,toluene,xylene, normal hexane, hexanaphthene, ethyl acetate, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF or dimethyl sulfoxide (DMSO).
Described acid is selected from: methylsulphonic acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid, acetic acid, phosphoric acid ester, or hydrochloric acid, sulfuric acid or phosphoric acid.
Described alkali is selected from organic bases: triethylamine, pyridine, 1,8-diaza-dicyclo (5,4,0) 11 carbon-7-alkene or DMA; Or mineral alkali: sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium methylate, sodium tert-butoxide or potassium tert.-butoxide;
The present invention also comprises compound of Formula I pharmacy acceptable salt.
The present invention also provides a kind of pharmaceutical composition, at least comprises a kind of pharmaceutically acceptable carrier and formula I or its solvate.
The present invention also provides formula I or the application of its solvate pharmaceutical composition at preparation antitumor (such as: human lung carcinoma cell, human hepatocellular carcinoma cell, ileocecum cancer cells) medicine aspect.Application particularly in preparation treatment solid tumor drugs, the formulation of medicine comprises injection, oral acceptable preparation, using topical preparations, sprays or drops.
Bisamide analog derivative of the present invention, has good anti-tumor activity.Particularly pass through human lung adenocarcinoma (A549), liver cancer (Bel7402) and intestinal cancer (HCT-8) three kinds of cancer cells bacterial strain body outer suppressioning tests, confirm that bisamide derivatives of the present invention has good anti-tumor activity, part of compounds to the extracorporeal inhibiting rate of three kinds of cancer cells bacterial strains all higher than control sample 5 FU 5 fluorouracil, part of compounds is to adenocarcinoma of lung (A549), the extracorporeal inhibiting rate of liver cancer (Bel7402) and intestinal cancer (HCT-8) three kinds of cancer cells bacterial strains is higher than 85%, the extracorporeal inhibiting rate of majority of compounds liver cancer (Bel7402) cell strain is higher than 80%.
Novel benzene bisamide derivatives of the present invention has significant cytotoxic activity to tumour cell, is expected to become antitumor drug.
Embodiment
Further illustrate the present invention below in conjunction with embodiment, its objective is that can better understand content of the present invention is embody substantive distinguishing features of the present invention, therefore the cited case should not be considered as limiting the scope of the invention.
The experimental technique of unreceipted actual conditions in embodiment, usually conveniently condition and the condition described in handbook, or according to the condition that manufacturer advises; Equipment used, material, reagent etc., if no special instructions, all can obtain from commercial channels.
Embodiment 1
N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2the synthesis of-(2-methyl isophthalic acid-(1-thiomethyl)-2-propyl group) phthalic diamide (derivative 01):
Steps A: preparation 2-iodo-6-carboxy-N-(1,1-dimethyl-2-methylmercaptoethyl) benzamide
The mixing of 3-iodo Tetra hydro Phthalic anhydride (2.74g), 1-methylthio group-2-methyl-2-amino propane (1.19g) and triethylamine (1.00g) is dissolved in q. s. methylene chloride.Reaction mixture stirring reaction 12h, aftertreatment obtains the iodo-6-carboxy-N of yellow solid 2--(1,1-dimethyl-2-methylmercaptoethyl) benzamide.Yield 75%, m.p.127-128 DEG C.
Step B: preparation N-ethanoyl-2-aminotoluene.
2-aminotoluene (5.1g), triethylamine (10.1g) and Acetyl Chloride 98Min. (3.9g) are dissolved in q. s. methylene chloride, stirred at ambient temperature 2h.Aftertreatment obtains N-ethanoyl-2-aminotoluene .Yield 95%, m.p.108-109 DEG C.
Step C: preparation N-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) ethanamide
N-ethanoyl-2-aminotoluene (2.98g), Acetyl Chloride 98Min. (3.12g), aluminum chloride (8.54g) are dissolved in 1,2-ethylene dichloride.Mixture heated and stirred 24 hours.Aftertreatment obtains light yellow solid.Productive rate 78%, m.p.157-158 DEG C.
Step D: preparation 2-methyl-5-dichloro-acetyl aniline
N-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) ethanamide (1.1g) and dilute hydrochloric acid be dissolved in methyl alcohol, be heated to back flow reaction 8h.When aftertreatment obtains yellow solid 2-methyl-5-dichloro-acetyl aniline.Productive rate 95%, m.p.70-71 DEG C.
Step e: preparation N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(1-thiomethyl)-2-propyl group) phthalic diamide
The iodo-6-carboxy-N-(1 of 2-; 1-dimethyl-2-methylmercaptoethyl) benzamide (1.97g), triethylamine (0.50g) be dissolved in dichloromethane solution; temperature less than 5 DEG C is kept to drip the dichloromethane solution being dissolved with methylsulfonyl chloride (0.57g); reaction mixture stirring reaction in ice bath is complete; then the dichloromethane solution being dissolved with 2-methyl-5-dichloro-acetyl aniline (1.09g) is slowly dripped; stirring at room temperature is reacted; aftertreatment obtains white solid stirring-(4-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) iodo-N of-3-
2-(2-methyl isophthalic acid-(1 thiomethyl) propane-2-base) phthalic diamide.
Embodiment two:
N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2the synthesis of-(2-methyl isophthalic acid-(1-methylsulfonyl)-2-propyl group) phthalic diamide (derivative 02):
By N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(1-thiomethyl)-2-propyl group) phthalic diamide (0.30g), metachloroperbenzoic acid (0.17g) are dissolved in tetrahydrofuran (THF), and stirred at ambient temperature, aftertreatment obtains white end product N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(1-methylsulfonyl)-2-propyl group) phthalic diamide.
Embodiment three:
N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2the synthesis of-(2-methyl isophthalic acid-(1-(N-aminocarboxyl thiocarbonyl) methylthio group)-2-propyl group) phthalic diamide (derivative 03):
Under ice bath, by N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(1-thiomethyl)-2-propyl group) phthalic diamide (0.30g), acetic acid phenyl-iodide (0.134g), cyanogen ammonia (0.1g, 1.5mmol) is dissolved in tetrahydrofuran (THF), be warming up to stirring at room temperature, aftertreatment obtains white solid N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(1-(N-aminocarboxyl thiocarbonyl) methylthio group)-2-propyl group) phthalic diamide.
Embodiment four:
N
1the iodo-N of-(4-cyano-phenyl)-3-
2-(2-methyl isophthalic acid-(1-methylthio group)-2-propyl group) phthalic diamide (compound 35)
Steps A: preparation 4-p-nitrile
4-nitrobenzaldehyde (7.56g), 300mL ammoniacal liquor and elemental iodine (13.9g) are dissolved in tetrahydrofuran (THF), stirred at ambient temperature, and aftertreatment obtains white solid 4-p-nitrile, yield 75%, m.p.115-116 DEG C.
Step B: preparation 4-cyano-aniline
4-p-nitrile (2.16g) and 0.216g palladium carbon are dissolved in methyl alcohol, then pass into hydrogen, stirred at ambient temperature.Aftertreatment obtains light yellow solid 4-cyano-aniline, productive rate 85%, m.p.75-76 DEG C.
Step C: preparation N
1the iodo-N of-(4-cyano-phenyl)-3-
2-(2-methyl isophthalic acid-(1-methylthio group)-2-propyl group) phthalic diamide
The iodo-6-carboxy-N-(1 of 2-, 1-dimethyl-2-methylmercaptoethyl) benzamide (1.97g), triethylamine (0.50g) be dissolved in dichloromethane solution, keep temperature less than 5 DEG C to drip and be dissolved with methylsulfonyl chloride (0.57g), add 4-cyano-aniline (0.59g) after reacting completely, stirring at room temperature aftertreatment obtains white solid N
1the iodo-N of-(4-cyano-phenyl)-3-
2-(2-methyl isophthalic acid-(1-methylthio group)-2-propyl group) phthalic diamide.
Embodiment five: N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-chloroethyl) phthalic diamide (derivative 421)
Steps A: preparation 2-iodo-6-carboxy-N-(2-chloroethyl) benzamide
3-iodo Tetra hydro Phthalic anhydride (2.74g), 2-chloroethyl amine hydrochloride (1.39g) and triethylamine (2.40g, 24mmol) be dissolved in dichloromethane solution, mixture stirring reaction 12h, aftertreatment obtains the iodo-6-carboxy-N of white solid 2--(2-chloroethyl) benzamide, yield 76%.
Step B: preparation N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-chloroethyl) phthalic diamide
2-iodo-6-carboxyl N-(1; 1-dimethyl-2-methylmercaptoethyl) benzamide (1.97g), triethylamine (0.50g) be dissolved in dichloromethane solution; keep temperature less than 5 DEG C to drip and be dissolved with methylsulfonyl chloride (0.57g); mixture reacts completely in ice bath; then 2-methyl-5-dichloro-acetyl aniline (1.09g) is added; stirring at room temperature is reacted, and aftertreatment obtains white solid N
1-(5-(2,2-dichloro-acetyl)-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-chloroethyl) phthalic diamide.
This analog derivative 01 ~ 508 now adopting different raw materials to prepare according to the preparation method of embodiment 1 ~ 5, lists table 1a ~ 1c in, partial derivatives
1h NMR (Bruker AV400 spectrometer using tetramethylsilane as the internalstandard) data list table 2 in.
Part of compounds structural formula of the present invention is as follows:
Table 1a
Table 1b
Table 1c
Table 2
Embodiment six: the anti-tumor activity of phthalic diamides derivative provided by the invention
1) anti-tumor activity experimental principle
Tetrazole [MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] is a kind of dyestuff that can accept hydrogen atom.The MTT of yellow can be changed into insoluble hepatic formazon by desaturase relevant to NADP in viable cell plastosome in cell, and dead cell is then without this function.After dissolving formazon with DMSO, under certain wavelength, measure optical density value by microplate reader, both quantitatively can measure the survival rate of cell.
2) anti-tumor activity experimental technique
A experiment material: A549 (human lung carcinoma cell), BEL-7402 (human hepatocellular carcinoma cell), HCT-8 (ileocecum cancer cells), 5-Fu (5 FU 5 fluorouracil), 1640 substratum (A549, HCT-8), MEM substratum (BEL7402), foetal calf serum, tetrazolium bromide (MTT), dimethyl sulfoxide (DMSO) (DMSO), physiological saline, 96 porocyte culture plates (Costar), water-jacket typ CO
2cell culture incubator (Sanyo, Japan), M5 micropore plate reading machine (MD, the U.S.).
B: testing sequence
A. the adherent A549 (human lung carcinoma cell) of logarithmic phase is selected, BEL-7402 (human hepatocellular carcinoma cell), HCT-8 (ileocecum cancer cells) three kinds of tumour cells (institute of Materia Medica,Chinese Academy of Medical Sciences national drug screening centrocyte storehouse provides), respectively with after trysinization, the cell suspension of 15000/ml is made into the RPMI1640 nutrient solution of 10% calf serum, be seeded in 96 well culture plates, 190 μ l are inoculated in every hole, 37 DEG C, 5%CO
2cultivate 24h.
B. experimental group adds sample 10 μ l, and every hole final volume is 200 μ l, supplies with RPMI-1640.37 DEG C, 5%CO
2cultivate 3d.
C. abandon supernatant liquor, every hole adds the serum-free medium of the freshly prepared 0.5mg/ml MTT of 100 μ l, and 37 DEG C are continued to cultivate 4h.Carefully abandon supernatant, and add 150 μ l DMSO dissolving MTT formazon precipitations, with microoscillator mixing, microplate reader measures the optical density value at wavelength 544nm place.
3) anti-tumor activity experimental technique
A. cell inhibitory rate calculates
Growth of tumour cell inhibiting rate (%)=(OD contrasts-OD experiment)/(it is blank that OD contrasts-OD) X 100%
Positive judgement criteria: inhibiting rate is greater than 50%.
B.IC
50value calculates
Style log concentration value and cell inhibitory rate linear regression, utilize software (GWBASIC software) to calculate the half-inhibition concentration IC of sample for cell
50value.
By the test of cell in vitro poison, obtain following result:
The cell inhibitory rate of table 3 part of compounds under the concentration of 5 μ g/mL
Inhibiting rate grade in table: A level is > 50%, B level be 50% ~ 20%, C level is < 20%.
Part of compounds activity exceedes contrast medicine 5 FU 5 fluorouracil (5-fu) and is exemplified below table 5:
The IC of table 4 compound 01 and 02 couple of BEL-7402, HCT-8 and A549
50value
Most of bisamide analog derivative of the present invention is at the concentration tested to A549 (human lung carcinoma cell) as can be seen from Table 3, BEL-7402 (human hepatocellular carcinoma cell), HCT-8 (ileocecum cancer cells) three kinds of tumour cells have extraordinary inhibition, the inhibiting rate of major part derivative all exceedes control sample 5-fu (5 FU 5 fluorouracil), the compound 01 tested as can be seen from Table 4 and the part IC of compound 02
50value is all less than control sample 5-fu (5 FU 5 fluorouracil).Therefore, novel bisamide derivatives of the present invention has good anti-tumor activity.
Claims (10)
1. a class bisamide derivatives (I), is characterized in that having following structural formula:
In formula: X is C or N;
R
1h, halogen, cyano group, nitro, amino, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group, C
1-C
6acyl group, halo C
1-C
6acyl group, C
1-C
6alkyl amido, halo C
1-C
6alkyl amido, C
1-C
6alkylamino, halo C
1-C
6alkylamino, C
1-C
6alkylthio, halo C
1-C
6alkylthio, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
3-C
6cycloalkyl, phenyl, chlorophenyl, phenoxy group, halogenated phenoxy, benzenesulfonyl, halobenzenelsulfonyl;
R
2c
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkylthio, halo C
1-C
6alkylthio, C
2-C
6alkene oxygen base, halo C
2-C
6alkene oxygen base, C
2-C
6alkynyloxy group, halo C
2-C
6alkynyloxy group, C
2-C
6alkanoyloxy or halo C
2-C
6alkanoyloxy, C
1-C
6alkyl-carbonyl, C
1-C
6alkoxy C
1-C
6alkyl, halo C
1-C
6alkoxy C
1-C
6alkyl, C
1-C
6alkylthio C
1-C
6alkyl or
M is 0,1 or 2;
N is 0 or 1;
R
3h, cyano group, nitro, thiocyanogen, hydroxyl, guanidine radicals, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group, C
1-C
6alkyl acyl, halo C
1-C
6alkyl acyl, aminoalkyl group acyl group, aminothiocarbonyl, haloacetamido thiocarbonyl;
R
4h, cyano group, nitro, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group;
R
5h, cyano group, nitro, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group;
R
6h, cyano group, nitro, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group; R
7h, C
1-C
6alkyl;
R
7h, cyano group, nitro, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group;
R
8h, C
1-C
6alkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, C
2-C
6cycloalkyl;
R
9h, C
1-C
6alkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, C
2-C
6cycloalkyl;
R
10haloacetyl, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group, C
2-C
6thiazolinyl, phenyl, phenoxy group, benzyl, benzamide, phenylamino, 5 or 6 yuan of heterocycle aromatic ring yls, naphthyl or aromatics 8,9 or 10 yuan of assorted bicyclic systems condensed, each ring or ring system optional by 1-5 separately independently substituting group replace, these substituting groups separately independence from halogen, cyano group, nitro, C
1-C
6alkyl acyl, halo C
1-C
6alkyl acyl, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkoxyl group, C
2-C
6thiazolinyl, halo C
2-C
6thiazolinyl, alkyl sulfenyl, haloalkylthio, alkyl sulfuryl, haloalkyl sulfuryl, C
1-C
6alkoxy carbonyl, halo C
1-C
6alkoxy carbonyl, C
1-C
6alkyl amino-carbonyl, halo C
1-C
6alkyl amino-carbonyl, C
1-C
6alkyl sulphonyl, halo C
1-C
6alkyl sulphonyl,
In the definition of above-claimed cpd, no matter term used is used alone or is used in compound word, represent following substituting group:
Halogen is fluorine, chlorine, bromine or iodine;
Alkyl is straight or branched alkyl;
Haloalkyl is straight or branched alkyl, and the hydrogen atom on these alkyl can partly or entirely be replaced by halogen atom;
Thiazolinyl is have the straight or branched of 2-6 carbon atom and can have double bond on any position;
Alkynyl is have the straight or branched of 2-6 carbon atom and can have triple bond on any position;
In five yuan or hexa-member heterocycle, heteroatoms is N, O and S.
2. bisamide derivatives according to claim 1, is characterized in that:
X is C or N;
R
1h, halogen, cyano group, nitro, amino, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, cyclohexyl, chloromethyl, one chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, seven fluorine sec.-propyls, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy, propoxy-, ethanoyl, one chloracetyl, dichloro-acetyl, tribromo-acetyl base, acetyl bromide, formamido-, kharophen, chloro acetylamino, acetyl fluoride is amino, methylthio group, chloromethane sulfenyl, fluorine methylthio group, methylsulfonyl, halo methylsulfonyl,
R
2c
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkylthio, halo C
1-C
6alkylthio, C
2-C
6alkene oxygen base, halo C
2-C
6alkene oxygen base, C
2-C
6alkynyloxy group, halo C
2-C
6alkynyloxy group, C
2-C
6alkanoyloxy or halo C
2-C
6alkanoyloxy, C
1-C
6alkyl-carbonyl, C
1-C
6alkoxy C
1-C
6alkyl, halo C
1-C
6alkoxy C
1-C
6alkyl, C
1-C
6alkylthio C
1-C
6alkyl or
M is 0,1 or 2;
N is 0 or 1;
R
3h, cyano group, nitro, thiocyanogen, hydroxyl, guanidine radicals, trifluoroacetyl group, trifluoroacetamido ethanoyl, aminothiocarbonyl;
R
4, R
5, R
6, R
7h, cyano group, nitro, methyl, ethyl, n-propyl, sec.-propyl, chloromethyl, a chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy;
R
8, R
9h, methyl;
R
10it is haloacetyl, methyl, ethyl, n-propyl, sec.-propyl, chloromethyl, one chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy, chlorovinyl, phenyl, phenoxy group, benzyl, benzamide, phenylamino, 5 or 6 yuan of heterocycle aromatic ring yls, 8,9 or 10 yuan of assorted bicyclic systems condensed of naphthyl or aromatics, or each ring ring system optional by 1-5 separately independently substituting group replace, these substituting groups separately independence from halogen, cyano group, nitro, methyl, ethyl, n-propyl, sec.-propyl, chloromethyl, one chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group, seven fluorine sec.-propyls, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy, chlorovinyl, methylthio group, chloromethane sulfenyl, methylsulfonyl, chloromethane sulfuryl, ethanoyl, one chloracetyl, dichloro-acetyl, tribromo-acetyl base, acetyl bromide, amino-carbonyl, chloromethane aminocarboxyl, methoxycarbonyl, chloromethVloxvcarbonyl, formamido-, chloroformyl amido, methanoyl, chloromethane acyloxy, methylsulfonyl, chloromethanesulfonyl.
3. bisamide derivatives according to claim 1, is characterized in that:
X is C and N
R
1h, halogen, CN, NO
2, NH
2, kharophen, a chloro acetylamino, dichloro acetamino;
R
2c
1-C
6alkyl, halo C
1-C
6alkyl or
r
3cyano group, trifluoroacetyl group, glycyl, trifluoroacetamido ethanoyl, kharophen ethanoyl;
R
8, R
9h, methyl;
R
10it is substituted-phenyl; ring by 1-5 separately independently substituting group replace, these substituting groups separately independence from halogen, cyano group, nitro, methyl, ethyl, n-propyl, sec.-propyl, a chloroethyl, methoxyl group, chlorine methoxyl group, oxyethyl group, fluorine oxyethyl group, a chloracetyl, dichloro-acetyl, tribromo-acetyl base, acetyl bromide, amino-carbonyl, chloromethane aminocarboxyl, methoxycarbonyl, chloromethVloxvcarbonyl.
4. bisamide derivatives according to claim 1, is characterized in that they are compounds of following synthesis:
Compound 1:N
1-(5-chloracetyl-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(methylthio group)-2-propyl group) phthalic diamide;
Compound 2:N
1-(5-dichloro-acetyl-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(methylthio group)-2-propyl group) phthalic diamide;
Compound 3:N
1-(5-dichloro-acetyl-2-aminomethyl phenyl)-3-nitro-N
2-(2-methyl isophthalic acid-(methylthio group)-2-propyl group) phthalic diamide;
Compound 4:N
1-(5-dichloro-acetyl-2-aminomethyl phenyl)-3-nitro-N
2-(2-methyl isophthalic acid-(methylsulfonyl)-2-propyl group) phthalic diamide;
Compound 5:N
1-(5-dichloro-acetyl-2-aminomethyl phenyl)-N
2the adjacent pyridine diformamide of-(2-methyl isophthalic acid-(methylthio group)-2-propyl group);
Compound 6:N
1-(5-dichloro-acetyl-2-aminomethyl phenyl)-N
2the adjacent pyridine diformamide of-(2-methyl isophthalic acid-(methylsulfonyl)-2-propyl group);
Compound 7:N
1-(5-dichloro-acetyl-2,6-3,5-dimethylphenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(methylthio group)-2-propyl group) phthalic diamide;
Compound 8:N
1-(5-dichloro-acetyl-2,6-3,5-dimethylphenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(methylsulfonyl)-2-propyl group) phthalic diamide;
Compound 9:N
1-(4-dichloro-acetyl phenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(methylthio group)-2-propyl group) phthalic diamide;
Compound 10:N
1-(4-dichloro-acetyl phenyl) the iodo-N of-3-
2-(2-methyl isophthalic acid-(methylsulfonyl)-2-propyl group) phthalic diamide;
Compound 11:N
1-(5-dichloro-acetyl-2-aminomethyl phenyl) the iodo-N of-3-
2-(2-chloroethyl) phthalic diamide;
Compound 12:N
1-(5-dichloro-acetyl-2-aminomethyl phenyl)-3-nitro-N
2-(2-chloroethyl) phthalic diamide.
5. the preparation method of bisamide derivatives according to claim 1, is characterized in that comprising following step:
Bisamide derivatives (I) synthetic method one:
Compounds of formula II and compound of formula III, mol ratio 1: 1, be dissolved in organic solvent, then organic bases is added, at room temperature react 0.5-48 hour, then add appropriate amount of acid acidifying and obtain compound IV, directly next step adds organic solvent, then organic bases and Methanesulfonyl chloride is added, the mol ratio of Methanesulfonyl chloride and compound IV is 1: 1, at temperature less than 10 DEG C reaction 0.5-3 hour, obtained compound V, the compound vI of monovalent is joined in a upper reaction system, then appropriate organic bases is added, 0.5-48 hour obtained target compound VII is reacted under temperature is for-10 DEG C to boiling point, compound VI I is dissolved in the organic solvent containing organic bases under condition of ice bath, then adds compound VI II, reacts 3-24h and obtain target compound I under 0 DEG C to room temperature condition, in reaction formula, each group is as shown in claim 1.
Bisamide derivatives (I) synthetic method two:
Compounds of formula II and compound of formula VI, mol ratio is 1: 1, is dissolved in acetic acid, reacts 0.5 at the boiling point
-12 hours obtained target compound IX; Formula IX compound and compound of formula III, mol ratio is 1: 1, is dissolved in organic solvent, then adds appropriate acid or alkali, under temperature is for-10 DEG C to boiling point, react 0.5-48 hour obtained compounds X.Compounds X is dissolved in the organic solvent containing organic bases under condition of ice bath, then adds compounds X I, reacts 3-24h and obtain target compound I under 0 DEG C to room temperature condition; In reaction formula, each group is as shown in claim 1; R
2except, R
2for C
1-C
5direct-connected alkyl or haloalkyl; Described organic solvent is selected from methylene dichloride, chloroform, tetracol phenixin, benzene,toluene,xylene, normal hexane, hexanaphthene, ethyl acetate, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF or dimethyl sulfoxide (DMSO); Described acid is selected from: methylsulphonic acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid, acetic acid, phosphoric acid ester, or hydrochloric acid, sulfuric acid or phosphoric acid.
6. preparation method according to claim 5, is characterized in that described alkali is selected from organic bases: triethylamine, pyridine, 1,8-diaza-dicyclo (5,4,0) 11 carbon-7-alkene or DMA; Or mineral alkali: sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium methylate, sodium tert-butoxide or potassium tert.-butoxide; Described oxygenant is potassium permanganate, m-CPBA, NaClO
2, NaIO
4/ RuO
2, H
2o
2or ozone.
7. the arbitrary described bisamide derivatives of claim 1-4 and new intermediate thereof are preparing the application in antitumor drug.
8. their mixture of the arbitrary described bisamide derivatives of claim 1-4 or its pharmacy acceptable salt or its positional isomers, steric isomer, optical isomer, cis-trans-isomer or any ratio is preparing the application in antitumor drug, comprise lung cancer, liver cancer or intestinal cancer.
9. a pharmaceutical composition, comprises the pharmaceutically acceptable carrier of at least one and formula I or its solvate as defined in claim 1.
10. pharmaceutical composition according to claim 9 is preparing the application in antitumor drug.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109020934A (en) * | 2018-07-30 | 2018-12-18 | 绍兴贝斯美化工股份有限公司 | The preparation method of intermediate containing halogenated benzene ring side chain fipronil bisamide structure |
| CN109574892A (en) * | 2018-11-29 | 2019-04-05 | 常州沃腾化工科技有限公司 | Microchannel plate should prepare the iodo- N-(1,1- dimethyl -2-methylmercaptoethyl of 3-) method of phthalamic acid |
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| CN101087601A (en) * | 2004-08-02 | 2007-12-12 | 根梅迪卡治疗公司 | Compounds for inhibiting copper-containing amine oxidases and uses thereof |
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