CN102503930B - 3, 4, 5-tri-substituted aminothiopene chemical compound and preparation and application thereof - Google Patents
3, 4, 5-tri-substituted aminothiopene chemical compound and preparation and application thereof Download PDFInfo
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- CN102503930B CN102503930B CN201110335127.5A CN201110335127A CN102503930B CN 102503930 B CN102503930 B CN 102503930B CN 201110335127 A CN201110335127 A CN 201110335127A CN 102503930 B CN102503930 B CN 102503930B
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- -1 aminothiophene compound Chemical class 0.000 claims description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明提供一类3,4,5,-三取代氨基噻吩类化合物，以取代苯为原料，经傅克酰基化反应、Knoevenagel缩合、环合反应、水解反应和缩合反应得3,4,5,-三取代氨基噻吩衍生物。本发明提供的化合物及其盐，经药理实验证实对阻断p53-MDM2相互作用具有明显功效，并对肿瘤细胞有显著的体外增殖抑制活性，IC50达到μM级。本发明设计合理，所用原料来源广泛，制备方法简便，反应条件温和，各步收率高，适于实用，可在制备抗肿瘤药物中应用；本发明结构通式为：。The invention provides a class of 3,4,5,-trisubstituted aminothiophene compounds, which use substituted benzene as a raw material to obtain 3,4,5 ,-Trisubstituted aminothiophene derivatives. The compounds and their salts provided by the present invention have been proved by pharmacological experiments to have obvious effects on blocking p53-MDM2 interaction, and have significant in vitro proliferation inhibitory activity on tumor cells, with IC 50 reaching μM level. The invention has reasonable design, wide sources of raw materials, simple and convenient preparation method, mild reaction conditions, high yield in each step, is suitable for practical use, and can be used in the preparation of antitumor drugs; the general structural formula of the invention is: .
Description
Technical field
The invention belongs to the synthetic of organic compound, relate to a class 3,4,5, the preparation method of-trisubstituted-amino thiophenes, and in the application of preparing in antitumor drug.
Background technology
Along with the continuous increase of population in the world and the continuous intensification of aging population trend, simultaneously also because the extensive existence of the various unhealthy life styles including smoking, tumour has become developed country and has threatened the No.1 killer of human health and developing country to threaten No. second killer (Jemal of human health, et al., CA-Cancer J.Clin.2011,61,69-90).Traditional chemotherapeutic agent greatly, easily produces the shortcomings such as resistance as the ubiquity such as alkylating agent, metabolic antagonist toxic side effect, and for the key protein in signal path or kinases and the antitumor drug designing is just obtained challenging effect at therapeutic field of tumor.
P53 has played keying action as an important tumor-inhibiting factor in the process that stops cancer development.P53 is mainly by cell-cycle arrest and impel two aspects of apoptosis to bring into play its function.Over nearly more than 20 years, many experimental results show that blocking-up p53-MDM2(p53 main negative regulator) interaction can effectively reactivate the p53 in tumour cell, thereby reach the effect of killing tumour cell.Past 10 years, the micromolecular compound of many structure species is found to have and suppresses the interactional activity of p53-MDM2 and have antitumour activity in various degree, and existing two compounds have entered clinical study, this has verified the validity (Wang of this therapeutic strategy more, et al., Medicinal Research Reviews.DOI10.1002/med.20236).This seminar has designed and synthesized the interactional micromolecular inhibitor of a series of brand-new p53-MDM2, with 3,4,5-trisubstituted-amino thiophenes is as its constructional feature, and this compounds carried out to the antitumor activity of protein level and cell levels.Result shows that this compounds has the interactional activity of obvious blocking-up p53-MDM2 and cell increment suppresses active, is promising p53-MDM2 interaction inhibitor, for the research of cancer treatment drugs provides new thinking.
Summary of the invention
The object of this invention is to provide 3,4,5 of a class formation novelty ,-trisubstituted-amino thiophenes and salt thereof, have following general structure A:
Wherein:
R
1be selected from hydrogen atom, chlorine atom or nitro;
R
2be selected from chlorine atom or bromine atoms;
R
3be selected from methoxyl group, oxyethyl group, anilino, benzamido group, cyclopropyl amino, cyclohexylamino, 4-hydroxyl-cyclohexylamino, pyrrolidine ring, morpholine ring, piperidine ring, 4-methyl piperidine ring, piperazine ring, 4-methylpiperazine ring, 2-piperidone ring, one in 4-piperidone ring or 2,4-, bis-piperidone rings.
Another object of the present invention is to provide 3,4,5, and the preparation method of-trisubstituted-amino thiophenes realizes by following steps:
(1) Compound I (can directly buy) obtains intermediate acylate II through Lewis acid (Lewis) catalysis with substituted benzene in inert solvent; this reaction is conventionally taking ether, dioxane, methylene dichloride, chloroform etc. as solvent, and Lewis acid used has iron(ic) chloride, zinc chloride, aluminum chloride, tin chloride, boron trifluoride diethyl etherate etc.Temperature of reaction is-15 DEG C-25 DEG C, reaction times 8-12 hour, and products therefrom II can obtain sterling through recrystallization;
(2) Compound I I can obtain compound III with methyl-cyanacetate condensation under acidity or alkaline condition, after aftertreatment, can be directly used in next step reaction without purifying.Reaction is carried out in as tetrahydrofuran (THF) (THF) at medium polar solvent conventionally, conventional alkali has diethylamine, triethylamine, diisopropylethylamine etc., conventional acid has titanium tetrachloride, tin chloride, boron trifluoride diethyl etherate etc., temperature of reaction can be carried out between 0 DEG C-50 DEG C, and the reaction times is 12-24 hour, products therefrom is the mixture of Z formula and E formula, can be directly used in next step reaction without separating;
(3) compound III obtains compound IV with the cyclization of sulphur powder under alkaline condition, reaction is carried out conventionally in polar aprotic solvent, as acetone and THF etc., conventional alkali has diethylamine, triethylamine, diisopropylethylamine etc., temperature of reaction is 0 DEG C-50 DEG C, and products therefrom can obtain sterling through recrystallization;
(4) compound IV is hydrolyzed to obtain compound V under alkaline condition, and reaction is carried out in polar solvent, and as methyl alcohol, ethanol and dioxane etc., conventional alkali has potassium hydroxide, sodium hydroxide and lithium hydroxide etc.Reaction can be carried out between 40 DEG C-80 DEG C, obtains crude product and can obtain sterling by recrystallization;
(5) compound V reacts to obtain target product VI under condensation reagent effect with aminated compounds, conventional condensation reagent has DCC (dicyclohexylcarbodiimide)/DMAP (DMAP), EDCI(N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride)/HOBt(1-hydroxy benzo triazole), HCTU(6-Chloro-Benzotriazole-1,1,3,3-tetramethyl-urea phosphofluoric acid ester) etc., temperature of reaction is 20 DEG C-60 DEG C, reaction times is 12-24 hour, and thick product can obtain sterling through column chromatography.Aminated compounds is selected aniline, benzylamine, cyclopropylamine, hexahydroaniline, 4-hydroxyl-hexahydroaniline, tetramethyleneimine, morpholine, piperidines, 4-methyl piperidine, piperazine, 4-methylpiperazine, 2-piperidone, the one in 4-piperidone or 2,4-, bis-piperidone.
Reaction formula one:
R wherein
1, R
2, R
3definition identical with general formula.
Provided by the invention 3,4,5 ,-trisubstituted-amino thiophenes also can prepare by following steps:
(1) Compound I (can directly buy) obtains intermediate acylate II through Lewis acid (Lewis) catalysis with substituted benzene in inert solvent; this reaction is conventionally taking ether, dioxane, methylene dichloride, chloroform etc. as solvent, and Lewis acid used has iron(ic) chloride, zinc chloride, aluminum chloride, tin chloride, boron trifluoride diethyl etherate etc.Temperature of reaction is-15 DEG C-25 DEG C, reaction times 8-12 hour, and products therefrom II can obtain sterling through recrystallization.
(2) methyl-cyanacetate obtains compound VI I with reacting under aminated compounds condition of no solvent, and the reaction times is 6-12 hour, conventionally at room temperature carries out, and products therefrom VII, without purifying, can be directly used in next step; Aminated compounds is selected the one in benzylamine, hexahydroaniline, cyclopropylamine, morpholine, piperidines or tetramethyleneimine.
(3) Compound I I can obtain compound VI II with compound VI I condensation under acidity or alkaline condition, reaction is carried out in as THF at medium polar solvent conventionally, conventional alkali has diethylamine, triethylamine, diisopropylethylamine etc., conventional acid has titanium tetrachloride, tin chloride, boron trifluoride diethyl etherate etc., temperature of reaction can be carried out between 0 DEG C-50 DEG C, reaction times is 12-24 hour, and products therefrom is the mixture of Z formula and E formula, can be directly used in next step reaction without separating.
(4) compound VI II obtains target compound VI with the cyclization of sulphur powder under alkaline condition, reaction is carried out conventionally in polar aprotic solvent, as acetone and THF etc., conventional alkali has diethylamine, triethylamine, diisopropylethylamine etc., temperature of reaction is 0 DEG C-50 DEG C, and thick product can obtain sterling through column chromatography.
Compound I can directly be bought, and Compound I I can make by literature method (L ü tjens et al.J.Med.Chem.2003,46,1870-1877), compound VI I can make by literature method (Wang et al.J.Comb.Chem.2009,11,920 – 927).
Reaction formula two:
R wherein
1, R
2, R
3definition identical with general formula.
A further object of the present invention is to provide 3,4,5-trisubstituted-amino thiophenes and physiologically acceptable salt thereof are in the application of preparing in tumour medicine, especially as a kind of interactional method of p53-MDM2 that regulates, the purposes in the medicine of preparing the treatment disease relevant with p53-MDM2 signal path.Prepared medicine also contains drug excipient, carrier or other antitumor drugs that preparation allows.
The present invention designs and has synthesized a series ofly 3,4,5, and-trisubstituted-amino thiophenes, to study the structure activity relationship of this compounds and to obtain the better and active better candidate compound of pharmacokinetic property.Pharmacological activity screening experiment shows that this compounds has the interactional ability of significant blocking-up p53-MDM2, and to A549, the tumor cell lines such as HCT116 have shown stronger vitro inhibition proliferation function.The synthetic desired raw material of the compounds of this invention is easy to get, and highway route design is reasonable, and reaction conditions gentleness respectively walks yield high, and easy and simple to handle, production cost is lower, is applicable to suitability for industrialized production.
Embodiment
The present invention is further described in conjunction with the embodiments.Following embodiment is only that explanation is of the present invention, instead of limits by any way the present invention.
Embodiment 1,1,2-bis-(4-chloro-phenyl-) ethyl ketone (Compound I Ia):
Reference literature method makes (L ü tjens et al.J.Med.Chem.2003,46,1870-1877).Chlorobenzene dry 50ml is placed in to reaction flask, adds 4-chlorobenzene Acetyl Chloride 98Min. 15.46g(100mmol), after stirring, under ice bath, add aluminum chloride 40g(300mmol) in batches.Finish, remove ice bath, stirred overnight at room temperature.Reaction solution is poured into the reaction of cancellation on ice, thin up, and ethyl acetate (300ml × 3) is extracted, saturated nacl aqueous solution (300ml × 3) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims to obtain white solid.Add the rear suction filtration of sherwood oil (100ml), with ice sherwood oil (30ml × 3) and ice ether (30ml × 3) washing, vacuum-drying, yield 71%.
Embodiment 2, (Z, E)-methyl-3,4-bis-(4-chloro-phenyl-)-2-cyano group-2-methyl acetate (compound III a):
Anhydrous 200ml THF is placed in to reaction flask, under ice bath, slowly drips titanium tetrachloride 20.6g(110mmol).By Compound I Ia5.0g(22mmol) and methyl-cyanacetate 4.3g(44mmol) THF solution (100ml) be slowly added drop-wise in reaction system.Finish, remove ice bath, add 0.8ml pyridine, stir and add again 2.4ml pyridine, stirred overnight at room temperature after 1 hour.Reaction solution removes under reduced pressure after solvent, thin up, and ethyl acetate (300ml × 3) is extracted, saturated nacl aqueous solution (300ml × 3) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims to obtain oily matter, and crude product is not purified directly carries out next step reaction.
Embodiment 3,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3 carboxylate methyl ester (compound IV a):
Compound III a is dissolved in THF(200ml) in, add sulphur powder 1.4g(44mmol) and diethylamine 4.0ml, stirring at room temperature 2h.Reaction solution removes under reduced pressure after solvent, thin up, and ethyl acetate (100ml × 3) is extracted, saturated nacl aqueous solution (100ml × 3) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims, and crude product obtains white solid 5.3g with ethyl alcohol recrystallization, two step yields 65%.
MS(m/z)：377.95[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.26(d,J=8.4Hz,2H),7.11(dd,J=6.4,4.6Hz,1H),7.07(dd,J=6.2,4.5Hz,1H),6.91(d,J=8.5Hz,2H),6.17(br,2H),3.51(s,3H).
Embodiment 4,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3 carboxylic acid (compound V):
Compound IV a5g(13mmol), the NaOH aqueous solution (75ml) of ethanol (125ml) and 2N is placed in reaction flask, reflux 2h.Reaction solution removes under reduced pressure after solvent, thin up, and with 1N hydrochloric acid soln adjusting pH=6, ethyl acetate (200ml × 3) is extracted, saturated nacl aqueous solution (200ml × 3) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims, and crude product obtains white solid 2.5g with ethyl alcohol recrystallization, yield 52%.
Embodiment 5,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3-(4-methyl piperidine) methane amide (compound VI a):
Compound V150mg(0.4mmol) be dissolved in anhydrous CH
2cl
2(20ml), add EDCI237mg(1.2mmol) and HOBt111mg(0.8mmol), stir 0.5h, drip methyl piperidine 82mg(1.2mmol), stirred overnight at room temperature.Reaction solution removes under reduced pressure after solvent, thin up, and ethyl acetate (20ml × 3) is extracted, saturated sodium bicarbonate washing (20ml × 3), saturated nacl aqueous solution (20ml × 3) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims, and crude product obtains faint yellow solid 112mg through column chromatography purification, yield 61%.
MS(m/z)：445.06[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.24(s,1H),7.21(d,J=8.1Hz,1H),7.17(d,J=6.9Hz,2H),7.13(d,J=8.2Hz,1H),7.07(d,J=8.1Hz,1H),7.01(d,J=7.9Hz,2H),2.64(m,2H),1.49(m,1H),1.36(m,2H),1.26(t,J=7.1Hz,1H),1.00(m,1H),0.86(m,2H),0.68(d,J=6.2Hz,3H)。
Embodiment 6,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3-(4-hydroxy piperidine) methane amide (compound VI b):
Operating process, referring to embodiment 5, just replaces methyl piperidine with 4-hydroxy piperidine, obtains faint yellow solid, yield 57%.
MS(m/z)：461.07[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.38(d,J=8.4Hz,2H),7.21(d,J=8.4Hz,2H),7.11(d,J=8.5Hz,2H),6.89(d,J=8.6Hz,2H),6.32(br,2H),4.65(d,J=7.3Hz,1H),3.65(m,1H),3.49(m,1H),1.76(m,4H),1.31(m,2H),0.70(m,2H).
Embodiment 7,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3-(4-methylpiperazine) methane amide (compound VI c):
Operating process, referring to embodiment 5, just replaces methyl piperidine with 4-methylpiperazine, obtains incarnadine solid, yield 70%.
MS(m/z)：446.09[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.24(d,J=8.4Hz,2H),7.18(d,J=8.5Hz,2H),7.09(d,J=8.3Hz,2H),6.98(d,J=8.4Hz,2H),3.23(m,4H),2.01(s,3H),1.67(m,4H).
Embodiment 8,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3-(2-piperidone) methane amide (compound VI d):
Operating process, referring to embodiment 5, just replaces methyl piperidine with 2-piperidone, obtains white solid, yield 45%.
MS(m/z)：445.03[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.24(d,J=8.4Hz,2H),7.18(d,J=8.5Hz,2H),7.10(d,J=8.4Hz,2H),6.99(d,J=8.5Hz,2H),4.01(m,2H),3.74(m,2H),3.45(m,1H),3.23(m,3H),2.83(m,2H).
Embodiment 9,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3-(2,4-dioxopiperidine) methane amide (compound VI e):
Operating process, referring to embodiment 5, just replaces methyl piperidine with 2,4-dioxopiperidine, obtains white solid, yield 83%.
MS(m/z)：458.98[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.37(d,J=8.3Hz,2H),7.24(d,J=8.3Hz,2H),7.12(d,J=8.5Hz,2H),6.89(d,J=8.5Hz,2H),6.46(br,2H),4.90(m,2H),3.43(m,1H),1.65(m,1H),1.33(m,2H).
Embodiment 10,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3-(4-piperidone) methane amide (compound VI f):
Operating process, referring to embodiment 5, just replaces methyl piperidine with 4-piperidone, obtains faint yellow solid, yield 66%.
MS(m/z)：444.98[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.24(d,J=8.3Hz,2H),7.18(m,2H),7.13(d,J=8.1Hz,2H),6.99(d,J=8.4Hz,2H),3.62(m,2H),3.43(m,2H),2.24(m,2H),1.87(m,2H).
Embodiment 11,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3-piperazine carboxamides (compound VI g):
Operating process, referring to embodiment 5, just replaces methyl piperidine with piperazine, obtains yellow solid, yield 39%.
MS(m/z)：432.02[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.24(d,J=8.4Hz,2H),7.17(dd,J=8.8,2.2Hz,2H),7.09(d,J=8.4Hz,2H),6.99(dd,J=8.4,6.6Hz,2H),4.57(s,2H),3.26–3.21(m,1H),3.16(dt,J=12.7,7.3Hz,2H),2.48(t,J=6.3Hz,1H),2.22–2.17(m,1H),1.68(dt,J=12.4,6.3Hz,1H),1.21(t,J=7.3Hz,1H),1.13(q,J=7.1Hz,2H).
Embodiment 12, (Z, E)-methyl-3,4-bis-(4-chloro-phenyl-)-2-cyano group-2-ethyl acetate (compound III b):
Operating process, referring to embodiment 2, just replaces methyl-cyanacetate with ethyl cyanacetate, obtains oily matter, directly carries out next step reaction without purifying.
Embodiment 13,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3 carboxylic acid, ethyl ester (compound IV b):
Operating process, referring to embodiment 3, obtains white solid, two step yields 70%.
MS(m/z)：392.00[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.24(s,d,J=8.6Hz,2H),7.11(d,J=8.6Hz,2H),7.09(d,J=8.3Hz,2H),6.94(d,J=8.2Hz,2H),6.15(br,2H),3.98(q,J=7.1Hz,2H),0.88(t,J=7.1Hz,3H).
Embodiment 14,1-(4-chloro-phenyl-)-2-methyl phenyl ketone (Compound I Ib):
Reference literature method makes (L ü tjens et al.J.Med.Chem.2003,46,1870-1877).
Operating process, referring to embodiment 1, just replaces 4-chlorobenzene Acetyl Chloride 98Min. with phenyllacetyl chloride, obtains white solid, yield 63%.
Embodiment 15,1-(4-chloro-phenyl-)-2-(4-nitrophenyl) ethyl ketone (Compound I Ic):
Reference literature method makes (L ü tjens et al.J.Med.Chem.2003,46,1870-1877).
Operating process, referring to embodiment 1, just replaces 4-chlorobenzene Acetyl Chloride 98Min. with 4-oil of mirbane Acetyl Chloride 98Min., obtains yellow solid, yield 67%.
Embodiment 16,1-(4-bromophenyl)-2-(4-chloro-phenyl-) ethyl ketone (Compound I Id):
Reference literature method makes (L ü tjens et al.J.Med.Chem.2003,46,1870-1877).
Operating process, referring to embodiment 1, just replaces chlorobenzene with bromobenzene, obtains white solid, yield 49%.
Embodiment 17, N-benzyl-2-malonamide nitrile (compound VI Ia):
Reference literature method makes (Wang et al.J.Comb.Chem.2009,11,920 – 927).
By benzylamine 1.6g(15mmol) and methyl-cyanacetate 1.49g(15mmol) be placed in reaction flask, stirring at room temperature 24 hours, gained solid filters, and with the washing of ice ether, drying under reduced pressure, obtains white solid, yield 87%.
Embodiment 18,2-cyano group-N-cyclohexyl ethanamide (compound VI Ib):
Reference literature method makes (Wang et al.J.Comb.Chem.2009,11,920 – 927).
Operating process, referring to embodiment 17, just replaces benzylamine with N-cyclohexyl, obtains white solid, yield 91%.
Embodiment 19,2-cyano group-N-cyclopropyl ethanamide (compound VI Ic):
Reference literature method makes (Wang et al.J.Comb.Chem.2009,11,920 – 927).
Operating process, referring to embodiment 17, just replaces benzylamine by N-cyclopropyl, obtains white solid, yield 82%.
Embodiment 20,2-cyano group-piperidines ethanamide (compound VI Id):
Reference literature method makes (Wang et al.J.Comb.Chem.2009,11,920 – 927).
Operating process, referring to embodiment 17, just replaces benzylamine with piperidines, obtains white solid, yield 71%.
Embodiment 21,2-cyano group-pyrrolidine acetamide (compound VI Ie):
Reference literature method makes (Wang et al.J.Comb.Chem.2009,11,920 – 927).
Operating process, referring to embodiment 17, just replaces benzylamine with tetramethyleneimine, obtains white solid, yield 76%.
Embodiment 22,2-cyano group-morpholine ethanamide (compound VI If):
Reference literature method makes (Wang et al.J.Comb.Chem.2009,11,920 – 927).
Operating process, referring to embodiment 17, is just replaced benzylamine with morpholino, obtains white solid, yield 73%.
Embodiment 23,2-amino-N-benzyl-4-(4-chloro-phenyl-)-5-phenyl thiophene-3-carboxylic acid amide (VIh):
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Ib, with compound VI Ia replacement methyl-cyanacetate, obtains faint yellow solid, two step yields 59%.
MS(m/z)：419.02[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.28(m,4H),7.16(m,6H),6.98(dd,J=7.6,1.8Hz,2H),6.94(dd,J=7.6,1.8Hz,,2H),6.34(br,2H),5.08(s,1H),4.28(d,J=5.2Hz,2H).
Embodiment 24,2-amino-N-cyclohexyl-4-(4-chloro-phenyl-)-5-phenyl thiophene-3-carboxylic acid amide (VIi):
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Ib, with compound VI Ib replacement methyl-cyanacetate, obtains faint yellow solid, two step yields 78%.
MS(m/z)：411.10[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.37(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),7.14(d,J=7.7Hz,2H),6.99(d,J=7.8,2H),6.31(br,2H),4.81(m,1H),3.71(m,1H),1.62(m,2H),1.45(m,1H),1.37(s,2H),1.26(m,2H),1.07(m,1H),0.74(m,2H).
Embodiment 25,2-amino-N-cyclopropyl-4-(4-chloro-phenyl-)-5-phenyl thiophene-3-carboxylic acid amide (VIj)
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Ib, with compound VI Ic replacement methyl-cyanacetate, obtains faint yellow solid, two step yields 70%.
MS(m/z)：368.99[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.37(m,2H),7.20(m,2H),7.16(m,3H),7.00(d,J=2.0Hz,1H),6.99(d,J=1.5Hz,1H),6.19(br,2H),4.88(s,1H),2.60(m,1H),0.63(dd,J=1.4Hz,2H),0.04(dd,J=1.4Hz,2H).
Embodiment 26,2-amino-4-(4-chloro-phenyl-)-5-phenyl thiophene-3-pyrrolidine formamide (VIk):
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Ib, with compound VI Ie replacement methyl-cyanacetate, obtains faint yellow solid, two step yields 54%.
MS(m/z)：382.96[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.21(m,5H),7.16(m,2H),7.11(m,1H),7.09(m,1H),2.81(m,4H),1.60(m,4H).
Embodiment 27,2-amino-4,5-bis-(4-chloro-phenyl-)-N-cyclohexyl thiophene-3-carboxylic acid amide (VIl):
Operating process, referring to embodiment 2 and embodiment 3, just replaces methyl-cyanacetate with compound VI Ib, obtains faint yellow solid, two step yields 70%.
MS(m/z)：445.01[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.40(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),7.13(d,J=8.5Hz,2H),6.91(d,J=8.5Hz,2H),6.05(br,2H),4.81(d,J=7.5Hz,1H),3.72(m,1H),1.63(m,2H),1.45(m,3H),1.27(m,2H),1.09(m,1H),0.75(d,J=9.9Hz,2H).
Embodiment 28,2-amino-4,5-bis-(4-chloro-phenyl-)-N-cyclopropyl thiophene-3-carboxylic acid amide (VIm):
Operating process, referring to embodiment 2 and embodiment 3, just replaces methyl-cyanacetate with compound VI Ic, obtains faint yellow solid, two step yields 80%.
MS(m/z)：403.02[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.39(d,J=8.4Hz,2H),7.18(d,J=8.4Hz,2H),7.13(d,J=8.6Hz,2H),6.91(d,J=8.6Hz,2H),6.26(br,2H),4.87(m,1H),2.60(dt,J=10.4,1H),0.64(m,2H),0.03(m,2H).
Embodiment 29,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3-piperidyl urea (VIn):
Operating process, referring to embodiment 2 and embodiment 3, just replaces methyl-cyanacetate with compound VI Id, obtains faint yellow solid, two step yields 71%.
MS(m/z)：430.96[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.25(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.12(d,J=8.5Hz,2H),7.01(d,J=8.5Hz,2H),3.92(br,2H),3.31(m,6H),1.42(m,4H).
Embodiment 30,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3-pyrrolidine formamide (VIo):
Operating process, referring to embodiment 2 and embodiment 3, just replaces methyl-cyanacetate with compound VI Ie, obtains faint yellow solid, two step yields 54%.
MS(m/z)：417.02[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.23(d,J=8.3Hz,2H),7.16(d,J=8.3Hz,2H),7.10(d,J=8.3Hz,2H),6.99(d,J=8.2Hz,2H),3.43(m,4H),1.40(m,4H).
Embodiment 31,2-amino-N-phenyl-4,5-bis-(4-chloro-phenyl-) thiophene-3-methane amide (VIp):
Operating process, referring to embodiment 2 and embodiment 3, just replaces methyl-cyanacetate with 2-cyano group-phenyl acetanilide,Phenacetylaniline (can directly buy), obtains faint yellow solid, two step yields 54%.
MS(m/z)：439.02[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.46(d,J=8.3Hz,2H),7.32(d,J=8.3Hz,2H),7.21(t,J=7.8Hz,2H),7.14(d,J=8.5Hz,2H),7.01(t,J=7.2Hz,3H),6.94(d,J=8.5Hz,2H),6.66(s,1H).
Embodiment 32,2-amino-4,5-bis-(4-chloro-phenyl-) thiophene-3-morpholine methane amide (VIq):
Operating process, referring to embodiment 2 and embodiment 3, just replaces methyl-cyanacetate with compound VI If, obtains faint yellow solid, two step yields 44%.
MS(m/z)：433.03[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.26(d,J=8.4Hz,2H),7.17(d,J=8.4Hz,2H),7.09(d,J=8.4Hz,2H),6.98(d,J=8.4Hz,2H),3.44(br,8H).
Embodiment 33,2-amino-4-bis-(4-chloro-phenyl-)-5-(4-nitrophenyl) thiophene-3-piperidyl urea (VIr):
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Ic, with compound VI Id replacement methyl-cyanacetate, obtains red solid, two step yields 66%.
MS(m/z)：442.06[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ8.03(d,J=8.7Hz,2H),7.28(d,J=8.3Hz,2H),7.17(d,J=8.7Hz,2H),7.13(d,J=8.3Hz,2H),3.57(m,2H),3.40(m,2H),1.67(m,4H),1.59(m,2H).
Embodiment 34,2-amino-N-cyclopropyl-4-bis-(4-chloro-phenyl-)-5-(4-nitrophenyls) thiophene-3-carboxylic acid amide (VIs):
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Ic, with compound VI Ic replacement methyl-cyanacetate, obtains red solid, two step yields 68%.
MS(m/z)：413.99[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.98(d,J=8.7Hz,2H),7.44(d,J=8.2Hz,2H),7.20(d,J=8.2Hz,2H),7.05(d,J=8.7Hz,2H),4.84(s,1H),2.59(dd,J=6.9,3.5Hz,1H),0.63(d,J=5.9Hz,2H),0.02(d,J=5.9Hz,2H).
Embodiment 35,2-amino-N-cyclohexyl-4-bis-(4-chloro-phenyl-)-5-(4-nitrophenyls)-3-carboxylic acid amide (VIt):
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Ic, with compound VI Ib replacement methyl-cyanacetate, obtains red solid, two step yields 60%.
MS(m/z)：456.10[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.98(d,J=8.7Hz,2H),7.45(d,J=8.2Hz,1H),7.25(d,J=8.3Hz,1H),7.06(d,J=8.7Hz,1H),6.51(br,2H),4.77(d,J=6.8Hz,1H),3.72(m,1H),1.62(m,2H),1.45(s,1H),1.37(m,2H),1.26(m,2H),1.14(m,1H),0.73(m,2H).
Embodiment 36,2-amino-4-bis-(4-chloro-phenyl-)-5-(4-nitrophenyl)-3-morpholine methane amide (VIu):
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Ic, with compound VI If replacement methyl-cyanacetate, obtains red solid, two step yields 48%.
MS(m/z)：443.99[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ8.04(d,J=8.9Hz,2H),7.31(d,J=8.5Hz,2H),7.17(d,J=8.9Hz,2H),7.12(d,J=8.4Hz,2H),3.75(m,1H),3.71(m,2H),3.65(m,2H),3.48(m,1H),3.35(m,2H).
Embodiment 37,2-amino-4-bis-(4-chloro-phenyl-)-5-(4-nitrophenyl)-3-pyrrolidine formamide (VIv):
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Ic, with compound VI Ie replacement methyl-cyanacetate, obtains red solid, two step yields 73%.
MS(m/z)：428.02[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ8.04(d,J=8.9Hz,2H),7.26d,J=8.9Hz,2H),7.17(t,J=8.6Hz,4H),3.41(m,2H),2.79(m,2H),1.66(m,2H),1.54(m,2H).
Embodiment 38,2-amino-4-(4-bromophenyl)-5-(4-chloro-phenyl-) thiophene-3-morpholine methane amide (VIw):
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Id, with compound VI If replacement methyl-cyanacetate, obtains faint yellow solid, two step yields 58%.
MS(m/z)：476.96[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.42(d,J=8.1Hz,2H),7.17(d,J=8.2Hz,2H),7.03(d,J=8.2Hz,2H),6.98(d,J=8.2Hz,2H),3.70–2.55(m,10H).
Embodiment 39,2-amino-4-(4-bromophenyl)-5-(4-chloro-phenyl-) thiophene-3-pyrrolidine formamide (VIx):
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia with Compound I Id, with compound VI Ie replacement methyl-cyanacetate, obtains faint yellow solid, two step yields 67%.
MS(m/z)：460.97[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.36(d,J=8.4Hz,2H),7.17(d,J=8.5Hz,2H),7.06(d,J=8.4Hz,2H),6.99(d,J=8.5Hz,2H),3.69(m,4H),1.59(m,4H).
Embodiment 40,2-amino-N-cyclopropyl-4-(4-bromophenyl)-5-(4-chloro-phenyl-) thiophene-3-carboxylic acid amide (VIy)
Operating process, referring to embodiment 2 and embodiment 3, just replaces Compound I Ia compound VI Ic to replace methyl-cyanacetate with Compound I Id, obtains faint yellow solid, two step yields 49%.
MS(m/z)：447.00[M+H]
+。
1H?NMR(500MHz,CDCl
3)δ7.55(d,J=8.4Hz,2H),7.12(d,J=8.5Hz,2H),7.11(d,J=8.4Hz,2H),6.92(d,J=8.5Hz,2H),5.97(br,2H),4.87(s,1H),2.58(dt,J=10.4,3.4Hz,1H),0.69(m,2H),0.10(m,2H).
The mensuration of embodiment 41:MDM2 protein binding activity:
Adopt the method for bibliographical information to express and purifying MDM2 albumen, and utilize fluorescence polarization competitive binding testing method to detect 3,4,5, the combination activity of-trisubstituted-amino thiophenes and MDM2 albumen.（Ding，et?al.,J.AM.CHEM.SOC.2005,127,10130-10131）。Result shows, the overwhelming majority 3,4,5, and-trisubstituted-amino thiophenes has shown medium to strong MDM2 binding ability, can effectively block p53-MDM2 and interact, and the activity of part of compounds and positive control Nutlin-1 are suitable with Nutlin-3.Experimental result (being the mean value of three tests) is referring to table 1.
Embodiment 42: anti tumor activity in vitro test
Adopt mtt assay to measure this compounds to human lung cancer cell A549 and human colon cancer cell HCT116, In-vitro Inhibitory Effect, and calculation of half inhibitory concentration (IC
50).Result shows, 3,4,5 of synthesized, and-trisubstituted-amino thiophenes all demonstrates good tumor proliferation and suppresses active in two cell strains, and the activity of nearly all compound is better than positive control Nutlin-1.Experimental result is referring to table 1.
Table 13,4,5, MDM2 protein binding activity and the anti tumor activity in vitro of-trisubstituted-amino thiophenes
Claims (5)
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