CN101565418A - Amide derivative and purpose thereof - Google Patents
Amide derivative and purpose thereof Download PDFInfo
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- CN101565418A CN101565418A CNA2008100365109A CN200810036510A CN101565418A CN 101565418 A CN101565418 A CN 101565418A CN A2008100365109 A CNA2008100365109 A CN A2008100365109A CN 200810036510 A CN200810036510 A CN 200810036510A CN 101565418 A CN101565418 A CN 101565418A
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Abstract
The invention relates to an amide derivative and a purpose thereof. The invention discloses an N-(4-substiguted aminoacyl phenyl)-5-substited furan-2-formamide compound and tests the activity of the compound for inhibiting falcipain-2 in experiment of enzyme level in vitro, and the result indicates that the compound has strong inhibitory activity to falcipain- 2. Therefore, the N-(4-substiguted aminoacyl phenyl)-5-substited furan-2-formamide compound provided in the invention can act as cysteine protease (falcipain-2) inhibitor in food vacuole of plasmodium to stop further proliferation of plasmodium in a host.
Description
Technical field
The present invention relates to a kind of amide derivatives and uses thereof, specifically, relate to a kind of N-(4-replaces the aminoacyl phenyl)-5-substituted furan-2-Carbox amide and uses thereof.
Background technology
Malaria is that the most frequent parasitosis takes place on the earth, is the disease of being propagated, had potential fatal risk by anopheles.Along with the chemical sproof continuous increase of existing antimalarial agent, the sickness rate of malaria increases day by day, demands having the discovery of the antimalarial agent of novel therapeutic effect urgently.
The plasmodium of erythrocytic phase hydrolysis host's in its acidic food bubble oxyphorase is to obtain required energy and the amino acid of self life.Biological study shows, forgives a series of lytic enzyme in plasmodial food vacuole, as aspartate protease (plasmepsins), and L-Cysteine HCL Anhydrous (falcipains), and metalloprotease (falcilysins).These enzymes have become the chemotherapeutical potential target of malaria.
L-Cysteine HCL Anhydrous is M
τBeing about 21000～30000 protein, is to have the highest hydrolytic activity at 4～6.5 o'clock in the pH value, and its reactive site has cysteine residues.Plasmodial L-Cysteine HCL Anhydrous belongs to papoid family.Known plasmodium L-Cysteine HCL Anhydrous has four hypotypes, facipain-1, facipain-2A, falcipain-2B, facipain-3.Falcipain 1 is the plasmodium L-Cysteine HCL Anhydrous that first expression obtains, and its biological study shows that it is to plasmodial monogony stage did not influence, but the function of energy remarkable influence egg capsule.Falcipain-2A, falcipain-2B have 97% homology, and be only different 7 of aminoacid sequence.Monitoring by oligonucleotide probe finds that the expression level of falcipain-2BmRNA is lower than falcipain-2A.Yet falcipain-2A is very similar with peak value at the time-dependent manner of plasmodium nourishing body its expression in late period with falcipain-2B, and this shows that two kinds of different hypotypes have similar biological function.Falcipain-3 and falcipain-2 have 66.6% homology at catalytic domain, but the stage that they are expressed is different.Falcipain-2 reaches the climax at vegetative stage, and falcipain-3 is in that more the sophisticated plasmodium stage peaks.In these several hypotypes, maximum for the research of falcipain-2, so the exploitation of its inhibitor also is subjected to paying close attention to more widely.
In recent years, " area of computer aided medicinal design " (Computer-Aided Drug Design CADD) has become the important method and the instrument of modern medicines research and development.The medicinal design of utilization area of computer aided can be shortened 0.9 year new drug research cycle on average, saves 1.3 hundred million dollars of research and development costs.Therefore, the CADD method has been widely used in the discovery and the optimization of lead compound.The virtual a kind of area of computer aided drug discovery method used always at present that become of area of computer aided high-throughput.Its principle be the utilization supercomputer by the method for molecular docking in reaching millions of micromolecular compound storehouses, seeks can with a certain specified disease target proteins bonded chemical structure, for further molecule, cell, animal and clinical study provide high-efficiency reliable small molecules lead compound.
In sum, as target, in conjunction with the biological activity test test of CADD and various levels, the micromolecular compound that designs and synthesizes has important practical significance to the exploitation antimalarial agent with L-Cysteine HCL Anhydrous falcipain-2.
Summary of the invention
Integrated use CADD of the present invention and based on the SPR of BIAcore experiment; the contriver has found a N-(4-replaces the aminoacyl phenyl)-5-substituted furan-2-benzamide compound; utilization rational drug method of design is carried out structural modification at this compound; and testing this compounds suppresses falcipain-2 in the horizontal experiment test of vitro enzyme activity, the result proves that it has stronger facipain-2 and suppresses active.
The said N-of the present invention (4-replaces the aminoacyl phenyl)-5-substituted furan-2-Carbox amide has structure shown in the formula I:
Among the formula I: R
1Be hydrogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Saturated or unsaturated cycloalkyl, 5-7 unit virtue (perfume (or spice)) cyclic group, 5-7 unit heterocyclic radical, the 5-7 unit heterocyclic radical of 5-7 unit virtue (perfume (or spice)) cyclic group of replacement or replacement;
R
2Be methyl or R
3OCH
2-, R
35-7 unit virtue (perfume (or spice)) cyclic group for 5-7 unit virtue (perfume (or spice)) cyclic group or replacement; X is C or S=O;
Wherein, the substituting group in the 5-7 unit heterocyclic radical of the 5-7 of described replacement unit virtue (perfume (or spice)) cyclic group and replacement is selected from: halogen, C
1-C
6Straight or branched alkyl, hydroxyl, C
1-C
4Alkoxyl group, C
1-C
4Unsaturated-oxyl, carboxyl, ester group, C
1-C
6Carboxyl alkoxyl group, C
1-C
6Ester group alkoxyl group, C
1-C
6Carboxyalkyl, C
1-C
6Ester group alkyl, cyano group, nitro, amino, methylol, trifluoromethyl, trifluoromethoxy, sulfydryl or C
1-C
4A kind of in the acyl group, two or more, substituent number is 1～4;
The heteroatoms of described heterocyclic radical is oxygen, sulphur or/and nitrogen, and heteroatomic number is 1～3.
In optimal technical scheme of the present invention, when X was S=O, it had formula I
AShown in structure:
Formula I
AIn: R
1Be hydrogen, 5-7 unit virtue (perfume (or spice)) cyclic group, 5-7 unit heterocyclic radical, the 5-7 unit heterocyclic radical of 5-7 unit virtue (perfume (or spice)) cyclic group of replacement or replacement;
R
2Be methyl or R
3OCH
2-, R
35-7 unit virtue (perfume (or spice)) cyclic group for 5-7 unit virtue (perfume (or spice)) cyclic group or replacement;
Wherein, the substituting group in the 5-7 unit heterocyclic radical of the 5-7 of described replacement unit virtue (perfume (or spice)) cyclic group and replacement is selected from: halogen, C
1-C
6Straight or branched alkyl or C
1-C
4A kind of in the alkoxyl group, two or more, substituent number is 1～4;
The heteroatoms of described heterocyclic radical is a nitrogen, and heteroatomic number is 1～3.
Preferred R
1For hydrogen, nitrogenous 6 yuan of heterocyclic radicals or by C
1-C
4Nitrogenous 6 yuan of heterocyclic radicals that alkoxyl group replaces;
Preferred R
2Be methyl or R
3OCH
2-, R
3Be 6 yuan of virtues (perfume (or spice)) cyclic group of 6 yuan of virtue (perfume (or spice)) cyclic groups or replacement, the substituting group of 6 yuan of virtues (perfume (or spice)) cyclic group of wherein said replacement is halogen or C
1-C
3Alkyl, substituent number are 1～4.
In another optimal technical scheme of the present invention, when X was C, it had formula I
BShown in structure:
Formula I
BIn: R
1Be hydrogen, 5-7 unit virtue (perfume (or spice)) cyclic group, 5-7 unit heterocyclic radical, the 5-7 unit heterocyclic radical of 5-7 unit virtue (perfume (or spice)) cyclic group of replacement or replacement;
R
2Be R
3OCH
2-, R
35-7 unit virtue (perfume (or spice)) cyclic group for 5-7 unit virtue (perfume (or spice)) cyclic group or replacement;
Wherein, the substituting group in the 5-7 unit heterocyclic radical of the 5-7 of described replacement unit virtue (perfume (or spice)) cyclic group and replacement is selected from: halogen, C
1-C
6Straight or branched alkyl or C
1-C
4A kind of in the alkoxyl group, two or more, substituent number is 1～4;
Preferred R
1For hydrogen, nitrogenous 6 yuan of heterocyclic radicals or by C
1-C
4Nitrogenous 6 yuan of heterocyclic radicals that alkoxyl group replaces;
Preferred R
2Be R
3OCH
2-, R
3Be 6 yuan of virtues (perfume (or spice)) cyclic group of 6 yuan of virtue (perfume (or spice)) cyclic groups or replacement, the substituting group of 6 yuan of virtues (perfume (or spice)) cyclic group of wherein said replacement is halogen or C
1-C
3Alkyl, substituent number are 1～4.
Description of drawings
Fig. 1 positive is shone and Compound I (Z-Phe-Arg-pNAHCl)
A-1 kinetic curve figure that combines with FP-2 albumen,
Wherein the compound concentration represented from top to bottom of each bar line is followed successively by 1 * 10
-5M, 5 * 10
-6M, 2.5 * 10
-6M, 1.25 * 10
-6M, 6.25 * 10
-7M, 3.125 * 10
-7M and 0.
Fig. 2. Compound I
A-1 and I
A-5 IC
50Value.
Embodiment
The method of a kind of preparation N-of the present invention (4-replaces the aminoacyl phenyl)-5-substituted furan-2-Carbox amide, its main synthetic route is as follows:
In the synthetic route: Ac is ethanoyl (CH
3CO), Y is halogen (F, Cl, Br or I), R
1Implication described identical with preamble.
Specifically comprise the steps:
Formula I
AShown in the preparation of compound:
1) with 5-chloromethyl furans-2-methyl-formiate, R
3OH (as substituted aryl phenol), mineral alkali mix with organic solvent, and backflow is spent the night; Steam and remove most of solvent, add water, organic solvent extraction, drying, solvent evaporated obtains 5-(substituted aryl oxygen methyl) furans-2-methyl-formiate (compound shown in the formula II).
2) the Compound I I and the mineral alkali that obtain in the step 1) are put in an amount of methyl alcohol, 50 ℃ of stirrings are spent the night; Steam and remove most of solvent, add water, transfer pH=1 with hydrochloric acid, separate out solid, suction filtration gets 5-(substituted aryl oxygen methyl) furans-2-formic acid (compound shown in the formula III).
3) R under the room temperature
1Replace amine and react with right-acetylsulphanilyl chloride in basic solution, temperature stirred 12～36 hours at 40 ℃～45 ℃.In reaction solution impouring water, organic solvent extraction, the organic layer drying that obtains is filtered, and removes solvent under reduced pressure, and the resistates column chromatography for separation gets 4-acetylaminohydroxyphenylarsonic acid N-R
1Substituted benzene sulfonic acid amide.This sulphonamide put in 10% the aqueous sodium hydroxide solution and refluxed 2 hours, the control reacting liquid temperature is at 70 ℃～80 ℃, and concentrated hydrochloric acid is transferred pH=4-5, separates out a large amount of solids, through suction filtration, and washing, dry product 4-amino-N-R
1Substituted benzene sulfonic acid amide (compound shown in the formula IV).
4) with step 2) in refluxed 2 hours in an amount of halogenating agent of compound input that obtains, concentrating under reduced pressure gets 5-(substituted aryl oxygen methyl) furans-2-formyl halide (compound shown in the formula V), the not purified the next step that is directly used in.
With a small amount of exsiccant halohydrocarbon (as methylene dichloride) dissolving formyl halide (compound shown in the formula V).Under the stirring at room, splash in the mixing solutions of the compound IV that obtains in the step 3) and pyridine.Room temperature reaction spends the night, and adds water, transfers pH=2～3 with hydrochloric acid, separates out solid, suction filtration, and washing, drying obtain compound N-[(4-R
1Replace sulphonamide) phenyl]-5-aryl oxide methyl furan-2-methane amide (one of target compound).
Or
1) sodium hydroxide is soluble in water, 0 ℃～5 ℃ of temperature controls, dropping oxidizing agent (as bromine etc.) and 5-methyl furan-2-formaldehyde successively, keep this temperature, stirring reaction 1～3 hour, twice of extracted with diethyl ether of reaction solution, water layer is transferred pH=1 with hydrochloric acid, separate out a large amount of solids, suction filtration, wash 5-methyl furan-2-formic acid (compound shown in the formula VII).
2) the compound VI I that obtains in the step 1) is dropped in an amount of halogenating agent and to reflux 2 hours, concentrating under reduced pressure gets 5-methyl furan-2-formyl halide (compound shown in the formula VIII), the not purified the next step that is directly used in.
With a small amount of exsiccant halohydrocarbon (as methylene dichloride) dissolved compound VIII.Under the stirring at room, splash into 4-amino-N-R
1In the mixing solutions of substituted benzene sulfonic acid amide (compound shown in the formula IV) and pyridine.Room temperature reaction spends the night, and adds water, transfers pH=2～3 with hydrochloric acid, separates out solid, suction filtration, and washing, drying obtain compound N-[(4-R
1Replace sulphonamide) phenyl]-5-methyl furan-2-methane amide (target compound two)
Formula I
BShown in the preparation of compound:
1) in tetrahydrofuran solvent, R
1Replace amine, right-the nitrobenzoyl carboxylic acid halides (right-nitrobenzoyl chloride) and organic bases back flow reaction, stirred 12～36 hours.In reaction solution impouring water, organic solvent extraction, the organic layer drying that obtains is filtered, and removes solvent under reduced pressure, and the resistates column chromatography for separation gets 4-nitro-N-R
1Substituted benzamide.With this acid amides put into 10%Pd-C aqueous acetic acid (70%, V/V) in reaction 30 hours, the control reacting liquid temperature is at 20 ℃～40 ℃, suction filtration, concentrate product 4-amino-N-R
1Substituted benzamide (compound shown in the formula VI).
2) 5-(substituted aryl oxygen methyl) furans-2-formyl halide (compound shown in the formula V) is dissolved in a small amount of exsiccant halohydrocarbon (as methylene dichloride), under the stirring at room, splashes in the mixing solutions by compound VI that obtains in the step 1) and pyridine.Room temperature reaction spends the night, and adds water, transfers pH=2～3 with hydrochloric acid, separates out solid, suction filtration, wash compound N-[(4-R
1Replace carboxamide) phenyl]-5-aryl oxide methyl furan-2-methane amide (three of target compound, formula I
BShown in compound).
In following embodiment, will further illustrate the present invention.These embodiment only are used to illustrate the present invention, but do not limit the present invention in any way.All parameters among the embodiment and remaining explanation unless otherwise indicated, all are to be unit with quality (gram).
Embodiment 1
The preparation of 5-(4-chloro-3-methylenedioxy phenoxy methyl) furans-2-methyl-formiate (Compound I I-1)
2.5 gram 5-chloromethyl furans-2-methyl-formiates, 2.2 gram 4-chloro-3-methylphenols, 2.6 gram salt of wormwood are mixed with 40 milliliters of acetonitriles, and backflow is spent the night; Steam and remove most of solvent, add water, ethyl acetate extraction, ester layer drying, solvent evaporated obtains white solid 3.8 grams, yield 94.5%.mp?56-58℃；
1H-NMR(DMSO-d
6，500MHz)δ2.29(s，3H)，3.81(s，3H)，5.14(s，2H)，6.80(d，1H)，6.91(dd，1H)，7.07(d，1H)，7.20(d，1H)，7.30-7.33(m，2H)；MS(EI)m/z?280(M
+)。
Embodiment 2
The preparation of 5-(4-chloro-3-methylenedioxy phenoxy methyl) furans-2-formic acid (compound III-1)
1.7 gram II-1 and 0.5 gram, one hydronium(ion) oxidation lithium are put in 20 ml methanol, and 50 ℃ of stirrings are spent the night.Steam and remove most of solvent, add water, transfer pH=1 with hydrochloric acid, separate out solid, suction filtration gets white solid (III-1) 1.58 grams, yield 97.5%.mp?194-195℃；
1H-NMR(DMSO-d
6，500MHz)δ2.28(s，3H)，5.11(s，2H)，6.74(d，1H)，6.89(dd，1H)，7.05(d，1H)，7.20(d，1H)，7.30(d，1H)；MS(EI)m/z?266(M
+)。
Embodiment 3
4-amino-N-(6-methoxy pyrimidine-4-) the preparation of benzsulfamide (compound IV-1)
Under the room temperature 1.0 gram 4-acetylsulphanilyl chloride are joined in 1.87 gram 6-methoxy pyrimidine-4-amine and 15 milliliters the pyridine solution, in 45 ℃ of stirrings 24 hours.In reaction solution impouring water, ethyl acetate extraction, ester layer anhydrous magnesium sulfate drying, filter, remove solvent under reduced pressure, the resistates column chromatography for separation (eluent: methyl alcohol/chloroform=1: 20) 4-acetylaminohydroxyphenylarsonic acid N-(benzsulfamide of 6-methoxy pyrimidine-4-) is orange solids 1.36 grams, yield 52.8%.mp?223-224℃；
1H-NMR(DMSO-d
6，500MHz)δ2.07(s，3H)，3.84(s，3H)，6.33(s，1H)，7.75(d，2H)，7.86(d，2H)，8.41(s，1H)；MS(EI)m/z?322(M
+)。
(benzsulfamide of 6-methoxy pyrimidine-4-) is put in 15 milliliter 10% the aqueous sodium hydroxide solution and was refluxed 2 hours with 1.2 gram 4-acetylaminohydroxyphenylarsonic acid N-; The control reacting liquid temperature is between 70～80 ℃, and concentrated hydrochloric acid is transferred pH=4～5, separates out a large amount of solids, through suction filtration, and washing, (benzsulfamide (IV-1) of 6-methoxy pyrimidine-4-) is yellow solid, 0.58 gram, yield 55.9% to dry 4-amino-N-.mp?201-203℃；
1H-NMR(DMSO-d
6，500MHz)δ3.81(s，3H)，6.29(s，1H)，6.57(d，2H)，7.53(d，2H)，8.37(s，1H)；MS(EI)m/z?280(M
+)。
Embodiment 4
N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-5-[(4-chloro-3-aminomethyl phenyl) the oxygen methyl] furans-2-methane amide (I
A-1) preparation
0.5 gram II-1 is mixed with 3 milliliters of thionyl chlorides, reflux and stirred 2 hours, concentrating under reduced pressure, resistates dissolves with a small amount of exsiccant methylene dichloride.Above-mentioned solution under stirring at room, is splashed in the mixing solutions of 0.58 gram IV-1 and pyridine.Room temperature reaction spends the night, and adds water, transfers pH=2～3 with hydrochloric acid, separates out solid, and washing obtains white solid (I
A-1) 0.5 gram, yield 50.5%.mp?134-136℃；
1H-NMR(DMSO-d
6，500MHz)δ2.28(s，3H)，3.77-3.81(m，5H)，6.28(s，1H)，6.81(d，1H)，6.91(dd，1H)，7.86-7.92(m，6H)，8.36(s，1H)；MS(EI)m/z?528(M
+)。
Embodiment 5
N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-the 5-[(4-chloro-phenyl-) the oxygen methyl] furans-2-methane amide (Compound I
AA kind of (I
A-2) preparation)
4-chloro-3-methylphenol is replaced to the 4-chlorophenol, and all the other desired raw materials, reagent and preparation method get brown solid 0.33 gram, yield 32.8% (final step yield) with embodiment 1-4.mp?71-74℃；
1H-NMR(DMSO-d
6，500MHz)δ3.94(s，3H)，4.93(s，2H)，6.62(d，2H)，6.66(d，1H)，6.95(d，2H)，7.00(d，1H)，7.23(s，1H)，7.34(d，2H)，7.55(d，2H)，8.57(s，1H)；MS(EI)m/z?515(M
+)。
Embodiment 6
N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-the 5-[(3-aminomethyl phenyl) the oxygen methyl] furans-2-methane amide (Compound I
AA kind of (I
A-3) preparation)
4-chloro-3-methylphenol is replaced to the 3-methylphenol, and all the other desired raw materials, reagent and preparation method get faint yellow solid 0.87 gram, yield 81.1% (final step yield) with embodiment 1-4.mp?195-197℃；
1H-NMR(DMSO-d
6，500MHz)δ2.29(s，3H)，3.85(s，3H)，5.14(s，2H)，6.35(s，1H)，6.81(t，2H)，6.85(m，1H)，6.88(s，1H)，7.19(t，1H)，7.41(m，1H)，7.90-7.95(m，4H)，8.42(s，1H)；MS(EI)m/z?494(M
+)。
Embodiment 7
N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-5-(phenyl oxygen methyl) furans-2-methane amide (Compound I
AA kind of (I
A-4) preparation)
4-chloro-3-methylphenol is replaced to phenol, and all the other desired raw materials, reagent and preparation method get faint yellow solid 1.01 grams, yield 92.4% (final step yield) with embodiment 1-4.mp?195-196℃；
1H-NMR(DMSO-d
6，500MHz)δ3.85(s，3H)，5.16(s，2H)，6.35(s，1H)，6.82(d，1H)，6.99(t，1H)，7.06(d，2H)，7.33(t，2H)，7.41(m，1H)，7.90-7.96(m，4H)，8.42(s，1H)；MS(EI)m/z?480(M
+)。
Embodiment 8
N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-5-[(2,4-two chloro-3,5-3,5-dimethylphenyl) the oxygen methyl] furans-2-methane amide (Compound I
AA kind of (I
A-5) preparation)
4-chloro-3-methylphenol is replaced to 2,4-two chloro-3, the 5-xylenol, all the other desired raw materials, reagent and preparation method get faint yellow solid 0.4 gram, yield 92.4% (final step yield) with embodiment 1-4.mp?214-216℃；
1H-NMR(DMSO-d
6，500MHz)δ2.34(s，3H)，2.40(s，3H)，3.74(s，3H)，5.23(s，2H)，6.08(s，1H)，6.83(d，1H)，7.27(s，1H)，7.40(d，1H)，7.78-7.81(m，4H)，8.20(s，1H)；MS(EI)m/z?576(M
+)。
Embodiment 9
N-(4-sulfamoyl phenyl)-5-[(4-chloro-3-aminomethyl phenyl) oxygen methyl] furans-2-methane amide (Compound I
AA kind of (I
A-6) preparation)
(the 6-methoxy pyrimidine-4-) benzsulfamide (IV-1) replaces to the 4-aminobenzene sulfonamide, and all the other desired raw materials, reagent and preparation method get faint yellow solid 0.52 gram, yield 65.4% (final step yield) with embodiment 1,2,4 with 4-amino-N-.mp?216-217℃；
1H-NMR(DMSO-d
6，500MHz)δ2.31(s，3H)，5.16(s，2H)，6.83(d，1H)，6.93(dd，1H)，7.09(d，1H)，7.33(d，1H)，7.41(m，1H)，7.80(d，2H)，7.92(m，2H)；MS(EI)m/z?420(M
+)。
4-amino-N-(6-methoxy pyrimidine-4-) the preparation of benzamide (compound VI-1)
In tetrahydrofuran solvent, 6-methoxy pyrimidine-4-amine, 4-nitrobenzoyl chloride and pyridine back flow reaction stirred 12 hours.In reaction solution impouring water, dichloromethane extraction, the organic layer drying that obtains is filtered, and removes solvent under reduced pressure, and the resistates column chromatography for separation gets 4-nitro-N-(benzamide of 6-methoxy pyrimidine-4-).This acid amides is put into the aqueous acetic acid (70% of 10%Pd-C, V/V) reaction is 30 hours in, controls reacting liquid temperature between 20～40 ℃, suction filtration, concentrate product 4-amino-N-(benzamide (VI-1) of 6-methoxy pyrimidine-4-) directly drops into the next step.
Embodiment 11
N-[[(4-(aminoacyl of 6-methoxy pyrimidine-4-)] phenyl]-5-[(4-chloro-3-aminomethyl phenyl) the oxygen methyl] furans-2-methane amide (I
B-1) preparation
(benzsulfamide (IV-1) of 6-methoxy pyrimidine-4-) replaces to 4-amino-N-(benzamide VI-1 of 6-methoxy pyrimidine-4-) with 4-amino-N-, all the other desired raw materials, reagent and preparation method are with embodiment 1,2,4, get white solid 0.26 gram, yield 28.6% (final step yield).mp?216-219℃；
1H-NMR(DMSO-d
6，400MHz)δ2.29(s，3H)，3.92(s，3H)，5.15(s，2H)，6.81(d，1H)，6.91(dd，1H)，7.08(d，1H)，7.32(d，1H)，7.40(d，1H)，7.60(s，1H)，7.88(d，2H)，8.03(d，2H)，8.60(s，1H)；MS(EI)m/z?492(M
+)。
Embodiment 12
N-(4-aminoacyl phenyl)-5-[(4-chloro-3-aminomethyl phenyl) oxygen methyl] furans-2-methane amide (Compound I
BA kind of (I
B-2) preparation)
(the 6-methoxy pyrimidine-4-) benzsulfamide (IV-1) replaces to the 4-aminobenzamide, and all the other desired raw materials, reagent and preparation method get white solid 0.36 gram, yield 49.3% (final step yield) with embodiment 1,2,4 with 4-amino-N-.mp?244-245℃；
1H-NMR(DMSO-d
6，500MHz)δ2.31(s，3H)，5.16(s，2H)，6.82(d，1H)，6.93(dd，1H)，7.09(d，1H)，7.33(d，1H)，7.39(d，1H)，7.82(d，2H)，7.87(d，2H)；MS(EI)m/z?384(M
+)。
Embodiment 13
2.9 gram sodium hydroxide are dissolved in 15 ml waters, and 2 ℃～3 ℃ of temperature controls once drip 2 gram bromines and 1 gram 5-methyl furan-2-formaldehyde, finish 0～5 ℃ of stirring reaction of temperature control 1 hour.Reaction solution twice of extracted with diethyl ether (5mL * 2), water layer is transferred pH=1 with concentrated hydrochloric acid, and suction filtration is washed to such an extent that yellow solid product 5-methyl furan-2-formic acid 0.63 restrains yield 55.3%.mp?109-110℃；
1H-NMR(DMSO-d
6，500MHz)δ2.34(s，3H)，6.29(d，1H)，7.12(d，1H)。
Embodiment 14
N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-5-methyl furan-2-methane amide (Compound I
A-7) preparation
With 5-methyl furan-2-formic acid is raw material, and all the other desired raw materials, reagent and preparation method get faint yellow solid 0.79 gram, yield 51.2% (final step yield) with embodiment 3-4.mp?234-236℃；
1H-NMR(DMSO-d
6，400MHz)δ2.37(s，3H)，3.83(s，3H)，6.33(s，2H)，7.27(s，1H)，7.90(m，4H)，8.39(s，1H)；MS(EI)m/z?388(M
+)。
Embodiment 15
N-(4-sulfamoyl phenyl)-5-methyl furan-2-methane amide (Compound I
A-8) preparation
With 5-methyl furan-2-formic acid and 4-aminobenzene sulfonamide is raw material, and all the other desired raw materials, reagent and preparation method get faint yellow solid 0.98 gram, yield 88.3% (final step yield) with embodiment 4.mp?249-262℃；
1H-NMR(DMSO-d
6，400MHz)δ2.38(s，3H)，6.33(s，1H)，7.27(s，1H)，7.76(d，2H)，7.89(s，2H)；MS(EI)m/z280(M
+)。
Embodiment 16
The compounds of this invention I
A-1 combines determination of activity with Falcipain-2 proteolytic enzyme:
Falcipain-2 proteolytic enzyme and I
A-1 in conjunction with the mensuration of active screening and kinetic constant based on SPR (surface plasma resonance) principle, the instrument of use be Biacore 3000 (Biacore AB, Uppsala, Sweden).
(1) structure of Falcipain-2 plasmid (pQE30-Fal2)
According to Falcipain-2cDNA sequences Design primer, forward and reverse primer are respectively
5 ' CGTGGATCCCAAATGAATTATGAAG3 ' and
5 ' ATATGTCGACTTATTCAATTAATGGAATG3 ', comprise BamHI and SalI restriction enzyme site, by pcr amplification Falcipain-2 fragment, the PCR product after enzyme cut is connected the back and identifies correctly with expression vector pQE30, be transformed into intestinal bacteria M15 (Qiagen) and express.
(2) the proteic expression and purification of Falcipain-2 (FP-2)
The plasmid pQE30-Fal2 that builds changed over to obtain expressing engineering bacteria among the intestinal bacteria M15, engineering bacteria is incubated at overnight incubation (peptone 10g/L in the 10mL LB substratum that contains 100 μ g/mL penbritins and 50 μ g/mL kantlex, yeast extract 5g/L, sodium-chlor 10g/L).Contain in the fresh LB substratum of penbritin and kantlex by the 1:100 1L that transfers then, under 37 ℃, 220 rev/mins of cultivations.When OD600 reaches about 0.8 the time, add IPTG to final concentration 0.5mM, reduce the temperature to 25 ℃ simultaneously and cultivate and carried out induction expression of protein in 12 hours.4000 rev/mins of centrifugal 30 minutes collection thalline are put in-80 ℃ of Ultralow Temperature Freezers preservations and spend the night after collection is good.Thalline is hanged with the buffer 1 of 20mL (and 10mM imidazole, pH 8.0 for 20mM Tris-Cl, 0.5MNaCl), with ultrasonic disruption on the suspension ice bath (300W worked 30 minutes, one time 5 seconds, midfeather 10 seconds).The cell homogenates that obtains after the fragmentation is at 4 ℃, centrifugal 30 minutes with 10000 rev/mins, abandon supernatant, with buffer 2 (6M guanidine HCl 20mM Tris-Cl 250mM NaCl 20mMimidazole, the pH 8.0) dissolution precipitation of 20mL, mild stirring is 1 hour under the room temperature, 10000 rev/mins of centrifugal 30min, and with sample on the supernatant to Binding buffer 2 (6M guanidine HCl, 20mM Tris-Cl, 250mM NaCl, pH 8.0) Ni that balance is good
2 +On-NTA the post, successively with Wash buffer 1 (8M urea, 20mM Tris-Cl, 500mM NaCl pH 8.0) and the foreign protein of each 30ml flush away non-specific binding of Washbuffer 2 (8M urea, 20mM Tris-Cl, 30mM imidazole), use Elution buffer (8M urea again, 20Mm Tris-Cl, 1M imidazole) 10ml flush away target protein, detect proteic molecular weight and purity with SDS-PAGE.
(3) renaturation of FP-2 inclusion body protein
The albumen that purifying is obtained adds 10mM DTT, 37 ℃ down temperature bathe after 45 minutes, protein solution is diluted to the 10 μ g/ml (dialyzate: 100mM Tris-Cl of dialysing, 1mM EDTA, 20%glycerol, 250mM L-arginine, 1mMGSH, 1mM SSG, pH 8.0) spend the night.The albumen that dialysis is good concentrates the mensuration that promptly can be used as enzyme inhibition activity.
(4) the proteic coupling of FP-2
After thoroughly cleaning Biacore 3000 machines, steady to baseline with HBS-EP damping fluid (3mMEDTA and 0.005% (v/v) surfactant P20, pH 7.4 for 10mM Hepes, 150mM NaCl) balancing machine.0.2MN-ethyl-N '-dimethylaminopropyl carbodiimide (N-ethyl-N '-dimethyl aminopropyl carbodiimide) and 50mMMN-N-Hydroxysuccinimide (EDC/NHS) 1: 1 are mixed, with 5 μ L/min sample introductions 7 minutes with the activation chip surface.FP-2 albumen 10mM sodium acetate, pH4.2, being diluted to final concentration is 69 μ g/ml, with 5 μ L/min flow velocity sample introductions.At last, use the 1M diethanolamine hydrochloride, pH 8.5 is with 5 μ L/min flow velocity sample introductions 7 minutes, the sealing chip surface, and the final proteic coupling amount of FP-2 is about 9300RU.
(5) screening compound
Substrate Z-Phe-Arg-pNA HCl (Bachem AG) is as positive control.I
A-1 usefulness 100%DMSO dissolving, mother liquid concentration is 10mM.With HBS-EP damping fluid diluted compounds, to final concentration be 1 μ M and 10 μ M, the final concentration of DMSO is 0.1%.According to I
A-1 with chip on the proteic bonded RU of FP-2 (Response Unit, resonance units) value, judge whether compound has in conjunction with activity.Have in conjunction with active compound and can carry out detailed dynamic experiment.The result proves I
A-1 has tangible the combination with FP-2 albumen.
(6) kinetic determination
I
A-1 usefulness work damping fluid HBS-EP (containing 0.1%DMSO) is made into different concentration gradients respectively, and with 30 μ l/min sample introduction 1min, the 2min that dissociates stablizes 2min with same buffer then.Obtain I
A-1 with the sensing figure of FP-2 protein-interacting, use 1: 1 (Langmuir) combination model or steady-state model in the Biacore analysis software to carry out match again, obtain definite kinetics and thermodynamic equilibrium constant.
(6) test-results: table 1 positive control and I
A-1 with the test result of FP-2 protein binding constant
Table 1
Embodiment 17
The compounds of this invention suppresses active mensuration to falcipain-2 proteolytic enzyme percentage
(1) renaturation of proteic expression and purification of Falcipain-2 (FP-2) and FP-2 inclusion body protein
Referring to embodiment 16
(2) The compounds of this invention is to the mensuration of FP-2 enzyme inhibition activity
100mM NaOAc at 197 μ L, 10mM DTT, add FP-2 albumen (final concentration 10 μ g/ml) in the buffer system of pH 5.5 and be dissolved in the testing compound solution of DMSO, final concentration 10 μ M and 0 μ M (negative control) are hatched under the room temperature behind the 30min with MD SpectraMax M5 microplate reader in excitation 355nm; Emission 460nm place surveys the RFU value in the 15min continuously, calculates speed of reaction K
m, draw testing compound percent inhibition under 10 μ M with following formula,
Calculation formula is:
(control group K
mValue-experimental group K
mValue)/control group K
mValue * 100%
(3) the compound activity test result sees Table 2.:N-(4-replaces the aminoacyl phenyl)-5-substituted furan-2-Carbox amide to falcipain-2 inhibiting rate data
Table 2.
Embodiment 18
Part of compounds of the present invention is to falcipain-2 proteolytic enzyme half effective inhibition concentration (IC
50) mensuration
Choose 10 μ M inhibiting rates and survey IC at the compound more than 50%
50, select the suitable compound concentration gradient, experimental technique and system such as embodiment 17.According to the compound speed of reaction K that the FP-2 enzyme is lived under different concns
m, the inhibiting rate that the computerized compound is lived to the FP-2 enzyme under different concns uses the Sigmoidal formula to carry out the IC that match obtains compound with orign software
50Value the results are shown in Table 3N-(4-replaces aminoacyl)-5-substituted furan-2-Carbox amide to the falcipain-2 enzyme IC of inhibition alive
50And Fig. 2.
Table 3.
Advantages such as the preparation method of N-of the present invention (4-replace aminoacyl phenyl)-5-substituted furan-2-Carbox amide has that reaction conditions gentleness, abundant raw material are easy to get, operation and aftertreatment are simple, and toxicity of compound of the present invention is very low.
N-of the present invention (4-replaces aminoacyl)-5-substituted furan-2-Carbox amide has all shown positive findings in computer virtual screening and at falcipain-2 proteolytic enzyme in conjunction with test and enzyme inhibition test.Should demonstrate,prove its pharmacological mechanism.Therefore, compound of the present invention can be used for preparing the falcipain-2 inhibitor.
Claims (10)
1, a kind of amide derivatives, it has structure shown in the formula I:
Among the formula I: R
1Be hydrogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Saturated or unsaturated cycloalkyl, 5-7 unit virtue (perfume (or spice)) cyclic group, 5-7 unit heterocyclic radical, the 5-7 unit heterocyclic radical of 5-7 unit virtue (perfume (or spice)) cyclic group of replacement or replacement; R
2Be methyl or R
3OCH
2-, R
35-7 unit virtue (perfume (or spice)) cyclic group for 5-7 unit virtue (perfume (or spice)) cyclic group or replacement; X is C or S=O;
Wherein, the substituting group in the 5-7 unit heterocyclic radical of the 5-7 of described replacement unit virtue (perfume (or spice)) cyclic group and replacement is selected from: halogen, C
1-C
6Straight or branched alkyl, hydroxyl, C
1-C
4Alkoxyl group, C
1-C
4Unsaturated-oxyl, carboxyl, ester group, C
1-C
6Carboxyl alkoxyl group, C
1-C
6Ester group alkoxyl group, C
1-C
6Carboxyalkyl, C
1-C
6Ester group alkyl, cyano group, nitro, amino, methylol, trifluoromethyl, trifluoromethoxy, sulfydryl or C
1-C
4A kind of in the acyl group, two or more, substituent number is 1～4; The heteroatoms of described heterocyclic radical is oxygen, sulphur or/and nitrogen, and heteroatomic number is 1～3.
2, amide derivatives as claimed in claim 1 is characterized in that, when X is S=O, and R
1Be hydrogen, 5-7 unit virtue (perfume (or spice)) cyclic group, 5-7 unit heterocyclic radical, the 5-7 unit heterocyclic radical of 5-7 unit virtue (perfume (or spice)) cyclic group of replacement or replacement; R
2Be methyl or R
3OCH
2-, R
35-7 unit virtue (perfume (or spice)) cyclic group for 5-7 unit virtue (perfume (or spice)) cyclic group or replacement;
Wherein, the substituting group in the 5-7 unit heterocyclic radical of the 5-7 of described replacement unit virtue (perfume (or spice)) cyclic group and replacement is selected from: halogen, C
1-C
6Straight or branched alkyl or C
1-C
4A kind of in the alkoxyl group, two or more, substituent number is 1～4; The heteroatoms of described heterocyclic radical is a nitrogen, and heteroatomic number is 1～3.
3, amide derivatives as claimed in claim 2 is characterized in that, wherein R
1For hydrogen, nitrogenous 6 yuan of heterocyclic radicals or by C
1-C
4Nitrogenous 6 yuan of heterocyclic radicals that alkoxyl group replaces.
4, amide derivatives as claimed in claim 2 is characterized in that, wherein R
2Be methyl or R
3OCH
2-, R
3Be 6 yuan of virtues (perfume (or spice)) cyclic group of 6 yuan of virtue (perfume (or spice)) cyclic groups or replacement, the substituting group of 6 yuan of virtues (perfume (or spice)) cyclic group of wherein said replacement is halogen or C
1-C
3Alkyl, substituent number are 1～4.
5, as claim 3 or 4 described amide derivatives, it is characterized in that, described amide derivatives be N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-5-[(4-chloro-3-aminomethyl phenyl) the oxygen methyl] furans-2-methane amide, N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-the 5-[(4-chloro-phenyl-) the oxygen methyl] furans-2-methane amide, N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-the 5-[(3-aminomethyl phenyl) the oxygen methyl] furans-2-methane amide, N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-5-(phenyl oxygen methyl) furans-2-methane amide, N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-5-[(2,4-two chloro-3, the 5-3,5-dimethylphenyl) the oxygen methyl] furans-2-methane amide, N-(4-sulfamoyl phenyl)-5-[(4-chloro-3-aminomethyl phenyl) oxygen methyl] furans-2-methane amide, N-[[(4-(sulphonamide of 6-methoxy pyrimidine-4-)] phenyl]-5-methyl furan-2-methane amide or N-(4-sulfamoyl phenyl)-5-methyl furan-2-methane amide.
6, amide derivatives as claimed in claim 1 is characterized in that, when X is C, and R
1Be hydrogen, 5-7 unit virtue (perfume (or spice)) cyclic group, 5-7 unit heterocyclic radical, the 5-7 unit heterocyclic radical of 5-7 unit virtue (perfume (or spice)) cyclic group of replacement or replacement; R
2Be R
3OCH
2-, R
35-7 unit virtue (perfume (or spice)) cyclic group for 5-7 unit virtue (perfume (or spice)) cyclic group or replacement;
Wherein, the substituting group in the 5-7 unit heterocyclic radical of the 5-7 of described replacement unit virtue (perfume (or spice)) cyclic group and replacement is selected from: halogen, C
1-C
6Straight or branched alkyl or C
1-C
4A kind of in the alkoxyl group, two or more, substituent number is 1～4.
7, amide derivatives as claimed in claim 6 is characterized in that, wherein R
1For hydrogen, nitrogenous 6 yuan of heterocyclic radicals or by C
1-C
4Nitrogenous 6 yuan of heterocyclic radicals that alkoxyl group replaces.
8, amide derivatives as claimed in claim 6 is characterized in that, wherein R
2Be R
3OCH
2-, R
3Be 6 yuan of virtues (perfume (or spice)) cyclic group of 6 yuan of virtue (perfume (or spice)) cyclic groups or replacement, the substituting group of 6 yuan of virtues (perfume (or spice)) cyclic group of described replacement is halogen or C
1-C
3Alkyl, substituent number are 1～4.
9, as claim 7 or 8 described amide derivatives; it is characterized in that, described amide derivatives be N-[[(4-(aminoacyl of 6-methoxy pyrimidine-4-)] phenyl]-5-[(4-chloro-3-aminomethyl phenyl) the oxygen methyl] furans-2-methane amide or N-(4-aminoacyl phenyl)-5-[(4-chloro-3-aminomethyl phenyl) the oxygen methyl] furans-2-methane amide.
10, as claim 1,2,3,4,6, the application of 7 or 8 described amide derivatives in the medicine of the malaria that preparation is caused by plasmodium.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105294576A (en) * | 2015-11-23 | 2016-02-03 | 和夏化学(太仓)有限公司 | Preparation method for sulfanilamide-6-methoxy pyrimidine sodium |
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| US7615563B2 (en) * | 2003-08-08 | 2009-11-10 | Gonzalez Iii Jesus E | Compositions useful as inhibitors of voltage-gated sodium channels |
| EP1673357A2 (en) * | 2003-08-08 | 2006-06-28 | Vertex Pharmaceuticals Incorporated | Heteroarylaminosulfonylphenyl derivatives for use as sodium or calcium channel blockers in the treatment of pain |
| KR101535678B1 (en) * | 2006-01-23 | 2015-07-09 | 조셉 피. 에리코 | Methods and compositions of targeted drug development |
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| CN106938997A (en) * | 2017-01-17 | 2017-07-11 | 华东理工大学 | N (4 substitution phenethyl) acetamides and application thereof |
| CN106938997B (en) * | 2017-01-17 | 2019-10-11 | 华东理工大学 | N- (4- replaces phenethyl) acetamides and application thereof |
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| CN115215806A (en) * | 2022-08-16 | 2022-10-21 | 江苏天和制药有限公司 | Method for synthesizing sulfanilamide-6-methoxypyrimidine |
| CN115215806B (en) * | 2022-08-16 | 2024-03-29 | 江苏天和制药有限公司 | Synthesis method of sulfanilamide-6-methoxypyrimidine |
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