CN108299246B - Compound and preparation method and application thereof - Google Patents
Compound and preparation method and application thereof Download PDFInfo
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- CN108299246B CN108299246B CN201710027385.4A CN201710027385A CN108299246B CN 108299246 B CN108299246 B CN 108299246B CN 201710027385 A CN201710027385 A CN 201710027385A CN 108299246 B CN108299246 B CN 108299246B
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- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
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Abstract
The compound provided by the invention can be used as a neuraminidase inhibitor, and experimental results show that the compound provided by the invention has a strong inhibition effect on neuraminidase of influenza viruses H1N1, H3N2 and H259Y (H1N1), and particularly has an inhibition effect on neuraminidase of influenza viruses H259Y (H1N1) which is more than or equal to that of oseltamivir carboxylic acid serving as a positive drug. Therefore, the compound has high activity, can be used for preparing neuraminidase inhibitors, and has the advantages of simple preparation method, readily available raw materials and low cost.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound, and a preparation method and application thereof.
Background
Influenza is an influenza (influenza) for short, is an acute upper respiratory infectious disease caused by influenza virus, and is a high-incidence stage in autumn and winter generally. The influenza has strong infectivity and high transmission speed, and is mainly transmitted through droplets in the air, contact between people or contact with contaminated products. Typical clinical symptoms are: acute high fever, general pain, marked weakness and mild respiratory symptoms. Influenza is still one of the major diseases threatening human life and health at present. According to incomplete statistics, about 25 to 50 million people die of influenza every year in the world on average.
Influenza viruses are also classified into many subtypes according to antigenic differences of Hemagglutinin (HA) and Neuraminidase (NA) on their surfaces. Wherein, there are 9 subtypes of NA (N1-N9) and 16 subtypes of HA (H1-H16), which can be combined with each other to form more than one hundred subtypes. Neuraminidase (NA), encoded by segment 6 (gene length 1407 nucleotide residues), is a tetramer consisting of 4 identical glycosylated polypeptides. NA hydrolyzes the terminal sialic acid residues of cell surface glycoprotein receptors, facilitating release and migration of the virus, preventing viral aggregation.
Neuraminidase inhibitors (NAIs) that have been approved by the FDA for marketing to date include zanamivir, oseltamivir, and peramivir. Oseltamivir is the only oral drug. However, the continued emergence of oseltamivir-resistant strains, such as neuraminidase mutants, e.g., H274Y, I117V, E119A, R292K, etc., has reduced the effectiveness of NA inhibitors. Therefore, there is an urgent need to develop new neuraminidase inhibitors.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is a compound, a preparation method and an application thereof, wherein the compound provided by the present invention can be used as a neuraminidase inhibitor and has high inhibitory activity.
The invention provides a compound, which has a structure shown in a formula (I),
wherein R is C1-C10 alkyl without substituent or C1-C30 alkyl with substituent.
Preferably, the substituent of the substituent-containing C1-C30 alkyl group is a carbon-carbon double bond, a carbon-carbon triple bond, a halogen, an unsubstituted aryl group or a substituted aryl group.
Preferably, the substituent in the substituted aryl is halogen, alkoxy of C1-C10 or alkyl of C1-C10.
Preferably, R is a linear alkyl group of C2-C5 without substituent, a branched alkyl group of C2-C5 without substituent or an alkyl group of C4-C15 with substituent.
Preferably, R is C2-C5 alkyl substituted by phenyl, methylphenyl, bromophenyl, methoxyphenyl, naphthyl or dimethoxyphenyl, unsaturated alkyl of C2-C5, straight-chain alkyl of C2-C5 without substituent or branched-chain alkyl of C2-C5 without substituent.
Preferably, R is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, allyl, 1-alkenylbutyl, 1-alkenylpentyl, o-methylbenzyl, p-bromobenzyl, o-bromobenzyl, p-methoxybenzyl, o-methoxybenzyl, naphthylmethyl, naphthylethyl, phenethyl, phenylpropyl, phenylbutyl or 4-dimethylphenylethyl.
Preferably, the compound is (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3-propionylguanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3-butyrylguanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3-pentanoylguanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3-propionylguanidino) -1-cyclohexene-1-carboxylic acid - (4-alkenylpentanoyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (2-methylacetyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (3-methylbutyryl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (2- (2-methylphenyl) acetyl) guanidino) -1-cyclohexa-none Alkene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (2- (4-methylphenyl) acetyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (2- (4-bromo-phenyl) acetyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (2-naphthylacetyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (3-phenylpropionyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (3- (3, 4-di-methoxyphenyl) propionyl) guanidino) -1-cyclohexene-1-carboxylic acid or (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (2- (4-phenylbutyryl) guanidino) -1-cyclohexene-1-carboxylic acid.
The invention also provides a preparation method of the compound, which comprises the following steps:
1) the oseltamivir phosphate is reacted with the compound with the structure of the formula (II) to obtain the compound with the structure of the formula (III),
wherein R is C1-C10 alkyl without substituent or C1-C30 alkyl with substituent;
2) converting the compound with the structure of the formula (III) into the compound with the structure of the formula (I),
the invention also provides a salt of the compound, which has a structure shown in a formula (I-S),
wherein R is C1-C10 alkyl without substituent or C1-C30 alkyl with substituent;
and X is a pharmaceutically acceptable acid.
The invention also discloses application of the compound and a salt of the compound in preparation of neuraminidase inhibitors.
Compared with the prior art, the compound provided by the invention can be used as a neuraminidase inhibitor, and experimental results show that the compound provided by the invention has a strong inhibition effect on neuraminidase of influenza virus H1N1, H3N2 and H259Y (H1N1), particularly the inhibition effect on neuraminidase of influenza virus H259Y (H1N1), and is more than or equal to that of oseltamivir carboxylic acid serving as a positive drug. Therefore, the compound has high activity, can be used for preparing neuraminidase inhibitors, and has the advantages of simple preparation method, readily available raw materials and low cost.
Detailed Description
The invention provides a compound, which has a structure shown in a formula (I),
wherein R is C1-C10 alkyl without substituent or C1-C30 alkyl with substituent.
According to the invention, the substituent of the substituent-containing C1-C30 alkyl group is preferably a carbon-carbon double bond, a carbon-carbon triple bond, halogen, unsubstituted aryl or substituted aryl, more preferably a carbon-carbon double bond, a carbon-carbon triple bond, chlorine, bromine, iodine, unsubstituted phenyl, unsubstituted naphthyl, unsubstituted anthryl, substituted phenyl, substituted naphthyl or substituted anthryl; among them, the substituent of the substituted phenyl group, the substituted naphthyl group or the substituted anthracenyl group is preferably halogen, alkoxy of C1 to C10 or alkyl of C1 to C10, and more preferably chlorine, bromine, iodine, methoxy, ethoxy, propoxy, methyl, ethyl, propyl, isopropyl or n-butyl.
Specifically, R is preferably a linear alkyl group of C2-C5 having no substituent, a branched alkyl group of C2-C5 having no substituent, or an alkyl group of C4-C15 having a substituent, more preferably a C2-C5 alkyl group substituted with phenyl, methylphenyl, bromophenyl, methoxyphenyl, naphthyl or dimethoxyphenyl, an unsaturated alkyl group of C2-C5, a linear alkyl group of C2-C5 having no substituent, or a branched alkyl group of C2-C5 having no substituent, more preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, allyl, 1-alkenylbutyl, 1-alkenylpentyl, o-methylbenzyl, p-bromobenzyl, o-bromobenzyl, p-methoxybenzyl, o-methoxybenzyl, naphthylmethyl, naphthylethyl, phenethyl, phenylpropyl, phenylbutyl or 4-dimethylphenylethyl.
More specifically, the compound of the present invention is preferably (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3-propionylguanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3-butyrylguanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3-valerylguanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino- 5- (3- (4-alkenylpentanoyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (2-methylacetyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (3-methylbutyryl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (2- (2-methylphenyl) acetyl) guanidino- 1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (2- (4-methylphenyl) acetyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (2- (4-bromo-phenyl) acetyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (2-naphthylacetyl) guanidino) -1-cyclohexene-1-carboxylic acid Acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (3-phenylpropionyl) guanidino) -1-cyclohexene-1-carboxylic acid, (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (3- (3- (3, 4-di-methoxyphenyl) propionyl) guanidino) -1-cyclohexene-1-carboxylic acid or (3R, 4R, 5S) -3- (1-ethylpropoxy) -4-acetylamino-5- (2- (4-phenylbutyryl) guanidino) -1-cyclohexene-1-carboxylic acid.
The invention also provides a preparation method of the compound, which comprises the following steps:
1) the oseltamivir phosphate is reacted with the compound with the structure of the formula (II) to obtain the compound with the structure of the formula (III),
wherein R is C1-C10 alkyl without substituent or C1-C30 alkyl with substituent;
2) converting the compound with the structure of the formula (III) into the compound with the structure of the formula (I),
according to the invention, the oseltamivir phosphate reacts with the compound with the structure of formula (II) to obtain the compound with the structure of formula (III); wherein R in the compound of formula (II) is as defined for R in the aforementioned compound; the catalyst for the reaction is preferably mercury (II) chloride and an organic base; the organic base is preferably triethylamine (Et)3N); the solvent of the reaction is preferably DMF; the temperature of the reaction is preferably room temperature; the mol ratio of the oseltamivir phosphate to the compound with the structure of the formula (II) is preferably (1-3) to 1, and more preferably (1-2) to 1.
In the present invention, the source of the compound having the structure of formula (II) is not particularly limited, and may be purchased or manufactured by the user, and in the present invention, the compound is preferably prepared by the following method:
reacting the compound with the structure of the formula (IV) with R-COOH to obtain a compound with the structure of the formula (II),
wherein R is C1-C10 alkyl without substituent or C1-C30 alkyl with substituent,
in this reaction, the catalyst for the reaction is preferably benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (Pybop) and methylmorpholine (NMM); the solvent of the reaction is preferably DMF; the temperature of the reaction is preferably room temperature; the molar ratio of the compound with the structure of the formula (IV) to the R-COOH is preferably 1: 1 to 5, and more preferably 1: 2 to 4.
In the invention, the compound with the structure of formula (IV) is preferably prepared according to the following method: mixing methylthiourea hydroiodide and di-tert-butyl dicarbonate (Boc)2O) mixed reaction to prepare a compound with a structure of a formula (IV); wherein the reaction isThe alkali of (2) is sodium hydroxide or potassium hydroxide; the solvent for the reaction is preferably a mixed solution of alcohol and water, wherein the volume ratio of the alcohol to the water in the mixed solution is (8-12) to 1, and more preferably 10 to 1; the alcohol is preferably ethanol or tert-butanol; the reaction temperature is preferably-10-40 ℃, and more preferably 0-30 ℃.
According to the invention, the compound with the structure of formula (III) is converted into the compound with the structure of formula (I), the method for converting the compound with the structure of formula (III) into the compound with the structure of formula (I) is not particularly limited, and a person skilled in the art can select a suitable synthetic method according to the common general knowledge in the field, and particularly, the compound with the structure of formula (III) is preferably converted into the compound with the structure of formula (V) firstly; then converting the compound with the structure of the formula (V) into a compound with the structure of the formula (I);
wherein, in the reaction for converting the compound with the structure of the formula (III) into the compound with the structure of the formula (V), the used catalyst is preferably trifluoroacetic acid (TFA), and the solvent for the reaction is preferably dichloromethane; in the reaction, the volume ratio of the trifluoroacetic acid to the dichloromethane is preferably 1 to (1-10), and more preferably 1 to (3-5); the temperature of the reaction is preferably room temperature.
In the reaction of converting the compound with the structure of the formula (V) into the compound with the structure of the formula (I), the base of the reaction is inorganic base, and sodium carbonate or potassium carbonate is more preferable; the solvent for the reaction is preferably one or two of methanol and ethanol; the molar ratio of the inorganic base to the compound with the structure of the formula (V) is preferably (1-10) to 1, and more preferably (4-6) to 1; the temperature of the reaction is preferably room temperature.
The invention also provides a salt of the compound, which has a structure shown in a formula (I-S),
wherein R is C1-C10 alkyl without substituent or C1-C30 alkyl with substituent;
and X is a pharmaceutically acceptable acid.
Wherein, X is preferably trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid or hydrochloric acid.
The invention also provides an application of the compound and the salt of the compound in the preparation of neuraminidase inhibitors, wherein the neuraminidase inhibitors are preferably H1N1-H259Y type neuraminidase inhibitors.
The compound provided by the invention can be used as a neuraminidase inhibitor, and experimental results show that the compound provided by the invention has a strong inhibition effect on neuraminidase of influenza viruses H1N1, H3N2 and H259Y (H1N1), and particularly has an inhibition effect on neuraminidase of influenza viruses H259Y (H1N1) which is more than or equal to that of oseltamivir carboxylic acid serving as a positive drug. Therefore, the compound has high activity, can be used for preparing neuraminidase inhibitors, and has the advantages of simple preparation method, readily available raw materials and low cost.
The following will clearly and completely describe the technical solutions of the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The reaction scheme of the compound of formula (I) is as follows
The specific structural formulas of the synthesized compounds are respectively marked as A1-A13, and are shown in Table 1:
TABLE 1
Taking A1 as an example, the preparation method comprises the following steps:
synthesis of intermediate 1: s-methylthiourea hydroiodide (11g, 50.4mmol) was dissolved in 100mL of t-butanol, and 10mL of an aqueous solution containing sodium hydroxide (2g, 50.4mmol) was added and stirred at room temperature for 30 min. Add 50mL of dissolved 9g Boc under ice bath2O in tert-butanol, emulsion, stirred overnight at rt for complete reaction, stopped reaction, 140mL dichloromethane was added, washed 2 times with saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, concentrated to dryness, and flash column chromatographed (PE: EA ═ 6: 1) to give intermediate 1, 7.1g, white solid, 74% yield.
Synthesis of intermediate 2: propionic acid (172mg, 2.32mmol), Pybop (1.21g, 2.32mmol), NMM (469mg, 4.64mmol) were dissolved in 4ml dmf and stirred at rt for 30min, intermediate 1(220mg, 1.16mmol) was added and stirred at rt overnight to complete the reaction. The reaction was stopped, water was added, extraction was performed with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and flash column chromatography was performed (PE: EA ═ 25: 1) to give intermediate 2.
Synthesis of intermediate 3: oseltamivir phosphate (200mg, 0.82mmol), intermediate 2(202mg, 0.82mmol) and triethylamine (274mg, 2.71mmol) are dissolved in 3mL of DMF solution, stirred at room temperature for 10min, mercury chloride (268mg, 0.98mmol) is added under ice bath, precipitate is separated after 5min, stirred at room temperature overnight, the reaction is stopped after the reaction is completed, the mixture is cooled to room temperature, water and ethyl acetate are added to dilute the reaction solution, the reaction solution is filtered by diatomite, solid precipitate is removed, the filtrate is extracted by ethyl acetate for 2 times, the filtrate is washed by saturated saline water for 2 times, anhydrous sodium sulfate is dried, the concentration is carried out until the reaction is dry, and the intermediate 3 is obtained through flash column chromatography (PE: EA is 3: 2).
Synthesis of intermediate 4: intermediate 3(200mg, 0.39mmol) was dissolved in 5mL TFA/dichloromethane-1/1 solution, stirred at room temperature for 5h, concentrated to dryness, ether was added and precipitate out, which was filtered to give intermediate 4.
Synthesis of target compound a 1: dissolving the intermediate 4(100mg, 0.24mmol) in 16ml of ethanol, adding 4ml of an aqueous solution dissolved with potassium carbonate (132mg, 0.96mmol) into the solution, precipitating a small amount of solid, performing ultrasonic treatment for 2min, stirring at room temperature for 12 hours, stopping the reaction, concentrating the reaction solution under reduced pressure to a small amount, adding 10% of HCl aqueous solution to adjust the pH to be 4-5, precipitating white solid, concentrating under reduced pressure to be dry, and preparing by HPLC (acetonitrile/0.1% formic acid water) to obtain products A1, 18mg and the yield of 36%.
Preparation of target compound a1 trifluoroacetate salt: the title compound A1 trifluoroacetate salt was prepared by stirring the title compound A1(100mg, 0.26mmol), dichloromethane (5 ml), and trifluoroacetic acid (5 ml) at room temperature for 12 hours, adding diethyl ether (5 ml) after completion of the reaction, and filtering.
Compound a 1:1H NMR(400MHz，DMSO-d6)，δ(ppm)：8.00(1H，d，J＝8.5Hz)，6.68(1H，s)，4.12-4.10(1H，m)，4.04-3.94(1H，m)，3.91-3.85(1H，m)，3.62-3.59(1H，m)，2.72(1H，dd，J＝17.4Hz，4.7Hz)，2.42(2H，q，J＝7.3Hz)，2.34-2.28(1H，m)，1.83(3H，s)，1.50-1.37(4H，m)，1.03(3H，t，J＝7.3Hz)，0.87-0.79(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：176.8，170.4，167.9，153.8，136.8，129.5，81.8，74.6，52.7，49.9，30.2，29.6，26.2，25.7，23.1，9.9，9.5，8.7；HR-MS(ESI)m/z：calcd for C18H30N4O5[M+H]+383.2294[M+Na]+405.2114，found 383.2294，405.2109.
preparation of compounds a2-a13 compound a2-a13 and its pharmaceutically acceptable salts were prepared according to the procedure of compound a1, by changing propionic acid to the corresponding carboxylic acid, charging the corresponding carboxylic acid and other starting materials in the equivalent ratio and amount of compound a1, and the same other experimental procedures.
Compound a 2: white solid, yield 27%.1H NMR(400MHz，DMSO-d6)δ(ppm)：12.77(1H，s)，8.98(1H，d，J＝7.8Hz)，8.85(2H，s)，8.00(1H，d，J＝8.4Hz)，6.69(1H，s)，4.12-4.05(1H，m)，4.04-3.95(1H，m)，3.95-3.85(1H，m)，3.44-3.36(1H，m)，2.72(1H，dd，J＝17.5Hz，4.3Hz)，2.39(2H，t，J＝7.2Hz)，2.34-2.29(1H，m)，1.82(3H，s)，1.61-1.52(2H，m)，1.49-1.37(4H，m)，0.91-0.78(9H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：175.6，170.2，167.5，153.4，137.2，129.0，81.8，74.6，52.6，50.0，38.5，29.4，26.2，25.7，23.1，17.8，13.7，9.9，9.5；HR-MS(ESI)m/z：calcd for C19H32N4O5[M+H]+397.2451，found 397.2478.
Compound a 3: white solid, yield 40%.1H NMR(400MHz，DMSO-d6)δ(ppm)：12.77(1H，s)，8.98(1H，d，J＝7.9Hz)，8.83(2H，s)，8.00(1H，d，J＝8.4Hz)，6.69(1H，s)，4.11-4.06(1H，m)，4.05-3.95(1H，m)，3.95-3.85(1H，m)，3.43-3.35(1H，m)，2.72(1H，dd，J＝17.4Hz，4.4Hz)，2.40(2H，t，J＝7.2Hz)，2.36-2.29(1H，m)，1.82(3H，s)，1.57-1.49(2H，m)，1.47-1.39(2H，m)，1.34-1.24(4H，m)，0.89-0.78(9H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：175.7，170.3，167.5，153.4，137.2，129.0，81.8，74.6，52.6，49.9，36.4，29.4，26.4，26.1，25.7，23.1，21.9，14.0，9.9，9.5；HR-MS(ESI)m/z：calcd for C20H34N4O5[M+H]+411.2607，found 411.2624.
Compound a 4: white solid, yield 46%.1H NMR(400MHz，DMSO-d6)δ(ppm)：12.77(1H，s)，8.98(1H，d，J＝7.7Hz)，8.84(2H，s)，8.01(1H，d，J＝8.4Hz)，6.69(1H，s)，5.86-5.76(1H，m)，5.08-4.99(2H，m)，4.15-4.06(1H，m)，4.06-3.94(1H，m)，3.94-3.85(1H，m)，3.42-3.38(1H，m)，2.71(1H，dd，J＝17.5Hz，4.4Hz)，2.54-2.51(2H，m)，2.36-2.28(3H，m)，1.82(3H，s)，1.49-1.37(4H，m)，0.87-0.78(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：174.9，170.3，167.5，153.4，137.2，137.0，129.0，116.2，81.8，74.6，52.6，50.0，35.8，29.5，28.2，26.2，25.7，23.1，9.9，9.5；HR-MS(ESI)m/z：calcd for C20H32N4O5[M+H]+409.2451，found 409.2458.
Compound a 5: white solid, yield 46%.1H NMR(400MHz，DMSO-d6)，δ(ppm)：12.78(1H，s)，8.96(1H，d，J＝8.2Hz)，8.84(2H，s)，8.00(1H，d，J＝8.5Hz)，6.70(1H，s)，4.13-4.05(1H，m)，4.05-3.95(1H，m)，3.95-3.87(1H，m)，3.42-3.39(1H，m)，2.72(1H，dd，J＝17.5Hz，4.6Hz)，2.65-2.58(1H，m)，2.37-2.30(1H，m)，1.82(3H，s)，1.48-1.39(4H，m)，1.10(6H，d，J＝6.8Hz)，0.86-0.78(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：179.3，170.3，167.5，153.7，137.1，129.0，81.8，74.5，52.5，49.9，35.8，29.4，26.1，25.7，23.1，18.9，18.8，9.9，9.5；HR-MS(ESI)m/z：calcd for C19H32N4O5[M+H]+397.2451，found 397.2478.
Compound a 6: white solid, yield 44%.1H NMR(400MHz，DMSO-d6)，δ(ppm)：12.77(1H，s)，9.00(1H，d，J＝7.6Hz)，8.83(2H，s)，7.99(1H，d，J＝8.4Hz)，6.69(1H，s)，4.12-4.05(1H，m)，4.05-3.96(1H，m)，3.96-3.88(1H，m)，3.42-3.37(1H，m)，2.72(1H，dd，J＝17.4Hz，4.3Hz)，2.37-2.32(1H，m)，2.28(2H，d，J＝7.0Hz)，2.07-1.97(1H，m)，1.82(3H，s)，1.49-1.38(4H，m)，0.92(6H，d，J＝6.7Hz)，0.87-0.78(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：175.0，170.3，167.5，153.4，137.1，129.1，81.8，74.6，52.7，49.9，45.6，29.4，26.2，25.7，25.3，23.1，22.4，9.9，9.5；HR-MS(ESI)m/z：calcd for C20H34N4O5[M+H]+411.2607，found 411.2612.
Compound a 7: white solid, yield 69%.1H NMR(400MHz，DMSO-d6)，δ(ppm)：12.77(1H，s)，9.00(1H，s)，8.89(2H，s)，7.99(1H，d，J＝8.5Hz)，7.22-7.13(4H，m)，6.68(1H，s)，4.12-4.05(1H，m)，4.05-3.94(1H，m)，3.92-3.88(1H，m)，3.80(2H，s)，3.39-3.37(1H，m)，2.72(1H，dd，J＝17.4Hz，4.6Hz)，2.36-2.30(1H，m)，2.24(3H，s)，1.81(3H，s)，1.45-1.36(4H，m)，0.85-0.77(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：173.4，170.3，167.5，153.5，137.4，137.2，132.6，130.8，130.5，129.0，127.9，126.4，81.8，74.5，52.7，50.1，41.2，29.4，26.1，25.7，23.1，19.6，9.9，9.5；HR-MS(ESI)m/z：calcd for C24H34N4O5[M+H]+459.2607，found 459.2610.
Compound A8: white solid, yield 36%.1H NMR(400MHz，DMSO-d6)δ(ppm)：12.76(1H，s)，8.95(1H，d，J＝8.1Hz)，8.85(2H，s)，7.98(1H，d，J＝8.4Hz)，7.18-7.13(4H，m)，6.68(1H，s)，4.12-4.05(1H，m)，4.05-3.94(1H，m)，3.92-3.88(1H，m)，3.71(2H，s)，3.39-3.37(1H，m)，2.71(1H，dd，J＝17.4Hz，4.5Hz)，2.35-2.30(1H，m)，2.28(3H，s)，1.81(3H，s)，1.46-1.36(4H，m)，0.86-0.76(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：173.7，170.3，167.5，153.5，137.2，136.8，130.8，129.8，129.5，129.0，81.8，74.6，52.6，50.0，42.9，29.4，26.1，25.7，23.1，21.1，9.9，9.5；HR-MS(ESI)m/z：calcd for C24H34N4O5[M+H]+459.2607，found 459.2650.
Compound a 9: white solid, yield 27%.1H NMR(400MHz，DMSO-d6)δ(ppm)：12.76(1H，s)，8.93(1H，s)，8.85(2H，s)，7.99(1H，d，J＝8.5Hz)，7.54(2H，d，J＝8.3Hz)，7.25(2H，d，J＝8.3Hz)，6.68(1H，s)，4.12-4.05(1H，m)，4.04-3.94(1H，m)，3.92-3.88(1H，m)，3.77(2H，s)，3.39-3.37(1H，m)，2.71(1H，dd，J＝17.5Hz，4.7Hz)，2.35-2.29(1H，m)，1.80(3H，s)，1.46-1.35(4H，m)，0.85-0.76(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：173.1，170.3，167.5，153.6，137.2，133.3，132.3，131.7，129.0，120.9，81.8，74.5，52.6，50.1，42.5，29.4，26.1，25.7，23.1，9.9，9.5；HR-MS(ESI)m/z：calcd for C23H31BrN4O5[M+H]+523.1556 found 523.1564，525.1546.
Compound a 10: white solid, yield 43%.1H NMR(400MHz，DMSO-d6)δ(ppm)：12.76(1H，s)，8.94(1H，d，J＝7.6Hz)，8.86(2H，s)，7.98(1H，d，J＝8.5Hz)，7.92-7.86(3H，m)，7.82(1H，s)，7.55-7.49(2H，m)，7.44(1H，d，J＝8.3Hz)，6.68(1H，s)，4.11-4.06(1H，m)，4.02-3.97(1H，m)，3.95(2H，s)，3.92-3.86(1H，m)，3.39-3.36(1H，m)，2.72(1H，dd，J＝17.4Hz，4.6Hz)，2.36-2.30(1H，m)，1.80(3H，s)，1.45-1.35(4H，m)，0.84-0.75(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：173.5，170.3，167.5，153.4，137.2，133.4，132.5，131.5，129.0，128.6，128.4，128.1，128.0，127.9，126.8，126.5，81.8，74.6，52.6，50.1，43.5，29.4，26.1，25.7，23.1，9.9，9.5；HR-MS(ESI)m/z：calcd for C27H34N4O5[M+H]+495.2607，found 495.2618.
Compound a 11: white solid, yield 45%.1H NMR(400MHz，DMSO-d6)δ(ppm)：12.78(1H，s)，9.04(1H，d，J＝7.0Hz)，8.78(2H，s)，8.00(1H，d，J＝8.4Hz)，7.31-7.18(5H，m)，6.69(1H，s)，4.13-4.07(1H，m)，4.03-3.95(1H，m)，3.93-3.86(1H，m)，3.42-3.36(1H，m)，2.87(2H，t，J＝7.3Hz)，2.76-2.68(3H，m)，2.35-2.29(1H，m)，1.81(3H，s)，1.47-1.38(4H，m)，0.87-0.78(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：174.9，170.3，167.5，153.4，140.6，137.2，129.0，128.9，128.7，126.7，81.9，74.6，52.6，50.0，38.2，29.9，29.5，26.2，25.7，23.1，9.9，9.5；HR-MS(ESI)m/z：calcd for C24H34N4O5[M+H]+459.2607，found 459.2610.
Compound a 12: white solid, yield 30%.1H NMR(400MHz，DMSO-d6)δ(ppm)：12.74(1H，s)，9.00(1H，d，J＝7.9Hz)，8.88(2H，s)，8.00(1H，d，J＝8.4Hz)，6.85(1H，d，J＝8.2Hz)，6.84(1H，s)，6.72(1H，d，J＝8.2Hz)，6.69(1H，s)，4.12-4.08(1H，m)，4.03-3.95(1H，m)，3.93-3.87(1H，m)，3.73(3H，s)，3.71(3H，s)，3.42-3.36(1H，m)，2.81(2H，t，J＝6.9Hz)，2.73-2.68(3H，m)，2.35-2.29(1H，m)，1.81(3H，s)，1.49-1.36(4H，m)，0.87-0.78(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：175.0，170.3，167.5，153.4，149.1，147.7，137.2，132.9，129.0，120.5，112.6，112.3，81.9，74.6，56.0，55.8，52.6，50.0，38.6，29.7，29.5，26.2，25.7，23.1，9.9，9.5；HR-MS(ESI)m/z：calcd for C26H38N4O7[M+H]+519.2819，found 519.2830.
Compound a 13: white solid, yield 30%.1H NMR(400MHz，DMSO-d6)δ(ppm)：12.76(1H，s)，8.92(1H，d，J＝7.4Hz)，8.78(2H，s)，8.01(1H，d，J＝8.4Hz)，7.29(2H，t，J＝7.5Hz)，7.21-7.17(3H，m)，6.69(1H，s)，4.11-4.07(1H，m)，4.03-3.95(1H，m)，3.93-3.88(1H，m)，3.41-3.38(1H，m)，2.71(1H，dd，J＝17.6Hz，4.2Hz)，2.60(2H，t，J＝7.3Hz)，2.42(2H，t，J＝7.3Hz)，2.36-2.29(1H，m)，1.91-1.85(2H，m)，1.82(3H，s)，1.49-1.39(4H，m)，0.87-0.78(6H，m)；13C NMR(100MHz，DMSO-d6)δ(ppm)：175.4，170.3，167.5，153.4，140.7，137.1，129.0，128.8，128.7，126.4，81.9，74.6，52.5，50.0，36.1，34.6，29.4，26.2，26.0，25.7，23.1，9.9，9.5；HR-MS(ESI)m/z：calcd for C25H36N4O5[M+H]+473.2764，found 473.2769.
Example 2 in vitro antiviral Activity assay of Oseltamivir guanidinocarboxylic acid derivatives
1. Experimental materials: a/puerto Rico/8/1934(H1N 1); a/hong kong/498/97 (H)3N2) (ii) a A/puerto Rico/8/1934(H259Y, NA restistant strain); oseltamivir hydrochloride (control); enzyme substrate MUNANA
(2 '-4-methylumbelliferyl-a-N-acetylneuraminate, 2' -4-methylumbelliferyl-alpha-N-acetylneuraminic acid, Sigma); PBS buffer or normal saline; a constant temperature incubator; a microplate reader.
2. The experimental principle is as follows: influenza virus neuraminidase is a surface glycoprotein with enzymatic activity and plays an important role in the replication of influenza virus. The laboratory uses MUNANA as a substrate to detect the NA activity of the influenza virus. MUNANA is a specific substrate of influenza virus NA, and a catalytic product generated under the action of NA can generate fluorescence under the irradiation of exciting light; the change of fluorescence intensity can sensitively reflect the activity of neuraminidase.
3. The method comprises the following steps:
1) drug dilution: diluting the test compound and oseltamivir carboxylate in a drug dilution plate with 8 concentration gradients in a DMSO 3-fold gradient;
2) the effect of the drug on influenza virus NA: transferring the compound to be tested after gradient dilution to a test plate, wherein each hole in the test plate contains PBS, and then adding influenza virus NA into the hole to be uniformly mixed with the compound;
3) substrate and NA and drug action: adding substrate to wells containing NB and compound, mixing and incubating; wherein the highest concentration tested was 1 μ M;
4) the experiment was set up with NA activity control, blank control, and Neuraminidase (NA) positive inhibitor oseltamivir carboxylate control.
5) After reaction at 37 ℃ for 40 minutes, fluorescence was detected on a multi-label analyzer.
Inhibition (%) 100- (sample well-blank)/(NA control-blank)% 100%
The compounds of the invention have activity against influenza virus neuraminidase, as shown in Table 2
TABLE 2 inhibitory Activity of Oseltamivir guanidinocarboxylic acid derivatives against NA (H1N1, H3N2 and H259Y (H1N1)) in vitro
As can be seen from table 2, the compounds of the present invention showed good inhibitory activity against neuraminidase of wild-type and mutant influenza viruses. Among them, compounds a4, a9 and a12 had slightly lower neuraminidase inhibitory activity against wild-type influenza virus but higher neuraminidase inhibitory activity against mutant influenza virus than oseltamivir, which is a positive drug. Other compounds have neuraminidase inhibitory activity against mutant influenza viruses superior to or comparable to positive drugs. The compound can be used for preparing medicaments for preventing and treating diseases caused by influenza viruses.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (4)
1. A compound has a structure shown in formula (I),
wherein R is one of the following groups:
2. a process for preparing the compound of claim 1, comprising:
1) the oseltamivir phosphate is reacted with the compound with the structure of the formula (II) to obtain the compound with the structure of the formula (III),
wherein R is one of the following groups:
2) converting the compound with the structure of the formula (III) into the compound with the structure of the formula (I),
3. a salt of the compound of claim 1, having a structure represented by formula (I-S),
wherein R is one of the following groups:
and X is a pharmaceutically acceptable acid.
4. Use of a compound according to claim 1 or a salt of a compound according to claim 3 in the preparation of a neuraminidase inhibitor.
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| CN103848762A (en) * | 2012-11-30 | 2014-06-11 | 北京普禄德医药科技有限公司 | Neuraminidase inhibitor prodrug and its composition and use |
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| CN103848762A (en) * | 2012-11-30 | 2014-06-11 | 北京普禄德医药科技有限公司 | Neuraminidase inhibitor prodrug and its composition and use |
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