CN108774193B - 5- (3-phenylpropenoyl) -2-benzoylaminothiazole and medical application thereof - Google Patents

5- (3-phenylpropenoyl) -2-benzoylaminothiazole and medical application thereof Download PDF

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CN108774193B
CN108774193B CN201810592829.3A CN201810592829A CN108774193B CN 108774193 B CN108774193 B CN 108774193B CN 201810592829 A CN201810592829 A CN 201810592829A CN 108774193 B CN108774193 B CN 108774193B
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CN108774193A (en
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胡艾希
易阳杰
张蒙
叶姣
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Hunan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Abstract

The invention relates to 5- (3-phenylpropenoyl) of formula I) -2-benzoylaminothiazole and pharmaceutically acceptable salts thereof, pharmaceutical compositions and use thereof in the preparation of influenza virus neuraminidase inhibitors.
Figure DDA0001786394860000011
Wherein R is selected from: c1～C4Straight chain or C3～C4A branched alkyl group; r1Selected from: hydrogen, amino, methylamino, dimethylamino, methoxy, ethoxy, hydroxy, dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy, or 4-hydroxy-3-ethoxy; y is selected from: H. deuterium, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, nitro, trifluoromethyl, trifluoromethoxy, 3-methyl-4-nitro, 2-methyl-4-nitro or 3-methyl-5-nitro.

Description

5- (3-phenylpropenoyl) -2-benzoylaminothiazole and medical application thereof
Technical Field
The invention relates to a novel compound, a preparation method and application thereof, in particular to 5- (3-phenylpropenoyl) -2-benzoyl aminothiazole, a preparation method and application thereof in preparing influenza virus neuraminidase inhibitors.
Background
Mills et al [ Bioorg Med Chem Lett,2010,20(1):87-91] describe a process for the preparation of 4-methyl-5-acetyl-2-benzoylaminothiazole 1 in 97% yield. Compound 2, prepared via 4-methyl-5-acetyl-2-benzoylaminothiazole, has good activity against cystic fibrosis.
Figure GDA0002525379120000011
Suciu et al [ Adv Synth Catal,1972,314(5-6): 961-.
Figure GDA0002525379120000012
Davison et al [ Bioorg Med ChemLett,2012,22(4): 1602-. Compound 6, which is designed and synthesized based on 4-methyl-5-acetyl-2- (4-fluorobenzamido) thiazole, has the effect of assisting in treating cystic fibrosis.
Figure GDA0002525379120000013
Sato et al [ WO 9502586A1] describe a process for the preparation of 4-methyl-5-acetyl-2- (4-cyanobenzoylamino) thiazole 7 in 83% yield; the compound 8 synthesized by 4-methyl-5-acetyl-2- (4-cyanobenzoylamino) thiazole has dual antagonistic actions of fibrinogen receptor and cell adhesion factor.
Figure GDA0002525379120000021
Suciu et al [ Adv Synth Catal,1971,313(2):193-204] describe the preparation of 4-methyl-5-acetyl-2- (3-nitrobenzoylamino) thiazole 9 by nitration of 4-methyl-5-acetyl-2-benzoylaminothiazole 1 in a yield of 78%.
Figure GDA0002525379120000022
Disclosure of Invention
The invention aims to provide 5- (3-phenylpropenoyl) -2-benzoyl aminothiazole, a preparation method, a pharmaceutical composition and application thereof.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides 5- (3-phenylpropenoyl) -2-benzoyl aminothiazole shown as a structural formula I and pharmaceutically acceptable salts thereof:
Figure GDA0002525379120000023
wherein R is selected from: methyl, ethyl, C3～C4Straight chain or C3～C4A branched alkyl group; r1Selected from: hydrogen, 2-amino group, 3-amino group, 4-amino group, 2-methylamino group, 3-methylamino group, 4-methylamino group, 2-dimethylamino group, 3-dimethylamino group, 4-dimethylamino group, 2-methoxy group, 3-methoxy group, 4-methoxy group, 2-ethoxy group, 3-ethoxy group, 4-ethoxy group, 2-ethoxy group, 3-ethoxy group, 2-methoxy group, 2-ethoxy group, 3-ethoxy group, 2-ethoxy group, 4-,2-hydroxy, 3-hydroxy, 4-hydroxy, 2, 3-dihydroxy, 2, 4-dihydroxy, 2, 5-dihydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy or 4-hydroxy-3-ethoxy; y is selected from: H. 2-deuterium, 2-methyl, 2-ethyl, 2-methoxy, 2-ethoxy, 2-fluoro, 2-chloro, 2-bromo, 2-nitro, 2-trifluoromethyl, 2-trifluoromethoxy, 3-deuterium, 3-methyl, 3-ethyl, 3-hydroxy, 3-methoxy, 3-ethoxy, 3-fluoro, 3-chloro, 3-bromo, 3-nitro, 3-trifluoromethyl, 3-trifluoromethoxy, 4-deuterium, 4-methyl, 4-ethyl, 4-hydroxy, 4-methoxy, 4-ethoxy, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4-trifluoromethyl, 4-nitro, 4-trifluoromethoxy, 2-ethoxy, 2-chloro, 3-nitro, 3-trifluoromethyl, 4-methoxy, 3-ethoxy, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4, 3-methyl-4-nitro, 2-methyl-4-nitro or 3-methyl-5-nitro.
In a first aspect, there is also provided a class of 5- (3-phenylpropenoyl) -2-benzoylaminothiazoles of formula II:
Figure GDA0002525379120000031
wherein R is selected from: methyl, ethyl, C3～C4Straight chain or C3～C4A branched alkyl group; r2Selected from: hydrogen, 2-amino, 3-amino, 2-methylamino, 3-methylamino, 2-dimethylamino, 3-dimethylamino, 2-methoxy, 3-methoxy, 2-ethoxy, 3-ethoxy, 2-hydroxy, 3-hydroxy, 2, 3-dihydroxy, 2, 5-dihydroxy, 3, 5-dihydroxy, or 2-hydroxy-3-methoxy; y is selected from: H. 2-deuterium, 2-methyl, 2-ethyl, 2-methoxy, 2-ethoxy, 2-fluoro, 2-chloro, 2-bromo, 2-nitro, 2-trifluoromethyl, 2-trifluoromethoxy, 3-deuterium, 3-methyl, 3-ethyl, 3-hydroxy, 3-methoxy, 3-ethoxy, 3-fluoro, 3-chloro, 3-bromo, 3-nitro, 3-trifluoromethyl, 3-trifluoromethoxy, 4-deuterium, 4-methyl, 4-ethyl, 4-hydroxy, 4-methoxy, 4-ethoxy, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4-trifluoromethyl, 4-nitro, 4-trifluoromethoxy, 2-ethoxy, 2-chloro, 3-nitro, 3-trifluoromethyl, 4-methoxy, 3-ethoxy, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4, 3-methyl-4-nitro, 2-methyl-4-nitro or 3-methyl-5-nitro.
The first aspect of the technical scheme of the invention also provides a 5- (3-phenylpropenoyl) -2-benzoyl aminothiazole selected from the following compounds:
Figure GDA0002525379120000032
the second aspect of the technical scheme of the invention provides a preparation method of 5- (3-phenyl acryloyl) -2-benzoyl aminothiazole, which is characterized in that the preparation reaction is as follows:
Figure GDA0002525379120000041
wherein R is selected from: methyl, ethyl, C3～C4Straight chain or C3～C4A branched alkyl group; r1Selected from: hydrogen, 2-amino, 3-amino, 4-amino, 2-methylamino, 3-methylamino, 4-methylamino, 2-dimethylamino, 3-dimethylamino, 4-dimethylamino, 2-methoxy, 3-methoxy, 4-methoxy, 2-ethoxy, 3-ethoxy, 4-ethoxy, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2, 3-dihydroxy, 2, 4-dihydroxy, 2, 5-dihydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy or 4-hydroxy-3-ethoxy; y is selected from: H. 2-deuterium, 2-methyl, 2-ethyl, 2-methoxy, 2-ethoxy, 2-fluoro, 2-chloro, 2-bromo, 2-nitro, 2-trifluoromethyl, 2-trifluoromethoxy, 3-deuterium, 3-methyl, 3-ethyl, 3-hydroxy, 3-methoxy, 3-ethoxy, 3-fluoro, 3-chloro, 3-bromo, 3-nitro, 3-trifluoromethyl, 3-trifluoromethoxy, 4-deuterium, 4-methyl, 4-ethyl, 4-hydroxy, 4-methoxy, 4-ethoxy, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4-trifluoromethyl, 4-nitro, 4-trifluoromethoxy, 2-ethoxy, 2-chloro, 3-nitro, 3-trifluoromethyl, 4-methoxy, 3-ethoxy, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4, 3-methyl-4-nitro, 2-methyl-4-nitro or 3-methyl-5-nitro; x is selected from: chlorine or bromine.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the 5- (3-phenylpropenoyl) -2-benzoylaminothiazole and the pharmaceutically acceptable salt thereof according to the present invention, and optionally a pharmaceutically acceptable carrier. Wherein the medicinal carrier refers to a medicinal carrier commonly used in the field of pharmacy; the pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention and the pharmaceutically acceptable salt thereof in the pharmaceutical composition thereof is usually 0.1 to 95% by weight.
The compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compounds of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the effective component of the compound and the pharmaceutically acceptable salt thereof can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salt tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.
In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture of the water, the ethanol, the isopropanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The fourth aspect of the technical scheme of the invention is to provide the 5- (3-phenylpropenoyl) -2-benzoylaminothiazole and the pharmaceutically acceptable salts thereof and the application of the pharmaceutical composition in the third aspect in preparing influenza virus neuraminidase inhibitors.
The beneficial technical effects are as follows:
the 5- (3-phenylpropenoyl) -2-benzoyl aminothiazole provided by the invention is a compound with the activity of inhibiting influenza virus neuraminidase.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2-benzoylaminothiazole (A)
Figure GDA0002525379120000061
(1) Preparation of 4-methyl-5-acetyl-2-benzoylaminothiazole
6.0mmol of benzoic acid was dissolved in 10mL of DMF solution, 0.972g (6.0mmol) of N, N' -Carbonyldiimidazole (CDI) was added in portions, stirred at room temperature for 30min, added with 4.0mmol of 4-methyl-5-acetyl-2-aminothiazole, and reacted at 85 ℃ for 8 h. Cooling to room temperature, pouring 30mL of ice water into the reaction solution, precipitating a large amount of solid, and recrystallizing the crude product by ethyl acetate/tetrahydrofuran to obtain the white solid 4-methyl-5-acetyl-2-benzoyl aminothiazole with the yield of 61.0 percent and m.p.228-230 ℃.
Or prepared according to the literature [ Bioorg Med Chem Lett,2010,20(1):87-91 ]:
Figure GDA0002525379120000062
(2) preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2-benzoylaminothiazole (A)
1.0mmol of 4-methyl-5-acetyl-2-benzoyl aminothiazole and 1.0mmol of p-hydroxybenzaldehyde solution are put into 6.0mL of ethanol solution, dried HCl gas is introduced to be saturated, the reaction is carried out for 6h at room temperature, and the crude product is recrystallized by ethanol to obtain yellow solid 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl group]-2-benzoylaminothiazole A, yield 67.7%, m.p.262-264 ℃.1H NMR(400MHz，DMSO-d6)：2.70(s，3H，CH3)，6.89(d，J＝8.0Hz，2H，C6H4)，7.24(d，J＝15.3Hz，1H，CH)，7.53～7.72，8.13～8.15(m，8H，C6H4+C6H5+CH)，9.79(s，1H，OH)，12.48(s，1H，NH)。13C NMR(101MHz，DMSO-d6)：18.64，116.45，121.57，125.86，125.93，128.79，129.15，131.30，132.09，133.43，143.87，154.81，160.49，160.82，166.22，182.75。
Example 2
Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-hydroxybenzamido) thiazole (B)
Figure GDA0002525379120000063
(1) Preparation of 4-methyl-5-acetyl-2- (4-hydroxybenzamido) thiazole
Prepared by the method of example 1, 6mmol 4-hydroxybenzoic acid reacts with 4.0mmol 4-methyl-5-acetyl-2-aminothiazole for 12h, and the crude product is recrystallized by ethyl acetate/tetrahydrofuran to obtain off-white solid 4-methyl-5-acetyl-2- (4-hydroxybenzamido) thiazole with the yield of 69.1 percent and m.p.244-246 ℃.1H NMR(400MHz，DMSO-d6)：2.50(s，3H，CH3)，2.61(s，3H，CH3CO)，6.89(d，J＝8.0Hz，2H，C6H4)，8.02(d，J＝8.0Hz，2H，C6H4)，10.43(s，1H，OH)，12.70(s，1H，NH)。13C NMR(101MHz，DMSO-d6)：18.47，30.57，115.77，122.41，125.69，131.07，154.74，160.97，162.37，165.47，191.15。
(2) Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-hydroxybenzamido) thiazole (B)
Prepared by the method of example 1, 1.0mmol 4-methyl-5-acetyl-2- (4-hydroxybenzamido) thiazole and 1.0mmol p-hydroxybenzaldehyde were reacted for 6h, the crude product was recrystallized from ethanol to obtain a pale yellow solid 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl group]-2- (4-hydroxybenzoylamino) thiazole B, yield 72.4%, m.p.268-270 ℃.1H NMR(400MHz，DMSO-d6)：2.69(s，3H，CH3)，6.88(d，J＝7.8Hz，2H，C6H4)，6.94(d，J＝7.8Hz，2H，C6H4CO)，7.24(d，J＝15.4Hz，1H，CH)，7.63(d，J＝15.4Hz，1H，CH)，7.68(d，J＝7.8Hz，2H，C6H4)，8.05(d，J＝7.8Hz，2H，C6H4CO)。13C NMR(101MHz，DMSO-d6)：18.71，115.82，116.42，121.64，122.38，125.68，125.82，131.05，131.28，143.69，155.09，160.73，160.76，162.46，165.51，182.69。
Example 3
Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-methoxybenzamido) thiazole (C)
Figure GDA0002525379120000071
(1) Preparation of 4-methyl-5-acetyl-2- (4-methoxybenzamido) thiazole
Prepared by the method of example 1, 6.0mmol of 4-methoxybenzoic acid reacts with 4.0mmol of 4-methyl-5-acetyl-2-aminothiazole for 8 hours, and the crude product is recrystallized by ethyl acetate/tetrahydrofuran to obtain white solid 4-methyl-5-acetyl-2- (4-methoxybenzamido) thiazole with the yield of 78.3 percent and m.p.217-219 ℃.
(2) Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-methoxybenzamido) thiazole (C)
According to the method of example 1The preparation method comprises the steps of reacting 1.0mmol of 4-methyl-5-acetyl-2- (4-methoxybenzamido) thiazole with 1.0mmol of p-hydroxybenzaldehyde for 6 hours, and recrystallizing a crude product with ethanol to obtain a yellow solid 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl group]The yield of the (E) -2- (4-methoxybenzoylamino) thiazole C is 61.5 percent, and the m.p.272-273 ℃.1H NMR(400MHz，DMSO-d6)：2.69(s，3H，CH3)，3.86(s，3H，CH3O)，6.85(d，J＝8.0Hz，2H，C6H4)，7.09(d，J＝8.0Hz，2H，C6H4CO)，7.23(d，J＝15.4Hz，1H，CH)，7.62(d，J＝15.4Hz，1H，CH)，7.67(d，J＝8.0Hz，2H，C6H4)，8.14(d，J＝8.0Hz，2H，C6H4CO)，10.14(s，1H，OH)，12.85(s，1H，NH)。13CNMR(101MHz，DMSO-d6)：18.69，56.04，114.48，116.40，121.56，121.66，124.06，125.78，125.88，130.90，131.32，143.72，155.18，160.66，163.47，165.42，182.70。
Example 4
Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-fluorobenzamido) thiazole (D)
Figure GDA0002525379120000081
(1) Preparation of 4-methyl-5-acetyl-2- (4-fluorobenzamido) thiazole
Prepared by the method of example 1, 6.0mmol 4-fluorobenzoic acid reacts with 4.0mmol 4-methyl-5-acetyl-2-aminothiazole for 8h, and the crude product is recrystallized by ethyl acetate/tetrahydrofuran to obtain white solid 4-methyl-5-acetyl-2- (4-fluorobenzamido) thiazole with the yield of 81.7 percent and m.p.242-244 ℃.
(2) Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-fluorobenzamido) thiazole (D)
Prepared by the method of example 1, 1.0mmol 4-methyl-5-acetyl-2- (4-fluorobenzamido) thiazole and 1.0mmol p-hydroxybenzaldehyde react for 6h, the crude product is recrystallized by ethanol to obtain yellow solid 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl]-2- (4-fluorobenzamido) thiazole D,yield 79.3%, m.p. > 300 ℃.1H NMR(400MHz，DMSO-d6)：2.69(s，3H，CH3)，6.88(d，J＝7.6Hz，2H，C6H4)，7.23(d，J＝15.3Hz，1H，CH)，7.63(d，J＝15.3Hz，1H，CH)，7.67(d，J＝7.6Hz，2H，C6H4)，7.39～7.43,8.20～8.23(m，4H，C6H4CO)，10.61(s，1H，OH)。13C NMR(101MHz，DMSO-d6)：18.60，116.22(d)，116.42，121.49，125.77，125.90，128.69，131.32，131.66，131.75，143.89，160.53，160.80，164.63，166.57，182.70。
Example 5
Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-cyanobenzoylamino) thiazole (E)
Figure GDA0002525379120000082
(1) Preparation of 4-methyl-5-acetyl-2- (4-cyanobenzoylamino) thiazole
Prepared according to the method of example 1, 6.0mmol 4-cyanobenzoic acid is reacted with 4.0mmol 4-methyl-5-acetyl-2-aminothiazole for 8h, and the crude product is recrystallized from ethyl acetate/tetrahydrofuran to give 4-methyl-5-acetyl-2- (4-cyanobenzoylamino) thiazole as a grey solid in 76.2% yield m.p. > 300 ℃.
(2) Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-cyanobenzoylamino) thiazole (E)
Prepared by the method of example 1, 1.0mmol 4-methyl-5-acetyl-2- (4-cyanobenzoylamino) thiazole and 1.0mmol p-hydroxybenzaldehyde reacted for 6h, the crude product was recrystallized from ethanol to give 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl as a dark yellow solid]-2- (4-cyanobenzoylamino) thiazole E in a yield of 64.5%, m.p. > 300 ℃.1H NMR(400MHz，DMSO-d6)：2.69(s，3H，CH3)，6.88(d，J＝7.7Hz，2H，C6H4)，7.22(d，J＝15.3Hz，1H，CH)，7.62(d，J＝15.3Hz，1H，CH)，7.67(d，J＝7.7Hz，2H，C6H4)，8.04(d，J＝7.6Hz，2H，C6H4CO)，8.25(d，J＝7.6Hz，2H，C6H4CO)，10.27(s，1H，OH)，13.30(s，1H，NH)。13C NMR(101MHz，DMSO-d6)：18.41，114.94，115.38，116.44，116.51，118.07，118.62，121.34，125.73，129.56，131.34，133.07，144.03，155.88，160.87，173.78，182.66。
Example 6
Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-trifluoromethylbenzoylamino) thiazole (F)
Figure GDA0002525379120000091
(1) Preparation of 4-methyl-5-acetyl-2- (4-trifluoromethylbenzamido) thiazole
Prepared by the method of example 1, 6.0mmol 4-trifluoromethylbenzoic acid reacts with 4.0mmol 4-methyl-5-acetyl-2-aminothiazole for 8h, and the crude product is recrystallized by ethyl acetate/tetrahydrofuran to obtain white solid 4-methyl-5-acetyl-2- (4-trifluoromethylbenzamido) thiazole with the yield of 83.3 percent and m.p.263-265 ℃.1H NMR(400MHz，DMSO-d6)：2.40(s，3H，CH3CO)，2.54(s，3H，CH3)，7.80(d，J＝7.6Hz，2H，C6H4)，8.31(d，J＝7.6Hz，2H，C6H4)。13C NMR(101MHz，DMSO-d6)：18.95，30.59，122.39，123.39，125.32(q)，126.09，129.37，130.96，141.77，155.98，169.01，189.99。
(2) Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-trifluoromethylbenzoylamino) thiazole (F)
Prepared by the method of example 1, 1.0mmol 4-methyl-5-acetyl-2- (4-trifluoromethylbenzamido) thiazole and 1.0mmol p-hydroxybenzaldehyde were reacted for 6 hours, and the crude product was recrystallized from ethanol to obtain yellow solid 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl group]-2- (4-trifluoromethylbenzamido) thiazole F, yield 88.0%, m.p. > 300 ℃.1H NMR(400MHz，DMSO-d6)：2.70(s，3H，CH3)，6.88(d，J＝7.8Hz，2H，C6H4)，7.23(d，J＝15.4Hz，1H，CH)，7.63(d，J＝15.4Hz，1H，CH)，7.68(d，J＝7.9Hz，2H，C6H4)，7.94(d，J＝7.9Hz，2H，C6H4CO)，8.30(d，J＝7.9Hz，2H，C6H4CO)，10.27(s，1H，OH)，13.30(s，1H，NH)。13C NMR(101MHz，DMSO-d6)：18.48，116.43，121.38，122.89，125.60，125.75，126.06，128.31，129.73，131.35，132.63，132.95，136.12，144.01，145.05，160.86，182.69。
Example 7
Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-nitrobenzamido) thiazole (G)
Figure GDA0002525379120000101
(1) Preparation of 4-methyl-5-acetyl-2- (4-nitrobenzamido) thiazole
Prepared by the method of example 1, 6.0mmol 4-nitrobenzoic acid reacts with 4.0mmol 4-methyl-5-acetyl-2-aminothiazole for 8h, and the crude product is recrystallized by ethyl acetate/tetrahydrofuran to obtain yellow solid 4-methyl-5-acetyl-2- (4-nitrobenzoylamino) thiazole with yield of 73.1 percent and m.p.294-296 ℃.
(2) Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (4-nitrobenzamido) thiazole (G)
Prepared by the method of example 1, 1.0mmol 4-methyl-5-acetyl-2- (4-nitrobenzoylamino) thiazole was reacted with 1.0mmol p-hydroxybenzaldehyde for 6h, and the crude product was recrystallized from ethanol to give 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] as a yellow solid]-2- (4-nitrobenzamido) thiazole G, yield 73.3%, m.p. > 300 ℃.1H NMR(400MHz，DMSO-d6)：2.68(s，3H，CH3)，6.85(d，J＝7.7Hz，2H，C6H4)，7.20(d，J＝15.2Hz，1H，CH)，7.61(d，J＝15.2Hz，1H，CH)，7.66(d，J＝7.7Hz，2H，C6H4)，8.31(d，J＝7.9Hz，2H，C6H4CO)，8.35(d，J＝7.9Hz，2H，C6H4CO)，10.15(s，1H，OH)，13.36(s，1H，NH)。13C NMR(101MHz，DMSO-d6)：18.39，121.16，121.25，121.30，121.36，124.02，124.10，125.79，126.04，130.32，131.36，137.88，143.98，150.18，160.75，182.58。
Example 8
Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (3-nitrobenzamido) thiazole (H)
Figure GDA0002525379120000102
(1) Preparation of 4-methyl-5-acetyl-2- (3-nitrobenzamido) thiazole
Prepared by the method of example 1, 6.0mmol 3-nitrobenzoic acid reacts with 4.0mmol 4-methyl-5-acetyl-2-aminothiazole for 8h, and the crude product is recrystallized by ethyl acetate/tetrahydrofuran to obtain yellow solid 4-methyl-5-acetyl-2- (3-nitrobenzoylamino) thiazole with yield of 72.7 percent and m.p.253 to 255 ℃.
(2) Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (3-nitrobenzamido) thiazole (H)
Prepared by the method of example 1, 1.0mmol 4-methyl-5-acetyl-2- (3-nitrobenzamido) thiazole was reacted with 1.0mmol p-hydroxybenzaldehyde for 6 hours, and the crude product was recrystallized from ethanol to give 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] as a dark yellow solid]-2- (3-nitrobenzamido) thiazole H, yield 56.9%, m.p. > 300 ℃.1H NMR(400MHz，DMSO-d6)：2.69(s，3H，CH3)，6.87(d，J＝7.8Hz，2H，C6H4)，7.21(d，J＝15.3Hz，1H，CH)，7.62(d，J＝15.3Hz，1H，CH)，7.66(d，J＝7.8Hz，2H，C6H4)，7.83～8.97(m，4H，C6H4CO)。13C NMR(101MHz，DMSO-d6)：18.22，116.42，121.24，123.59，125.68，125.75，125.79，127.59，130.87，131.33，134.07，135.06，143.99，148.24，153.57，160.76，165.10，182.64。
Example 9
Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (3-methyl-4-nitrobenzamido) thiazole (J)
Figure GDA0002525379120000111
(1) Preparation of 4-methyl-5-acetyl-2- (3-methyl-4-nitrobenzamido) thiazole (M)
Prepared by the method of example 1, 6.0mmol 3-methyl-4-nitrobenzoic acid reacts with 4.0mmol 4-methyl-5-acetyl-2-aminothiazole for 10h, and the crude product is recrystallized by ethyl acetate/tetrahydrofuran to obtain yellow solid 4-methyl-5-acetyl-2- (3-methyl-4-nitrobenzoylamino) thiazole (M), the yield is 82.4%, m.p.267 to 269 ℃.1H NMR(400MHz，DMSO-d6)：2.51(s，3H，CH3CO)，2.56(s，3H，CH3)，2.62(s，3H，CH3C6H3)，8.09～8.20(m，3H，C6H3)，13.29(s，1H，NH)。13C NMR(101MHz，DMSO-d6)：18.21，19.72，30.55，120.03，125.03，125.99，127.68，133.17，133.30，136.02，151.61，160.81，165.13，191.27。
(2) Preparation of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (3-methyl-4-nitrobenzamido) thiazole (J)
Prepared by the method of example 1, 1.0mmol 4-methyl-5-acetyl-2- (3-methyl-4-nitrobenzoylamino) thiazole (M) was reacted with 1.0mmol p-hydroxybenzaldehyde for 6h, and the crude product was recrystallized from ethanol to give 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] as a yellow solid]-2- (3-methyl-4-nitrobenzamido) thiazole J, yield 70.0%, m.p. > 300 ℃.1HNMR(400MHz，DMSO-d6)：2.56(s，3H，CH3)，2.69(s，3H，CH3C6H3)，6.88(d，J＝8.2Hz，2H，C6H4)，7.21(d，J＝15.2Hz，1H，CH)，7.62(d，J＝15.2Hz，1H，CH)，7.66(d，J＝8.2Hz，2H，C6H4)，8.11～8.21(m，3H，C6H3)，10.30(s，1H，OH)，13.20(s，1H，NH)。13C NMR(101MHz，DMSO-d6)：18.39，19.76，116.44，121.30，125.04，125.72，127.71，131.25，131.33，133.18，133.29，136.04，136.12，143.74，144.03，151.61，159.67，160.89，182.67。
Example 10
Anti-influenza virus neuraminidase activity of 5- (3-phenylpropenoyl) -2-benzoylaminothiazole
1. Principle of experiment
The compound MUNANA is a specific substrate of neuraminidase, metabolites generated under the action of neuraminidase can generate 450nm fluorescence under the irradiation and excitation of 360nm, and the change of fluorescence intensity can sensitively reflect neuraminidase activity. The enzymes are all from A/PR/8/34 (H)1N1) A viral strain.
2. Experimental methods
In an enzyme reaction system, a sample with a certain concentration and influenza virus RNA are suspended in a reaction buffer solution (pH6.5), a fluorescent substrate MUNANA is added to start the reaction system, and after incubation for 40 minutes at 37 ℃, a reaction stopping solution is added to stop the reaction. The fluorescence intensity values were determined under the parameters of an excitation wavelength of 360nm and an emission wavelength of 450 nm. The fluorescence intensity of the reaction system may reflect the activity of the enzyme. The inhibition rate of the compound on the NA activity can be calculated according to the reduction of the fluorescence intensity.
3. Detecting a sample: EXAMPLES Compounds
4. Active results
Inhibition rate and IC of compound on neuraminidase when concentration of compound in reaction system is detected to be 40.0 mu g/mL50Are shown in Table 1.
TABLE 15 inhibitory Activity of- (3-Phenylacryloyl) -2-benzoylaminothiazole on neuraminidase H1N1 and IC50
Figure GDA0002525379120000121
Figure GDA0002525379120000122
The 5- (3-phenylpropenoyl) -2-benzoylaminothiazole has the activity of resisting influenza virus neuraminidase and can be used for preparing influenza virus neuraminidase inhibitors.
Example 11
Comparative experiment of neuraminidase Activity against influenza Virus
A comparative experiment was conducted against influenza virus neuraminidase activity as in example 10: the national drug screening center of the institute of pharmaceutical research of Chinese academy of medical sciences selects compounds 4-methyl-5-acetyl-2- (3-methyl-4-nitrobenzamido) thiazole (M) and 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl]-2- (3-methyl-4-nitrobenzoylamino) thiazole J4-methyl-5-acetyl-2- (3-methyl-4-nitrobenzoylamino) thiazole and 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl in the reaction System at a concentration of 40.0. mu.g/mL]The inhibition rate of the-2- (3-methyl-4-nitrobenzamido) thiazole on the neuraminidase is 50.13 +/-1.71 percent and 94.39 +/-1.15 percent respectively; 4-methyl-5-acetyl-2- (3-methyl-4-nitrobenzamido) thiazole and 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl]IC of (E) -2- (3-methyl-4-nitrobenzoylamino) thiazole50The values were 125.0. + -. 10.3. mu.M and 14.5. + -. 3.3. mu.M, respectively.
Figure GDA0002525379120000131
4-methyl-5-acetyl-2- (3-methyl-4-nitrobenzamido) thiazole (M) also has anti-influenza virus neuraminidase activity and can be used for preparing influenza virus neuraminidase inhibitors.
The 5- [ 3-phenylpropenoyl ] -2-benzoyl aminothiazole has higher activity of neuraminidase resisting influenza viruses than the 5-acetyl-2-benzoyl aminothiazole.

Claims (6)

1. A5- (3-phenylpropenoyl) -2-benzoylaminothiazole and pharmaceutically acceptable salts thereof represented by a chemical structural formula I:
Figure FDA0002525322420000011
wherein R is selected from: methyl, ethyl, C3～C4Straight chain or C3～C4A branched alkyl group; r1Selected from: hydrogen, 4-amino, 2-methoxy, 3-methoxy, 4-methoxy, 2-ethoxy, 3-ethoxy, 4-ethoxy, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2, 3-dihydroxy, 2, 4-dihydroxy, 2, 5-dihydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy or 4-hydroxy-3-ethoxy; y is selected from: H. 2-deuterium, 2-methyl, 2-ethyl, 2-methoxy, 2-ethoxy, 2-fluoro, 2-chloro, 2-bromo, 2-nitro, 2-trifluoromethyl, 2-trifluoromethoxy, 3-deuterium, 3-methyl, 3-ethyl, 3-hydroxy, 3-methoxy, 3-ethoxy, 3-fluoro, 3-chloro, 3-bromo, 3-nitro, 3-trifluoromethyl, 3-trifluoromethoxy, 4-deuterium, 4-methyl, 4-ethyl, 4-hydroxy, 4-methoxy, 4-ethoxy, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4-trifluoromethyl, 4-nitro, 4-trifluoromethoxy, 2-ethoxy, 2-chloro, 3-nitro, 3-trifluoromethyl, 4-methoxy, 3-ethoxy, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4, 3-methyl-4-nitro, 2-methyl-4-nitro or 3-methyl-5-nitro.
2. A class of 5- (3-phenylpropenoyl) -2-benzoylaminothiazoles of the formula II:
Figure FDA0002525322420000012
wherein R and Y are as defined in claim 1; r2Selected from: hydrogen, 3-hydroxy, 3-methoxy or 3-ethoxy.
3. 5- (3-phenylpropenoyl) -2-benzoylaminothiazole and pharmaceutically acceptable salts thereof are selected from the following compounds:
Figure FDA0002525322420000013
Figure FDA0002525322420000021
4. the process for preparing 5- (3-phenylpropenoyl) -2-benzoylaminothiazole according to claim 1, wherein it is prepared by the following reaction:
Figure FDA0002525322420000022
in the formula, R, R1And Y is as defined in claim 1; CDI is an abbreviation for N, N' -carbonyldiimidazole; DMF is N, N-dimethylformamide.
5. Use of 5- (3-phenylpropenoyl) -2-benzoylaminothiazole and the pharmaceutically acceptable salts thereof according to any one of claims 1 to 3 for the preparation of influenza virus neuraminidase inhibitors.
6. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
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