CN108864073B - N-thiazolyl pyridine carboxamide derivative and preparation method and application thereof - Google Patents
N-thiazolyl pyridine carboxamide derivative and preparation method and application thereof Download PDFInfo
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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- 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 N-thiazolyl pyridinecarboxamides of formula IThe derivatives and pharmaceutically acceptable salts thereof, a pharmaceutical composition and application thereof in preparing influenza virus neuraminidase inhibitors.
R is selected from: methyl, ethyl; r1Selected from: hydrogen, 3-hydroxy, 4-hydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy; r2Selected from: H. 3-methyl, 4-methyl, 5-methyl or 6-methyl; or R2Selected from: H. 2-methyl, 4-methyl, 5-methyl or 6-methyl; or R2Selected from: H. 2-methyl group and 3-methyl group.
Description
Technical Field
The invention relates to a novel compound, a preparation method and application thereof, in particular to an N-thiazolyl pyridine carboxamide derivative, a preparation method thereof 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.
The Koch topic group [ Bioorg Med Chem Lett,2006,16(3):663-667] describes the synthesis of novel thiazole compounds 3, which have very good inhibitory activity against HIV virus.
Ian A. yule et al [ Eur J Med Chem,2014,86:31-38]Based on the structural design, a series of antibacterial agents are synthesized, wherein a compound 4 containing an N-thiazolyl pyridine carboxamide structure has inhibitory activity (IC) on Escherichia coli adenosine triphosphatase500.42 μ M); optimizing on the basis of the compound 4 to obtain a compound 5 (IC) with higher activity500.098μM)。
Qun-Li Luo et al [ Bioorg Med Chem Lett,2005,15(3): 635-638]A series of methionyl aminopeptidase class I inhibitors containing a pyridine-2-carboxythiazole-2-amine structure are described, in which compound 6 has inhibitory activity against both E.coli methionyl aminopeptidase and Salmonella typhimurium methionyl aminopeptidase, the IC thereof500.26. mu.M and 0.35. mu.M, respectively.
World patent [ WO2013/082324A1,2012-11-29]The anticancer cell proliferation activity of a series of thiazole amide compounds is described, and the compounds with an N-thiazolyl pyridine carboxamide structure are found to have obviously superior anticancer cell proliferation activity. Wherein, the compound 7 has outstanding antiproliferative activity on Hela cells, K562 cells, MDA-MB-468 cells and MDA-MB-231 cells; compound 8 has optimal antiproliferative activity on Hela cells, its IC50The value was 8.3 nM.
Disclosure of Invention
The invention aims to provide N-thiazolyl pyridine carboxamide derivatives, a preparation method thereof, 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 N-thiazolyl pyridine carboxamide derivatives shown as a structural formula I and pharmaceutically acceptable salts thereof:
the N-thiazolyl pyridine carboxamide derivative shown in the formula I is selected from N-thiazolyl pyridine carboxamide derivatives shown in the formula II, III or IV:
wherein in formulas II, III and IV, R is selected from: methyl, ethyl; r1Selected from: hydrogen, 3-hydroxy, 4-hydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy;
in the formula II, R2Selected from: H. 3-methyl, 4-methyl, 5-methyl or 6-methyl;
in the formula III, R2Selected from: H. 2-methyl, 4-methyl, 5-methyl or 6-methyl;
in the formula IV, R2Selected from: H. 2-methyl group and 3-methyl group.
In the first aspect of the technical scheme of the invention, the N-thiazolyl pyridine carboxamide derivatives are selected from the following compounds:
the second aspect of the technical scheme of the invention provides a preparation method of N-thiazolyl pyridine carboxamide derivatives, which is characterized in that the preparation reaction is as follows:
the N-thiazolyl pyridine carboxamide derivative shown in the formula I is selected from N-thiazolyl pyridine carboxamide derivatives shown in the formula II, III or IV:
wherein in formulas II, III and IV, R is selected from: methyl, ethyl; r1Selected from: hydrogen, 3-hydroxy, 4-hydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy;
in the formula II, R2Selected from: H. 3-methyl, 4-methyl, 5-methyl or 6-methyl;
in the formula III, R2Selected from: H. 2-methyl, 4-methyl, 5-methyl or6-methyl;
in the formula IV, R2Selected from: H. 2-methyl group and 3-methyl group.
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 N-thiazolyl picolinamide derivative and a pharmaceutically acceptable salt thereof, 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 N-thiazolyl pyridine carboxamide derivative and the pharmaceutically acceptable salt thereof and the application of the pharmaceutical composition of the third aspect in the preparation of influenza virus neuraminidase inhibitors.
The beneficial technical effects are as follows:
the N-thiazolyl pyridine carboxamide derivative is a compound which has inhibitory activity on 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)
(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, 4.0mmol of 4-methyl-5-acetyl-2-aminothiazole was added, 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 ]:
(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 until the mixture is saturated, the mixture reacts for 6 hours 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
Synthesis of 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] -2- (3-pyridinecarboxamido) thiazole (C)
(1) Synthesis of N- [ 4-methyl-5-acetylthiazol-2-yl ] -3-pyridinecarboxamide
By the method of example 1, 6.0mmol nicotinic 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 N- [ 4-methyl-5-Acetyl thiazol-2-yl]-3-pyridinecarboxamide, yield 55.7%, m.p. 226-228 ℃.1H NMR(400MHz，DMSO-d6)：2.48(s，3H，CH3CO)，2.60(s，3H，CH3) 7.56-9.24 (m, 4H, pyridine ring).13C NMR(101MHz，DMSO-d6)：18.50，30.57，123.95，124.84，129.74，136.32，149.86，152.96，154.70，163.30，166.39，190.83。
(2) Synthesis of N- [ 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl ] thiazol-2-yl ] -3-pyridinecarboxamide (C)
Following the procedure of example 1, 1.0mmol of N- [ 4-methyl-5-acetylthiazol-2-yl]-3-pyridine carboxamide reacts with 1.0mmol of p-hydroxybenzaldehyde for 6 hours, and the crude product is recrystallized by ethanol to obtain yellow solid N- [ 4-methyl-5- [3- (4-hydroxyphenyl) acryloyl group]Thiazol-2-yl]-3-pyridinecarboxamide C, yield 67.7%, m.p.243-245 ℃.1H NMR(400MHz，DMSO-d6)：2.69(s，3H，CH3)，6.89(d，J＝7.6Hz，2H，C6H4)，7.20(d，J＝15.3Hz，1H，CH)，7.61(d，J＝15.3Hz，1H，CH)，7.66(d，J＝7.6Hz，2H，C6H4) 8.02-9.38 (m, 4H, pyridine ring).13C NMR(101MHz，DMSO-d6)：17.80，116.45，120.94，125.34，125.62，126.47，131.12，131.37，142.20，144.20，144.98，147.83，152.22，160.97，161.90，164.70，182.50。
Example 3
Anti-influenza virus neuraminidase activity of N-thiazolyl pyridinecarboxamide derivatives
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 (pH 6.5), a fluorescent substrate MUNANA is added to start the reaction system, and after incubation for 40 minutes at 37 ℃, a reaction termination solution is added to terminate 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 of neuraminidase and IC of Compounds A and C in the reaction System at a concentration of 40.0. mu.g/mL50The values are shown in Table 1.
TABLE 1 inhibitory Activity of Compounds A and C on neuraminidase H1N1 and IC50
The N-thiazolyl pyridine carboxamide derivative has the activity of resisting influenza virus neuraminidase and can be used for preparing influenza virus neuraminidase inhibitors.
The inhibitory activity of compound C on neuraminidase H1N1 was higher than that of compound a.
Claims (5)
1. A class of N-thiazolyl picolinamide derivatives represented by the chemical structural formula I:
the N-thiazolyl pyridine carboxamide derivative shown in the formula I is selected from N-thiazolyl pyridine carboxamide derivatives shown in the formula II, III or IV:
wherein in formulas II, III and IV, R is selected from: methyl, ethyl; r1Selected from: hydrogen, 3-hydroxy, 4-hydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy or 4-hydroxy-3-methoxy;
in the formula II, R2Selected from: H. 3-methyl, 4-methyl, 5-methyl or 6-methyl;
in the formula III, R2Selected from: H. 2-methyl, 4-methyl, 5-methyl or 6-methyl;
in the formula IV, R2Selected from: H. 2-methyl or 3-methyl.
2. A class of N-thiazolyl pyridine carboxamide derivatives and pharmaceutically acceptable salts thereof, selected from the following compounds:
3. a process for the preparation of an N-thiazolylpyridine carboxamide derivative according to claim 1, characterized in that it is prepared by the following reaction:
in formula I, R, R1And R2As defined in claim 1; CDI is an abbreviation for N, N' -carbonyldiimidazole; DMF is N, N-dimethylformamide.
4. Use of the N-thiazolyl picolinamide derivatives of claim 1 or claim 2, and pharmaceutically acceptable salts thereof, in the manufacture of influenza virus neuraminidase inhibitors.
5. A pharmaceutical composition comprising at least one compound of claim 1 or 2 and a pharmaceutically acceptable carrier.
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