CN107286147B - N- [5- (1,2, 4-triazol-1-yl) thiazol-2-yl ] morpholinylamide and medical application thereof - Google Patents
N- [5- (1,2, 4-triazol-1-yl) thiazol-2-yl ] morpholinylamide and medical application thereof Download PDFInfo
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- CN107286147B CN107286147B CN201710324236.4A CN201710324236A CN107286147B CN 107286147 B CN107286147 B CN 107286147B CN 201710324236 A CN201710324236 A CN 201710324236A CN 107286147 B CN107286147 B CN 107286147B
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- thiazol
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D417/04—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 directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to N- [5- (1,2, 4-triazole-1-yl) thiazole-2-yl shown as a chemical structural formula I]Morpholinyl amides and pharmaceutically acceptable salts thereof, and their use in the preparation of influenza virus neuraminidase inhibitors:
wherein R is selected from: hydrogen, C1～C2Alkyl radical, C3～C4A linear alkyl group; x1～X3Selected from: hydrogen, fluorine, chlorine, bromine or iodine; n is selected from: 1.2, 3, 4 or 5.
Description
Technical Field
The invention relates to a compound and application thereof, in particular to N- [5- (1,2, 4-triazole-1-yl) thiazole-2-yl ] morpholinyl amide and application thereof in preparation of influenza virus neuraminidase inhibitors.
Background
World invention patent [ WO 2014145642A2, 2014-9-18 disclosure]A series of anti-cancer compounds targeting nuclear transcription factor Nrf2 are described, wherein the inhibitory activity of compound 1 on human lung cancer cells A549 and H1437 is scored as B grade (5 muM < IC)50< 25. mu.M). Chinese invention patent publication [ CN 103524535A,2014-1-22]Describes the IC of hedgehog signaling channel antagonist 2, 2 on GRE-fluorescein expressing NIH3T3 cells50Is 134.3nM, close to the positive control, vismodegib.
Wittayanarakul et al [ Medicinal Chemistry Letters,2010,1(8):376-380] describe the preparation of compound 3 and its affinity for DNA.
Disclosure of Invention
The invention aims to provide N- [5- (1,2, 4-triazole-1-yl) thiazole-2-yl ] morpholinyl amide and a preparation method 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- [5- (1,2, 4-triazole-1-yl) thiazole-2-yl ] morpholinyl amide shown as a structural formula I and pharmaceutically acceptable salts thereof:
wherein R is selected from: hydrogen, C1～C2Alkyl radical, C3～C4A linear alkyl group; x1～X3Selected from: hydrogen, fluorine, chlorine, bromine or iodine; n is selected from: 1.2, 3, 4 or 5.
Further, preferred compounds are selected from: n- [5- (1,2, 4-triazol-1-yl) -4- (2, 4-dichlorophenyl) thiazol-2-yl ] -2-morpholinylacetamide and N- [5- (1,2, 4-triazol-1-yl) -4- (2, 4-dichloro-5-fluorophenyl) thiazol-2-yl ] -2-morpholinylacetamide.
The second aspect of the technical scheme of the invention provides a preparation method of N- [5- (1,2, 4-triazole-1-yl) thiazole-2-yl ] morpholinyl amide, which is characterized by comprising the following preparation reactions:
wherein R is selected from: hydrogen, C1～C2Alkyl radical, C3～C4A linear alkyl group; x1～X3Selected from: hydrogen, fluorine, chlorine, bromine or iodine; n is selected from: 1.2, 3, 4 or 5.
According to 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- [5- (1,2, 4-triazol-1-yl) thiazol-2-yl ] morpholinylamide of the present invention 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 provides a compound containing the compound and the pharmaceutically acceptable salt thereof in the first aspect and application of the pharmaceutical composition in the third aspect in preparing influenza virus neuraminidase inhibitors.
The beneficial technical effects are as follows: the invention relates to an application of N- [5- (1,2, 4-triazole-1-yl) thiazole-2-yl ] morpholinyl amide in preparation of an influenza virus neuraminidase inhibitor.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of N- [5- (1,2, 4-triazol-1-yl) -4- (2, 4-dichlorophenyl) thiazol-2-yl ] -2-morpholinyl acetamide
1mmol of N- [4- (1,2, 4-triazol-1-yl) -5- (2, 4-dichlorophenyl) thiazol-2-yl]Reacting at normal temperature for 24 hours by using-2-chloroacetamide, 2mmol of morpholine, 10mL of THF and 1.20mmol of TEA, and monitoring by TCL; desolventizing, washing with ethyl acetate solvent and saturated salt water, back-extracting the organic layers, combining the organic layers, drying with anhydrous sodium sulfate, desolventizing, and recrystallizing with ethanol to obtain 0.27g yellow solid N- [5- (1,2, 4-triazole-1-yl) -4- (2, 4-dichlorophenyl) thiazole-2-yl]-2-morpholinyl acetamide, yield 60.9%, melting point 156-159 ℃;1H NMR(400MHz，DMSO)δ：2.53(s，4H，CH2×2)，3.37(s，2H，CH2)，3.61(s，4H，OCH2×2)，7.51-7.53(m，2H，C6H3 5,6-H)，7.70(s，1H，C6H3 3-H)，8.19(s，1H，C2N3H2 3-H)，8.58(s，1H，C2N3H2 5-H)，12.52(s，1H，CONH)。
example 2
Preparation of N- [5- (1,2, 4-triazol-1-yl) -4- (2, 4-dichloro-5-fluorophenyl) thiazol-2-yl ] -2-morpholinyl acetamide
1mmol of N- [4- (1,2, 4-triazol-1-yl) -5- (2, 4-dichloro-5-fluorophenyl) thiazol-2-yl]2-chloroacetamide, 2mmol of morpholine, 10mL of THF and 1.20mmol of TEA, reacting at normal temperature, monitoring by TCL, and reacting for 24 hours; desolventizing, washing with ethyl acetate solvent and saturated salt water, back-extracting the organic layers, combining the organic layers, drying over anhydrous sodium sulfate, desolventizing, and recrystallizing with ethanol to obtain 0.28g of yellow solid N- [5- (1,2, 4-triazol-1-yl) -4- (2, 4-dichloro-5-fluorophenyl) thiazol-2-yl]-2-morpholinyl acetamide, yield 62.2%, melting point 145-147 ℃;1H NMR(400MHz，CDCl3)δ：2.60～2.72(m，4H，CH2×2)，3.33(s，2H，CH2)，3.74～3.86(m，4H，CH2×2)，7.29(s，1H，C6H2 3-H)，7.51(d，J＝6.6Hz，1H，C6H26-H)，8.00(s，1H，C2N3H2 3-H)，8.05(s，1H，C2N3H2 5-H)，10.36(s，1H，CONH)。
example 3
Anti-influenza virus neuraminidase activity of N- [5- (1,2, 4-triazol-1-yl) thiazol-2-yl ] morpholinylamide
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 neuraminidase NA 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 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 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
When the concentration of N- [5- (1,2, 4-triazol-1-yl) -4- (2, 4-dichlorophenyl) thiazol-2-yl ] -2-morpholinyl acetamide and N- [5- (1,2, 4-triazol-1-yl) -4- (2, 4-dichloro-5-fluorophenyl) thiazol-2-yl ] -2-morpholinyl acetamide were detected to be 40.0. mu.g/mL in the reaction system, the inhibition rate of neuraminidase was 34% and 31%, respectively.
The N- [5- (1,2, 4-triazole-1-yl) thiazole-2-yl ] morpholinylamide has good activity of resisting influenza virus neuraminidase, and can be used for preparing influenza virus neuraminidase inhibitors.
Claims (3)
1. A class of N- [5- (1,2, 4-triazol-1-yl) thiazol-2-yl ] morpholinylamides of formula I:
wherein R is selected from: hydrogen; x1And X2Selected from: chlorine; x3Selected from: hydrogen or fluorine; n is selected from: 1.
2. a process for producing N- [5- (1,2, 4-triazol-1-yl) thiazol-2-yl ] morpholinylamide according to claim 1, characterized by the following reaction:
formula (III) R, X1～X3And n is as defined in claim 1.
3. The use of N- [5- (1,2, 4-triazol-1-yl) thiazol-2-yl ] morpholinylamide of claim 1 and pharmaceutically acceptable salts thereof for the preparation of influenza virus neuraminidase inhibitors.
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Citations (5)
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| CN1834095A (en) * | 2005-03-18 | 2006-09-20 | 中国科学院上海药物研究所 | Nonnucleoside antivirus inhibitor, its prepn. and use |
| WO2007147336A1 (en) * | 2006-06-13 | 2007-12-27 | Shanghai Institue Of Materia Medica, Chinese Academy Of Sciences | Heterocyclic non-nucleoside compounds, their peparation, pharmaceutical composition and their use as antiviral agents |
| CN103705511A (en) * | 2014-01-14 | 2014-04-09 | 长沙理工大学 | Medical application of N-{5-(1,2,4-triazole-1-yl) thiazole-2-yl} fatty acid amide |
| CN104771399A (en) * | 2014-01-09 | 2015-07-15 | 湖南大学 | N-[5-(1,2,4-triazole-1-yl)thiazole-2-yl]aromatic amide, and pharmaceutical applications thereof |
| CN105367564A (en) * | 2014-09-01 | 2016-03-02 | 湖南大学 | N-[4-phenyl-5-(1,2,4-triazole-1-yl)thiazole-2-yl]amide and preparation and application thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1834095A (en) * | 2005-03-18 | 2006-09-20 | 中国科学院上海药物研究所 | Nonnucleoside antivirus inhibitor, its prepn. and use |
| WO2007147336A1 (en) * | 2006-06-13 | 2007-12-27 | Shanghai Institue Of Materia Medica, Chinese Academy Of Sciences | Heterocyclic non-nucleoside compounds, their peparation, pharmaceutical composition and their use as antiviral agents |
| CN104771399A (en) * | 2014-01-09 | 2015-07-15 | 湖南大学 | N-[5-(1,2,4-triazole-1-yl)thiazole-2-yl]aromatic amide, and pharmaceutical applications thereof |
| CN103705511A (en) * | 2014-01-14 | 2014-04-09 | 长沙理工大学 | Medical application of N-{5-(1,2,4-triazole-1-yl) thiazole-2-yl} fatty acid amide |
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Non-Patent Citations (1)
| Title |
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| 胡椒基修饰的噻唑类化合物的合成与生物活性研究;伍智林;《中国博士学位论文全文数据库 医药卫生科技辑》;20170215(第02期);第E057-13页 * |
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