WO2014117318A1 - Nouveaux composés antifongiques à base de triazoles, composition pharmaceutique les contenant, procédé de préparation et application associés - Google Patents

Nouveaux composés antifongiques à base de triazoles, composition pharmaceutique les contenant, procédé de préparation et application associés Download PDF

Info

Publication number
WO2014117318A1
WO2014117318A1 PCT/CN2013/001661 CN2013001661W WO2014117318A1 WO 2014117318 A1 WO2014117318 A1 WO 2014117318A1 CN 2013001661 W CN2013001661 W CN 2013001661W WO 2014117318 A1 WO2014117318 A1 WO 2014117318A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mmol
group
substituted
unsubstituted
Prior art date
Application number
PCT/CN2013/001661
Other languages
English (en)
Chinese (zh)
Inventor
杨玉社
曹旭峰
李站
李纬
Original Assignee
中国科学院上海药物研究所
南京长澳医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院上海药物研究所, 南京长澳医药科技有限公司 filed Critical 中国科学院上海药物研究所
Publication of WO2014117318A1 publication Critical patent/WO2014117318A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61P31/10—Antimycotics

Definitions

  • Novel triazole antifungal compound novel triazole antifungal compound, pharmaceutical composition thereof, preparation method and use thereof
  • the invention belongs to the field of pharmacy and relates to the fields of drug synthesis and pharmacology. More specifically, it relates to a triazole antifungal compound containing an azacyclic ring, a pharmaceutical composition thereof, a process for the preparation thereof, and its use in the preparation of an antifungal drug. Background technique
  • existing antifungal drugs have shortcomings such as narrow antibacterial spectrum, high toxicity, poor water solubility, etc., and their drug resistance problems are becoming more and more serious, so look for new ones. The more ideal antifungal drugs have always been a hot and difficult topic for pharmaceutical chemists.
  • anti-deep fungal infection drugs include polyenes, triazoles, and newly developed echinocanins.
  • the representative drug of polyenes is amphotericin B and its liposomes, and its serious side effects limit its clinical use.
  • Azole antifungal drugs are the largest of all types of antifungal drugs.
  • the original azole antifungal drugs can only be used for the treatment of superficial fungal infections due to their toxic side effects.
  • Ketoconazole is the first azole antifungal drug that can be taken orally for the treatment of deep fungal infections, but it still has problems with large side effects. Until the 1970s, fluconazole and itraconazole emerged as the first oral antifungal drugs.
  • Itraconazole is poorly water-soluble and has low bioavailability. Another serious problem caused by poor water solubility is that these drugs must be made into special preparations. Oral effective, which greatly increases the cost of treatment for patients. Itraconazole is used to rescue critically ill patients. In order to increase water solubility, cyclodextrin must be added, and cyclodextrin will have additional side effects, especially for patients with renal insufficiency.
  • Preferred is hydrogen, COOR 3 or CONR4R 5 ;
  • it is a d- 6 straight-chain alkyl group or a C 3 -6 branched-chain alkyl group which is unsubstituted or substituted by 1 to 3 halogen atoms; most preferably a methyl group which is unsubstituted or substituted by 1 to 3 halogen atoms , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl;
  • substituent-substituted or unsubstituted phenyl group wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, N0 2 , cyano, hydroxy, R 3 , OR 3 , NHS0 2 R 3 , N(; C 6 ⁇ 6 alkyl) S0 2 R 3 , S0 2 R 3 , S0 2 NR4R 5 , NR4R 5 , CONR4R 5 COOH and B COOR 3 ;
  • Preferred is a substituent-substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, N0 2 , cyano, hydroxy, R 3 and OR 3 ;
  • phenyl group More preferably, it is a substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is one to three substituents independently selected from the group consisting of halogen, cyano, R 3 and OR 3 ;
  • the substituent of the group is independently selected from the group consisting of 1-3 substituents: halogen, N0 2 , cyano, hydroxy, R 3 , OR 3 , NHS0 2 R 3 , N(Cw alkyl) S0 2 R 3 , S0 2 R 3 , S0 2 NR4R 5 , NR4R 5 , CONR4R 5 COOH and COOR 3 ;
  • Preferred is a substituent-substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group having 1 to 4 hetero atoms independently selected from N, S and 0, wherein the 5- or 6-membered aromatic hetero
  • the substituent of the ring group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, cyano, R 3 and OR 3 ;
  • the substituent is substituted or unsubstituted, and a 5- or 6-membered aromatic heterocyclic group having 1-2 hetero atoms independently selected from N, S and 0, wherein the 5- or 6-membered aromatic
  • the substituent of the heterocyclic group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, cyano, R 3 and OR 3 ;
  • a substituted or unsubstituted pyridyl, pyrimidinyl or thienyl group wherein the substituent of the pyridyl, pyrimidinyl or thienyl group is independently selected from the group consisting of 1-3 substituents of the following substituents : halogen, cyano, R 3 and OR 3 ;
  • R 2 is:
  • a substituted or unsubstituted phenyl group wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, N0 2 , cyano, hydroxy, R 3 , OR 3 , NHS0 2 R 3 , NCd_ 6 alkyl) S0 2 R 3 , S0 2 R 3 , S0 2 NR4R 5 , NR4R 5 , CONR4R 5 COOH and B COOR 3 ;
  • Preferred is a substituent-substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, N0 2 , cyano, hydroxy, R 3 and OR 3 ;
  • phenyl group More preferably, it is a substituted or unsubstituted phenyl group, wherein the substituent of the phenyl group is one to three substituents independently selected from the group consisting of halogen, cyano, R 3 and OR 3 ; or
  • the substituent of the group is 1-3 substituents independently selected from the group consisting of: halogen, N0 2 , cyano, hydroxy, R 3 , OR 3 , NHS0 2 R 3 , N(Cw alkyl) S0 2 R 3 , S0 2 R 3 , S0 2 NR4R 5 , NR4R 5 , CONR4R 5 COOH and COOR 3 ;
  • Preferred is a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group having 1 to 4 hetero atoms independently selected from N, S and 0, wherein the 5- or 6-membered heterocyclic ring
  • the substituent of the group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, cyano, R 3 and OR 3 ;
  • the substituent is substituted or unsubstituted and contains 1-2 heteroatoms independently selected from N, S and 0. a 5- or 6-membered aromatic heterocyclic group, wherein the substituent of the 5- or 6-membered heterocyclic group is independently selected from the group consisting of 1-3 substituents: halogen, cyano, R 3 and OR 3 ;
  • a substituted or unsubstituted pyridyl or pyrimidinyl group wherein the substituent of the pyridyl or pyrimidinyl group is independently selected from the group consisting of 1-3 substituents of the following substituents: halogen, cyano, R 3 and OR 3 ;
  • R 3 is a d- 6 straight chain alkyl group, a C 3 -6 branched alkyl group or a cycloalkyl group which is unsubstituted or substituted by 1 to 3 halogen atoms;
  • R 3 is a d- 6 straight-chain alkyl group or a C 3 -6 branched-chain alkyl group which is unsubstituted or substituted by 1 to 3 halogen atoms; more preferably, R 3 is unsubstituted or is 1-2 a halogen atom substituted methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl;
  • R4 and R 5 are each independently:
  • halogen atom is? , Cl, Br or I; preferably F, C1 or Br.
  • the compound of the formula (I) of the present invention is one of the following compounds
  • the pharmaceutically acceptable salt of the compound of the formula ⁇ of the present invention is a pharmaceutically acceptable inorganic or organic salt, and for example, may be a compound of the formula (I) with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, Fumar.
  • the optical isomer of the compound of the formula (I) of the present invention formed with hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, fumaric acid or maleic acid is the S-isomer and the R-isomer. Or a racemate.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound of the above formula ⁇ , various optical isomers thereof, and pharmaceutically acceptable salts thereof And pharmaceutically acceptable excipients.
  • a further object of the present invention is to provide a use of a compound of the formula (I), various optical isomers thereof or a pharmaceutically acceptable salt thereof for the preparation of an antifungal drug, in particular for the preparation of Candida albicans, Uses in drugs for near Candida glabrata, Candida glabrata, Cryptococcus neoformans, Microsporum gypsum, Trichophyton rubrum and/or Aspergillus fumigatus. It is a further object of the present invention to provide a method of treating a fungal infection comprising administering to a subject a therapeutically effective amount of a compound of formula (I), various optical isomers thereof, or a pharmaceutically acceptable salt thereof.
  • a further object of the present invention is to provide a compound of the formula (I), various optical isomers thereof or a pharmaceutically acceptable salt thereof for use as an antifungal agent; or a formula (I for providing a disease for the treatment of fungal infections) a compound, various optical isomers thereof, or a pharmaceutically acceptable salt thereof.
  • the compound of the formula (I) of the present invention can also be used as an antifungal drug in the form of a hydrate and a solvate.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof is used for the preparation of an antifungal drug, it may be used alone or diluted with a pharmaceutically acceptable excipient.
  • the agent or the like is mixed and prepared into a tablet, a capsule, a granule or a syrup for oral administration, or an elixirs or injections for parenteral administration.
  • a further object of the present invention is to provide a process for the preparation of the compound of the formula (I), but these specific methods do not limit the scope of the invention.
  • the compound of the present invention can be produced by the following method, however, the conditions of the method, such as the reactant, the solvent, the acid, the base, the amount of the compound used, the reaction temperature, the reaction time and the like are not limited to the following description.
  • the compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known to those skilled in the art, and those skilled in the art can easily carry out the above combination.
  • the compound of the formula (I) of the present invention can be produced according to the method of the reaction formula (1).
  • R 2 are as defined above.
  • compound 2A [Chem. Pharm. Bull. 1993, 41 (6), 1035-1042] is respectively subjected to epoxy ring-opening reaction with the compound of the formula 3a-3d to obtain a compound of the formula.
  • the equivalent ratio of each of the compounds of the formula 3a-3d to the compound 2A is preferably from 1 to 3.
  • the base used in the reaction formula (1) is an inorganic base or an organic base, and the inorganic base is sodium hydride, potassium carbonate and/or sodium methoxide, and the organic base is triethylamine and/or 1,8-diaza Bicyclo [5.4.0] ⁇ - carbon-7-ene (DBU).
  • the inorganic base is sodium hydride, potassium carbonate and/or sodium methoxide
  • the organic base is triethylamine and/or 1,8-diaza Bicyclo [5.4.0] ⁇ - carbon-7-ene (DBU).
  • the acid used in the reaction formula (1) is a Lewis acid which is lithium perchlorate, sodium perchlorate, potassium perchlorate and/or cesium perchlorate.
  • the solvent used in the reaction formula (1) is a polar organic solvent
  • the polar organic solvent is methanol, ethanol, acetonitrile, ethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide and / or tetrahydrofuran.
  • the reaction temperature of the reaction formula (1) is from 0 ° C to 200 ° C, preferably from 30 ° C to 200 ° C.
  • the reaction of the reaction formula (1) can be carried out by a conventional synthesis method or a microwave reaction synthesis method, and the reaction time is preferably from 2 minutes to 24 hours, preferably from 6 hours to 12 hours.
  • the above compounds 3a-1 to 3a-19 can be produced according to the method of the reaction formula (2) by referring to the synthesis method of the patent [WO2010125101].
  • Ri is as defined above; (1) hydrogen, halogen, COOR 3 , carboxyl, CONF Rs or NF R5;
  • substituent-substituted or unsubstituted phenyl group wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, NO 2 , hydroxyl group, R 3 , OR 3 , NHS0 2 R 3 , N(C ⁇ alkyl) S0 2 R 3 , S0 2 R 3 , S0 2 NR4R 5 , NR4R 5 , CONR4R 5 COOH and B COOR 3 ;
  • R 3 is a d- 6 straight-chain alkyl group, a C 3 -6 branched-chain alkyl group or a cyclodecyl group which is unsubstituted or substituted by 1 to 3 halogen atoms;
  • R4 and R 5 are each independently:
  • halogen atom is? , Cl, Br or I.
  • the above compounds 3a-20 to 3a-25 can be produced according to the method of the reaction formula (3).
  • the substituent of the group is independently selected from the group consisting of 1-3 substituents: halogen, N0 2 , cyano, hydroxy, R 3 , OR 3 , NHS0 2 R 3 , N(Cw alkyl) S0 2 R 3 , S0 2 R 3 , S0 2 NR4R 5 , NR4R 5 , CONR4R 5 COOH and COOR 3 ;
  • R 3 is a d- 6 straight-chain alkyl group, a C 3 -6 branched-chain alkyl group or a cyclodecyl group which is unsubstituted or substituted by 1 to 3 halogen atoms;
  • R4 and R 5 are each independently: (1) hydrogen; or
  • halogen atom is? , Cl, Br or I.
  • the compound of the formula 91 is a substituted boronic acid ester, and the compound of the formula 92 is a substituted boronic acid.
  • Compound 84 [Preparation method see WO2009090055] Hydrolyzed under basic conditions in ethanol and water to give compound 85.
  • Compound 85 undergoes a curtius rearrangement reaction with triethylamine, diphenylphosphoryl azide, and tert-butanol in toluene to form compound 86.
  • Compound 86 is deprotected from tert-butoxycarbonyl in 4N HC1/1,4-dioxane solution
  • Compound 87 is brominated with sodium nitrite, cuprous bromide, hydrobromic acid in acetic acid and water to form a compound
  • the above compounds 3b-1 to 3b-18 can be used according to the literature [S oorga 'c cfe Medicinal Chemistry Letters 17 (2007) 5934-5939] ⁇ & ⁇ (corresponding to compound 26-43), Wherein the definition corresponding to the compound of formula I is:
  • substituent-substituted or unsubstituted phenyl group wherein the substituent of the phenyl group is 1-3 substituents independently selected from the group consisting of halogen, NO 2 , hydroxyl group, R 3 , OR 3 , NHS0 2 R 3 , N(C ⁇ alkyl) S0 2 R 3 , SO2R3 , S0 2 NR4R 5 , NR4R 5 , CONR4R 5 COOH and B COOR 3 ;
  • R 3 is a d- 6 straight-chain alkyl group, a C 3 -6 branched-chain alkyl group or a cyclodecyl group which is unsubstituted or substituted by 1 to 3 halogen atoms;
  • R4 and R 5 are each independently:
  • halogen atom is? , Cl, Br or I.
  • the above compounds 3b-19 to 3b-28 can be produced according to the method of the reaction formula (4).
  • the substituent of the group is independently selected from the group consisting of 1-3 substituents: halogen, N0 2 , cyano, hydroxy, R 3 , OR 3 , NHS0 2 R 3 , N(Cw alkyl) S0 2 R 3 , S0 2 R 3 , S0 2 NR4R 5 , NR4R 5 , CONR4R 5 COOH and COOR 3 ;
  • R 3 is a d- 6 straight-chain alkyl group, a C 3 -6 branched-chain alkyl group or a cyclodecyl group which is unsubstituted or substituted by 1 to 3 halogen atoms;
  • R4 and R 5 are each independently: (1) hydrogen; or
  • halogen atom is? , Cl, Br or I.
  • the compound of the formula 91 is a substituted boronic acid ester, and the compound of the formula 92 is a substituted boronic acid.
  • Compound 94 [Preparation method see US2010099684] bromination reaction with sodium nitrite, cuprous bromide, hydrobromic acid in acetic acid and water to form compound 95.
  • Compound 95 is refluxed with lithium borohydride in ethanol to cause a reduction reaction to give compound 96.
  • the compound 96 is subjected to a tert-butoxycarbonyl protecting reaction of a N atom with a boc anhydride and triethylamine in dichloromethane to give a compound 97.
  • the compound 97 is reacted with the compound of the formula 91 or the compound of the formula 92 in 1,4-dioxane and water to obtain the compound of the formula 98 b-19 ⁇ 98b-28, followed by HC1/1,4 at 4N. -
  • the tert-butoxycarbonyl group is removed from the dioxane solution to form the compounds of the formula 3b-19 to 3b-28.
  • the above compounds 3c-1 to 3c-24 can be produced according to the method of the literature [O2iWS_3S] (corresponding to the compound 54-77), wherein, corresponding to the definition of R 2 in the compound of the formula I, General formula (I).
  • the group is 1-3 substituents independently selected from the group consisting of: halogen, N0 2 , cyano, hydroxy, R 3 , OR 3 , NHS0 2 R 3 , N(C 1-6 alkyl) S0 2 R 3 , S0 2 R 3 , S0 2 NR4R 5 , NR4R 5 , CONR4R 5 COOH and COOR 3 ;
  • R 3 is a d- 6 straight-chain alkyl group, a C 3 -6 branched-chain alkyl group or a cyclodecyl group which is unsubstituted or substituted by 1 to 3 halogen atoms;
  • R4 and R 5 are each independently selected from:
  • halogen atom is? , Cl, Br or I.
  • the compound of the formula 100 is an R 2 -substituted boronic acid ester, and the compound of the formula 101 is an R 2 -substituted boronic acid.
  • the pharmaceutically acceptable salt of the compound of the formula (I) is prepared by a conventional method in the art.
  • Figure 1 is a graph showing the results of experiments on the antifungal activity of preferred compounds of the invention in vivo.
  • the product was obtained in the same manner as in Example 1 to give 101. 1 mg of white. 0% ⁇ The solid compound 8, a melting point: 185-187 ° C, a yield of 36.0%.
  • Step 2 Under the protection of Ar gas, triethylamine (13.1 g, 0.12 mol) was slowly added dropwise to the toluene solution of compound 85 at 0-5 ° C. After stirring for 30 minutes, the azide diphenyl phosphate was slowly added. The ester (23.61 g, 85.79 mmol) was stirred slowly to room temperature and stirred for 3 hours, then t-butanol (50.0 ml) was slowly added, the mixture was heated to 80 ° C, stirred overnight, cooled to room temperature, and the reaction mixture was evaporated. Concentrated to dryness, the residue was crystallised eluted with ethyl acetate.
  • the third step Compound 86 (3.20 g, 13.61 mmol) was dissolved in 4N hydrogen chloride in 1,4-dioxane solution (20 mL), stirred at room temperature overnight, and the mixture was concentrated to dryness. The methane was dissolved, and the mixture was neutralized with a saturated sodium hydrogen carbonate solution. The organic phase was washed three times with a saturated NaCI solution, dried over anhydrous Na 2 SO 4 , and evaporated to dryness to give a pale yellow solid powder compound 87, 1.84 g (13.61 mmol). The yield was 71.0%.
  • Step 5 Add lithium borohydride (1.00 g, 45.50 mmol) to a solution of compound 88 (2.25 g, 11.30 mmol) in ethanol at 0-5 ° C, slowly warm to 50 ° C, stir for 12 hours, cool To the room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The mixture was adjusted to pH 2-3 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 9-10 with sodium carbonate.
  • the sixth step Compound 89 G.30 g, 6.43 mmol was dissolved in dichloromethane (20.0 ml), and triethylamine (0.78 g, 7.73 mmol) and di-tert-butyl dicarbonate were slowly added at 0-5 ° C. (1.55 g, 7.08 m mol), after completion of the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred overnight. After adding 3 ⁇ 40, the organic phase was washed three times with a saturated NaCl solution, dried over anhydrous Na 2 SO 4 , filtered, and evaporated to dryness. The white solid 90 was obtained in a total of 1.60 g (5.30 mmol), yield 83.0%.
  • Step 7 Compound 90 (0.30 g, 1.0 mmol), compound 103 (0.27 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.10 mmol), cesium carbonate (0.65 g, 2.0 mmol
  • the solution was dissolved in dioxane in an aqueous solution (20 mL, 4:1) and reacted at 80 ° C for 12 h under argon atmosphere. Concentrated to dryness, ethyl acetate and EtOAc (EtOAc)EtOAc.EtOAc. : 10-1 : 6) gave white solid compound 93a-20, 0.21 g (0.70 mmol), yield 70.0%.
  • the eighth step a solution of the compound 93a-20C (0.21 g, 0.70 mmol) in THF (4 mL) The mixture was dissolved in dichloromethane, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was washed three times with a saturated NaCI solution, dried over anhydrous Na 2 SO 4 , and evaporated to dryness to give a white powder compound 3a-20 (0.11 g, 0.53 mmol) , yield 76.0%.
  • the ninth step Compound 2A (125.0 mg, 0.50 mmol) was added to compound 3a-20 (200.1 mg, 1.0 mmol) and lithium perchlorate (106.4 mg, 1.0 mmol). 5% ⁇ The yield of 70.8mg of a white solid compound 20, the melting point: 110-112 ° C, the yield of 31. 5%.
  • the compound 93a-21 (0.22 g, 0.75 mmol) was obtained m. m.
  • the compound 93a-24 (0.20 g, 0.61 mmol) was obtained m. m.
  • the compounds 3b-1 to 3b-18 can be produced by the method described in the paper Bioorganic & Medicinal Chemistry Letters 17 (2007) 5934-5939.
  • the second step lithium borohydride (2.86 g, 131.3 mmol) was added to a solution of compound 95 (2.25 g, 32.8 mmol) in ethanol at 0-5 ° C, slowly rising to 50 ° C, stirring for 12 hours, cooling To the room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The mixture was adjusted to pH 2-3 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 9-10 with sodium carbonate under ice bath.
  • the third step Compound 96 (2.50 g, 12.4 mmol) was dissolved in dichloromethane (50.0 ml), and triethylamine (1.51 g, 14.90 mmol) and di-tert-butyl dicarbonate were slowly added at 0-5 ° C. (2.96 g, 13.6 m mol), after completion of the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred overnight.
  • the compound 98b-23 (0.35 g, 1.08 mmol) was obtained from the white solid solid compound 3b-23 (yield: 0.19 g (0.83 mmol), yield 76.8%.
  • the compound 98b-28 (0.19 g, 0.59 mmol) was obtained from white solid compound 3b-28 (yield: 68.2%).
  • the second step Compound 102d-lC 0.50 g (1.64 mmol) was dissolved in 4N EtOAc EtOAc EtOAc EtOAc. Dichloromethane was dissolved, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was washed three times with a saturated NaCI solution, dried over anhydrous Na 2 SO 4 , and evaporated to dryness to give a white powder compound 3d-1, 0.29 g. , the yield was 86.6%.
  • the compound 102d-3 (0.21 g, 0.70 mmol) was obtained in a white solid solid compound 3d-3 (0.13 g, 0.62 mmol).
  • the compound 77 (200.0 mg, 0.42 mmol) was dissolved in 2.0 ml of ethyl acetate, and a solution of methanesulfonic acid in ethyl acetate (43.0 mg, 0.44 mmol) was added dropwise at room temperature, and stirred at room temperature for 1.0 hour to precipitate a precipitate.
  • test strain was provided by the fungal strain library of the New Drug Research Center of the Second Military Medical University School of Pharmacy.
  • Candida albicans SC5314 Candida parapsilosis ATCC 22019 Candida glabrata 537
  • Cryptococcus neoformans cryptococcus neoformans 32609
  • RPMI 1640 medium RPMI1640 (Gibco BRL, Invitrogen, USA) 10g, NaHC0 3 2.0g, morpholinepropanesulfonic acid (MOPS, Sigma, USA) 34.5 g (0.165 M), plus three steaming Dissolve 900 ml of water, adjust the pH to 7.0 (25 °C) with l M NaOH, dilute to l000 ml, filter and sterilize, and store at 4 °C.
  • (2) YEPD culture solution yeast extract 10g, peptone 20g, glucose 20g, add three distilled water 900ml dissolved, add 2ml / ml chloramphenicol aqueous solution 50ml, dilute to 1000ml, stored at 4 ° C after autoclaving.
  • PDA medium 200 g of peeled potatoes, 20 g of glucose, and 20 g of agar. Add 3 ml of distilled water to dissolve in 900 ml, dilute to 1 000 ml, autoclave, and store at 4 °C.
  • Control drug fluconazole (FCZ, purchased from Pfizer Pharmaceuticals, Inc.), voriconazole (VCZ, purchased from Sigma, USA).
  • FCZ 0.5 0.5 2 0.25 0.25 >64 4 16
  • FCZ positive control drug fluconazole
  • the inhibitory activity of the compound of Example 48 against Candida albicans was 32 times that of fluconazole and 4 times that of voriconazole; its inhibitory activity against Candida parapsilosis was 8 times that of fluconazole and twice that of voriconazole;
  • the inhibitory activity of Cryptococcus neoformans is 32 times that of fluconazole and 8 times that of voriconazole. Its inhibitory activity against Candida glabrata is 32 times that of fluconazole and 16 times that of voriconazole.
  • Aspergillus fumigatus is 16 times of fluconazole, twice as much as voriconazole; its inhibitory activity against Rhodobacter sphaeroides is 64 times that of fluconazole and twice that of voriconazole; its inhibitory activity against gypsum-like microsporum is fluconazole 32 times, comparable to voriconazole.
  • the inhibitory activity of the compound of Example C against Candida albicans was 16 times that of fluconazole and twice that of voriconazole; its inhibitory activity against Candida parapsilosis was 8 times that of fluconazole and twice that of voriconazole;
  • the inhibitory activity of Cryptococcus neoformans is 4 times that of fluconazole, which is equivalent to voriconazole.
  • Its inhibitory activity against Candida glabrata is 2 times that of fluconazole, which is equivalent to voriconazole.
  • Its inhibitory activity against Aspergillus fumigatus is fluconazole.
  • Voriconazole 16 times, twice as much as voriconazole: its inhibitory activity against Trichophyton is 16 times that of fluconazole, comparable to voriconazole; its inhibitory activity against gypsum-like microsporum is 32 times that of fluconazole, Voriconazole is equivalent.
  • the inhibitory activity of the compound of Example 77 against Candida albicans was 16 times that of fluconazole and twice that of voriconazole; its inhibitory activity against Candida parapsilosis was 32 times that of fluconazole and 4 times that of voriconazole;
  • the inhibitory activity of Cryptococcus neoformans is 8 times that of fluconazole and twice that of voriconazole. Its inhibitory activity against Candida glabrata is 4 times that of fluconazole and twice that of voriconazole.
  • the inhibitory activity of the compound of Example 80 against Candida albicans was 16 times that of fluconazole and twice that of voriconazole; its inhibitory activity against Candida parapsilosis was 32 times that of fluconazole and 4 times that of voriconazole;
  • the inhibitory activity of Cryptococcus neoformans is 4 times that of fluconazole, which is equivalent to voriconazole; its inhibitory activity against Candida glabrata is twice that of fluconazole, comparable to voriconazole; its inhibitory activity against Aspergillus fumigatus is fluconazole 64 times, it is 8 times that of voriconazole: its inhibitory activity against Trichophyton is 16 times that of fluconazole, and its inhibitory activity against gypsum-like microsporum is 32 times that of fluconazole, which is equivalent to voriconazole.
  • sample solution and the reference solution were each injected 20 ⁇ l, and the HPLC chromatographic conditions were as follows:
  • Flow rate l.OmL/min; Detection wavelength: 210 nm; Column: Dikma C18 5 ⁇ 4.6*250mm; Column temperature: 30.0 ° C; Injection volume: 20 ⁇ l; Mobile phase 25/75 (acetonitrile: water).
  • sample solution and the reference solution were each injected 20 ⁇ l, and the HPLC chromatographic conditions were as follows:
  • Flow rate l.OmL/min; Detection wavelength: 210 nm; Column: Dikma C18 5 ⁇ 4.6*250mm; Column temperature: 30.0 ° C; Injection volume: 20 ⁇ l; Mobile phase 25/75 (acetonitrile: water).
  • C ffiW is the concentration of the sample saturated solution
  • C ⁇ is the concentration of the reference solution
  • a f ⁇ is the peak area of the sample solution after dilution of the saturated solution, which is the peak area of the reference solution
  • Voriconazole was purchased from Sigma, USA.
  • test compounds were administered by intragastric or intravenous injection.
  • the specific arrangements are shown in Table 5 below:
  • the compound was formulated in 5% DMSO/5% Tween 80/90% physiological saline.
  • Intravenous administration 5 min after administration, 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 24 h; at the above set time points, 0.3 ml of venous blood was taken from the posterior venous plexus of the rat eye. In heparinized tubes, the plasma was separated by centrifugation at llOOO rpm, and frozen in a refrigerator at -20 °C.
  • the plasma concentration in the body was 1.75 h
  • the peak concentration C max was 1420 ⁇ 104 ng/ml
  • the area under the plasma concentration-time curve was 7785 946 946.
  • Ng-h/ml, elimination half-life t 1/2 is 3.63 ⁇ 1.27 h.
  • AUC0-t was 2219 ⁇ 346 ng-h/ml
  • t 1/2 was 1.20 ⁇ 0.16 h
  • plasma clearance CLz was 1.36 ⁇ 0.21 L/h/kg.
  • each guinea pig was intraperitoneally injected with cyclophosphamide (300 mg/kg) once.
  • each guinea pig was injected subcutaneously with triamcinolone acetonide acetate (20 mg/kg) twice a day for 4 consecutive days to induce immunosuppression.
  • blood was drawn from the small saphenous vein of the hind legs of the guinea pig, and the white blood cell count was ⁇ 1000/mm 3 , which was considered to be successful in induction of immunosuppression.
  • test compounds Examples Compound 48 and Compound 118
  • fluconazole were administered orally, respectively, at a dose of 0.5 mg/Kg.
  • the remaining group was used as a comfort. Agent control group.
  • the experimental results are shown in Figure 1.
  • the results of the in vivo test showed that the compound synthesized by the present invention can significantly increase the survival number of guinea pigs, has a good in vivo anti-Candida infection activity, and its therapeutic effect is superior to that of fluconazole.
  • the in vitro antifungal activity, pharmacokinetic properties, in vivo antifungal activity, and water solubility of the compound of Formula I of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof are superior to the existing drugs. . Therefore, the compounds of the present invention can be used for the preparation of a medicament for the treatment of fungal infectious diseases, particularly fungal infections caused by deep fungal diseases.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés triazoles exprimés par la formule générale (I), et leurs isomères optiques ou leurs sels pharmaceutiquement acceptables; et l'application des composés, et de leurs isomères optiques ou leurs sels pharmaceutiquement acceptables dans la préparation de médicaments contre un champignon, notamment candida albicans, candida parapsilosis, candida glabrata, cryptococcus neoformans, bactéries à microspores de gypse, trichophyton rubrum, et/ou aspergillus fumigatus. La présente invention concerne également une composition pharmaceutique, qui comprend un ou plusieurs des composés exprimés par la formule générale (I) et de leurs isomères optiques ou leurs sels pharmaceutiquement acceptables, et des excipients pharmaceutiques en quantités thérapeutiquement efficaces.
PCT/CN2013/001661 2013-01-29 2013-12-30 Nouveaux composés antifongiques à base de triazoles, composition pharmaceutique les contenant, procédé de préparation et application associés WO2014117318A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310034677.2A CN103965194B (zh) 2013-01-29 2013-01-29 三氮唑类抗真菌化合物、其药物组合物及其制备方法和用途
CN201310034677.2 2013-01-29

Publications (1)

Publication Number Publication Date
WO2014117318A1 true WO2014117318A1 (fr) 2014-08-07

Family

ID=51235245

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2013/001661 WO2014117318A1 (fr) 2013-01-29 2013-12-30 Nouveaux composés antifongiques à base de triazoles, composition pharmaceutique les contenant, procédé de préparation et application associés

Country Status (2)

Country Link
CN (1) CN103965194B (fr)
WO (1) WO2014117318A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106032385A (zh) * 2015-03-18 2016-10-19 中国科学院上海药物研究所 三氮唑类化合物、其药物组合物、制备方法和用途
CN115444852A (zh) * 2022-09-13 2022-12-09 中国疾病预防控制中心传染病预防控制所 靶向线粒体的酰胺类化合物在制备抗真菌药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008153325A1 (fr) * 2007-06-15 2008-12-18 Korea Research Institute Of Chemical Technology Dérivés triazoles ayant une activité antifongique, leur procédé de preparation, et composition pharmaceutique comportant de tels dérivés
EP2128155A1 (fr) * 2008-05-30 2009-12-02 Fujifilm Finechemicals Co. Ltd. Dérivé de triazole ou son sel
CN102762542A (zh) * 2010-02-12 2012-10-31 大熊制药株式会社 一种新型抗真菌三唑衍生物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008153325A1 (fr) * 2007-06-15 2008-12-18 Korea Research Institute Of Chemical Technology Dérivés triazoles ayant une activité antifongique, leur procédé de preparation, et composition pharmaceutique comportant de tels dérivés
EP2128155A1 (fr) * 2008-05-30 2009-12-02 Fujifilm Finechemicals Co. Ltd. Dérivé de triazole ou son sel
CN102762542A (zh) * 2010-02-12 2012-10-31 大熊制药株式会社 一种新型抗真菌三唑衍生物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OGURA, H. ET AL.: "Synthesis and Antifungal Activities of (2R,3R)-2-Aryl-1-Azolyl-3-(Substituted Amino)-2-Butanol Derivatives as Topical Antifungal Agents", CHEM, PHARM, BULL, vol. 47, no. 10, pages 1417 - 1425 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106032385A (zh) * 2015-03-18 2016-10-19 中国科学院上海药物研究所 三氮唑类化合物、其药物组合物、制备方法和用途
CN106032385B (zh) * 2015-03-18 2018-09-11 中国科学院上海药物研究所 三氮唑类化合物、其药物组合物、制备方法和用途
CN115444852A (zh) * 2022-09-13 2022-12-09 中国疾病预防控制中心传染病预防控制所 靶向线粒体的酰胺类化合物在制备抗真菌药物中的应用
CN115444852B (zh) * 2022-09-13 2023-09-01 中国疾病预防控制中心传染病预防控制所 靶向线粒体的酰胺类化合物在制备抗真菌药物中的应用

Also Published As

Publication number Publication date
CN103965194B (zh) 2016-08-17
CN103965194A (zh) 2014-08-06

Similar Documents

Publication Publication Date Title
JP7051703B2 (ja) ピラゾロピリミジン誘導体
ES2274302T3 (es) Benzimidazoles y benzotiazoles como inhibidores de la map quinasa.
CA2897513C (fr) Derives pyrazoles
US10023534B2 (en) Carbazole and tetrahydrocarbazole compounds useful as inhibitors of BTK
TW201908306A (zh) 作為ask抑制劑的雜環化合物及其應用
KR20110093731A (ko) 신규한 항진균성 트리아졸 유도체
US20220079928A1 (en) Lysophosphatidic acid receptor antagonist and preparation method therefor
JP7492597B2 (ja) Ｇｐｒ５２モジュレーター化合物
CN112707854B (zh) 吡咯酰胺类化合物及其用途
US20160168118A1 (en) N-(5-quinolin-6-yl)pyridin-3-yl) benzsulfamide derivatives, preparation method and therapeutic use thereof
KR20180128953A (ko) 항 b형 간염 바이러스 피라졸-옥사졸리디논계 화합물
JP6803907B2 (ja) 新規な縮合したピリミジノン及びトリアジノン誘導体、それらの調製方法、並びに抗真菌薬及び／又は抗寄生虫薬としてのそれらの治療での使用
WO2015172732A1 (fr) Dérivé d'aminotétrahydropyrane utilisé en tant qu'inhibiteur de la dipeptidyl peptidase-iv
CN110872285A (zh) 作为受体相互作用蛋白1(rip1)激酶抑制剂的杂环化合物
CN111718349A (zh) 含氟吡唑并嘧啶化合物和药物组合物及其应用
WO2014117318A1 (fr) Nouveaux composés antifongiques à base de triazoles, composition pharmaceutique les contenant, procédé de préparation et application associés
MXPA05002735A (es) Derivados de pirazol.
EP1380296A1 (fr) Inducteur hsp
CA3057586A1 (fr) Compose de pyrrolopyridine, methode de preparation et utilisationon
CN110437235B (zh) 3-酰胺氮杂吲哚类化合物作为肥大细胞调节剂及其制备方法和用途
KR20230133396A (ko) Rip2 키나아제 억제제로서의 헤테로아릴 화합물, 이의 조성물 및 용도
AU2017329111B2 (en) Compositions for the treatment of hypertension and/or fibrosis
KR20160102568A (ko) 아자인돌 유도체
CN114671878B (zh) 取代的含氮双环化合物及其用途
JPH01149792A (ja) ６‐クロロ‐４‐ヒドロキシ‐２‐メチル‐Ｎ‐（２‐ピリジル）‐２Ｈ‐チエノ〔２，３‐ｅ〕‐１，２‐チアジン‐３‐カルボキサミド‐１，１‐ジオキシドのエノールエーテル、その製造方法および用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13873996

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13873996

Country of ref document: EP

Kind code of ref document: A1