[go: up one dir, main page]

WO2015034271A1 - Nouveaux dérivés antifongiques de pyridinylhydrazide - Google Patents

Nouveaux dérivés antifongiques de pyridinylhydrazide Download PDF

Info

Publication number
WO2015034271A1
WO2015034271A1 PCT/KR2014/008287 KR2014008287W WO2015034271A1 WO 2015034271 A1 WO2015034271 A1 WO 2015034271A1 KR 2014008287 W KR2014008287 W KR 2014008287W WO 2015034271 A1 WO2015034271 A1 WO 2015034271A1
Authority
WO
WIPO (PCT)
Prior art keywords
fluoro
methoxypyridin
carbohydrazide
fluoropyridin
biphenyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2014/008287
Other languages
English (en)
Inventor
Joon Seok Park
Youn Jung Yoon
Chang Min Park
Yun Soo Na
Min Jae Cho
Ho Bin Lee
Mi Ryeong Han
Yeon Jung Park
Ji Duck Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daewoong Pharmaceutical Co Ltd
Original Assignee
Daewoong Pharmaceutical Co Ltd
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 Daewoong Pharmaceutical Co Ltd filed Critical Daewoong Pharmaceutical Co Ltd
Publication of WO2015034271A1 publication Critical patent/WO2015034271A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates, in general, to a novel pyridinylhydrazide derivative with excellent antifungal activities, a method for preparing the same, an antifungal composition containing the same, and its use for the prevention or treatment of fungal infectious diseases.
  • antifungal agents available at present is much less than that of antibiotics used for the treatment of bacterial infections.
  • examples of the antifungal agents developed so far include polyene antifungals, amphotericin B or azole antifungals such as fluconazole, itraconazole, voriconazole, posaconazole, etc.
  • polyene antifungals amphotericin B or azole antifungals such as fluconazole, itraconazole, voriconazole, posaconazole, etc.
  • azole-resistant bacteria has become a problem.
  • cyclic hexapeptide type echinocandins from natural products caspofungin, micafungin, and anidulafungin
  • 1,3- ⁇ -glucan synthase inhibitors 1,3- ⁇ -glucan synthase inhibitors.
  • the antifungal agents may be classified into fungistatics and fungicides depending on the effects of their actions. Generally, fungicidal agents have a high clinical value due to their rapid and strong actions. Amphotericin B and echinocandins as fungicidal agents are known to be effective for the treatment of systemic mycoses. However, these fungicidal agents have only a limited use as they can be used in the form of injection only, and thus there is an unmet need for the development of a fungicidal agent for oral administration.
  • an objective of the present invention is to provide a novel pyridinylhydrazide derivative with an excellent antifungal activity, and a pharmaceutically acceptable salt thereof.
  • Another objective of the present invention is to provide a method for preparing the above compound.
  • a further objective of the present invention is to provide a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.
  • a further objective of the present invention is to provide a pharmaceutical composition for treating or preventing fungal infections comprising the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a further objective of the present invention is to provide a method for treating or preventing fungal infections in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof:
  • R 1 is H; or halogen
  • R 2 is halogen; or C 1 -4 alkoxy, and
  • R 3 is 1,3-benzodioxolyl; 2,3-dihydrobenzo[1,4]dioxinyl; biphenyl; naphthyl; isoquinolinyl; phenyl; pyridinyl; pyrimidinyl; tetrazolo[1,5-a]pyridinyl; pyridazinyl; dibenzofuranyl; or fluorenyl, wherein R 3 is unsubstituted; or substituted with one to three substituents selected from the group consisting of halogen; C 1-4 alkyl; C 1-4 haloalkyl; cyano; C 1-4 alkoxy; nitro; dimethylamino; thiazolyl; pyrazolyl unsubstituted or substituted with one or two C 1-4 alkyl groups; tetrazolyl; phenyl unsubstituted or substituted with one or two of the same or different groups selected from C 1 -4
  • R 1 is H; or fluoro.
  • R 2 is fluoro; or methoxy.
  • R 1 is fluoro
  • R 2 is methoxy
  • R 1 is H
  • R 2 is fluoro
  • R 3 is unsubstituted benzo[1,3]dioxolyl; 2,3-dihydrobenzo[b][1,4]dioxinyl; isoquinolinyl; tetrazolo[1,5-a]pyridinyl; pyridazinyl; or fluorenyl.
  • R 3 is biphenyl, wherein the biphenyl is unsubstituted or substituted with one to three of the same or different groups selected from halogen, hydroxy, methoxy, methyl, and .
  • R 3 is naphthyl, wherein the naphthyl is unsubstituted or substituted with one or two of the same or different groups selected from methoxy and dimethylamino.
  • R 3 is phenyl, wherein the phenyl is unsubstituted or substituted with one to three of the same or different groups selected from halogen, methyl, trifluoromethyl, cyano, methoxy, nitro, dimethylamino, thiazolyl, pyrazolyl, tetrazolyl, phenoxy, pyrrolyl, benzoyl, hydroxy(phenyl)methyl, benzyloxy, and hydroxydiphenylmethyl.
  • R 3 is pyridinyl, wherein the pyridinyl is unsubstituted or substituted with one to three of the same or different groups selected from methoxy; fluoro; methyl; and phenyl unsubstituted or substituted with halogen, trifluoromethyl or cyano.
  • R 3 is pyridinyl, wherein the pyridinyl is substituted with halophenyl; halophenyl and methoxy; (trifluoromethyl)phenyl and methoxy; or cyanophenyl and methoxy.
  • R 3 is pyrimidinyl, wherein the pyrimidinyl is unsubstituted or substituted with one or two of the same or different groups selected from piperidinyl; methyl; phenyl unsubstituted or substituted with halogen; and methoxy.
  • R 3 is dibenzofuranyl, wherein the dibenzofuranyl is unsubstituted or substituted with hydroxy.
  • the compound represented by Chemical Formula 1 of the present invention may be provided in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid.
  • the salts to be used in the present invention may include inorganic or organic salts known in the art of antifungal agents, and they may be manufactured by a known method.
  • the salts are inorganic acids such as hydrochloric acid and nitric acid; sulfonic acid such as methanesulfonic acid; or an acid addition salt formed by an organic carbonic acid such as oxalic acid.
  • the compound represented by Chemical Formula 1 of the present invention may include a hydrate and a solvate that can be manufactured therefrom.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for treating or preventing fungal infections comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for treating or preventing fungal infections in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
  • the compound represented by Chemical Formula 1 may be useful for the prevention and treatment of various types fungal infections such as infections by Candida spp ., Aspergillus spp ., Cryptococcus neoformans and Trichophyton spp .
  • the present invention provides a pharmaceutical composition for treating or preventing fungal infections comprising a compound selected from the group consisting of a compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, and a solvate thereof, as an active ingredient.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier or vehicle as well.
  • the pharmaceutical composition of the present invention may be formulated into various types via a conventional method in the art by mixing the compound of the present invention with a pharmaceutically acceptable inert carrier or vehicle suitable for oral or parenteral, or topical administration.
  • the pharmaceutical composition of the present invention has a fungicidal activity and may be orally administered.
  • Examples of the preparations for oral administration may include tablets, capsules, etc., which may include, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose or glycine, etc.), a lubricant(e.g., silica, talc, stearic acid and magnesium stearate or calcium stearate, or polyethylene glycol, etc.) or a binder (e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose or polyvinyl pyrrolidone, etc.), and may further include starch, agar, a disintegrating agent such as alginic acid or sodium alginate, an azeotropic mixture, an absorbent, a coloring agent, a flavoring agent, a sweetener, etc., as necessary.
  • a diluent e
  • the dose of the active ingredient including the compound of the present invention may vary depending on various factors such as the subject to be treated, severity of diseases, routes of administration, sex, and physician's prescription, and the effective dose may be easily determined by one of ordinary skill in the art.
  • the compound of the present invention may be administered for the treatment of mammals including humans with fungal infections in the amount of from 0.05 mg/kg/day to 200 mg/kg/day, more preferably from 0.05 mg/kg/day to 100 mg/kg/day, orally or via an injection.
  • the present invention provides a method for preparing a compound represented by Chemical Formula 1, the method comprising:
  • R 1 , R 2 , and R 3 are the same as defined above.
  • R 1 , R 2 , and R 3 are the same as defined above, and each reaction is preferably performed in a reaction solvent.
  • the compounds represented by Chemical Formula 2 and Chemical Formula 6, being known compounds, can be manufactured by conventional methods, and may be commercially available.
  • the reaction solvent is a polar organic solvent, and more preferably, a polar solvent such as tert -butanol, acetonitrile, dioxane or tetrahydrofuran.
  • a compound represented by Chemical Formula 4 may be prepared in the form of a hydrazide derivative by reacting a compound represented by Chemical Formula 3 with hydroxylamine in the presence of a base.
  • the hydroxylamine is activated in the presence of a base.
  • the reaction solvent to be used is a polar organic solvent, and more preferably, a polar solvent such as dimethylformamide, dioxane or tetrahydrofuran.
  • the base to be used in the present invention may be a conventional inorganic base or organic base, for example, an inorganic base such as sodium hydride (NaH) or sodium methoxide (MeONa), or a conventional organic base such as triethylamine or n-butyl lithium.
  • an inorganic base such as sodium hydride (NaH) or sodium methoxide (MeONa)
  • a conventional organic base such as triethylamine or n-butyl lithium.
  • a compound represented by Chemical Formula 5 may be prepared by reacting a compound represented by Chemical Formula 4 with an acid to remove a protecting group.
  • the acid is preferably hydrochloric acid (HCl).
  • the prepared compound of Chemical Formula 5 is present in the form of a salt with 2 equivalents of HCl.
  • a compound represented by Chemical Formula 1 of the present invention may be finally prepared by reacting a compound represented by Chemical Formula 5 with a compound represented by Chemical Formula 6.
  • the compound represented by Chemical Formula 1 may be prepared at a reaction temperature of from 0°C to 50°C, more preferably from 50°C to room temperature and under stirring condition for from 30 minutes to 24 hours.
  • the present invention provides a compound represented by Chemical Formula 5 below, an intermediate for preparing a pyridinylhydrazide derivative of the present invention.
  • R 1 and R 2 are the same as defined above.
  • the present invention provides a method for preparing a compound represented by Chemical Formula 1 above (a compound represented by Chemical Formula 1, wherein R 1 is H, and R 2 is F), as shown in Reaction Scheme 2 below.
  • R 3 is the same as defined above, and the above reaction is preferably performed in a reaction solvent, more specifically, in a polar organic solvent such as methanol, ethanol, acetonitrile, dimethoxyethane, dimethylformamide, dimethylsulfoxide, or tetrahydrofuran.
  • a reaction solvent more specifically, in a polar organic solvent such as methanol, ethanol, acetonitrile, dimethoxyethane, dimethylformamide, dimethylsulfoxide, or tetrahydrofuran.
  • a compound represented by Chemical Formula 1 (wherein R 1 is H, and R 2 is F) may be prepared by reacting a compound represented by Chemical Formula 6 with a compound represented by Chemical Formula 7.
  • the carboxylic acid of Chemical Formula 6 may be used in the form of a methyl or ethyl carboxylate or acyl chloride, according to a conventional method.
  • a compound represented by Chemical Formula 1 (wherein R 1 is H, and R 2 is F) may be prepared at a reaction temperature of from 0°C to 50°C, more preferably from 50°C to room temperature and under stirring condition for from 30 minutes to 24 hours.
  • the novel antifungal pyridinylhydrazide derivative of the present invention has excellent antifungal and fungicidal activities, and thus will be useful for the prevention and treatment of various fungal infections such as Candida spp ., Aspergillus spp ., Cryptococcus neoformans and Trichophyton spp . Additionally, the pyridinylhydrazide derivative of the present invention is advantageous in that it can be orally administered unlike other fungicidal agents.
  • Step 1 Preparation of t - butyl (5- fluoro -6- methoxypyridin -3- yl ) carbamate
  • Step 2 Preparation of t- butyl 1-(5- fluoro -6- methoxypyridin -3- yl ) hydrazine -1- carboxylate
  • N,N -dimethylformamide (21 ml, 1.0 M) was added to 60% NaH (1.8 g, 51.6 mmol), and maintained under the nitrogen condition.
  • the t-butyl (5-fluoro-methoxypyridin-3-yl) carbamate (5 g, 20.6 mmol) obtained in Step 1 was dissolved in N,N -dimethylformamide (3 ml, minimum amount), and added dropwise to the previously prepared mixed solution, and stirred. After 30 minutes, P,P -diphenylphosphinic amide (8.7 g, 37.1 mmol) was added thereto at once, N,N -dimethylformamide (21 ml) was further added thereto, and the mixed solution was stirred.
  • Step 3 Preparation of 5- fluoro -6- methoxy - pyridin -3- yl hydrazine hydrochloride
  • Step 4 Preparation of N ' -(5- fluoro -6- methoxypyridin -3- yl ) benzohydrazide
  • Example 58 Preparation of 4'- chloro -6- fluoro -N'-(5- fluoro -6- methoxypyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
  • Example 80 Preparation of N' -(5- fluoro -6- methoxypyridin -3- yl ) tetrazolo [1,5-a] pyridine -6- carbohydrazide
  • 2-fluoro-5-hydrazinylpyridine (17.4 mg, 0.08 mmol) and benzoic acid (9.8 mg, 0.08 mmol) were dissolved in 1 ml of N,N -dimethylformamide.
  • HBTU (45.4 mg, 0.12 mmol) and DIPEA (34.8 ⁇ l, 0.2 mmol) were added thereto at room temperature, and the reactants were stirred at room temperature for 6 hours. Upon completion of the reaction, the solvent was removed, and the resultant was diluted with ethylacetate, and washed with saturated sodium chloride.
  • Example 85 The title compound (15.6 mg, yield 71%) was obtained in the same manner as in Example 85 except that 4-cyano-3-fluorobenzoic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (16.7 mg, yield 79%) was obtained in the same manner as in Example 85 except that 4-fluoro-3-methylbenzoic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (19.1 mg, yield 76%) was obtained in the same manner as in Example 85 except that 4-methyl-3-(trifluoromethyl)benzoic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (18.0 mg, yield 82%) was obtained in the same manner as in Example 85 except that 3-cyano-4-fluorobenzoic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (14.9 mg, yield 61%) was obtained in the same manner as in Example 85 except that 3-(dimethylamino)-4-methoxybenzoic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (11.8 mg, yield 63%) was obtained in the same manner as in Example 85 except that pyrimidine-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (12.5 mg, yield 67%) was obtained in the same manner as in Example 85 except that pyrimidine-2-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (12.1 mg, yield 65%) was obtained in the same manner as in Example 85 except that pyrimidine-5-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (11.2 mg, yield 60%) was obtained in the same manner as in Example 85 except that pyridazine-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (18.9 mg, yield 69%) was obtained in the same manner as in Example 85 except that 4'-chloro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (15.7 mg, yield 57%) was obtained in the same manner as in Example 85 except that 5-(4-chlorophenyl)nicotinic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (15.7 mg, yield 57%) was obtained in the same manner as in Example 85 except that 6-phenylpyrimidine-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 102 Preparation of 6-(4- fluorophenyl )- N' -(6- fluoropyridin -3- yl ) pyrimidine -4- carbohydrazide
  • Example 85 The title compound (17.6 mg, yield 67%) was obtained in the same manner as in Example 85 except that 6-(4-fluorophenyl)pyrimidine-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 104 Preparation of 4'- chloro -6- fluoro - N '-(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
  • Example 85 The title compound (17.0 mg, yield 59%) was obtained in the same manner as in Example 85 except that 4'-chloro-6-fluoro-[1,1'-biphenyl]-3-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 105 Preparation of 6- chloro - N ' -(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-3- carbohydrazide
  • Example 106 Preparation of 5-(4- fluorophenyl )- N ' -(6- fluoropyridin -3- yl )-6- methoxynicotinohydrazide
  • Example 85 The title compound (19.7 mg, yield 66%) was obtained in the same manner as in Example 85 except that 5-(4-chlorophenyl)-6-methoxynicotinic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (16.7 mg, yield 68%) was obtained in the same manner as in Example 85 except that [1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 112 Preparation of 4'- fluoro - N '-(6- fluoropyridin -3- yl )-[1,1'- biphenyl ]-4- carbohydrazide
  • Example 85 The title compound (17.7 mg, yield 68%) was obtained in the same manner as in Example 85 except that 4'-fluoro-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (18.1 mg, yield 66%) was obtained in the same manner as in Example 85 except that 4'-chloro-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (15.9 mg, yield 61%) was obtained in the same manner as in Example 85 except that 2-fluoro-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (15.2 mg, yield 59%) was obtained in the same manner as in Example 85 except that 2-methyl-[1,1'-biphenyl]-4-carboxylic acid was used instead of benzoic acid in Example 85.
  • Example 85 The title compound (18.4 mg, yield 71%) was obtained in the same manner as in Example 85 except that 4-phenoxybenzoic acid was used instead of benzoic acid in Example 85.
  • Example 1 50 mg of the compound prepared in Example 1, was granulated, in combination with 20 mg of magnesium stearate, using 35 mg of soluble starch and dried. The granules were then mixed with 65 mg of lactose and 30 mg of corn starch using a mechanical shaker and a mixer for 30 minutes. The resulting mixture was compressed and formulated into tablets.
  • the antifungal activities of the compounds of the present invention were evaluated using Candida albicans as a yeast fungus, and Aspergillus fumigatus as a filamentous fungus.
  • Candida albicans as a yeast fungus
  • Aspergillus fumigatus as a filamentous fungus.
  • the above fungi used were all purchased from American Type Culture Collection (ATCC).
  • the strains used in the experiment were inoculated into a Sabouraud dextrose agar medium, and then cultured at 35°C for a sufficient period of time, e.g., 24 hours for Candida albicans , and about 7 days for Aspergillus fumigatus .
  • a sufficient period of time e.g. 24 hours for Candida albicans
  • Aspergillus fumigatus about 7 days for Aspergillus fumigatus .
  • As for Candida albicans about 5 to 7 single colonies were taken from the cultured medium, sufficiently suspended in 1 ml of 0.85% sterile saline solution, and adjusted to have an optical density of from 0.095 to 0.107 at 530 nm.
  • the prepared strain dilutions were diluted in RPMI (Roswell park memorial institute) 1640 medium at a 1:10 ratio, and the resultant was diluted again at a 1:100 ratio to prepare inoculums having a cell density of from 1.0 x 10 3 to 5.0 x 10 3 CFU/ml.
  • Aspergillus fumigatus to the cultured Sabouraud dextrose agar was added 1 mL of 0.2% Tween 20 diluted with 0.85% sterile saline solution, and then the plate was shaken to detach conidiums from the plate. The solution collected from the plate surface was transferred into a sterile tube, and placed at room temperature for 5 minutes to sediment heavy substances such as medium.
  • strain dilutions were prepared with a cell density of from 0.4 x 10 6 to 5.0 x 10 6 CFU/ml using a hemocytometer.
  • the thus prepared strain dilutions were diluted in RPMI 1640 medium at a 1:100 ratio to obtain inoculums for Aspergillus fumigatus .
  • Candida albicans was cultured at 35°C for 24 hours and Aspergillus fumigatus was cultured at 35°C for 48 hours, and the concentrations, at which growth is inhibited by 80% or 50% compared to a negative control group, were determined using Alamar blue color developing reagent. All experiments were repeated twice for each concentration, and the results of antifungal activities (MIC 80 and MIC 50 ⁇ g/ml) are shown in Tables 1 to 3.
  • Example No. Candida albicans MIC 80 Aspergillus fumigatus MIC 50 1 0.03 0.4 21 0.07 - 2 0.03 - 22 0.12 - 3 0.03 - 23 0.04 0.3 4 0.03 - 24 0.03 0.6 5 0.03 - 25 0.04 0.3 6 0.03 - 26 0.08 1.3 7 0.03 - 27 ⁇ 0.01 - 8 0.03 - 28 0.06 1.0 9 0.03 - 29 0.06 - 10 0.03 - 30 0.03 0.5 11 0.03 - 31 0.03 0.5 12 0.03 - 32 0.03 - 13 0.06 - 33 0.04 - 14 0.03 - 34 0.06 - 15 0.06 - 35 0.07 - 16 0.03 - 36 0.03 - 17 0.06 - 37 0.25 - 18 0.06 - 38 0.04 - 19 0.03 - 39 0.03 - 20
  • Example No. Candida albicans MIC 80 Aspergillus fumigatus MIC 50 41 0.04 - 61 0.07 - 42 0.12 - 62 0.06 - 43 0.05 0.4 63 0.29 - 44 0.02 - 64 0.01 0.2 45 0.04 - 65 ⁇ 0.01 0.3 46 0.03 - 66 0.02 0.3 47 0.26 0.5 67 0.04 0.7 48 ⁇ 0.01 0.6 68 0.04 0.6 49 0.02 - 69 0.53 1.1 50 ⁇ 0.01 0.3 70 0.02 1.1 51 ⁇ 0.01 0.3 71 ⁇ 0.01 - 52 ⁇ 0.01 0.6 72 0.02 0.3 53 ⁇ 0.01 - 73 0.03 - 54 0.04 - 74 0.03 0.3 55 ⁇ 0.01 0.3 75 0.02 0.6 56 ⁇ 0.01 0.3 76 0.03 0.3 57 ⁇
  • Example No. Candida albicans MIC 80 Aspergillus fumigatus MIC 50 81 0.15 - 106 0.14 0.6 82 0.07 - 107 0.04 0.6 83 ⁇ 0.01 - 108 0.04 0.6 84 ⁇ 0.01 - 109 0.07 0.6 85 0.05 0.4 110 0.07 0.5 86 0.11 0.9 111 0.06 1.0 87 0.01 0.01 112 0.13 1.0 88 0.12 1.0 113 0.27 1.1 89 0.11 - 114 0.13 0.5 90 0.06 - 115 0.06 - 91 0.09 - 116 0.12 0.5 92 0.09 - 117 0.13 1.1 93 0.09 - 118 0.12 0.5 94 0.18 - 119 0.06 - 95 0.06 0.9 120 0.13 0.5 96 0.06 1.0 121 0.13 0.5 97
  • the compounds of the present invention have exhibited significantly excellent antifungal effects compared to the traditional antifungal agents such as caspofungin and fluconazole.
  • Test Example 2 In vitro fungicidal activity test (Minimum Fungicidal Concentration, MFC )
  • the evaluations of the fungicidal activity of Candida albicans were performed using the test plate already completed of antifungal activity, from the highest concentration of a given sample to the concentration right next to the concentration determined to be MIC. Test solutions at each concentration were pipetted about 5 times, all were collected (about a total of 225 ⁇ L), and added into a 12-well Sabouraud dextrose agar plate. The test plate was cultured at 35°C for 48 hours, and the minimum concentration at which no fungal growth was observed with the naked eye. The result of fungicidal activity (MFC ⁇ g/mL) is shown in Table 4.
  • the compounds of the present invention have exhibited a significantly excellent fungicidal effect over the traditional fungicides such as caspofungin and fluconazole.

Landscapes

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

Abstract

La présente invention porte sur de nouveaux dérivés de pyridinylhydrazide et sur un procédé pour leur fabrication. Les dérivés de pyridinylhydrazide de la présente invention ont d'excellentes activités antifongiques et fongicides, et vont donc être utiles pour la prévention et le traitement de différentes infections fongiques. En outre, les dérivés de pyridinylhydrazide la présente invention peuvent, au contraire d'autres préparations fongicides, être administrés par voie orale.
PCT/KR2014/008287 2013-09-04 2014-09-04 Nouveaux dérivés antifongiques de pyridinylhydrazide Ceased WO2015034271A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20130106098A KR20150027922A (ko) 2013-09-04 2013-09-04 신규한 항진균성 피리디닐하이드라자이드 유도체
KR10-2013-0106098 2013-09-04

Publications (1)

Publication Number Publication Date
WO2015034271A1 true WO2015034271A1 (fr) 2015-03-12

Family

ID=52628655

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2014/008287 Ceased WO2015034271A1 (fr) 2013-09-04 2014-09-04 Nouveaux dérivés antifongiques de pyridinylhydrazide

Country Status (2)

Country Link
KR (1) KR20150027922A (fr)
WO (1) WO2015034271A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016160552A1 (fr) * 2015-03-27 2016-10-06 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Agents antimicrobiens à base de pyridinohydrazide et d'hydrazométhylpyridine
US10689371B2 (en) 2018-04-18 2020-06-23 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
CN111533687A (zh) * 2020-05-08 2020-08-14 张建蒙 肉桂酰胺吡啶类衍生物及其在抗真菌药物中的应用
US10934256B2 (en) * 2015-06-05 2021-03-02 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer
CN113072497A (zh) * 2021-01-12 2021-07-06 西湖大学 蛋白酶抑制剂、其制备和用途
CN113968852A (zh) * 2020-07-23 2022-01-25 同济大学 一种噻唑酰肼类衍生物及其制备方法和应用
CN114478382A (zh) * 2022-02-08 2022-05-13 贵州大学 一种异喹啉-3-酰肼类化合物及其制备方法和应用
EP3842426A4 (fr) * 2018-08-22 2022-05-18 Jiangsu Hengrui Medicine Co., Ltd. Procédé de préparation d'un composé de pyrrolo-amino-pyridazinone et son intermédiaire
US11919912B2 (en) 2018-05-21 2024-03-05 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101657678B1 (ko) * 2013-11-05 2016-09-20 주식회사 대웅제약 신규한 화합물, 이의 제조방법 및 이를 포함하는 항진균제 조성물
CN114601829B (zh) * 2022-01-24 2023-05-16 中国人民解放军海军军医大学 一种n2化合物在制备抗真菌的药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010078906A2 (fr) * 2008-12-18 2010-07-15 Bayer Cropscience Ag Hydrazides, procédé permettant leur préparation et leur utilisation en tant qu'herbicides et insecticides
WO2012046050A1 (fr) * 2010-10-07 2012-04-12 Astrazeneca Ab Nouvelles combinaisons
WO2012116277A1 (fr) * 2011-02-25 2012-08-30 Arena Pharmaceuticals, Inc. Modulateurs du récepteur cannabinoïde

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010078906A2 (fr) * 2008-12-18 2010-07-15 Bayer Cropscience Ag Hydrazides, procédé permettant leur préparation et leur utilisation en tant qu'herbicides et insecticides
WO2012046050A1 (fr) * 2010-10-07 2012-04-12 Astrazeneca Ab Nouvelles combinaisons
WO2012116277A1 (fr) * 2011-02-25 2012-08-30 Arena Pharmaceuticals, Inc. Modulateurs du récepteur cannabinoïde

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
0. V. SURIKOVA ET AL.: "Synthesis and antifungal activity of 2-(3,3- dimethyl-1,2,3,4-tetrahydroquinolin-1-idene)-2-oxopropanoic acid amides and hydrazides", PHARMACEUTICAL CHEMISTRY JOURNAL, vol. 44, no. 2, 2010, pages 58 - 60 *
CHANDRASEKHAR, T. ET AL.: "Synthesis and biological evaluation of some new Aryl acid N'-(1Hindazole-3-carbonyl)-hydrazide derivatives", J. CHEMICAL PHARMACEUTICAL RES., vol. 4, no. 5, 2012, pages 2795 - 2802 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016160552A1 (fr) * 2015-03-27 2016-10-06 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Agents antimicrobiens à base de pyridinohydrazide et d'hydrazométhylpyridine
US12441685B2 (en) 2015-06-05 2025-10-14 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer
US10934256B2 (en) * 2015-06-05 2021-03-02 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer
US11845728B2 (en) 2015-06-05 2023-12-19 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer
US10689371B2 (en) 2018-04-18 2020-06-23 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US11274095B2 (en) 2018-04-18 2022-03-15 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US11919912B2 (en) 2018-05-21 2024-03-05 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
EP3842426A4 (fr) * 2018-08-22 2022-05-18 Jiangsu Hengrui Medicine Co., Ltd. Procédé de préparation d'un composé de pyrrolo-amino-pyridazinone et son intermédiaire
CN111533687A (zh) * 2020-05-08 2020-08-14 张建蒙 肉桂酰胺吡啶类衍生物及其在抗真菌药物中的应用
CN113968852B (zh) * 2020-07-23 2023-08-15 同济大学 一种噻唑酰肼类衍生物及其制备方法和应用
CN113968852A (zh) * 2020-07-23 2022-01-25 同济大学 一种噻唑酰肼类衍生物及其制备方法和应用
JP2022108241A (ja) * 2021-01-12 2022-07-25 ウエストレイク・ファーマシューティカル・（ハンヂョウ）・カンパニー・リミテッド プロテアーゼ阻害剤、その調製、および使用
CN113072497A (zh) * 2021-01-12 2021-07-06 西湖大学 蛋白酶抑制剂、其制备和用途
US11958830B2 (en) 2021-01-12 2024-04-16 Westlake Pharmaceuticals (Hangzhou) Co., Ltd. Protease inhibitors, preparation, and uses thereof
JP7611045B2 (ja) 2021-01-12 2025-01-09 ウエストレイク・ファーマシューティカルズ・（ハンヂョウ）・カンパニー・リミテッド プロテアーゼ阻害剤、その調製、および使用
CN114478382A (zh) * 2022-02-08 2022-05-13 贵州大学 一种异喹啉-3-酰肼类化合物及其制备方法和应用

Also Published As

Publication number Publication date
KR20150027922A (ko) 2015-03-13

Similar Documents

Publication Publication Date Title
WO2015034271A1 (fr) Nouveaux dérivés antifongiques de pyridinylhydrazide
EP2536697A2 (fr) Nouveaux dérivés de triazole antifongiques
WO2012115479A2 (fr) Dérivés de diaminopyrimidine et leurs procédés de préparation
WO2022039460A1 (fr) Composé d'imidazolquinoline ou de benzoindazolone et intermédiaire pour sa préparation
WO2020262996A1 (fr) Composé dérivé introduisant un groupe biphényle dans un nouvel acide aminoalcanoïque et composition pharmaceutique antifongique le comprenant
WO2015060613A1 (fr) Nouveau dérivé oxodihydropyridinecarbohydrazide antifongique
WO2013043002A1 (fr) Dérivé de benzothiazole contenant imide ou son sel et composition pharmaceutique le comprenant
WO2023085785A1 (fr) Dérivé d'isoindolinone ayant un noyau mère de glutarimide et son utilisation
WO2015069011A1 (fr) Nouveau composé, procédé de préparation de celui-ci, et composition antifongique le comprenant
WO2021040393A1 (fr) Dérivé d'indole carboxamide et composition pharmaceutique le contenant
WO2017131425A1 (fr) Nouveau dérivé d'imidazole présentant une activité inhibitrice de la jnk et son utilisation
WO2019235879A1 (fr) Composition pour prévenir ou traiter le cancer, contenant un nouvel inhibiteur de mtor
WO2020242245A1 (fr) Composés de phtalazinone et leur utilisation
WO2010032986A2 (fr) Nouveaux dérivés de 5-(4-aminophenyl)-isoquinoline, leurs sels pharmaceutiquement acceptables, procédé de production associé et composition contenant les dérivés comme principe actif pour la prophylaxie et le traitement d'états pathologiques induits par l'hyperactivité de la kinase raf
WO2023224371A1 (fr) Nouveau composé dérivé d'oxadiazole, et composition pharmaceutique pour la prévention ou le traitement de maladies neuroinflammatoires le comprenant
WO2018021762A1 (fr) Nouveau composé, son procédé de préparation, et composition pharmaceutique le contenant
WO2011081280A2 (fr) Nouveaux activateurs de glucokinase et procédés pour les préparer
WO2022203332A1 (fr) Nouveaux inhibiteurs de l'indoléamine 2,3-dioxygénase, leurs procédés de préparation et compositions pharmaceutiques les comprenant
WO2019098785A1 (fr) Dérivé de 7-amino-1h-indole-5-carboxamide et utilisation correspondante
EP3867249A1 (fr) Nouveaux dérivés de benzooxazinone ou de benzothiazinone substitués par (isopropyl-triazolyl)pyridinyle et leur utilisation
WO2023090908A1 (fr) Nouveau dérivé de flavonoïde et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement d'une maladie métabolique
WO2023055124A1 (fr) Dérivé à noyau condensé bicyclique ou sel de celui-ci et composition pharmaceutique le comprenant
WO2019194556A1 (fr) Nouveau composé 6-hétéroarylamino-2,4,5-triméthylpyridine-3-ol, ou composition pharmaceutique pour la prévention ou le traitement de maladies intestinales inflammatoires et de maladies auto-immunes le comprenant
WO2023229099A1 (fr) Dérivé d'oxime de benzofuranyle hydroxyphénylméthanone et ses utilisations
WO2023063697A1 (fr) Nouveaux inhibiteurs d'assemblage de capside

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: 14842438

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: 14842438

Country of ref document: EP

Kind code of ref document: A1