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WO2005092304A2 - Agents antifongiques - Google Patents

Agents antifongiques Download PDF

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Publication number
WO2005092304A2
WO2005092304A2 PCT/GB2005/001146 GB2005001146W WO2005092304A2 WO 2005092304 A2 WO2005092304 A2 WO 2005092304A2 GB 2005001146 W GB2005001146 W GB 2005001146W WO 2005092304 A2 WO2005092304 A2 WO 2005092304A2
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WO
WIPO (PCT)
Prior art keywords
dihydro
methyl
thiadiazol
phenyl
thiadiazole
Prior art date
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PCT/GB2005/001146
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English (en)
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WO2005092304A3 (fr
Inventor
Samantha Patricia Thomson
Rhian Tereas Davies
Nigel Mark Allanson
Alexander Kuvshinov
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F2G Ltd
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Publication of WO2005092304A2 publication Critical patent/WO2005092304A2/fr
Publication of WO2005092304A3 publication Critical patent/WO2005092304A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • 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
    • C07D513/10—Spiro-condensed systems

Definitions

  • This invention relates to 2,3-dihydro-l,3,4-thiadiazole compounds and their therapeutic use in prevention or freatment of fungal diseases. It also relates to the use of the compounds as agricultural fungicides.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for treatment of the human or animal body by therapy:
  • RI is aryl, heterocyclyl, -CR8R9-X-aryl, -CR8R9-X-heterocyclyl, -CR8R9-X- (C1-C4 alkylene)-aryl, -CR8R9-X-(C1-C4 alkylene)-heterocyclyl, -(C2-C4 alkenylene)- aryl or -(C2-C4 alkenylene)-heterocyclyl; R8 and R9 independently represent hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-
  • R2 and R3 independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2- C8 alkynyl, aryl, heterocyclyl, -CO 2 R ⁇ -CONR'R", -COR', -CN, -CF 3 or -Y-Z; or R2 represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heterocyclyl, -CO 2 R' 5 -CONR'R", -COR', -CN, -CF 3 or -Y-Z and R3 is an aryl or heterocyclyl group which is substituted with a group (lb)
  • ⁇ TM" represents the position of attachment to R3, RI' is aryl, heterocyclyl, -CR8R9-X-aryl, -CR8R9-X-heterocyclyl, -CR8R9-X-(C1-C4 alkylene)- aryl, -CR8R9-X-(C1-C4 alkylene)-heterocyclyl, -(C2-C4 alkenylene)-aryl or -(C2-C4 alkenylene)-heterocyclyl, wherein R8, R9 and X are, independently, as defined above, and -R2' represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heterocyclyl, -CO 2 R', -CONR'R", -COR', -CN, -CF 3 or -Y-Z; or R2 and R3, together with the carbon atom to which they
  • the compounds of formula (I) are typically those wherein: RI is aryl, heterocyclyl, -CR8R9-X-aryl, -CR8R9-X-heterocyclyl, -CR8R9-X- (C1-C4 alkylene)-aryl, -CR8R9-X-(C1-C4 alkylene)-heterocyclyl, -(C2-C4 alkenylene)- aryl or -(C2-C4 alkenylene)-heterocyclyl; R8 and R9 independently represent hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, halogen or hydroxy; X is a bond, -O-, -S-, -SO-, -SO 2 - or --NR'-; either R2 and R3 independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkyny
  • a C1-C8 alkyl group or moiety can be linear, branched or cyclic but is preferably linear. It is preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, most preferably a C1-C3 alkyl group. Suitable such alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and tert-butyl, as well as pentyl, hexyl, heptyl and octyl and isomers thereof.
  • a C2-C8 alkenyl group or moiety can be linear, branched or cyclic but is preferably linear. It contains one or more carbon-carbon double bonds. It is preferably a C2-C6 alkenyl group, more preferably a C2-C4 alkenyl group, most preferably a C2-C3 alkyl group. Suitable such alkenyl groups and moieties include vinyl, allyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl and isomers thereof.
  • a C2-C8 alkynyl group or moiety can be linear, branched or cyclic but is preferably linear.
  • It contains one or more carbon-carbon triple bonds. It is preferably a C2-C6 alkynyl group, more preferably a C2-C4 alkynyl group, most preferably a C2-C3 alkynyl group. Suitable such alkynyl groups and moieties include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl and isomers thereof.
  • An alkyl, alkenyl or alkynyl group or moiety can be substituted or unsubstituted. Typically, it carries up to three substituents, e.g. one or two substituents.
  • Suitable substituents include halogen such as fluorine, hydroxy, amino, (C1-C4 alkyl)amino, di(Cl-C4 alkyl)amino, and C1-C4 alkoxy such as methoxy or ethoxy.
  • the substituents are typically themselves unsubstituted.
  • a C1-C6 alkylene group or moiety can be linear or branched, but is preferably linear. It is preferably a C1-C4 alkylene group, more preferably a C1-C3 alkylene group.
  • Suitable such alkylene groups or moieties include methylene, ethylene, propylene, butylene, pentylene and hexylene and isomers thereof.
  • a C2-C6 alkenylene group or moiety can be linear or branched, but is preferably linear. It is preferably a C2-C4 alkenylene group, more preferably a C2 or C3 alkenylene group. Suitable such alkenylene groups include ethenylene, propenylene, butenylene, pentenylene and hexenylene and isomers thereof.
  • a C2-C6 alkynylene group or moiety can be linear or branched, but is preferably linear. It is preferably a C2-C6 alkynylene group, more preferably a C2 or C3 alkynylene group.
  • Suitable such alkynylene groups include ethynylene, propynylene, butynylene, pentynylene and hexynylene and isomers thereof.
  • a cycloalkyl group is typically a C3-C6 cycloalkyl group, preferably a C5 or C6 cycloalkyl group.
  • a cycloalkyl group is unsubstituted or substituted with up to three substituents, e.g. one or two substituents.
  • Suitable substituents include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined.
  • a cycloalkyl group is unsubstituted.
  • Rl is -R8R9-X-(C1-C4 alkylene)-aryl or -R8R9-X-(C1-C4 alkylene)- heterocyclyl
  • the C1-C4 alkylene moiety is preferably methylene.
  • the C2-C4 alkenylene moiety is preferably ethenylene.
  • R8 and R9 preferably independently represent hydrogen, C1-C4 alkyl, halogen or hydroxy. When R8 or R9 is halogen, it is preferably fluorine. Typically, R8 is hydrogen. Typically, R9 is hydrogen.
  • R2 or R3 is C1-C8 alkyl, it is preferably C1-C4 alkyl, more preferably methyl, ethyl or propyl, e.g. methyl.
  • R2 or R3 is C2-C8 alkenyl, it is preferably C2-C4 alkenyl, more preferably ethenyl.
  • R2 or R3 is C2-C8 alkynyl, it is preferably C2-C4 alkynyl, more preferably ethynyl.
  • RI is optionally substituted phenyl and one of R2 and R3 is hydrogen or C1-C4 alkyl, the other of R2 and R3 is not unsubstituted pyridyl. In this embodiment, for example, R2 and R3 are not unsubstituted pyridyl, or, R2 and R3 are not pyridyl.
  • Y is C1-C6 alkylene, it is preferably C1-C4 alkylene, more preferably methylene or ethylene.
  • Y is C2-C6 alkenylene, it is preferably C2-C4 alkenylene, more preferably ethenylene.
  • Y is C2-C6 alkynylene, it is preferably C2-C4 alkynylene, more preferably ethynylene.
  • R' or R" is C1-C6 alkyl, it is preferably C1-C4 alkyl, more preferably methyl or ethyl.
  • R' or R" is C2-C6 alkenyl, it is preferably C2-C4 alkenyl, more preferably ethenyl.
  • R' or R" is C2-C6 alkynyl, it is preferably C2-C4 alkynyl, more preferably ethynyl.
  • an aryl group or moiety is typically a C6-C10 aryl group or moiety. Suitable such aryl groups and moieties include phenyl and naphthyl.
  • An aryl group or moiety may be substituted or unsubstituted. Each ring atom may be substituted or unsubstituted.
  • an aryl group or moiety carries up to three substituents, e.g. one or two substituents.
  • Suitable substituents include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined.
  • an aryl group or moiety is substituted with a substituent containing a further aryl or a heterocyclyl group
  • the aryl or heterocyclyl group of the substituent is itself unsubstituted or substituted with one, two or three halogen atoms.
  • a heterocyclyl group or moiety can be saturated or unsaturated. It is typically a 5- to 12-membered ring system in which the ring contains at least one heteroatom.
  • the ring contains up to three divalent heteroatom groups, e.g. one or two divalent heteroatom groups.
  • Suitable divalent heteroatom groups include - O-, -S-, -SO-, -SO 2 -, -NR'- and -NCOR'-, wherein R' is as hereinbefore defined.
  • heterocyclyl groups and moieties include, for example, monocyclic saturated 5- to 8-membered rings such as tetrahydrofixranyl, piperidinyl, morpholinyl, piperazinyl and tetrahydropyranyl, e.g tefrahydrofuranyl, piperidinyl, morpholinyl and piperazinyl; monocyclic unsaturated 5- to 8-membered rings such as furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and di- and tefrahydropyridinyl, e.g.
  • a heterocyclyl group or moiety may be substituted or unsubstituted. Each ring atom may be unsubstituted or may carry one or two substituents. Typically, a heterocyclyl group or moiety carries up to three substituents, e.g.
  • substituents include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined.
  • the heterocycle may be connected to the remainder of the molecule by a bond to any of its available ring positions.
  • a heterocyclyl group or moiety is substituted with a substituent containing an aryl or a further heterocyclyl group
  • the aryl or heterocyclyl group of the substituent is itself unsubstituted or substituted with one, two or three halogen atoms.
  • a halogen is typically chlorine, fluorine, bromine or iodine, and is preferably chlorine, fluorine or bromine.
  • Z is halogen, aryl, heterocyclyl, -OR', - SR', -SOR', -SO 2 R ⁇ -SO 2 NR'R", -SO 3 H, -NR'R", -NR'COR", -NO 2 , -CO 2 R ⁇ - CONR'R", -COR', -CN or -CF 3 .
  • RI is aryl, heterocyclyl or CR8R9-X-aryl wherein X is typically a bond and R8 and R9 are typically hydrogen.
  • RI may be aryl or heterocyclyl.
  • R2 represents hydrogen, C1-C4 alkyl, -C0 2 R ⁇ -CONR'R", -COR', -CN, -CF 3 , -Y-Z or heterocyclyl;
  • R3 is aryl or heterocyclyl;
  • Y is C1-C3 alkylene;
  • Z is fluorine, -OR', -SR', -SOR', -SO 2 R', -?NR'R", - -NR'COR", -CO 2 R', -CO-NR'R", -OCOR', -CN or -CF 3 ; and
  • R' and R" independently represent hydrogen, C1-C6 alkyl, aryl or heterocyclyl.
  • R2 is heterocyclyl it is typically pyridyl.
  • R2 represents hydrogen, C1-C4 alkyl, - CO 2 R', -CONR'R", -COR', -CN, -CF 3 or -Y-Z ;
  • R3 is aryl or heterocyclyl;
  • Y is C1-C3 alkylene;
  • Z is fluorine, -OR', -SR', -SOR', -SO 2 R', -NR'R", -NR'COR", -CO 2 R', - CONR'R", -CN or -CF 3 ;
  • R' and R" independently represent hydrogen, C1-C6 alkyl, aryl or heterocyclyl.
  • R3 is aryl or heterocyclyl.
  • R3 is aryl it is typically phenyl which is unsubstituted or substituted with one or two substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined.
  • substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined.
  • the aryl or heterocyclyl group of the substituent is itself unsubstituted or substituted with one, two or three halogen atoms.
  • R3 is heterocyclyl, it is typically a 5- to 12-membered heterocyclic group having one or two divalent heteroatom groups selected from -O-, -S-, -SO-, -SO 2 -, - NR'- and -NCOR'-, wherein R' is as hereinbefore defined.
  • the heterocyclyl group may be unsubstituted or substituted with one or two substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined.
  • RI and R2 are as defined above and R3 is an aryl or heterocyclyl group which is substituted with a group of formula (lb).
  • RI ' is typically a group RI as defined above.
  • RI is identical to RI '.
  • R2' is typically a group R2 as defined above.
  • R2 and R2' are independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2- C8 alkynyl, -C0 2 R', -CO-NR'R", -COR', -CN, -CF 3 or -Y-Z, more preferably C1-C4 alkyl or hydrogen, most preferably hydrogen.
  • R2 is identical to R2' .
  • Preferably ? 2 and R2' are hydrogen.
  • R3 is typically a phenyl or pyridyl group, for example a pyridyl group, which is substituted with a group of formula (lb) and optionally with one or more, e.g.
  • R3 is substituted with a single substituent of formula (lb).
  • both of the ring atoms attached to the spiro carbon are preferably carbon atoms.
  • the non-aromatic monocyclic 5- to 16, e.g. 5- to 12-membered carbocyclyl group can be saturated or partially unsaturated. It is preferably a 5- to 8-membered ring. Typically, it is a saturated hydrocarbon ring, i.e. a cycloalkyl group.
  • Suitable such carbocyclyl groups include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and cyclohexadecyl, e.g. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • each ring atom may be unsubstituted or may carry one or two substituents or may be fused to an aryl or heterocyclyl group.
  • Suitable substituents include oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined.
  • the non-aromatic monocyclic 5- to 16-, e.g. 5- to 12-membered heterocyclyl group can be saturated or unsaturated. It is preferably a 5- to 8-membered ring.
  • the ring contains up to three divalent heteroatom groups, e.g. one or two divalent heteroatom groups.
  • Suitable divalent heteroatom groups include -O-, -S-, -SO-, -SO -, -?NR'- and -N(-COR')-, wherein R' is as hereinbefore defined.
  • Suitable non- aromatic monocyclic 5- to 12-membered heterocyclyl groups include 3-oxacyclopentyl, 4-azacyclohexyl, 3-thiacycloheptyl and 3-oxa,5-azacyclononyl. Further examples of suitable non-aromatic monocyclic 5- to 12-membered heterocyclyl groups are given in the general list of heterocyclyl groups and moieties above.
  • each ring atom maybe unsubstituted or may carry one or two substituents or may be fused to an aryl or heterocyclyl group.
  • Suitable substituents include oxo, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined.
  • RI is a substituted or unsubstituted phenyl ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted benzyl group or a substituted or unsubstituted naphthylene group.
  • RI may be a substituted or unsubstituted phenyl ring, a substituted or unsubstituted thiophene ring or a substituted or unsubstituted pyridine ring, e.g.
  • substituents on RI include halogen, e.g. chlorine, C1-C4 alkyl, e.g. methyl, and hydroxyl.
  • halogen e.g. chlorine, C1-C4 alkyl, e.g. methyl, and hydroxyl.
  • a pyridine, t-hiophene, benzyl or naphthalene group at RI is unsubstituted.
  • ?R2 represents hydrogen, methyl, ethyl, propyl, -CF 3 , -CH 2 O-(Cl-C4 alkyl), -CO 2 R', -CONR'R", CH 2 OCO-(Cl- C4-alkyl), -CN or pyridinyl;
  • R3 is aryl or heterocyclyl; and
  • R' and R" independently represent hydrogen, C1-C3 alkyl, aryl, heterocyclyl or optionally substituted benzyl.
  • ?R2 represents methyl, ethyl, -CF 3 , -CH O-(Cl-C4 alkyl), -CO 2 R', -CONR'R" or -CN;
  • R3 is aryl or heterocyclyl; and
  • R' and R" independently represent hydrogen, C1-C3 alkyl, aryl, heterocyclyl or optionally substituted benzyl.
  • ?R2 represents methyl, ethyl, propyl, -CF 3 , - CH 2 O-(Cl-C4 alkyl), -CO 2 R', -CONR'R", CH 2 OCO-(Cl-C4-alkyl) or -CN wherein R' and R' ' are as defined above.
  • the compound of formula (I) is a compound of formula (la):
  • RI is as hereinbefore defined;
  • R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -Y-Z as hereinbefore defined; and
  • R5, R6 and R7 independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or Z as hereinbefore defined.
  • RI is preferably aryl, heterocyclyl, -CH 2 -aryl, -CH 2 CH -aryl, -CH 2 -heterocyclyl or -CH 2 CH 2 -heterocyclyl.
  • RI is substituted or unsubstituted phenyl, substituted or unsubstituted naphthalenyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted -CH 2 -phenyl, or substituted or unsubstituted -CH 2 CH 2 -phenyl, e.g. RI is substituted or unsubstituted phenyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted -CH 2 -phenyl, or substituted or unsubstituted -CH 2 CH 2 -phenyl.
  • RI may be chlorophenyl such as 4-chloro ⁇ henyl, hydroxyphenyl such as 3-hydroxyphenyl, tolyl, naphthalenyl, pyrazin-2-yl, methylphenyl such as 4-methylphenyl, or phenethyl, e.g RI may be chlorophenyl such as 4-chlorophenyl, hydroxyphenyl such as 3-hydroxyphenyl, pyrazin-2-yl, methylphenyl such as 4-methylphenyl, or phenethyl.
  • R4 is preferably hydrogen, C1-C4 alkyl or substituted benzyl. More preferably, R4 is hydrogen or methyl.
  • R5, R6 and R7 preferably independently represent hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, aryl, heterocyclyl, hydroxy, C1-C4 alkoxy, -CN, -CO 2 H, -CO 2 -(Cl-C4 alkyl), -COR', - CO-NR'R", (Cl-4 alkyl)thio, -SO 3 H, -SO 2 -(Cl-C4 alkyl), -SO 2 NR'R", -NR'R", - NR'COR” or -NO 2 .
  • R5 is preferably hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, --NR'R", -NR'COR", -OR', -CN or -SO 2 NR'R". More preferably, R5 is hydrogen, methyl, -CN or -SO 2 ?NHCH 3 .
  • R6 is preferably hydrogen.
  • R7 is preferably hydrogen.
  • R' and R" preferably independently represent hydrogen, C1-C4 alkyl, aryl or heterocyclyl.
  • R2 is methyl;
  • R3 is - CO?NR'R"; and
  • R' and R" independently represent hydrogen, C1-C4 alkyl, aryl or heterocyclyl, -(C1-C4 alkylene)-aryl or -(C1-C4 alkylene)-heterocyclyl.
  • the most preferred embodiments of the invention are those in which: RI is unsubstituted phenyl or phenyl substituted with one or two substituents selected from halogen, e.g. chlorine, C1-C4 alkyl, e.g.
  • R2 represents hydrogen, methyl, ethyl, propyl, -CF 3 , -CH 2 O-(Cl-C4 alkyl), - CO 2 R', -CONR'R", CH 2 OCO-(Cl-C4-alkyl), -CN or pyridinyl;
  • R3 is phenyl which is xmsubstituted or substituted with one or two substituents selected from C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z, or R3 is a 5- to 12-membered heterocyclic group having one or two divalent heteroatom groups selected from -O-, -S-, -SO-
  • R2 and R3 together with the carbon atom to which they are attached, form a substituted or unsubstituted indol-2-on-3-yl ring; or R2 is methyl and R3 is a substituted or unsubstituted furanyl or thiophenyl ring, such as a substituted or unsubstituted furan-2-yl or thiophen-2-yl ring.
  • R2 is methyl and R3 is a 5- to 12-membered heterocyclyl group containing at least one nitrogen atom, e.g. pyridyl, pyrazinyl, 5-phenyl-pyridin-2-yl or quinoxaline.
  • the invention specifically provides the following compoxxnds of formula (I): 4-(2-Methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine, Spiro 5'-(2-pyrazinyl)-2 , ,3 , -dihydro-[ 1 ',3',4']thiadiazol-2',3- 1 ,3-dihydro-indol-2-one, Spiro S'- henethy ⁇ ' ⁇ '-dihydro-tl' ⁇ ' ⁇ thiadiazol ⁇ ' ⁇ -l ⁇ -dihydro-indol ⁇ -one, Spiro 5 , -(4-hydroxy)-2 , ,3'-dihydro-[r,3 , ,4']thiadiazol-2',3-l,3-dihydro-indol-2-one, 2-(4-Chlorophenyl)-2-methyl-5-
  • Suitable salts include salts with pharmaceutically acceptable acids, both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Salts may also be formed with pharmaceutically acceptable bases such as alkali metal (e.g. sodium or potassium) and alkaline earth metal (e.g.
  • alkali metal e.g. sodium or potassium
  • alkaline earth metal e.g.
  • Some of the compounds of the invention include one or more chiral centre.
  • the present invention includes enantiomers and diastereoisomers of such compounds. An example of this is at C2 of the thiadiazole ring which becomes a chiral cenfre when its ring substituents are different from one another.
  • the 2,3-dihydro-l,3,4-thiadiazole compounds of the invention can be synthesised by one of three main methods: 1) The conversion of one 2,3-dihydro-l,3,4-thiadiazole compound to another by chemical manipulation of one or more of its substituent groups. 2) The reaction of an acylhydrazone with a chlorinating agent to give a 1 -chloro 2,3-diazabuta-l,3-diene analogue and its subsequent reaction with hydrogen sulphide to give a 2,3-dihydro-l,3,4-thiadiazole. 3) The reaction of a thioacyl hydrazide with a ketone or aldehyde. These methods are shown in Scheme A.
  • Groups U,V, W, X, Y represent different substituents.
  • the first method a 2,3-dihydro-l,3,4-thiadiazole (intermediate 1) with substituents U, V and W is converted to another 2,3-dihydro-l,3,4-thiadiazole with substituents X, Y and Z wherein one or more substituents U, V and W is different from X, Y and Z.
  • groups U, V or W may contain a protected form of a chemical group, such as an ester, ether, amide or carbamate which can be selectively deprotected using methods known in the art to different groups X, Y or Z containing carboxylic acids, alcohols or amines.
  • U, V or W can be converted by chemical reaction to other types of group.
  • alcohols may be selectively converted to ethers or esters; amines to other amines, amides, ureas or carbamates; carboxylic acids to esters, amides or cyano groups.
  • aliphatic halides, epoxides or O-sulfate esters can be converted to ethers or amines by reaction with alcohols or amines; and aromatic or heterocyclic halides may be converted to carbon-based substituents by the action of a Suzuki, Stille, Sonigashira or Heck reaction, or into substituted amines using a Buchwald reaction.
  • Intermediates of type 1 may be synthesised by methods 2 or 3 described below.
  • an acyl hydrazide (intermediate 2) is converted to a 1- chloro-2,3-diazabuta-l,3-diene using a chlorinating agent and then into a 2,3-dihydro- 1,3,4-thiadiazole using hydrogen sulphide or an alkali metal sulphide.
  • the acyl hydrazone is converted into the 1-chloro 2,3-diazabuta-l,3-diene intermediate by the action of a chlorinating agent such as thionyl chloride, phosphorus oxychloride or phosphorus pentachloride in a suitable inert solvent such as dichloromethane, chloroform or toluene at between 0°C and 100°C.
  • a chlorinating agent such as thionyl chloride, phosphorus oxychloride or phosphorus pentachloride
  • a suitable inert solvent such as dichloromethane, chloroform or toluene at between 0°C and 100°C.
  • the intermediate 1-chloro 1,3- diazabutene is reacted with hydrogen sulphide or an alkali metal sulphide according to the method of US 4,699,913 to give a 2,3 -dihydro- 1,3,4-thiadiazole.
  • a thioacyl hydrazide (intermediate 3) is reacted with an aldehyde or ketone (intermediate 4) to give a 2,3-dihydro-l,3,4-thiadiazole in a manner -known per se (D. M. Evans et al., J. Chem. Soc. Chem. Commun. 1982, pg 188., K.N. Zelenin et al., -Khim. Geterotsikl. Soedin, 1982,7, pg 904).
  • Suitable solvents for this reaction are aromatic hydrocarbons, tetrahydrofuran, dioxane, diethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, aliphatic alcohols such as methanol, ethanol or propanol, esters of aliphatic acids such as ethyl acetate, aliphatic amides such as dimethyl formamide and dimethyl acetamide, dimethyl sulfoxide or other solvents that do not impair the reaction, hi some instances the reaction maybe performed without solvent in the presence of one or more equivalents of the ketone or aldehyde reactant (for example acetone or cyclohexanone) which can itself act as the solvent.
  • aromatic hydrocarbons such as methanol, ethanol or propanol
  • esters of aliphatic acids such as ethyl acetate
  • aliphatic amides such as dimethyl formamide and dimethyl
  • the reaction temperature may be varied over a wide range from -10 °C to +100 °C.
  • the reaction may also be performed in the presence of an acidic catalyst such as an aliphatic carboxylic acid catalyst, preferably formic or acetic acid.
  • an acidic catalyst such as an aliphatic carboxylic acid catalyst, preferably formic or acetic acid.
  • Acyl hydrazones (intermediate 2) can be prepared from a ketone or aldehyde (intermediate 4) and an acyl hydrazide (intermediate 5) according to method 4 (Scheme B).
  • Scheme B Synthetic route to acyl hydrazones Method 4
  • intermediate 5 intermediate 4 intermediate 2 X, Y and Z represent different substituents
  • Suitable solvents for this reaction are aromatic hydrocarbons, tetrahydrofuran, dioxane, diethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, alcohols such as methanol, ethanol or propanol, esters of aliphatic acids such as ethyl acetate, aliphatic amides such as dimethyl formamide and dimethyl a.cetamide, dimethyl sulfoxide or other solvents that do not impair the reaction.
  • the reaction may be performed without solvent in the presence o-f an excess of the ketone or aldehyde reactant (for example acetone or cyclohexanone).
  • the reaction temperature may be varied over a wide range from -10 °C to +100 °C.
  • Th_e reaction may also be performed in the presence of an aliphatic carboxylic acid catalyst such as formic or acetic acid.
  • Acyl hydrazides (intermediate 5) can be obtained commercially or prepared by reaction of known carboxylic acid chlorides with hydrazi ⁇ e, or from -known carboxylic acids, hydrazine and a coupling agent.
  • reactions of this type include those described in Synthesis, 549,1974 and references therein; benzotriazole-1- yl-oxy-tris-(dimethylamino)-phospho-t ⁇ iumhexafluorophospha.te (BOP) as coupling reagent: B. Casfro, et al. (1975) Tetrahedron Lett. (1975) 16 1219; carbonyl diimidazole as coupling reagent: T. Kamijo, et al. (1984) Chem. Pharm.
  • the coupling agent used may be dicyclohexylcarbodimide (with or without 1-hy roxybenzotriazole or HATU), 2-ethoxy-l-ethoxycarbonyl-l,2-dihydro-quinoline (IEEDQ), 2-(lH-7aza- benzotriazole-l-yl)-l,l,3,3-tetramethylxxronivim hexafluoroptiosphate (?HATU), 2-(lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU) in a suitable inert solvent such as dimethylformamide, dichloromethane, ethyl acetate, tetrahydrofuran or dioxane.
  • a suitable inert solvent such as dimethylformamide, dichloromethane, ethyl acetate, tetrahydrofuran or dioxane.
  • Thiahydrazides may be prepared by one of three methods shown in Scheme C. These are: 1) By conversion of thioamide products of the Willgerodt reaction with hydrazine to give thiohydrazides (Method 6). 2) By reaction of a Grignard reagent with carbon disulfide followed by conversion of the dithio carboxylic acid intermediate to the thiohydrazide either directly or via an alkyl dithioester intermediate (Method 7).
  • a mixture of the carbonyl compound, sulfur and an amine is heated at b>etween 50°C and 150°C, either neat or with an inert solvent present.
  • Preferred solvents include higher boiling solvents such as dimethylformamide, toluene and dioxane.
  • A_ particularly preferred method is the -known -Kindler modification (Saus & Triem, -Angew. Chem. Int. Ed. Engl. 1964, 3, 19-28) wherein the carbonyl component is heated in piperidine or morpholine at about 100°C.
  • thioamide is treated with hydrazine either neat or in a suitable solvent such as methanol, ethanol, tetrahyclrofuran or dioxane at a temperature between 0°C and 90 °C to give a thiohydrazide.
  • a suitable solvent such as methanol, ethanol, tetrahyclrofuran or dioxane
  • Thiohydrazides (intermediate 3) may be obtained from Grignard reagents by other -known procedures (Method 7) (see, for example, WO 94/0787L , pgl2).
  • aryl magnesium halides prepared from the corresponding aryl bromides, chlorides and iodides are added to carbon disulfide in anhydrous tetrahydrofuran and dioxane at between 0°C and 20°C to form an aryldithiocarboxyhc acid.
  • the crude aryldithiocarboxyhc acid can be reacted with neat hydrazine or with hydrazine in a suitable solvent such as methanol or ethanol at between 0°C and 50 " °C to give a thiahydrazide (intermediate 3).
  • the crude aryldithiocarboxyhc acid can be converted to the corresponding alkyl aryldit-hiocarboxylic ester with a base such as an alkali metal carbonate or hydroxide and an alkylation agent, such as methyl iodide or other lower alkyl halide.
  • a base such as an alkali metal carbonate or hydroxide
  • an alkylation agent such as methyl iodide or other lower alkyl halide.
  • Thiohydrazides (intermediate 3) may be obtained by a two-step -known procedure involving intermediate alkyl dithiocarboxyhc esters (method 8) (see, for example, Wei Yean et al, J. Org. Chem., 1989, 54, 906-910).
  • Carboxylic acids containing at least one alpha hydrogen are dilithiated using a strong hindered base such as lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (Li-EIMDS) in the presence of hexamethylphosphoramide (HMPA) in an inert anhydrous solvent such as tetrahydrofuran or dioxane at between -78°C and 0°C, and then condensed with carbon disulfide at between -50°C and 0°C. Subsequent alkylation using a lower alkyl halide such as methyl iodide furnishes an alkyl dithioester.
  • a strong hindered base such as lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (Li-EIMDS) in the presence of hexamethylphosphoramide (HMPA) in an inert anhydrous solvent such as tetrahydro
  • Ketones and aldehydes are either commercially available or can be readily synthesised using methods known in the art from other starting materials (see, for example, R. C. Larock, Comprehensive Organic Transformations, NCR 1989, pg 583-817).
  • a group of compounds that are not all commercially available are the isatins.
  • Scheme D indicates -known routes to these compounds.
  • substituted anilines can be reacted in a one or two pot procedure with oxalyl chloride and a Lewis acid to give isatins. The substitution pattern of the products depends upon the relative orientation of the substituents in the aniline.
  • para-substituted anilines will give 5- substituted isatins
  • ortho substituted anilines give 7-substituted isatins
  • meta substituted anilines give a mixture of 4-substituted isatins and 6-substituted isatins.
  • the reaction can be applied to multiply substituted anilines having at least one hydrogen ortho to the amino group to furnish multiply substituted isatins.
  • Bicyclic ketones related to isatins in which the phenyl ring is replaced by a 5- or 6-membered heterocycle such as thiophene or pyridine can be prepared in an analoguous manner to method 8.
  • the starting materials for these ring systems are amino-substituted heterocycles with one or more unsubstituted positions ortho to the amino group.
  • Scheme E Methods for synthesising ketones
  • Scheme E illustrates synthetic routes to other examples of ketones that are not commercially available. These are: 1) Reacting the appropriate aryl bromide with a strong base, typically sec-BuLi or n-BuLi, and N,N-dimethylacetamide (Method 10). 2) Biaryl ketones may be obtained by reacting the appropriate aniline with bromine, hydrobromic acid and sodium nitrite, followed by Suzuki coupling, and finally displacement of the bromine, using base and N,N-dimethylacetamide (Method 11).
  • the compounds of the invention have antifungal activity. Accordingly, they may be used in a method of treating a subject suffering from or susceptible to a fungal disease.
  • fungal diseases which can be prevented or treated using the compounds of the invention include both systemic and superficial infections.
  • the fungal diseases include invasive fungal diseases caused by AspergiUus and Candida species such as aspergillosis or candidiasis, but also local forms of these infections.
  • the compounds of the invention are particularly useful against diseases caused by
  • AspergiUus species for which a fungicidal drug is required which has lower toxicity than amphotericin.
  • the invention also provides for the treatment of dermatological infections.
  • the diseases caused by AspergiUus species include diseases caused by A. fumigatus, A. flavus, A. terreus and A. niger.
  • the diseases cause by Candida species include diseases caused by C. albicans, C. glabrata, C. -krusei, C. tropicalis and C. parapsillosis.
  • the relative importance of the human fungal pathogens by prevalence is approximately, for AspergiUus species: A. fumigatus 85% A. flavus 8% A. terreus 5% A. niger 2% and for Candida species: C.
  • systemic infections which can be prevented or treated using the compounds of the invention include: systemic candidiasis; pulmonary aspergillosis, e.g. in immunosuppressed patients such as bone marrow recipients or AIDS patients; systemic aspergillosis; cryptococcal meningitis; rhinocerebral mucomycosis; blastomycosis; histoplasmosis; coccidiomycosis; paracoccidiomycosis; and disseminated sporotrichosis.
  • Examples of superficial infections which can be prevented or treated using the compounds of the invention include: ring worm; athlete's foot; tinea unguium (nail infection); candidiasis of s-kin, mouth or vagina; and chronic mucocutaneous candidiasis.
  • the present invention includes a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable carrier or diluent.
  • the compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
  • the compounds of the invention may also be administered parenterally, either subcutaneously, intravenously, intramuscularly, intrasternally, fransdermally or by infusion techniques.
  • the compounds may also be administered as suppositories.
  • a compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent.
  • solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g.
  • disaggregating agents e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film coating processes.
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginte, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for intravenous or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • a therapeutically effective amount of a compound of the invention is administered to a patient.
  • a typical daily dose is up to 50 mg per kg of body weight, for example from 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
  • daily dosage levels are from 0.05 mg to 2 g, preferably from 0.1 mg to 10 mg.
  • the present invention also provides a method of controlling a fungal disease of plants, which comprises applying to the locus of the plants a compound of formula (I) or an agriculturally acceptable salt thereof.
  • the compounds of the invention may, for example, be applied to the seeds of the plants, to the medium (e.g. soil or water) in which the plants are grown, or to the foliage of the plants.
  • the present invention includes a composition comprising a compound of formula (T), or an agriculturally acceptable salt thereof, and an agriculturally acceptable carrier or diluent.
  • Suitable agriculturally acceptable salts include salts with agriculturally acceptable acids, both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Salts may also be formed with agriculturally acceptable bases such as alkali metal (e.g.
  • a preferred agriculturally acceptable salt is the hydrochloride salt.
  • the compounds of the invention may be applied in combination with inert carriers or diluents, as in aqueous sprays, granules and dust formulations in accordance with established practice in the art.
  • An aqueous spray is usually prepared by mixing a wettable powder or emulsifiable concentrate formulation of a compound of the invention with a relatively large amount of water to form a dispersion.
  • Wettable powders may comprise an intimate, finely divided mixture of a compound of the invention, an inert solid carrier and a surface-active agent.
  • the inert solid carrier is usually chosen from among the attapulgite clays, the kaolin clays, the montmorillonite clays, the diatomaceous earths, finely divided silica and purified silicates.
  • Effective surfactants which have wetting, penetrating and dispersing ability are usually present in a wettable powder formulation in proportions of from 0.5 to 10 percent by weight.
  • Emulsifiable concentrates may comprise a solution of a compound of the invention in a liquid carrier which is a mixture of a water-immiscible solvent and a surfactant, including an emulsifier.
  • Useful solvents include aromatic hydrocarbon solvents such as the xylenes, alkylnaphthalenes, petroleum distillates, terpene solvents, ether-alcohols and organic ester solvents.
  • Suitable emulsifiers, dispersing and wetting agents may be selected from the same classes of products which are employed in formulating wettable powders.
  • the fungicide formulations desirably contain from 0.1 percent to 95 percent by weight of the compound of the invention and from 0.1 to 75 percent of an inert carrier or surfactant.
  • the direct application to plant seeds prior to planting may be accomplished in some instances by mixing either a powdered solid compound of the invention or a dust formulation with seed to obtain a substantially uniform coating which is very thin and represents only one or two percent by weight or less, based on the weight of the seed.
  • a non-phytotoxic solvent such as methanol is conveniently employed as a carrier to facilitate the uniform distribution of the compound of the invention on the surface of the seed.
  • granular formulations or dusts are sometimes more convenient than sprays.
  • a typical granular formulation comprises a compound of the invention dispersed on an inert carrier such as coarsely ground clay, or clay which has been converted to granules by treatment of a rolling bed of the powdered material with a small amount of liquid in a granulating drum.
  • an inert carrier such as coarsely ground clay, or clay which has been converted to granules by treatment of a rolling bed of the powdered material with a small amount of liquid in a granulating drum.
  • a solution of the active compound is sprayed on the granules while they are being agitated in a suitable mixing apparatus, after which the granules are dried with a current of air during continued agitation.
  • Dust formulations customarily employ essentially the same inert diluents as wettable powders and granules, but are well-mixed in powder form and do not usually contain emulsifiers.
  • Dusts may contain some surface active agents to facilitate uniform distribution of the active ingredient in the formulation and to improve the uniformity and adhesion of the dust coating on seeds and plants.
  • the colloidal dispersion of dust formulations in the air is usually prevented by incorporation of a minor amount of an oily or waxy material in the formulation to cause agglomeration of colloidal size particles. In this way the dust may be applied to seeds or plants without generation of an air-polluting aerosol.
  • Example 12 4-(2-Methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine Procedure is the same as with example 8, using 3-acetyl pyridine (218mg, 1.8mMol). Off-white crystals of the titled compound (292mg, 60.2% yield) were obtained.
  • Example 20 3-Methyl-thiobenzoic acid hydrazide a) Preparation of m-tolylmagnesixxm bromide. m-Bromotoluene (14.1 g, 82 mMol) was added dropwise to a mixture of (2.2 g, 92 mMol) of magnesium turnings and 1,2-dibromoethane (0.2 mL) in anhydrous tetrahydrofuran (100 mL) under the nitrogen atmosphere. After the addition was complete, 0.2 mL of 1,2-dibromoethane was added to the vigorously stirred mixture which was cooled using an ice bath. The most of the magnesium dissolved within 1 hr. b) Preparation of m-toluic thiohydrazide.
  • the tetrahydrofuran solution of m-tolylmagnesixxm bromide was transferred into an oven-dried addition fixnnel under nitrogen and was then added dropwise to an ice-bath cooled mixture of carbon disulfide (5.5 mL) in anhydrous tetrahydrofuran (50 mL).
  • the resulting deep red solution was stirred at room temperature for l?hr, poured onto ice, acidified with 2N HCl(aq) to pH 0.5 and extracted with dichloromethane until the water layer became colourless.
  • the dichloromethane phase was then stirred with 50 mL of hydrazine monohydrate dissolved in 50 mL of water.
  • the hydrazine layer was then taken out and neutralised with glacial acetic acid until pH 5.0.
  • the hydrazine phase was then extracted with toluene and dried over MgSO 4 overnight. The solvent was then evaporated to give 5g of product. Yield 37 %.
  • 3-Phenyl-dithiopropionic acid methyl ester (2g,10 mMol) was dissolved in 40 mL of methanol and 4 mL of hydrazine monohydrate were added to the solution. The mixture was stirred at room temperature for 1.5hrs. Water (50m?L) was added to the mixture which was then neutralised with glacial acetic acid and extracted with 100 mL of ethyl acetate. The organic solution of 3-phenyl-thio ⁇ ropionic acid hydrazide was used immediately in the -further reactions.
  • Example 25 3-Phenyl-dithiopropionic acid methyl ester
  • LiAlH 4 (4g, 100 mMol) was slowly added to a solution of pyrazinecarboxylic acid methyl ester (12.8g, 100 mMol) in tetrahydrofuran (400 mL) at -70° C. The mixture was stirred at this temperature for 40 min, followed by neutralisation with 20 mL of glacial acetic acid. The solvent was evaporated in vacuo and the residue was partitioned between 30 mL of 2N HCL and dichloromethane. A large amount of brown solid precipitated which was filtered off. The dichloromethane layer was passed through a pad of silica, the solvent was evaporated to give the pyrazine 2-carboxaldehyde (1.4g) as a yellow oil.
  • Examples 32 to 65 set out below were prepared in the same way as in Example 31, using appropriate starting materials. Some examples required purification by silica gel column chromatography.
  • 2-Bromo-5-phenyl-pyridine (2.2g, 9mmol) was added to dry diethyl ether (250ml). The mixture was cooled to -60°C and a solution of n-BuLi (2.5M in hexane, 4mL) was added dropwise and the mixture was stirred for 2hrs. N,N-dimethylacetamide (lmL) in diethyl ether (15ml) was then added slowly dropwise and the solution was left to stir for 3?hrs. The system was brought to room temperature, hydrolysed with 2N HC1 and exfracted with DCM. The organic phase was washed with water, dried over MgSO4 and evaporated to give l-(5-phenyl-pyridin-2-yl)-ethanone (l.Og, 54%). Examples 67 to 69.
  • Example 67 to 69 set out below were prepared in the same way as in Example 66, using appropriate starting materials.
  • Example Name 67 1-(2'Methoxy-[3,3']bipyridinyl-6-yl)-ethsnone 68 1-(4-Pyridin-2-yl-phenyl)-ethanone 69 1-(6-Chloro-pyridazin-3-yl)-ethanone
  • 2-Bromo-5-iodopyridine (4.4g, 16mmol) was dissolved in toluene (70ml). To this solution benzene boronic acid (2.6g, 20mmol) was added-, followed by aqueous K2CO3 (8.5M, 70ml) and Pd(Ph 3 P) (23mg, 0.02mmol). The mi xtxxre was vigorously stirred at 120°C for 4 days. The solvent was evaporated in vacuo and the residue was purified by column chromatography to give 2-bromo-5-phenyl-pyridi:ne (3.5g, 93%).
  • Examples 71 to 72 were prepared in the same way as in Example 70, using appropriate starting materials.
  • Example 75 l-Quinolin-3-yl-ethanone l-Quinolin-3-yl-ethanol (0.92g, 5.3mmol) and Dess-Martin periodane (2.48g, 5.8 mmol) in DCM (12ml) were stirred at room temperature for 3 hrs. The reaction mixture was diluted with ether and neutralised with NaOH (IM). The mixture was extracted with ether, washed with brine and dried over MgSO 4 . Recrystallisation from ether gave pure l-quinolin-3-yl-ethanone (0.8 lg, 89%).
  • Example 77 l-Quinoxalm-2-yl-ethanone Quinoxaline (0.65g, 5 mmol), pyruvic acid (1.32g, 15 mmol), AgN0 3 (0.068g, 0.4 mmol), (NH 4 ) 2 S 2 O 8 (1.71g, 7.5 mmol), CF 3 CO 2 H (1.7g, 15 mmol) were dissolved in a 1:1 mixture of DCM/H 2 O (50ml). The reaction mixture was stirred at 40° C. After cooling to room temperature the mixture was exfracted with DCM, wa-shed with brine and dried over Mg SO 4 , then evaporated to give l-quinoxalin-2-yl-ethanone (0.89g, 100%).
  • Example 78 Analytical data for compounds representative of Examples 1 to 77.
  • Examples 79 to 96 are available commercially and have also been shown to have anti- fungal activity in accordance with the present invention.
  • Example 88 2-(4-Cyclohexylphenyl)-2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazole
  • Example 89 3-(Phenylmethyl)-4-thia-l,2-diazaspiro[4.11]hexadec-2-ene
  • Example 97 2-Methyl-2-thiophen-2-yl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole,
  • Example 100 4-(5-Furan-2-yl-5-methyl-4,5-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine,
  • Example 102 2-(5-Bromothiophen-2-yl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole.
  • MICs minimum inhibitory concentrations
  • MIC plates 80 ⁇ L of an organism suspension was added to each well of the plate containing drug dilutions. This produced MIC plates with a drug range 50-0.05 mg/L and organism inocula of l-2xl0 4 cfu/ml for AspergiUus spp and 1-2 xlO 3 cfix/ml for yeasts. AU plates were incubated for 44-48hrs at 35°C. Growth was assessed by monitoring the optical density at 485nm for each well. The MIC of a compound is the lowest drug concentration that inhibits growth of an organism by >80% compared with a drug free confrol. MICs are recorded as mg/L.
  • Table 1 shows the antifungal MICs of selected compounds of the invention against AspergiUus and Candida species. Table 1: MICs in ⁇ g/mL against AspergiUus and Candida spp
  • Table 2 MICs of commercial compounds in ⁇ g/mL against AspergiUus and Candida spp

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Abstract

Cette invention se rapporte à des composés représentés par la formule (I), et à des sels de ces composés acceptables sur le plan pharmaceutique, qui peuvent être utilisés à des fins thérapeutiques, par exemple comme agents antifongiques. Dans ladite formule, R1, R2 et R3 sont tels que définis dans les pièces descriptives de la demande. Certains composés représentés par la formule (I) sont également présentés. Des composés représentés par la formule (I), et des sels de ceux-ci acceptables en agriculture, peuvent également être utilisés comme fongicides dans l'agriculture.
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Cited By (19)

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WO2020214896A1 (fr) * 2019-04-17 2020-10-22 University Of Maryland, Baltimore Inhibiteurs à petites molécules de rcpg gpr68 et récepteurs associés pour le traitement du cancer, du glioblastome et d'autres indications
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WO2007146138A3 (fr) * 2006-06-09 2008-05-08 Wyeth Corp Composés de thiadiazole et procédés les utilisant
US8324257B2 (en) 2006-10-03 2012-12-04 Array Biopharma Inc. Mitotic kinesin inhibitors and methods of use thereof
US8466188B2 (en) 2006-10-12 2013-06-18 Xenon Pharmaceuticals Inc. Use of spiro-oxindole compounds as therapeutic agents
US20110104565A1 (en) * 2008-06-25 2011-05-05 Hisayuki Utsumi Flame retardant-containing nonaqueous secondary battery
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