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US 5,859,027 AGranted
Antimicrobial agent
AssigneeChektec Corporation
InventorsLawrence Ivan Kruse, Sheldon E. Broedel, Jr.
Life of this patent
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Abstract
The invention provides a method of treating a fungal infection comprising administering to an animal having a fungal infection a composition comprising an infection treating effective amount of a compound of formula I, wherein said compound is the following or a pharmaceutically acceptable salt of the following: ##STR1## The invention further provides such compounds and related methods.
Claims28
A method of treating a fungal infection comprising administering to an animal having a fungal infection a composition comprising an infection treating effective amount of a compound of formula I:
- ##STR12## or a pharmaceutically acceptable salt thereof, wherein (1) Y.sup.1 and Y.sup.2 are independently O or S;
- (2) R.sup.1
- (i) is a straight-chained aliphatic group having about 2 to about 12 carbon atoms,
- (ii) the aliphatic group which additionally comprises an about 3 to about 8-membered carbocyclic ring consisting of three or more additional carbon atoms, or
- (iii) the aliphatic group which additionally comprises an about 3 to about 8-membered heterocyclic ring, wherein the heterocyclic ring contains up to 4 nitrogen atoms, up to 2 sulfur atoms, up to 2 oxygen atoms or additional carbon atoms,
- (2a) wherein the carbocyclic or heterocyclic ring atoms can have 1 to 4 substituents chosen from one or more of the following groups fluoro, chloro, bromo, iodo, hydroxy, (C1-C6) alkoxy, (C1-C6) alkyl, amino which c an be substituted with one or two (C1-C3) alkyl groups, nitro, aminocarbonyl which can be N-substituted with one or two (C1-C6) alkyl groups, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, hydroxycarbonyl, cyano, (C1-C3) alkylsulfonamido, (C1-C3) haloalkylsulfonamido which can be fully or partially halogenated wherein halo is fluoro, chloro, bromo or iodo, (C1-C8) alkanoylamino, (C1-C3) haloalkyl, which can be fully or partially halogenated wherein halo is fluoro, chloro, bromo or iodo, and alkanoylalkyl wherein alkanoyl is C2-C6 and alkyl is C1-C6;
- (2b) wherein the non-ring portions of the straight-chained aliphatic group can be substituted with up to 4 of a (C1-C6) aliphatic group, fluoro, chloro, bromo, iodo, hydroxy, (C1-C6) alkoxy, amino which can be substituted with one or two (C1-C3) alkyl groups, nitro, aminocarbonyl which can be N-substituted with one or two (C1-C6) alkyl groups, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, hydroxycarbonyl, cyano, (C1-C3) alkylsulfonamido, (C1-C3) haloalkylsulfonamido which can be fully or partially halogenated wherein halo is fluoro, chloro, bromo or iodo, (C1-C8) alkanoylamino, (C1-C6) alkyl, (C1-C3) haloalkyl, which can be fully or partially halogenated wherein halo is fluoro, chloro, bromo or iodo, or alkanoylalkyl wherein alkanoyl is C2-C6 and alkyl is C1-C6;
- (3) X is oxygen or sulfur or NR.sup.2 ;
- (4) R.sup.2 is hydroxy, amino which can be substituted with one or two (C1-C8) alkyl groups, (C1-C8) alkyl, (C7-C10) arylalkyl, (C1-C8) alkoxy, (C1-C8) alkanoylamino or aminocarbonyl which can be N-substituted with one or two (C1-C8) alkyl groups,
- wherein R.sup.2 can be substituted with up to 4 of alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, hydroxycarbonyl, fluoro, chloro, bromo, iodo, hydroxy, (C1-C3) alkoxy, amino which can be substituted with one or two (C1-C6) alkyl groups, nitro, aminocarbonyl which can be N-substituted with one or two (C1-C6) alkyl groups, cyano, (C1-C3) alkylsulfonamido, (C1-C8) alkanoylamino, (C1-C3) haloalkylsufonamido, (C1-C3) alkyl, (C1-C3) haloalkyl, or alkanoylalkyl wherein alkanoyl is C2-C3 and alkyl is C1-C3;
- (5) R.sup.3 and R.sup.5 either (a) each represent a half bond that together forms a double bond, or (b) R.sup.3 is hydrogen and R.sup.5 is hydrogen, aliphatic group having 1 to 3 carbons, fluoro, chloro, bromo, iodo, nitro, cyano, hydrocarbonyl, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, hydroxycarbonyl, (C1-C8) alkoxy, (C1-C8) alkanoylamino, (C1-C5) alkylsulfonamido, hydroxy, amino which can be substituted with one or two (C1-C3) alkyl groups, aminocarbonyl that can be N-substituted with one or two (C1-C6) alkyl groups, (C1-C3) haloalkylsulfonamido, (C1-C3) haloalkyl, or alkanoylalkyl wherein alkanoyl is C2-C3 and alkyl is C1-C3;
- (6) R.sup.4 is an aliphatic group having 1 to 3 carbons, cyano, hydroxycarbonyl, alkylcarbonyloxy wherein alkyl can be C1-C6, or alkoxycarbonyl wherein alkoxy can be C1-C6;
- (7) R.sup.8 and R.sup.9 are independently hydrogen, aliphatic group having 1 to 3 carbons, fluoro, chloro, bromo, iodo, nitro, cyano, carboxyaldhyde, hydroxycarbonyl, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, (C1-C8) alkoxy, (C1-C8) alkanoylamino or (C1-C5) alkylsulfonamido;
- (8) R.sup.6 is a (C1-C6) aliphatic group, (C6-C10) aryl, (C7-C10) aralkyl, or a (C1-C3) aliphatic group substituted with a 5 or 6-membered heteroaromatic ring having up to 4 heteroatoms comprising nitrogen, sulfur or oxygen atoms;
- and
- (9) R.sup.7 is --O--R.sup.10 or --O--(C.dbd.O)--R.sup.11 where R.sup.10 is a hydrogen or R.sup.10 and R.sup.11 are
- (9a) an aliphatic group with 1 to 6 carbons, which aliphatic group may be substituted with one to 3 of:
- hydroxy, fluoro, chloro, bromo, iodo, cyano, amino which can be substituted with one or two (C1-C3) alkyl groups, (C1-C6) alkanoylamino, hydroxycarbonyl, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, aminocarbonyl which can be N-substituted with one or two (C1-C6) alkyl groups, (C1-C5) alkylsulfonate which can be partially or fully halogenated wherein halo is fluoro, chloro, bromo or iodo, (C1-C3) alkoxy, nitro, (C1-C6) alkyl, (C1-C3) haloalkyl, alkanoylalkyl wherein alkanoyl is C2-C3 and alkyl is C1-C3, or hydrocarbonyl, and wherein the aliphatic group can be substituted with an aryl or heteroaryl group where the aryl or heteroaryl moiety comprises a 6 or 10-membered aromatic ring, of which up to 4 ring atoms can be nitrogen heteroatoms,
- (9a1) wherein the aryl or heteroaryl group can be substituted with up to 4 substituents selected from the group consisting of (C1-C3) aliphatic group, fluoro, chloro, nitro, cyano, carboxyaldhyde, carboxyl, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, aminocarbonyl which can be substituted with one or two (C1-C6) alkyl groups, amino, amino substituted with one or two (C1-C3) hydrocarbons, (C1-C6) alkanoylamino, hydroxy, (C1-C3) alkoxy, amino, (C1-C3) alkylsulfonate, (C1-C3) haloalkylsufonate, (C1-C3) haloalkyl, and alkanoylalkyl wherein alkanoyl is C2-C6 and alkyl is C1-C6 or
- (9b) an aryl or heteroaryl group where the aryl or heteroaryl group comprises a 6 or 10-membered aromatic ring, of which up to 4 ring atoms can be nitrogen, wherein the aryl or heteroaryl group can be substituted with up to 4 substituents selected from the group consisting of (C1-C3) alkyl, (C1-C3) alkenyl, fluoro, chloro, iodo, bromo, nitro, cyano, carboxyaldhyde, hydroxycarbonyl, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, aminocarbonyl which can be N-substituted with one or two (C1-C6) alkyl groups, amino, amino substituted with one or two (C1-C3) aliphatic groups, (C1-C6) alkanoylamino, carboxyl (C1-C6) ester, hydroxy, (C1-C3) alkoxy, (C1-C3) alkylsulfonamido, (C1-C3) haloalkylsulfonamido, (C1-C3) haloalkyl, or alkanoylalkyl wherein alkanoyl is C2-C3 and alkyl is C1-C3;
- (p1) with the proviso that when R.sup.7 is acetyl the compound differs from chrysodin by at least one of (a) the presence or absence of a methylene, (b) the presence of sulfur or nitrogen in the compound in place of an oxygen, (c) the presence of halo, hydroxy, alkoxy, amino, nitro, alkanoylamino, aminocarbonyl, substituted aminocarbonyl, alkoxycarbonyl, hydroxycarbonyl, cyano, alkylsulfonamido, haloalkylsulfonamido, mono or di-alkylamino, alkanoylalkyl or hydrocarbonyl or (d) the presence in R.sup.1 or R.sup.7 of a carbocyclic or heterocyclic ring.
18 more elements
A composition comprising a compound according to:
- ##STR15## or a pharmaceutically acceptable salt thereof, wherein (1) Y.sup.1 and Y.sup.2 are independently O or S;
- (2) R.sup.1
- (i) is a straight-chained aliphatic group having about 2 to about 12 carbon atoms,
- (ii) the aliphatic group which additionally comprises an about 3 to about 8-membered carbocyclic ring consisting of three or more additional carbon atoms, or
- (iii) the aliphatic group which additionally comprises an about 3 to about 8-membered heterocyclic ring, wherein the heterocyclic ring contains up to 4 nitrogen atoms, up to 2 sulfur atoms, up to 2 oxygen atoms or additional carbon atoms,
- (2a) wherein the carbocyclic or heterocyclic ring atoms can have 1 to 4 substituents chosen from one or more of the following groups fluoro, chloro, bromo, iodo, hydroxy, (C1-C6) alkoxy, (C1-C6) alkyl, amino which can be substituted with one or two (C1-C3) alkyl groups, nitro, aminocarbonyl which can be N-substituted with one or two (C1-C6) alkyl groups, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, hydroxycarbonyl, cyano, (C1-C3) alkylsulfonamido, (C1-C3) haloalkylsulfonamido which can be fully or partially halogenated wherein halo is fluoro, chloro, bromo or iodo, (C1-C8) alkanoylamino, (C1-C3) haloalkyl, which can be fully or partially halogenated wherein halo is fluoro, chloro, bromo or iodo, and alkanoylalkyl wherein alkanoyl is C2-C6 and alkyl is C1-C6;
- (2b) wherein the non-ring portions of the straight-chained aliphatic group can be substituted with up to 4 of a (C1-C6) aliphatic group, fluoro, chloro, bromo, iodo, hydroxy, (C1-C6) alkoxy, amino which can be substituted with one or two (C1-C3) alkyl groups, nitro, aminocarbonyl which can be N-substituted with one or two (C1-C6) alkyl groups, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, hydroxycarbonyl, cyano, (C1-C3) alkylsulfonamido, (C1-C3) haloalkylsulfonamido which can be fully or partially halogenated wherein halo is fluoro, chloro, bromo or iodo, (C1-C8) alkanoylamino, (C1-C6) alkyl, (C1-C3) haloalkyl, which can be fully or partially halogenated wherein halo is fluoro, chloro, bromo or iodo, or alkanoylalkyl wherein alkanoyl is C2-C6 and alkyl is C1-C6;
- (3) X is oxygen or sulfur or NR.sup.2 ;
- (4) R.sup.2 is hydroxy, amino which can be substituted with one or two (C1-C8) alkyl groups, (C1-C8) alkyl, (C7-C10) arylalkyl, (C1-C8) alkoxy, (C1-C8) alkanoylamino or aminocarbonyl which can be N-substituted with one or two (C1-C8) alkyl groups,
- wherein R.sup.2 can be substituted with up to 4 of alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, hydroxycarbonyl, fluoro, chloro, bromo, iodo, hydroxy, (C1-C3) alkoxy, amino which can be substituted with one or two (C1-C6) alkyl groups, nitro, aminocarbonyl which can be N-substituted with one or two (C1-C6) alkyl groups, cyano, (C1-C3) alkylsulfonamido, (C1-C8) alkanoylamino, (C1-C3) haloalkylsufonamido, (C1-C3) alkyl, (C1-C3) haloalkyl, or alkanoylalkyl wherein alkanoyl is C2-C3 and alkyl is C1-C3;
- (5) R.sup.3 and R.sup.5 either (a) each represent a half bond that together forms a double bond, or (b) R.sup.3 is hydrogen and R.sup.5 is hydrogen, aliphatic group having 1 to 3 carbons, fluoro, chloro, bromo, iodo, nitro, cyano, hydrocarbonyl, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, hydroxycarbonyl, (C1-C8) alkoxy, (C1-C8) alkanoylamino, (C1-C5) alkylsulfonamido, hydroxy, amino which can be substituted with one or two (C1-C3) alkyl groups, aminocarbonyl that can be N-substituted with one or two (C1-C6) alkyl groups, (C1-C3) haloalkylsulfonamido, (C1-C3) haloalkyl, or alkanoylalkyl wherein alkanoyl is C2-C3 and alkyl is C1-C3;
- (6) R.sup.4 is an aliphatic group having 1 to 3 carbons, cyano, hydroxycarbonyl, alkylcarbonyloxy wherein alkyl can be C1-C6, or alkoxycarbonyl wherein alkoxy can be C1-C6;
- (7) R.sup.8 and R.sup.9 are independently hydrogen, aliphatic group having 1 to 3 carbons, fluoro, chloro, bromo, iodo, nitro, cyano, carboxyaldhyde, hydroxycarbonyl, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, (C1-C8) alkoxy, (C1-C8) alkanoylamino or (C1-C5) alkylsulfonamido;
- (8) R.sup.6 is a (C1-C6) aliphatic group, (C6-C10) aryl, (C7-C10) aralkyl, or a (C1-C3) aliphatic group substituted with a 5 or 6-membered heteroaromatic ring having up to 4 heteroatoms comprising nitrogen, sulfur or oxygen atoms;
- and
- (9) R.sup.7 is --O--R.sup.10 or --O--(C.dbd.O)--R.sup.11 where R .sup.10 is a hydrogen or R.sup.10 and R.sup.11 are
- (9a) an aliphatic group with 1 to 6 carbons, which aliphatic group may be substituted with one to 3 of:
- hydroxy, fluoro, chloro, bromo, iodo, cyano, amino which can be substituted with one or two (C1-C3) alkyl groups, (C1-C6) alkanoylamino, hydroxycarbonyl, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, (C1-C6) aminocarbonyl which can be N-substituted with one or two (C1-C6) alkyl groups, (C1-C5) alkylsulfonate which can be partially or fully halogenated wherein halo is fluoro, chloro, bromo or iodo, (C1-C3) alkoxy, nitro, (C1-C6) alkyl, (C1-C3) haloalkyl, alkanoylalkyl wherein alkanoyl is C2-C3 and alkyl is C1-C3, or hydrocarbonyl, and wherein the aliphatic group can be substituted with an aryl or heteroaryl group where the aryl or heteroaryl moiety comprises a 6 or 10-membered aromatic ring, of which up to 4 ring atoms can be nitrogen heteroatoms,
- (9a1) wherein the aryl or heteroaryl group can be substituted with up to 4 substituents selected from the group consisting of (C1-C3) aliphatic group, fluoro, chloro, nitro, cyano, carboxyaldhyde, carboxyl, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, aminocarbonyl which can be substituted with one or two (C1-C6) alkyl groups, amino, amino substituted with one or two (C1-C3) hydrocarbons, (C1-C6) alkanoylamino, hydroxy, (C1-C3) alkoxy, amino, (C1-C3) alkylsulfonate, (C1-C3) haloalkylsufonate, (C1-C3) haloalkyl, and alkanoylalkyl wherein alkanoyl is C2-C6 and alkyl is C1-C6 or
- (9b) an aryl or heteroaryl group where the aryl or heteroaryl group comprises a 6 or 10-membered aromatic ring, of which up to 4 ring atoms can be nitrogen, wherein the aryl or heteroaryl group can be substituted with up to 4 substituents selected from the group consisting of (C1-C3) alkyl, (C1-C3) alkenyl, fluoro, chloro, iodo, bromo, nitro, cyano, carboxyaldhyde, hydroxycarbonyl, alkylcarbonyloxy wherein alkyl can be C1-C6, alkoxycarbonyl wherein alkoxy can be C1-C6, aminocarbonyl which can be N-substituted with one or two (C1-C6) alkyl groups, amino, amino substituted with one or two (C1-C3) aliphatic groups, (C1-C6) alkanoylamino, carboxyl (C1-C6) ester, hydroxy, (C1-C3) alkoxy, (C1-C3) alkylsulfonamido, (C1-C3) haloalkylsulfonamido, (C1-C3) haloalkyl, or alkanoylalkyl wherein alkanoyl is C2-C3 and alkyl is C1-C3;
- (p1) with the proviso that when R.sup.7 is acetyl the compound differs from chrysodin by at least one of (a) the presence or absence of a methylene, (b) the presence of sulfur or nitrogen in the compound in place of an oxygen, (c) the presence of halo, hydroxy, alkoxy, amino, nitro, alkanoylamino, aminocarbonyl, substituted aminocarbonyl, alkoxycarbonyl, hydroxycarbonyl, cyano, alkylsulfonamido, haloalkylsulfonamido, mono or di-alkylamino, alkanoylalkyl or hydrocarbonyl or (d) the presence in R.sup.1 or R.sup.7 of a carbocyclic or heterocyclic ring
- (p2) with the further proviso that when R.sup.7 is 2,4-dihydroxypentyl the compound of the invention differs from patulodin by at least one of (a) the presence or absence of a methylene, (b) the presence of sulfur or nitrogen in the compound in place of an oxygen, (c) the presence of halo, hydroxyl, alkoxyl, amino, nitro, alkanoylamino, aminocarbonyl, substituted aminocarbonyl, alkoxycarbonyl, carboxylate, cyano, alkylsulfonamido, haloalkylsulfonamido, alkylamino, alkanoylalkyl or carboxyaldehyde, (d) the presence in R.sup.1 or R.sup.7 of a carbocyclic or heterocyclic ring or (e) the absence of an epoxide moiety;
- (p3) with the further proviso that either the 7-position of the A ring is not substituted with chloro or the R.sup.1 position differs from a 3,5-dimethyl-hepta-1,3-dienyl group;
- and
- (p4) with the further proviso that R.sup.7 is either (a) not one of 2-methyl-3,5-dihydroxy-phenylcarbonyl or methyl or (b) R.sup.1 is not one of propyl-2-enyl, 1-hydroxypropyl-2-enyl or 1-carboxyl-ethylenyl.
22 more elements
Dependencies are inferred from the claim text.