New furanone derivatives, processes for preparation thereof and use thereof

Claim 2

A compound of the general formula:- wherein R 1 is a hydroxyl or protected hydroxyl group or a carboxyl group or a lower alkoxycarbonyl or benzyloxy radical, R 2 is a hydrogen or halogen atom or a halo(lower)alkyl radical, R 3 is a hydrogen atom, a hydroxyl group or a lower alkoxy radical and A is a lower alkylene radical; and the pharmaceutically acceptable salts thereof.

Claim 3

A compound of the formula : wherein 1) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is methoxy and A is ethylene; or 2) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is propoxy and A is ethylene; or 3) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is butoxy and A is ethylene; or 4) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is pentoxy and A is ethylene; or 5) R 1 is ethoxycarbonyl, R 2 is chlorine, R 3 is methoxy and A is ethylene; or 6) R 1 is ethoxycarbonyl, R 2 is trifluoromethyl, R 3 is methoxy and A is ethylene; or 7) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is ethoxy and A is ethylene; or 8) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is propoxy and A is ethylene; or 9) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is butoxy and A is ethylene; or 10) R 1 is benzyloxy, R 2 is hydrogen, R 3 is hydroxy and A is ethylene; or 11) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is methoxy and A is trimethylene; or 12) R 1 is a lower alkoxycarbonyl group, R 2 is hydrogen, halogen or a halo(lower)alkyl group, R 3 is hydroxy and A is a lower alkylene group; or 13) R 1 is a carboxy, hydroxy or protected hydroxy group, R 2 is hydrogen, halogen or a halo(lower)-alkyl group, R 3 is lower alkoxy and A is a lower alkylene group; or 14) R 1 is a carboxy, hydroxy, protected hydroxy or lower alkoxycarbonyl group, R 2 is hydrogen, halogen or a halo(lower)alkyl group, R 3 is hydrogen and A is a lower alkylene group; and a pharmaceutically acceptable salt thereof. A compound of claim 2, which is selected from ethyl 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)-propionate, ethyl 3-(5-oxo-3-phenyl-4-propoxy-2,5-dihydro-2-furyl)propionate, ethyl 3-(4-butoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate, ethyl 3-(5-oxo-4-pentyloxy-3-phenyl-2,5-dihydro-2-furyl)-propionate, ethyl 3-[3-(4-chlorophenyl)-4-methoxy-5-oxo-2,5-dihydro-2-furyl]propionate, ethyl 3-[4-methoxy-5-oxo-3-(3-trifluoromethylphenyl)-2,5-dihydro-2-furyl]propionate, methyl 3-(4-ethoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate, methyl 3-(4-propoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)-propionate, methyl 3-(4-butoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate, 3-hydroxy-4-phenyl-5-(2-benzyloxyethyl)-2(5H)-furanone and methyl 4-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)butyrate. A compound of claim 3, which is ethyl 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate. A compound of claim 1, wherein R 1 is a lower alkoxycarbonyl group, R 2 is hydrogen, halogen or a halo(lower)alkyl group, R 3 is hydroxy and A is a lower alkylene group.

Claim 4

A compound of claim 5, which is selected from ethyl 3-[3-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-2-furyl]propionate, ethyl 3-[4-hydroxy-5-oxo-3-(3-trifluoromethylphenyl)-2,5-dihydro-2-furyl]propionate, ethyl 3-(4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate and methyl 3-(4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate.

Claim 5

A compound of claim 1, wherein R 1 is a carboxy, hydroxy or protected hydroxy group, R 2 is hydrogen, halogen or a halo(lower)alkyl group, R 3 is lower alkoxy and A is a lower alkylene group. A compound of claim 7, which is selected from 3-(5-oxo-4-pentyloxy-3-phenyl-2,5-dihydro-2-furyl)-propionic acid, 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid, 3-[3-(4-chlorophenyl)-4-methoxy-5-oxo-2,5-dihydro-2-furyl]propionic acid, 3-[4-methoxy-5-oxo-3-(3-trifluoromethylphenyl)-2,5-dihydro-2-furyl]propionic acid, 4-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)butyric acid, 3-(4- ethoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid, 3-(4-propoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid, 3-(4-butoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid, 3-methoxy-5-(2-hydroxyethyl)-4-phenyl-2(5H)-furanone, 5-(3-hydroxypropyl)-3-methoxy-4-phenyl-2(5H)-furanone, 2-(2,5-dihydro-4-methoxy-5-oxo-3-phenyl-2-furyl)-acetic acid and 3-methoxy-4-phenyl-5-(2-benzyloxyethyl)-2(5H)-furanone.

Claim 6

A compound of claim 1, wherein R 1 is a carboxy, hydroxy, protected hydroxy or lower alkoxycarbonyl group, R 2 is hydrogen, halogen or a halo(lower)alkyl group, R 3 is hydrogen and A is a lower alkylene group.

Claim 7

A compound of claim 9, which is selected from 5-(3-hydroxypropyl)-4-phenyl-2(5H)-furanone 5-(3-tert-butyl-diphenylsilyloxypropyl)-4-phenyl-2(5H)-furanone and 3-(2,5-dihydro-5-oxo-3-phenyl-2-furyl)-propionic acid.

Claim 8

A process for preparing a compound of the formula : wherein 1) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is methoxy and A is ethylene; or 2) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is propoxy and A is ethylene; or 3) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is butoxy and A is ethylene; or 4) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is pentoxy and A is ethylene; or 5) R 1 is ethoxycarbonyl, R 2 is chlorine, R 3 is methoxy and A is ethylene; or 6) R 1 is ethoxycarbonyl, R 2 is trifluoromethyl, R 3 is methoxy and A is ethylene; or 7) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is ethoxy and A is ethylene; or 8) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is propoxy and A is ethylene; or 9) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is butoxy and A is ethylene; or 10) R 1 is benzyloxy, R 2 is hydrogen, R 3 is hydroxy and A is ethylene; or 11) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is methoxy and A is trimethylene; or 12) R 1 is a lower alkoxycarbonyl group, R 2 is hydrogen, halogen or a halo(lower)alkyl group, R 3 is hydroxy and A is a lower alkylene group; or 13) R 1 is a carboxy, hydroxy or protected hydroxy group, R 2 is hydrogen, halogen or a halo(lower)-alkyl group, R 3 is lower alkoxy and A is a lower alkylene group; or 14) R 1 is a carboxy, hydroxy, protected hydroxy or lower alkoxycarbonyl group, R 2 is hydrogen, halogen or a halo(lower)alkyl group, R 3 is hydrogen and A is a lower alkylene group; and a pharmaceutically acceptable salt thereof, which comprises a) reacting a compound of the formula : wherein R 2 being as defined above, or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula : wherein A and R 1 being each as defined above, or its salt to give a compound of the formula : wherein A, R 1 and R 2 being each as defined above, or its pharmaceutically acceptable salt, or b) reacting a compound of the formula : wherein A, R 1 and R 2 being each as defined above, or its salt with diazomethane or a compound of the formula : wherein R 4 being a lower alkyl group and X being a leaving group, to give a compound of the formula : wherein R 3 being a lower alkoxy group, and A, R 1 and a R 2 being each as defined above, or its pharmaceutically acceptable salt, or c) subjecting a compound of the formula : wherein A and R 2 being each as defined above, or its reactive derivative at the carboxy group or a salt thereof to esterification reaction to give a compound of the formula : wherein R being a lower alkoxycarbonyl group, and A and R 2 being each as defined above, or its pharmaceutically acceptable salt, or d) subjecting a compound of the formula : wherein A, R 1 a , R 2 and R 3 being each as defined a above, or its salt to deesterification reaction to give a compound of the formula : wherein A, R 2 and R 3 being each as defined above, or its pharmaceutically acceptable salt, or e) subjecting a compound of the formula : wherein R 1 b being a protected hydroxy group, and A, R 2 and R 3 being each as defined above, or its salt to elimination reaction of the hydroxy protective group to give a compound of the formula : wherein A, R 2 and R 3 being each as defined above, or its pharmaceutically acceptable salt, or f) reducing a compound of the formula : wherein A' being a C l -C 4 alkylene group, and R 2 and R 3 being each as defined above, or its reactive derivative at the carboxy group or a salt thereof to give a compound of the formula : wherein A', R 2 and R 3 being each as defined above, or its pharmaceutically acceptable salt, or g) oxidizing a compound of the formula : wherein A', R 2 and R 3 being each as defined above, or its salt to give a compound of the formula : wherein A ', R 2 and R 3 being each as defined above, or its pharmaceutically acceptable salt, or h) subjecting a compound of the formula : wherein R 3 b being hydrogen or a lower alkoxy group, and A ' and R 2 being each as defined above, to Wolff rearrangement reaction, and then reacting the resultant product with the compound of the formula : wherein R 5 being hydrogen or a lower alkyl group, to give a compound of the formula : wherein R 1 being a carboxy or lower alkoxycarbonyl c group, and A ', R 2 and R 3 b being each as defined above, or its pharmaceutically acceptable salt, i) subjecting a compound of the formula : wherein A, R 1 b and R 2 being each as defined above, to elimination reaction of the phenylsulfinyl group to give a compound of the formula : 2 wherein A, R 1 b and R 2 being each as defined above.

Claim 9

A process for preparing a compound of the formula : wherein 1) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is methoxy and A is ethylene; or 2) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is propoxy and A is ethylene; or 3) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is butoxy and A is ethylene; or 4) R 1 is ethoxycarbonyl, R 2 is hydrogen, R 3 is pentoxy and A is ethylene; or 5) R 1 is ethoxycarbonyl, R 2 is chlorine, R 3 is methoxy and A is ethylene; or 6) R 1 is ethoxycarbonyl, R 2 is trifluoromethyl, R 3 is methoxy and A is ethylene; or 7) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is ethoxy and A is ethylene; or 8) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is propoxy and A is ethylene; or 9) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is butoxy and A is ethylene; or 10) R 1 is benzyloxy, R 2 is hydrogen, R 3 is hydroxy and A is ethylene; or 11) R 1 is methoxycarbonyl, R 2 is hydrogen, R 3 is methoxy and A is trimethylene; or 12) R 1 is a lower alkoxycarbonyl group, R 2 is hydrogen, halogen or a halo(lower)alkyl group, R 3 is hydroxy and A is a lower alkylene group; or 13) R 1 is a carboxy, hydroxy or protected hydroxy group, R 2 is hydrogen, halogen or a halo(lower)-alkyl group, R 3 is lower alkoxy and A is a lower alkylene group; or 14) R 1 is a carboxy, hydroxy, protected hydroxy or lower alkoxycarbonyl group, R 2 is hydrogen, halogen or a halo(lower)alkyl group, R 3 is hydrogen and A is a lower alkylene group; and a pharmaceutically acceptable salt thereof, which comprises a) reacting a compound of the formula : wherein R 2 being as defined above, or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula : wherein A and R 1 being each as defined above, or its salt to give a compound of the formula : wherein A, R 1 and R 2 being each as defined above, or its pharmaceutically acceptable salt, or b) reacting a compound of the formula : wherein A, R 1 and R 2 being each as defined above, or its salt with diazomethane or a compound of the formula : wherein R 4 being a lower alkyl group and X being a leaving group, to give a compound of the formula : wherein R 3 being a lower alkoxy group, and A, R 1 and a R 2 being each as defined above, or its pharmaceutically acceptable salt, or c) subjecting a compound of the formula : wherein A and R 2 being each as defined above, or its reactive derivative at the carboxy group or a salt thereof to esterification reaction to give a compound of the formula : wherein R being a lower alkoxycarbonyl group, and A and R 2 being each as defined above, or its pharmaceutically acceptable salt, or d) subjecting a compound of the formula : wherein A, R 1 a , R 2 and R 3 being each as defined a above, or its salt to deesterification reaction to give a compound of the formula : wherein A, R 2 and R 3 being each as defined above, or its pharmaceutically acceptable salt, or e) subjecting a compound of the formula : wherein R 1 b being a protected hydroxy group, and A, R 2 and R 3 being each as defined above, or its salt to elimination reaction of the hydroxy protective group to give a compound of the formula : wherein A, R 2 and R 3 being each as defined above, or its pharmaceutically acceptable salt, or f) reducing a compound of the formula : wherein A' being a C l -C 4 alkylene group, and R 2 and R 3 being each as defined above, or its reactive derivative at the carboxy group or a salt thereof to give a compound of the formula : wherein A', R 2 and R 3 being each as defined above, or its pharmaceutically acceptable salt, or g) oxidizing a compound of the formula : wherein A', R 2 and R 3 being each as defined above, or its salt to give a compound of the formula : wherein A ', R 2 and R 3 being each as defined above, or its pharmaceutically acceptable salt, or h) subjecting a compound of the formula : wherein R 3 b being hydrogen or a lower alkoxy group, and A ' and R 2 being each as defined above, to Wolff rearrangement reaction, and then reacting the resultant product with the compound of the formula : wherein R 5 being hydrogen or a lower alkyl group, to give a compound of the formula : wherein R 1 being a carboxy or lower alkoxycarbonyl c group, and A ', R 2 and R 3 b being each as defined above, or its pharmaceutically acceptable salt, i) subjecting a compound of the formula : wherein A, R 1 b and R 2 being each as defined above, to elimination reaction of the phenylsulfinyl group to give a compound of the formula : 2 wherein A, R 1 b and R 2 being each as defined above.

Claim 10

A pharmaceutical composition comprising as an effective ingredient a compound as defined in claim 1 or its pharmaceutically acceptable salt.

Claim 11

A use of a compound as defined in claim 1 or its pharmaceutically acceptable salt for manufacturing a medicament for the treatment of diabetic cataract and/or neuropathy.

Claim 12

A process for preparing a compound of the formula: wherein R 1 ' is a carboxy, hydroxy, protected hydroxy or lower alkoxycarbonyl group, R 2 is hydrogen, a halogen or a halo(lower)alkyl group,and A" is a lower alkylene group; and a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula: wherein R 2 a being as defined above, a or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula: wherein A" and R1 being each as defined above, or its salt.

Claim 13

A process for preparing a compound of the formula: wherein R 1 ' is a carboxy, hydroxy, protected hydroxy or lower alkoxycarbonyl group, R 2 is hydrogen, a halogen or a halo(lower)alkyl group,and A" is a lower alkylene group; and a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula: wherein R 2 a being as defined above, a or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula: wherein A" and R1 being each as defined above, or its salt.