Claims
- 1. A 4-phenyl-4-oxo-butanoic acid compound of formula (IA): either as single isomer, as a mixture of isomers thereof, or as a pharmaceutically acceptable salt thereof wherein:X and Y are, each independently, fluorine or chlorine; R is hydroxy; —OR5 in which R5 is C1-C6 alkyl, phenyl benzyl, C2-C4 alkenyl or C2-C4 alkynyl; —N(R6)2 or —N(R6)OR6 in which each of R6 is hydrogen, C1-C6 alkyl, C2-C4alkenyl, C2-C4 alkynyl, phenyl or benzyl; R1, R2, R3 and R4 are, each independently, hydrogen, halogen hydroxy, cyano, thiol, C1-C6alkoxy, C1-C6 alkylthio, C1-C6 alkyl C2-C4 alkenyl, phenyl or benzyl, or R1 and R3 or R2 and R4 together form a group ═CHR8 in which R8 is hydrogen, a straight C1-C5 alkyl chain or phenyl; provided that: (i) when X and Y are both chlorine and R1, R2 and R4 are simultaneously hydrogen, R3 is different from hydrogen, hydroxy, methoxy, ethylthio or isopropylthio; and (ii) when X and Y are both fluorine, R1, R2, R3 and R4 are not simultaneously hydrogen.
- 2. A compound as claimed in claim 1, whereinX and Y are, each independently, fluorine or chlorine; R is hydroxy or —OR5 in which R5 is C1-C6 alkyl; R1, R2, R3 and R4 are, each independently, hydrogen, halogen, cyano, hydroxy, thiol, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkyl, phenyl, benzyl or C2-C4 alkenyl, or R1 and R3 or R2 and R4 together form a group ═CHR8 in which R8 is hydrogen, a straight C1-C5 alkyl or phenyl; or a pharmaceutically acceptable salt thereof.
- 3. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
- 4. A compound selected from the group consisting of:2-hydroxy-4-(3′,4′-difluorophenyl)-4-oxo-butanoic acid; 2-methoxy-4-(3′,4′-difluorophenyl)-4-oxo-butanoic acid; 2-hydroxy-3-methyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 2-hydroxy-3-phenyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 2-hydroxy-3-benzyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 2-methyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 2-methyl-4-(3′,4′-difluororophenyl)-4-oxo-butanoic acid; 2-chloro-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 2-chloro-4-(3′,4′-difluorophenyl)-4-oxo-butanoic acid; 2-fluoro-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 2-fluoro-4-(3′,4′-difluorophenyl)-4-oxo-butanoic acid; 2-thiomethyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 2-methyliden-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 2-phenyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 2-benzyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 3-methyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 3-methyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 3-phenyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoic acid; 3-benzyl-4-(3′,4′-dichloropheny )-4-oxo-butanoic acid; (R,S)-methyl-2-hydroxy-4-(3′,4′-dichlorophenyl)-4-oxo-butanoate; and (R,S)-methyl-2-benzyl-4-(3′,4′-dichlorophenyl)-4-oxo-butanoate; wherein said compounds may be single isomers, isomer mixtures, or pharmaceutically acceptable salts thereof.
- 5. A method of inhibiting kynurenine-3-hydroxylase comprising providing or administering, to a patient in need thereof, an effective amount of a 4-phenyl-oxo-butanoic acid compound of formula (I): either as a single isomer, as a mixture of isomers thereof, or as pharmaceutically acceptable salt wherein:X, Y and Z are, each independently, hydrogen, halogen, cyano, nitro, C1-C6 alkyl, phenyl, benzyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 alkoxy or C1-C6 alkylthio; R is hydroxy; —OR5 in which R5 is C1-C6 alkyl, phenyl, benzyl, C2-C4 alkenyl or C2-C4 alkynyl; —N(R6)2 or —N(R6)OR6 in which each R6 is, independently, hydrogen, C1-C6 alkyl, C2-C4 alkenyl, C2—C4 alkynyl, phenyl or benzyl; R1, R2, R3 and R4 are, each independently, hydrogen, halogen, hydroxy, thiol, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkyl, C2-C4 alkenyl, phenyl or benzyl, or R1 and R3 or R2 and R4 together form a group ═CHR8 in which R8 is hydrogen, a straight C1-C5 alkyl chain or phenyl; and wherein when, at the same time, X is hydrogen, halogen or phenyl; Y is hydrogen or C1-C6 alkoxy; R1and R3 together form a ═CH2 group and R is hydroxy or C1-C6 alkoxy, then at least one of Z, R2 and R4 is other than hydrogen; wherein when, at the same time, X is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy; Y is phenyl; R3 is methyl and Z, R1, R2 and R4 are hydrogen, then R is other than hydroxy; andwherein when, at the same time, Y is isopropyl or tertiary-butyl; X is chlorine or nitro; R is hydroxy, C1-C6 alkoxy or alkoxy or —N(R6)2 in which each R6 is hydrogen or C1-C6 alky then at least one of R1, R2 R3, R4 and Z is other than hydrogen.
- 6. A method of preventing and/or treating a neurodegenerative disease comprising providing or administering, to a patient in need thereof, an effective amount of a 4-phenyl-oxo-butanoic acid compound of formula (I): either as a single isomer, as a mixture of isomers, or as pharmaceutically acceptable salt thereof wherein:X, Y and Z are, each independently, hydrogen, halogen, cyano, nitro, C1-C6 alkyl, phenyl, benzyl, C2-C4 alkenyl, C2-C4 alkynyl, C1C6 alkoxy or C1-C6 alkylthio; R is hydroxy; —OR5 in which R5 is C1-C6 alkyl, phenyl, benzyl, C2-C4 alkenyl or C2C4 alkynyl; —NR6)2 or —NR6)OR6 in which each R6 is, independently, hydrogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or benzyl; R1, R2, R3 and R4 are, each independently, hydrogen, halogen, hydroxy, thiol, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkyl, C2-C4 alkenyl, phenyl or benzyl, or R1 and R3 or R2 and R4 together form a group ═CHR8 in which R8 is hydrogen, a straight C1-C5 alkyl chain or phenyl; and wherein when, at the same time, X is hydrogen, halogen or phenyl; Y is hydrogen or C1-C6 alkoxy; R1 and R3 together form a ═CH2 group and R is hydroxy or C1-C6 alkoxy, then at least one of Z, R2 and R4 is other than hydrogen; wherein when, at the same time, X is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy; Y is phenyl; R3 is methyl and Z, R1, R2 and R4 are hydrogen, then R is other than hydroxy; andwherein when, at the same time, Y is isopropyl or tertiary-butyl; X is chlorine or nitro; R is hydroxy, C1-C6 alkoxy or alkoxy or —N(R6)2 in which each R6 is hydrogen or C1-C6 alky then at least one of R1, R2, R3, R4 and Z is other than hydrogen.
- 7. The method according to claim 6, wherein the neurodegenerative disease is:Huntington's chorea, Alzheimer's disease, dementia caused by Acquired Immunodeficiency Syndrome (AIDS), infarctual dementia, cerebral ischemia, cerebral hypoxia, Parkinson's disease epilepsy, head and spinal cord injury, amyotrophic lateral sclerosis, glaucoma retinopathy, infections of the brain or inflammations of the brain.
- 8. A method of inhibiting kynurenine-3-hydroxylase comprising providing or administering, to a patient in need thereof, an effective amount of the compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof.
- 9. A method of treating a patient in need of a kynurenine-3-hydroxylase inhibitor comprising providing or administering, to a patient in need thereof, to said patient an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.
- 10. A method of preventing and/or treating a neurodegenerative disease comprising providing or administering, to a patient in need thereof, an effective amount of the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof.
- 11. The method of claim 9 wherein the neurodegenerative disease is Huntington's chorea, Alzheimer's disease, dementia caused by Acquired Immunodeficiency Syndrome (AIDS), infarctual dementia, cerebral ischemia, cerebral hypoxia, Parkinson's disease, epilepsy, head and spinal cord injury, amyotrophic lateral sclerosis, glaucoma retinopathy, infections of the brain or inflammations of the brain.
- 12. A method of inhibiting kynurenine-3-hydroxylase comprising providing or administering, to a patient in need thereof, an effective amount of the compound of claim 4.
- 13. A method of preventing and/or treating a neurodegenerative disease comprising providing or administering, to patient in need thereof, an effective amount of the compound of claim 4.
- 14. The method of claim 13 wherein the neurodegenerative disease is Huntington's chorea, Alzheimer's disease, dementia caused by Acquired Immunodeficiency Syndrome (AIDS), infarctual dementia, cerebral ischemia, cerebral hypoxia, Parkinson's disease, epilepsy, head and spinal cord injury, amyotrophic lateral sclerosis, glaucoma retinopathy, infections of the brain or inflammations of the brain.
Priority Claims (1)
Number |
Date |
Country |
Kind |
9522615 |
Nov 1995 |
GB |
|
Parent Case Info
This application is a Rule 371 of PCT/EP96/04518 filed Oct. 16, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/EP96/04518 |
|
WO |
00 |
5/1/1998 |
5/1/1998 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/17317 |
5/15/1997 |
WO |
A |
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
5519055 |
Schwarcz et al. |
May 1996 |
|
5708030 |
Schwarcz et al. |
Jan 1998 |
|