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US 6,071,965 AGranted
Phosphinic alkanoic acid derivatives
AssigneeGuilford Pharmaceuticals Inc.
InventorsPaul F. Jackson, Weixing Li, Keith M. Maclin, Kevin L. Tays, Takashi Tsukamoto, Barbara S. Slusher
Life of this patent
Estimating the term…
Abstract
The present invention relate to phosphinic alkanoic acid derivatives that inhibit N-Acetylated .alpha.-Linked Acidic Dipeptidase (NAALADase) enzyme activity, pharmaceutical compositions comprising the same, and methods of using the same to inhibit NAALADase activity and to treat glutamate abnormalities and prostate diseases.
Claims20
A compound of formula I:
- ##STR14## or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein:
- X is CR.sub.6 R.sub.7, O or NR.sub.8 ;
- R.sub.1 is selected from the group consisting of C.sub.1 -C.sub.9 straight or branched chain alkyl, C.sub.2 -C.sub.9 straight or branched chain alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl and Ar, wherein said R.sub.1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.2 -C.sub.6 straight or branched chain alkenyl, C.sub.1 -C.sub.9 alkoxy, C.sub.2 -C.sub.9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar;
- R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.9 straight or branched chain alkyl, C.sub.2 -C.sub.9 straight or branched chain alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl and Ar, wherein said R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are independently unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.2 -C.sub.6 straight or branched chain alkenyl, C.sub.1 -C.sub.9 alkoxy, C.sub.2 -C.sub.9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar;
- provided that when X is --CH.sub.2 --, R.sub.1 is --(CH.sub.2).sub.2 --, R.sub.2 is --(CH.sub.2).sub.2 COOCH.sub.2 C.sub.6 H.sub.5, R.sub.3 is benzyl, and R.sub.4 is hydrogen, then R.sub.5 is not benzyl;
- and
- Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, [2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,] benzyl and phenyl, wherein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, halo, hydroxy, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.2 -C.sub.6 straight or branched chain alkenyl, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyloxy, phenoxy, benzyloxy, and amino.
4 more elements
A method of inhibiting NAALADase enzyme activity in an animal, comprising administering to said animal an effective amount of a compound of formula I:
- ##STR15## or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein:
- X is CR.sub.6 R.sub.7, O or NR.sub.8 ;
- R.sub.1 is selected from the group consisting of C.sub.1 -C.sub.9 straight or branched chain alkyl, C.sub.2 -C.sub.9 straight or branched chain alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl and Ar, wherein said R.sub.1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.2 -C.sub.6 straight or branched chain alkenyl, C.sub.1 -C.sub.9 alkoxy, C.sub.2 -C.sub.9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar;
- R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.9 straight or branched chair alkyl, C.sub.2 -C.sub.9 straight or branched chain alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl and Ar, wherein said R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are independently unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.2 -C.sub.6 straight or branched chain alkenyl, C.sub.1 -C.sub.9 alkoxy, C.sub.2 -C.sub.9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar;
- and
- Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, [2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,] benzyl and phenyl, therein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, halo, hydroxy, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.3 -C.sub.6 straight or branched chain alkenyl, C.sub.l -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyloxy, phenoxy, benzyloxy, and amino.
3 more elements
A pharmaceutical composition comprising:
- (i) A therapeutically effective amount of a compound of formula I:
- ##STR16## or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein:
- X is CR.sub.6 R.sub.7, O or NR.sub.8 ;
- R.sub.1 is selected from the group consisting of C.sub.1 -C.sub.9 straight or branched chain alkyl, C.sub.2 -C.sub.9 straight or branched chain alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl and Ar, wherein said R.sub.1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.2 -C.sub.6 straight or branched chain alkenyl, C.sub.1 -C.sub.9 alkoxy, C.sub.2 -C.sub.9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar;
- R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.9 straight or branched chain alkyl, C.sub.2 -C.sub.9 straight or branched chain alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.6 -C.sub.7 cycloalkenyl and Ar, wherein said R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are independently unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.2 -C.sub.6 straight or branched chain alkenyl, C.sub.1 -C.sub.9 alkoxy, C.sub.2 -C.sub.9 alkenyloxy, phenoxy, benzyloxy, amino, and Ar;
- and
- Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, [2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,] benzyl and phenyl, wherein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, halo, hydroxy, nitro, trifluoromethyl, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.2 -C.sub.6 straight or branched chain alkenyl, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyloxy, phenoxy, benzyloxy, and amino;
- and
- (ii) a pharmaceutically acceptable carrier.
6 more elements
Dependencies are inferred from the claim text.