NAALADase inhibitors useful as pharmaceutical compounds and compositions
AssigneeGuilford Pharmaceutical Inc.
InventorsPaul F. Jackson, Keith M. Maclin, Eric Wang, Barbara S. Slusher, Rena S. Lapidus, Pavel Majer
Life of this patent
Estimating the term…
Abstract
The present invention relates to N-Acetylated α-Linked Acidic Dipeptidase (NAALADase) inhibitors enzyme activity, pharmaceutical compositions comprising such inhibitors, and methods of their use to inhibit NAALADase enzyme activity, thereby effecting neuronal activities, inhibiting angiogenesis, and treating glutamate abnormalities, compulsive disorders, prostate diseases, pain and diabetic neuropathy.
Claims55
A method for inhibiting NAALADase enzyme activity in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula I
- or a pharmaceutically acceptable equivalent, wherein:
- X is a moiety of formula II, III or IV
- m and n are independently 0, 1, 2, 3 or 4;
- Z is SR13, SO3R13, SO2R13, SOR13, SO(NR13)R14 or S(NR13R14)2R15;
- B is N or CR16;
- A is O, S, CR17R18 or (CR17R18)mS;
- R9 and R13 are hydrogen;
- R8, R10, R11, R12 , R14, R15, R16, R17 and R18 are independently hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar1, hydroxy, carboxy, carbonyl, amino, amido, cyano, isocyano, nitro, sulfonyl, sulfoxy, thio, thiocarbonyl, thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl, trifluoromethyl or oxy, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are independently unsubstituted or substituted with one or more substituent(s);
- and
- Ar1 is a carbocyclic or heterocyclic moiety, which is unsubstituted or substituted with one or more substituent (s)
- provided that when X is a moiety of formula II and A is O, then n is 2, 3 or 4;
- when X is a moiety of formula II and A is S, then n is 2, 3 or 4;
- and when X is a moiety of formula II and A is (CR17R18)mS, then n is 0, 2, 3 or 4.
A method for treating a glutamate abnormality in a mammal in need thereof, comprising administering to said mammal in need thereof an effective amount of a compound of formula I
- or a pharmaceutically acceptable equivalent, wherein:
- X is a moiety of formula II, III or IV
- m and n are independently 0, 1, 2, 3 or 4;
- Z is SR13, SO3R13, SO2R13, SOR13, SO(NR13)R14 or S(NR13R14)2R15;
- B is N or CR16;
- A is O, S, CR17R18 or (CR17R18)mS;
- R9 and R13 are hydrogen;
- R8, R10 , R11, R12, R14, R15, R16, R17 and R18 are independently hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar1, hydroxy, carboxy, carbonyl, amino, amido, cyano, isocyano, nitro, sulfonyl, sulfoxy, thio, thiocarbonyl, thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl, trifluoromethyl or oxy, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are independently unsubstituted or. substituted with one or more substituent(s);
- and
- Ar1 is a carbocyclic or heterocyclic moiety, which is unsubstituted or substituted with one or more substituent(s);
- provided that when X is a moiety of formula III, B is N, and R8 is —(CH2)2COOH, then R11 is not hydrogen;
- when X is a moiety of formula II and A is O, then n is 2, 3 or 4;
- when X is a moiety of formula II and A is S, then n is 2, 3 or 4;
- and when X is a moiety of formula II and A is (CR17R18)mS, then n is 0,2,3 or 4, and
- provided that when X is a moiety of formula II, R8 is —(CH2)2COOH, A is O or CR17R18, and n is 0, then Z is not SO2R13, SOR13, or SO(NR13)R14.
A method for treating a glutamate abnormality selected from the group consisting of compulsive disorder, stroke, demyelinating disease, schizophrenia, Parkinson's disease and ALS in a mammal is need thereof, comprising administering to said mammal an effective amount of a compound of formula I
- or a pharmaceutically acceptable equivalent, wherein:
- X is a moiety of formula II, III or IV
- m and n are independently 0, 1, 2, 3 or 4;
- Z is SR13, SO3R13, SO2R13, SOR13, SO(NR13)R14 or S(NR13R14)2R15;
- B is N or CR16;
- A is O, S, CR17R18 or (CR17R18)mS;
- R9 and R13 are hydrogen;
- R8, R10, R11, R12, R14, R15, R16, R17 and R18 are independently hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar1, hydroxy, carboxy, carbonyl, amino, amido, cyano, isocyano, nitro, sulfonyl, sulfoxy, thio, thiocarbonyl, thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl, trifluoromethyl or oxy, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are independently unsubstituted or substituted with one or more substituent(s);
- and
- Ar1 is a carbocyclic or heterocyclic moiety, which is unsubstituted or substituted with one or more substituent(s);
- provided that when X is a moiety of formula II and A is O, then n is 2, 3 or 4;
- when X is a moiety of formula II and A is S, then n is 2, 3 or 4;
- and when X is a moiety of formula II and A is (CR17R18)mS, then n is 0, 2, 3 or 4, and
- provided that when X is a moiety of formula II, R8 is —(CH2)2COOH, A is O or CR17R18, and n is 0, then Z is not SO2R13, SOR13, or SO(NR13)R14.
A method for effecting a neuronal activity in a mamnmal in need thereof, comprising administering to said mammal an effective amount of a compound of formula I
- or a pharmaceutically acceptable equivalent, wherein:
- X is a moiety of formula II, III, or IV
- m and n are independently 0, 1, 2, 3 or 4;
- Z is SR13, SO3R13, SO2R13, SOR13, SO(NR13)R14 or S(NR13R14)2R15;
- B is N or CR16;
- A is O, S, CR17R18 or (CR17R18)mS;
- R9 and R13 are hydrogen;
- R8, R10, R11, R12, R14, R15, R16, R17 and R18 are independently hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar1, hydroxy, carboxy, carbonyl, amino, amido, cyano, isocyano, nitro, sulfonyl, sulfoxy, thio, thiocarbonyl, thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl, trifluoromethyl or oxy, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are independently unsubstituted or substituted with one or more substituent(s);
- and
- Ar1 is a carbocyclic or heterocyclic moiety, which is unsubstituted or substituted with one or more substituent(s);
- provided that when X is a moiety of formula II and A is O, then n is 2, 3 or 4;
- when X is a moiety of formula II and A is S, then n is 2, 3 or 4;
- and when X is a moiety of formula II and A is (CR17R18)mS, then n is 0, 2, 3 or 4, and
- provided that when X is a moiety of formula II, R8 is —(CH2)2COOH, A is O or CR17R18, and n is 0, then Z is not SO2R13, SOR13, or SO(NR13)R14.
A method for treating a prostate disease in a mammal is need thereof, comprising administering to said mammal an effective amount of a compound of formula I
- or a pharmaceutically acceptable equivalent, wherein:
- X is a moiety of formula II, III or IV
- m and n are independently 0, 1, 2, 3 or 4;
- Z is SR13, SO3R13, SO2R13, SOR13, SO(NR13)R14 or S(NR13R14)2R15;
- B is N or CR16;
- A is O, S, CR17R18 or (CR17R18)mS;
- R9 and R13 are hydrogen;
- R8, R10, R11, R12, R14, R15, R16, R17 and R18 are independently hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar1, hydroxy, carboxy, carbonyl, amino, amido, cyano, isocyano, nitro, sulfonyl, sulfoxy, thio, thiocarbonyl, thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl, trifluoromethyl or oxy, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are independently unsubstituted or substituted with one or more substituent(s);
- and
- Ar1 is a carbocyclic or heterocyclic moiety, which is unsubstituted or substituted with one or more substituent(s);
- provided that when X is a moiety of formula II and A is O, then n is 2, 3 or 4;
- when X is a moiety of formula II and A is S, then n is 2, 3 or 4;
- and when X is a moiety of formula II and A is (CR17R18)mS, then n is 0, 2, 3 or 4.
A method for treating cancer in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula I
- or a pharmaceutically acceptable equivalent, wherein:
- X is a moiety of formula II, III or IV
- m and n are independently 0, 1, 2, 3 or 4;
- Z is SR13, SO3R13, SO2R13, SOR13, SO(NR13) R14 or S(NR13R14)2R15;
- B is N or CR16;
- A is O, S, CR17R18 or (CR17R18)mS;
- R9 and R13 are hydrogen;
- R8, R10, R11, R12, R14, R15, R16, R17 and R18 are independently hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar1, hydroxy, carboxy, carbonyl, amino, amido, cyano, isocyano, nitro, sulfonyl, sulfoxy, thio, thiocarbonyl, thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl, trifluoromethyl or oxy, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are independently unsubstituted or substituted with one or more substituent(s);
- and
- Ar1 is a carbocyclic or heterocyclic moiety, which is unsubstituted or substituted with one or more substituent(s);
- provided that when X is a moiety of formula II and A is O, then n is 2, 3 or 4;
- when X is a moiety of formula II and A is S, then n is 2, 3 or 4;
- and when X is a moiety of formula II and A is (CR17R18)mS, then n is 0, 2, 3 or 4.
A method for inhibiting angiogenesis in a mammal in need thereof comprising administering to said mammal an effective amount of a NAALADase inhibitor.
A method for treating acute pain in a mammal in need thereof comprising administering to said mammal an effective amount of a NAALADase inhibitor.
A method for treating diabetic neuropathic pain in a mammal in need thereof comprising administering to said mammal an effective amount of a NAALADase inhibitor.
A method for treating diabetic neuropathy in a mammal in need thereof comprising administering to said mammal an effective amount of a NAALADase inhibitor.
A method for treating pain in a mammal in need thereof comprising administering to said mammal an effective amount of a compound of formula I
- or a pharmaceutically acceptable equivalent, wherein:
- X is a moiety of formula II, III or IV
- m and n are independently 0, 1, 2, 3 or 4;
- Z is SR13, SO3R13, SO2R13, SOR13, SO(NR3)R14 or S(NR13R14)2R15;
- B is N or CR16;
- A is O, S, CR17R18 or (CR17R18)mS;
- R9 and R13 are hydrogen;
- R8, R10, R11, R12, R14, R15, R16, R17 and R18 are independently hydrogen, branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Ar1, hydroxy, carboxy, carbonyl, amino, amido, cyano, isocyano, nitro, sulfonyl, sulfoxy, thio, thiocarbonyl, thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl, trifluoromethyl or oxy, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are independently unsubstituted or substituted with one or more substituent(s);
- and
- Ar1 is a carbocyclic or heterocyclic moiety, which is unsubstituted or substituted with one or more substituent(s);
- provided that when X is a moiety of formula II and A is O, then n is 2, 3 or 4;
- when X is a moiety of formula II and A is S, then n is 2, 3 or 4;
- and when X is a moiety of formula II and A is (CR17R18)mS, then n is 0, 2, 3 or 4, and
- provided that when X is a moiety of formula II, R8 is —(CH2)2COOH, A is O or CR17R18, and n is 0, then Z is not SO2R13, SOR13, or SO(NR13)R14.
Dependencies are inferred from the claim text.