US2003083374A1PendingUtilityA1
NAALADase inhibitors useful as pharmaceutical compounds and compositions
Priority: Jul 6, 1998Filed: Jun 10, 2002Published: May 1, 2003
Est. expiryJul 6, 2018(expired)· nominal 20-yr term from priority
A61P 9/10A61P 9/00A61P 43/00A61P 35/00A61P 25/28A61P 25/04A61P 25/18A61P 25/00A61P 25/16A61P 25/30A61P 13/08C07C 329/12C07C 309/17C07C 333/14C07C 327/18C07C 323/52C07C 323/56C07C 317/44C07C 323/12C07D 213/55C07C 327/36C07C 333/20C07C 309/24C07C 319/00
47
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Claims
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.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . 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 SR 13 , SO 3 R 13 , SO 2 R 13 , SOR 13 , SO(NR 13 )R 14 or S(NR 13 R 14 ) 2 R 15 ;
B is N or CR 16 ;
A is O, S, CR 17 R 18 or (CR 17 R 18 ) m S;
R 9 and R 13 are hydrogen;
R 9 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are independently hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar 1 , hydroxy, carboxy, carbonyl, amino, amido, cyaho, 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
Ar 1 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, R 8 is —(CH 2 ) 2 COOR 19 or —(CH 2 ) 2 CONHR 19 , A is CH 2 , n is 0, Z is SR 13 , then R 13 is not hydrogen or COR 19 ; when X is a moiety of formula III, B is N, and R 8 is —(CH 2 ) 2 COOH, then R 11 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 (CR 17 R 18 ) m S, then n is 0, 2, 3 or 4.
2 . The compound of claim 1 , wherein:
X is a moiety of formula II; n is 0, 1, 2 or 3; Z is SH, SO 3 H, SO 2 H, SOH or S(NRHR 14 ) 2 R 15 ; and A is O, S or CR 17 R 18 .
3 . The compound of claim 2 , wherein z is SH.
4 . The compound of claim 3 , wherein R 8 is —(CH 2 ) 2 CCOH.
5 . The compound of claim 3 , wherein the compound of formula I is selected from the group consisting of:
2-(2-sulfanylethyl)pentanedioic acid; 3-(2-sulfanylethyl)-1,3,5-pentanetricarboxylic acid; 2-(2-sulfanylpropyl)pentanedioic acid; 2-(2-sulfanylbutyl)pentanedioic acid; 2-(2-sulfanyl-2-phenylethyl) pentanedioic acid; 2-(2-sulfanylhexyl)pentanedioic acid; 2-(2-sulfanyl-1-methylethyl)pentanedioic acid; 2-[1-(sulfanylmethyl)propyl]pentanedioic acid; 2-(3-sulfanylpentyl)pentanedioic acid; 2-(3-sulfanylpropyl)pentanedioic acid; 2-(3-sulfanyl-2-methylpropyl)pentanedioic acid; 2-(3-sulfanyl-2-phenylpropyl)pentanedioic acid; 2-(3-sulfanylbutyl)pentanedioic acid; 2-[3-sulfanyl-2-(phenylmethyl)propyl]pentanedioic acid; 2-[2-(sulfanylmethyl)butyl]pentanedioic acid; 2-[2-(sulfanylmethyl)pentyl]pentanedioic acid; 2-(3-sulfanyl-4-methylpentyl)pentanedioic acid; and pharmaceutically acceptable equivalents.
6 . The compound of claim 5 , wherein the compound of formula I is selected from the group consisting of 2-(2-sulfanylethyl)pentanedioic acid, 2-(2-sulfanylpropyl)pentanedioic acid, 2-(3-sulfanylpropyl)pentanedioic acid and pharmaceutically acceptable equivalents.
7 . The compound of claim 6 , wherein the compound of formula I is an enantiomer or an enantiomer-enriched mixture.
8 . A compound containing both sulfur and an acid group which is effective in treating stroke in a mammal when administered more than 60 minutes following onset of stroke.
9 . The compound of claim 8 which is effective in treating stroke in a mammal when administered more than 180 minutes following onset of stroke.
10 . The compound of claim 9 which is effective in treating stroke in a mammal when administered more than 360 minutes following onset of stroke.
11 . A method for inhibiting NAALADase enzyme activity in a mammal, 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, IIIV
m and n are independently 0, 1, 2, 3 or 4;
Z is SR 13 , SO 3 R 13 , SO 2 R 13 , SOR 13 , SO(NR 13 )R 14 or S(NR 13 R 14 ) 2 R 15 ;
B is N or CR 16 ;
A is O, S, CR 17 R 18 or (CR 17 R 18 ) m S;
R 9 and R 13 are hydrogen;
R 8 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 and R 18 are independently hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar 1 , 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
Ar 1 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 (CR 17 R 18 ) m S, then n is 0, 2, 3 or 4.
12 . The method of claim 11 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
13 . A method for treating a glutamate abnormality in a mammal, 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 SR 13 , SO 3 R 13 , SO 2 R 13 , SOR 13 , SO(NR 13 )R 14 or S(NR 13 R 14 ) 2 R 15 ;
B is N or CR 16 ;
A is O, S, CR 17 R 18 or (CR 17 R 18 ) m S;
R 9 and R 13 are hydrogen;
R 8 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 and R 18 are independently hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar 1 , 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
Ar 1 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 R 8 is —(CH 2 ) 2 COOH, then R 11 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 (CR 17 R 18 ) m S, then n is 0, 2, 3 or 4.
14 . The method of claim 13 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
15 . The method of claim 13 , wherein the glutamate abnormality is ischemia.
16 . The method of claim 15 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
17 . 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, 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 SR 13 , SO 3 R 13 , SO 2 R 13 , SOR 13 , SO(NR 13 )R 14 or S(NR 13 R 14 ) 2 R 15 ;
B is N or CR 16 ;
A is O, S, CR 17 R 18 or (CR 17 R 18 ) m S;
R 9 and R 13 are hydrogen;
R 8 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 and R 18 are independently hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 1 -C 7 cycloalkenyl, Ar 1 , 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
Ar 1 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 (CR 17 R 18 )MS, then n is 0, 2, 3 or 4.
18 . The method of claim 17 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
19 . The method of claim 17 wherein the glutamate abnormality is schizophrenia.
20 . The method of claim 19 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
21 . The method of claim 17 wherein the glutamate abnormality is compulsive disorder.
22 . The method of claim 21 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
23 . The method of claim 21 , wherein the compulsive disorder is selected from the group consisting of drug dependence and eating disorder.
24 . The method of claim 23 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
25 . The method of claim 23 , wherein the drug dependence is alcohol dependence, nicotine dependence or cocaine dependence.
26 . The method of claim 25 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
27 . A method for effecting a neuronal activity in a mammal, 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 SR 13 , SO 3 R 131 SO 2 R 13 , SOR 13 , SO(NR 13 )R 14 or S(NR 13 R 14 ) 2 R 15 ;
B is N or CR 16 ;
A is O, S, CR 17 R 18 or (CR 17 R 18 ) m S;
R 9 and R 13 are hydrogen;
R 8 , R 10 , R 11 , R 12 , R 14 , R 41 s, R 16 , R 17 and R 18 are independently hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar 1 , 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
Ar 1 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 (CR 17 R 18 ) m S, then n is 0, 2, 3 or 4.
28 . The method of claim 27 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
29 . The method of claim 27 , wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of a neurological disorder.
30 . The method of claim 29 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
31 . The method of claim 29 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to spinal cord, stroke associated with brain damage, demyelinating disease and neurological disorder relating to neurodegeneration.
32 . The method of claim 31 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
33 . The method of claim 31 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Parkinson's disease and ALS.
34 . The method of claim 33 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
35 . A method for treating a prostate disease in a mammal, 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 SR 13 , SO 3 R 13 , SO 2 R 13 , SOR 13 , SO(NR 13 )R 14 or S(NR 13 R 14 ) 2 R 15 ;
B is N or CR 16 ;
A is O, S, CR 17 R 18 or (CR 17 R 18 ) m S;
R 9 and R 13 are hydrogen;
R 8 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 and R 18 are independently hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar 1 , hydroxy, carboxy, carbonyl, amino, amido, cyano, isocyano, nitro, sulfonyl, sulfoxy, thio, thiocarbonyl, thiocyano, formanilido, thiofor, amido, 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
Ar 1 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 (CR 17 R 18 ) m S, then n is 0, 2, 3 or 4.
36 . The method of claim 35 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
37 . The method of claim 35 , wherein the prostate disease is prostate cancer.
38 . The method of claim 37 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.
39 . A method for treating cancer in a mammal, 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 SR 13 , SO 3 R 13 , SO 2 R 13 , SOR 13 , SO(NR 13 )R 14 or S(NR 13 R 14 ) 2 R 15 ;
B is N or CR 16 ;
A is O, S, CR 17 R 18 or (CR 17 R 18 ) m S;
R 9 and R 13 are hydrogen;
R 8 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 and R 18 are independently hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar 1 , 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
Ar 1 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 (CR 17 R 18 ) m S, then n is 0, 2, 3 or 4.
40 . The method of claim 39 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COH.
41 . A method for treating stroke in a mammal, comprising administering an effective amount of a compound containing both sulfur and an acid group to said mammal more than 60 minutes following onset of stroke.
42 . The method of claim 41 , wherein the compound is administered to said mammal more than 180 minutes following onset of stroke.
43 . The method of claim 42 , wherein the compound is administered to said mammal more than 360 minutes following onset of stroke.
44 . A method for inhibiting angiogenesis in a mammal comprising administering to said mammal an effective amount of a NAALADase inhibitor.
45 . A method for treating pain in a mammal comprising administering to said mammal an effective amount of a NAALADase inhibitor.
46 . The method of claim 45 , wherein the pain is diabetic neuropathic pain.
47 . A method for treating diabetic neuropathy in a mammal comprising administering to said mammal an effective amount of a NAALADase inhibitor.
48 . A method for preparing a compound containing both sulfur and an acid group, comprising the step of reacting a thiolactone with a substituted ester to form a compound of formula VI
wherein:
D is (CR 21 R 22 ) n ;
n is 0, 1, 2, 3 or 4; and
R 20 , R 21 and R 22 are independently selected from the group consisting of hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar 1 , 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
Ar 1 is a carbocyclic or heterocyclic moiety, which is unsubstituted or substituted with one or more substituent(s).
49 . A compound prepared by the method of claim 48 .
50 . A method for preparing a compound containing both sulfur and an acid group comprising the steps of:
(i) reacting Meldrum's acid with a sulfur containing reactant to form a Meldrum's acid sulfur containing derivative; and (ii) reacting the Meldrum's acid sulfur containing derivative with an ester to form a compound of formula VII wherein: E is a sulfur containing moiety; and F is a propionic acid ester containing moiety.
51 . A compound prepared by the method of claim 50 .
52 . A pharmaceutical composition comprising:
(i) 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 SR 13 , SO 3 R 13 , SO 2 R 13 , SOR 13 , SO(NR 13 )R 14 or S(NR 13 R 14 ) 2 R 15 ;
B is N or CR 16 ;
A is O, S, CR 17 R 18 or (CR 17 R 18 ) m S;
R 9 and R 13 are hydrogen;
R 8 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 and R 18 are independently hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar 1 , 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
Ar 1 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 (CR 17 R 18 ) m S, then n is 0, 2, 3 or 4; and
(ii) a pharmaceutically acceptable carrier.
53 . The pharmaceutical composition of claim 52 , wherein:
Z is SH; and R 8 is —(CH 2 ) 2 COOH.Cited by (0)
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