Note: Claims are shown in the official language in which they were submitted.
-44-
CLAIMS:
1. A compound of formula I:
Image
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to
which they are respectively attached, form a 5-7 membered
saturated or unsaturated heterocyclic ring containing any
combination of CH2, O, S, SO, SO2, NH, or NR2 in any
chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C2-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-45-
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof.
-46-
2. The compound of claim 1, wherein said Ar1 and Ar2 are
independently selected from the group consisting of naphthyl,
indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl,
isoquinolinyl, fluorenyl, and phenyl.
3. A compound of formula II:
Image
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl,
-C2-C5 straight or branched chain alkenyl, and
-Ar1,
wherein said R1 is unsubstituted or substituted in
one or more positions with halo, nitro, C1-C6
-47-
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl, hydroxy, C1-C4 alkoxy,
C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1,
or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or
naphthyl, wherein said Ar1 is unsubstituted or
substituted in one or more positions with halo,
hydroxy, nitro, C1-C6 straight or branched chain alkyl,
C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy,
C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a
combination thereof.
4. The compound of claim 3, wherein:
n is 1; and
X is O.
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5. The compound of claim 4, which is selected from the
group consisting of:
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
1-(2-[(benzo[b]thiophen-3-ylmethylthio)carbonyl]
pyrrolidinyl}-3-,3-dimethylpentane-l,2-dione;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
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pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
4-Phenyl-l-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
3-(3-Pyridyl)-i-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-
2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-
2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-
2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
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4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl)phenyl]propyl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2--
pyrrolidinecarbothioate;
3-(2-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate; and
3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-
-51-
oxopentanoyl)-2-pyrrolidinecarbothioate.
6. The compound of claim 3, wherein:
n is 2; and
X is O.
7. The compound of claim 6, which is selected from the
group consisting of:
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-
piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-
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piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-
piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-
piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-
piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-
piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-
dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(-2-phenyl-1,2-
dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-
dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
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piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-
2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate; and
3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate.
8. A compound which is 3,3-Diphenyl-1-propyl (2S)-1-(3,3-
dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate.
9. A compound which is 3-(1-Naphthyl)-1-propyl (2S)-1-
(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate
10. A compound which is 2,2-Diphenylethyl (2S)-1-(3,3-
dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate.
-54-
11. A compound which is 3,3-Diphenylpropyl 1-(3,3-dimethyl-
2-oxopentanoyl)-2-piperidinecarbothioate.
12. A compound which is 3-[4-(Trifluoromethyl)phenyl)
propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
pyrrolidinecarbothioate.
13. A compound which is 3-(2-Naphthyl)propyl (2S)-1-(3,3-
dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate.
14. A compound of formula III:
Image
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
-55-
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position (s) with (Ar1) n,
-C2-C6 straight or branched chain alkenyl,substituted
in one or more position(s) with (Ar1) n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
-56-
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof.
15. The compound of claim 14, selected from the group
consisting of:
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-
thiazolidine)carbothioate; and
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-
azolidine)carbothioate.
16. A compound of formula IV:
-57-
Image
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or
NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C2-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-58-
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof.
17. The compound of claim 16, consisting of:
-59-
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
morpholinecarbothioate.
18. A pharmaceutical composition comprising:
(i) a compound of formula I:
Image
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to
which they are respectively attached, form a 5-7 membered
saturated or unsaturated heterocyclic ring containing any
combination of CH2, O, S, SO, SO2, NH, or NR2 in any
chemically stable oxidation state;
X is either O or S;
Z is S;
-60-
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C2-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
-61-
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof; and
(ii) a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising:
(i) a compound of formula II:
Image
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
-62-
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl,
-C2-C5 straight or branched chain alkenyl, and
-Ar1,
wherein said R1 is unsubstituted or substituted in
one or more positions with halo, nitro, C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl, hydroxy, C1-C4 alkoxy,
C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1,
or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or
naphthyl, wherein said Ar1 is unsubstituted or
substituted in one or more positions with halo,
hydroxy, nitro, C1-C6 straight or branched chain alkyl,
C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy,
C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a
combination thereof; and
(ii) a pharmaceutically acceptable carrier.
-63-
20. The pharmaceutical composition of claim 19, wherein
said compound is selected from the group consisting of:
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
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3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-
2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-
2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-
2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1, 2-
dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
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pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl) phenyl]propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl)propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
pyrrolidinecarbothioate;
3-(2-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
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2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-
piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-
piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-
piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-
piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-
piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-
piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-
dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-
dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-
dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
-67-
piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-
2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate; and
3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate.
21. A pharmaceutical composition comprising:
(i) a compound of formula III:
Image
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
-68-
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C2-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
-69-
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof; and
(ii) a pharmaceutically acceptable carrier.
22. The pharmaceutical composition of claim 21, wherein
said compound is selected from the group consisting of:
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-
thiazolidine)carbothioate; and
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-
azolidine)carbothioate.
23. A pharmaceutical composition comprising:
(i) a compound of formula IV:
-70-
Image
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or
NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C3-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-71-
-C3-C6 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1l,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof; and
(ii) a pharmaceutically acceptable carrier.
24. The pharmaceutical composition of claim 23, wherein
said compound is:
-72-
morpholine;
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
morpholinecarbothioate.
25. The pharmaceutical composition according to any one
of claims 18-24, further comprising one or more additional
neurotrophic agent(s).
26. The pharmaceutical composition of claim 25, wherein
said one or more additional neurotrophic agent(s) is/are
independently selected from the group consisting of neurotrophic
growth factor (NGF), glial derived growth factor, brain derived
growth factor, ciliary neurotrophic factor and neurotropin-3.
27. The pharmaceutical composition of claim 26, wherein
said one or more additional neurotrophic agent(s) is neurotrophic
growth factor (NGF).
28. Use of a compound for treating a neurological
disease in an animal, wherein the compound is of formula I:
-73-
Image
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to
which they are respectively attached, form a 5-7 membered
saturated or unsaturated heterocyclic ring containing any
combination of CH2, O, S, SO, SO2, NH, or NR2 in any
chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C2-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
-74-
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof.
-75-
29. Use of a compound for treating a neurological
disease in an animal, wherein the compound is of formula II:
Image
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl,
-C2-C5 straight or branched chain alkenyl, and
-Ar1,
wherein said R1 is unsubstituted or substituted in
one or more positions with halo, nitro, C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl, hydroxy, C1-C9 alkoxy,
C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1,
or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-76-
-C5-C7 cycloalkenyl, and
-Ar1,
Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or
naphthyl, wherein said Ar1 is unsubstituted or
substituted in one or more positions with halo,
hydroxy, nitro, C1-C6,straight or branched chain alkyl,
C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy,
C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a
combination thereof.
30. The use of claim 29, wherein said compound is selected
from the group consisting of:
-77-
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
1-{2-[(benzo[b]thiophen-3-ylmethylthio)carbonyl]
pyrrolidinyl}-3-,3-dimethylpentane-1,2-dione;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-
2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-
2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-
-78-
2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
pyrrolidinecarbothioate;
3-(2-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
-79-
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl(2S)-1-(3,3- dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
2-({1-Oxo-6-phenyl}-hexyl-1-(3,3-dimethyl-1,2-dioxobutyl)
piperidine;
3,3-Dimethyl-1-[2-(4-phenylbutanoyl)piperidino]-1,2-
pentanedione;
3,3-Dimethyl-1-[2-(5-phenylpentanoyl)piperidino]-1,2-
pentanedione;
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-
piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-
piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-
piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbuty-1)-2-
piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-
piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-
piperidinecarbothioate;
-80-
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-
dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-
dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-
dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-di.methyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-
2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate; and
2-((1-Oxo-[2-(2'-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-
dimethyl-1,2-dioxobutyl)piperidine.
-81-
31. Use of a compound for treating a neurological
disease in an animal, wherein the compound is of formula III:
Image
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C2-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-82-
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof.
32. The use of claim 31, wherein said compound is selected
from the group consisting of:
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-
thiazolidine)carbothioate; and
-83-
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-
azolidine)carbothioate.
33. Use of a compound for treating a neurological
disease in an animal, wherein the compound is of formula IV:
Image
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or
NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C2-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
-84-
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
-85-
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof.
34. The use of claim 33, wherein said compound is:
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
morpholinecarbothioate.
35. Use of a compound for effecting a neuronal activity in
an animal, wherein the compound is of formula I:
Image
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to
which they are respectively attached, form a 5-7 membered
saturated or unsaturated heterocyclic ring containing any
-86-
combination of CH2, O, S, SO, SO2, NH, or NR2 in any
chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C2-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
-87-
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof.
36. Use of a compound for effecting a neuronal activity in
an animal, wherein the compound is of formula II:
Image
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
-88-
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl,
-C2-C5 straight or branched chain alkenyl, and
-Ar1,
wherein said R1 is unsubstituted or substituted in
one or more positions with halo, nitro, C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl, hydroxy, C1-C4 alkoxy,
C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1,
or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or
naphthyl, wherein said Ar1 is unsubstituted or
substituted in one or more positions with halo,
hydroxy, nitro, C1-C6 straight or branched chain alkyl,
C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy,
C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a
combination thereof.
-89-
37. The use of claim 36, wherein said compound is selected
from the group consisting of:
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
-90-
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethy1-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-
pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-
2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-
2-pyrrolidinecarbothioate;
3,3-Diphenyl-l-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-
2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-
dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
-91-
pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
pyrrolidinecarbothioate;
3-(2-Fluorophenvl)propvl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl(2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)-2-pyrrolidinecarbothioate;
-92-
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-
piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-
piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-
piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-
piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-
piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-
piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-
dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-
dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-
dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
-93-
piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-
2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate; and
3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarbothioate.
38. Use of a compound for effecting a neuronal activity in
an animal, wherein the compound is of formula III:
Image
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
-94-
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C2-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
-95-
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof.
39. The use of claim 38, wherein said compound is selected
from the group consisting of:
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-
thiazolidine)carbothioate; and
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-
azolidine)carbothioate.
40. Use of a compound for effecting a neuronal activity in
an animal, wherein the compound is of formula IV:
-96-
Image
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or
NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in
one or more position(s) with (Ar1)n,
-C2-C6 straight or branched chain alkenyl substituted
in one or more position(s) with (Ar1)n,
-C3-C8 cycloalkyl,
-C3-C8 cycloalkyl connected by a C1-C6 straight or
branched chain alkyl or a C2-C6 straight or branched
chain alkenyl, and
-Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl,
-C2-C9 straight or branched chain alkenyl,
-97-
-C3-C8 cycloalkyl,
-C5-C7 cycloalkenyl, and
-Ar1,
wherein said alkyl, alkenyl, cycloalkyl, or
cycloalkenyl is either unsubstituted or
substituted in one or more position(s) with C1-C4
straight or branched chain alkyl, C2-C4 straight
or branched chain alkenyl, hydroxyl, or a
combination thereof; and
Ar1 and Ar2 are independently a mono-, bi-, or tricyclic,
carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted
in one to three position(s) with halo, hydroxyl, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or
a combination thereof; wherein the individual ring
sizes are 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) selected from the group
consisting of O, N, S, and a combination thereof.
41. The use of claim 40, wherein said compound is:
-98-
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-
morpholinecarbothioate.
42. The use according to any one of claim 35-41, 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
neurological disorder.
43. The use of claim 42, wherein the neurological disorder
is selected from the group consisting of peripheral neuropathy
caused by physical injury or disease state, traumatic injury to
the brain, physical damage to the spinal cord, stroke associated
with brain damage, and neurological disorder relating to
neurodegeneration.
44. The use of claim 43, wherein the neurological disorder
relating to neurodegeneration is selected from the group
consisting of Alzheimer's Disease, Parkinson's Disease, and
amyotrophic lateral sclerosis.
-99-
45. A process of preparing a compound of the formula:
Image
comprising reacting a compound of formula
Image
or activated derivatives thereof with a compound of formula
-100-
HS-R1, wherein
n is 1 or 2;
R1 is a C1-C6 straight or branched chain alkyl substituted
with phenyl, and
R2 is a C1-C9 straight or branched chain alkyl.