US2002016341A1PendingUtilityA1
Heterocyclic thioester and ketone hair growth compositions and uses
Est. expiryJun 3, 2018(expired)· nominal 20-yr term from priority
A61K 31/4545C07D 401/12A61K 31/40C07D 417/12A61K 31/445A61Q 7/00A61K 31/4025A61K 31/00A61K 8/4913A61K 31/401A61K 45/06C07D 401/06A61K 31/426A61K 2800/70A61K 31/4439
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Claims
Abstract
This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using heterocyclic thioesters and ketones.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a heterocyclic thioester or ketone.
2 . The method of claim 1 , wherein the heterocyclic thioester or ketone is non-immunosuppressive.
3 . The method of claim 1 , wherein the heterocyclic thioester or ketone has an affinity for an FKBP-type immunophilin.
4 . The method of claim 3 , wherein the FKBP-type immunophilin is FKBP-12.
5 . The method of claim 1 , wherein the heterocyclic thioester or ketone is a compound of formula T
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more additional O, S, SO, SO 2 , N, NH, or NR 2 heteroatom(s);
X is either O or S;
Z is either S, CH 2 , CHR 1 or CR 1 R 3 ;
W and Y are independently O, S, CH 2 or H 2 ;
R 1 and R 3 are independently C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n , C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with (Ar 1 ) n , C 3 -C 8 cycloalkyl, C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with C 3 -C 8 cycloalkyl, and Ar 2 ;
n is 1 or 2;
R 2 is either 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 or Ar 1 , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C 1 -C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, and hydroxy; and
Ar 1 and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.
6 . The method of claim 5 , wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl, and phenyl.
7 . The method of claim 1 , wherein the heterocyclic thioester or ketone is a compound of formula II
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1 or 2;
X is O or S;
Z is selected from the group consisting of S, CH 2 , CHR 1 , and CR 1 R 3 ;
R 1 and R 3 are independently selected from the group consisting of C 1 -C 5 straight or branched chain alkyl, C 2 -C 5 straight or branched chain alkenyl, and Ar 1 , wherein said R 1 is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, nitro, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, hydroxy, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, and Ar 1 ;
R 2 is selected from the group consisting of 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, and Ar 1 ; and
Ar 1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said Ar 1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, trifluoromethyl, hydroxy, nitro, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino.
8 . The method of claim 7 , wherein:
n is 1; and X is O.
9 . The method of claim 8 , wherein Z is CH 2 .
10 . The method of claim 9 , wherein the compound is selected from the group consisting of:
(2S)-2-({1- Oxo-5-phenyl}-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine; 3,3-Dimethyl-1-[(2S)-2-(5-(3-pyridyl)pentanoyl)-1pyrrolidine]-1,2-pentanedione; (2S)-2-({1-Oxo-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine; (2S)-2-({1-Oxo-4-phenyl}-butyl-1-(2-cyclohexyl-1,2-dioxoethyl)pyrrolidine; 2-({1-Oxo-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine; 1-{(2S)-2-[5,5-di(4-Fluorophenyl)pentanoyl]-2-pyrrolidine}-3,3-dimethyl-1,2-pentanedione; and pharmaceutically acceptable salts, esters, and solvates thereof.
11 . The method of claim 8 , wherein Z is S.
12 . The method of claim 11 , wherein the compound is selected from the group consisting of:
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; (3-Thioindolyl)methyl (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-(1-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-dioxoethyl)-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)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)tetrahydro-1H-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-(1-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; and pharmaceutically acceptable salts, esters, and solvates thereof.
13 . The method of claim 12 , wherein the compound is 3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
14 . The method of claim 12 , wherein the compound is 3-(1-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
15 . The method of claim 12 , wherein the compound is 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)tetrahydro-1H-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
16 . The method of claim 12 , wherein the compound is 3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
17 . The method of claim 12 , wherein the compound is 3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
18 . The method of claim 7 , wherein:
n is 1; and X is S.
19 . The method of claim 18 , wherein Z is CH 2 .
20 . The method of claim 18 , wherein Z is S.
21 . The method of claim 7 , wherein:
n is 2; and X is O.
22 . The method of claim 21 , wherein Z is CH 2 .
23 . The method of claim 22 , wherein the compound is selected from the group consisting of:
2-({1-Oxo-6-phenyl}-hexyl-1-(2-cyclohexyl-1,2-dioxoethyl)piperidine; 3,3-Dimethyl-1-[2-(4-phenylpentanoyl)piperidino]-1,2-pentanedione; and pharmaceutically acceptable salts, esters, and solvates thereof.
24 . The method of claim 21 , wherein Z is S.
25 . The method of claim 24 , wherein the compound 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-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-mercaptopentyl 1-(3-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate; 3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-2,3-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-(2-Naphthyl)propyl (2R,S)-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-piperidinecarbothioate; 3-(2-Chlorophenyl)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 pharmaceutically acceptable salts, esters, and solvates thereof.
26 . The method of claim 25 , wherein the compound is3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
27 . The method of claim 7 , wherein:
n is 2; and X is S.
28 . The method of claim 27 , wherein Z is CH 2 .
29 . The method of claim 27 , wherein Z is S.
30 . The method of claim 27 , wherein Z is CHR 1 .
31 . The method of claim 30 , wherein the compound is 2-({1-Oxo-[2-{2′-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine, or a pharmaceutically acceptable salt, ester, or solvate thereof.
32 . The method of claim 1 , wherein the heterocyclic thioester or ketone is a compound of formula III
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B, and C are independently CH 2 , O, S, SO, SO 2 , NH or NR 2 ;
X is O or S;
Z is S, CH 2 , CHR 1 , or CR 1 R 3 ;
R 1 and R 3 are independently C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n , C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with (Ar 1 ) n , C 3 -C 8 cycloalkyl, C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with C 3 -C 8 cycloalkyl, and Ar 2 ;
R 2 is either C 1 -C 9 straight or branched chain alkyl or C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl or Ar 1 , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C 1 -C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, and hydroxy; and
Ar 1 and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O. N, and S.
33 . The method of claim 32 , wherein:
A is CH 2 ; B is CH 2 or S; C is CH 2 or NH; X is C or S; Z is S or CH 2 ; R 1 is 2-phenethyl or 3-phenylpropyl; and R 2 is 1,1-dimethylpropyl.
34 . The method of claim 1 , wherein the heterocyclic thioester or ketone is a compound of formula IV
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B, C and D are independently CH 2 , O, S, SO, SO 2 , NH, or NR 2 ;
X is O or S;
Z is S, CH 2 , CHR 1 , or CR 1 R 3 ;
R 1 and R 3 are independently C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n , C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with (Ar 1 ) n , C 3 -C 8 cycloalkyl, C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with C 3 -C 8 cycloalkyl, and Ar 2 ;
n is 1 or 2;
R 2 is either C 1 -C 9 straight or branched chain alkyl or C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl or Ar 1 , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C 1 -C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, and hydroxy; and
Ar 1 and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.
35 . The method of claim 34 , wherein:
A is CH 2 ; B is CH 2 ; C is S or O; D is CH 2 ; X is O; Z is CH 2 or S; R 1 is 3-phenylpropyl or 2-phenethyl; and R 2 is 1,1-dimethylpropyl.
36 . The method of claim 1 , wherein the heterocyclic thioester or ketone is a compound of formula V
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is C, N, or S;
A and B, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO 2 , N, NH, and NR 4 ;
R 4 is either C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 9 cycloalkyl, C 5 -C 7 cycloalkenyl, or Ar 3 , wherein R 4 is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 4 ;
Ar 3 and Ar 4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and
R 1 , R 2 , W, X, Y, and Z are as defined in claim 5 above.
37 . A pharmaceutical composition which comprises:
(i) an effective amount of a heterocyclic thioester or ketone for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
38 . The pharmaceutical composition of claim 37 , wherein the heterocyclic thioester or ketone is non-immunosuppressive.
39 . The pharmaceutical composition of claim 37 , wherein the heterocyclic thioester or ketone has an affinity for an FKBP-type immunophilin.
40 . The pharmaceutical composition of claim 39 , wherein the FKBP-type immunophilin is FKBP-12.
41 . The pharmaceutical composition of claim 37 , wherein the heterocyclic thioester or ketone is a compound of formula I
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more additional O, S, SO, SO 2 , N, NH, or NR 2 heteroatom(s);
X is either O or S;
Z is either S, CH 2 , CHR 1 or CR 1 R 3 ;
W and Y are independently O, S, CH 2 or H 2 ;
R 1 and R 3 are independently C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n , C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with (Ar 1 ) n , C 3 -C 8 cycloalkyl, C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with C 3 -C 8 cycloalkyl, and Ar 2 ;
n is 1 or 2;
R 2 is either 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 or Ar 1 , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C 1 -C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, and hydroxy; and
Ar 1 and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.
42 . The pharmaceutical composition of claim 41 , wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl, and phenyl.
43 . The pharmaceutical composition of claim 37 , wherein the heterocyclic thioester or ketone is a compound of formula II
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1 or 2;
X is O or S;
Z is selected from the group consisting of S, CH 2 , CHR 1 , and CR 1 R 3 ;
R, and R 3 are independently selected from the group consisting of C 1 -C 5 straight or branched chain alkyl, C 2 -C 5 straight or branched chain alkenyl, and Ar 1 , wherein said alkyl, alkenyl or Ar 1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, nitro, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, hydroxy, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, amino, and Ar 1 ;
R 2 is selected from the group consisting of 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, and Ar n ; and
Ar 1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said Ar 1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, trifluoromethyl, hydroxy, nitro, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino.
44 . The pharmaceutical composition of claim 43 , wherein:
n is 1 and X is O.
45 . The pharmaceutical composition of claim 44 , wherein Z is CH 2 .
46 . The pharmaceutical composition of claim 45 , wherein the compound is selected from the group consisting or:
(2S)-2-({1-Oxo-5-phenyl}-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine; 3,3-Dimethyl-1-[(2S)-2-(5-(3-pyridyl)pentanoyl)-1-pyrrolidine]-1,2-pentanedione; (2S)-2-({1-Oxo-4-phenyl}1-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine; (2S)-2-({1-Oxo-4-phenyl}-butyl-1-(2-cyclohexyl-1,2-dioxoethyl) pyrrolidine; 2-({1-Oxo-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine; 1-{(2S)-2-[5,5-di(4-Fluorophenyl)pentanoyl]-2-pyrrolidine}-3,3-dimethyl-1,2-pentanedione; and pharmaceutically acceptable salts, esters, and solvates thereof.
47 . The pharmaceutical composition of claim 44 , wherein Z is S.
48 . The pharmaceutical composition of claim 47 , wherein the compound is selected from the group consisting of:
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate; (3-Thioindolyl)methyl (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-(1-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)-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)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)tetrahydro-1H-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-(1-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; and pharmaceutically acceptable salts, esters, and solvates thereof.
49 . The pharmaceutical composition of claim 48 , wherein the compound is 3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
50 . The pharmaceutical composition or claim 48 , wherein the compound is 3-(1-Naphthyl)propyl (2S)-1-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
51 . The pharmaceutical composition of claim 48 , wherein the compound is 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)tetrahydro-1H-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
52 . The pharmaceutical composition of claim 48 , wherein the compound is 3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
53 . The pharmaceutical composition of claim 48 , wherein the compound is 3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl-2-pyrrolidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
54 . The pharmaceutical composition of claim 43 , wherein:
n is 1; and X is S.
55 . The pharmaceutical composition of claim 54 , wherein Z is CH 2 .
56 . The pharmaceutical composition of claim 54 , wherein Z is S.
57 . The pharmaceutical composition of claim 43 , wherein:
n is 2; and X is O.
58 . The pharmaceutical composition of claim 57 , wherein Z is CH 2 .
59 . The pharmaceutical composition of claim 58 , wherein the compound is selected from the group consisting of:
2-({1-Oxo-6-phenyl}-hexyl-1-(2-cyclohexyl-1,2-dioxoethyl)piperidine; 3,3-Dimethyl-1-[2-(4-phenylpentanoyl)piperidino]-1,2-pentanedione; and pharmaceutically acceptable salts, esters, and solvates thereof.
60 . The pharmaceutical composition or claim 57 , wherein Z is S.
61 . The pharmaceutical composition of claim 60 , wherein the compound 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-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-mercaptopentyl 1-(3-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-(2-Naphthyl)propyl (2R,S)-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-piperidinecarbothioate; 3-(2-Chlorophenyl)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 pharmaceutically acceptable salts, esters, and solvates thereof.
62 . The pharmaceutical composition of claim 61 , wherein the compound is 3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate or a pharmaceutically acceptable salt, ester, or solvate thereof.
63 . The pharmaceutical composition of claim 43 , wherein:
n is 2; and X is S.
64 . The pharmaceutical composition of claim 63 , wherein Z is CH 2 .
65 . The pharmaceutical composition of claim 63 , wherein Z is S.
66 . The pharmaceutical composition of claim 63 , wherein Z is CHR 1 .
67 . The pharmaceutical composition of claim 66 , wherein the compound is 2-({1-Oxo-[2-{2′-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine.
68 . The pharmaceutical composition of claim 37 , wherein the heterocyclic thioester or ketone is a compound of formula III
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B, and C are independently CH 2 , O, S, SO, SO 2 , NH or NR 2 ;
X is O or S;
Z is S, CH 2 , CHR 1 , or CR 1 R 3 ;
R 1 and R 3 are independently C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n , C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with (Ar 1 ) n , C 3 -C 8 cycloalkyl, C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with C 3 -C 8 cycloalkyl, and Ar 2 ;
R 2 is either C 1 -C 9 straight or branched chain alkyl or C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl or Ar 1 , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C 1 -C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, and hydroxy; and
Ar 1 and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.
69 . The pharmaceutical composition of claim 68 , wherein:
A is CH 2 ; B is CH 2 or S; C is CH 2 or NH; X is O or S; Z is S or CH 2 ; R 1 is 2-phenethyl or 3-phenylpropyl; and R 2 is 1,1-dimethylpropyl.
70 . The pharmaceutical composition of claim 36 , wherein the heterocyclic thioester or ketone is a compound of formula IV
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B, C and D are independently CH 2 , O, S, SO, SO 2 , NH, or NR 2 ;
X is O or S;
Z is S, CH 2 , CHR 1 , or CR 1 R 3 ;
R 1 and R 3 are independently C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar 1 ) n , C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with (Ar 1 ) n , C 3 -C 8 cycloalkyl, C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl substituted with C 3 -C 8 cycloalkyl, and Ar 2 ;
n is 1 or 2;
R 2 is either C 1 -C 9 straight or branched chain alkyl or C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl or Ar 1 , wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C 1 -C 4 straight or branched chain alkyl, C 2 -C 4 straight or branched chain alkenyl, and hydroxy; and
Ar 1 and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.
71 . The pharmaceutical composition of claim 70 , wherein:
A is CH 2 ; B is CH 2 ; C is S or O; D is CH 2 ; X is O; Z is CH 2 or S; R 1 is 3-phenylpropyl or 2-phenethyl; and R 2 is 1,1-dimethylpropyl.
72 . The pharmaceutical composition of claim 37 , wherein the heterocyclic thioester or ketone is a compound of formula V
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is C, N, or S;
A and B, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO 2 , N, NH, and NR 4 ;
R 4 is either C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 9 cycloalkyl, C 5 -C 7 cycloalkenyl, or Ar 3 , wherein R 4 is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 4 ;
Ar 3 and Ar 4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) in-dependently selected from the group consisting of O, N, and S; and
R 1 , R 2 , W, X, Y, and Z are as defined in claim 41 above.Join the waitlist — get patent alerts
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