Methods of using thiazolidinedithione derivatives
Methods of using thiazolidinedithione derivatives to treat cancer, neurodegenerative disease, diabetes, renal disease or inflammation in a mammal and pharmaceutical compositions containing such derivatives are disclosed.
1 - 23 . (canceled)
24 . A pharmaceutical composition useful in treating cancer or inflammation in a human, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (I):
wherein:
R is heterocyclyl;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl; and
each R 7 is independently hydrogen, alkyl or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a solvate or polymorph; or as a pharmaceutically acceptable salt thereof;
provided, however, that when R 1 and R 2 are both hydrogen, R can not be unsubstituted thien-2-yl.
25 . The pharmaceutical composition of claim 24 wherein the compound of formula (I) is a compound of formula (Ia):
wherein:
p is 0 to 3;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
R 3 is —O— or —S—;
each R 4 is independently selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —R 8 —N═N—O—R 7 , —OR 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )C(O)R 6 , —N(R 6 )C(O)OR 7 , —S(O) t R 6 (where t is 0 to 2), —S(O) t N(R 6 ) 2 (where t is 0 to 2), —C(O)R 6 , —N(R 6 )C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , or —N(R 6 )S(O) t R 6 (where t is 0 to 2), heterocyclyl and heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl;
each R 7 is independently hydrogen, alkyl or aralkyl; and
R 8 is a direct bond or an optionally substituted straight or branched alkylene or alkenylene chain.
26 . The pharmaceutical composition of claim 25 wherein the compound of formula (I) is a compound of formula (Ia) wherein:
p is 1;
R 1 is hydrogen, alkyl, or aralkyl;
R 2 is hydrogen or alkyl;
R 3 is —O— or —S—; and
R 4 is halo, haloalkyl, or haloalkoxy.
27 . A compound of formula (I):
wherein:
R is heterocyclyl;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl; and
each R 7 is independently hydrogen, alkyl or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a solvate or polymorph; or as a pharmaceutically acceptable salt thereof;
provided, however, that when R 1 and R 2 are both hydrogen, R can not be unsubstituted thien-2-yl; and
provided, however, that when R 1 and R 2 are both hydrogen; R can not be unsubstituted furan-2-yl; 3-nitrofuran-2-yl, 4-nitrofuran-2-yl or 4-bromofuran-2-yl.
28 . The compound of claim 27 of the formula (Ia):
wherein:
p is 0 to 3;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
R 3 is —O— or —S—;
each R 4 is independently selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —R 8 —N═N—O—R 7 , —OR 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )C(O)R 6 , —N(R 6 )C(O)OR 7 , —S(O) t R 6 (where t is 0 to 2), —S(O) t N(R 6 ) 2 (where t is 0 to 2), —C(O)R 6 , —N(R 6 )C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , or —N(R 6 )S(O) t R 6 (where t is 0 to 2), heterocyclyl and heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl;
each R 7 is independently hydrogen, alkyl or aralkyl; and
R 8 is a direct bond or an optionally substituted straight or branched alkylene or alkenylene chain.
29 . A method of treating cancer in a mammal, which method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I):
wherein:
R is heterocyclyl;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl; and
each R 7 is independently hydrogen, alkyl or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a solvate or polymorph; or as a pharmaceutically acceptable salt thereof.
30 . The method of claim 29 wherein the compound of formula (I) is a compound of formula (Ia):
wherein:
p is 0 to 3;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
R 3 is —O— or —S—;
each R 4 is independently selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —R 8 —N═N—O—R 7 , —OR 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )C(O)R 6 , —N(R 6 )C(O)OR 7 , —S(O) t R 6 (where t is 0 to 2), —S(O) t N(R 6 ) 2 (where t is 0 to 2), —C(O)R 6 , —N(R 6 )C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , or —N(R 6 )S(O) t R 6 (where t is 0 to 2), heterocyclyl and heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl;
each R 7 is independently hydrogen, alkyl or aralkyl; and
R 8 is a direct bond or an optionally substituted straight or branched alkylene or alkenylene chain.
31 . The method of claim 30 wherein the mammal is a human.
32 . The method of claim 31 wherein the cancer is associated with hyperproliferation or tissue remodelling or repair.
33 . The method of claim 32 wherein the cancer is associated with the activity of an enzyme selected from the group consisting of PTPN12, PTPN2, PRKD2, and GSK3β.
34 . The method of claims 29 - 33 wherein the compound of formula (I) is a compound of formula (Ia) wherein:
p is 1;
R 1 is hydrogen, alkyl, or aralkyl;
R 2 is hydrogen or alkyl;
R 3 is —O— or —S—; and
R 4 is halo, haloalkyl, or haloalkoxy.
35 . A method of treating inflammation in a mammal, which method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I):
wherein:
R is heterocyclyi;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 5 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl; and
each R 7 is independently hydrogen, alkyl or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a solvate or polymorph; or as a pharmaceutically acceptable salt thereof.
36 . The method of claim 35 wherein the compound of formula (I) is a compound of formula (Ia):
wherein:
p is 0 to 3;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
R 3 is —O— or —S—;
each R 4 is independently selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —R 8 —N═N—O—R 7 , —OR 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )C(O)R 6 , —N(R 6 )C(O)OR 7 , —S(O) t R 6 (where t is 0 to 2), —S(O) t N(R 6 ) 2 (where t is 0 to 2), —C(O)R 6 , —N(R 6 )C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , or —N(R 6 )S(O) t R 6 (where t is 0 to 2), heterocyclyl and heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl;
each R 7 is independently hydrogen, alkyl or aralkyl; and
R 8 is a direct bond or an optionally substituted straight or branched alkylene or alkenylene chain.
37 . The method of claim 36 wherein the mammal is a human.
38 . The method of claim 37 wherein the inflammation is associated with hyperproliferation or tissue remodelling or repair.
39 . The method of claim 38 wherein the inflammation is associated with the activity of an enzyme selected from the group consisting of PTPN12, PTPN2, PRKD2, and GSK3β.
40 . The method of claims 36 - 39 wherein the compound of formula (I) is a compound of formula (Ia) wherein:
p is 1;
R 1 is hydrogen, alkyl, or aralkyl;
R 2 is hydrogen or alkyl;
R 3 is —O— or —S—; and
R 4 is halo, haloalkyl, or haloalkoxy.
41 . A method of treating a mammal having a disorder or condition associated with hyperproliferation and tissue remodelling or repair, wherein said method comprises administering to the mammal having the disorder or condition a therapeutically effective amount of a compound of formula (I):
wherein:
R is heterocyclyl;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl; and
each R 7 is independently hydrogen, alkyl or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a solvate or polymorph; or as a pharmaceutically acceptable salt thereof.
42 . The method of claim 41 wherein the compound of formula (I) is a compound of formula (Ia):
wherein:
p is 0 to 3;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
R 3 is —O— or —S—;
each R 4 is independently selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —R 8 —N═N—O—R 7 , —OR 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )C(O)R 6 , —N(R 6 )C(O)OR 7 , —S(O) t R 6 (where t is 0 to 2), —S(O) t N(R 6 ) 2 (where t is 0 to 2), —C(O)R 6 , —N(R 6 )C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , or —N(R 6 )S(O) t R 6 (where t is 0 to 2), heterocyclyl and heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl;
each R 7 is independently hydrogen, alkyl or aralkyl; and
R 8 is a direct bond or an optionally substituted straight or branched alkylene or alkenylene chain.
43 . A method of treating a mammalian cell with a compound of formula (I):
wherein:
R is heterocyclyl;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl; and
each R 7 is independently hydrogen, alkyl or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a solvate or polymorph; or as a pharmaceutically acceptable salt thereof;
wherein the method comprises administering the compound of formula (I) to a mammalian cell and the compound of formula (I) is capable of inhibiting the activity of PTPN12, PTPN2, PRKD2, and/or GSK3β within the mammalian cell.
44 . The method of claim 43 wherein the compound of formula (I) is a compound of formula (Ia):
wherein:
p is 0 to 3;
R 1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heterocyclylalkyl, —R 5 —O—R 6 , —R 5 —N(R 6 ) 2 , —R 5 —C(O)OR 6 , —R 5 —C(O)N(R 6 ) 2 , —R 5 —N═N—OR 7 , or —R 5 —N(R 6 )C(O)OR 7 ;
R 2 is hydrogen, alkyl, aralkyl, aryl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
R 3 is —O— or —S—;
each R 4 is independently selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, —R 8 —N═N—O—R 7 , —OR 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )C(O)R 6 , —N(R 6 )C(O)OR 7 , —S(O) t R 6 (where t is 0 to 2), —S(O) t N(R 6 ) 2 (where t is 0 to 2), —C(O)R 6 , —N(R 6 )C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , or —N(R 6 )S(O) t R 6 (where t is 0 to 2), heterocyclyl and heterocyclylalkyl;
each R 5 is independently an optionally substituted straight or branched alkylene or alkenylene chain;
each R 6 is independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl;
each R 7 is independently hydrogen, alkyl or aralkyl; and
R 8 is a direct bond or an optionally substituted straight or branched alkylene or alkenylene chain.
45 . The method of claim 41 wherein the mammalian cell is treated in vitro.
46 . The method of claim 41 wherein the mammalian cell is treated in vivo.
47 . The method of claim 41 wherein the inhibition of activity results in a reduction of cell adhesion.
48 . The method of claim 41 wherein the inhibition of activity results in a reduction of cell division.
49 . The method of claim 41 , wherein the inhibition of activity results in a reduction of cell migration.
50 . The method of claim 41 , wherein the inhibition of activity results in control of tumor growth.
51 . The method of claim 41 wherein the inhibition of activity results in control of lymphocyte activation.
52 - 56 . (canceled)