Methods of using isothiazole derivatives to treat cancer or inflammation
Methods of using substituted 3,5-dithio-, disulfinyl-or disulfonyl-isothiazole derivatives to treat cancer or inflammation in a mammal and pharmaceutical compositions containing such derivatives are disclosed.
1 .- 14 . (canceled)
15 . 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 (II):
wherein:
each t is independently 0, 1 or 2;
R 1 and R 3 are each independently alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkoxyalkenyl, —R 4 —N═N—O—R 5 , —N(R 6 ) 2 or heterocyclylalkyl;
R 2 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, halo, haloalkyl, haloalkenyl, nitro, —R 4 —N═N—O—R 5 , —OR 6 , —C(O)OR 6 , —N(R 6 ) 2 , —C(O)N(R 6 ) 2, —N(R 6 )C(O)OR 5 , —N(R 6 ) C(O)N(R 6 ) 2 , heterocyclyl or heterocyclylalkyl;
R 4 is a bond or a straight or branched alkylene or alkenylene chain;
each R 5 is independently hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl; and
each R 6 is independently hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl;
provided that when t is 0 and R 1 and R 3 are both methyl, R 2 can not be —C(O)OH, —C(O)NH 2 , carboxymethyl or unsubstituted phenyl;
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.
16 . The pharmaceutical composition of claim 15 wherein the R 1 substituent of the compound of formula (II) is alkyl or alkenyl.
17 . The pharmaceutical composition of claim 15 wherein the R 1 substituent of the compound formula (II) is aryl, aralkyl or aralkenyl.
18 . The pharmaceutical composition of claim 15 wherein the R 1 substituent of the compound formula (II) is cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl.
19 . The pharmaceutical composition of claim 15 wherein the R 1 substituent of the compound of formula (II) is haloalkyl, haloalkenyl, haloalkoxyalkyl or haloalkoxyalkenyl.
20 . The pharmaceutical composition of claim 15 wherein the R 1 substituent of the compound of of formula (II) is —R 4 —N═N—O—R 5 .
21 . The pharmaceutical composition of claim 15 wherein the R 1 substituent of the compound of of formula (II) is —N(R 6 )2.
22 . The pharmaceutical composition of claim 15 wherein the R 1 substituent of the compound of formula (II) is heterocyclylalkyl.
23 . The pharmaceutical composition of claim 15 wherein the R 2 substituent of the compound of formula (II) is hydrogen, alkyl or alkenyl.
24 . The pharmaceutical composition of claim 15 wherein the R 2 substituent of the compound of formula (II) is aryl, aralkyl or aralkenyl.
25 . The pharmaceutical composition of claim 15 wherein the R 2 substituent of the compound of formula (II) is cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl.
26 . The pharmaceutical composition of claim 15 wherein the R 2 substituent of the compound of formula (II) is halo, haloalkyl or haloalkenyl.
27 . The pharmaceutical composition of claim 15 wherein the R 2 substituent of the compound of formula (II) is nitro or —R 4 —N═N—O—R 5 .
28 . The pharmaceutical composition of claim 15 wherein the R 2 substituent of the compound of formula (II) is —OR 6 .
29 . The pharmaceutical composition of claim 15 wherein the R 2 substituent of the compound of formula (II) is —C(O)OR 6 .
30 . The pharmaceutical composition of claim 15 wherein the R 2 substituent of the compound of formula (II) is —N(R 6 ) 2 .
31 . The pharmaceutical composition of claim 15 wherein the R 2 substituent of the compound of formula (II) is —C(O)N(R 6 ) 2 or —N(R 6 )C(O)OR 5 .
32 . The pharmaceutical composition of claim 15 wherein the R 2 substituent of the compound of formula (II) is heterocyclyl or heterocyclylalkyl.
33 . The pharmaceutical composition of claim 15 wherein t is 0.
34 . The pharmaceutical composition of claim 15 wherein t is 1.
35 . The pharmaceutical composition of claim 15 wherein t is 2.
36 . A method of treating cancer, inflammation or a hyperproliferative disorder in a mammal, which method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I):
wherein:
each t is independently 0, 1 or 2;
R 1 and R 3 are each independently alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkoxyalkenyl, —R 4 —N═N—O—R 5 , —N(R 6 ) 2 or heterocyclylalkyl;
R 2 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, —R 4 —N═N—O—R 5 , —OR 6 , —C(O)OR 6 , —N(R 6 ) 2 , —C(O)N(R 6 ) 2 ,—N(R 6 )C(O)OR 5 , —N(R 6 )C(O)N(R 6 ) 2 , heterocyclyl or heterocyclylalkyl;
R 4 is a bond or a straight or branched alkylene or alkenylene chain;
each R 5 is independently hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl; and
each R 6 is independently hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl;
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.
37 . (canceled)
38 . The method according to claim 36 wherein the cancer, inflammation or hyperproliferative disorder is associated with tissue remodelling or repair.
39 . The method according to claim 36 wherein the cancers, inflammation or hyperproliferative disorder is associated with the activity of PTPN12.
40 . (canceled)
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:
each t is independently 0, 1 or 2;
R 1 and R 3 are each independently alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkoxyalkenyl, —R 4 —N═N—O—R 5 , —N(R 6 ) 2 or heterocyclylalkyl;
R 2 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, —R 4 —N═N—O—R 5 , —OR 6 , —C(O)OR 6 , —N(R 6 ) 2 , —C(O)N(R 6 ) 2 , —N(R 6 )C(O)OR 5 , —N(R 6 )C(O)N(R 6 ) 2 , heterocyclyl or heterocyclylalkyl;
R 4 is a bond or a straight or branched alkylene or alkenylene chain;
each R 5 is independently hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl; and
each R 6 is independently hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl;
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 according to claim 41 wherein the mammal is a human.
43 . A method of treating a mammalian cell with a compound of formula (I):
wherein:
each t is independently 0, 1 or 2;
R 1 and R 3 are each independently alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkoxyalkenyl, —R 4 —N═N—O—R 5 , —N(R 6 ) 2 or heterocyclylalkyl;
R 2 is hydrogen, alkyl alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, —R 4 —N═N—O—R 5 , —OR 6 , —C(O)OR 6 , —N(R 6 ) 2 , —C(O)N(R 6 ) 2, —N(R 6 )C(O)OR 5 , —N(R 6 )C(O)N(R 6 ) 2 , heterocyclyl or heterocyclylalkyl;
R 4 is a bond or a straight or branched alkylene or alkenylene chain;
each R 5 is independently hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl; and
each R 6 is independently hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl;
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 within the mammalian cell.
44 . The method of claim 43 wherein the mammalian cell is treated in vitro.
45 . The method of claim 43 wherein the mammalian cell is treated in vivo.
46 . The method of claim 43 wherein the inhibition of activity results in a reduction of cell adhesion.
47 . The method of claim 43 wherein the inhibition of activity results in a reduction of cell division.
48 . The method of claim 43 , wherein the inhibition of activity results in a reduction of cell migration.
49 . The method of claim 43 , wherein the inhibition of activity results in control of tumor growth.
50 . The method of claim 43 wherein the inhibition of activity results in control of lymphocyte activation.
51 . The method of claim 36 wherein the R 1 substituent of the compound of formula (I) is alkyl or alkenyl.
52 . The method of claim 36 wherein the R 1 substituent of the compound of formula (I) is aryl, aralkyl or aralkenyl.
53 . The method of claim 36 wherein the R 1 substituent of the compound of formula (I) is cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl.
54 . The method of claim 36 wherein the R 1 substituent of the compound of formula (I) is haloalkyl, haloalkenyl, haloalkoxyalkyl or haloalkoxyalkenyl.
55 . The method of claim 36 wherein the R 1 substituent of the compound of formula (I) is —R 4 —N═N—O—R 5 .
56 . The method of claim 36 wherein the R 1 substituent of the compound of formula (I) is —N(R 6 ) 2 .
57 . The method of claim 36 wherein the R 1 substituent of the compound of formula (I) is heterocyclylalkyl.
58 . The method of claim 36 wherein the R 2 substituent of the compound of formula (I) is hydrogen, alkyl or alkenyl.
59 . The method of claim 36 wherein the R 2 substituent of the compound of formula (I) is aryl, aralkyl or aralkenyl.
60 . The method of claim 36 wherein the R 2 substituent of the compound of formula (I) is cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl.
61 . The method of claim 36 wherein the R 2 substituent of the compound of formula (I) is halo, haloalkyl or haloalkenyl.
62 . The method of claim 36 wherein the R 2 substituent of the compound of formula (I) is nitro or —R 4 —N═N—O—R 5 .
63 . The method of claim 36 wherein the R 2 substituent of the compound of formula (I) is —OR 6 .
64 . The method of claim 36 wherein the R 2 substituent of the compound of formula (I) is —C(O)OR 6 .
65 . The method of claim 36 wherein the R 2 substituent of the compound of formula (I) is —N(R 6 ) 2 .
66 . The method of claim 36 wherein the R 2 substituent of the compound of formula (I) is —C(O)N(R 6 ) 2 or —N(R 6 )C(O)OR 5 .
67 . The method of claim 36 wherein the R 2 substituent of the compound of formula (I) is heterocyclyl or heterocyclylalkyl.
68 . The method of claim 36 wherein t is 0.
69 . The method of claim 36 wherein t is 1.
70 . The method of claim 36 wherein t is 2.