Isothiazole derivatives useful as anticancer agents
First Claim
Patent Images
1. A compound of the formula or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein,X1 is O or S;
- R1 is —
(CH2)t(4-5 membered heterocyclic), wherein t is an integer from 0 to 5;
said heterocyclic group is optionally fused to a C6-C10aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group; and
said R1 group, including the optionally fused portions of said R1 group, is optionally substituted by 1 or 2 substituents independently selected from C1-C4 alkyl, hydroxy and hydroxymethyl;
R2 is H;
R3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —
(CH2)t(C6-C10 aryl), or —
(CH2)t(5-10 membered heterocyclic), wherein t is an integer from 0 to 5;
said alkyl group optionally include 1 or 2 hetero moieties selected from O, S and —
N(R6)—
with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
said aryl and heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group;
1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═
O) moiety;
the —
(CH2)t—
moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4 groups;
each R4 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —
OR5, —
C(O)R5, —
C(O)OR5, —
NR6C(O)OR5, —
OC(O)R5, —
NR6SO2R5, —
SO2NR5R6, —
NR6C(O)R5, —
C(O)NR5R6, —
NR5R6, —
S(O)jR7 wherein j is an integer ranging from 0 to 2, —
SO3H, —
NR5(CR6R7)tOR6, —
(CH2)t(C6-C10 aryl), —
SO2(CH2)t(C6-C10 aryl), —
S(CH2)t(C6-C10 aryl), —
O(CH2)t(C6-C10 aryl), —
(CH2)t(5-10 membered heterocyclic), and —
(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5;
said alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —
N(R6)—
with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
said aryl and heterocyclic R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group;
1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═
O) moiety; and
the alkyl, aryl and heterocyclic moieties of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —
NR6SO2R5, —
SO2NR5R6, —
C(O)R5, —
C(O)OR5, —
OC(O)R5, —
NR6C(O)R5, —
C(O)NR5R6, —
NR5R6, —
(CR6R7)mOR6 wherein m is an integer from 1 to 5, —
OR5 and the substituents listed in the definition of R5;
each R5 is independently selected from H, C1-C10 alkyl, —
(CH2)t(C6-C10 aryl), and —
(CH2)t(5-10 membered heterocyclic), wherein t is an integer from 0 to 5;
said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —
N(R6)—
with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
said aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group; and
the foregoing R5 subsituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —
C(O)R6, —
C(O)OR6, —
CO(O)R6, —
NR6C(O)R7, —
C(O)NR6R7, —
NR6R7, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; and
each R6 and R7 is independently H or C1-C6 alkyl.
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Abstract
The present invention relates to compounds of the formula 1
and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein X1, R1, R2 and R3 are as defined herein. The invention also relates to pharmaceutical compositions containing the above compounds and to methods treating hyperproliferative disorders in mammals by administering the above compounds.
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Citations
23 Claims
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1. A compound of the formula
or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein, X1 is O or S; -
R1 is —
(CH2)t(4-5 membered heterocyclic), wherein t is an integer from 0 to 5;
said heterocyclic group is optionally fused to a C6-C10aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group; and
said R1 group, including the optionally fused portions of said R1 group, is optionally substituted by 1 or 2 substituents independently selected from C1-C4 alkyl, hydroxy and hydroxymethyl;
R2 is H;
R3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —
(CH2)t(C6-C10 aryl), or —
(CH2)t(5-10 membered heterocyclic), wherein t is an integer from 0 to 5;
said alkyl group optionally include 1 or 2 hetero moieties selected from O, S and —
N(R6)—
with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
said aryl and heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group;
1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═
O) moiety;
the —
(CH2)t—
moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4 groups;
each R4 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —
OR5, —
C(O)R5, —
C(O)OR5, —
NR6C(O)OR5, —
OC(O)R5, —
NR6SO2R5, —
SO2NR5R6, —
NR6C(O)R5, —
C(O)NR5R6, —
NR5R6, —
S(O)jR7 wherein j is an integer ranging from 0 to 2, —
SO3H, —
NR5(CR6R7)tOR6, —
(CH2)t(C6-C10 aryl), —
SO2(CH2)t(C6-C10 aryl), —
S(CH2)t(C6-C10 aryl), —
O(CH2)t(C6-C10 aryl), —
(CH2)t(5-10 membered heterocyclic), and —
(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5;
said alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —
N(R6)—
with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
said aryl and heterocyclic R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group;
1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═
O) moiety; and
the alkyl, aryl and heterocyclic moieties of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —
NR6SO2R5, —
SO2NR5R6, —
C(O)R5, —
C(O)OR5, —
OC(O)R5, —
NR6C(O)R5, —
C(O)NR5R6, —
NR5R6, —
(CR6R7)mOR6 wherein m is an integer from 1 to 5, —
OR5 and the substituents listed in the definition of R5;
each R5 is independently selected from H, C1-C10 alkyl, —
(CH2)t(C6-C10 aryl), and —
(CH2)t(5-10 membered heterocyclic), wherein t is an integer from 0 to 5;
said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —
N(R6)—
with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
said aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 5-10 membered heterocyclic group; and
the foregoing R5 subsituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —
C(O)R6, —
C(O)OR6, —
CO(O)R6, —
NR6C(O)R7, —
C(O)NR6R7, —
NR6R7, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; and
each R6 and R7 is independently H or C1-C6 alkyl. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)
mesylate salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido}-isothiazole-4-carboxylic acid amide;
hydrochloride salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl)-pentyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido-}-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(3,4-dihydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(2,5-Difluoro-4-methyl-benzyloxy)-5-{3-[4-(3-hydroxy-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl]-ureido]-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylic acid amide;
5-[3-(4-Pyrrolidin-1-yl-butyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-[3-(3-Hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-{3-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-butyl]-ureido}-isothiazole-4-carboxylic acid amide;
5-{3-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-ureido}-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
5-[3-(3-Pyrrolidin-1-yl-propyl)-ureido]-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,6-difluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(3-hydroxy-5-pyrrolidin-1-yl-pentyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-{3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-isothiazole-4-carboxylic acid amide;
3-(4-Bromo-2,3,6-trifluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide;
3-(4-Chloro-2,3,6-trifluoro-benzyloxy)-5-[3-(4-imidazol-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide; and
3-(2,6-Difluoro-4-methyl-benzyloxy)-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylic acid amide; and
the pharmaceutically acceptable salts, prodrugs and solvates of said compounds.
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11. The compound of claim 9, wherein said compound is the hydrochloride salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide.
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12. The compound of claim 9, wherein said compound is the mesylate salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide.
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13. A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
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14. The pharmaceutical composition of claim 13 wherein said hyperproliferative disorder is a cancer selected from brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesophageal, gynecological and thyroid cancer.
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15. The pharmaceutical composition of claim 13 wherein said disorder is a non-cancerous hyperproliferative disorder.
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16. The pharmaceutical composition of claim 15 wherein said disorder is a benign hyperplasia of the skin or prostate.
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17. The pharmaceutical composition of claim 13, wherein said compound is the hydrochloride salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide.
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18. The pharmaceutical composition of claim 13, wherein said compound is the mesylate salt of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide.
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19. A method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound according to claim 1.
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20. The method of claim 19 wherein said method is for the treatment of a cancer selected from brain, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, lung, renal, kidney, ovarian, gynecological and thyroid cancer.
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21. The method of claim 20 wherein said method is for the treatment of a non-cancerous hyperproliferative disorder.
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22. The method of claim 21 wherein said method is for the treatment of a benign hyperplasia of the skin or prostate.
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23. A method for the treatment of a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound according to claim 1 in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, NK1 receptor antagonist, 5-HT3 receptor antagonist, COX-2 inhibitor, an EGFR inhibitor, and anti-androgens.
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10. 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide, or a pharmaceutically acceptable salt of said compound, or a prodrug of said compound or said pharmaceutically acceptable salt of said compound.
Specification