Isothiazole derivatives useful as anticancer agents

Details Isothiazole derivatives useful as anticancer agents Isothiazole derivatives useful as anticancer agents

2001-03-09

2003-04-15

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S326000, C514S254040, C544S367000, C546S209000, C548S213000

Reexamination Certificate

active

06548526

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel isothiazole derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins which are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype. It has been shown that certain tyrosine kinases may be mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Furthermore, the overexpression of a ligand for a tyrosine kinase receptor may result in an increase in the activation state of the receptor, resulting in proliferation of the tumor cells or endothelial cells. Thus, it is believed that inhibitors of receptor tyrosine kinases, such as the compounds of the present invention, are useful as selective inhibitors of the growth of mammalian cancer cells.
It is known that polypeptide growth factors, such as vascular endothelial growth factor (VEGF) having a high affinity to the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor, have been associated with the proliferation of endothelial cells and more particularly vasculogenesis and angiogenesis. See PCT international application publication number WO 95/21613 (published Aug. 17, 1995). Agents, such as the compounds of the present invention, that are capable of binding to or modulating the KDR/FLK-1 receptor may be used to treat disorders related to vasculogenesis or angiogenesis such as diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
Isothiazole derivatives useful as herbicides are referred to in U.S. Pat. Nos. 4,059,433 and 4,057,416, both assigned to FMC Corporation.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula 1
and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
wherein X
1
is 0 or S;
R
1
is H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —C(O)(C
1
-C
10
alkyl), —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(4-10 membered heterocyclic), —C(O)(CH
2
)
t
(C
6
-C
10
aryl), or —C(O)(CH
2
)
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(R
6
)— 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 R
1
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
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 —(CH
2
)
t
— moieties of the foregoing R
1
groups optionally include a carbon—carbon double or triple bond where t is an integer from 2 to 5; and the foregoing R
1
groups, except H, are optionally substituted by 1 to 3 R
4
groups;
R
2
is selected from the list of substituents provided in the definition of R
1
, —SO
2
(CH
2
)
t
(C
6
-C
10
aryl), —SO
2
(CH
2
)
t
(5-10 membered heterocyclic), and —OR
5
, t is an integer ranging from 0 to 5, the —(CH
2
)
t
— moieties of the foregoing R
2
groups optionally include a carbon—carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R
2
groups are optionally substituted by 1 to 3 R
4
groups;
or R
1
and R
2
may be taken together with the nitrogen to which each is attached to form a 4-10 membered saturated monocyclic or polycyclic ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R
6
)— in addition to the nitrogen to which R
1
and R
2
are attached, said —N(R
6
)— is optionally ═N— or —N═ where R
1
and R
2
are taken together as said heteroaryl group, said saturated ring optionally may be partially unsaturated by including 1 or 2 carbon—carbon double bonds, and said saturated and heteroaryl rings, including the R
6
group of said —N(R
6
)—, are optionally substituted by 1 to 3 R
4
groups;
R
3
is H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
t
(C
6
-C
10
aryl), or —(CH
2
)
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(R
6
)— 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 R
3
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
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 —(CH
2
)
t
— moieties of the foregoing R
3
groups optionally include a carbon—carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R
3
groups are optionally substituted by 1 to 5 R
4
groups;
each R
4
is independently selected from C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR
5
, —C(O)R
5
, —C(O)OR
5
, —NR
6
C(O)OR
5
, —OC(O)R
5
, —NR
6
SO
2
R
5
, —SO
2
NR
5
R
6
, —NR
6
C(O)R
5
, —C(O)NR
5
R
6
, —NR
5
R
6
, —S(O)
j
R
7
wherein j is an integer ranging from 0 to 2, —SO
3
H, —NR
5
(CR
6
R
7
)
t
OR
6
, —(CH
2
)
t
(C
6
-C
10
aryl), —SO
2
(CH
2
)
t
(C
6
-C
10
aryl), —S(CH
2
)
t
(C
6
-C
10
aryl), —O(CH
2
)
t
(C6-C
10
aryl), —(CH
2
)
t
(5-10 membered heterocyclic), and —(CR
6
R
7
)
m
OR
6
, 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(R
6
)— 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 R
4
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
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 R
4
groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR
6
SO
2
R
5
, —SO
2
NR
5
R
6
, —C(O)R
5
, —C(O)OR
5
, —OC(O)R
5
, —NR
5
C(O)R
5
, —C(O)NR
5
R
6
, —NR
5
R
6
, —(CR
6
R
7
)
m
OR
6
wherein m is an integer from 1 to 5, —OR
5
and the substituents listed in the definition of R
5
;
each R
5
is independently selected from H, C
1
-C
10
alkyl, —(CH
2
)
t
(C
6
-C
10
aryl), and —(CH
2
)
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(R
6
)— 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 R
5
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 5-10 membered heterocyclic group; and the foregoing R
5
subsituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R
6
, —C(O)OR
6
, —CO(O)R
6
, —NR
6
C(O)R
7
, —C(O)NR
6
R
7
, —NR
6
R
7
, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy; and,
each R
6
and R
7
is

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