3,3-disubstituted-oxindole derivatives useful as anticancer...

Details 3,3-disubstituted-oxindole derivatives useful as anticancer... 3,3-disubstituted-oxindole derivatives useful as anticancer...

2000-03-31

2003-07-01

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S314000, C514S333000, C514S339000, C514S397000, C546S142000, C546S152000, C546S256000, C546S275400, C548S312100

Reexamination Certificate

active

06586447

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a series of 3,3-disubstituted-oxindole 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, to pharmaceutical compositions containing such compounds, and to methods of preparing such compounds. Oxindole derivatives alleged to have CNS activity have been described in EP 0311010 B1 and EP 241 006.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To become functional, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as agents to combat tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and 90% pancreatic carcinomas (Kohl et al.,
Science,
Vol. 260, 1834 to 1837, 1993). The compounds of the present invention exhibit activity as inhibitors of the enzyme farnesyl protein transferase and are therefore believed to be useful as anti-cancer and anti-tumor agents. Further, the compounds of the present invention may be active against any tumors that proliferate by virtue of farnesyl protein transferase.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula 1
and to pharmaceutically acceptable salts, prodrugs, and solvates thereof wherein:
n is 0 or 1;
R
1
is C
1
-C
3
alkylpyridyl or C
1
-C
3
alkylimidazolyl;
R
2
is selected from the group consisting of C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
p
(C
6
-C
10
aryl), and —(CH
2
)
p
(4-10 membered unsaturated heterocyclyl), wherein p is an integer from 0 through 3, and wherein any of said R
1
and R
2
groups are optionally substituted with 1 to 3 R
6
groups;
R
3
is —(CH
2
)
m
(1- or 2-adamantyl), C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl),
X
1
, X
2
, and X
3
are each independently C
1
-C
7
alkylene optionally containing 1 or 2 carbon-carbon double bonds, X
4
is a bond or C
1
-
7
alkylene optionally containing 1 or 2 carbon-carbon double or triple bonds, and, in formula (1b), the X
4
moiety is attached to the X
1
moiety at any available carbon in the X
1
moiety,
and each of the foregoing R
3
groups are optionally substituted with an R
5
group and optionally with 1 to 4 R
6
groups,
or R
3
is —(CH
2
)
t
SO
2
R
9
, —(CH
2
)
t
C(O)R
9
, or —(CH
2
)
m
(4-10 membered heterocyclyl) optionally substituted with 1 to 5 R
6
groups;
m, in the aforementioned R
3
groups, is independently an integer from 0 through 6 and t is independently an integer from 1 through 5;
R
4
is C
6
-C
10
aryl or 4-10 membered heterocyclyl, each of said R
4
groups being optionally substituted by 1 to 3 R
6
groups;
each R
5
is independently selected from halo, C
1
-C
6
alkyl optionally substituted by 1 to 3 halo, nitro, cyano, —OR
9
, —C(O)R
9
, SR
9
, —SO
2
R
9
, —SO
3
H, —S(O)R
9
, —NR
7
R
8
, —CH═NOR
7
, —C(O)OR
9
, —OC(O)R
9
, —SO
2
NR
9
R
8
, —C(O)NR
9
R
8
, —NR
8
C(O)R
9
, —OC(O)NR
9
R
8
, —C(O)ONR
7
R
9
, —NR
8
C(O)NR
9
R
8
, —NR
8
C(O)O(C
1
-C
4
alkyl), —C(NR
8
)NR
9
R
8
, —C(NCN)NR
9
R
8
, —C(NCN)S(C
1
-C
4
alkyl or C
1
-C
4
haloalkyl), —NR
8
C(NCN)S(C
1
-C
4
alkyl or C
1
-C
4
haloalkyl), —NR
8
C(NCN)NR
7
R
8
, —NR
8
SO
2
(C
1
-C
4
alkyl or C
1
-C
4
haloalkyl), —NR
8
C(O)C(O)R
8
, —NR
8
C(O)C(O)NR
9
R
8
, —P(O)(OR
7
)
2
, and —CH
2
)
q
(4-10 membered heterocyclyl), each q is independently an integer from 0 through 3, and the alkyl and heterocyclyl moieties of the foregoing R
5
groups are optionally substituted by 1 to 3 R
10
groups;
each R
6
is independently selected from R
5
, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl and —(CH
2
)
t
(C
6
-C
10
aryl) optionally substituted with 1 to 3 R
10
groups, t is an integer from 0 through 3;
each R
7
is independently hydrogen or C
1
-C
4
alkyl optionally substituted by 1 to 3 halo;
each R
8
is independently R
7
or —OR
7
;
each R
9
is independently selected from hydrogen, C
1
-C
6
alkyl, —(CH
2
)
q
(C
6
-C
10
aryl) and —(CH
2
)
q
(4-10 membered heterocyclyl), said R
9
groups, except H, are optionally substituted with 1 to 3 R
10
groups, and each q is independently an integer from 0 through 3; and,
each R
10
is independently selected from halo, nitro, cyano, C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
1
-C
6
haloalkoxy, —C(O)O(C
1
-C
6
alkyl), and C
6
-C
10
aryl.
Preferably, in the compounds of formula 1, each p integer in R
2
is an integer independently selected from 0 to 3, more preferably an integer independently selected from 1 to 3, 1 being most preferred.
Preferred compounds of formula 1 include those wherein one or both of R
1
and R
2
is —(CH
2
)
p
(4-10 membered unsaturated heterocyclyl) optionally substituted with 1 to 3 R
6
groups, more preferably —(CH
2
)
p
(5 or 6 membered unsaturated heterocyclyl). Preferably, each heterocyclyl of R
1
and R
2
is independently imidazolyl or pyridinyl. In different embodiments, one or both R
1
and R
2
is 2-, 3-, or 4-pyridinylmethyl; preferably, one or both of R
1
and R
2
is 4-pyridinylmethyl. In other embodiments, R
1
and R
2
are each independently imidazol-1-ylmethyl, imidazol-2-ylmethyl, or imidazol-4-ylmethyl, optionally substituted with 1 to 3 R
6
groups; preferably, R
1
and R
2
are both imidazol-4-ylmethyl, each optionally substituted with 1 to 3 R
6
groups. When only one of R
1
and R
2
is a —(CH
2
)
p
(4-10 membered unsaturated heterocyclyl) optionally substituted with 1 to 3 R
6
groups, the other of R
1
or R
2
is a C
1
-C
10
alkyl substituted by one R
6
group, wherein the Re group is preferably, —SR
9
; preferably, both of R
1
or R
2
is imidazolyl or pyridinyl, more preferably imidazol-1-ylmethyl, imidazol-2-ylmethyl, imidazol-4-ylmethyl or 4-pyridinylmethyl.
Preferred compounds of formula 1 include those wherein R
3
is —(CH
2
)
m
(1- or 2-adamantyl) or —(CH
2
)
m
(C
6
-C
10
aryl), wherein the aryl group is optionally substituted with 1 to 5 R
6
groups, preferably wherein m is an integer 1. Preferably the aryl group is phenyl or naphthyl and R
6
is R
5
, wherein R
5
is —SO
2
R
9
, —SO
2
NR
9
R
8
, or —C(O)OR
9
, preferably, —SO
2
NR
9
R
8
.
Other preferred compounds of formula 1 include those wherein R
4
is C
6
-C
10
aryl substituted by R
6
, preferably, wherein the R
6
is cyano. Other preferred compounds of formula 1 include those wherein R
4
is C
6
-C
10
aryl substituted by R
6
, wherein the R
6
is preferably halo or formyl, provided that when the R
6
is bromo, then R
3
is substituted by R
5
, wherein R
5
is sulfonamide.
Specific preferred compounds include the following:
4-[6-(4-Cyano-phenyl)-3,3-bis-(1H-imidazol-4-ylmethyl)-2-oxo-2,3-dihydro-indol-1-ylmethyl]-N,N-dimethyl-benzenesulfonamide;
4-[3,3-Bis-(3H-imidazol-4-ylmethyl)-1-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]-benzonitrile;
4-[1-Adamantan-1-ylmethyl-3-(1H-imidazol-4-ylmethyl)-3-(3H-imidazol-4-ylmethyl)-2-oxo-2,3-dihydro-1H-indol-6-yl]-benzonitrile;
4-[3-(1H-imidazol-4-ylmethyl)-3-(3H-imidazol-4-ylmethyl)-2-oxo-1-quinolin-4-ylmethyl-2,3-dihydro-1H-indol-6-yl]-benzonitrile;
4-[6-(4-Formyl-phenyl)-2-oxo-3,3-bis-pyridin-4-ylmethyl-2,3-dihydro-indol-1-ylmethyl]-N,N-dimethyl-benzenesulfonamide;
4-[6-(4-Cyano-phenyl)-2-oxo-3,3-bis-pyridin-4-ylmethyl-2,3-dihydro-indol-1-ylmethyl]-N,N-dimethyl-benzenesul

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