Alkynyl-substituted quinolin-2-one derivatives useful as...

Details Alkynyl-substituted quinolin-2-one derivatives useful as... Alkynyl-substituted quinolin-2-one derivatives useful as...

2001-07-06

2003-06-17

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S157000, C546S158000

Reexamination Certificate

active

06579887

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a series of alkynyl-substituted quinolin-2-one 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.
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 acquire transforming potential, 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 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 anticancer 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:
the dashed line indicates that the bond between C-3 and C-4 of the quinolin-2one ring is a single or double bond;
R
1
is selected from H, C
1
-C
10
alkyl, —(CR
13
R
14
)
q
C(O)R
12
, —(CR
13
R
14
)
q
C(O)OR
15
, —(CR
13
R
14
)
q
OR
12
, —(CR
13
R
14
)
q
SO
2
R
15
, —(CR
13
R
14
)
t
(C
3
-C
10
cycloalkyl), —(CR
13
R
14
)
t
(C
6
-C
10
aryl), and —(CR
13
R
14
)
t
(4-10 membered heterocyclic), wherein t is an integer from 0 to 5 and q is an integer from 1 to 5, said cycloalkyl, 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 4-10 membered heterocyclic group; and the foregoing R
1
groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R
6
groups;
R
2
is halo, cyano, —C(O)OR
15
, or a group selected from the substituents provided in the definition of R
12
;
each R
3
, R
4
, R
5
, R
6
, and R
7
is independently selected from H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, halo, cyano, nitro, mercapto, trifluoromethyl, trifluoromethoxy, azido, —OR
12
, —C(O)R
12
, —C(O)OR
12
, —NR
13
C(O)OR
15
, —OC(O)R
12
, —NR
13
SO
2
R
15
, —SO
2
NR
12
R
13
, —NR
13
C(O)R
12
, —C(O)NR
12
R
13
, —NR
12
R
13
, —CH═NOR
12
, —S(O)
j
R
12
wherein j is an integer from 0 to 2, —(CR
13
R
14
)
t
(C
6
-C
10
aryl), —(CR
13
R
14
)
t
(4-10 membered heterocyclic), —(CR
13
R
14
)
t
(C
3
-C
10
cycloalkyl), and —(CR
13
R
14
)
t
C≡CR
15
, and wherein in the foregoing R
3
, R
4
, R
5
, R
6
, and R
7
groups t is an integer from 0 to 5; the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR
13
SO
2
R
15
, —SO
2
NR
12
R
13
, —C(O)R
12
, —C(O)OR
12
, —OC(O)R
12
, —NR
13
C(O)OR
15
, —NR
13
C(O)R
12
, —C(O)NR
12
R
13
, —NR
12
R
13
, —OR
12
, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CR
13
R
14
)
t
(C
6
-C
10
aryl), and —(CR
13
R
14
)
t
(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
R
8
is H, —OR
12
, —NR
12
R
13
, —NR
12
C(O)R
13
, cyano, —C(O)OR
13
, —SR
12
, —(CR
13
R
14
)
t
(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, or C
1
-C
6
alkyl, wherein said heterocyclic and alkyl moieties are optionally substituted by 1 to 3 R
6
substituents;
R
9
is —(CR
13
R
14
)
t
(imidazolyl) wherein t is an integer from 0 to 5 and said imidazolyl moiety is optionally substituted by 1 or 2 R
6
substituents;
each R
10
and R
11
is independently selected from the substituents provided in the definition of R
6
;
each R
12
is independently selected from H, C
1
-C
10
alkyl, —(CR
13
R
14
)
t
(C
3
-C
10
cycloalkyl), —(CR
13
R
14
)
t
(C
6
-C
10
aryl), and —(CR
13
R
14
)
t
(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said cycloalkyl, aryl and heterocyclic R
12
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R
12
substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R
13
, —C(O)OR
13
, —OC(O)R
13
, —NR
13
C(O)R
14
, —C(O)NR
13
R
14
, —NR
13
R
14
, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
each R
13
and R
14
is independently H or C
1
-C
6
alkyl, and where R
13
and R
14
are as —(CR
13
R
14
)
q
or (CR
13
R
14
)
t
each is independently defined for each iteration of q or t in excess of 1;
R
15
is selected from the substituents provided in the definition of R
12
except R
15
is not H;
R
16
is selected from the list of substituents provided in the definition of R
12
and —SiR
17
R
18
R
19
;
R
17
, R
18
and R
19
are each independently selected from the substituents provided in the definition of R
12
except R
17
, R
18
and R
19
are not H; and
provided that at least one of R
3
, R
4
and R
5
is —(CR
13
R
14
)
t
C≡CR
16
wherein t is an integer from 0 to 5 and R
13
, R
14
, and R
16
are as defined above.
Preferred compounds of formula 1 include those wherein R
1
is H, C
1
-C
6
alkyl, or cyclopropylmethyl; R
2
is H; R
3
is —C≡CR
16
; and R
8
is —NR
12
R
13
, —OR
12
, or a heterocyclic group selected from triazolyl, imidazolyl, pyrazolyl, and piperidinyl, wherein said heterocyclic group is optionally substituted by an R
6
group. More preferred compounds include those wherein R
9
is imidazolyl optionally substituted by C
1
-C
6
alkyl; R
8
is hydroxy, amino, or triazolyl; and R
4
, R
5
, R
10
and R
11
are each independently selected from H and halo.
Other preferred compounds formula 1 include those wherein R
1
is —(CR
13
R
14
)
t
(C
3
-C
10
cycloalkyl) wherein t is an integer from 0 to 3; R
2
is H; R
3
is —C≡CR
16
; and R
8
is —NR
12
R
13
, —OR
12
, or a heterocyclic group selected from triazolyl, imidazolyl, pyrazolyl, and piperidinyl, wherein said heterocyclic group is optionally substituted by an R
6
group. More preferred compounds include those wherein R
9
is imidazolyl optionally substituted by C
1
-C
6
alkyl; R
8
is hydroxy, amino, or triazolyl; R
4
, R
5
, R
10
and R
11
are each independently selected from H and halo; and R
1
is cyclopropylmethyl.
Other preferred compounds formula 1 include those wherein R
3
is ethynyl and the other substituents are as defined above.
Specific preferred compounds include the following:
6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one (enantiomer A);
6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one (enantiomer B);
6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imidazol4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one (enantiomer A);
6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-

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