Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-28
2003-07-22
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, C514S311000, C546S159000, C546S169000, C546S173000, C546S168000, C546S170000
Reexamination Certificate
active
06596735
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a series of quinoline 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, incorporated herein in its entirety by reference). 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.
Other compounds that are indicated as having activity inhibiting farnesyl protein transferase are referred to in International Publication Number WO 97/21701, entitled “Farnesyl Protein Transferase Inhibiting (Imidazol-5-yl)methyl-2-quinolinone Derivatives”, which has an International Publication Date of Jun. 19, 1997; in International Publication Number WO 97/16443, entitled “Farnesyl Transferase Inhibiting 2-Quinolone Derivatives”, which has an International Publication Date of May 9, 1997; U.S. Provisional Application No. 60/098,136, filed Aug. 27, 1998, entitled “Quinolin-2-one Derivatives Useful as Anticancer Agents”; U.S. Provisional Application No. 60/098,145, filed Aug. 27, 1998, entitled “Alkynyl-Substituted Quinolin-2-one Derivatives Useful as Anticancer Agents”; and U.S. Provisional Application No. 60/119,702, filed Feb. 11, 1999; all of which are incorporated herein by reference in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula 1
and to pharmaceutically acceptable salts and solvates thereof wherein:
Y is —(CR
13
R
14
)
n
— or —NR
13
—, wherein n is zero, 1 or 2;
R
1
is H, —(CR
13
R
14
)—O—(C
1
-C
6
)alkyl, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, cyano, —C(O)NR
13
R
14
, —C(O)R
13
, —C(O)OR
13
, —OC(O)R
13
, —C(O)NR
13
R
14
, C
3
-C
8
cycloalkyl, phenyl, or —(4 to 6 membered heterocyclic); and wherein when Y is —(CR
13
R
14
)
n
— then R
1
can be further selected from —NR
13
R
14
, nitro, hydroxy, and azido; and wherein alkyl, cycloalkyl, phenyl, and heterocyclic moieties of the aforementioned R
1
substituents are optionally substituted with from one to three halogens;
R
2
is H, halo, cyano, R
11
or —C(O)OR
11
, wherein cycloalkyl, aryl and heterocyclic moieties of said R
2
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4 to 10 membered heterocyclic group, and wherein the foregoing R
2
groups, except H, halo, and cyano, but including any optional fused rings, 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
3
, R
4
, R
5
, R
6
, and R
7
is independently selected from H, R
11
, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxy, —OR
11
, —C(O)H, —C(O)OH, —C(O)R
11
, —C(O)OR
11
, —NR
13
C(O)OR
11
, —OC(O)H, —OC(O)R
11
, —NR
13
SO
2
R
11
, —SO
2
NHR
13
, —SO
2
NR
11
R
13
, —NR
13
C(O)H, —NR
13
C(O)R
11
, —C(O)NR
13
H, —C(O)NR
11
R
13
, —NHR
13
, —NR
11
R
13
, —CH═NOH, —CH═NOR
11
, —S(O)
j
H, —S(O)
j
R
11
, wherein j is an integer from 0 to 2, —(CR
13
R
14
)
t
C≡CH, —(CR
13
R
14
)
t
C═CR
11
, —(CR
13
R
14
)
t
C≡CSiH
2
(R
11
), —(CR
13
R
14
)
t
C≡CsiH(R
11
)
2
, and —(CR
13
R
14
)
t
C≡CSi(R
11
)
3
; and wherein alkyl, alkenyl, cycloalkyl, aryl, and heterocyclic moieties of the foregoing R
3
, R
4
, R
5
, R
6
, and R
7
groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR
13
SO
2
(C
1
-C
6
alkyl), —SO
2
NR
13
R
14
, —C(O)H, —C(O)(C
1
-C
6
alkyl), —C(O)OH, —C(O)O(C
1
-C
6
alkyl), —OC(O)H, —OC(O)(C
1
-C
6
alkyl), —NR
13
C(O)O(C
1
-C
6
alkyl), —NR
13
C(O)H, —NR
13
C(O)(C
1
-C
6
alkyl), —C(O)NR
13
R
14
, —NR
13
R
14
, hydroxy, C
1
-C
6
alkoxy, 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), —(CR
13
R
14
)
t
(C
3
-C
10
cycloalkyl), and —(CR
13
R
14
)
t
(4 to 10 membered heterocyclic);
R
8
is H, cyano, hydroxy, —(CR
13
R
14
)
t
(4 to 10 membered heterocyclic), —OR
11
, —OC(O)H, —OC(O)R
11
, —NR
13
H, —NR
11
R
13
, —NR
13
C(O)H, —C(O)OH, —C(O)OR
11
, —SH, or —SR
11
, wherein heterocyclic groups of said R
8
groups are optionally substituted by 1 to 4 R
6
groups;
R
9
is —(CR
13
R
14
)
t
(imidazolyl) or —(CR
13
R
14
)
t
(pyridinyl), wherein said imidazolyl or pyridinyl moiety is optionally substituted by 1 or 2 R
6
substituents;
R
10
is phenyl or an aromatic 4 to 10 membered heterocyclic group, and said R
10
group is optionally substituted by 1 to 4 R
6
substituents;
each R
11
is independently 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), or (CR
13
R
14
)
t
(4 to 10 membered heterocyclic);
each R
13
and R
14
is independently H or C
1
-C
3
alkyl;
and each t is an integer independently selected from 0 through 4.
In one embodiment, this invention provides compounds of formula 1, wherein R
10
is phenyl optionally substituted by 1 to 4 R
6
substituents.
In another embodiment, this invention provides compounds of formula 1 wherein Y is —NR
13
— or wherein n is zero.
In another embodiment, this invention provides compounds of formula 1 wherein —Y—R
1
is cyano or —C(O)NR
13
R
14
.
In another embodiment, this invention provides compounds of formula 1 wherein —Y—R
1
is —C(O)NH
2
.
In another embodiment, this invention provides, compounds of formula 1 wherein —Y—R
1
is —C(O)OR
13
.
In another embodiment, this invention provides, compounds of formula 1 wherein —Y—R
1
is —NR
13
R
14
.
In another embodiment, this invention provides compounds of formula 1 wherein —Y—R
1
is hydrogen.
In another embodiment, this invention provides compounds of formula 1 wherein —Y—R
1
is methyl.
In another embodiment, this invention provides compounds of formula 1, wherein —Y—R
1
is —CH═CH
2
.
In another embodiment, this invention provides compounds of formula 1 wherein R
8
is hydrogen, methyl or —CH═CH
2
.
In another embodiment, this invention provides compounds of formula 1 wherein R
8
is hydrogen, hydroxy, —NR
13
H, or —NR
11
R
13
.
The structures of preferred compounds of the invention are set forth in the following Table 1:
TABLE 1
Y—R
1
R
8
Me
OH
Me
NH
2
Vinyl
OH
—CN
OH
—CN
NH
2
—CONH
2
OH
—CONH
2
NH
2
—CONHMe
OH
—CONMe
2
OH
NH
2
OH
NHMe
OH
NMe
2
OH
NHEt
OH
In Table 1, “Et” represents an ethyl moiety, and “Me” represents a methyl moiety.
This invention also relates to a method of inhibiting abnormal cell growth in a mammal, including a human, comprising administering to sa
Banerjee Krishna G.
Ginsburg Paul H.
Huang Evelyn Mei
Pfizer Inc
Richardson Peter C.
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