Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-02
2001-02-27
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S256000, C548S265800, C548S265800, C514S341000
Reexamination Certificate
active
06194438
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a series of novel derivatives of 2-(2-oxo-ethylidene)-imidazolidin-4-one. The compounds exhibit activity as inhibitors of the enzyme farnesyl protein transferase and are believed to be useful as anti-cancer and anti-tumor agents. This invention also relates to methods of using such compounds in the treatment or prevention of cancer in a mammal, in particular a human, and to pharmaceutical compositions comprising such compounds.
Other compounds that inhibit farnesyl protein transferase and are believed to be useful as anti-cancer and anti-tumor agents are referred to in U.S. patent application 08/863,514, entitled “Adamantyl Substituted Oxindoles as Pharmaceutical Agents”, filed Apr. 27, 1997, and PCT/IB97/00584, entitled “Derivatives of 2-(2-Oxo-Ethylidene)-Imidazolidin-4-one”, designating the United States, filed May 22, 1997. United States Provisional Application 60/065,097, entitled “Thienopyrimidine and Thienopyridine Derivatives Useful as Anticancer Agents”, filed Nov. 11, 1997, also refers to compounds which are believed to be useful as agents for treating cancer and other hyperproliferative diseases, for example psoriasis. The foregoing patent applications are incorporated herein by reference in their entireties.
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 anticancer agents for 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 may be active against any tumors that proliferate by virtue of farnesyl protein transferase.
The preceding Kohl et al. publication, as well as all other references discussed below in this application, are also hereby incorporated by reference in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the Formula I
and to pharmaceutically acceptable salts thereof, wherein:
R
1
and R
2
are each independently 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, or R
1
and R
2
form a C
3
-C
6
cycloalkyl ring, and wherein any of said R
1
and R
2
groups are optionally substituted with 1 to 3 R
6
groups, provided that when R
1
and R
2
form a C
3
-C
6
cycloalkyl ring, said C
3
-C
6
cycloalkyl ring is substituted with at least one R
6
selected from C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, and —(CH
2
)
t
(C
6
-C
10
aryl wherein t is an integer from 1 to 3;
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 or triple bonds, X
4
is a bond or C
1
-C
7
alkylene optionally containing 1 or 2 carbon-carbon double or triple bonds, and, in Formula (Ib), the X
4
moiety is attached to the X
1
moiety at any available carbon in the X
1
moiety, each of the foregoing R
3
groups are substituted with an R
5
group and optionally with 1 to 4 R
6
groups;
or R
3
is —SO
2
R
9
, —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′ groups is independently an integer from 0 through 6; and R
4
is C
6
-C
10
aryl, 4-10 membered heterocyclyl, or C
1
-C
6
alkyl, 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 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
, —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), q is 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
7
is independently selected from R
5
, C
1
-C
6
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl and —(CH
2
)
t
(C
6
-C
10
aryl), such as phenyl or naphthyl, optionally substituted with 1 to 3 R
10
groups, t being 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
alkoxy, C
1
-C
6
haloalkoxy, —C(O)O(C
1
-C
6
alkyl), and C
6
-C
10
aryl;
with the proviso that R
1
and R
2
are not both simultaneously C
1
-C
10
alkyl.
Preferably in the compounds of Formula 1, each p integer in R
1
and 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 I 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 of 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 subsituted with 1 to 3 R
6
groups; preferably, R
1
and R
2
are both imidazol-4-ylmethyl, each optionally subsituted with 1 to 3 R
6
groups, for example R
1
and R
2
are both 3-methyl-imidazol-4-ylmethyl or unsubstituted imidazol-4-ylmethyl.
Other preferred compounds of Formula I include those wherein one or both of R
1
and R
2
is C
1
-C
10
alkyl, C
2
-C
10
alkenyl, or C
2
-C
10
alkynyl, optionally substituted with 1 to 3 R
6
groups, provided that R
1
and R
2
are not both simultaneously C
1
-C
10
alkyl. For example, one or both of R
1
and R
2
can be allyl, 3-methyl-but-2-enyl, or 3-chloro-but-2-enyl.
When R
9
is a —(CH
2
)
q
(4-10 membered heterocyclyl) group, the heterocyclyl ring of R
9
preferably has 5 or 6 members in its ring. Said 5 or 6 membered heterocyclyl may, however, be substituted with 1 to 3 R
10
groups as defined above. When R
9
is a —(CH
2
)
q
(C
6
-C
10
aryl) group, the aryl ring of R
9
preferably is phenyl or naphthyl, which may be substituted with 1 to 3 R
10
groups as defined above.
Other preferred compounds of Formula I include those wherein R
3
is —(CH
2
)
m
(4-10 membered heterocyclyl)
Lyssikatos Joseph P.
Yang Bingwei V.
Aulakh C. S.
Ginsburg Paul H.
Myers Jeffrey N.
Pfizer Inc.
Richardson Peter C.
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