Imidazolidin-4-one derivatives useful as anticancer agents

Details Imidazolidin-4-one derivatives useful as anticancer agents Imidazolidin-4-one derivatives useful as anticancer agents

1999-04-30

2001-01-16

Kight, John (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S274400

Reexamination Certificate

active

06174903

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a series of novel imidazolidin-4-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.
Compounds that are useful in the treatment of hyperproliferative diseases are also disclosed in the following co-pending patent applications: PCT international patent application number PCT/IB97/00675, which designates the United States and was filed on Jun. 11, 1997; U.S. provisional patent application Ser. No. 60/041846 (filed Apr. 9, 1997); U.S. provisional patent application Ser. No. 60/031862 (filed Nov. 27, 1996); U.S. provisional patent application Ser. No. 60/028881 (filed Oct. 17, 1996); PCT international patent application number PCT/IB97/00584, which designates the United States and was filed on May 22, 1997; U.S. patent application Ser. No. 08/653,786 (filed May 28, 1996); PCT international patent application publication number WO 96/40142, which designates the United States and was published on Dec. 19, 1996; PCT international patent application publication number WO 97/13771, which designates the United States and was published on Apr. 17, 1997; PCT international patent application publication number WO 95/23141, which designates the United States and was published on Aug. 31, 1995; U.S. provisional patent application number 60/020696 (filed Jun. 27, 1996); International Patent Application PCT/US92/11292, which designates the United States and was published on Jul. 22, 1993 as WO 93/14085; U.S. Patent 4,876,259, which issued on Oct. 24, 1989; International Patent Application PCT/IB95/00189, which designates the United States and was filed on Mar. 20, 1995; U.S. patent application Ser. No. 08/236,743, which was filed on Apr. 29, 1994.
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 anti-cancer and anti-tumor agents.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula 1
and to pharmaceutically acceptable salts and solvates thereof, wherein:
Z is —(CH
2
)
n
-(imidazol-1-yl) wherein n is 1 or 2 or Z is a group of the formula
R is pyridin-4-yl or a group of the formula
R
1
and R
2
are each independently selected from the group consisting of H, C
1
-C
10
alkyl, —OR
6
, —C(O)(C
1
-C
10
alkyl), —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(5-10 membered heterocyclic), —C(O)(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
O(CH
2
)
j
(C
6
-C
10
aryl), —C(O)(CH
2
)
t
(5-10 membered heterocyclic), —SO
2
(CH
2
)
t
(C
6
-C
10
aryl), or —SO
2
(CH
2
)
t
(5-10 membered heterocyclic), wherein j is an integer ranging from 0 to 2, t is an integer ranging from 0 to 5, the —(CH
2
)
t
— moieties of the foregoing R
1
and R
2
groups optionally include a carbon-carbon double or triple bond where t is an integer between 2 and 5, and the foregoing R
1
and R
2
groups, other than H, are optionally substituted by 1 to 3 R
5
substituents;
R
3
is —(CH
2
)
m
(1- or 2-adamantyl), —(CH
2
)
m
(C
6
-C
10
aryl), C
1
-C
15
alkyl,
wherein m is an integer ranging from 0 to 6;
X
1
, X
2
, and X
3
are each independently C
1
-C
7
alkylene optionally containing 1 or 2 double or triple bonds where said alkylene contains at least two carbon atoms, X
4
is a bond or C
1
-C
7
alkylene optionally containing 1 or 2 double or triple bonds where said alkylene contains at least two carbon atoms, and, in formula 3, the X
4
moiety is attached to the X
1
moiety at any available carbon in the X
1
moiety's alkylene chain;
R
4
is C
1
-C
6
alkyl, —(CH
2
)
t
(C
6
-C
10
aryl), or —(CH
2
)
t
(5-10 membered heterocyclic), wherein said t is an integer ranging from 0 to 5 and said R
4
groups are optionally substituted by 1 to 3 R
5
substituents;
each R
5
is independently selected from the group consisting of halo, nitro, cyano, —C(O)OR
5
, —SO
2
NR
6
R
8
, —NR
6
R
8
, —C(O)R
6
, —OR
6
, —C(O)NR
6
R
6
R
8
, —OC(O)NR
6
R
8
, —NR
8
C(O)NR
8
R
6
, —NR
8
C(O)R
6
, —NR
8
C(O)O(C
1
-C
6
alkyl), —C(NR
8
)NR
8
R
6
, —C(NCN)NR
8
R
6
, —C(NCN)S(C
1
-C
6
alkyl), —NR
8
C(NCN)S(C
1
-C
6
alkyl), —NR
8
C(NCN)NR
8
R
6
, —NR
8
SO
2
(C
1
-C
6
alkyl), —S(O)
n
(C
1
-C
6
alkyl) wherein n is an integer ranging from 0 to 2,—NR
8
C(O)C(O)NR
8
R
6
, —NR
8
C(O)C(O)R
8
, —SO
2
(C
6
-C
10
aryl), —SO
2
(5-10 membered heterocyclic), C
6
-C
10
aryl, 5-10 membered heterocyclic, and C
1
-C
4
alkyl optionally substituted by 1 to 3 fluoro substituents, wherein the aryl and heterocyclic moieties of said C
6
-C
10
aryl, 5-10 membered heterocyclic, —SO
2
(C
6
-C
10
aryl) and —SO
2
(5-10 membered heterocyclic) groups are optionally substituted by 1 or 2 groups independently selected from halo, nitro, cyano, —C(O)OR
6
, —SO
2
NR
6
R
8
, —NR
6
R
8
, —C(O)R
6
, —OR
6
, and —S(O)
n
(C
1
-C
6
alkyl) wherein n is 0 to 2;
each R
6
is independently hydrogen or C
1
-C
6
alkyl;
each R
7
is independently selected from cyano, —OR
6
,—OC(O)R
6
, —C(O)OR
6
, —C(O)NR
6
R
8
, —NR
6
R
8
, —SO
2
NR
6
R
8
, and C
1
-C
6
alkyl optionally substituted by hydroxy or up to three halo groups; and,
each R
8
is independently R
6
or —OR
6
.
Preferred compounds of formula 1 include those wherein Z is a group of the formula
R is a group of the formula
and R
1
and R
2
are each independently selected from H and C
1
-C
6
alkyl.
Other preferred compounds formula 1 include those wherein R
3
is a moiety of formula 2 or 3. More preferred are those compounds in which R
3
is 2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl.
Other preferred compounds of formula 1 include those wherein R
4
is phenyl optionally substituted by 1 to 3 R
5
substituents.
Specific preferred compounds include the following:
4-{[4,4-Bis-(1H-imidazol-4-ylmethyl)-5-oxo-1-((−)-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl))-imidazolidin-2-ylidene]-acetyl}-benzonitrile;
4-{[4,4-Bis-(3-methyl-3H-imidazol-4-ylmethyl)-5-oxo-1-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl)-imidazolidin-2-ylidene]-acetyl}-benzonitrile;
4-{[4,4-Bis-(1H-imidazol-4-ylmethyl)-5-oxo-1-((+)-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl))-imidazolidin-2-ylidene]-acetyl}-benzonitrile;
4-{[4-(2-Imidazol-1-yl-ethyl)-5-oxo-4-pyridin-4-ylmethyl-1-((+)-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl))-imidazolidin-2-ylidene]-acetyl}-benzonitrile;
4-{[1-Adamantan-1-ylmethyl-4,4-bis-(3-methyl-3H-imidazol-4-ylmethyl)-5-oxo-imidazolidin-2-ylidene]-acetyl}-benzonitrile;
and the pharmaceutically acceptable salts and solvates of the foregoing compounds.
This invention also relates to a method of inhibiting abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 1,

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