Farnesyl protein transferase inhibiting...

Details Farnesyl protein transferase inhibiting... Farnesyl protein transferase inhibiting...

1999-07-29

2001-01-02

Seaman, D. Margaret (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S154000, C546S157000, C546S158000

Utility Patent

active

06169096

ABSTRACT:

The present invention is concerned with novel (imidazol-5-yl)methyl-2-quinolinone derivatives, the preparation thereof, pharmaceutical compositions comprising said novel compounds and the use of these compounds as a medicine as well as methods of treatment by administering said 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. A particular group of oncogenes is known as ras which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian ras oncogenes consists of three major members (“isoforms”): H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highly related proteins generically known as p21
ras
. Once attached to plasma membranes, the mutant or oncogenic forms of p21
ras
will provide a signal for the transformation and uncontrolled growth of malignant tumor cells. To acquire this transforming potential, the precursor of the p21
ras
oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, will prevent the membrane attachment of p21
ras
and block the aberrant growth of ras-transformed tumors. Hence, it is generally accepted in the art that farnesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contributes to transformation.
Since 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, 1834-1837, 1993), it has been suggested that farnesyl tranferase inhibitors can be very useful against these types of cancer.
In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substituted quinoline and quinolinone derivatives which suppress the plasma elimination of retinoic acids. Some of these compounds also have the ability to inhibit the formation of androgens from progestines and/or inhibit the action of the aromatase enzyme complex.
Unexpectedly, it has been found that the present novel compounds, all having a phenyl substituent on the 4-position of the 2-quinolinone-moiety and wherein the imidazole moiety is bound via a carbon atom to the rest of the molecule, show farnesyl protein transferase inhibiting activity.
The present invention encompasses compounds of formula (I)
the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond;
X is oxygen or sulfur;
R
1
is hydrogen, C
1-12
alkyl, Ar
1
, Ar
2
C
1-6
alkyl, quinolinylC
1-6
alkyl, pyridylC
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl, aminoC
1-6
alkyl, or a radical of formula —Alk
1
—C(═O)—R
9
, —Alk
1
—S(O)—R
9
or —Alk
1
—S(O)
2
—R
9
,
wherein Alk
1
is C
1-6
alkanediyl,
R
9
is hydroxy, C
1-6
alkyl, C
1-6
alkyloxy, amino, C
1-8
alkylamino or C
1-8
alkylamino substituted with C
1-6
alkyloxycarbonyl;
R
2
, R
3
and R
16
each independently are hydrogen, hydroxy, halo, cyano, C
1-6
alkyl, C
1-6
alkyloxy, hydroxyC
1-6
alkyloxy, C
1-6
alkyloxyC
1-6
alkyloxy, aminoC
1-6
alkyloxy, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyloxy, Ar
1
, Ar
2
C
1-6
alkyl, Ar
2
oxy, Ar
2
C
1-6
alkyloxy, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C
2-6
alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R
2
and R
3
taken together may form a bivalent radical of formula
—O—CH
2
—O—  (a-1),
—O—CH
2
—CH
2
—O—  (a-2),
—O—CH═CH—  (a-3),
 —O—CH
2
—CH
2
—  (a-4),
—O—CH
2
—CH
2
—CH
2
—  (a-5), or
—CH═CH—CH═CH   (a-6);
R
4
and R
5
each independently are hydrogen, halo, Ar
1
, C
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, C
1-6
alkyloxy, C
1-6
alkylthio, amino, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylS(O)C
1-6
alkyl or C
1-6
alkylS(O)
2
C
1-6
alkyl; R
6
and R
7
each independently are hydrogen, halo, cyano, C
1-6
alkyl, C
1-6
alkyloxy, Ar
2
oxy, trihalomethyl, C
1-6
alkylthio, di(C
1-6
alkyl)amino, or when on adjacent positions R
6
and R
7
taken together may form a bivalent radical of formula
—O—CH
2
—O—  (c-1), or
—CH═CH—CH═CH—  (c-2);
R
8
is hydrogen, C
1-6
alkyl, cyano, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylcarbonylC
1-6
alkyl, cyanoC
1-6
alkyl, C
1-6
alkyloxycarbonylC
1-6
alkyl, carboxyC
1-6
alkyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl, imidazolyl, haloC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, aminocarbonylC
1-6
alkyl, or a radical of formula
—O—R
10
  (b-1),
—S—R
10
  (b-2),
—N—R
11
R
12
  (b-3),
wherein R
10
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, Ar
1
, Ar
2
C
1-6
alkyl, C
1-6
alkyloxycarbonylC
1-6
alkyl, or a radical or formula —Alk
2
—OR
13
or —Alk
2
—NR
14
R
15
;
R
11
is hydrogen, C
1-12
alkyl, Ar
1
or Ar
2
C
1-6
alkyl;
R
12
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylaminocarbonyl, Ar
1
, Ar
2
C
1-6
alkyl, C
1-6
alkylcarbonylC
1-6
alkyl, a natural amino acid, Ar
1
carbonyl, Ar
2
C
1-6
alkylcarbonyl, aminocarbonylcarbonyl, C
1-6
alkyloxyC
1-6
alkylcarbonyl, hydroxy, C
1-6
alkyloxy, aminocarbonyl, di(C
1-6
alkyl)aminoC
1-6
alkylcarbonyl, amino, C
1-6
alkylamino, C
1-6
alkylcarbonylamino, or a radical or formula —Alk
2
—OR
13
or —Alk
2
—NR
14
R
15
;
wherein Alk
2
is C
1-6
alkanediyl;
R
13
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, hydroxyC
1-6
alkyl, Ar
1
or Ar
2
C
1-6
alkyl;
R
14
is hydrogen, C
1-6
alkyl, Ar
1
or Ar
2
C
1-6
alkyl;
R
15
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, Ar
1
or Ar
2
C
1-6
alkyl;
R
17
is hydrogen, halo, cyano, C
1-6
alkyl, C
1-6
alkyloxycarbonyl, Ar
1
;
R
18
is hydrogen, C
1-6
alkyl, C
1-6
alkyloxy or halo;
R
19
is hydrogen or C
1-6
alkyl;
Ar
1
is phenyl or phenyl substituted with C
1-6
alkyl, hydroxy, amino, C
1-6
alkyloxy or halo; and
Ar
2
is phenyl or phenyl substituted with C
1-6
alkyl, hydroxy, amino, C
1-6
alkyloxy or halo.
R
4
or R
5
may also be bound to one of the nitrogen atoms in the imidazole ring. In that case the hydrogen on the nitrogen is replaced by R
4
or R
5
and the meaning of R
4
and R
5
when bound to the nitrogen is limited to hydrogen, Ar
1
, C
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylS(O)C
1-6
alkyl, C
1-6
alkylS(O)
2
C
1-6
alkyl.
As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C
1-6
alkyl defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; C
1-8
alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C
1-6
alkyl as well as the higher homologues thereof containing 7 or 8 carbon atoms such as, for example heptyl or octyl; C
1-12
alkyl again encompasses C
1-8
alkyl and the higher homologues thereof containing 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl; C
1-6
alkyl again encompasses C
1-12
alkyl and the higher homologues thereof containing 13 to 16 carbon atoms, such as, for example, tridecyl, tetradecyl, pentedecyl and hexadecyl; C
2-6
alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; C
1-6
alkanediyl define

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