1,2-annelated quinoline derivatives

Details 1,2-annelated quinoline derivatives 1,2-annelated quinoline derivatives

2001-08-29

2002-10-01

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S082000, C546S084000, C514S293000, C514S292000, C544S251000

Reexamination Certificate

active

06458800

ABSTRACT:

The present invention is concerned with novel 1,2-annelated quinoline 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 p
21
ras
oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzymes that catalyzes this modification, i.e. farnesyl transferase, will prevent the membrane attachment of p
21
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.
The K-ras B isoform has been observed to be the dominant isoform which is mutated in human cancers, particular in colon (50% incidence) and pancreatic (90% incidence) cancers. However, it was also found that ras protein activation in the K-ras B isoform transformed cancers is resistant to inhibition of farnesyl transferase. The isoform confers resistance to farnesyl transferase inhibitors, but makes this isoform also substrate for geranylgeranyl transferase I. Therefore, inhibitors of geranylgeranyl transferase may inhibit the aberrant growth of K-ras transformed tumors which are resistant to famesyl transferase inhibitors.
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.
In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, there are described 2-quinolone derivatives which exhibit farnesyl transferase inhibiting activity.
Unexpectedly, it has been found that the present novel 1,2-annelated quinoline compounds, bearing a nitrogen- or carbon-linked imidazole, show farnesyl protein transferase and geranylgeranyl transferase inhibiting activity.
The present invention concerns compounds of formula
or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
═X
1
—X
2
—X
3
— is a trivalent radical of formula
═N—CR
6
═CR
7
— (x-1),
═N—N═CR
6
— (x-2),
═N—NH—C(═O)— (x-3),
═N—N═N— (x4),
═N—CR
6
═N— (x-5),
═CR
6
—CR
7
═CR
8
— (x-6),
═CR
6
—N═CR
7
— (x-7),
═CR
6
—NH—C(═O)— (x-8), or
═CR
6
—N═N— (x-9);
 wherein each R
6
, R
7
and R8 are independently hydrogen, C
1-4
alkyl, hydroxy, C
1-4
alkyloxy, aryloxy, C
1-4
alkyloxycarbonyl, hydroxyC
1-4
alkyl, C
1-4
alkyloxyC
1-4
alkyl, mono- or di(C
1-4
alkyl)aminoC
1-4
alkyl, cyano, amino, thio, C
1-4
alkylthio, arylthio or aryl;
>Y
1
—Y
2
— is a trivalent radical of formula
>CH—CHR
9
— (y-1),
>C═N— (y-2),
>CH—NR
9
— (y-3), or
>C═CR
9
— (y-4);
 wherein each R
9
independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyC
1-4
alkyl, cyano, carboxyl, C
1-4
alkyl, C
1-4
alkyloxy, C
1-4
alkyloxyC
1-4
alkyl, C
1-4
alkyloxycarbonyl, mono- or di(C
1-4
alkyl)amino, mono- or di(C
1-4
alkyl)aminoC
1-4
alkyl, aryl;
r and s are each independently 0, 1, 2, 3, 4 or 5;
t is 0, 1, 2 or 3;
each R
1
and R
2
are independently hydroxy, halo, cyano, C
1-6
alkyl trihalomethyl, trihalomethoxy, C
2-6
alkenyl, C
1-6
alkyloxy, hydroxyC
1-6
alkyloxy, C
1-6
alkylthio, C
1-6
alkyloxyC
1-6
alkyloxy, C
1-6
alkyloxycarbonyl, aminoC
1-6
alkyloxy, mono- or di(C
1-6
alkyl)amino, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyloxy, aryl, arylC
1-6
alkyl, aryloxy or arylC
1-6
alkyloxy, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, aminocarbonyl, aminoC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminocarbonyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl; or
two R
1
or R
2
substituents adjacent to one another on the phenyl ring may independently form together 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
3
is hydrogen, halo, C
1-6
alkyl, cyano, haloC
1-6
alkyl, hydroxyC
1-6
alkyl, cyanoC
1-6
alkyl, aminoC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, C
1-6
alkylthioC
1-6
alkyl, aminocarbonylC
1-6
alkyl, hydroxycarbonyl, hydroxycarbonylC
1-6
alkyl, C
1-6
alkyloxycarbonylC
1-6
alkyl, C
1-6
alkylcarbonylC
1-6
alkyl, C
1-6
alkyloxycarbonyl, aryl, arylC
1-6
alkyloxyC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl;
or a radical of formula
—O—R
10
(b-1),
—S—R
10
(b-2),
—NR
11
R
12
(b-3),
wherein R
10
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, aryl, arylC
1-6
alkyl, C
1-6
alkyloxycarbonylC
1-6
alkyl, or a radical of formula -Alk-OR
3
or -Alk—NR
14
R
15
;
R
11
is hydrogen, C
1-6
alkyl, aryl or arylC
1-6
alkyl;
R
12
is hydrogen, C
1-6
alkyl, aryl, hydroxy, amino, C
1-6
alkyloxy, C
1-6
alkylcarbonylC
1-6
alkyl, arylC
1-6
alkyl, C
1-6
alkylcarbonylamino, mono- or di(C
1-6
alkyl)amino, C
1-6
alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloC
1-6
alkylcarbonyl, arylC
1-6
alkylcarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkyloxyC
1-6
alkylcarbonyl, mono- or di(C
1-6
alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or C
1-3
alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkylcarbonyl, or a radical or formula -Alk-OR
13
or -Alk—NR
14
R
15
;
 wherein Alk is C
1-6
alkanediyl;
R
13
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, hydroxyC
1-6
alkyl, aryl or arylC
1-6
alkyl;
R
14
is hydrogen, C
1-6
alkyl, aryl or arylC
1-6
alkyl;
R
15
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, aryl or arylC
1-6
alkyl;
R
4
is a radical of formula
wherein R
16
is hydrogen, halo, aryl, C
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, C
1-6
alkyloxy, C
1 6
alkylthio, amino, mono- or di(C
1-4
alkyl)amino, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylthioC
1-6
alkyl, C
1-6
alkylS(O)C
1-6
alkyl or C
1-6
alkylS(O)
2
C
1-6
alkyl;
R
16
may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R
16
when bound to the nitrogen is limited to hydrogen, aryl, 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 or C
1-6
alkylS(O)
2
C
1-6
alkyl;
R17 is hydrogen, C
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, arylC
1-6
alkyl, trifluoromethyl or di(C
1-4
alkyl)aminosulfonyl;
R
5
is C
1-6
alkyl , C
1-6
alkyloxy or halo;
aryl is phenyl, naphthalenyl or phenyl substituted with 1 or

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