Intermediate compounds in the preparation of farnnesyl...

Details Intermediate compounds in the preparation of farnnesyl... Intermediate compounds in the preparation of farnnesyl...

2000-11-29

2002-09-03

Huang, Evelyn Mei (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen in the nitrogen containing substituent

C544S032000, C546S094000, C546S089000, C546S084000, C546S082000, C546S080000, C514S291000, C514S292000, C514S294000, C514S230200, C514S224200

Reexamination Certificate

active

06444812

ABSTRACT:

The present invention is concerned with novel 1,8-annelated 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 1,8-annelated 2-quinolinone-moiety bearing a nitrogen- or carbon-linked imidazole, show farnesyl protein transferase inhibiting activity.
The present invention concerns compounds of formula
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
the dotted line represents an optional bond;
X is oxygen or sulfur;
—A— is a bivalent radical of formula
—CH═CH—
(a-1),
—CH
2
—S—
(a-6),
—CH
2
—CH
2
—
(a-2),
—CH
2
—CH
2
—S—
(a-7),
—CH
2
—CH
2
—CH
2
—
(a-3),
—CH═N—
(a-8),
—CH
2
—O—
(a-4),
—N═N—
(a-9), or
—CH
2
—CH
2
—O—
(a-5),
—CO—NH—
(a-10);
 wherein optionally one hydrogen atom may be replaced by C
1-4
alkyl or Ar
1
;
R
1
and R
2
each independently are hydrogen, hydroxy, halo, cyano, C
1-6
alkyl, trihalomethyl, trihalomethoxy, C
2-6
alkenyl, C
1-6
alkyloxy, hydroxyC
1-6
alkyloxy, C
1-6
alkyloxyC
1-6
alkyloxy, C
1-6
alkyloxycarbonyl, aminoC
1-6
alkyloxy, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyloxy, Ar
2
, Ar
2
—C
1-6
alkyl, Ar
2
-oxy, Ar
2
—C
1-6
alkyloxy; or when on adjacent positions R
1
and R
2
taken together may form a bivalent radical of formula
—O—CH
2
—O—
(b-1),
—O—CH
2
—CH
2
—O—
(b-2),
—O—CH═CH—
(b-3),
—O—CH
2
—CH
2
—
(b-4),
—O—CH
2
—CH
2
—CH
2
—
(b-5), or
—CH═CH—CH═CH—
(b-6);
R
3
and R
4
each independently are hydrogen, halo, cyano, C
1-6
alkyl, C
1-6
alkyloxy, Ar
3
-oxy, C
1-6
alkylthio, di(C
1-6
alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R
3
and R
4
taken together may form a bivalent radical of formula
—O—CH
2
—O—
(c-1),
—O—CH
2
—CH
2
—O—
(c-2), or
—CH═CH—CH═CH—
(c-3);
R
5
is a radical of formula
 wherein
R
13
is hydrogen, halo, Ar
4
, C
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, C
1-6
alkyloxy, C
1-6
alkylthio, amino, 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
14
is hydrogen, C
1-6
alkyl or di(C
1-4
alkyl)aminosulfonyl;
R
6
is hydrogen, hydroxy, 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, C
1-6
alkyloxycarbonylC
1-6
alkyl, C
1-6
alkylcarbonyl-C
1-6
alkyl, C
1-6
alkyloxycarbonyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl, Ar
5
, Ar
5
—C
1-6
alkyloxyC
1-6
alkyl; or a radical of formula
—O—R
7
(e-1),
—S—R
7
(e-2),
—N—R
8
R
9
(e-3),
 wherein
R
7
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, Ar
6
, Ar
6
—C
1-6
alkyl, C
1-6
alkyloxycarbonylC
1-6
alkyl, or a radical of formula -Alk-OR
10
or -Alk-NR
11
R
12
;
R
8
is hydrogen, C
1-6
alkyl, Ar
7
or Ar
7
—C
1-6
alkyl;
R
9
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylaminocarbonyl, Ar
8
, Ar
8
—C
1-6
alkyl, C
1-6
alkylcarbonyl-C
1-6
alkyl, Ar
8
-carbonyl, Ar
8
—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-OR
10
or -Alk-NR
11
R
12
;
wherein Alk is C
1-6
alkanediyl;
R
10
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, hydroxyC
1-6
alkyl, Ar
9
or Ar
9
—C
1-6
alkyl;
R
11
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, Ar
10
or Ar
10
—C
1-6
alkyl;
R
12
is hydrogen, C
1-6
alkyl, Ar
11
or Ar
11
—C
1-6
alkyl; and
Ar
1
to Ar
11
are each independently selected from phenyl; or phenyl substituted with halo, C
1-6
alkyl, C
1-6
alkyloxy or trifluoromethyl.
R
13
may also be bound to one of the nitrogen atoms in the imidazole ring of formula (d-1). In that case the meaning of R
13
when bound to the nitrogen is limited to hydrogen, Ar
4
, 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.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C
1-6
alkyl includes C
1-4
alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C
1-6
alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof; 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. The term “S(O)” refers to a sulfoxide and “S(O)
2
” to a sulfon.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for e

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