Farnesyltransferase inhibiting quinazolinones

Details Farnesyltransferase inhibiting quinazolinones Farnesyltransferase inhibiting quinazolinones

2000-10-13

2002-03-19

Goldberg, Jerome D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S274000

Reexamination Certificate

active

06358961

ABSTRACT:

The present invention is concerned with novel quinazolinone 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.
Genetic research has led to the identification of a variety of gene families in which mutations can lead to the development of a wide variety of tumors. A particular group of genes, known as ras, have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian ras genes consists of three major members (“isoforms”): H-ras, K-ras and N-ras genes. These ras genes code for highly related proteins generically known as p21
ras
. These p21
ras
proteins comprise a family of proteins that regulate cell growth when bound to the inner surface of the plasma membrane. However, overproduction of p21
ras
proteins, or mutations of said ras genes thereby coding for mutant or oncogenic forms of p21
ras
proteins, lead to uncontrolled cell division. In order to regulate cell growth, the ras proteins need to be attached to the inner leaflet of the plasma membranes. If mutated or oncogenic forms of p21
ras
, the p21
ras
as oncoproteins, become attached to plasma membranes, they provide a signal for the transformation of normal cells to tumor cells and promote their uncontrolled growth. 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 or 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 transferase inhibitors can be very useful against these types of cancer.
EP-0,371,564 discloses (1H-azol-1-ylmethyl) substituted quinoline, quinazoline and quinoxaline 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.
It has been found that the present novel compounds, all having a phenyl substituent on the 4-position of the 2-quinazolinone-moiety bearing a carbon or nitrogen-linked imidazolyl moiety, show faesyl 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;
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
1
, Ar
1
C
1-6
alkyl, Ar
1
oxy or Ar
1
C
1-6
alkyloxy;
R
3
and R
4
each independently are hydrogen, halo, cyano, C
1-6
alkyl, C
1-6
alkyloxy, Ar
1
oxy, C
1-6
alkylthio, di(C
1-6
alkyl)amino, trihalomethyl or trihalomethoxy;
R
5
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, 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
1
, Ar
1
C
1-6
alkyloxyC
1-6
alkyl; or a radical of formula
—O—R
10
  (a-1),
—S—R
10
  (a-2),
—N—R
11
R
12
  (a-3),
 wherein
R
10
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, Ar
1
, Ar
1
C
1-6
alkyl, C
1-6
alkyloxycarbonylC
1-6
alkyl, or a radical of formula -Alk-OR
13
or -Alk-NR
14
R
15
;
R
11
is hydrogen, C
1-6
alkyl, Ar
1
or Ar
1
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
1
C
1-6
alkyl, C
1-6
alkylcarbonyl-C
1-6
alkyl, Ar
1
carbonyl, Ar
1
C
1-6
alkylcarbonyl, aminocarbonylcarbonyl, C
1-6
alkyloxyC
1-6
alkylcarbonyl, hydroxyl, 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
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, Ar
1
or Ar
1
C
1-6
alkyl;
R
14
is hydrogen, C
1-6
alkyl, Ar
1
or Ar
1
C
1-6
alkyl;
R
15
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, Ar
1
or Ar
1
C
1-6
alkyl;
R
6
is a radical of formula
 wherein
R
16
is 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, 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
17
is hydrogen, C
1-6
alkyl or di(C
1-4
alkyl)aminosulfonyl;
R
7
is hydrogen or C
1-6
alkyl provided that the dotted line does not represent a bond;
R
8
is hydrogen, C
1-6
alkyl or Ar
2
CH
2
or Het
1
CH
2
;
R
9
is hydrogen, C
1-6
alkyl, C
1-6
alkyloxy or halo; or
R
8
R
9
taken together to form a bivalent radical of formula
—CH═CH—  (c-1),
—CH
2
—CH
2
—  (c-2),
—CH
2
—CH
2
—CH
2
—  (c-3),
—CH
2
—O—  (c-4),
or
—CH
2
—CH
2
—O—  (c-5);
Ar
l
is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C
1-6
alkyl, C
1-6
alkyloxy or trifluoromethyl;
Ar
2
is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C
1-6
alkyl, C
1-6
alkyloxy or trifluoromethyl; and
Het
1
is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, C
1-b
alkyl, C
1-6
alkyloxy or trifluoromethyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
1-2
alkyl defines methyl or ethyl; C
1-4
alkyl includes C
1-2
alkyl and the higher homologues thereof having 3 to 4 carbon atoms such as e.g. 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-methyl-butyl, hexyl, 2-methylpentyl and the like; 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 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, 1,4butanediyl, 1,5-pentanediyl, 1,6-hexane-diyl and the branched isomers thereof. 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 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 example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (ie. butane-dioic acid), maleic, fumaric, malic, tartaric, citric, meth

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