Tricyclic carbamate compounds useful for inhibition of...

Details Tricyclic carbamate compounds useful for inhibition of... Tricyclic carbamate compounds useful for inhibition of...

1999-07-07

2001-10-09

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S093000, C544S361000

Reexamination Certificate

active

06300338

ABSTRACT:

BACKGROUND
International Publication Number WO92/11034, published Jul. 9, 1992, discloses a method of increasing the sensitivity of a tumor to an antineoplastic agent, which tumor is resistant to the antineoplastic agent, by the concurrent administration of the antineoplastic agent and a potentiating agent of the formula:
wherein the dotted line represents an optional double bond, X′ is hydrogen or halo, and Y′ is hydrogen, substituted carboxylate or substituted sulfonyl. For example, Y′ can be, amongst others, —COOR′ wherein R′ is C1 to C6 alkyl or substituted alkyl, phenyl, substituted phenyl, C7 to C12 aralkyl or substituted aralkyl or -2, -3, or -4 piperidyl or N-substituted piperidyl. Y′ can also be, amongst others, SO
2
R′ wherein R′ is C1 to C6 alkyl, phenyl, substituted phenyl, C7 to C12 aralkyl or substituted aralkyl. Examples of such potentiating agents include 11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines such as Loratadine.
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 anticancer agents for 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).
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
SUMMARY OF THE INVENTION
Inhibition of farnesyl protein transferase by tricyclic compounds of this invention has not been reported previously. Thus, this invention provides a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras. One compound disclosed in this invention has been demonstrated to have anti-tumor activity in animal models.
This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
Compounds useful in the claimed methods are represented by Formula 1.0:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of a, b, c and d represents N or NR
9
wherein R
9
is O—, —CH
3
or —(CH
2
)
n
CO
2
H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR
1
or CR
2
;
each R
1
and each R
2
is independently selected from H, halo, —CF
3
, —OR
10
(e.g. —OH), —COR
10
, —SR
10
, —N(R
10
)
2
, —NO
2
, —OC(O)R
10
, —CO
2
R
10
, —OCO
2
R
11
, benzotriazol-1-yloxy, CN, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, —OR
10
or —CO
2
R
10
;
R
3
and R
4
are the same or different and each independently represents H, any of the substituents of R
1
and R
2
, or R
3
and R
4
together can represent a saturated or unsaturated C
5
-C
7
fused ring to the benzene ring (Ring III);
R
5
, R
6
, R
7
and R
8
each independently represents H, —CF
3
, alkyl or aryl, said alkyl or aryl optionally being substituted with —OR
10
, —SR
10
, —N(R
10)
2
, —NO
2
, —COR
10
, —OCOR
10
, —OCO
2
R
11
, —CO
2
R
10
, OPO
3
R
10
or one of R
5
, R
6
, R
7
and R
8
can be taken in combination with R as defined below to represent —(CH
2
)
r
— wherein r is 1 to 4 which can be substituted with lower alkyl, lower alkoxy, —CF
3
or aryl;
R
10
represents H, alkyl, aryl, or aralkyl (preferably benzyl);
R
11
represents alkyl or aryl;
R
16
and R
18
represent H and F respectively, or F and H respectively, when the bond to X is a single bond and X is carbon, preferably R
16
is F and R
18
is H; or
R
16
and R
18
each represent H when the bond to X is a single bond;
X represents N or C, which C may contain an optional double bond (represented by the dotted line) to carbon atom 11;
the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent —R
10
, halo, —OR
11
, —OCO
2
R
11
or —OC(O)R
10
, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H
2
, —(OR
11
)
2
; H and halo, dihalo, alkyl and H, (alkyl)
2
, —H and —OC(O)R
10
, H and —OR
10
, ═O, aryl and H, ═NOR
10
or —O—(CH
2
)
p
—O— wherein p is 2, 3 or 4;
Z represents O; and
R represents —SR
65
wherein R
65
is alkyl, aryl, heteroaryl (e.g. pyridyl or pyridyl N-oxide), 2-,3-, or 4-piperidyl or N-substituted piperidyl, wherein the substituent on said N-substituted piperidyl is C
1
to C
4
alkyl, alkylcarbonyl or —C(O)NH(R
10
) wherein R
10
is H or alkyl; or
R represents —OR
20
wherein R
20
is C
1
to C
12
alkyl, substituted C
1
to C
12
alkyl, phenyl, substituted phenyl, C
7
to C
12
phenylalkyl (e.g., benzyl), C
7
to C
12
phenylalkyl wherein the phenyl moiety is substituted, heteroaryl (e.g., pyridyl or pyridyl N-oxide), or R
20
is -2, -3, or -4 piperidyl or N-substituted piperidyl, wherein the substituents on said substituted C
1
to C
12
alkyl are selected from amino or substituted amino, with the proviso that said amino or said substituted amino for said C
1
to C
12
alkyl is not on C
1
, and the substitutents on said substituted amino are selected from C
1
to C
6
alkyl, the substituents on said substituted phenyl and on said substituted phenyl moiety of the C
7
to C
12
phenylalkyl are selected from C
1
to C
6
alkyl and halo, and the substituent on said N-substituted piperidyl is Cto C
4
alkyl, alkylcarbonyl (e.g., CH
3
C(O)—) or —C(O)NH(R
10
) wherein R
10
is H or alkyl.
This invention also provides novel compounds of Formula 1.1:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
a, b, c, d, A, B, R
5
, R
6
, R
7
, and R
8
are as defined for Formula 1.0;
R
22
and R
24
are the same or different and each independently represents any of the substituents of R
1
and R
2
;
R
26
and R
28
are the same or different and each independently represents any of the substituents of R
3
and R
4
;
V represents —OR
30
or —SR
70
;
R
30
represents aralkyl (e.g., benzyl), aryl (e.g., phenyl or substituted phenyl—i.e., phenyl substituted with 1 to 3, preferably 1, group selected from halo, alkyl, haloalkyl or alkoxy), heteroaryl (e.g., pyridyl, such as 3- or 4-pyridyl, or pyridyl N-oxide, such as 3- or 4-pyridyl N-oxide), alkyl (e.g., ethyl), or -2, -3, or -4

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