Tricyclic compounds useful for inhibition of G-protein...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S253030, C514S254110, C514S255010, C514S255030, C514S318000, C514S320000, C514S324000, C514S325000, C544S361000, C544S375000, C544S381000, C546S080000, C546S089000, C546S196000, C546S202000, C546S203000

Reexamination Certificate

active

06214827

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 Y′ is hydrogen, substituted carboxylate or substituted sulfonyl. Examples of such potentiating agents include 11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines such as Loratadine.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo famesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, famesyl 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).
A welcome contribution to the art would be compounds useful for the inhibition of famesyl protein transferase. Such a contribution is provided by this invention.
SUMMARY OF THE INVENTION
Inhibition of famesyl protein transferase by tricyclic compounds of this invention has not been reported previously. Thus, this invention provides a method for inhibiting famesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit famesyl 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 famesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a famesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
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.
The compounds useful in the claimed methods are novel compounds represented by Formula (1.0)
wherein:
—A and B are independently selected from H, halo or C
1
-C
6
alkyl;
Z is N or CH;
W is CH, CH
2
, O or S, wherein the dotted line to W represents a double bond which is present when W is CH;
X is C, CH or N, wherein the dotted line connecting X to the tricyclic ring system represents a double bond which is present when X is C;
R
1
is selected from:
1 ) a group of the formula:
 or disulfide dimers thereof;
2) a group of the formula:
3) a group of the formula:
 wherein W, A and B are as defined above;
4) a group of the formula:
5) a group of the formula:
wherein R
80
is selected from H or —C(O)OR
90
wherein R
90
is a C
1
-C
6
alkyl group (e.g., —C(CH
3
)
3
), and R
85
is a C
1
-C
6
alkoxy group (e.g., p-OCH
3
); and
6) a group of the formula:
 wherein:
(a) T is selected from:
(b) x is 0, 1, 2, 3, 4, 5or 6;
(c) each R
a
and each R
b is
independently selected from H, aryl, alkyl, alkoxy, aralkyl, amino, alkylamino, heterocyloalkyl, —COOR
60
, —NH{C(O)}
z
R
60
(wherein z is 0 or 1), or —(CH)
w
S(O)
m
R
60
(wherein w is 0, 1, 2 or 3, and m is 0, 1 or 2); or R
a
and R
b
taken together can represent cycloalkyl, ═N—O-alkyl, ═O or heterocycloalkyl; with the proviso that for the same carbon, R
a
is not selected from alkoxy, amino, alkylamino or —NH{C(O)}
z
R
60
when R
b
is selected from alkoxy, amino, alkylamino or —NH{C(O)}
z
R
60
; and with the proviso that when T is a single bond, for the first carbon containing R
a
and R
b
, R
a
and R
b
are not selected from alkoxy, alkylamino, amino or —NHR
60
(i.e., —NH{C(O)}
z
R
60
wherein z is 0) (i.e., R
a
and R
b
on the first carbon bound to T, when T is a single bond, are not alkoxy, alkylamino, amino or —NHR
60
); and
(d) R
92
can represent H, alkyl, aryl, aryloxy, arylthio, aralkoxy, aralkyl, heteroaryl or heterocycloalkyl;
R
60
represents H, alkyl, aryl or aralkyl;
R
4
is H or C
1
-C
6
alkyl;
R
2
is selected from: H, —C(O)OR
6
, —C(O)NR
6
R
7
, C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, substituted (C
1
-C
8
)alkyl, substituted (C
2
-C
8
)alkenyl, substituted (C
2
-C
8
)alkynyl, wherein said substituted groups have one or more substituents selected from:
1) aryl, arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, B-substituted aryl, B-substituted arylalkyl, B-substituted heteroarylalkyl, B-substituted heteroaryl or B-substituted heterocycloalkyl, wherein B is selected from C
1
-C
4
alkyl, —(CH
2
)
n
OR
6
, —(CH
2
)
n
NR
6
R
7
and halo;
2) C
3
-C
6
cycloalkyl;
3) —OR
6
;
4) —SH or —S(O)
t
R
6
;
5) —NR
6
R
7
;
6) —N(R
6
)—C(O)R
7
;
7) —N(R
6
)—C(O)NR
7
R
12
;
8) —O—C(O)NR
6
R
7
;
9) —O—C(O)OR
6
;
10) —SO
2
NR
6
R
7
;
11) —N(R
6
)—SO
2
—R
7
;
12) —C(O)NR
6
R
7
;
13) —C(O)OR
6
; and
provided where R
1
is D, R
2
is not H or C
1
-C
8
alkyl, and where R
1
is D and R
2
is substituted C
1
-C
8
alkyl, the substituents on said alkyl group are not substituents 3), 4), 5), 9), or 13); D is —C(O)—CH
2
—R
5
, —C(O)—O—R
5
or —C(O)—NH—R
5
, wherein R
5
is pyridyl, pyridyl N-oxide,
or a piperidinyl group of the formula
wherein R
11
represents H, C
1
-C
6
alkyl, haloalkyl or —C(O)—R
9
wherein R
9
is C
1
-C
6
alkyl, C
1
-C
6
alkoxy or —NH(R
10
) wherein R
10
is H or alkyl, or the group —C(O)—R
9
represents an acyl radical of a naturally occurring amino acid;
R
6
, R
7
and R
12
are independently selected from H, C
1
-C
4
alkyl, (C
3
-C
6
)cycloalkyl, aryl, arylalkyl (i.e., aralkyl), heteroaryl, heteroarylalkyl, heterocycloalkyl, substituted (C
1
-C
4
)alkyl, substituted (C
3
-C
6
)cycloalkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl or substituted heterocycloalkyl, wherein said substituted groups have one or more substituents (e.g., 1-3) selected from: C
1
-C
4
alkoxy, aralkyl, heteroarylalkyl, —NO
2
, C
3
-C
10
-alkoxyalkoxy (e.g.,—O—(C
1
-C
4
)alkyl—O—(C
1
-C
4
)alkyl), (C
3
-C
6
) cycloalkyl (e.g., cyclopropyl or cyclohexyl), aryl, —CN, nitrophenyl, methylenedioxy-phenyl, heteroaryl, heterocycloalkyl, halo, —OH, —C(O)R
14
, —C(O)NR
6
R
7
, —N(R
6
)C(O)R
14
, —S(O)
t
R
14
(e.g., —S—(C
1
-C
4
)alkyl and —SO
2
R
14
) or —NR
95
R
15
; provided that R
6
, R
7
and R
12
are not —CH
2
OH or —CH
2
NR
95
R
15
when said R
6
, R
7
or R
12
is directly bonded to a heteroatom, and further provided that R
6
is not H for groups 4) and 9), and R
7
is not H for group 6);
optionally, when R
6
and R
7
are bound to the same nitrogen, R
6
and R
7
together with the nitrogen to which they are bound, form a 5 to 7 membered heterocycloalkyl ring which optionally contains O, NR
6
, or S(O)
t
wherein t is 0, 1 or 2;
optionally, when R
7
and R
12
are bound to the same nitrogen, R
7
and R
12
together with the nitrogen to which they are bound, form a 5 to 7 membered heterocycloalkyl ring which optionally contains O, NR
6
, or S(O)
t
wherein t is 0, 1 or 2;
R
95
and R
15
are independently H, C
1
-C
4
alkyl or arylalkyl;
R
14
is C
1
-C
4
alkyl, aryl or arylalkyl;
n=0, 1, 2, 3or 4; and
t=0, 1 or 2;
or pharmaceutically acceptable salts thereof.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular

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