Compounds useful for inhibition of farnesyl protein transferase

Details Compounds useful for inhibition of farnesyl protein transferase Compounds useful for inhibition of farnesyl protein transferase

2001-03-01

2002-05-14

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S290000, C544S361000, C546S093000

Reexamination Certificate

active

06387905

ABSTRACT:

BACKGROUND
WO 95/10516, published Apr. 20, 1995 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.
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
This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula:
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
; or
each of a, b, c, and d are independently selected from CR
1
or CR
2
;
each R
1
and each R
2
is independently selected from H, halo, —CF
3
, —OR
10
(e.g., —OCH
3
), —COR
10
, —SR
10
(e.g., —SCH
3
and —SCH
2
C
6
H
5
), —S(O)
t
R
11
(wherein t is 0, 1 or 2, e.g., —SOCH
3
and —SO
2
CH
3
), —SCN, —N(R
10
)
2
, —NR
10
R
11
, —NO
2
, —OC(O)R
10
, —CO
2
R
10
, —OCO
2
R
11
, —CN, —NHC(O)R
10
, —NHSO
2
R
10
, —CONHR
10
, —CONHCH
2
CH
2
OH, —NR
10
COOR
11
,
 —SR
11
C(O)OR
11
(e.g., —SCH
2
CO
2
CH
3
), —SR
11
N(R
75
)
2
wherein each R
75
is independently selected from H and —C(O)OR
11
(e.g., —S(CH
2
)
2
NHC(O)O-t-butyl and —S(CH
2
)
2
NH
2
), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol-5-ylthio such as 1-methyl-tetrazol-5-ylthio), 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
taken together 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
, —COR
10
, alkyl or aryl, said alkyl or aryl optionally being substituted with —OR
10
, —SR
10
, —S(O)
t
R
11
, —NR
10
COOR
11
, —N(R
10
)
2
, —NO
2
, —COR
10
, —OCOR
10
, —OCO
2
R
11
, —CO
2
R
10
, OPO
3
R
10
, or R
5
is combined with R
6
to represent ═O or ═S and/or R
7
is combined with R
8
to represent ═O or ═S;
R
10
represents H, alkyl, aryl, or arallyl (e.g., benzyl);
R
11
represents alkyl or aryl;
X represents N, CH 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; and
W represents a group selected from the group consisting of:
 wherein;
R
12
is selected from the group consisting of: (a) H: (b) alkyl: (c) aralkyl (e.g., benzyl); and (d) heteroarylalkyl (heteroaralkyl) (e.g., —CH
2
-imidazolyl):
R
13
and R
14
are each independently selected from the group consisting of: (a) H; (b) —C(O)OR
16
wherein R
16
represents alkyl, aralkyl, and heteroaralkyl; (c) —SO
2
R
17
wherein R
17
is selected from the group consisting of; —NH
2
, —N(alkyl)
2
wherein each alkyl is the same or different (e.g., —N(CH
3
)
2
), alkyl (e.g., C
1-6
alkyl, such as methyl), aryl, aralkyl, heteroaryl and heteroaralkyl; (d) —C(O)R
18
wherein R
18
is selected from the group consisting of: aryl (e.g., phenyl), alkyl, aralkyl, heteroaryl, and heteroaralkyl; (e) C
1-6
alkyl; (f) alkaryl; and (g) C
3-6
cycloalkyl;
r is 0, 1 or 2;
s represents 1, 2, 3, 4, or 5 (preferably 3 or 4), and each Y for each —CY
2
— group is independently selected from H or —OH, provided that both Y substituents of each —CY
2
— group are not —OH, and provided that for the —CY
2
— group alpha to the nitrogen both Y substituents are H, preferably each Y is H such that each —CY
2
— group is a —CH
2
— group, such that the group
 forms a 3, 4, 5, 6, or 7 (preferably 5 or 6) membered ring (e.g., piperidyl or pyrrolidinyl),;
v is 0, 1 or 2;
R
15
is selected from the group consisting of:
(a) heteroaryl (e.g., imidazolyl);
(b) a group selected from:
(5) —CH(OCH
2
CH
3
)
2
,
(6) —OH, and
(7) —CN; and
(c) heterocycloalkyl selected from the group consisting of:
z is 0, 1, 2, 3, 4, or 5 wherein each —CH
2
— group is optionally substituted with a —OH group, i.e., each H of each —CH
2
— group can optionally be replaced with a —OH group and the optional substitution on each —CH
2
— group is independent of the substitution on any other —CH
2
— group, generally each —CH
2
— is unsubstituted;
R
22
represents a group selected from:
(5) alkyl (e.g., —CH
3
),
(6) —OR
23
wherein R
23
is selected from the group consisting of: alkyl, aryl and H, and
 wherein R
24
and R
25
are independently selected from the group consisting of: —NH
2
, alkoxy (e.g., —OCH
3
), —OH, —CH
2
CO
2
H, —OCH
2
Ph (i.e., —OCH
2
C
6
H
5
), —CH(OCH
3
)CH(CH
3
)
2
 alkyl, aryl, H, aralkyl, and heteroaralkyl; or R
24
and R
25
taken together form a carbon chain having 4 or 5 (—CH
2
—) groups such that R
24
and R
25
taken together with the nitrogen to which they are bound form a 5 or 6 membered heterocycloalkyl ring.
The compounds of this invention: (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.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating 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.
This invention also provides a method for inhibiting or treating 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, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelo

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