Farnesyl protein transferase inhibitors

Details Farnesyl protein transferase inhibitors Farnesyl protein transferase inhibitors

1999-12-16

2002-04-16

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S254050, C514S255010, C514S252010, C514S290000, C514S326000, C544S361000, C544S370000, C546S093000, C546S210000

Reexamination Certificate

active

06372747

ABSTRACT:

BACKGROUND
WO 95/10516, published Apr. 20, 1995, WO96/31478, published Oct. 10, 1996, and copending application Ser. No. 09/094,687 filed Jun. 15, 1998 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 thererof, wherein:
one of a, b, c and d represents N or N
+
O
−
, 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
;
X represents N or CH when the optional bond (represented by the dotted line) is absent, and represents C when the optional bond is present;
the dotted line between carbon atoms 5 and 6 represents an optional bond, such that when a double bond is present, A and B independently represent —R
15
, halo, —OR
16
, —OCO
2
R
16
or —OC(O)R
15
, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H
2
, —(OR
16
)
2
, H and halo, dihalo, alkyl and H, (alkyl)
2
, —H and —OC(O)R
15
, H and —OR
15
, ═O, aryl and H, ═NOR
15
or —O—(CH
2
)
p
—O— wherein p is 2, 3 or 4;
each R
1
and each R
2
is independently selected from H, halo, —CF
3
, —OR
15
(e.g., —OCH
3
), —COR
15
, —SR
15
(e.g., —SCH
3
and —SCH
2
C
6
H
5
), —S(O)
t
R
16
(wherein t is 0, 1 or 2, e.g., —SOCH
3
and —SO
2
CH
3
), —N(R
15
)
2
, —NO
2
,—OC(O)R
15
, —CO
2
R
15
, —OCO
2
R
16
, —CN, —NR
15
COOR
16
, —SR
16
C(O)OR
16
(e.g., —SCH
2
CO
2
CH
3
), —SR
16
N(R
17
)
2
(provided that R
16
in —SR
16
N(R
17
)
2
is not —CH
2
—) wherein each R
17
is independently selected from H or —C(O)OR
16
(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
15
or —CO
2
R
15
;
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
, and R
7
each independently represents H, —CF
3
, —COR
15
, alkyl or aryl, said alkyl or aryl optionally being substituted with —OR
15
, —SR
15
, —S(O)
t
R
16
, —NR
15
COOR
16
, —N(R
15
)
2
, —NO
2
, —COR
15
, —OCOR
15
, —OCO
2
R
16
, —CO
2
R
15
, OPO
3
R
15
, or R
5
is combined with R
6
to represent ═O or ═S;
R
8
is selected from: H, C
3
to C
4
alkyl (preferably branched chain alkyl, and most preferably C
4
to C
7
branched chain alkyl), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl;
the substutuents for the R
8
substituted groups being selected from: alkyl, aryl, arylalkyl, cycloalkyl, —N(R
18
)
2
, —OR
18
, cycloalkyalkyl, halo, CN, —C(O)N(R
18
)
2
, —SO
2
N(R
18
)
2
or —CO
2
R
18
; provided that the —OR
18
and —N(R
18
)
2
substituents are not bound to the carbon that is bound to the N of the —C(O)NR
8
— moiety;
each R
18
is independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl;
R
9
and R
10
are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or —CON(R
18
)
2
(wherein R
18
is as defined above); and the substitutable R
9
and R
10
groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl (i.e., the R
9
and/or R
10
groups can be unsubtituted or can be substituted with 1-3 of the substitutents described above, except when R
9
and/or R
10
is H); or
R
9
and R
10
together with the carbon atom to which they are bound, form a C
3
to C
6
cycloalkyl ring;
R
11
and R
12
are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, —CON(R
18
)
2
—OR
18
or —N(R
18
)
2
; wherein R
18
is as defined above; provided that the —OR
18
and —N(R
18
)
2
groups are not bound to a carbon atom that is adjacent to a nitrogen atom; and wherein said substitutable R
11
and R
12
groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl; or
R
11
and R
12
together with the carbon atom to which they are bound, form a C
3
to C
6
cycloalkyl ring;
R
13
is an imidazolyl ring selected from:
 wherein
R
19
is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl wherein the substituents are selected from halo (e.g., F and Cl) or CN, (7) —C(aryl)
3
(e.g., —C(phenyl)
3
, i.e., trityl) or (8) cycloalkyl;
said imidazolyl ring 2.0 or 2.1 optionally being substituted with one or two substituents and said imidazole ring 4.0 optionally being substituted with 1-3 substituents and said imidazole ring 4.1 being optionally substituted with one substituent wherein said optional substituents for rings 2.0, 2.1, 4.0 and 4.1 are bound to the carbon atoms of said imidazole rings and said optional substituents are independently selected from: —NHC(O)R
18
, —C(R
34
)
2
OR
35
, —OR
18
, —SR
18
, F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or —N(R
18
)
2
(wherein each R
18
is independently selected); R
18
is as defined above; each R
34
is independently selected from H or alkyl (preferably —CH
3
), preferably H; R
35
is selected from H, —C(O)OR
20
, or —C(O)NHR
20
, and R
20
is as defined below (preferably R
20
is alkyl or cycloalkyl, most preferably cyclopentyl or cyclohexyl); Q represents an aryl ring (e.g., phenyl), a cycloalkyl ring (e.g., cyclopentyl or cyclohexyl) or a heteroaryl ring (e.g., furanyl, pyrrolyl, thienyl, oxazolyl or thiazolyl), said Q is optionally substituted with 1 to 4 substituents inedependently selected from halo (e.g., F or Cl), alkyl, aryl, —OR
18
, —N(R
18
)
2
(wherein each R
18
is independently selected), —OC(O)R
18
, or —C(O)N(R
18
)
2
(wherein each R
18
is independently selected), and wherein R
18
is as defined above; (examples of the —C(R
34
)
2
OR
35
group include —CH
2
OH, —CH
2
OC(O)OR
20
and —CH
2
OC(O)NHR
20
);
R
14
is selected from:
 R
15
is selected from: H, alkyl, aryl or arylalkyl;
R
16
is selected from: alkyl or aryl;
R
20
is selected from: H, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, provided that R
20
is not H when R
14
is group 5.0 or 8.0;
when R
20
is other than H, then said R
20
group is optionally substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aryl, —OC(O)R
18
(e.g., —OC(O)CH
3
), —OR
18
or —N(R
18
)
2
, wherein each R
18
group is the same or different, and wherein R
18
is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom;
R
21
is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl;
when R
21
is other than H, then said R
21
group is optionally substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aryl, —OR
18
or —N(R
18
)
2
, wherein each R
18
group is the same or different, and wherein R
18
is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom;
n is 0-5;
each R
32
and R
33
for each n (i.e.

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