Farnesyl protein transferase inhibitors

Details Farnesyl protein transferase inhibitors Farnesyl protein transferase inhibitors

1999-12-16

2002-03-26

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S217050, C514S228200, C514S232800, C514S218000, C540S544000, C540S598000, C540S575000, C544S060000, C544S121000, C544S361000, C544S370000, C544S360000

Reexamination Certificate

active

06362188

ABSTRACT:

BACKGROUND
WO 95/10516, published Apr. 20, 1995, WO96/31478, published Oct. 10, 1996, and copending application Ser. No. 09/094687 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:
A compound of 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
;
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
), —N(R
10
)
2
, —NO
2
, —OC(O)R
10
, —CO
2
R
10
, —OCO
2
R
11
, —CN, —NR
10
COOR
11
, —SR
11
C(O)OR
11
, (e.g., —SCH
2
CO
2
CH
3
), —SR
11
N(R
75
)
2
(provided that R
11
in —SR
11
N(R
75
)
2
is not —CH
2
—) wherein each R
75
is independently selected from H or —C(O)OR
11
(e.g., —S(CH
2
)
2
NHC(O)O-t-butyl and —S(CH
2
)
2
NH
2
), benzotriazol1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol5-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
, and R
7
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; provided that for the groups —OR
10
, —SR
10
, and —N(R
10
)
2
R
10
is not H;
R
10
represents H, alkyl, aryl, or aralkyl (e.g., benzyl);
R
11
represents alkyl or aryl;
X represents N, CH or C, and when X is C the optional bond (represented by the dotted line) to carbon atom 11 is present, and when X is CH the optional bond (represented by the dotted line) to carbon atom 11 is absent:
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
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;
R
8
represents a heterocyclic ring selected from:
 said heterocyclic rings (2.0 to 7.0 and 2.1 to 7.1) being optionally substituted with one or more substituents independently selected from:
(a) alkyl (e.g., methyl, ethyl, isopropyl, and the like),
(b) substituted alkyl wherein said substituents are selected from: halo, aryl, —OR
15
or —N(R
15
)
2
, heteroaryl, heterocycloalkyl, cycloalkyl, wherein each R
15
group is the same or different, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom, and wherein R
15
is selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
(c) hydroxyl, with the proviso that carbon atoms adjacent to the nitrogen, sulfur or oxygen atoms of the ring are not substituted with hydroxyl;
(d) alkyloxy or
(e) arylalkyloxy;
(i.e., each substitutable H atom on each substitutable carbon atom in said heterocyclic rings is optionally replaced with substituents selected from (a) to (e) defined above);
Y represents CH
2
, NR
16
, O, S, SO, or SO
2
wherein R
16
is selected from: H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, aroyl, carbamoyl, carboxamido, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido and arylalkylsulfonamido;
n is 0 to 6 (preferably 1-3);
Q represents O or N, provided that Q is not adjacent to a heteroatom in the heterocycloalkyl rings of 2.1, 3.1, 4.1, 5.1, 6.1 and 7.1;
R
12
is selected from:
 (e.g., R
12
is 9.0):
wherein R
17
is selected from; (1) H, (2) alkyl, (3) aryl, (4) arylalkyl, (5) substituted arylalkyl wherein the substituents are selected from halo (e.g., F and Cl) or CN, (6) —C(aryl)
3
(e.g., —C(phenyl)
3
, i.e., trityl), (7) cycloalkyl, (8) substituted alkyl (as defined above in (b)), or (9) cycloalkylalkyl;
R
12A
is selected from rings 8.0, 8.1 or 9.1, defined above;
said imidazolyl ring 8.0 and 8.1 optionally being substituted with one or two substituents, said imidazole ring 9.0 optionally being substituted with 1-3 substituents, and said pyridyl ring 9.1 optionally being substituted with 1-4 substituents, wherein said optional substituents for rings 8.0, 8.1, 9.0 and 9.1 are bound to the carbon atoms of said rings and are independently selected from: —NHC(O)R
15
, —C(R
18
)
2
OR
19
, —OR
15
, —SR
15
, F, Cl, Br, alkyl (e.g., methyl, such as 4-methyl in 9.0), substituted alkyl (as defined above in (b)), aryl, arylalkyl, cycloalkyl, or —N(R
15
)
2
; R
15
is as defined above; each R
18
is independently selected from H or alkyl (preferably —CH
3
), preferably H; R
19
is selected from H or —C(O)NHR
20
, and R
20
is as defined below;
R
13
and R
14
for each n are independently selected from: H, F, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl or —CON(R
15
)
2
(wherein R
15
is as defined above), —OR
15
or —N(R
15
)
2
provided that the —OR
15
and —N(R
15
)
2
groups are not bound to a carbon atom that is adjacent to a nitrogen atom, and provided that there can be only one —OH group on each carbon; and the substitutable R
13
and R
14
groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: F, alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heteroarylalkyl (i.e., the R
13
and/or R
14
groups can be unsubtituted or can be substituted with 1-3 of the substituents described above, except when R
13
and/or R
14
is H); or
R
13
and R
14
, for each n, together with the carbon atom to which they are bound, form a C
3
to C
6
cycloalkyl ring;
R
9
is selected from:
R
20
is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocyloalkylalkyl, provided that R
20
is not H when R
9
is group 12.0 or 16.0;
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
15
(e.g., —OC(O)CH
3
), —OR
15
or —N(R
15
)
2
, wherein each R
15
group is the same or different, and wherein R
15
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, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
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: alkyl, aryl, wherein each R
15
group is the same or different, and wherein R
15
is as defined above; and
R
22
is selected from cycloalkyl (e.g., cyclopropylmethyl, i.e.,
 heterocycloalkyl, aryl (e.g., phenyl), substituted aryl (e.g., halo as a substituent, such as F or Cl),

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