Inhibitors of protein isoprenyl transferases

Details Inhibitors of protein isoprenyl transferases Inhibitors of protein isoprenyl transferases

1998-05-07

2001-04-24

Shah, Mukund J. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S326000, C514S424000, C514S428000, C544S141000, C546S208000, C548S541000, C548S567000

Reexamination Certificate

active

06221865

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel compounds which are useful in inhibiting protein isoprenyl transferases (for example, protein farnesyltransferase and protein geranylgeranyltransferase) and the farnesylation or geranylgeranylation of the oncogene protein Ras and other related small g-proteins, compositions containing such compounds and methods of using such compounds.
BACKGROUND OF THE INVENTION
Ras oncogenes are the most frequently identified activated oncogenes in human tumors. Transformed protein Ras is involved in the proliferation of cancer cells. The Ras must be farnesylated before this proliferation can occur. Farnesylation of Ras by farnesyl pyrophosphate (FPP) is effected by protein farnesyltransferase. Inhibition of protein farnesyltransferase, and thereby farnesylation of the Ras protein, blocks the ability of transformed cells to proliferate. Inhibition of protein geranylgeranyltransferase and, thereby, of geranylgeranylation of Ras proteins, also results in down regulation of Ras protein function.
Activation of Ras and other related small g-proteins that are farnesylated and/or geranylated also partially mediates smooth muscle cell proliferation (Circulation, I-3: 88 (1993), which is hereby incorporated herein by reference). Inhibition of protein isoprenyl transferases, and thereby farnesylation or geranylgeranylation of the Ras protein, also aids in the prevention of intimal hyperplasia associated with restenosis and atherosclerosis, a condition which compromises the success of angioplasty and surgical bypass for obstructive vascular lesions.
There is therefore a need for compounds which are inhibitors of protein farnesyltransferase and protein geranylgeranyltransferase.
SUMMARY OF THE INVENTION
In its principle embodiment, the invention provides a compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein
R
1
is selected from the group consisting of
(1) hydrogen,
(2) alkenyl,
(3) alkynyl,
(4) alkoxy,
(5) haloalkyl,
(6) halogen,
(7) loweralkyl,
(8) thioalkoxy,
(9) aryl-L
2
— wherein aryl is selected from the group consisting of
(a) phenyl,
(b) naphthyl,
(c) dihydronaphthyl,
(d) tetrahydronaphthyl,
(e) indanyl, and
(f) indenyl
wherein (a)-(f) are unsubstituted or substituted with at least one of X, Y, or Z wherein X, Y, and Z are independently selected from the group consisting of
alkenyl,
alkynyl,
alkoxy,
aryl,
carboxy,
cyano,
halogen,
haloalkyl,
hydroxy,
hydroxyalkyl,
loweralkyl,
nitro,
N-protected amino, and
—NRR′ wherein R and and R′ are independently selected from the group consisting of
 hydrogen and
 loweralkyl,
oxo (═O), and
thioalkoxy and
L
2
is absent or is selected from the group consisting of
—CH
2
—,
—CH
2
CH
2
—,
—CH(CH
3
)—,
—O—,
—C(O)—,
—S(O)
q
wherein q is 0, 1 or 2, and
—N(R)—, and
(10) heterocycle-L
2
— wherein L
2
is as defined above and the heterocycle is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of
(a) loweralkyl,
(b) hydroxy,
(c) hydroxyalkyl,
(d) halogen
(e) cyano,
(f) nitro,
(g) oxo (═O),
(h) —NRR′,
(i) N-protected amino,
(j) alkoxy,
(k) thioalkoxy,
(l) haloalkyl,
(m) carboxy, and
(n) aryl;
R
2
is selected from the group consisting of
(1)
 wherein L
11
is selected from the group consisting of
(a) a covalent bond,
(b) —C(W)N(R)— wherein R is defined previously and W is selected from the group consisting of and S,
(c) —C(O)—,
(d) —N(R)C(W)—,
(e) —CH
2
O—,
(f) —C(O)O—, and
(g) —CH
2
N(R)—,
R
12a
is selected from the group consisting of
(a) hydrogen,
(b) loweralkyl, and
(c) —C(O)OR
13
wherein R
13
is selected from the group consisting of
hydrogen and
a carboxy-protecting group, and
R
12b
is selected from the group consisting of
(a) hydrogen and
(b) loweralkyl,
with the proviso that R
12a
and R
12b
are not both hydrogen,
(2) —L
11
—C(R
14
)(R
v
)—C(O)OR
15
wherein L
11
is defined previously,
R
v
is selected from the group consisting of
(a) hydrogen and
(b) loweralkyl,
R
15
is selected from the group consisting of
(a) hydrogen,
(b) alkanoyloxyalkyl,
(c) loweralkyl, and
(b) a carboxy-protecting group, and
R
14
is selected from the group consisting of
(a) alkoxyalkyl,
(b) alkoxyarylalkyl,
(c) alkoxycarbonylalkyl,
(d) alkylsulfinyalkyl,
(e) alkylsulfonylalkyl,
(f) alkynyl,
(g) aminoalkyl,
(h) aminocarbonylalkyl,
(i) aminothiocarbonylalkyl,
(j) aryl,
(k) arylalkyl,
(l) carboxyalkyl,
(m) cyanoalkyl,
(n) cycloalkyl,
(o) cycloalkylalkoxyalkyl,
(p) cycloalkylalkyl,
(q) (heterocyclic)alkyl,
(r) hydroxyalkyl,
(s) hydroxyarylalkyl,
(t) loweralkyl,
(u) sulfhydrylalkyl,
(v) thioalkoxyalkyl wherein the thioalkoxyalkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen,
(w) thioalkoxyalkylamino, and
(x) thiocycloalkyloxyalkyl,
(3)
 wherein is 1-3,
(4) —C(O)NH—CH(R
14
)—C(O)NHSO
2
R
16
wherein R
14
is defined previously and R
16
is selected from the group consisting of
(a) loweralkyl,
(b) haloalkyl,
(c) aryl wherein the aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
loweralkyl,
hydroxy,
hydroxyalkyl,
halogen,
cyano,
nitro,
oxo (═O),
—NRR′
N-protected amino,
alkoxy,
thioalkoxy,
haloalkyl,
carboxy, and
aryl, and
(d) heterocycle wherein the heterocycle is unsubstituted or substituted with substituents independently selected from the group consisting of
loweralkyl,
hydroxy,
hydroxyalkyl,
halogen,
cyano,
nitro,
oxo (═O),
—NRR′,
N-protected amino,
alkoxy,
thioalkoxy,
haloalkyl,
carboxy, and
aryl;
(5) —C(O)NH—CH(R
14
)-tetrazolyl wherein the tetrazole ring is unsubstituted or substituted with loweralkyl or haloalkyl,
(6) —L
11
-heterocycle,
(7) —C(O)NH—CH(R
14
)—C(O)NR
17
R
18
wherein R
14
is defined previously and R
17
and R
18
are independently selected from the group consisting of
(a) hydrogen,
(b) loweralkyl,
(c) arylalkyl,
(d) hydroxy, and
(e) dialkylaminoalkyl,
(8) —C(O)OR
15
, and
(9) —C(O)NH—CH(R
14
)-heterocycle wherein R
14
is as previously defined and the heterocycle is unsubstituted or substituted with loweralkyl or haloalkyl;
L
1
is absent or is selected from the group consisting of
(1) —L
4
—N(R
5
)—L
5
— wherein L
4
is absent or selected from the group consisting of
(a) C
1
-to-C
10
-alkylene and
(b) C
2
-to-C
16
-alkenylene,
wherein the alkylene and alkenylene groups are unsubstituted or substituted with 1, 2, 3 or 4 substitutents independently selected from the group consisting of
alkenyl,
alkenyloxy,
alkenyloxyalkyl,
alkenyl[S(O)
q
]alkyl,
alkoxy,
alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or substituted with 1 or 2 hydroxyl substituents,
with the proviso that no two hydroxyls are attached to the same carbon,
alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of
 halogen and
 cycloalkyl,
alkylsilyloxy,
alkyl[S(O)
q
],
alkyl[S(O)
q
]alkyl,
aryl wherein the aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
 alkoxy wherein the alkoxy is unsubstituted or substituted with substituents selected from the group consisting of cycloalkyl,
aryl,
arylalkyl,
aryloxy wherein the aryloxy is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of,
 halogen,
 nitro, and
 —NRR′,
cycloalkyl,
halogen,
loweralkyl,
hydroxyl,
nitro,
—NRR′, and
—SO
2
NRR′,
arylalkoxy wherein the arylalkoxy is unsubstituted or substituted with substituents selected from the group consisting of alkoxy,
arylalkyl,
arylalkyl[S(O)
q
]alkyl,
aryl[S(O)
q
],
aryl[S(O)
q
]alkyl wherein the aryl[S(O)
q
]alkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from
alkoxy and
loweralkyl,
arylalkoxyalkyl wherein the arylalkoxyalkyl is unsubstituted or substituted

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