Inhibitors of protein isoprenyl transferases

Details Inhibitors of protein isoprenyl transferases Inhibitors of protein isoprenyl transferases

1999-11-18

2001-08-21

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S323000

Reexamination Certificate

active

06277871

ABSTRACT:

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 present invention provides a compound of Formula I
or a pharmaceutically acceptable salt or prodrug thereof, where
L
1
is selected from
(1) phenyl,
(2) naphthyl,
(3) dihydronaphthyl,
(4) tetrahydronaphthyl,
(5) indanyl,
(6) indenyl, and
(7) cycloalkyl
 where (1)-(7) can be optionally substituted with 1 or 2 substituents independently selected from
(a) alkyl,
(b) halogen,
(c) perfluoroalkyl, and
(d) —OR
3
where R
3
is selected from
(a) hydrogen and
(b) alkyl;
R
1
and R
2
are independently selected from
(1) hydrogen and
(2) alkyl where alkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from
(a) —CO
2
R
4
where R
4
is selected from
(i) hydrogen,
(ii) alkyl, and
(iii) a carboxy-protecting group,
(b) —C(O)NR
5
R
6
where R
5
and R
6
are independently selected from
(i) hydrogen,
(ii) alkyl,
(iii) an amino-protecting group, and
(iv) —S(O)
t
R
7
where R
7
is selected from
hydrogen,
alkyl, and
aryl, and
t is an integer from 0 to 2,
(c) —S(O)
t
R
7
,
(d) aryl,
(e) heterocycle,
(f) —OR
8
where R
8
is selected from
(i) hydrogen,
(ii) cycloalkyl,
(iii) a hydroxy-protecting group, and
(iv) alkyl where alkyl can be optionally substituted with 1 or 2 substituents independently selected from
cycloalkyl,
aryl, and
heterocycle,
(g) —SO
3
H,
(h) —NR
5
R
6
,
(i) —NR
9
C(O)NR
10
R
11
where R
9
, R
10
, and R
11
are independently selected from
(i) hydrogen,
(ii) alkyl, and
(iii) —OH,
(j) —NHC(O)NHNH
2
,
(k) —NHC(NH)NH
2
, and
(l) cycloalkyl;
Z is selected from
(1) —C(O)R
12
where R
12
is selected from
(a) —NR
13
R
14
where R
13
and R
14
are independently selected from
(i) hydrogen,
(ii) aryl,
(iii) heterocycle,
(iv) an amino-protecting group,
(v) cycloalkyl, and
(vi) alkyl where alkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from
—CO
2
R
4
,
—C(O)NR
5
R
6
,
—NR
5
R
6
,
—S(O)
t
R
7
,
—OR
15
where R
15
is selected from
 hydrogen,
 cycloalkyl,
 alkyl where alkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from
 —CO
2
R
4
,
 —C(O)NR
5
R
6
,
 —NR
5
R
6
,
 —S(O)
t
R
7
,
 cycloalkyl,
 aryl, and
 heterocycle,
 aryl,
 heterocycle, and
 a hydroxy-protecting group,
cycloalkyl,
aryl, and
heterocycle,
(b) alkyl where alkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from
(i) —CO
2
R
4
,
(ii) —C(O)NR
13
R
14
,
(iii) —NR
13
R
14
,
(iv) —OR
16
where R
16
is selected from
hydrogen,
cycloalkyl,
 alkyl where alkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from
 —CO
2
R
4
,
 —C(O)NR
13
R
14
,
 —NR
13
R
14
,
 —OR
8
,
 —S(O)
t
R
7
,
 cycloalkyl,
 aryl, and
 heterocycle,
aryl,
heterocycle, and
a hydroxy-protecting group,
(v) —S(O)
t
R
7
,
(vi) cycloalkyl,
(vii) aryl, and
(viii) heterocycle,
(c) —OR
16
, and
(d) alkenyl where alkenyl can be optionally substituted with 1 or 2 substituents independently selected from
(i) —CO
2
R
4
,
(ii) —C(O)NR
13
R
14
,
(iii) —NR
13
R
14
,
(iv) —OR
16
,
(v) —S(O)
t
R
7
,
(vi) cycloalkyl,
(vii) aryl, and
(viii) heterocycle,
(2) alkyl where alkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from
(a) —CO
2
R
4
,
(b) —C(O)NR
13
R
14
,
(c) —C(O)R
12
,
(d) —NR
13
R
14
,
(e) —NR
13
C(O)R
12
,
(f) —OC(O)R
12
,
(g) —OR
16
,
(h) —SO
2
NR
13
R
14
,
(i) cycloalkyl,
(j) aryl, and
(k) heterocycle, and
(3) —SO
2
NR
13
R
14
;
 where at each occurrence in R
1
, R
2
, and Z aryl can be optionally substituted with 1, 2, or 3 substituents independently selected from
(1) alkenyl where alkenyl can be optionally substituted with 1 or 2 substituents independently selected from
(a) —CO
2
R
4
,
(b) —C(O)NR
13
R
14
,
(c) —C(O)R
12
,
(d) —NR
13
R
14
,
(e) —NR
13
C(O)R
12
,
(f) —OC(O)R
12
,
(g) —OR
16
,
(h) —SO
2
NR
13
R
14
,
(i) cycloalkyl,
(j) aryl, and
(k) heterocycle,
(2) alkyl where alkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from
(a) —CO
2
R
4
,
(b) —C(O)NR
13
R
14
,
(c) —C(O)R
12
,
(d) —NR
13
R
14
,
(e) —NR
13
C(O)R
12
,
(f) —OC(O)R
12
,
(g) —OR
16
,
(h) —SO
2
NR
13
R
14
,
(i) cycloalkyl,
(j) aryl, and
(k) heterocycle,
(3) alkynyl where alkynyl can be optionally substituted with 1 or 2 substituents independently selected from
(a) —CO
2
R
4
,
(b) —C(O)NR
13
R
14
,
(c) —C(O)R
12
,
(d) —NR
13
R
14
,
(e) —NR
13
C(O)R
12
,
(f) —OC(O)R
12
,
(g) —OR
16
,
(h) —SO
2
NR
13
R
14
,
(i) cycloalkyl,
(j) aryl, and
(k) heterocycle,
(4) aryl where aryl can be optionally substituted with 1, 2, or 3 substituents independently selected from
(a) alkenyl,
(b) alkyl,
(c) alkynyl,
(d) —CO
2
R
4
,
(e) —CN,
(f) halogen,
(g) haloalkyl,
(h) —NO
2
,
(i) —NR
5
R
6
,
(j) —OR
8
,
(k) perfluoroalkyl,
(l) oxo (═O), and
(m) —S(O)
t
R
7
,
(5) heterocycle where heterocycle can be optionally substituted with 1, 2, or 3 substituents independently selected from
(a) alkenyl,
(b) alkyl,
(c) alkynyl,
(d) —CO
2
R
4
,
(e) —CN,
(i) halogen,
(g) haloalkyl,
(h) —NO
2
,
(i) —NR
13
R
14
,
(j) —OR
16
,
(k) perfluoroalkyl,
(l) oxo (═O), and
(m) —S(O)
t
R
7
,
(6) —CO
2
R
4
,
(7) —CN,
(8) halogen,
(9) haloalkyl,
(10) —NO
2
,
(11) —NR
13
R
14
,
(12) —OR
16
,
(13) perfluoroalkyl,
(14) oxo (═O), and
(15) —S(O)
t
R
7
;
 where at each occurrence in R
1
, R
2
, and Z heterocycle can be optionally substituted with 1 or 2 substituents independently selected from
(1) alkenyl where alkenyl can be optionally substituted with 1 or 2 substituents independently selected from
(a) —CO
2
R
4
,
(b) —C(O)NR
13
R
14
,
(c) —C(O)R
12
,
(d) —NR
13
R
14
,
(e) —NR
13
C(O)R
12
,
(f) —OC(O)R
12
,
(g) —OR
16
,
(h) —SO
2
NR
13
R
14
,
(i) cycloalkyl,
(j) aryl, and
(k) heterocycle,
(2) alkyl where alkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from
(a) —CO
2
R
4
,
(b) —C(O)NR
13
R
14
,
(c) —C(O)R
12
,
(d) —NR
13
R
14
,
(e) —NR
13
C(O)R
12
.
(f) —OC(O)R
12
,
(g) —OR
16
,
(h) —SO
2
NR
13
R
14
,
(i) cycloalkyl,
(j) aryl, and
(k) heterocycle,
(3) alkynyl where alkynyl can be optionally substituted with 1 or 2 substituents independently selected from
(a) —CO
2
R
4
,
(b) —C(O)NR
13
R
14
,
(c) —C(O)R
12
,
(d) —NR
13
R
14
,
(e) —NR
13
C(O)R
12
,
(f) —OC(O)R
12
,
(g) —OR
16
,
(h) —SO
2
N

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