Prenyl transferase inhibitors

Details Prenyl transferase inhibitors Prenyl transferase inhibitors

1998-06-16

2001-01-30

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S453000, C540S455000, C544S359000, C544S361000, C544S363000, C544S399000, C514S250000, C514S255030

Reexamination Certificate

active

06180619

ABSTRACT:

BACKGROUND OF THE INVENTION
The Ras family of proteins are important in the signal transduction pathway modulating cell growth. The protein is produced in the ribosome, released into the cytosol, and post-translationally modified. The first step in the series of post-translational modifications is the alkylation of Cys
168
with farnesyl or geranylgeranyl pyrophosphate in a reaction catalyzed by prenyl transferase enzymes such as farnesyl transferase and geranylgeranyl transferase (Hancock, J F, et al., Cell 57:1167-1177 (1989)). Subsequently, the three C-terminal amino acids are cleaved (Gutierrez, L., et al., EMBO J. 8:1093-1098 (1989)), and the terminal Cys is converted to a methyl ester (Clark, S., et al., Proc. Nat'l Acad. Sci. (USA) 85:4643-4647 (1988)). Some forms of Ras are also reversibly palmitoylated on cysteine residues immediately N-terminal to Cys
168
(Buss, J E, et al., Mol. Cell. Biol. 6:116-122 (1986)). It is believed that these modifications increase the hydrophobicity of the C-terminal region of Ras, causing it to localize at the surface of the cell membrane. Localization of Ras to the cell membrane is necessary for signal transduction (Willumsen, B M, et al., Science 310:583-586 (1984)).
Oncogenic forms of Ras are observed in a relatively large number of cancers including over 50 percent of colon cancers and over 90 percent of pancreatic cancers (Bos, J L, Cancer Research 49:4682-4689 (1989)). These observations suggest that intervention in the function of Ras mediated signal transduction may be useful in the treatment of cancer.
Previously, it has been shown that the C-terminal tetrapeptide of Ras has the “CAAX” motif (wherein C is cysteine, A is an aliphatic amino acid, and X is any amino acid). Tetrapeptides having this structure have been shown to be inhibitors of prenyl transferases (Reiss, et al., Cell 62:81-88 (1990)). Poor potency of these early farnesyl transferase inhibitors has prompted the search for new inhibitors with more favorable pharmacokinetic behavior (James, G L, et al., Science 260:1937-1942 (1993); Kohl, N E, et al., Proc. Nat'l Acad. Sci. USA 91:9141-9145 (1994); deSolms, S J, et al., J. Med. Chem. 38:3967-3971 (1995); Nagasu, T, et al., Cancer Research 55:5310-5314 (1995); Lerner, E C, et al., J. Biol. Chem. 270:26802-26806 (1995); Lerner, E C, et al., J. Biol. Chem. 270:26770 (1995); and James, et al., Proc. Natl. Acad. Sci. USA 93:4454 (1996)).
Recently, it has been shown that a prenyl transferase inhibitor can block growth of Ras-dependent tumors in nude mice (Kohl, N E, et al., Proc. Nat'l Acad. Sci. USA 91:9141-9145 (1994)). In addition, it has been shown that over 70 percent of a large sampling of tumor cell lines are inhibited by prenyl transferase inhibitors with selectivity over non-transformed epithelial cells (Sepp-Lorenzino, I, et al., Cancer Research, 55:5302-5309 (1995)). Inhibiting farnesylation has been disclosed as a method of treating hepatitis delta virus infection, (Casey, P, et al., WO 97/31641).
SUMMARY OF THE INVENTION
In one aspect, the invention features a compound of formula I or formula II
wherein
R
1
is N (R
10
) (R
11
);
R
2
is thio lower alkyl;
each of R
3
and R
5
, independently, is CH
2
or C(O);
R
4
is substituted or unsubstituted thio lower alkyl, wherein said substituent is CH
2
NHC(O)R
13
and said substituent is attached to said thio group;
R
6
is a residue of a natural or synthetic &agr;-amino acid;
R
7
is a residue of a natural or synthetic &agr;-amino acid;
R
8
is OH or lower alkoxy, or, together with R
7
, forms homoserinelactone;
each of R
9
, R
10
and R
11
, independently, is H or lower alkyl;
R
12
is substituted or unsubstituted cycloalkyl, cycloalkyl lower alkyl, aryl, aryl lower alkyl, heterocycle, or heterocycle lower alkyl, wherein said substituent is lower alkyl, aryl, halo, lower alkoxy, or C(O)—R
7
—R
8
;
R
13
is lower alkyl, aryl, or aryl lower alkyl;
R
18
is H or, together with R
9
, forms CH
2
CH
2
;
provided if R
4
is unsubstituted thio lower alkyl, the free thio group of R
2
and the free thio group of R
4
may form a disulfide bond;
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention is directed to a process for preparing a compound of Formula I or Formula II.
In one embodiment, the compound is of formula I where R
6
is —N(R
14
)CH(R
15
)C(O)—, where R
14
is H or lower alkyl, and R
15
is substituted or unsubstituted lower alkyl, aryl, aryl lower alkyl, heterocycle, or heterocycle lower alkyl where said substituent is lower alkyl, halo, or lower alkoxy, or where R
15
, together with NR
14
C attached thereto, form heterocycle; and R
7
is —N(R
16
)CH(R
17
)C(O)— where R
16
is H or lower alkyl, and R
17
is (CH
2
)
m
S(O)
n
CH
3
or substituted or unsubstituted lower alkyl, thio lower alkyl, where said substituent is C(O)N(R
10
)(R
11
), m is 1-6, n is 0-2, and R
8
is OH or lower alkoxy. In this embodiment, R
2
can be CH
2
SH; R
4
can be C(CH
3
)
2
SH or CH
2
SH wherein the free thio group of R
2
and the free thio group of R
4
form a disulfide bond; R
15
, together with NR
14
C attached thereto, can form heterocycle; R
16
can be H; and R
17
can be (CH
2
)
2
S(O)
n
CH
3
; furthermore, R
1
can be NH
2
; R
3
can be CH
2
; R
5
can be CO; and R
8
can be OH or OCH
3
. In the same embodiment, R
2
can be (CH
2
)SH; R
4
can be C(CH
2
)
2
SCH
2
NHCOCH
3
or CH
2
SCH
2
NHCOCH
3
; R
15
, together with NR
14
C attached thereto, can form heterocycle; R
16
can be H, and R
17
can be (CH
2
)
2
S(O)
n
CH
3
; furthermore, R
1
is NH
2
; R
3
is CH
2
; R
5
is C(O); and R
8
is OH or OCH
3
.
In another embodiment, the compound is of formula II, wherein R
2
is CH
2
SH; R
4
is C(CH
3
)
2
SH or CH
2
SH wherein the free thio group of R
2
and the free thio group of R
4
form a disulfide bond; R
12
is substituted or unsubstituted aryl or aryl lower alkyl, and R
18
is H. In this embodiment, R
1
can be NH
2
; R
3
can be CH
2
; R
5
can be C(O); R
9
can be H; and R
12
can be substituted or unsubstituted phenyl or benzyl, wherein said substituent is lower alkyl or halo.
In a still further embodiment, R
2
is (CH
2
)SH; R
4
is C(CH
2
)
2
SCH
2
NHCOCH
3
or CH
2
SCH
2
NHCOCH
3
; and R
12
is substituted or unsubstituted aryl or aryl lower alkyl. In this embodiment, R
1
can be NH
2
; R can be CH
2
; R
5
can be CO; R
9
can be H; and R
12
can be substituted or unsubstituted phenyl or benzyl, wherein said substituent is lower alkyl or halo.
Examples of the present invention include the following:
In another aspect, the invention features a compound of formula III or formula IV
where
Y is CH
2
or C(O);
R
1
, R
2
, R
3
, and R
4
, each is, independently, H, lower alkyl, optionally substituted arylalkyl, optionally substituted alkenyl, (C
1
-C
18
)-aliphatic acyl, or arylacyl;
R
5
and R
6
each is, independently, H or CH
3
;
R
9
and R
10
each is independently selected from the group consisting of H, lower alkyl, and C
3
-C
6
cycloalkyl;
Ar is optionally substituted aryl or optionally substituted heterocycle;
n is 0 or an integer from 1 to 4;
wherein each substituent is, independently, aryl, heterocycle, halogen, OR
9
, NR
9
R
10
, CN, NO
2
, CF
3
, or lower alkyl, said lower alkyl optionally substituted with C
1
-C
4
alkoxy, NR
9
R
10
, C
3
-C
6
cycloalkyl, or OH;
or a pharmaceutically acceptable salt thereof.
In still another aspect, the present invention is directed to a process for preparing a compound of Formula III or Formula IV.
A preferred group of compounds of Formula III or Formula IV include the following:
In yet another aspect, the invention features a compound of formula V:
wherein
Ar is optionally substituted aryl or optionally substituted heterocycle, wherein each substituent is independently selected from the group consisting of aryl, heterocycle, halogen, OR
9
, N
9
R
10
, CN, NO
2
, CF
3
, and lower alkyl, said lower alkyl optionally substituted with (C
1
-C
4
)-alkoxy, NR
9
R
10
, C
3
-C
6
cycloalkyl, or OH;
R
1
and R
2
each is, independently, CH
2
or C(O);
R
3
and R
4
each is, independ

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