Imidazolyl derivatives

Details Imidazolyl derivatives Imidazolyl derivatives

2002-05-20

2003-01-21

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S254050, C514S339000, C514S397000

Reexamination Certificate

active

06509336

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is directed to imidazolyl derivatives which are useful as prenyl transferase inhibitors.
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) 85:4643-647 (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 is a “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, SJ, 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)).
SUMMARY OF THE INVENTION
In one aspect, this invention provides a compound of formula (I),
or a pharmaceutically acceptable salt thereof,
wherein
———————represents an optional bond;
m, n, p, and q are each independently 0 or 1;
T for each occurrence is independently selected from the group consisting of CR
26
R
27
, S, O, C(O), S(O)
2
and NR
28
;
X is N—Y, O or S where Y is selected from the group consisting of H, CR
14
R
15
R
16
, S(O)R
17
, S(O)
2
R
18
, C(O)R
19
, C(O)NR
20
R
21
, C(S)NR
22
R
23
, C(O)OR
24
, C(S)OR
25
, S(O)NR
29
R
30
and S(O)
2
NR
31
R
32
;
Z is selected from the group consisting of H, cyano, halo, CR
14
R
15
R
16
, S(O)R
17
, S(O)
2
R
18
and C(O)R
19
;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
26
and R
27
are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;
or R
1
and R
2
when on adjacent positions, or R
4
and R
5
, or R
11
and R
12
, are taken together to form a bivalent radical selected from the group consisting of —O—CH
2
—O—, —O—CH
2
—CH
2
—O—, —O—CH═CH—, —O—CH
2
—CH
2
—, —O—CH
2
—CH
2
—CH
2
— and —CR
33
═CR
34
—CR
35
═CR
36
—; R
7
, R
8
and R
9
are each independently selected from the group consisting of H, halo, aryl, alkyl, substituted alkyl, alkyloxy, alkylthio, aryloxy, arylthio amino, mono- or di-alkylamino, hydroxycarbonyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)
2
-alkyl, cyanoarylalkyl, arylalkyl and substituted arylakyl;
R
10
is selected from the group consisting of H, amino, azido, hydroxy, halo, alkyl, substituted alkyl, cyano, hydroxyalkyl, hydroxycarbonyl, aminoalkyl, mono- or di-alkylaminoalkyl, mono- or di-alkylamino, alkoxy, alkylcarbonylalkyl, cyanoalkyl, alkyloxycarbonylalkyl, carboxyalkyl, cycloalkyl, cycloalkylamino, cycloalkylhydroxy, imidazoyl, substituted imidazoyl, aminocarbonylalkyl, aryloxy, thio, alkylthio, OS(O
2
)R
18
, OC(O)R
19
, OC(O)NR
20
R
21
, OC(S)NR
22
R
23
, OS(O)NR
29
R
30
, OS(O)
2
NR
31
R
32
and arylthio; and R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, R
25
, R
28
, R
29
, R
30
, R
31
, R
32
and R
37
for each occurrence are each independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl and arylalkyl;
or R
20
and R
21
, or R
22
and R
23
, or R
29
and R
30
, or R
31
and R
32
are taken together to form a bivalent radical selected from the group consisting of —(CH
2
)
r
—NR
37
—(CH
2
)
s
—, —(CH
2
)
r
—O—(CH
2
)
s
— and —(CR
38
R
39
)
t
—, where r and s are each independently 1 to 3 and t is 2 to 6;
R
33
, R
34
, R
35
, R
36
, R
38
and R
39
are each independently selected from the group consisting of H, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, hydroxy and thio.
A preferred group of compounds of the immediately foregoing compounds is where m, n, p and q are each 0.
A preferred group of compounds of the immediately foregoing compounds is where R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
11
, R
12
and R
13
are each H, halo, alkyl, substituted alkyl, cyano or alkyloxy.
A preferred group of compounds of the immediately foregoing compounds is where R
10
is OH, H, halo, azido, amino, mono- or di-alkylamino, OS(O
2
)R
18
, OC(O)NR
20
R
21
or OS(O)
2
NR
31
R
32
.
A preferred group of compounds of the immediately foregoing compounds is where R
7
, R
8
and R
9
are each H, alkyl, substituted alkyl, amino or cyanoarylalkyl.
A preferred group of compounds of the immediately foregoing compounds is where X is N—Y and Y is H, CR
14
R
15
R
16
, S(O)
2
R
18
, C(O)NR
20
R
21
or S(O)
2
NR
29
R
30
.
A preferred group of compounds of the immediately foregoing compounds is where R
1
, R
2
, R
3
, R
11
, R
12
and R
13
are each halo or hydrogen.
A preferred group of compounds of the immediately foregoing compounds is where R
1
, R
2
, R
3
, R
11
, R
12
and R
13
are each chloro or hydrogen.
A preferred group of compounds of the immediately foregoing compounds is where R
7
, R
8
, and R
9
are each (C
1
-C
4
)alkyl or hydrogen.
A preferred group of compounds of the immediately foregoing compounds is where R
7
, R
8
, and R
9
are each methyl or hydrogen.
A preferred group of compounds of the immediately foregoing compounds is where R
10
is OH, amino, OS(O
2
)R
18
, or OC(O)NR
20
R
21
.
A preferred group of compounds of the immediately foregoing compounds is where R
4
, R
5
and R
6
are each H.
A preferred group of compounds of the immediately foregoing compounds is where Z is hydrogen.
A preferred group of compounds of the immediately foregoing compounds is where Y is H, methyl, S(O)
2
R
18
, C(O)NR
20
R
21
or S(O)
2
R
29
R
30
.
A preferred group of compounds of the immediately foregoing compounds is where said compounds are of the formula:
wherein
R
10
is OH and Y is H;
R
10
is NH
2
and

Affiliated with

Also associated with

Rating

Imidazolyl derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Imidazolyl derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Imidazolyl derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3042654