Farnesyl transferase inhibitors

Details Farnesyl transferase inhibitors Farnesyl transferase inhibitors

1996-11-20

2004-01-06

Bernhardt, Emily (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C514S249000, C514S250000, C514S365000, C514S374000, C514S400000, C544S346000, C548S203000, C548S204000, C548S205000, C548S335500, C548S338100, C548S235000, C548S236000

Reexamination Certificate

active

06673927

ABSTRACT:

BACKGROUND OF THE INVENTION
Ras is a 21,000 molecular weight protein important in the signal transduction pathway for normal 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 pyrophosphate in a reaction catalyzed by the enzyme farnesyl 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
168
is methyl esterified (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)). 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 normal function (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, over 30 percent of lung 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 farnesyl transferase (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)).
Recently, it has been shown that a farnesyl transferase inhibitor will 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 farnesyl 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, the invention features a compound having the formula (I) or formula (II):
wherein:
R
1
is H, lower alkyl, cycloalkylthio, or lower alkylthio, or, together with R
2
, form —CH
2
— or —C(CH
3
)
2
—;
each of R
2
and R
3
, independently, is H, lower alkyl, and cycloalkyl;
R
4
is H
2
or O;
R
5
is H, or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent is lower alkyl, —O—R
10
, —S(O)
m
R
10
(where m is 0, 1, or 2), —N(R
10
) (R
11
), —N—C(O)—R
10
, —NH—(SO
2
)—R
10
; —CO
2
—R
10
, —C(O)—N(R
10
)(R
11
), or —(SO
2
)—N(R
10
)(R
11
);
each of R
6
and R
7
, independently, is H, —C(O)—NHCHR
13
CO
2
R
14
, or substituted or unsubstituted lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent is OH, lower alkyl, lower alkoxy, aryloxy, aryl lower alkoxy, —N(R
10
)(R
11
), —COOH, —CON(R
10
)(R
11
), or halo, or R
6
and R
7
, together, form aryl or heterocyclyl;
each of R
8
and R
9
, independently, is H, or substituted or unsubstituted lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent is OH, lower alkyl, lower alkoxy, —N(R
10
)(R
11
), COOH, —C(O)N—(R
10
)(R
11
), or halo, or R
8
and R
9
, together, form aryl or heterocyclyl;
each of R
10
and R
11
, independently, is H, lower alkyl, aryl, aryl lower alkyl, cycloalkyl, cycloalkyl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl;
R
12
is NR
9
, S, or O;
R
13
is substituted or unsubstituted lower alkyl wherein the substituent is lower alkyl, —OR
10
, —S(O)
m
R
10
(wherein m is 0, 1, or 2) or —N(R
10
)(R
11
); and
R
14
is H or lower alkyl; or
a pharmaceutically acceptable salt thereof.
Examples of the present invention include the following:
7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine (Compound 1);
7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(4-fluorophenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine (Compound 2);
7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine (Compound 3);
7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(3-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine Compound 4);
7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine Compound 5);
7-(2-amino-1-oxo-3-thio-propyl)-8-(2-hydroxy-ethyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine (Compound 6);
7-(2-amino-3-thio-propyl)-8-butyl-3-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine (Compound 7);
2-(1-(N-(2-amino-1-oxo-3-thiopropyl)-N-methyl)-amino-pentyl)-5-phenyl-imidazole (Compound 8);
2-(((2-amino-1-oxo-3-mercapto-propyl)-amino)-methyl)-5-phenyl-thiazole-4-carbonyl-methionine (Compound 9);
7-(2-amino-1-oxo-3-thio-propyl)-2-(2-methoxyphenyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydro-imidazol[1,2a]pyrazine (Compound 11);
7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-ethoxyphenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine (Compound 13);
7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-hydroxyphenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine (Compound 14);
2-(1-(N-(2-amino-1-oxo-3-thiopropyl)-N-methyl)-amino-pentyl-5-(2-methoxyphenyl)-imidazole (Compound 15);
7-(2-amino-1-oxo-3-thiopropyl)-8-(2-methylpropyl)-2-(1-naphthyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine (Compound 17);
7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine (Compound 18);
S-(dimethylethyl)-s′-[2-amino-3-oxo-3(8-butyl-2-(2-methoxyphenyl;)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine-7-yl)propyl]disulfide (Compound 21);
7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine (Compound 22);
7-(2-amino-1-oxo-3-thiopropyl)-8-(1,1-dimethylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine (Compound 24);
7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-(phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine (Compound 25);
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine (Compound 26);
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1,2a]]pyrazine (Compound 27);
7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2(2-hydroxy-6-methoxyphenyl)-5,6,7,8-tetrahydro[1,2a]pyrazine (Compound 29);
2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydro-7-((thiazolidin-4-yl)carbonyl)-imidazo[1,2a]pyrazine (Compound 31);
7-(2-amino-1-oxo-3-thiopropyl)-3-bromo-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine (Compound 32);
7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2,3-diphenyl-5,6,7,8-tetrahydroimidazo-[1,2a]pyrazine (Compound 34);
7-(2-amino-1-oxo-3-thiopropyl)-3-bromo-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]pyraz

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