Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-01
2001-11-06
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S450000, C540S451000, C540S484000, C540S485000, C540S544000, C514S211070
Reexamination Certificate
active
06313109
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 posttranslationally 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 7 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 tree 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 is 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
3
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.
REFERENCES:
patent: 5736539 (1998-04-01), Graham et al.
patent: WO 95/00497 (1995-01-01), None
Bishop et al., “Novel Tricyclic Inhibitors of Farnesyl Protein Transferase”, The Journal of Biological Chemistry 270:30611-30618, 1995.
Bhide et al., “Rational Design of Potent Carboxylic Acid Based Bisubstrate Inhibitors of Ras Farnesyl Protein Transferase” Bioorganic & Medicinal Chemistry Letters 4:2107-2112, 1994.
Buss et al., “Farnesyl Transferase Inhibitors: The Successes and Surprises of a New Class of Potential Cancer Chemotherapeutics”, Chemistry & Biology 2:787-791, Dec. 1995.
Clerc et al., “Constrained Analogs of KCVFM With Improved Inhibitory Properties Against Farnesyl Transferase” Biorganic & Medicinal Chemistry Letters 16:1779-1784, 1995.
deSolmes et al., “Pseudodipeptide Inhibitors of Protein Farnesyltransferase”, J. Med. Chem, 38:3967-3971, 1995.
Garcia et al., “Peptidomimetic Inhibitors of Ras Farnesylation and Function in Whole Cells”, The Journal of Biology Chemistry vol. 268, No. 25, pp. 18415-18418, 1993.
Graham et al., “Pseudopeptide Inhibitors of Ras Farnesyl-Protein Transferase”, J. Med. Chem. 37:725-732, 1994.
Gibbs et al., “Farnesyltransferase Inhibitors: Ras Research Yields a Potential Cancer Therapeutic”, Cell 77:175-1 Apr. 22, 1994.
Harrington et al., “Cysteine and Methionine Linked by Carbon Pseudopeptides Inhibit Farnesyl Transferase”, Bioo & Medicinal Chemistry Letters vol. 4, No. 23, pp. 2775-2780. 1994.
Hunt et al., “Potent, Cell Active, Non-Thiol Tetrapeptide Inhibitors of Farnesyltransferase”, J. Med. Chem. 39:353-1996.
James et al., “Benzodiazepine
Aulakh Charanjit S.
Conway John D.
Fish & Richardson
Morrill Brian R.
Societe de Conseils de Recherches d'Applications Scientifiq
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