5-Substituted-3(2H)-furanones useful for inhibition of...

Details 5-Substituted-3(2H)-furanones useful for inhibition of... 5-Substituted-3(2H)-furanones useful for inhibition of...

2002-08-23

2004-03-23

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S473000, C514S471000, C514S444000, C514S255050, C549S475000, C549S060000, C546S290000

Reexamination Certificate

active

06710078

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel series of 5-substituted-3(2H)-furanones, to pharmaceutical compositions containing them, to their use in cancer therapy and to a process for their preparation. The compounds inhibit Ras FPTase, and may be used as an alternative to, or in conjunction with, traditional cancer therapy for treating ras oncogene-dependent tumors, such as cancers of the pancreas, colon, bladder, and thyroid. Compounds in the invention may also be useful for controlling metastasis, suppressing angiogenesis, inducing apoptosis, and in treating Ras-associated proliferative diseases other than cancer, such as restenosis, neuro-fibromatosis, endometriosis, and psoriasis. These compounds may also inhibit prenylation of proteins other than Ras, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.
BACKGROUND OF THE INVENTION
Mammalian H-, K-, and N-Ras proteins, encoded by H-, K-, and N-ras proto-oncogenes, respectively, are 21 kD GTP-binding proteins which possess intrinsic GTPase activity and play a fundamental role in cell proliferation and differentiation (G. L. Bolton, J. S. Sebolt-Leopold, and J. C. Hodges,
Annu. Rep. Med. Chem.,
1994, 29, 165; R. J. A. Grand in “New Molecular Targets in Cancer Chemotherapy” J. D. Kerr, and P. Workman, Eds.,
CRC Press,
Boca Raton, Fla., 1994, p. 97). Specific mutations in the ras gene impair GTPase activity of Ras, leading to uninterrupted growth signals and to the transformation of normal cells into malignant phenotypes. Mutant ras oncogenes are found in approximately 25% of all human cancers, including 90% of pancreatic, 50% of colon, and 50% of thyroid tumors (J. L. Bos,
Cancer Res.,
1989, 49, 4682). It has been shown that normal cells transfected with mutant ras gene become cancerous and that unfarnesylated, cytosolic mutant Ras protein does not anchor in cell membranes and cannot induce this transformation (J. F. Hancock, H. Paterson, and C. J. Marshall,
Cell,
1990, 63, 133). Posttranslational modification and plasma membrane association of mutant Ras is essential for this transforming activity. The first and required step in the processing of Ras is farnesylation at the cysteine residue of its carboxyl terminal motif, CAAX (C=Cys−186, A=aliphatic amino acid, X=usually methionine, serine or glutamine). Since its identification, the enzyme farnesyl-protein transferase (FPTase) that catalyzes this first processing step has emerged as a promising target for therapeutic intervention (H.-W. Park, S. R. Boduluri, J. F. Moomaw, P. J. Casey, and L. S. Beese,
Science,
1997, 275, 1800; P. J. Casey, P. A. Solski, C. J. Der, and J. E. Buss,
Proc. Natl. Acad. Sci. U.S.A.,
1989, 86, 8323; S. Ayral-Kaloustian and J. S. Skotnicki,
Annu. Rep. Med. Chem.,
1996, 31, 165, and references therein). Major milestones have been achieved with small molecules, such as mimics of the tetrapeptide CAAX and analogs of farnesyl pyrophosphate, that show efficacy without toxicity in vitro as well as in mouse models bearing ras-dependent tumors or human xenografts with H-, N-, or K-ras mutations (S. Ayral-Kaloustian and J. S. Skotnicki,
Annu. Rep. Med. Chem.,
1996, 31, 165, and references therein; T. M. Williams,
Exp. Opin. Ther. Patents,
1998, 8, 553, and references therein). Several low-molecular weight compounds that inhibit FPTase have entered Phase I trials in humans (SCH-66336,
Pharmaprojects,
1998, No. 5128; R-115777,
Pharmaprojects,
1998, No. 5532).
Accordingly, there is still a need for drugs for treating and preventing cancer. In particular, there is a need for drugs which inhibit or treat the growth of tumors expressing an activated Ras oncogene and which include cancers of the pancreas, colon, bladder and thyroid.
The present invention further provides a method of treatment of ras oncogene-dependent tumors, such as cancers of the pancreas, colon, bladder, and thyroid; a method of controlling metastasis, suppressing angiogenesis, and inducing apoptosis; a method of treating Ras-associated proliferative diseases other than cancer, such as restenosis, neuro-fibromatosis, endometriosis, and psoriasis. The compounds of the present invention may also inhibit prenylation of proteins other than Ras, and thus provide a method of treatment of diseases associated with other prenyl modifications of proteins.
BRIEF SUMMARY OF THE INVENTION
The present invention discloses compounds represented by Formula (I):
wherein:
R
1
is alkyl of 1 to 10 carbon atoms optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl of 1 to 10 carbon atoms, —OH, —SH, —NH
2
, and halogen, alkenyl of 2 to 12 carbon atoms, optionally substituted aralkyl of 7 to 13 carbon atoms, optionally substituted aryl of 6 to 12 carbon atoms, and optionally substituted heteroaryl;
R
2
is phenyl, substituted phenyl (having from 1 to 3 substituents each independently selected from the group consisting of halogen, alkyl of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, alkylamino of 1 to 10 carbon atoms, amino, carboxy, alkylsulfonyl of 1 to 10 carbon atoms, cyano, nitro, perfluoroalkyl of 1 to 10 carbon atoms, and alkoxy of 1 to 10 carbon atoms),or naphthyl;
R
3
is optionally substituted aryl and optionally substituted heteroaryl;
X is —O—, —S—, or —NH—;
Y is —OH, —SH, —SR
4
, —NH
2
, —NHR
5
, —CO
2
H, —CONHOH, halogen, or heteroaryl;
R
4
is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, and aralkyl of 7 to 13 carbon atoms;
R
5
is alkyl of 1 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, and aralkyl of 7 to 13 carbon atoms;
Z is H or methyl;
Q is an alkyl chain of 2 to 6 carbon atoms optionally substituted with 1 to 4 substituents selected from the group consisting of alkyl of 1 to 10 carbon atoms, —OH, —SH, —NH
2
, halogen and alkenyl of 2 to 6 carbon atoms;
or a pharmacologically acceptable salt thereof.
Among the preferred groups of compounds of Formula (I) of this invention including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
a.) X is S;
b.) X is S;
Y is SH;
c.) X is S;
Y is SH;
R
3
is thienyl;
d.) X is S;
Y is SH, tetrazole or imidazole;
R
3
is thienyl;
e.) X is S;
Y is SH;
R
2
is phenyl optionally substituted with one to three substituents each independently selected from the group consisting of halogen, alkyl of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, alkylamino of 1 to 10 carbon atoms, amino, carboxy, alkylsulfonyl of 1 to 10 carbon atoms, cyano, nitro, perfluoroalkyl of 1 to 10 carbon atoms, and alkoxy of 1 to 10 carbon atoms;
R
3
is phenyl optionally substituted with one to three substituents each independently selected from the group consisting of halogen, alkyl of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, alkylamino of 1 to 10 carbon atoms, amino, carboxy, alkylsulfonyl of 1 to 10 carbon atoms, cyano, nitro, perfluoroalkyl of 1 to 10 carbon atoms, and alkoxy of 1 to 10 carbon atoms;
More preferred aspects of this invention includes compounds of Formula (I) including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein: X is S; Z is H or methyl; and R
1
is methyl;
a) R
2
is phenyl optionally substituted with one to three substituents each independently selected from the group consisting of halogen, alkyl of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, alkylamino of 1 to 10 carbon atoms, amino, carboxy, alkylsulfonyl of 1 to 10 carbon atoms, cyano, nitro, perfluoroalkyl of 1 to 10 carbon atoms, and alkoxy of 1 to 10 carbon atoms when R
3
is thienyl and Y is SH;
b) R
2
is phenyl optionally substituted with one to three substituents each independently selected from the group consisting of halogen, alkyl of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, alkylamino of 1 to 10 carbon atom

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