Inhibitors of isoprenyl transferase

Details Inhibitors of isoprenyl transferase Inhibitors of isoprenyl transferase

1999-04-01

2001-07-24

Barts, Samuel (Department: 1621)

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

Organic compounds

Carboxylic acid esters

C560S010000, C560S016000, C562S426000, C562S427000, C549S493000

Reexamination Certificate

active

06265603

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention concerns peptidomimetic isoprenyl transferase inhibitor compounds useful in the treatment of human cancers.
Ras oncogenes are prevalent in over 20% of all human cancers. The compounds of the invention inhibit the posttranslational processing of ras proteins, thereby inhibiting ras protein function.
Ras proteins are present in all cell types, and are thought to take part in normal cellular signal transduction mechanisms. Ras mutations are thought to cause hyperproliferation of cells; mutated ras genes are known as oncogenes. In particular, ras oncogenes are found in approximately 30% of all lung cancer, 30% of all myeloid leukemia, 50% of all colorectal carcinoma, and 90% of all pancreatic carcinoma. Barbacid, M.,
Ann. Rev. Biochem.,
56:779 (1987), Bos, J. L.,
Cancer Res.
49:4682 (1989). Examples of ras mutations include H-ras, K-ras, and N-ras.
Like other members of the superfamily of small GTP-hydrolyzing proteins, ras-encoded proteins, both normal and mutated, require post-translational processing for cell membrane association and biological activity. Maltese, W. A.,
FASEB Journal,
4:3319 (1990), Hancock, J. F. et al.,
Cell,
57:1167 (1989).
The post-translational processing of ras proteins is signaled by a short carboxyl-terminus consensus sequence, known as the CAAX box. This sequence signals which of two isoprenyl groups, farnesyl or geranylgeranyl, is to be attached to ras proteins by cellular enzymes. A farnesyl group is a 15 carbon isoprenyl group, while a geranylgeranyl group is a 20 carbon isoprenyl group. Isoprenyl groups are multimers of isoprene, a 5 carbon compound. For farnesylated proteins, such as ras, lamin B, and &ggr;-transducin, C is cysteine, A is an aliphatic amino acid, and X (the carboxyl-terminal amino acid) is methionine, serine, or glutamine. Geranylgeranylated proteins such as Rap, Rho and other small GTP-binding proteins, have similar CAAX sequences in which X is usually leucine, or occasionally is phenylalanine. In vivo, ras proteins are preferentially farnesylated.
Post-translational processing of the ras-encoded protein includes at least three steps. First, reaction with farnesyl pyrophosphate attaches a farnesyl group to the Cys residue on the sulfhydryl side chain. Second, a specific protease cleaves the three carboxy-terminal amino acids. Third, the carboxylic acid moiety of the now-terminal cysteine is methylated to a methyl ester. The farnesyl transferase enzyme (FTase) mediates the attachment of the farnesyl group to a protein. The geranylgeranyl transferase I enzyme (GGTase I) mediates the attachment of the geranylgeranyl group to a protein. Post-translational processing, particularly farnesylation, of ras proteins is critical for in vivo ras protein function. Among other things, farnesylation of ras oncogene products is known to be essential for ras-induced cellular transformation. Cox, A. D. and Der, C. A. Critical Rev. in Oncogenesis, 3 (4) 365-400 (1992). Upstream of FTase, farnesylation of a ras protein can be inhibited by mevalonate synthesis inhibitors such as lovastatin or compactin, which are HMG-CoA reductase inhibitors. Direct inhibition of FTase by short peptides or peptide-like substrates has also been demonstrated. Since ras proteins mediate the transformation of normal cells to cancer cells in many human cancers, compounds which inhibit prenylation will, therefore, inhibit the growth of ras-related cancers.
SUMMARY OF THE INVENTION
This invention is directed to novel peptidomimetic isoprenyl transferase inhibitor compound useful in the treatment of ras-associated human cancers. Ras-associate a human cancers are those in which a mutated form of the ras gene product are commonly found, e.g., lung cancers, myeloid leukemia, colorectal carcinoma, pancreatic carcinoma, and the like.
The invention concerns the compounds themselves, the preparation of these compounds, and the in vitro and in vivo isoprenyl transferase activity of these compounds. Another aspect of the invention is directed to the clinical use of the compounds to decrease isoprenyl transferase activity in biological systems, and to the physiological consequences of inhibition of isoprenyl transferase.
The compounds of the invention possess advantages for pharmaceutical use such as enhanced pharmacological selectivity and efficacy.
The compounds of the invention may be used clinically to treat medical conditions where a decrease in isoprenyl transferase activity is beneficial. The compounds of the invention can be used to inhibit post-translational modification of oncogenic ras proteins by FTase, thereby down-regulating ras protein-stimulated cell proliferation. Accordingly, the invention is directed to the treatment of various forms of ras-associated cancer. Some compounds of the invention inhibit post-translational modification of ras proteins by the related GGTase I, which also results in down-regulation of ras protein function. Certain compounds of the invention are selective or specific for FTase and are preferred over compounds which are selective for GGTase I.
Further, compounds of the present invention may contain asymmetric carbon atoms and hence can exist as stereoisomers, both enantiomers and diastereomers. All stereoisomers and mixtures thereof are considered to fall within the scope of the present invention. The synthetic examples cited herein provide the most preferred isomer.
The invention is also directed to prodrugs and pharmaceutically acceptable salts of the compounds described, and to pharmaceutical compositions suitable for different routes of drug administration and which comprise a therapeutically effective amount of a described compound admixed with a pharmacologically acceptable carrier.
DEFINITIONS
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term “aryl” refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, and the like, all of which may be optionally substituted.
Carbocyclic aryl groups are groups wherein the ring atoms of the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and optionally substituted naphthyl groups.
The term “optionally substituted” means the substitution on aryl groups, whether carbocyclic, heterocyclic, or biaryl, with one to four substituents, the substituents being independently selected from lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, carboxy, carboxyalkyl, cyano, nitro, trihalomethyl, amino, lower alkylamino, lower acylamino or lower alkoxycarbonyl.
The term “aralkyl” refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like. The aryl group of an aralkyl moiety may be optionally substituted. Aralkyl groups may be described herein as (C
x-y
aryl)(C
a-b
alkyl) where “x-y” denotes the range of the number of carbon atoms in the aryl moiety of the aralkyl group and “a-b” denotes the range of the number of carbon atoms in the alkyl moiety of the aralkyl group.
The term “lower” when used herein in connection with organic radicals or compounds respectively, defines them as comprising up to and including 10, preferably up to and including 6 and preferably one or two carbon atoms. Such organic radicals or compounds may have straight chain or branched chain structures.
The terms (a) “alkylamino”, (b) “arylamino”, and (c) “aralkylamino”, respectively, refer to the groups —NR
1
R
2
where each of R
1
and R
2
is

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