Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-19
2002-06-11
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S318000, C514S323000, C514S333000, C514S339000, C514S394000, C514S397000, C514S411000
Reexamination Certificate
active
06403581
ABSTRACT:
BACKGROUND OF THE INVENTION
a) Field of the Invention
The present invention provides a method of treating or controlling ras oncogene-dependent tumors and associated proliferative diseases in a mammal in need thereof by inhibition of farnesyl-protein transferase(FPTase) which comprises administering to said mammal an effective amount of a substituted benz[cd]indol-2-imine and -amine derivatives and pharmaceutically acceptable salts thereof.
These compounds may also inhibit other prenyl modifications of proteins.
b) Description of the Prior Art
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 accordingly provides a method of treating Ras-associated proliferative diseases including cancer, or in the treatment of diseases associated with other prenyl modifications of proteins.
SUMMARY OF THE INVENTION
This invention provides a method of treating, inhibiting or controlling a ras-associated disease by inhibiting farnesyl-protein transferase enzyme in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula I:
wherein:
the dotted line ------ at position a is an optional additional bond;
the dotted line ------ at position b is an optional additional bond;
R
1
is selected from the group consisting of H, alkyl of 1 to 6 carbon atoms, phenyl, and a moiety of the following:
R
2
is selected from alkoxy of 1 to 8 carbon atoms, trifluoromethyl and halogen;
c is an integer of 0 to 3;
d is an integer of 1 to 3;
n is an integer of 1 to 6;
A is a monocyclic ring having 5 or 6 ring atoms optionally having saturated or unsaturated bonds and containing 1 or 2 nitrogen atoms and 0 or 1 oxygen atoms;
R
2
is selected from the group consisting of hydrogen, alkoxy of 1 to 8 carbon atoms, alkylthio of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 8 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, hydroxy, hydroxyalkyl of 1 to 8 carbon atoms, mercapto, alkylcarbonyloxy of 1 to 8 carbon atoms, amino, mono(alkyl)amino of 1 to 8 carbon atoms, di(alkyl)amino of 1 to 16 carbon atoms, (alpha, omega-alkylene)amino of 2 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms, arylalkyl of 7 to 20 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkoxy of 3 to 10 carbon atoms, alkylcarbonyl of 1 to 8 carbon atoms, arylcarbonyl of 6 to 12 carbon atoms, cyano, sulfonamido, N-alkylsulfonamido of 1 to 8 carbon atoms, N,N-(dialkyl)sulfonamido of 2 to 16 carbon atoms, alpha-hydroxyalkyl of 1 to 8 carbon atoms, alpha-aminoalkyl of 1 to 8 carbon atoms, alpha-alkylaminoalkyl of 2 to 16 carbon atoms, alpha-(dialkyl)amino(alkyl) of 3 to 24 carbon atoms, carboxamido, N-(alkyl)carboxamido of 1 to 8 carbon atoms, N,N-(dialkyl)carboxamido of 2 to 16 carbon atoms, and halogen;
Q is selected from
a) a chain—(CH
2
)
m
— optionally containing one or more—CH═CH— or —C≡C— linkages and further optionally replacing one of the chain —CH
2
— groups with —O—, —S—, —SO
2
—, —NH—, —N-alkyl of 1 to 8 carbon atoms, —N-aryl of 6 to 12 carbon atoms, or —(C═O)NH— and further optionally substituting said chain with substitutents selected from alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, arylalkyl of 7 to 20 carbon atoms, aryl of 6 to 12 carbon atoms, hydroxy, alkoxy of 1 to 8 carbon atoms, and fluoro; or
b) a moiety of the formula
c) a moiety of the formula
k, 1 and m are independently selected from an integer of 1 to 12;
B is a monocyclic cycloalkyl ring having 3 to 10 ring atoms;
R
3
is selected from hydrogen, and a substituted or unsubstituted heterocycle;
R
4
is selected from hydrogen, halogen, and alkyl of 1 to 6 carbon atoms;
R
5
is selected from hydrogen and alkyl of 1 to 8 carbon atoms;
R
5
and Q taken together with the nitrogen atom to which they are attached form a monocyclic ring having the moiety
provided that at either position a or b is present an additional bond and if at b, is present an additional bond, R
1
is not present and a is not present, and if at a, is present an additional bond, R
5
is not present and b is not present;
or a pharmaceutically acceptable salt thereof.
For the compounds defined above and referred to herein, unless otherwise noted, the following terms are defined. The term halogen may be selected from fluorine, chlorine, bromine, and iodine.
The term alkyl means a branched or branched saturated or unsaturated hydrocarbon radical of 1 to 8 carbon atoms optionally containing double or triple bonds. Examples of alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, butenyl, pentyl, butynyl and pentynyl and the like unless otherwise specified.
Alkylthio as used here means an alkyl-S— in which the alkyl group is as previously described. Thioalkyl groups include thiomethyl and the like.
Mono(alkyl)amino is defined as a nitrogen atom substituted with alkyl of 1 to 8 carbon atoms.
Di(alkyl)amino is defined as a nitrogen atom independently substituted with two alkyl groups of 1 to 8 carbon atoms.
Alkylsulfonyl as used herein refers to the radical —SO
2
alkyl where alkyl is previously defined.
The term alkoxy means a branched or unbranched hydrocarbon radical of 1 to 8 carbon atoms attached through an oxygen bridge and inclu
Ayral-Kaloustian Semiramis
Kitchen Douglas Bruce
Shavnya Andrei
American Cyanamid Company
Moran Daniel B.
Reamer James H.
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