Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-21
2002-10-01
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S080000, C514S221000, C540S542000, C540S557000, C540S573000
Reexamination Certificate
active
06458783
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds that inhibit farnesyl-protein transferase and ras protein farnesylation, thereby making them useful as anti-cancer agents. The compounds are also useful in the treatment of diseases, other than cancer, associated with signal transduction pathways operating through ras and those associated with proteins other than ras that are also post-translationally modified by the enzyme farnesyl protein transferase. The compounds may also act as inhibitors of other prenyl transferases, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.
BACKGROUND OF THE INVENTION
The mammalian ras gene family comprises three genes, H-ras, K-ras and N-ras. The ras proteins are a family of GTP-binding and hydrolyzing proteins that regulate cell growth and differentiation. Overproduction of normal ras proteins or mutations that inhibit their GTPase activity can lead to uncontrolled cell division.
The transforming activity of ras is dependent on localization of the protein to plasma membranes. This membrane binding occurs via a series of post-translational modifications of the cytosolic Ras proteins. The first and mandatory step in this sequence of events is the farnesylation of these proteins. The reaction is catalyzed by the enzyme farnesyl protein transferase (FPT), and farnesyl pyrophosphate (FPP) serves as the farnesyl group donor in this reaction. The ras C-terminus contains a sequence motif termed a “Cys-Aaa
1
-Aaa
2
-Xaa” box (CAAX box), wherein Cys is cysteine, Aaa is an aliphatic amino acid, and Xaa is a serine or methionine. Farnesylation occurs on the cysteinyl residue of the CAAX box (cys-186), thereby attaching the prenyl group on the protein via a thio-ether linkage.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, compounds of the formulas I, and
their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof inhibit farnesyl protein transferase which is an enzyme involved in ras oncogene expression. In formulas I and II, and throughout the specification, the above symbols are defined as follows:
r, s and t are each independently 0 or 1;
Z is CHR
9
, SO
2
, CO, CO
2
, O, NR
10
, —SO
2
NR
11
, —CONR
12
,
or Z may be absent;
Y is CHR
23
, SO
2
, CO, NR
24
,
—SO
2
NR
25
or —CONR
26
or Y may be absent;
R
6
, R
9
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, R
25
, R
26
, R
28
, R
29
, R
30
, R
31
, R
32
, R
33
, R
34
, R
35
, R
36
, R
37
, R
38
, R
39
, R
41
, R
42
, R
43
, R
44
, R
45
and R
46
are each independently hydrogen, lower alkyl, substituted alkyl, aryl or substituted aryl;
R
4
,R
5
, R
47
, R
48
, R
49
, R
50
and R
51
are each independently hydrogen, halo, nitro, cyano or U-R
27
;
U is sulfur, oxygen, NR
28
, CO, SO, SO
2
, CO
2
, NR
29
CO
2
, NR
30
CONR
31
, NR
32
SO
2
, NR
33
SO
2
NR
34
, SO
2
NR
35
, NR
36
CO, CONR
37
, PO
2
R
38
or PO
3
R
39
or U is absent;
R
4
and R
5
may join together to form a ring;
R
1
, R
2
and R
3
are each independently hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl or substituted carbamyl;
R
8
and R
27
are each independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo or substituted heterocyclo;
any two of R
1
, R
2
and R
3
may join to form a cycloalkyl group;
R, S and T are each independently CR
40
R
41
or NR
42
;
R
40
is H, NR
44
R
45
, OR
46
or CN;
G is —S—, —SO
2
NH—, —NHSO
2
—, —N(OR
46
)SO
2
—,
or heterocycles other than imidazole;
with the provisos that:
1) R
27
may be hydrogen except when U is SO, SO
2
, CO
2
, NR
29
CO
2
or NR
32
SO
2
, or
2) R
8
may be hydrogen except when Z is SO
2
, CO
2
,
3) only one of Y, R, S and T may be nitrogen, or
4) any of Y, R, S and T may be nitrogen except when G is —S—, —NHSO
2
—, —N(OR
46
)SO
2
—,
or
5) R
6
may be hydrogen except when G is —NHSO
2
— or —N(OR
46
)SO
2
—, or
6) the sum of r, s and t together may not be zero.
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term “alkyl” refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression “lower alkyl” refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The term “substituted alkyl” refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SO
2
NH
2
, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. CONH
2
, substituted carbamyl e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.
The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
The term “aralkyl” refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term “substituted aryl” refers to an aryl group substituted by, for example, one to four substituents such as alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
The term “alkenyl” refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four double bonds.
The term “substituted alkenyl” refers to an alkenyl group substituted by, for example, one to two substituents, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g. indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term “alkynyl” refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four triple bonds.
The term “substituted alkynyl” refers to an alkynyl group substituted by, for example, a substituent, such as, halo, hydroxy, alkoxy, alkanoyl,
Bhide Rajeev S.
Ding Charles Z.
Hunt John T.
Leftheris Katerina
Bristol--Myers Squibb Company
Coleman Brenda
Gibbons Maureen S.
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