Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-05
2003-08-05
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C514S313000, C514S314000
Reexamination Certificate
active
06602883
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 CAAX-containing proteins other than ras that are also post-translationally modified by the enzyme farnesyl protein transferase. The compounds also act as inhibitors of other prenyl transferases, and thus are 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 upon 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.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, a compound of the formulas I, II
its enantiomers and diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof inhibit S-farnesyl protein transferase which is an enzyme involved in ras oncogene function. In formulas I and II and throughout this specification, unless otherwise specified, the symbols are defined as follows:
l, m, r, s and t are 0 or 1;
n is 0, 1 or 2;
Y is selected from the group consisting of CHR
12
, SO
2
, SO
3
, CO, CO
2
, O, NR
13
, SO
2
NR
14
, CONR
15
, C(NCN), C(NCN)NR
16
, NR
17
CO, NR
18
SO
2
, CONR
19
NR
20
, SO
2
NR
21
NR
22
, S(O)(NR
23
), S(NR
24
)(NR
25
), or without Y;
Z is selected from the group consisting of CR
12
, S, SO, SO
2
, SO
3
, CO, CO
2
, O, NR
13
, SO
2
NR
14
, CONR
15
, NR
26
NR
27
, ONR
28
, NR
29
O, NR
30
SO
2
NR
31
, NR
32
SO
2
, NR
33
C(NCN), NR
34
C(NCN)NR
35
, NR
36
CO, NR
37
CONR
38
, NR
39
CO
2
, OCONR
40
, S(O)(NR
41
), S(NR
42
)(NR
43
) or CHR
12
; or without Z;
R
7
, R
8
are selected from the group consisting of hydrogen, halo, nitro, cyano and U—R
44
;
U is selected from the group consisting of S, O, NR
45
, CO, SO, SO
2
, CO
2
, NR
46
CO
2
, NR
47
CONR
48
, NR
49
SO
2
, NR
50
SO
2
NR
51
, SO
2
NR
52
, NR
53
CO, CONR
54
, PO
2
R
55
and PO
3
R
56
or without U;
R
9
, R
10
, 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
27
, 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
40
, R
41
, R
42
, R
43
, R
45
, R
46
, R
47
, R
48
, R
49
, R
50
, R
51
, R
52
, R
53
, R
54
, R
55
, R
56
, R
57
, R
58
and R
59
are selected from the group consisting of hydrogen, lower alkyl, aryl, heterocyclo, substituted alkyl or aryl or sustituted hetercyclo;
R
11
and R
44
are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo;
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl (e.g. CONH
2
), substituted carbamyl (where nitrogen may be substituted by groups selected from hydrogen, alkyl, substituted alkyl, aryl or aralkyl, substituted aryl, heterocyclo, substituted heterocyclo), alkoxycarbonyl; any two of R
1
, R
2
, R
3
, R
4
, R
5
and
R
6
can join to form a cycloalkyl group; any two of R
1
, R
2
, R
3
, R
4
, R
5
and R
6
together can be oxo, except when the carbon atom bearing the substituent is part of a double bond;
R, S and T are selected from the group consisting of CH
2
, CO and CH(CH
2
)
p
Q wherein Q is NR
57
R
58
, OR
59
, or CN; and p is 0, 1 or 2;
A, B and C are carbon, oxygen, sulfur or nitrogen; D is carbon, oxygen, sulfur or nitrogen or without D.
With the provisos that
1. When l and m are both 0, n is not 0.
2. R
11
may be hydrogen except when Z is SO, or when Z is O, NR
13
or S and the carbon to which it is attached is part of a double bond or when Y is SO
2
, CO
2
, NR
18
SO
2
, S(O)(NR
23
), or S(NR
24
)(NR
25
).
3. R
44
may be hydrogen except when U is SO, SO
2
, NR
46
CO
2
or NR
49
SO
2
.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
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, cycloalkyloxy, heterocylooxy, 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 alkyl, alkoxy, aryl, aralkyl or halogen.
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 str
Bhide Rajeev S.
Ding Charles Z.
Hunt John T.
Kim Soong-Hoon
Leftheris Katerina
Bristol--Myers Squibb Company
Gibbons Maureen S.
Kifle Bruck
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