Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-13
2002-09-24
Kifle, Bruck (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06455523
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.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, compounds of the formulas I, II, III and IV
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-IV and throughout their specification, the above symbols are defined as follows:
m, n, r, s and t are 0 or 1;
p is 0, 1 or 2;
V, W and X are selected from the group consisting of oxygen, hydrogen, R
1
, R
2
or R
3
;
Z and Y are selected from the group consisting of CHR
9
, SO
2
, SO
3
, CO, CO
2
, O, NR
10
, SO
2
NR
11
, CONR
12
,
or Z may be absent;
R
6
, R
7
, R
9
, R
10
, 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
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
, and R
38
are selected from the group consisting of hydrogen, lower alkyl, substituted alkyl, aryl, or substituted aryl;
R
4
, R
5
are selected from the group consisting of hydrogen, halo, nitro, cyano and U-R
23
;
U is selected from the group consisting of sulfur, oxygen, NR
24
, CO, SO, SO
2
, CO
2
, NR
25
CO
2
, NR
26
CONR
27
, NR
28
SO
2
, NR
29
SO
2
NR
30
, SO
2
NR
31
, NR
32
CO, CONR
33
, PO
2
R
34
and PO
3
R
35
or U is absent;
R
1
, R
2
, and R
3
are selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl (e.g. CONH
2
) or substituted carbamyl further selected from CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; R
8
and R
23
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;
Any two of R
1
, R
2
, and R
3
can be joined to form a cycloalkyl group;
R, S and T are selected from the group consisting of CH
2
, CO and CH(CH
2
)pQ wherein Q is NR
36
R
37
, OR
38
, or CN; and
A, B, C and D are carbon, oxygen, sulfur or nitrogen.
with the provisos that
1. When m is zero then V and W are not both oxygen or
2. W and X together can be oxygen only if Z is either absent, O, NR
10
,
in formulas I and II, and V and X together can be oxygen only if Y is O, NR
10
,
in formulas III and IV or
3. R
23
may be hydrogen except when U is SO, SO
2
, NR
25
CO
2
or NR
28
SO
2
, or
4. R
8
may be hydrogen except when Z is SO
2
, CO
2
, or
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
Bhide Rajeev
Ding Charles Z.
Hunt John T.
Kim Soong-Hoon
Leftheris Katerina
Bristol--Myers Squibb Company
Gibbons Maureen S.
Kifle Bruck
LandOfFree
Inhibitors of farnesyl protein transferase does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Inhibitors of farnesyl protein transferase, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibitors of farnesyl protein transferase will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2907400