Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
BACKGROUND OF THE INVENTION
The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras)
are part of a signalling pathway that links cell surface growth factor
receptors to nuclear signals initiating cellular proliferation. Biological
and biochemical studies of Ras action indicate that Ras functions like
a G-regulatory protein. In the inactive state, Ras is bound to GDP.
Upon growth factor receptor activation Ras is induced to exchange
GDP for GTP and undergoes a conformational change. The GTP-
bound form of Ras propagates the growth stimulatory signal until the
signal is termin~ted by the intrinsic GTPase activity of Ras, which
returns the protein to its inactive GDP bound form (D.R. Lowy and
D.M. Willumsen, AnM. Rev. Biochem. 62:851-891 (1993)). Mutated
ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many
human cancers, including colorectal carcinoma, exocrine pancreatic
carcinoma, and myeloid leukemias. The protein products of these
genes are defective in their GTPase activity and constitutively
transmit a growth stimulatory .signal.
Ras must be localized to the plasma membrane for
both normal and oncogenic functions. At least 3 po.st-translational
modifications are involved with Ras membrane localization, and all
3 modifications occur at the C-terminus of Ras. The Ras C-terminus
contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa2-Xaa"
box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any
amino acid) (Willumsen et al., N~lture 310:583-586 (1984)). Depend-
ing on the specific sequence, this motif serves as a signal sequence for
the enzymes farnesyl-protein transferase or geranylgeranyl-protein
transferase, which catalyze the alkylation of the cysteine residue
of the CAAX motif with a Cls or C20 isoprenoid, respectively.
(S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer
and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). The Ras protein
is one of several proteins that are known to undergo post-translational
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farnesylation. Other farnesylated proteins include the Ras-related GTP-
binding proteins such as Rho, fungal mating factors, the nuclear lamins,
and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269,
14182 (1994) have identified a peroxisome associated protein Pxf which
is also farnesylated. James, et al., have also suggested that there are
farnesylated proteins of unknown structure and function in addition to
those listed above.
Inhibition of farnesyl-protein transferase has been
shown to block the growth of Ras-transformed cells in soft agar and to
modify other aspects of their transformed phenotype. It has also been
demonstrated that certain inhibitors of farnesyl-protein transferase
selectively block the processing of the Ras oncoprotein intracellularly
(N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al.,
Science, 260:1937-1942 (1993). Recently, it has been shown that an
inhibitor of farnesyl-protein transferase blocks the growth of ras-
dependent tumors in nude mice (N.E. Kohl et al.~ Proc. Natl. Acad.
Sci U.S.A., 91:9141-9145 (1994) and induces regression of m~mm~ry
and salivary carcinomas in ras transgenic mice (N.E. Kohl et al.,
Nat~re Medicine, 1 :792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo
has been demonstrated with lovastatin (Merck & Co., Rahway, NJ)
and compactin (Hancock et al., il~id; Casey et al., ibid; Schafer et al.,
Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the
rate limiting enzyme for the production of polyisoprenoids including
farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl
pyrophosphate to covalently modify the Cys thiol group of the Ras
CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-~ (1990);
Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al.,
Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci
USA, 87:7541 -7545 (1990)). Inhibition of farnesyl pyrophosphate
biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane
localization in cultured cells. However, direct inhibition of farnesyl-
protein transferase would be more specific and attended by fewer side
effects than would occur with the required dose of a general inhibitor
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of isoprene biosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have
been described in four general classes (S. Graham, Expert Opinion
Ther. Patents, (1995) 5:1269-12~5). The first are analogs of farnesyl
S diphosphate (FPP), while a second class of inhibitors is related to the
protein substrates (e.g., Ras) for the enzyme. Bisubstrate inhibitors and
inhibitors of farnesyl-protein transferase that are non-competitive with
the substrates have also been described. The peptide derived inhibitors
that have been described are generally cysteine cont~inin~ molecules
10 that are related to the CAAX motif that is the signal for protein
prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al.,
PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein
prenylation while serving as alternate substrates for the farnesyl-
protein transferase enzyme, or may be purely competitive inhibitors
15 (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al.,
Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem.,
37, 725 (1994)). In general, deletion of the thiol from a CAAX
derivative has been shown to dramatically reduce the inhibitory
potency of the compound. However, the thiol group potentially
20 places limitations on the therapeutic application of FPTase inhibitors
with respect to pharrnacokinetics, pharmacodynamics and toxicity.
Therefore, a functional replacement for the thiol is desirable.
It has recently been disclosed that certain tricyclic
compounds which optionally incorporate a piperidine moiety are
25 inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
Imidazole-cont~ining inhibitors of farnesyl protein transferase have also
been disclosed (WO 95/09001 and EP 0 675 112 Al).
It has recently been reported that farnesyl-protein
transferase inhibitors are inhibitors of proliferation of vascular
30 smooth muscle cells and are therefore useful in the prevention
and therapy of arteriosclerosis and diabetic disturbance of blood
vessels (JP H7-112930).
It is, therefore, an object of this invention to develop
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low molecular weight compounds that will inhibit farnesyl-protein
transferase and thus, the post-translational farnesylation of proteins.
It is a further object of this invention to develop chemotherapeutic
compositions containing the compounds of this invention and methods
5 for producing the compounds of this invention.
SUMMARY OF THE INVENTION
The present invention comprises arylheteroaryl-
cont~ining compounds which inhibit the farnesyl-protein transferase.
10 Further contained in this invention are chemotherapeutic compositions
cont~ining these farnesyl transferase inhibitors and methods for their
production.
The compounds of this invention are illustrated by the
formula A:
,f ~ f
(R8)r /(lj~ ~ R2~;~
V - A1(CR1a2)nA2(CR1a2)n t W ~ -(CR1b2)p- X -(CR1b P R4
A
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhibition
of farnesyl-protein transferase and the farnesylation of the oncogene
20 protein Ras. In a first embodiment of this invention, the inhibitors of
farnesyl-protein transferase are illustrated by the formula A:
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,f ~ f
(R8)r (/~(9~ R2~ f
V-A (CR 2)nA (CR 2)ntW~ -(CR1b2)p-X-(CR1b2)/p~\RR
wherem:
from 1-3 of f(s) are independently N or N->O, and the remaining f's
5 are independently CR6;
R 1 a and R 1 b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R100-, Rl lS(O)m-, RlOC(O)NR10-,
R 1 1 C(O)O-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, NO2,
R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10,
c) unsubstituted or substituted Cl-C6 alkyl wherein the
substituent on the substituted Cl-C6 alkyl is selected from
unsubstituted or substituted aryl, heterocyclic,
C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R100-, Rl lS(O)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
Rlloc(o) NR10;
R2, R3, R4 and R5 are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-c6 alkenyl,
C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-,
RllS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o), RllC(o)o
-
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R 1 02N-C(NR 10), CN, N()2, R 1 ~C(O)-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsub.stituted or substituted heterocyclic,
C3-Clo cycloal~yl, C2-C6 alkenyl, C2-C6 alkynyl,
R120, Rl lS(O)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, Rl ~C(O)-, N3, -N(R10)2, and
Rlloc(o) NRlO;
each R6 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-c6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
Rl 20, R 1 1 S(O)m-, R 1 OC(O)NR 10, (R 1 0)2NC(O)-,
R 1 1 C(O)O-, R 1 02N-C(NR 10) , CN, N02, R 1 ~C(O)-,
N3, -N(R10)2, or Rl 10C(O)NR10-,
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from un.substituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 1 20, R 1 1 S(O)m-, R 1 OC(O)NR 10 , (R 1 0)2NC(O)-,
R102N-C(NR10)-, CN, R1OC(O)-, N3, -N(R10)2, and
R 1 1 OC(O)-NR 10; or
any two of R6 on adjacent carbon atoms are combined to form a
diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-,
-(CH2)4- and -(CH2)3-;
provided that when R2, R3, R4, RS, or R6 is unsubstituted or
substituted heterocycle, attachment of R2, R3, R4, RS, or
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R6 to the phenyl ring, or 6-membered heteroaryl ring
respectively, is through a substitutable heterocycle ring
carbon;
S R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or
substituted with:
a) Cl 4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
o
f) --SO2R
g) N(R10)2 or
h) C 1-4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, C3-Clo cycloalkyl,
C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br,
R 1 ~O-, R 1 1 S(O)m-~ R 1 0C(O)NR 10, (R 1 0)2NC(O)-,
R 1 02N-C(NR 1 0)-, CN, NO2, R 1 ~C(O)-, N3, -N(R 1 0)2, or
R 1 1 OC(O)NR 10, and
c) Cl-C6 alkyl unsubstituted or substituted by aryl,
cyanophenyl, heterocycle, C3-Clo cycloalkyl,
C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F,
Cl, Br, R 1 0O-, R 1 I S(O)m-~ R 1 0C(O)NH-, (R 1 0)2NC(O)-,
R 1 02N-C(NR 10), CN, R I ~C(O)-, N3, -N(R 1~)2, or
R 1 0OC(o)NH-;
provided that when R8 is heterocycle, attachment of R8 to V is
through a substitutable ring carbon;
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R9 is independently selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F,
Cl, Br, R1 lo, Rl 1S(O)m-, Rl0C(O)NR10-,
(R 10)2NC(o)-~ R l 02N-C(NR 1 0)-, CN, NO2, R 1 ~C(O)-,
N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, and
c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, R 1 1S(O)m-, R10C(O)NR10-,
(R l 0)2NC(O)-, R l 02N-C(NR 10), CN, R 10C(O)-, N3,
-N(R10)2, or Rl lOC(O)NRl0-;
Rl0 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
15 R11 is independently .selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-c6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
C1-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, sub~stituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C_C-,
-C(O)-, -C(O)NR 1 0, -NR 1 ~C(O)-, O, -N(R 1 0),
-S(0)2N(R 10), -N(R 1 ~)S(O)2- or S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are
- replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl,
.
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provided that V is not hydrogen if Al is S(O)m and V is not hydrogen
if Al is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is
through a substitutable ring carbon;
s
W is a heterocycle;
X is a bond, -CH=CH-, O, -C(=O)-, -C(o)NR7-, -NR7C(o)-, -C(O)O-,
-OC(O)-, -C(o)NR7C(o)-, -NR7-, -S(O)2N(R 1 0)-,
-N(R10)S(0)2- or-s~=o)m-;
mis 0, l or2;
n is independently 0, l, 2, 3 or 4;
p is independently 0, l, 2, 3 or 4;
q is 0, 1, 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and
t is 0 or 1;
or the pha~naceutically acceptable salts thereof.
A preferred embodiment of the compounds of this
invention is illustrated by the following formula:
V - A~ (CR1 a2)nAZ(CR 1a2)n ~ - (CR~b2)p - X -(Cl~
wherem:
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- 10 -
from 1-3 of f(s) are independently N or N->O, and the remaining fs
are independently CR6;
R1a is independently selected from: hydrogen, C3-Clo cycloalkyl,
S R l~o, -N(R 1~)2, F or C 1 -C6 alkyl;
Rlb is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C l o cycloalkyl, R 1 00-, -N(R 1 0)2, F
or C2-C6 alkenyl,
c) unsubstituted or substituted Cl-C6 alkyl wherein the
substituent on the substituted Cl-C6 alkyl is selected from
unsubstituted or sub.stituted aryl, heterocycle, C3-Clo
cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;
R2, R3, R4 and RS are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C 10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120, Rl lS(o)m, RlOc(o)NR10-, (R10)2NC(o)-,
R102N-C(NR10)-, CN, N02, R1OC(O)-, N3, -N(R10)2,
or Rl 1 OC(O)NR 10-,
c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 1 20, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(O)-
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
R 1 1 OC(O)-NR 10;
each R6 is independently selected from:
a) hydrogen,
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b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 120, R l l S(O)m-~ R l OC(0)NR l O, (R 1 0)2NC(0)-,
R l 02N-C(NR 10), CN, N02, R I ~C(0)-, N3, -N(R 1~)2,
or R l 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-c6 alkynyl, R120-,
R 1 1 S(O)m-~ R 1 OC(O)NR l O, (R 1 0)2NC(0)-, R 1 02N-
C(NR 10), CN, R 1 ~C(0)-, N3, -N(R 1~)2, and R 1 l OC(0)-
NRlO; or
any two of R6 on adjacent carbon atom.s are combined to form a
diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-,
-(CH2)4- and -(CH2)3-;
provided that when R2, R3, R4, R5, or R6 is unsubstituted or
substituted heterocycle, attachment of R2, R3, R4, R5, or
R6 to the phenyl ring, or 6-membered heteroaryl ring
respectively, i~s throu~h a substitutable heterocycle ring
carbon;
R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or
substituted with:
a) C 1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) H0,
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- 12 -
e) ~R1
o
f) --So2R
g) N(R10)2 or
h) C 1-4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
R10O, Rl0C(o)NR10, CN, NO2, (R10)2N-C(NR10)-,
R10C(O)-, -N(R10)2, or Rl lOC(O)NR10-, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-,
R 1 0C(O)NR 1 ~, (R 1 0)2N-C(NR 1 0), R 1 ~C(O)-,
-N(R10)2, or Rl 1OC(O)NR10-;
provided that when R~ is heterocycle, attachment of R8 to V is
lS through a substitutable ring carbon;
R9 is independently selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F,
Cl, Rl lo, Rl lS(O)m-, R10C(O)NR10-, (R10)2Nc(o)
CN, NO2, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, -N(R 1~)2, or
Rl lOC(O)NR10-, and
c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6
perfluoroalkyl, F, Cl, R10O-, Rl lS(O)m-~ RlOC(o)NR 10,
(R10)2Nc(o)-~ CN, (R10)2N-C(NR 10), R10C(O)-,
-N(R 1~)2, or R 1 1 OC(O)NR 10;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
.. . . . . .
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- 13 -
R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-C6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
S heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
Al and A2 are independently selected from: a bond, -CH=CH-, -C-C-,
-C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl,
imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl,
quinolinyl, isoquinolinyl, triazolyl and thienyl,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and
20 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen
if Al is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, a~tachment of V to R8 and to Al is
through a substitutable ring carbon;
25 W is a heterocycle selected from pyrrolidinyl, irnidazolyl, imidazolinyl,
pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or
isoquinolinyl;
X is a bond, O, -C(=O)-, -CH=CH-, -C(o)NR7-, -NR7C(o)-, -NR7-,
-S(O)2N(R 1 0) , -N(R 1 ~)S(O)2- or -S(=O)m-;
mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
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p is independently 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r i.s 0 when V is hydrogen; and
t is 0 or 1;
S or the phalmaceutically acceptable salt~s thereof.
A preferred embodiment of the compounds of this
invention are illustrated by the formula B:
V A (CR 2)nA (C~ 2)--N/ \J
wherein:
from 1-3 of f(s) are independently N or N->O, and the remaining f's
are independently CR6;
Rla is independently selected from: hydrogen, C3-Clo cycloalkyl,
R l~o, -N(R 1~)2, F or C 1 -C6 alkyl;
Rlb is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3 -C 1 o cycloalkyl, R l OO-, -N(R 1 0)2, F
or C2-C6 alkenyl,
c) unsubstituted or substituted Cl-C6 alkyl wherein the
substituent on the substituted Cl -C6 alkyl i~s selected from
unsubstituted or substituted aryl, heterocycle, C3-Clo
cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;
R2 and R3 are independently selected from:
a) hydrogen,
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- 15 -
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10 , (R 1 0)2NC(O)-,
R102N-C(NR10)-, CN, N02, RlOC(O)-, N3, -N(R10)2,
or R 1 1 OC(O)NR 10
c) unsub,stituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, R1OC(O)-, N3, -N(R10)2, and
Rlloc(o) NR10;
each R6 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R 120 , R l l S(O)m , R l OC(O)NR 10-, (R 1 0)2NC(O)-,
R102N-C(NR10)-, CN, N02, RlOC(O)-, N3, -N(R10)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120, RllS(o)m, RlOc(o)NRlo-~ (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
R 1 1 OC(O)-NR 10; or
.
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- 16 -
any two of R6 on adjacent carbon atoms are combined to forrn a
diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-,
-(CH2)4- and -(CH2)3-;
provided that when R2, R3, or R6 is unsubstituted or substituted
heterocycle, attachment of R2, R3, or R6 to the phenyl
ring, or 6-membered heteroaryl ring respectively, is
through a substitutable heterocycle ring carbon;
10 R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
R 1 0O, R 1 0C(O)NR 10, CN, NO2, (R 1 0)2N-C(NR 10),
R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and
c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-,
RlOC(O)NR10-, (R10)2N-C(NR10)-, RlOC(O)-,
-N(R 1~)2, or R 1 1 OC(O)NR 10 ;
provided that when R~ is heterocycle, attachment of R8 to V is
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl
and halogen;
~5 R10 is independently ,selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
~0 R12 is independently selected from hydrogen, Cl-C6 alkyl, C1-C6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
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A1 and A2 are independently selected from: a bond, -CH=CH-, -C_C-,
-C(O)-, -C(O)NR 10, -NR 1 ~C(O)-, O, -N(R 10), or
S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl,
imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl,
quinolinyl, isoquinolinyl, triazolyl and thienyl,
c) aryl,
d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and
15 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen
if A1 is a bond, n i~s 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to Rg and to Al is
through a substitutable ring carbon;
20 X is a bond, -CH=CH-, -C(O)NR10-, -NR1OC(O)-, -NR10-, O or
-C(=O)-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
25 pis 0, 1, 2, 3 or4; and
r is 0 to 5, provided that r is O when V is hydrogen;
or the pharmaceutically acceptable salts thereof.
Another preferred embodiment of the compounds of this
30 invention are illustrated by the formula C:
CA 02249650 1998-09-23
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f--f,
V A1 a(CR12)nA2(CR 1 a2)n~/N ~R3
C R9b (CR1b2~
wherein:
from 1-3 of f(s) are independently N or N->O, and the remaining f~s
5 are independently CR6;
Rla is independently selected from: hydrogen, C3-Clo cycloalkyl,
R1OO-, -N(R10)2, F or Cl-C6 alkyl;
10 R1b i~s independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C l o cycloalkyl, R l OO-, -N(R 1 o)2, F
or C2-C6 alkenyl,
c) unsubstituted or substituted Cl-C6 alkyl wherein the
substituent on the substituted Cl-C6 alkyl is selected from
unsubstituted or sub.stituted aryl, heterocycle, C3-Clo
cycloalkyl, C2-C6 alkenyl, RlOO- and -N(R10)2;
R2 and R3 are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120, Rl lS(O)m, RlOC(O)NR10-~ CN(RlO)2Nc(o)-~
R102N-C(NR10)-, CN, NO2, R1OC(O)-, N3, -N(R10)2,
or Rl 1OC(O)NR10
c) unsubstituted C1-C6 alkyl,
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- 19 -
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 120 , R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(O)-,
R102N-C(NR10)-, CN, R1OC(O)-, N3, -N(R10)2, and
R l l OC(o)-NR 10 ;
each R6 is independently selected from:
a~ hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 1 20 , R 1 1 S(O)m ~ R 1 OC(O)NR 10, CN(R 1 0)2NC(O)-,
R 1 02N-C(NR 10), CN, N02, R 1 ~C(O)-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10
c) unsubstituted C I -C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
RlO2N-c(NRlo)-7 CN, RlOC(O)-, N3, -N(R10)2, and
R 1 1 OC(O)-NR 10; or
any two of R6 on adjacent carbon atoms are combined to form a
diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-,
-(CH2)4- and -(CH2)3-;
provided that when R2, R3, or R6 is unsubstituted or substituted
heterocycle, attachment of R2, R3, or R6 to the phenyl
ring, or 6-membered heteroaryl ring respectively, is
through a substitutable heterocycle ring carbon;
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- 20 -
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
S R100-, R10C(O)NR10-~ CN, r~O2, (R~0)2N-C(NR10)-,
R 10c(O)-, -N(R 1 0)2, or R 1 1 OC(O)NR 10, and
c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R100-,
R 1 0C(O)NR 10 , (R 1 0)2N-C(NR 10) , R 1 ~C(O)-,
-N(R10)2, or R1 lOC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl
and halogen;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C~-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, CI-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
Al and A2 are independently .selected from: a bond, -CH=CH-, -C~C-,
-C(O)-, -C(O)NR 1 0-, O, -N(R 1 0)-, or S(O)m;
~0 V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl,
imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl,
quinolinyl, isoquinolinyl, triazolyl and thienyl,
.
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- 21 -
c) aryl,
d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if Al is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R~ and to Al is
through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR ~ ~-, -NR l ~C(O)-, -NR l O , O or
-C(--O)-;
mis 0, l or2;
n is independently 0, l, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond,
-NR l OC(O)-, -NR l 0- or O; and
r is 0 to 5, provided that r is 0 when V is hydrogen;
or the pharmaceutically acceptable salts thereof.
In a more preferred embodiment of this invention, the
inhibitors of farnesyl-protein transferase are illustrated by the formula
D:
"f_ f
~R 1 b2)p
R8 D
- wherein:
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- 22 -
from 1-3 of f(s) are independently N or N->0, and the remaining ~s
are independently CR6;
R1a is independently selected from: hydrogen, C3-Clo cycloalkyl or
S Cl-C6 alkyl;
Rlb is independently seiected from:
a) hydrogen,
b) aryl, heterocycle, C3-C1o cycloalkyl, R100-, -N(Rl0)2, F
or C2-C6 alkenyl,
c) Cl-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or
-N(R 1 ~)2;
15 R2 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R l 20 , R l l S(O)m-~ R 1 OC~O)NR l O , (R 1 0)2NC(0)-,
RlO2N-c(NRlo)-~ CN, N02, RlOC(0)-, N3, -N(Rl0)2,
or R l l OC(O)NR l O
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl,
R l 20 R l l S(O)m-, R l OC(O)NR 10 , (R l 0)2NC(0)-,
R l 02N-C(NR l O)-, CN, R l ~C(0)-, N3, -N(R l ~)2, and
RllOc(o) NRlO;
R3 is selected from H, halogen, Cl-C6 alkyl and CF3;
each R6 is independently selected from:
,
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- 23 -
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 1 2O, R 1 1 S(O)m-~ R 1 0C(O)NR 10 , (R 1 0)2NC(O)-,
R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10-,
c) unsubstituted C 1 -C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 1 20, R 1 1 S(O)m-~ R 1 0C(O)NR 10 , (R 1 0)2NC(o)-,
R 1 02N-C(NR 1 0)-, CN, R 1 ~C(O)-, N3, -N(R 1 0)2, and
R1 1OC(O)-NR10; or
any two of R6 on adjacent carbon atoms are combined to form a
diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-,
-(CH2)4- and -(CH2)3-;
provided that when R2 or R6 i.s unsubstituted or substituted
heterocycle, attachment of R2 or R6 to the phenyl ring, or
6-membered heteroaryl ring respectively, is through a
substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, Cl-c6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-,
R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and
- c) C 1 -C6 alkyl substituted by C I -C6 perfluoroalkyl, R 1 0O-,
RlOC(O)NR10-, (Rlo)2N-c(NRlo)-~ RlO
-N(R10)2, or Rl lOC(O)NR10-;
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- 24 -
provided that when RP~ i~s heterocycle, attachment of R~ to V is
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
RlO is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl alld aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-C6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
Al is selected from: a bond, -C(0)-, 0, -N(Rl0)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR l O, -NR l ~C(0)-, -NR l O , o or
20 -C(=0)-;
n is 0 or l; provided that n is not 0 if Al is a bond, 0,
-N(R 10) , or S(O)m;
m is 0, l or 2; and
pis 0,1,2,30r4;
or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention,
the inhibitors of farnesyl-protein transferase are illustrated by the
30 formula E:
CA 02249650 1998-09-23
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- 25 -
f '
N~R9a R ~f
R8
wherein:
from 1-3 of f(s) are independently N or N->O, and the rem~ining f's
S are independently CR6;
R1a is independently selected from: hydrogen, RlOO-, -N(Rl0)2, F,
C3-Clo cycloalkyl or Cl-C6 alkyl;
10 Rlb is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C l o cycloalkyl, R 1 OO-, -N(R 1 0)2, F
or C2-C6 alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R1OO-,
-N(R l ~)2;
R2 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120, Rl lS(O)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
RlO2N-c(NRlo)-~ CN, NO2, R1OC(O)-, N3, -N(Rl0)2
or K1 1OC(O)NR10
c) unsubstituted C1-C6 alkyl,
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- 26 -
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O RllS(o)m, Rl0c(o)NRlo-~ (Rl0)2Nc(o)-~
R 1 02N-C(NR 1 0)-, CN, R 1 ~C(O)-, N3, -N(R 1 0)2, and
RllOC(O) NR10;
R3 is selected from H, halogen, Cl-C6 alkyl and CF3;
each R6 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the .substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R 1 1 OC(O)-NR 10; or
any two of R6 on adjacent carbon atoms are combined to forrn a
diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-,
-(CH2)4- and -(CH2)3-;
- provided that when R2 or R6 is unsubstituted or substituted
heterocycle, attachment of R2 or R6 to the phenyl ring, or
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- 27 -
6-membered heteroaryl ring respectively, is through a
substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-,
R 1 ~C(O)-, -N(R 1 ~)2, or R 1 1 OC(O)NR 10, and
c) C1-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-,
R 1 0C(O)NR 10, (R 1 0)2N-C(NR 10), R 1 ~C(O)-,
-N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R~ is heterocycle, attachment of R8 to V is
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6
aralkyl, Cl-C6 substituted araLkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR10-, NR10C(O)-~ NR10, O or
-C(=O)-;
n is 0 or 1;
m is 0, 1 or 2; and
.,
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- 2~g -
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond,
-NR l ~C(O)-, -NR 10 or O;
or the pharmaceutically acceptable salts thereof.
S In a further embodiment of this invention, the inhibitors of
farnesyl-protein transferase are illustrated by the formula F:
"f_ f
R9a~N R ~f
/==~ \~b ~ R
~ (CR1 2)p X
NC F
wherein:
lO from 1-3 of f(s) are independently N or N->O, and the rem~ining f's
are independently CR6;
Rla is independently selected from: hydrogen, C3-Clo cycloalkyl or
Cl-C6 alkyl;
Rlb is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C l O cycloalkyl, R l OO , -N(R 1 ~)2 or
F,
c) Cl-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-CIo cycloalkyl, R1OO-, or-N(R10)2;
R2 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
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- 29 -
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120, RllS(o)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R 1 1 OC(O)NR 10
S c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl i,s selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120-, Rl lS(O)m-, RlOC(O)NR 10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2~ and
R 1 1 OC(O)-NR 10-;
R3 is selected from H, halogen, CH3 and CF3;
each R6 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-c6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R 1 1 OC(O)NR 10
c) unsubstituted C1-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o)
R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R 1 1 OC(O)-NR 10; or
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- 30 -
any two of R6 on adjacent carbon atoms are combined to form a
diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-,
-(CH2)4- and -(CH2)3-;
provided that when R2 or R6 i.s unsubstituted or substituted
heterocycle, attachment of R2 or R6 to the phenyl ring, or
6-membered heteroaryl ring respectively, is through a
substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 sub.stituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR 10, -NR I ~C(O)-, -NR 10 , O or
-C(=O)-;
m is 0, 1 or 2; and
pis 0, 1, 2, 3 or4;
or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of
farnesyl-protein transferase are illustrated by the formula G:
.
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W O 97/36896 PCTAUS97/05357
NC f ~ ;~
wherein:
from 1-3 of f(s) are independently N or N->0, and the remaining ~s
5 are independently CR6;
Rla is independently selected from: hydrogen, R100-, -N(R10)2, F,
C3-C l o cycloalkyl or C l -C6 alkyl;
10 Rlb is independently selected from:
a) hydrogen,
b) aryl, heterocycle or C3-Clo cycloalkyl,
c) Cl-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-C1o cycloalkyl, C2-C6 alkenyl, R100-, or
-N(R 1~)2;
R2 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 120, R 1 1 S(O)m-, R 1 OC(O)NR 10, (R 1 0)2NC(0)-,
R102N-C(NR10)-, CN, N02, RlOC(0)-, N3, -N(R10)2,
or R l I OC(O)NR 1 0-
- 25 c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
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- 32 -
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120, Rl lS(o)m, RlOC(O)NR1O-, (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
R 1 1 OC(O)-NR 10;
R3 is selected from H, halogen, CH3 and CF3;
each R6 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloa~kyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 1 20 , R I 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(o)-
R102N-C(NR10)-, CN, N02, RlOC(O)-, N3, -N(R10)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 1 20 , R 1 1 S(O)m-~ R 1 OC(O)NR 10 , (R 1 0)2NC(O)-,
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
R 1 1 OC(O)-NR 10; or
any two of R6 on adjacent carbon atoms are combined to form a
diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-,
-(CH2)4- and -(CH2)3-;
provided that when R2 or R6 is unsubstituted or substituted
heterocycle, attachment of R2 or R6 to the phenyl ring, or
6-membered heteroaryl ring respectively, is through a
substitutable heterocycle ring carbon;
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R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
s
Rl l is independently selected from Cl-c6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-c6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
m is 0, 1 or 2;
n is 0 or 1;
or the pharmaceutically acceptable salts thereof.
Specific examples of the compounds of the invention are:
1 -(4-[Pyrid-2-yl ~phenylmethyl)-5-(4-cyanobenzyl)imidazole
NC_~
1 -(4-[3-Methylpyrazin-2-yl]phenylmethyl)-5 -(4-cyanobenzyl)imidazole
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- 34 -
NC ~3
~.
~N~ N~
1 -(4-(Pyrimidinyl-S-yl)phenylmethyl)-5 -(4-cyanobenzyl)imidazole
NC _~
~N~
J
S N
or the pharmaceutically acceptable salts thereof.
The compounds of the present invention may have
- asymmetric centers and occur as racemates, racemic mixtures, and as
individual diastereomers, with all possible isomers, including optical
isomers, being included in the present invention. When any variable
(e.g. aryl, heterocycle, Rla, Rlb etc.) occurs more than one time in
any constituent, it.s definition on each occurence is independent at every
other occurence. Also, combinations of substituents/or variables are
permissible only if such combinations result in stable compounds.
As used herein, "alkyl" and the alkyl portion of aralkyl and
similar terms, is intended to include both branched and straight-chain
saturated aliphatic hydrocarbon groups having the specified number of
carbon atoms; "alkoxy" represents an alkyl group of indicated number
of carbon atoms attached through an oxygen bridge.
As used herein, "cycloalkyl" is intended to include non-
aromatic cyclic hydrocarbon groups having the specified number of
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carbon atoms. Examples of cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkenyl" groups include those groups having the specified
number of carbon atoms and having one or several double bonds.
Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl,
hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl,
farnesyl, geranyl, geranylgeranyl and the like.
"Alkynyl" groups include those groups having the specified
number of carbon atoms and having one triple bonds. Examples of
alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and
the like.
"Halogen" or "halo" as used herein means fluoro, chloro,
bromo and iodo.
As used herein, "aryl," and the aryl portion of aralkyl and
aroyl, is intended to mean any stable monocyclic or bicyclic carbon ring
of up to 7 members in each ring, wherein at least one ring is aromatic.
Examples of such aryl elements include phenyl, naphthyl, tetrahydro-
\naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein,
represents a stable 5- to 7-membered monocyclic or stable 8- to
11-membered bicyclic heterocyclic ring which is either saturated
or unsaturated, and which consists of carbon atoms and from one to
four heteroatoms selected from the group consisting of N, O, and S,
and including any bicyclic group in which any of the above-defined
heterocyclic rings is fused to a benzene ring. The heterocyclic ring
may be attached at any heteroatom or carbon atom which results in the
creation of a stable structure. Examples of such heterocyclic elements
include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl,
benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl,
- dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl,
imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl,
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isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl,
naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, pyridyl,
pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl,
pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,
5 tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl,
thienofuryl, thienothienyl, and thienyl.
As used herein, "heteroaryl" is intended to mean any stable
monocyclic or bicyclic carbon ring of up to 7 members in each ring,
10 wherein at least one ring is aromatic and wherein from one to four
carbon atoms are replaced by heteroatoms selected from the group
consisting of N, O, and S. Examples of such heterocyclic elements
include, but are not limited to, benzimidazolyl, benzisoxazolyl,
benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
15 benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl,
dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl,
isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,
20 pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl,
thienothienyl, and thienyl.
As used herein in the definition of R7, the substituted C1 8
alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl,
25 substituted heteroaroyl, substituted arylsulfonyl, substituted hetero-
arylsulfonyl and substituted heterocycle include moieties containing
from 1 to 3 substituent s in addition to the point of attachment to the
rest of the compound.
As used herein, when no specific substituents are set forth,
30 the terms "substituted aryl", "substituted heterocycle" and "substituted
cycloaL~yl" are intended to include the cyclic group which is substituted
- on a substitutable ring carbon atom with 1 or 2 substitutents selected
from the group which includes but is not limited to F, Cl, Br, CF3,
NH2, N(Cl-C6 alkyl)2, NO2, CN, (Cl-C6 alkyl)O-, -OH, (Cl-C6
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alkyl)S(O)m-, (Cl-C6 alkyl)C(O)NH-, H2N-C(NH)-, (C1-C6
alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(O)NH-,
phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl,
furyl, isothiazolyl and Cl-C20 alkyl.
S Lines drawn into the ring systems from substituents (such
as from R2, R3, R4 etc.) indicate that the indicated bond may be
attached to any of the substitutable ring carbon atoms.
The moiety designated by the following structure
f '
~,~f'
represents an aromatic 6-membered heterocyclic ring and includes the
following ring systems:
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- 38 -
6 ~ ~ R6 ~ ~ ~6 ~ ~ R
R6 R6 R6
R6 R6 ,1~
,~, R6 R6~ R6 R6~Nq~ R6 HN NH
,~f N ~ N~ N ~'''f N O
R6 R6
R6 0
NJ~N R6~N~N ~ R6 N R6
-~.J~ R6 ,~J~ R6 ~o ~ R6
R6 R6 R6 R6
R6
N ~
-~J~ R6
R6
wherein R6 is as defined hereinabove.
The moiety described as
f '
~,,~f'
5 where any two of R6 on adjacent carbon atoms are combined to forrn a
- diradical selected from -CH=CH-CH=CH-, -CH=CH-CH-, -(cH2)4- and
-(CH2)4- includes, but is not limited to the following structures:
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- 39 -
~ N~
N~ ~J~ N~
~r
~r
Nf~3 ~,~> ~,~>
It is understood that such fused ring moieties may be further substituted
by the rem~ining R6s as defined hereinabove.
Preferably, from 1-3 of f(s) are independently N, and the
5 rem~ining fs are independently CR6.
Preferably, Rla and Rlb are independently selected from:
hydrogen, R1 Ic(o)o-~ -N(Rlo)2~ R10C(o)NR10, R10O- or
unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or substituted
10 phenyl, -N(R 1 ~)2, R l ~O and R 1 OC(O)NR 10 .
Preferably, R2 is selected from:
a) hydrogen,
b) C3-C l o cycloalkyl, halogen, C l -C6 perfluoroalkyl, R 1 20,
CN, N02, R 1 ~C(0)- or -N(R 1~)2,
c) unsubstituted Cl-C6 alkyl,
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- 40 -
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 120, K l l S(O)m ~ R l OC(O)NR 10-, (R 1 0)2NC(O)-,
R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2, and
R11OC(O) NR10
Preferably, R3 is selected from: hydrogen, halogen,
trifluoromethyl, trifluoromethoxy and Cl-C6 alkyl.
Preferably, R4 and R5 are hydrogen.
Preferably, R6 is independently selected from:
a) hydrogen,
b) C3-C1o cycloalkyl, halogen, Cl-C6 perfluoroalkyl,
R12O-, Rl 1S(O)m-, CN, NO2, RlOC(O)- or -N(R10)2,
c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, C3-Clo cycloalkyl, R120-, Rl lS(O)m-,
R 1 ~C(O)- or -N(R 1~)2; or
any two R6s on adjacent carbon atoms are combined to form a diradical
selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and
-(CH2)3--
Preferably, R8 is independently selected from:
a) hydrogen, and
b) aryl, substituted aryl, heterocycle, substituted heterocycie,
Cl-C6 perfluoroalkyl or CN.
Preferably, R9 is hydrogen, halogen or methyl.
Preferably, R10 is selected from H, Cl-C6 alkyl and
benzyl.
Preferably, A1 and A2 are independently selected from: a
bond, -C(O)NR 1 0-, -NR 1 OC(O)-, O, -N(R 1 0)- -S (O)2N(R 1 0) and
N(R 1 ~)S(O)2-.
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Preferably, V is selected from hydrogen, heterocycle and
aryl. More preferably, V is phenyl.
Preferably, W i.s .selected from imidazolinyl, imidazolyl,
oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More
5 preferably, W is selected from imidazolyl and pyridyl.
Preferably, n and r are independently 0, 1, or 2.
Preferably s is 0.
Preferably t is 1.
Preferably, the moiety
(R8) ~9~
V - A1(CR1a2)nA2(CR1a2)n ~W~!- (CRlb2~p X -(CR1b2~_
is selected from:
R9a R9b
~= N \)--N
N,~ Rgb ,~ ~ R9a
~ CH2~ d CH2--~.
NC NC
It is intended that the definition of any substituent or
variable (e.g., Rla, R9, n, etc.) at a particular location in a molecule
15 be independent of its definitions elsewhere in that molecule. Thus,
-N(RI0)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood
that substituents and substitution patterns on the compounds of the
instant invention can be selected by one of ordinary skill in the art
to provide compound.s that are chemically stable and that can be
20 synthesized by techniques known in the art, as well as those methods
- set forth below, from readily available starting materials.
The pharrnaceutically acceptable salts of the compounds of
this invention include the conventional non-toxic salts of the compounds
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- 42 -
of this invention as formed, e.g., from non-toxic inorganic or organic
acids. For example, such conventional non-toxic salts include those
derived from inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared
5 from organic acids such as acetic, propionic, succinic, glycolic, stearic,
lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,
isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds
of this invention can be synthesized from the compounds of this
invention which contain a basic moiety by conventional chemical
methods. Generally, the salts are prepared either by ion exchange
chromatography or by reacting the free base with stoichiometric
15 amounts or with an exces,s of the desired salt-fo~ning inorganic or
organic acid in a suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention
are prepared by employing reactions as shown in the Schemes 1-23,
in addition to other standard manipulations such as ester hydrolysis,
20 cleavage of protecting groups, etc., as may be known in the literature
or exemplified in the experimental procedures. Substituents R2, R6 and
R8, as shown in the Schemes, represent the substituents R2, R3, R4, R5,
R6 and R8; although only one such R2, R6 or R~ is present in the
intermediates and products of the schemes, it is understood that the
25 reactions shown are also applicable when such aryl or heteroaryl
moieties contain multiple substituents.
These reactions may be employed in a linear sequence
to provide the compounds of the invention or they may be used to
synthesize fragments which are subsequently joined by the alkylation
30 reactions described in the Schemes. Other reactions useful in the
preparation of heteroaryl moieties are described in "Comprehensive
- Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G.
Sammes, Oxford (1979) and references therein. Aryl-aryl coupling
_ _ . .. ....
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is generally described in "Comprehensive Organic Functional Group
Transformations," Katritsky et al. eds., pp 472-473, Pergamon Press
(1 995).
Synopsis of Schemes 1-23:
The requisite intermediates are in some cases commercially
available, or can be prepared according to literature procedures,
for the most part. Schemes 1-14 illustrate synthesis of the instant
arylheteroaryl compound which incorporate a preferred benzyl-
imidazolyl sidechain. Thus, in Scheme 1, for example, a arylheteroaryl
intermediate that is not commercially available may be synthesized by
methods known in the art. Thus, a suitably substituted pyridyl boronic
acid I may be reacted under Suzuki coupling conditions (Pure Appl.
Chem., 63:419 (1991)) with a suitably substituted halogenated benzoic
acid, such as 4-bromobenzoic acid, to provide the arylheteroaryl
carboxylic acid II. The acid may be reduced and the triflate of the
interrnediate alcohol III may be formed in situ and coupled to a suitably
substituted benzylimidazolyl IV to provide, after deprotection, the
instant compound V.
Schemes 2-5 illustrate other methods of synthesizing the
key alcohol intermediates, which can then be processed as described
in Scheme 1. Thus, Scheme 2 illustrates the analo~ous series of
arylheteroaryl alcohol forming reaction~s starting with the halogenated
arylaldehyde. The corresponding boronic benzaldehyde may also be
employed as illustrated.
Scheme 3 illustrates the reaction wherein the "terminal"
heteroaryl moiety is employed in the Suzuki coupling as the halogenated
reactant. Such a coupling reaction is also compatible when one of the
reactants incorporates a suitably protected hydroxyl functionality as
illustrated in Scheme 4.
Negishi chemistry (Org. Synth., 66:67 (1988)) may
also be employed to form the arylheteroaryl component of the instant
compounds, as shown in Scheme 5. Thus, a suitably substituted zinc
bromide adduct may be coupled to a suitably substituted aryl halide
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- 44 -
in the presence of nickel (II) to provide the arylheteroaryl VII. The
heteroaryl halide and the zinc bromide adduct may be selected based
on the availability of the starting reagents.
Scheme 6 illu~strates the preparation of the suitably
5 substituted arylheteroaryl methanol from the pyridyltoluene.
Scheme 6a illustrates the preparation of the suitably
substituted pyrazinylaryl methanol starting with alanine.
As illustrated in Scheme 7, the sequence of coupling
reactions may be modified such that the arylheteroaryl bond is formed
10 last. Thus, a suitably substituted imidazole may first be alkylated
with a suitably sub.stituted benzyl halide to provide intermediate VIII.
Intermediate VIII can then undergo Suzuki type coupling to a suitably
substituted heteroaryl boronic acid.
Scheme ~ illustrates synthesis of an instant compound
15 wherein a non-hydrogen R9b is incorporated in the instant compound.
Thus, a readily available 4-substituted imidazole IX may be selectively
iodinated to provide the 5-iodoimidazole X. That imidazole may then
be protected and coupled to a .suitably sub~stituted benzyl moiety to
provide intermediate XI. Intermediate XI can then undergo the
20 alkylation reactions that were described hereinabove.
Scheme 9 illustrates synthesis of instant compounds
that incorporate a preferred imidazolyl moiety connected to the
arylheteroaryl via an alkyl amino, sulfonamide or amide linker. Thus,
the 4-aminoalkylimidazole XII, wherein the primary amine is protected
25 as the phthalimide, is selectively alkylated then deprotected to provide
the amine XIII. The amine XIII may then react under condition.s well
known in the art with various activated arylheteroaryl moieties to
provide the instant compounds shown.
Compounds of the instant invention wherein the
30 A 1 (CR 1 a2)nA2(CR 1 a2)n linker is oxygen may be synthesized
by methods known in the art, for example as shown in Scheme
10. The suitably substituted phenol XIV may be reacted with methyl
N-(cyano)meth~nimidate to provide the 4-phenoxyimidazole XV.
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After selective protection of one of the imidazolyl nitrogens, the
intermediate XVI can undergo alkylation reactions as described
for the phenylmethylimidazoles hereinabove.
Scheme 11 illustrates an analogous series of reactions
5 wherein the (cRlb2)px(cRlb2)p linker of the instant compounds
is oxygen. Thus, a .suitably substituted haloaryl alcohol, such as
4-bromophenol, is reacted witll methyl N-(cyano)meth~nimidate to
provide intermediate XVI. Intermediate XVI is then protected and, if
desired to form a compound of a preferred embodiment, alkylated with
10 a suitably protected benzyl. The intermediate XVII can then be coupled
to a heteroaryl moiety by Suzuki chemistry to provide the instant
compound.
Compounds of the instant invention wherein the
A 1 (CR 1 a2)nA2(CR 1 a2)n linker is a substituted methylene may be
15 synthesized by the methods shown in Scheme 12. Thus, the N-protected
imidazolyl iodide XVIII is reacted, under Grignard conditions with a
suitably protected benzaldehyde to provide the alcohol XIX. Acylation,
followed by the alkylation procedure illustrated in the Schemes above
(in particular, Scheme 1) provides the instant compound XX. If other
20 Rl substituent s are desired, the acetyl moiety can be manipulated as
illustrated in the Scheme.
Addition of various nucleophiles to an imidazolyl aldehyde
may also be employed to form a substituted alkyl linker between the
arylheteroaryl and the preferred W (imidazolyl) as shown in Scheme
25 14. Thus a halogenated arylheteroaryl, such as 4-(3-pyridyl)bromo-
benzene, may undergo metal halogen exchange followed by reaction
with a suitably substituted imidazolyl aldehyde and acteylation to form
the alcohol. Then, similar substituent manipulation as shown in Scheme
13 may be performed on a fully functionalized compound which
30 incorporates an R2 hydroxyl moiety.
Scheme 14 illustrates the synthesis of a suitably substituted
- pyrimidinebromobenzene, which may be employed in the reaction
illustrated in Scheme 13. This reaction and other reactions useful in
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- 46 -
the preparation of heteroaryl moieties are described in "Comprehensive
Organic Chemistly, Volume 4: Heterocyclic Compounds" ed. P.G.
Sammes, Oxford (1979).
S SCHEME 1
~ R6
Br (HO)2B N
o R2 pd(pph3)4
1~ R6
~ N~ LiAlH4
Ho~J~\J
0 11
r R
111
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SCHEME 1 (continued)
N C ~ h~)z
R8
R8 IV
~ (CF3SO2)20,;78 C ~ r
HO 2 NEtipr2 -78~C-20~C
R CH2cl2
Tr ~--R6
R8 ~ R6
/~ V
R8
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SCHEME 2
(H~)2B
~R/2 Pd(PPh3)4
~N R6
NaBH4
~N, R6
HOJ~
B(~H)2 BrJ~N
o~2 Pd(PPh3)4, NEt3
~,N~
J~,~N N BH
~\~N
HO~,~R2
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- 49 -
S C~DE~DE 3
B(OH)
MeO ~
Pd(PPh3)4
~ ~ R6
fi r LiAlH4
MeO~
o R2
~ ~ R6
HO~,\
R2
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- 50-
SCHEME 4
~N R6
~ Br~
R3SiO ~,\R2 pd(pph3)4
~N R6
~/ Bu4NF
R3SiO~,\
R2
HO~ ~ - R6
~N
~,~ (HO)2B
R3SiO R2 Pd(PPh3)4
~N R6
~ Bu4NF
R3SiO ~'\R2
~1 R6
HO~
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SCHEME 5
BrZn/[~
R3SiO
R2 NiCl2(Pph3)2
~,N ~
~J Bu4NF
R3SiO~,\
Vll R
HOJ~
N
Br/~
R3SiO ~'\R2 NiCI2(PPh3)2
~I R6
~J Bu4NF
R3SiO,~,~R2
~N~, R6
HOJ~'~R2
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- 52 -
SCHEME 6
~I R6
~V/ KMnO4
H3C \R2
J~ R LiAlH4
~\R2
o
f~ R6
,~
H~~J~,~
R2
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SC~EME 6a
C02CH3 NH3 lONH2
H3Cl NH2 EtOH H3C NH2
¢N~CH3 POC13
NaOH OH H2SO4
¢ N~CH3 Nal/HI ¢N~XcH3
o
H~ H3C~,N
B(OH)2 ~N3 NaBH4
Pd(OAc)2 ~ \R2
H3C~"
~N
HO~\R2
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- 54 -
SCHEME 7
T~ i.
N~ Br
~N j;. MeOH
~ reflux
R8/~l
R6
~ - ~ 2 Pd(PPh3)~
R8 Vlll
R6
~,~N
R8~J R2
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- 55 -
SCHEME 8
H H
9b ~ ~ Nal, NaHCO3,!2 Rsb~ TrCI, NEt~ r
IX X
T~NiCI2(PPh3)2 .
R3 ZnBr ~/
f~ 'f R6
Tr~ ~f'
~_ ~ R2
~/ i. -78 C-20 C
/~ ii. MeOH, reflux
R8 Xl
f~ ~f R6
R9b~
~J R2
R8
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SCHEME 9
0~
<O Rs~~Br
<N~ O 55~C,CH3CN
N N~i. EtOH,80~C, NH2NH2
Xll N
<'11
N----NH2
R 8~9J
Xlll
acylation, sulfonylation </N3'~ ~ R2
o;alkylation R8~ ,f~ f
</ ~ ~~ "~ f'f'~f
R8~N N~S~
N~ f R6
R8~ H~\~
f~ f~f 6
... ..
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SCHEME 10
OH i, Na, MeOH
NC ~/ ii. 1 20~C
XIV H3C~o
~N--~N
H Tr~
~N TrCI, NEt3
~0 ~0
NC ~/ NC ~J
XV XVI
~ f--~ R6
TrN~ R2 ~ i. -78~C-20~C
~N + ~/ ii. MeOH reflux
NC ~ OTf
XVI
f ~;f--~_ R5
~_N
~0
NC~
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SCHEMlE 1 1
N
OH i, Na, MeOH ~r~N
Br~~ \J ii. 1 20~C ~__o
R2 H3C~ ,o Br--~, \J
N~N R2 XVI
R8
Tr~
N
TrCI, NEt3 <~\ N OTf
~ r i-78~c-20~c
~~ ii. MeOH reflux
Br ~\J
R2 R8 B(OH)2
r 'J~ R f_f~/
Br~O DMF, Pd(PPh3)4
~ K3PO4, 80~C
R2 XVII
R8
~,r~N~,~
,~ f\~O
6 f= f R2
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SCHEME 12
T~ ~N~
N~ EtMgBr ~_N
~_N ~ ~OH
XVIII R R8 XIX
f ~f'
Tr~ ~f~ f
<\--N HO J~ 2
Ac20, PY ,. ~ R
~OAc (cF3so2)2o~-78oc
/~ NEtiPr2,CH2Cl2
R8
N~ f~ f LiOH
~OAc R2
R8 XX
~ ~5 ~f R6
R8
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SCHEME 12 (continued)
f~ f R6
~, J~ NH3, MeOH
~CI R2
R8
~q ~f'--R6
~NH2 R2
R8
f~f' f
~<OMe R2
R8
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SCHEME 13
R6
2 f~f~f BuLi
R , " r
~f,f -1 o0~C
Br~ <N~3
N--\
Li~ f R6 ~J o
f~f'/f
</ ~ ~f' f
~J OH
R8
SCHEME 14
Br~ HCONH2 ,~\~N
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Schemes 15-24 illustrate reactions wherein the moiety
(l 8)r (/R9~
V - A (CR 2)nA (CR1a2)n tW~ - (CR1b2)p-X
incorporated in the compounds of the instant invention is represented by
5 other than a substituted imidazole-containing group.
Thus, the intermediates who.se synthesis are illustrated in
Schemes hereinabove and other arylheteroaryl intermediates obtained
commercially or readily synthesized, can be coupled with a variety of
aldehydes. The aldehyde~s can be prepared by standard procedures, such
10 as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in
Or~anic Syntheses. 1988, 67, 69-75, from the appropriate amino acid.
Metalation chemistry may be utilized, as shown in Scheme 15, to
incorporate the arylheteroaryl moiety. Thus, a suitably substituted
arylheteroaryl lithium reagent, prepared in situ, is reacted with an
15 aldehyde to provide the C-alkylated instant compound XXI. Compound
XXI can be deoxygenated by methods known in the art, such as a
catalytic hydrogention, then deprotected with trifluoroacetic acid in
methylene chloride to give the final compound XXII. The final
product XXII may be isolated in the salt form, for example, as a
20 trifluoroacetate, hydrochloride or acetate salt, among others. The
product diamine XXII can further be selectively protected to obtain
XXIII, which can subsequently be reductively alkylated with a second
aldehyde to obtain XXIV. Removal of the protecting group, and
conversion to cyclized products such as the dihydroimidazole XXV
25 can be accomplished by literature procedures.
If the biaryl subunit reagent is reacted with an aldehyde
which also has a protected hydroxyl group, such as XXVI in Scheme
16, the protecting groups can be subsequently removed to unmask the
hydroxyl group (Schemes 16, 17). The alcohol can be oxidized under
30 standard conditions to e.g. an aldehyde, which can then be reacted with
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a variety of organometallic reagents such as Grignard reagents, to
obtain secondary alcohols such as XXX. In addition, the fully
deprotected amino alcohol XXXI can be reductively alkylated (under
conditions described previously) with a variety of aldehydes to obtain
5 secondary amines, such as XXXII (Scheme 17), or tertiary amines.
The Boc protected amino alcohol XXVIII can aLso be
utilized to synthesize 2-aziridinylmethylbiaryl such as XXXIII
(Scheme 18). Treating XXVIII with 1,1'-sulfonyldiimidazole and
sodium hydride in a solvent such as dimethylformamide led to the
10 formation of aziridine XXXIII . The aziridine is reacted with a
nucleophile, such as a thiol, in the presence of base to yield the ring-
opened product XXXIV .
In addition, the arylheteroaryl subunit reagent can be
reacted with aldehydes derived from amino acids such as O-alkylated
15 tyrosines, according to standard procedures, to obtain compounds such
as XL, as shown in Scheme 19. When R' is an aryl group, XL can first
be hydrogenated to llnm~k the phenol, and the amine group deprotected
with acid to produce XLI. Alternatively, the amine protecting group in
XL can be removed, and O-alkylated phenolic amines such as XLII
20 produced.
Schemes 20-23 illustrate syntheses of suitably substituted
aldehydes useful in the syntheses of the instant compounds wherein the
variable W is present as a pyridyl moiety. Similar synthetic strategies
for preparing alkanols that incorporate other heterocyclic moieties for
25 variable W are also well known in the art.
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SCHEME 15
R6 Boc NH
,~3,1~ " Boc NH CHO
2 f R6 1 catalytic
R f~ ~f hydrogenation
r ~
NHBoc
XXI
F 2 f~f~R
NH2 ~f~i cHc2c0
NH2 XXII
~ ~,C HO
BocN H ~
\~ NaBH(OAc)3
NH2 Et3N, CICH2CH2CI
XXIII
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SCHEME 15 (continued)
BocNH ~_~ CF3CO2H, CH2C1
~=~ NH NaHCO3
XXIV
NH2~\
NH AgCN
R2
~f--~ R6
N~,N~
¢~ XXV
~3
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SCHEME 16
R6
f~f~!f Et20
f'f
Li J~J BnO l
BocNH CHO
R2 XXVI
BnO~ R6 20% Pd(OH)2 H2
NHBoc CH3CO2H
R2
HO /=1=\ f= f,~ R CICOCOCI
\~\f_f~/ DMSO CH2CI2
NHBoc (C2Hs)3N
XXVII
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SCHEME 16 (continued)
R2
H~f f~ R6
NHBoc
XXIX
HO~<f--~ R6
NHBoc
XXX
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SCHEME 17
,=1=, f=f,~ R6 CF3CO2H
HO~<f_ f CH2CI2
NHBoc
XXVIII
R2
f=f,~ R6 R'CHO
HO ~f_ f NaBH(OAc)3
NH2 CICH2CH2CI
XXXI
R2
HO ~f--~ R6
NH
R'CH2 XXXII
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SCHEME 18
R2 N=\ N
HO~f= f~ R6 ~ ' o'
f fNaH, DMF 0~C
NHBoc XXVIII
f=f,~R6R"SH
<~f--f ' C H30H
H XXXIII
R"S~_f~R6
NH2
XXXIV
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SCHEME 19
HO~ 1 ) BoczO, K2CO3 HO~
~/ THF-H20
~ 2) CH2N2, EtOAc ,1~
HzNCO2H BocNH CO2CH3
XXXV XXXVI
HO~
LiAlH4 ~ R"'CH2X
THF ,1~ Cs2CO3
0-20~C BocNH CH2OH DMF
XXXVII
R"'CH20~ R"'CH20
pyndine SO ~
BocNH CH2OH 20~C BocNH CHO
XXXVIII IXL
-
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SCHEME 19 (continued)
R"'CH~3 --~ R6
~,ocNH CHO
IXL ~ R"' notaryl
Et20 1. Et20
2. 20% Pd(oH)2l H2 \
R2 CH30H, CH3C02H \
F\ 1 3. HCI, EtOAc
R"'CH20~(\f_ f~ R6
NHBoc
1) 20% Pd(OH)2, H2 / R2
CH30H, CH3C02H / ~ ~=1=\ f=f~R6
2) HCI, EtOAc / R"'CH20 \~\ "f
NH2
XLII
Ho~\f_ ~ R 6
NH2 R2
XLI
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SCHEME 20
~CH3 1) HNO2,Br2~ CO2CH3
2) KMnO
H2N N 3) MeOH, H+ Br~N~
R6
r ~\MgCI R6
Zncl2~Nicl2(ph3p)2 ~CO2CH3
NaBH4 (excess) ~,CH20H
SO3 Py Et3N ~CHO
.
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SCHEME 21
1. EtO(CO)CI R6
Zn ClltN ~COzCH3
N 3. S, xylene, heat N
R6 R6
NaBH4 ~j~ SO3Py, Et3N ~
(excess) ~CH20H DMSO ~CHO
R6 R6
Br~,CO2CH3 1~
N ~ CO2CH3
ZnCI2, NiC12(Ph3P)2 N~
R6 R6
NaBH4 ~SO3 Py, Et3N [~
~ ~CH20H ~ ~,CHO
(excess) NDMSO N
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SCHEME 22
co2CH3
Br~3 1. LDA, CO2 Br~
N2. MeOH, H+ N
R6
ZnCI2, Nicl2(ph3p)2 N
~R6
NaBH4 (excess) \~ CH20H SO3 Py, Et3N
~ DMSO
N
R6
CHO
. . . ~
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SCHEME 23
co2CH3
~3~ 1. LDA, CO2 ~Br
2. (CH3)3SiCHN2
R6 3~\ Br R6 3~
Zn, NiC12(Ph3P)2 N~Co2cH3
excess NaBH4 ~1~ SO3Py, Et3N
N~CH20H DMSO
R6 ~
N~3~CH~
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The instant compounds are useful as pharmaceutical a
gents for m~mm~l.s, especially for humans. These compounds may be
~lmini.~tered to patients for use in the treatment of cancer. Examples
of the type of cancer which may be treated with the compounds of this
5 invention include, but are not limited to, colorectal carcinoma, exocrine
pancreatic carcinoma, myeloid leukemias and neurological tumors.
Such tumors may arise by mutations in the ras genes themselves,
mutations in the proteins that can regulate Ras activity (i.e.,
neurofibromin (NF-l), neu, scr, abl, lck, fyn) or by other mechanisms.
The compounds of the instant invention inhibit farnesyl-
protein transferase and the farnesylation of the oncogene protein Ras.
The instant compounds may also inhibit tumor angiogenesis, thereby
affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575-
4580 (1995)). Such anti-angiogenesis properties of the instant
compounds may also be useful in the treatment of certain forms of
blindness related to retinal vascularization.
The compounds of this invention are also useful for
inhibiting other proliferative diseases, both benign and malignant,
wherein Ras proteins are aberrantly activated as a result of oncogenic
mutation in other genes (i.e., the Ras gene itself is not activated by
mutation to an oncogenic form) with said inhibition being accomplished
by the a~lmini~tration of an effective amount of the compounds of the
invention to a m~mm~l in need of such treatment. For example, a
component of NF-l is a benign proliferative disorder.
The instant compounds may also be useful in the treatment
of certain viral infections, in particular in the treatment of hepatitis
delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333
(1992).
The compounds of the instant invention are also useful in
the prevention of restenosis after percutaneous transluminal coronary
angioplasty by inhibiting neointimal forrnation (C. Indolfi et al. Nature
- medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment
and prevention of polycystic kidney disease (D.L. Schaffner et al.
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American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley,
Jr. et al.FASEB Journal, 2:A3160 (198~)).
The instant compounds may also be useful for the treatment
of fungal infections.
The compounds of this invention may be ~lministered
to m~mm~l.s, preferably humans, either alone or, preferably, in
combination with pharmaceutically acceptable carriers or diluents,
optionally with known adjuvants, such as alum, in a pharmaceutical
composition, according to standard pharmaceutical practice. The
compounds can be ~lmini.~tered orally or parenterally, including the
intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and
topical routes of ~(lministration.
For oral use of a chemotherapeutic compound accordin~,
to this invention, the selected compound may be a~lministered, for
example, in the form of tablets or capsules, or as an aqueous solution
or suspension. In the case of tablets for oral use, carriers which are
commonly used include lactose and corn starch, and lubricating agents,
such as magnesium stearate, are commonly added. For oral
~tlministration in capsule form, useful diluents include lactose and dried
corn starch. VVhen aqueous suspension.s are required for oral use, the
active ingredient is combined with emulsifying and suspending agents.
If desired, certain sweetening and/or flavoring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenous use,
sterile solutions of the active ingredient are usually prepared, and the
pH of the solutions should be suitably adjusted and buffered. For
intravenous use, the total concentration of solutes should be controlled
in order to render the preparation isotonic.
The compounds of the instant invention may also be
co-~-lministered with other well known therapeutic agents that are
selected for their particular usefulne,ss against the condition that is
being treated. For example, the instant compounds may be useful in
combination with known anti-cancer and cytotoxic agents. Similarly,
the instant compounds may be useful in combination with agents that are
effective in the treatment and prevention of NF-l, restinosis, polycystic
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kidney disease, infections of hepatitis delta and related viruses and
fungal infections.
If formulated as a fixed dose, such combination products
employ the compounds of this invention within the dosage range
S described below and the other pharmacçutically active agent(s) within
its approved dosage range. Compounds of the instant invention may
alternatively be used sequentially with known pharmaceutically
acceptable agent(s) when a combination formulation is inappropriate.
The present invention also encompasses a pharmaceutical
10 composition useful in the treatment of cancer, comprising the
~lministration of a therapeutically effective amount of the compounds
of this invention, with or without pharmaceutically acceptable carriers
or diluents. Suitable compositions of this invention include aqueous
solutions comprising compounds of this invention and pharmacolo-
15 gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. Thesolutions may be introduced into a patient's blood-stream by local
bolus injection.
As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the specific
20 amounts, as well a,s any product which results, directly or indirectly,
from combination of the specific ingredients in the specified amount~s.
When a compound according to this invention is
~lmini~tered into a human subject, the daily dosage will normally be
determined by the prescribing physician with the dosage generally
25 varying according to the age, weight, and response of the individual
patient, as we~l as the severity of the patient's symptoms.
In one exemplary application, a suitable amount of
compound is administered to a m~mm~l undergoing treatment for
cancer. Aflministration occurs in an amount between about 0.1 mg/kg
30 of body weight to about 60 mg/kg of body weight per day, preferably
of between 0.5 mg~g of body weight to about 40 mg/kg of body weight
per day.
The compounds of the instant invention are also useful
as a component in an assay to rapidly determine the presence and
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quantity of farnesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two
portions contacted with mixtures which comprise a known substrate
of FPTase (for example a tetrapeptide having a cysteine at the amine
S terminus) and farnesyl pyrophosphate and, in one of the mixtures,
a compound of the instant invention. After the assay mixtures are
incubated for an sufficient period of time, well known in the art,
to allow the FPTase to farnesylate the substrate, the chemical
content of the assay mixtures may be determined by well known
10 immunological, radiochemical or chromatographic techniques.
Because the compounds of the instant invention are selective
inhibitors of FPTase, absence or quantitative reduction of the amount
of substrate in the assay mixture without the compound of the instant
invention relative to the presence of the unchanged substrate in the
15 assay cont~inin~ the instant compound is indicative of the presence of
FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the
art that such an assay as described above would be useful in identifying
tissue samples which contain farnesyl-protein transferase and quantitat-
20 ing the enzyme. Thus, potent inhibitor compounds of the instantinvention may be used in an active ~site titration assay to determine the
quantity of enzyme in the ,sample. A serie,s of samples composed of
aliquots of a tissue extract containing an unknown amount of farnesyl-
protein transferase, an excess amount of a known substrate of FPTase
25 (for example a tetrapeptide having a cysteine at the amine terminus) and
farnesyl pyrophosphate are incubated for an appropriate period of time
in the presence of varying concentrations of a compound of the instant
invention. The concentration of a sufficiently potent inhibitor (i.e., one
that has a Ki substantially smaller than the concentration of enzyme in
30 the assay vessel) required to inhibit the enzymatic activity of the sample
by 50% is approximately e4ual to half of the concentration of the
enzyme in that particular sample.
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EXAMPI~ES
Examples provided are intended to assist in a further
understanding of the invention. Particular materials employed, species
and conditions are intended to be ~urther illustrative of the invention
and not limitative of the reasonable scope thereof.
EXAMPLE 1
}0 1-(4-[Pyrid-2-yl]phenylmethyl)-5-(4-cyanobenzyl)imidazole
hydrochloride salt
Step A: l-Trityl-4-(4-cyanobenzyl)-imidazole
To a suspension of activated zinc dust (3.57g? 54.9~
15 mmol) in THF (50 mL)was added dibromoethane (0.315 mL, 3.60
mmol) and the reaction stirred for 45 minutes under argon at 20~C.
The suspension was cooled to 0~C and a-bromo-p-tolunitrile (9.33g,
47.6 mmol) in THF (100 mL) was added dropwise over a period of 10
minutes. The reaction was then allowed to stir at 20~C for 6 hours and
20 bis(triphenylphosphine)Nickel II chloride (2.40g, 3.64 mmol) and 4-
iodo-l-tritylimidazole (15.95g, 36.6 mmol, S. V. Ley, et al., J. Org.
Chem. 56, 5739 (1991)) were added in one portion. The resulting
mixture was stirred 16 hours at 20~C and then quenched by addition of
saturated NH4Cl solution (100 mL) and the mixture stirred for 2 hours.
25 Saturated aq. NaHCO3 solution wa,s added to give a pH of ~ and the
solution was extracted with EtOAc (2 x 250 mL), dried, (MgSO4)
and the solvent evaporated in vacuo. The residue was chromatographed
(Silica gel, 0-20% EtOAc in CH2C12) to afford the title compound
as a white solid.
30 lH NMR (CDC13, 400MHz) ~ (7.54 (2H, d, J=7.9Hz), 7.38(1H, s),
7.36-7.29 (llH, m), 7.15-7.09(6H, m), 6.5~(1H, s), and 3.93(2H,
s)ppm.
Step B: 4-(Pyrid-2-yl)benzoic acid
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A suspension of 2-(p-tolyl)pyridine (2.00g, 11.8 mmol)
and potassium permanganate (5.60g, 35.5 mmol), in water (25 mL)
was heated at reflux for 2 hours. The reaction was allowed to cool to
ambient temperature and filtered through celite to remove the solids.
S Acetic acid (1 mL) w~s added to the colorless filtrate and the product
was collected as a white solid by filtration.
lH NMR (CD30D, 400MHz) ~ 8.65(1H, dt, J=4.7 and 1.4Hz),
8.13(2H, d, J=8.6Hz), 8.05(2H, d, J=8.6Hz), 7.97-7.90(2H, m) and
7.41(1H, q, J=4.8Hz) ppm.
Step C: 4-~Pyrid-2-yl)benzyl alcohol
To a solution of 4-(pyrid-2-yl)benzoic acid(1.01 g, 5.09
mmol) in tetrahydrofuran (lS mL) at 0~C was added 1.0 M lithium
15 aluminum hydride in tetrahydrofuran (5.09 mL, 5.09 mmol) over 10
minutes. The reaction was allowed to stir at ambient temperature for
3 hours, cooled to 0~C, and quenched by dropwise addition of water
(0.25 mL), 4 N aq. NaOH (0.25 mL), and water (0.75 mL). The
reaction was filtered through a pad of Celite and the filtrate evaporated
20 in vacuo. The residue was chromatographed (silica gel, 4-8% MeOH
in CH2C12) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 8.69(1H, dt, J=4.4 and 1.4Hz), 7.99(2H,
d, J=8.4Hz), 7.80-7.70(2H, m), 7.47(2H, d, J=8.2Hz), 7.23(1H, m)
4.76(2H, d, J=6.1Hz) and 1.77(1H, m) ppm.
Step D: 1-(4-[Pyrid-2-yl]phenylmethyl)-5-(4-
cyanobenzyl)imidazole hvdrochloride salt
To a solution of 4-(pyrid-2-yl)benzyl alcohol (500 mg,
2.70 mmol) and diisopropylethylamine (0.517 mL, 2.97 mmol) in
30 dichloromethane (15 mL) at -78~C was added trifluoromethanesulfonic
anhydride (0.500 mL, 2.97 mmol) and the mixture stirred at -78~C
for 1 hour. To this mixture was added a solution of l-trityl-4-(4-
cyanobenzyl)imidazole (1.15g, 2.70 mmol) in dichloromethane (10
mL). The mixture was allowed to warm to ambient temperature and
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stirred for 2 hours. The solvent was evaporated in vacuo. The residue
was dissolved in methanol (50 mL), heated at reflux for 1 hour, and
the solvent evaporated in vacuo. The residue was partitioned between
CH2C12 and sat. aq. NaHCO3 solution. The organic layer was dried,
5 (Na2SO4) and the solvent evaporated in vacuo. The re.sidue was
chromatographed (silica gel, 0-4% NH40H in CH2C12) and further
purified by preparative HPLC, (gradient elution, 95 :5 to 5:95%
water:acetonitrile cont~ining 0.1% trifluoroacetic acid) to afford the
trifluoroacetic acid salt. The salt was partitioned between EtOAc and
10 saturated NaHCO3 solution, the organic layer dried, ~Na2SO4) and the
solvent evaporated in vacuo to afford the imidazole. The amine was
converted to the HCI salt by treatment with 1.0M HCl in aqueous
acetonitrile. Evaporation of the solvent in vacuo afforded the title
compound as a white solid.
15 FAB MS 418 (MH+)
lH NMR (CD30D, 400MHz) ~ 9.19(1H, m), ~.~7(1H, d, J=5.9Hz),
8.70(1H, dt, J=0.4 and 6.6Hz), ~.40(1H, d, J=~.2Hz), 8.08(1H, brt,
J=6.4Hz), 7.88(2H, d, J=~.6Hz), 7.53(2H, d, J=P~.4Hz), 7.51(1H, s),
7.38(2H, d, J=8.4Hz), 7.26(2H, d, J=P~.4Hz), 5.60(2H, s) and 4.20(2H, s)
20 ppm.
EXAMPLE 2
1 -(4-[3-Methylpyrazin-2-yl]phenylmethyl)-5-(4-
cyanobenzyl)imidazole hydrochloride salt
Step A: 4-(3-Methyl-pyrazin-2-yll-benzaldehyde
To a 100 ml round bottomed flask with stirring bar and
an argon inlet was added Pd(OAc)2 (.036g, .lS mmol), bisdiphenyl-
phosphinoferrocene (DPPF, .12g, .2mmol), andlS ml of DMF were
30 heated to 50~ for lS minutes. Cooled the reaction to room tempera-
ture then added 2-iodo-3-methyl-pyrazine (1.2g, 5.4 mmol)(5). (a
prep from Albert Hirschberg et al. J.Org. Chem. June,1961 pl907-
1912) and 4-formylbenzenboronic acid (.90g, 6.0 mmol) and Et3N
(1.05ml, 7.5 mmol). The mixture was heated to 90~C for 10 h.
35 Removed solvent in vacuo, taken up with CHC13 and washed with
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diluted NH40H. The organic layer was dried (MgSO4), filtered and
concentrated to yield a black oil. This material was chromatographed
(silica gel, 30% EtOAc/Hexane) to affort the title product.
1H NMR (CDC13, 400MHz) ~ 2.65(s,1H), 7.76(d, J=8.0Hz, 2H),
8.0(d,J=2.5Hz, 2H), 8.5 l(m, 2H), 10.1 l(s,l H).
Step B: 4-(3-methyl-pyrazin-2-yl)-phenyll-methanol
To a solution from step A (.14g, .70mmol) in 5 ml of
methanol was added NaBH4 (.067g, 1.76 mmol) in one portion. The
reaction was stirred at ambient temperature for 0.5 h . Quenched the
reaction with 2 ml of 2 N HCI. Concentrated in vacuo then basified
with 20% NaOH. Extracted the aliquot with EtOAc. Drying
(MgSO4), filtration and removal of the solvent gave the title
product.
lH NMR (CDC13, 400MHz) ~ 2.64(s,3H), 4.78(s, 2H),
7.48(d,J=7.69Hz, 2H), 7.58(d, J=7.897Hz, 2H), 8.48(dd, J=2.2,
14.6Hz, 2H).
Step C: 1-(4-[3-Methylpyrazin-2-yl]phenylmethyl)-5-(4-
cyanobenzyl) imidazole hydrochloride salt
To a solution of 4-(3-methyl-pyrazin-2-yl)-phenyl]-
methanol (.14g, .70 mmol) and diisopropylethylamine (.183 mL,
1.05 mmol) in CH2C12 (3 mL) at -7X~C was added trifluoromethane-
sulfonic anhydride (0.176 mL, 1.05 mmol) and the mixture stirred
at -78~C for lh. To this mixture was added a solution of 1-trityl-
4-(4-cyanobenzyl)imidazole (.298g, .70 mmol) in CH2Cl2 (2 mL).
The mixture was allowed to warm to ambient temperature and
stirred for 24 hours. The solvent was evaporated in vacuo. The
residue was dissolved in methanol (5 mL), heated at reflux for 4
hour, removal of solvent in vacuo. The residue was partitioned
between CH2C12 and sat. aq. NaHCO3 solution. The organic layer
was dried, (MgSO4) and the solvent evaporated in vacuo. The
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residue was chromatographed (Silica gel, 0-5% 2-propanol in
ammonia saturated CHC13). The amine was converted to the
HCI salt by treatment with 4.0M HCI in 1,4 dioxane. Evaporation
of the solvent in vacuo and triturated with EtOAc to afford the title
5 compound as a light yellow solid.
1H NMR (DMSO-d6, 400MHz) ~ 2.5(s, 3H), 4.1(s, 2H), 5.5(s,
2H), 7.26(dd, J=8.0,8.2Hz, 4H), 7.55(d, J=~.2Hz, 3H), 7.68(d,
J=8.2Hz, 2H), 8.55(d, J-9.9Hz, 2H), 9.29(s, lH).
EXAMPLE 3
1 -(4-(Pyrimidinyl-S-yl)phenylmethyl)-5 -(4-cyanobenzyl)imidazole
hydrochloride salt
Step A: 4-Pyrimidin-5-yl-benzaldehyde
A solution of Pd(OAc)2 (0.17 mmol, 38 mg),
bisdiphenylphosphinoferrocene (DPPF, 0.23 mmol, 125 mg),
and DMF were heated to 50~ for 15 minute,s. The reaction mixture
20 was cooled. 4-FoImyl-benzeneboronic acid (6.93 mmol, 1.0g), 5-
bromopyridine (6.3 mmol, 1.0 g), and Net3 (8.2 mmo}; 1.11 mL)
were added and the reaction mixture wa~ heated to 90~ ovemight.
The reaction mixture was concentrated to yield a gummy oil. Flash
chromatography (EtOAc) yielded 1 3 cont~min~ted with a small
25 amount of I 1 . The tan solid was taken up in EtOAc and washed
with saturated NaHCO3 and brine. The organic layer was dried
(MgSO4), filtered and concentrated to afford the title compound as
an off-white solid.
IH NMR (400 MHz, CDCI~ 10.11 (s, lH); 9.28 (s, lH); 9.02 (s,
30 2H); 8.05 (d, 2H); 7.77 (d, 2H).
Step B: 4-Pyrimidin-5-yl-phenyl-methanol
- 4-Pyrimidin-5-yl-benzaldehyde (1.89 mmol, 350 mg)
was dissolved in MeOH. NaBH4 (9.4 mmol, 357 mg) was added and
35 the reaction mixture was stirred at room temperature overnight.
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The reaction mixture was cooled to 0~ and 9M HCI (0.25 mL) was
added dropwise. The reaction mixture was stirred for one half hour.
The reaction mixture was then basified with 20% NaOH (pH=10).
EtOAc and H2O were added and the layers were separated. The
5 aqueous layer was back extracted with EtOAc (3x). The organic
layers were combined, washed with brine, dried (MgSO4), filtered
and concentrated to yield a tan solid. Flash chromatography
(EtOAc) afforded the title compound as a white solid.
1H NMR (400 MHz, CDCI3) ~ 9.21 (s, lH); 8.95 (s, 2H); 7.59-7.55
10 (m, 4H); 4.80 (d, 2H).
Step C: 1-(4-(Pyrimidinyl-5-yl)phenylmethyl)-5-(4-
cyanobenzyl)imidazole hydrochloride salt
In oven dried glassware: 4-pyrimidin-5-yl-
15 phenyl-methanol (0.823 mmol, 150 mg) was dissolved in dry
CH2CI2. Diisopropylethylamine (0.91 mmol, 0.158 mL) was added
and the reaction mixture was cooled to -78~. Triflic anhydride (0.91
mmol, 0.153 mL) was added dropwise and the reaction mixture was
stirred for 1 hour at -78~. 1 5 wa~s added in dry CH2Cl2 via syringe.
20 The resulting homogeneous solution wa~ stirred at -78~ for 15
minutes, then at room temperature for 5 hours. The CH2CI2 was
removed in-vacuo and the residue was refluxed in MeOH for 1 hour
and then stirred ar room temperature overnight. The reaction
mixture was diluted with EtOAc and washed with NaHCO3 and
25 brine. The organic layer was dried (Na2SO4), filtered and
concentrated to yield a brown solid. This material was purified by
preperative HPLC followed by fla.sh chromatography. The pruduct
was eluted with a 1%-5% MeOH/CHCI3 (saturated with NH3). The
resulting white solid wa~s converted to the HCl salt to afford the title
30 compound as a white solid.
lH NMR (400 MHz, CDCl3) â 9.09 (s, 2H); 7.77 (s, lH); 7.67-7.65
(m, 4H); 7.22 (d, 2H); 7.09 (d, 2H); 6.75 (s, lH); 5.18 (s, 2H) 3.96
(d, 2H).
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E~AMPLE 4
ln vitro inhibition of ras farnesyl transferase
Assays offarnesyl-protein transferase. Partially purified
bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL)
were prepared as described by Schaber et al., J. Biol. Chem. 265:14701-
14704 (1990), Pompliano, et al., Biochemistry 31:3~00 (1992) and
Gibbs et ah, PNAS U.S.A. 86:6630-6634 (1989), respectively. Bovine
Fl'Tase was assayed in a volume of 100 ,ul cont~ining 100 mM N-(2-
hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4,
5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl
diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650
nM Ras-CVLS and 10 ~lg/ml FPTase at 31 ~C for 60 min. Reactions
were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in
ethanol. Precipitates were collected onto filter-mats using a TomTec
Mach II cell harvestor, washed with 100% ethanol, dried and counted in
an LKB ,B-plate counter. The assay was linear with respect to both
substrates, FPTase levels and time; less than 10% of the [3H]-FPP was
utilized during the reaction period. Purified compounds were dissolved
in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the
assay. Percentage inhibition is measured by the amount of
incorporation of radioactivity in the presence of the test compound
when compared to the amount of incorporation in the absence of the test
compound.
Human FPTa.se was prepared as described by Omer
et aL, Biochemistry 32:5167-5176 (1993). Human FPTase activity
was assayed as described above with the exception that 0.1 % (w/v)
polyethylene glycol 20,000, 10 ,UM ZnC12 and 100 nM Ras-CVIM were
added to the reaction mixture. Reactions were performed for 30 min.,
stopped with 100 111 of 30% (v/v) trichloroacetic acid (TCA) in ethanol
and processed as described above for the bovine enzyme.
The compounds of the instant invention described in the
above Example 1 wa.s tested for inhibitory activity against human
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FPTase by the assay described above and were found to have IC50 ~f
50 ~lM.
EXAMPLE 5
In vivo ras farnesylation assay
The cell line used in this assay i.s a v-ras line derived from
either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The
assay is performed essentially as described in DeClue, J.E. et ah, Cancer
10 Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75%
confluency are treated with the test compound (final concentration of
solvent, methanol or dimethyl sulfoxide, is 0.1 %). After 4 hours at
37~C, the cells are labelled in 3 ml methionine-free DMEM supple-
meted with 10% regular DMEM, 2% fetal bovine serum and 400
15 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the
cells are lysed in 1 ml Iysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5
mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml
antipain/0.5 mM PMSF) and the lysate.s cleared by centrifugation at
100,000 x g for 45 min. Aliquots of lysates containing equal numbers
20 of acid-precipitable counts are bought to 1 ml with IP buffer (ly.sis
buffer lacking DTT) and immunoprecipitated with the ras-specific
monoclonal antibody Yl3-259 (Furth, M.E. et ah, J. Virol. 43:294-304,
(1982)). Following a 2 hour antibody incubation at 4~C, 200 ml of a
25% suspension of protein A-Sepharose coated with rabbit anti rat IgG
25 is added for 45 min. The imrnunoprecipitates are washed four times
with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-
100Ø5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE
sample buffer and loaded on 13% acrylamide gels. When the dye front
reached the bottom, the gel is fixed, soaked in Enlightening, dried and
30 autoradiographed. The intensities of the bands corresponding to
farnesylated and nonfarnesylated ras proteins are compared to
- determine the percent inhibition of farnesyl transfer to protein.
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EXAMPLE 6
In vivo growth inhibition assay
To determine the biological consequences of FPTase
5 inhibition, the effect of the compounds of the instant invention on the
anchorage-independent growth of Ratl cells transformed with either a
v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf
and v-Mos maybe included in the analysis to evaluate the specificity of
instant compounds for Ras-induced cell transformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos
are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in
a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's
medium supplemented with 10% fetal bovine serum) over a bottom
agarose layer (0.6%). Both layers contain 0.1% methanol or an
15 appropriate concentration of the instant compound (dissolved in
methanol at 1000 times the final concentration used in the assay).
The cells are fed twice weekly with 0.5 ml of medium A containing
0.1% methanol or the concentration of the instant compound.
Photomicrographs are taken 16 days after the cultures are seeded
20 and comparisons are made.
, . .
